Components:
Budesonide
Budesonide
Method of action:
Analgesic, Antiallergic, Antiexudative, Anti-Inflammatory, Bronchodilator, Drugs For Obstructive Airway Diseases, Endocrine-Metabolic Agent, Gastrointestinal Agent, Glucocorticoid, Immunosuppressive, Nasal Preparations
Analgesic, Antiallergic, Antiexudative, Anti-Inflammatory, Bronchodilator, Drugs For Obstructive Airway Diseases, Endocrine-Metabolic Agent, Gastrointestinal Agent, Glucocorticoid, Immunosuppressive, Nasal Preparations
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Name of the medicinal product

Abelitan

Qualitative and quantitative composition

Budesonide

Therapeutic indications

The information provided in Therapeutic indications of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

Treatment of persistent bronchial asthma in patients where use of a pressurised inhaler or dry powder formulation is unsatisfactory or inappropriate.

Very serious pseudocroup (laryngitis subglottica) in which hospitalisation is indicated.

For the treatment of active ulcerative colitis that is limited to the rectum and the sigmoid colon.

Abelitan Respules contain the potent, non-halogenated, corticosteroid, budesonide, for use in bronchial asthma, in patients where use of a pressurised inhaler or dry powder formulation is unsatisfactory or inappropriate.

Abelitan Respules are also recommended for use in infants and children with croup (acute viral upper respiratory tract infection also known as viral laryngotracheobronchitis or laryngitis subglottica), in which hospitalisation is indicated.

UCERIS rectal foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

Pulmicort is recommended in patients with bronchial asthma.

Abelitan is indicated in adults for induction of remission in patients with mild to moderate active ulcerative colitis (UC) where 5-ASA treatment is not sufficient.

Prevention and treatment of seasonal allergic rhinitis (hay fever).

Abelitan rectal foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

Abelitan foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

Crohn's disease - Induction of remission in patients with mild to moderate active Crohn's disease affecting the ileum and/or the ascending colon.

Microscopic colitis - Induction of remission in patients with active microscopic colitis

Dosage (Posology) and method of administration

The information provided in Dosage (Posology) and method of administration of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

Posology

Asthma

The dose should be given twice daily.

Administration once daily may be considered in cases of mild to moderate stable asthma.

Initial dosage:

The initial dose should be tailored to the severity of the disease and thereafter should be adjusted on an individual basis. The following doses are recommended but the minimum effective dose should always be sought:

Children aged 6 months and above:

0.25 – 1.0mg daily. For patients in maintenance therapy with oral steroids a higher initial dosage up to 2.0 mg daily should be considered.

Adults (including the elderly) and children/adolescents over 12 years of age:

0.5 - 2 mg daily. In very severe cases the dosage may be increased further.

Maintenance dose:

The maintenance dose should be adjusted to meet the requirements of the individual patient taking account of the severity of the disease and the clinical response of the patient. When the desired clinical effect has been obtained, the maintenance dose should be reduced to the minimum required for control of the symptoms.

Children aged 6 months and above:

0.25 - 1.0mg daily.

Adults (including the elderly) and children/adolescents over 12 years of age:

0.5 - 2.0mg daily. In very severe cases the dose may be further increased.

Administration once daily:

Administration once daily should be considered for children and adults with mild to moderate stable asthma and with a maintenance dose between 0.25 mg and 1 mg Abelitan daily. Once-daily administration may be initiated both in patients who are not receiving corticosteroid treatment and in well-controlled patients who are already taking inhaled steroids. The dose may be given in the morning or evening. If a worsening of the asthma occurs, the daily dose should be increased by administering the dose twice daily.

Onset of effect:

An improvement of the asthma following administration of Abelitan may occur within 3 days after initiation of therapy. The maximum effect will only be obtained after 2-4 weeks of treatment.

Patients in maintenance therapy with oral glucocorticosteroids:

Asthma

Abelitan nebuliser suspension may permit replacement or significant reduction in dosage of oral glucocorticosteroids while maintaining asthma control. When transferral from oral steroids to Abelitan nebuliser suspension is started, the patient should be in a relatively stable phase. A high dose of Abelitan nebuliser suspension is then given in combination with the previously used oral steroid dose for about 10 days.

After that, the oral steroid dose should be gradually reduced (by for example 2.5 milligrams prednisolone or the equivalent each month) to the lowest possible level.

When tapering off systemic corticosteroids some patients will experience steroid withdrawal symptoms, e.g. joint and/or muscle pain, lack of energy and depression or even a decreased lung function. Such patients must be advised to continue the inhaled Abelitan therapy, but they should also be examined for any objective signs of adrenocortical insufficiency. If such signs are present, the dose of the systemic corticosteroid should be temporarily increased and then tapered off even more slowly. In periods of stress or severe asthma attacks, patients in the transition phase may require treatment with systemic corticosteroids.

Pseudocroup

In infants and children with pseudocroup, the commonly used dose is 2 mg of nebulised Abelitan. This is given as a single administration, or as two 1 mg doses separated by 30 minutes. Dosing can be repeated every 12 hours for a maximum of 36 hours or until clinical improvement.

Method of administration

For inhalation use only.

Dosage schedule:

Dosage in mg

Volume of Abelitan Nebuliser Suspension

 

0.25

0.5

0.75

1

1.5

2

0.25 mg/ml

1 ml*

2 ml

3 ml

-

-

-

0.5 mg/ml

-

-

-

2 ml

3 ml

4 ml

*) Should be mixed with 0.9 % saline to a volume of 2 ml.

Division of the dose and miscibility:

The contents of the single-dose container may be divided for adjustment of the dose.

Half the ampoule contents should be placed in the nebuliser cup and mixed with an equal volume of 0.9% sodium chloride solution. To ensure accurate dosing the use of a measuring syringe is recommended.

Abelitan Nebuliser Suspension may be mixed with 0.9% sodium chloride solution and with solutions for inhalation containing terbutaline, salbutamol, sodium cromoglycate or ipratropium.

Nebuliser:

Abelitan Nebuliser Suspension must be administered with a jet nebuliser supplied with a mouthpiece or mask. The nebuliser should be connected to an air compressor with adequate air flow (5-8 l/min), and the filling volume should be 2-4 ml.

There can be variation in the performance (dose delivered) between nebulizers, even those of the same make and model.

Note! Ultrasound nebulisers are not suitable for nebulisation of Abelitan Nebuliser Suspension and therefore cannot be recommended.

Instruction for use:

The spray container should be shaken before use.

To minimise the risk of oropharyngeal candida infection, the patient should rinse their mouth out with water after inhaling.

To prevent irritation of the facial skin the face should be washed after using the nebuliser with a mask.

The nebuliser should be cleaned after each use.

Wash the nebuliser container and mouthpiece or face-mask in warm water using a mild detergent in accordance with the manufacturer's instructions. Rinse well and dry it by connecting the nebuliser container to the compressor or the air inlet.

Posology

Adults aged > 18 years

One actuation of 2 mg budesonide daily.

Paediatric population

Abelitan 2mg rectal foam should not be used in children due to insufficient experience in this age group.

Method of administration

Abelitan 2mg rectal foam can be applied in the morning or evening.

The canister is first fitted with an applicator and then shaken for about 15 seconds before the applicator is inserted into the rectum as far as comfortable. Note that the dose is only sufficiently accurate when the pump dome is held downwards as vertically as possible. To administer a dose of Abelitan 2mg rectal foam, the pump dome is fully pushed down and very slowly released. Following the activation the applicator should be held in position for 10 - 15 seconds before being withdrawn from the rectum.

The best results are obtained when the intestine is evacuated prior to administration of Abelitan 2mg rectal foam.

Duration of treatment

The attending physician determines the duration of use. An acute episode generally subsides after 6 to 8 weeks. Abelitan 2mg rectal foam should not be used after this period of time.

Posology

The dosage of Abelitan Respules should be adjusted to the need of the individual.

Dosage schedules: The dose delivered to the patient varies depending on the nebulising equipment used. The nebulisation time and the dose delivered is dependent on flow rate, volume of nebuliser chamber and fill volume. An air-flow rate of 6 - 8 litres per minute through the device should be employed. A suitable fill volume for most nebulisers is 2 - 4 ml. The dosage of Abelitan Respules should be adjusted to the need of the individual. The dose should be reduced to the minimum needed to maintain good asthma control. The highest dose (2 mg per day) for children under 12 years should only be considered in children with severe asthma and during limited periods.

Bronchial asthma

Initiation of therapy

When treatment is started, during periods of severe asthma and while reducing or discontinuing oral glucocorticosteroids, the recommended dose of Abelitan Respules is:

Adults (including the elderly): Usually 1 - 2 mg twice daily. In very severe cases the dosage may be further increased.

Paediatric population

Children 12 years and older: Dosage as for adults.

Children 3 months to 12 years: 0.5 – 1 mg twice daily.

Maintenance

The maintenance dose should be individualised and be the lowest dose which keeps the patient symptom-free.

Adults (including the elderly and children 12 years and older): 0.5 - 1 mg twice daily.

Paediatric population

Children 3 months to 12 years: 0.25 - 0.5 mg twice daily.

Patients maintained on oral glucocorticosteroids

Abelitan Respules may permit replacement or significant reduction in dosage of oral glucocorticosteroids while maintaining asthma control.

Dose division and miscibility

Abelitan Respules can be mixed with 0.9% saline and with solutions for nebulisation of terbutaline, salbutamol, fenoterol, acetylcysteine, sodium cromoglycate or ipratropium bromide. The admixture should be used within 30 minutes.

Recommended Dosage Table

Abelitan Respules 0.5 mg (0.25 mg/ml)

Dose (mg)

Volume (ml)

0.25

1

0.5

2

0.75

3

1.0

4

1.5

6

2.0

8

Where an increased therapeutic effect is desired, especially in those patients without major mucus secretion in the airways, an increased dose of Abelitan Respules is recommended, rather than combined treatment with oral corticosteroids, because of the lower risk of systemic effects.

Croup

In infants and children with croup, the usual dose is 2 mg of nebulised budesonide. This dose is given as a single administration, or as two 1 mg doses separated by 30 minutes. Dosing can be repeated every 12 hour for a maximum of 36 hours or until clinical improvement.

Method of administration

Abelitan respules should be administrated from suitable nebulisers.

Instruction for correct use of Abelitan Respules

The Respule should be detached from the strip, shaken gently and opened by twisting off the wing tab. The contents of the Respule should be gently squeezed into the nebuliser cup. The empty Respule should be thrown away and the top of the nebuliser cup replaced.

Abelitan Respules should be administered via a jet nebuliser equipped with a mouthpiece or suitable face mask. The nebuliser should be connected to an air compressor with an adequate air flow (6-8 L/min), and the fill volume should be 2-4ml.

Note: It is important to instruct the patient

• to carefully read the instructions for use in the patient information leaflet which are packed together with each nebuliser

• that Ultrasonic nebulisers are not suitable for the administration of Abelitan Respules and therefore are not recommended

• Abelitan Respules can be mixed with 0.9% saline and with solutions for nebulisation of terbutaline, salbutamol, fenoterol, acetylcysteine, sodium cromoglycate and ipratropium bromide. The admixture should be used within 30 minutes.

• to minimise the risk of oropharyngeal candida infection, the patient should rinse their mouth out with water after inhaling.

• to wash the facial skin with water after using the face mask to prevent facial skin irritation

• to adequately clean and maintain the nebuliser according to the manufacturer's instructions

Dosage

The recommended dosage regimen is 1 metered dose administered rectally twice daily for 2 weeks followed by 1 metered dose administered rectally once daily for 4 weeks.

Administration Instructions

Advise patients:

  • UCERIS rectal foam is only to be applied rectally. It is not for oral use.
  • Before using UCERIS rectal foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • UCERIS rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply UCERIS rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid concomitant use of CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) during treatment with UCERIS rectal foam.

Posology

When transferring patients to Turbohaler from other devices, treatment should be individualised, whether once or twice daily dosing is being used. The drug and method of delivery should be considered.

Divided doses (twice daily):

The dosage should be individualised.

The dose should always be reduced to the minimum needed to maintain good asthma control.

Adults (including the elderly) and children over 12 years of age: When starting treatment, during periods of severe asthma and while reducing or discontinuing oral glucocorticosteroids, the dosage in adults should be 200 - 1600 micrograms daily, in divided doses.

In less severe cases and children over 12 years of age, 200 - 800 micrograms daily, in divided doses, may be used. During periods of severe asthma, the daily dosage can be increased to up to 1600 micrograms, in divided doses.

Children 5 - 12 years of age: 200 - 800 micrograms daily, in divided doses. During periods of severe asthma, the daily dose can be increased up to 800 micrograms.

Once daily dosage:

The dosage should be individualised.

The dose should always be reduced to the minimum needed to maintain good asthma control.

Adults (including the elderly) and children over 12 years of age: 200 micrograms to 400 micrograms may be used in patients with mild to moderate asthma who have not previously received inhaled glucocorticosteroids.

Up to 800 micrograms may be used by patients with mild to moderate asthma already controlled on inhaled steroids (e.g. budesonide or beclomethasone dipropionate), administered twice daily.

Children 5 - 12 years of age: 200 micrograms to 400 micrograms may be used in children with mild to moderate asthma who have not previously received inhaled glucocorticosteroids, or who are already controlled on inhaled steroids (e.g. budesonide or beclomethasone dipropionate), administered twice daily.

The patient should be transferred to once daily dosing at the same equivalent total daily dose; the drug and method of delivery should be considered. The dose should subsequently be reduced to the minimum needed to maintain good asthma control.

Patients should be instructed to take the once daily dose in the evening. It is important that the dose is taken consistently and at a similar time each evening.

There are insufficient data to make recommendations for the transfer of patients from newer inhaled steroids to once daily Abelitan.

Patients, in particular those receiving once daily treatment, should be advised that if their asthma deteriorates (e.g. increased frequency of bronchodilator use or persistent respiratory symptoms) they should double their steroid dose, by administering it twice daily, and should contact their doctor as soon as possible.

In patients where an increased therapeutic effect is desired, an increased dose of Pulmicort is recommended because of the lower risk of systemic effects as compared with a combined treatment with oral glucocorticosteroids.

Patients maintained on oral glucocorticosteroids

Abelitan may permit replacement or significant reduction in dosage of oral glucocorticosteroids while maintaining asthma control.

Patients should be reminded of the importance of taking prophylactic therapy regularly, even when they are asymptomatic. A short-acting inhaled bronchodilator should be made available for the relief of acute asthma symptoms.

Method of administration

Abelitan is for oral inhalation.

Turbohaler is inspiratory flow-driven which means that, when the patient inhales through the mouthpiece, the substance will follow the inspired air into the airways.

Note: It is important to instruct the patient:

• To carefully read the instructions for use in the patient information leaflet, which is packed with each Turbohaler

• To breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is delivered to the lungs

• Never to breathe out through the mouthpiece

• To minimise the risk of oropharyngeal candida infection, the patient should rinse their mouth out with water after inhaling.

The patient may not taste or feel any medication when using Turbohaler due to the small amount of drug dispensed.

Posology

Adults

The recommended daily dose for induction of remission is one 9 mg tablet in the morning, for up to 8 weeks.

When treatment is discontinued, it may be useful to gradually reduce the dose .

Paediatric population

The safety and efficacy of Abelitan tablets in children aged 0-18 years have not yet been established. No data are available, therefore the use in paediatric population is not recommended until further data become available.

Elderly

No special dose adjustment is recommended. However, experience of the use of Abelitan in the elderly is limited.

Hepatic and renal impairment population

Abelitan 9 mg was not studied in patients with hepatic and renal impairment, therefore caution should be exercised in the administration and monitoring of the product in these patients.

Method of administration

One tablet of Abelitan 9 mg is taken orally in the morning, with or without food. The tablet should be swallowed with a glass of water and must not be broken, crushed or chewed as the film coating is intended to ensure a prolonged release.

Posology

Dosage should be individualised.

Rhinitis (Adults including the elderly)

Recommended start dose

Once daily dosing

Twice daily dosing

256 micrograms per day

Two applications of 64 micrograms into each nostril each morning

or

If good effect is achieved, one application of 64 micrograms

One application of 64 micrograms into each nostril morning and evening

The minimum dose should be used at which effective control of symptoms is maintained. The patient should be informed that the full effect of Abelitan is not achieved until after a few days treatment. Treatment of seasonal rhinitis should, if possible, start before exposure to the allergens. If symptoms are not controlled, or persist for longer than 2 weeks of treatment, medical advice must be sought. Concomitant treatment may sometimes be necessary to counteract eye symptoms caused by the allergy. Abelitan should not be used continuously for longer than 3 months without consulting your doctor or pharmacist.

Patients should be reminded of the importance of taking this medicine regularly.

The dose should be titrated to the lowest dose at which effective control of symptoms is achieved.

Paediatric population: This spray should not be used in children and adolescents under 18 years of age. There is insufficient data to recommend the use of Abelitan in children.

Method of administration

For nasal inhalation.

Dosage

The recommended dosage regimen is 1 metered dose administered rectally twice daily for 2 weeks followed by 1 metered dose administered rectally once daily for 4 weeks.

Administration Instructions

Advise patients:

  • Abelitan rectal foam is only to be applied rectally. It is not for oral use.
  • Before using Abelitan rectal foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • Abelitan rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply Abelitan rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid concomitant use of CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) during treatment with Abelitan rectal foam.

Dosage

The recommended dosage regimen is 1 metered dose administered rectally twice daily for 2 weeks followed by 1 metered dose administered rectally once daily for 4 weeks.

Administration Instructions

Advise patients:

  • Abelitan foam is only to be applied rectally. It is not for oral use.
  • Before using Abelitan foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • Abelitan foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply Abelitan foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid concomitant use of CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) during treatment with Abelitan foam.

Posology

Adults

Active Crohn's disease: The recommended daily dose for induction of remission is 9 mg once daily in the morning, for up to eight weeks. The full effect is usually achieved within 2–4 weeks.

When treatment is to be discontinued, the dose should normally be reduced for the last 2 to 4 weeks of therapy.

Active Microscopic colitis: The recommended dose is 9 mg once daily in the morning (corresponding to 3 capsules).

Paediatric population

There are limited data on the use of Abelitan CR Capsules in children . The available data are insufficient to support safety and efficacy in the paediatric population, therefore such use cannot be recommended until further data become available.

Older people

No special dose adjustment is recommended. However, experience with Abelitan CR Capsules in older people is limited.

Method of administration

The capsules should be swallowed whole with water. The capsules must not be chewed.

Contraindications

The information provided in Contraindications of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

UCERIS rectal foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of UCERIS rectal foam. Reactions have included anaphylaxis .

Hypersensitivity to the active substance.

Abelitan rectal foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of Abelitan rectal foam. Reactions have included anaphylaxis .

Abelitan foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of Abelitan foam. Reactions have included anaphylaxis .

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Special warnings and precautions for use

The information provided in Special warnings and precautions for use of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

Abelitan is not indicated for the treatment of acute dyspnoea or status asthmaticus. These conditions should be treated with short acting β-sympathomimetics and other bronchodilators.

The transfer of patients treated with oral corticosteroids to the inhaled corticosteroid and their subsequent management requires special care. The patients should be in a reasonably stable state before initiating a high dose of inhaled corticosteroid in addition to their usual maintenance dose of systemic corticosteroid. After about 10 days, withdrawal of the systemic corticosteroid is started by reducing the daily dose gradually (by for example 2.5 milligrams prednisolone or the equivalent each month) to the lowest possible level. It may be possible to completely replace the oral corticosteroid with inhaled corticosteroid. Transferred patients whose adrenocortical function is impaired may need supplementary systemic corticosteroid during periods of stress e.g. surgery, infection or worsening asthma attacks.

Patients who have required high dose emergency corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk of impaired adrenal function. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid treatment should be considered during periods of stress or elective surgery.

During transfer from oral therapy to inhaled Abelitan, symptoms may appear that had previously been suppressed by systemic treatment with glucocorticosteroids, for example symptoms of allergic rhinitis, eczema, muscle and joint pain. Specific treatment should be co-administered to treat these conditions.

Some patients may feel unwell in a non-specific way during the withdrawal of systemic corticosteroids despite maintenance or even improvement in respiratory function. Such patients should be encouraged to continue treatment with inhaled Abelitan and withdrawal of oral corticosteroid unless there are clinical signs to indicate the contrary, for example signs which might indicate adrenal insufficiency.

As with other inhalation therapies paradoxical bronchospasm may occur, manifested by an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straight away. Abelitan should be discontinued immediately, the patient should be assessed and, if necessary, alternative treatment instituted.

When an acute episode of dyspnoea occurs despite a well monitored treatment, a rapid-acting inhaled bronchodilator should be used and medical reassessment should be considered. If despite maximum doses of inhaled corticosteroids, asthma symptoms are not adequately controlled, patients may require short-term treatment with systemic corticosteroids. In such cases, it is necessary to maintain the inhaled corticosteroid therapy in association with treatment by the systemic route.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids.

Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Influence on growth

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid. The benefits of the corticosteroid therapy and the possible risks of growth suppression must be carefully weighed. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Patients who have previously been dependent on oral corticosteroids may, as a result of prolonged systemic corticosteroid therapy, experience effects of impaired adrenal function. Recovery may take a considerable amount of time after cessation of oral corticosteroid therapy and hence oral steroid-dependent patients transferred to Abelitan may remain at risk from impaired adrenocortical function for some considerable time. In such circumstances hypothalamic pituitary adrenocortical (HPA) axis function should be monitored regularly.

Oral candidiasis may occur during the therapy with inhaled corticosteroids.).

Exacerbation of clinical symptoms of asthma may be due to acute respiratory tract bacterial infections and treatment with appropriate antibiotics may be required. Such patients may need to increase the dose of inhaled Abelitan and a short course of oral corticosteroids may be required. A rapid-acting inhaled bronchodilator should be used as “rescue” medication to relieve acute asthma symptoms.

Special care and adequate specific therapeutic control of patients with active and quiescent pulmonary tuberculosis is necessary before commencing treatment with inhaled Abelitan. Similarly patients with fungal, viral or other infections of the airways require close observation and special care and should use Abelitan only if they are also receiving adequate treatment for such infections.

In patients with excessive mucous secretion in the respiratory tract, short-term therapy with oral corticosteroids may be necessary.

In patients with severe hepatic dysfunction, treatment with inhaled Abelitan can result in a reduced elimination rate and hence enhanced systemic availability. Possible systemic effects may then result and therefore HPA axis function in these patients should be monitored at regular intervals.

Concomitant treatment with ketoconazole, HIV protease inhibitors or other potent CYP3A4 inhibitors should be avoided . If this is not possible the time interval between administration of the two drugs should be as long as possible.

Recent epidemiological studies show that there is an increased incidence of pneumonia in patients with Chronic Obstructive Pulmonary Disease (COPD) treated with inhaled corticosteroids, with an adjusted odds ratio of 1.7 (Reference). Care should be exercised in prescribing Abelitan for those patients whose respiratory disease might have a component of COPD.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Abelitan Nebuliser Suspension should be used with a jet nebuliser device. An ultrasonic nebuliser should not be used as this is not appropriate for nebuliser suspensions.

Treatment with Abelitan 2mg rectal foam results in lower systemic steroid levels than conventional oral glucocorticosteroid therapy with systemically acting corticoids. Transfer from other glucocorticosteroid therapy may result in reappearance or recurrence of symptoms relating to the change in systemic steroid levels.

Caution is required in patients with tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma, cataracts, family history of diabetes, family history of glaucoma, or any other condition in which glucocorticosteroids may have undesirable effects.

Systemic effects of glucocorticosteroids may occur, particularly when prescribed at high doses and for prolonged periods. Such effects may include Cushing's syndrome, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma and a wide range of psychiatric/behavioural effects .

Infection

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The risk of deterioration of bacterial, fungal, amoebic and viral infections during glucocorticosteroid treatment should be carefully considered. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked, and therefore may reach an advanced stage before being recognised.

Chickenpox

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. If the patient is a child, parents must be given the above advice. Passive immunisation with varicella-zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic glucocorticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Glucocorticosteroids should not be stopped and the dose may need to be increased.

Measles

Patients with compromised immunity who have come into contact with measles should, wherever possible, receive normal immunoglobulin as soon as possible after exposure.

Vaccines

Live vaccines should not be given to individuals with chronic glucocorticosteroid use. The antibody response to other vaccines may be diminished.

Patients with liver function disorders

Based on the experience with patients suffering from late stage primary biliary cirrhosis (PBC) with hepatic cirrhosis an increased systemic availability of budesonide in all patients with severely impaired hepatic function is to be expected. However, in patients with liver disease without hepatic cirrhosis budesonide in daily oral doses of 9 mg was safe and well tolerated. There is no evidence that a specific dose recommendation for patients with non-cirrhotic liver diseases or only slightly impaired liver function is necessary.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Others

Glucocorticosteroids may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis and reduce the stress response. When patients are subject to surgery or other stresses, supplementary systemic glucocorticosteroid treatment is recommended.

Concomitant treatment with ketoconazole or other CYP3A4 inhibitors should be avoided .

This medicine contains cetyl alcohol and propylene glycol which can cause local skin reactions (e.g. contact dermatitis).

Special caution is necessary in patients with active or quiescent pulmonary tuberculosis and in patients with fungal or viral infections in the airways.

Non steroid-dependent patients: A therapeutic effect is usually reached within 10 days. In patients with excessive mucus secretion in the bronchi, a short (about 2 weeks) additional oral corticosteroid regimen can be given initially. After the course of the oral drug, Abelitan Respules alone should be sufficient therapy.

Steroid-dependent patients: When transfer from oral corticosteroid to treatment with Abelitan Respules is initiated, the patient should be in a relatively stable phase. Abelitan Respules is then given, in combination with the previously used oral steroid dose, for about 10 days.

After that, the oral steroid dose should be gradually reduced (by, for example, 2.5 mg prednisolone or the equivalent each month), to the lowest possible level. In many cases, it is possible to completely substitute Abelitan Respules for the oral corticosteroid.

During transfer from oral therapy to Abelitan Respules, a generally lower systemic corticosteroid action will be experienced, which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary.

As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. If this occurs, treatment with inhaled budesonide should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Patients, who have required high dose emergency corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk of impaired adrenal function. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid treatment should be considered during periods of stress or elective surgery.

Systemic effects may occur with any inhaled corticosteroids, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Abelitan Respules is not intended for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required. If patients find short-acting bronchodilator treatment ineffective, or they need more inhalations than usual, medical attention must be sought. In this situation consideration should be given to the need for or an increase in their regular therapy, e.g., higher doses of inhaled budesonide or the addition of a long-acting beta agonist, or for a course of oral glucocorticosteroid.

Reduced liver function affects the elimination of corticosteroids, causing lower elimination rate and higher systemic exposure. Be aware of possible systemic sides effects.

The plasma clearance following an intravenous dose of budesonide however was similar in cirrhotic patients and in healthy subjects. After oral ingestion systemic availability of budesonide was increased by compromised liver function due to decreased first pass metabolism. The clinical relevance of this to treatment with Abelitan Respules is unknown as no data exist for inhaled budesonide, but increases in plasma levels and hence an increased risk of systemic adverse effects could be expected.

Co-treatment with CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products is expected to increase the risk of systemic corticosteroid side effects. Therefore, the combination should be avoided unless the benefit outweighs this increased risk, in which case patients should be monitored for systemic corticosteroid side effects. This is of limited clinical importance for short-term (1-2 weeks) treatment with itraconazole or ketoconazole or other potent CYP3A inhibitors, but should be taken into consideration during long-term treatment. A reduction in the dose of budesonide should also be considered .

The nebuliser chamber should be cleaned after every administration. Wash the nebuliser chamber and mouthpiece or face-mask in hot water using a mild detergent. Rinse well and dry, by connecting the nebuliser chamber to the compressor or air inlet.

Oral candidiasis may occur during the therapy with inhaled corticosteroids.).

Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Paediatric population

Influence on growth

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. The benefits of the corticosteroid therapy and the possible risks of growth suppression must be carefully weighed. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypercorticism And Adrenal Axis Suppression

When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS rectal foam contains a glucocorticosteroid, general warnings concerning glucocorticoids should be followed .

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis .

Impaired Adrenal Suppression In Patients Transferred From Other Glucocorticoids

Monitor patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS rectal foam, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic glucocorticosteroids with UCERIS rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (See prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered.

Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.

Other Glucocorticosteroid Effects

Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

Flammable Contents

The contents of UCERIS rectal foam include n-butane, isobutane and propane as propellants which are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following administration. Patients should temporarily discontinue use of UCERIS rectal foam before initiation of bowel preparation for colonoscopy and consult their health care provider before resuming therapy.

Patient And Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Administration

Advise patients:

  • UCERIS rectal foam is only to be applied rectally. It is not for oral use.
  • Before using UCERIS rectal foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • UCERIS rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply UCERIS rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid consumption of grapefruit or grapefruit juice during treatment with UCERIS rectal foam.
  • Avoid fire, flame, and smoking during and immediately following administration since UCERIS rectal foam is flammable.
Hypercorticism And Adrenal Suppression

Advise patients that UCERIS rectal foam may cause hypercorticism and adrenal suppression and that they should taper slowly from systemic corticosteroids if transferring to UCERIS rectal foam . Advise patients that replacement of systemic glucocorticosteroids with UCERIS rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Advise patients to avoid exposure to people with chicken pox or measles and if exposed, consult a physician. Also, inform patients that they are at increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex and to contact their physician if they develop any symptoms of infection .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.24 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

Mutagenesis

Budesonide showed no evidence of mutagenic potential in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test or the mouse micronucleus test.

Impairment Of Fertility

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg(approximately 0.20 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.05 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No such effects were noted at 5 mcg/kg.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

Risk Summary

There are no adequate and well controlled studies with UCERIS rectal foam in pregnant women. Animal reproduction studies have been conducted with budesonide. In these studies, subcutaneous administration of budesonide to rats and rabbits at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, produced skeletal abnormalities, fetal loss and decreased pup weight. UCERIS rectal foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4 percent for major malformations, and 15 to 20 percent for pregnancy loss.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Hypoadrenalism may occur in neonates exposed to glucocorticosteroids in-utero. Carefully observe these neonates for signs and symptoms of hypoadrenalism.

Animal Data

Budesonide is teratogenic and embryocidal in rabbits and rats. In subcutaneous embryofetal development studies, fetal loss, decreased pup weights, and skeletal abnormalities were observed at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area).

Nursing Mothers

Use of UCERIS rectal foam is likely to result in budesonide in human milk as budesonide delivered by inhalation from a dry powder inhaler is present in human milk at low concentrations. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for UCERIS rectal foam and any potential adverse effects on the breastfed child from UCERIS rectal foam or from the underlying maternal condition. Exercise caution when administering UCERIS rectal foam to a nursing woman.

Pediatric Use

The safety and effectiveness of UCERIS rectal foam has not been established in pediatric patients

Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

Geriatric Use

Clinical studies with UCERIS rectal foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

No dosage adjustment is needed for patients with mild (Child-Pugh Class A) hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS rectal foam should be considered in these patients if signs of hypercorticism are observed .

Special caution is necessary in patients with active or quiescent pulmonary tuberculosis, and in patients with fungal or viral infections in the airways.

Non steroid-dependent patients: A therapeutic effect is usually reached within 10 days. In patients with excessive mucus secretion in the bronchi, a short (about 2 weeks) additional oral corticosteroid regimen can be given initially.

Steroid-dependent patients: When transferral from oral steroids to Abelitan is started, the patient should be in a relatively stable phase. A high dose of Abelitan is then given in combination with the previously used oral steroid dose for about 10 days.

After that, the oral steroid dose should be gradually reduced (by for example 2.5 milligrams prednisolone or the equivalent each month) to the lowest possible level. In many cases, it is possible to completely substitute Pulmicort for the oral steroid.

During transfer from oral therapy to Pulmicort, a generally lower systemic steroid action will be experienced which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. During the withdrawal of oral steroids, patients may feel unwell in a non-specific way, even though respiratory function is maintained or improved. Patients should be encouraged to continue with Pulmicort therapy whilst withdrawing the oral steroid, unless there are clinical signs to indicate the contrary. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary.

As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. If this occurs, treatment with inhaled budesonide should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Patients who have previously been dependent on oral steroids may, as a result of prolonged systemic steroid therapy, experience the effects of impaired adrenal function. Recovery may take a considerable amount of time after cessation of oral steroid therapy, hence oral steroid-dependent patients transferred to budesonide may remain at risk from impaired adrenal function for some considerable time. In such circumstances, HPA axis functions should be monitored regularly.

Acute exacerbations of asthma may need an increase in the dose of Pulmicort or additional treatment with a short course of oral corticosteroid and/or an antibiotic, if there is an infection. The patient should be advised to use a short-acting inhaled bronchodilator as rescue medication to relieve acute asthma symptoms.

Pulmicort is not intended for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required.

If patients find short-acting bronchodilator treatment ineffective or they need more inhalations than usual, medical attention must be sought. In this situation consideration should be given to the need for or an increase in their regular therapy, e.g., higher doses of inhaled budesonide or the addition of a long-acting beta agonist, or for a course of oral glucocorticosteroid.

Patients, who have required high dose emergency corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk of impaired adrenal function. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid treatment should be considered during periods of stress or elective surgery. These patients should be instructed to carry a steroid warning card indicating their needs. Treatment with supplementary systemic steroids or Pulmicort should not be stopped abruptly.

Systemic effects may occur with any inhaled corticosteroids, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Reduced liver function affects the elimination of corticosteroids causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects.

The plasma clearance following an intravenous dose of budesonide however was similar in cirrhotic patients and in healthy subjects. After oral ingestion systemic availability of budesonide was increased by compromised liver function due to decreased first pass metabolism. The clinical relevance of this to treatment with Pulmicort is unknown as no data exist for inhaled budesonide, but increases in plasma levels and hence an increased risk of systemic adverse effects could be expected.

Co-treatment with CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products is expected to increase the risk of systemic corticosteroid side effects. Therefore, the combination should be avoided unless the benefit outweighs this increased risk, in which case patients should be monitored for systemic corticosteroid side effects. This is of limited clinical importance for short-term (1-2 weeks) treatment with itraconazole or ketoconazole or other potent CYP3A inhibitors, but should be taken into consideration during long-term treatment. A reduction in the dose of budesonide should also be considered .

Oral candidiasis may occur during the therapy with inhaled corticosteroids. This infection may require treatment with appropriate antifungal therapy and in some patients discontinuation of treatment may be necessary .

Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCS) which have been reported after use of systemic and topical corticosteroids.

Paediatric populations

Influence on growth

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. The benefit of the corticosteroid therapy and the possible risk of growth suppression must be carefully weighed. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Abelitan tablets should be used with caution in patients with infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts or with a family history of diabetes or glaucoma or with any other condition where the use of glucocorticoids may have unwanted effects.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare condition diseases such as Central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Reduced liver function may affect the elimination of glucocorticoids including budesonide, causing higher systemic exposure. Be aware of possible systemic side effects. Potential systemic effects include glaucoma.

When treatment is to be discontinued, it may be useful to gradually reduce the dose at the discretion of the treating physician.

Treatment with Abelitan tablets results in lower systemic steroid levels than conventional oral glucocorticoid therapy. Transfer from other steroid therapy may result in symptoms relating to the change in systemic steroid levels. Some patients may feel unwell in a non-specific way during the withdrawal phase, e.g., pain in muscles and joints. A general insufficient corticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of systemic corticosteroids is sometimes necessary.

As corticosteroids are known to have immunological effects the co-administration of Abelitan tablets is likely to reduce the immune response to vaccines.

Concomitant administration of ketoconazole or other potent CYP3A4 inhibitors should be avoided.).

Abelitan tablets contain lecithin (soya oil). If a patient is hypersensitive to peanut or soya, this medicine should not be used.

Abelitan tablets contain lactose monohydrate and should not be taken by patients with rare hereditary problems such as galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

The following warnings and precautions have been generally identified for corticosteroids:

• Adrenocortical suppression has been observed when patients are transferred from systemic corticosteroid treatment with higher systemic effect.

• Suppression of the inflammatory response and immune system increases the susceptibility to infections.

• Corticosteroids may cause suppression of the HPA axis and reduce the stress response. Where patients are subject to surgery or other stresses, supplementary systemic corticosteroid treatment is recommended.

• Chicken pox and measles may follow a more serious course in patients on oral glucocorticoids. Particular care should be taken to avoid exposure in patients who have not previously had these diseases. If patients are infected or suspected of being infected, consider reduction or discontinuation of glucocorticosteroid treatment at the discretion of the treating physician.

• Systemic effects of steroids may occur, particularly when prescribed at high doses and for prolonged periods. Such effects may include Cushing's syndrome, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma and very rarely a wide range of psychiatric/behavioural effects .

• Particular care is required when considering the use of systemic corticosteroids in patients with current or previous history of severe affective disorders in the patient or any first degree relatives.

• Replacement of high systemic effect corticosteroid treatment sometimes unmasks allergies, e.g. rhinitis and eczema that were previously controlled by the systemic drug.

Treatment should be stopped or the advice of a doctor or pharmacist should be sought if an improvement is not seen within 2 weeks or if symptoms have improved but are not adequately controlled.

This medicine should not be used for more than 3 months continuously without consulting a doctor or pharmacist.

Special care is demanded in treatment of patients transferred from oral steroids to this medicine where disturbances of the hypothalamic-pituitary-adrenal (HPA) axis could be expected.

Special care is needed in patients with fungal and viral infections of the airways and in patients with active or quiescent pulmonary tuberculosis.

Special care is needed where there is an infection in the nasal passages or sinuses, or in the case of recent surgery to the nose, or problems with ulceration in the nose.

Concomitant treatment of seasonal rhinitis may sometimes be necessary to counteract eye symptoms caused by the allergy.

Reduced liver function affects the elimination of corticosteroids, causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects.

Systemic effects of nasal corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Potential systemic effects may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Paediatric population

The long-term effects of nasal glucocorticosteroids in children are not fully known. Physicians should closely follow the growth of children taking glucocorticosteroids for longer term by any route, and weigh the benefits of the glucocorticosteroid therapy against the possibility of growth suppression.

This medicine should not be used for children or adolescents under 18 years of age.

Treatment with higher than recommended doses may result in clinically significant adrenal suppression. If there is evidence for higher than recommended doses being used, additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Co-treatment with CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products is expected to increase the risk of systemic corticosteroid side effects. Therefore, the combination should be avoided unless the benefit outweighs this increased risk, in which case patients should be monitored for systemic corticosteroid side effects. This is of limited clinical importance for short-term (1-2 weeks) treatment with itraconazole or ketoconazole or other potent CYP3A inhibitors, but should be taken into consideration during long-term treatment. A reduction in the dose of budesonide should also be considered .

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypercorticism And Adrenal Axis Suppression

When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since Abelitan rectal foam contains a glucocorticosteroid, general warnings concerning glucocorticoids should be followed .

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis .

Impaired Adrenal Suppression In Patients Transferred From Other Glucocorticoids

Monitor patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as Abelitan rectal foam, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic glucocorticosteroids with Abelitan rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (See prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered.

Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.

Other Glucocorticosteroid Effects

Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

Flammable Contents

The contents of Abelitan rectal foam include n-butane, isobutane and propane as propellants which are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following administration. Patients should temporarily discontinue use of Abelitan rectal foam before initiation of bowel preparation for colonoscopy and consult their health care provider before resuming therapy.

Patient And Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Administration

Advise patients:

  • Abelitan rectal foam is only to be applied rectally. It is not for oral use.
  • Before using Abelitan rectal foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • Abelitan rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply Abelitan rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid consumption of grapefruit or grapefruit juice during treatment with Abelitan rectal foam.
  • Avoid fire, flame, and smoking during and immediately following administration since Abelitan rectal foam is flammable.
Hypercorticism And Adrenal Suppression

Advise patients that Abelitan rectal foam may cause hypercorticism and adrenal suppression and that they should taper slowly from systemic corticosteroids if transferring to Abelitan rectal foam . Advise patients that replacement of systemic glucocorticosteroids with Abelitan rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Advise patients to avoid exposure to people with chicken pox or measles and if exposed, consult a physician. Also, inform patients that they are at increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex and to contact their physician if they develop any symptoms of infection .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.24 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

Mutagenesis

Budesonide showed no evidence of mutagenic potential in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test or the mouse micronucleus test.

Impairment Of Fertility

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg(approximately 0.20 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.05 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No such effects were noted at 5 mcg/kg.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

Risk Summary

There are no adequate and well controlled studies with Abelitan rectal foam in pregnant women. Animal reproduction studies have been conducted with budesonide. In these studies, subcutaneous administration of budesonide to rats and rabbits at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, produced skeletal abnormalities, fetal loss and decreased pup weight. Abelitan rectal foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4 percent for major malformations, and 15 to 20 percent for pregnancy loss.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Hypoadrenalism may occur in neonates exposed to glucocorticosteroids in-utero. Carefully observe these neonates for signs and symptoms of hypoadrenalism.

Animal Data

Budesonide is teratogenic and embryocidal in rabbits and rats. In subcutaneous embryofetal development studies, fetal loss, decreased pup weights, and skeletal abnormalities were observed at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area).

Nursing Mothers

Use of Abelitan rectal foam is likely to result in budesonide in human milk as budesonide delivered by inhalation from a dry powder inhaler is present in human milk at low concentrations. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Abelitan rectal foam and any potential adverse effects on the breastfed child from Abelitan rectal foam or from the underlying maternal condition. Exercise caution when administering Abelitan rectal foam to a nursing woman.

Pediatric Use

The safety and effectiveness of Abelitan rectal foam has not been established in pediatric patients

Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

Geriatric Use

Clinical studies with Abelitan rectal foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

No dosage adjustment is needed for patients with mild (Child-Pugh Class A) hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of Abelitan rectal foam should be considered in these patients if signs of hypercorticism are observed .

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypercorticism And Adrenal Axis Suppression

When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since Abelitan foam contains a glucocorticosteroid, general warnings concerning glucocorticoids should be followed .

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis .

Impaired Adrenal Suppression In Patients Transferred From Other Glucocorticoids

Monitor patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as Abelitan foam, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic glucocorticosteroids with UCERIS rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (See prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered.

Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.

Other Glucocorticosteroid Effects

Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

Flammable Contents

The contents of Abelitan foam include n-butane, isobutane and propane as propellants which are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following administration. Patients should temporarily discontinue use of Abelitan foam before initiation of bowel preparation for colonoscopy and consult their health care provider before resuming therapy.

Patient And Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Administration

Advise patients:

  • Abelitan foam is only to be applied rectally. It is not for oral use.
  • Before using Abelitan foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • Abelitan foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply Abelitan foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid consumption of grapefruit or grapefruit juice during treatment with Abelitan foam.
  • Avoid fire, flame, and smoking during and immediately following administration since Abelitan foam is flammable.
Hypercorticism And Adrenal Suppression

Advise patients that UCERIS rectal foam may cause hypercorticism and adrenal suppression and that they should taper slowly from systemic corticosteroids if transferring to UCERIS rectal foam . Advise patients that replacement of systemic glucocorticosteroids with Abelitan foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Advise patients to avoid exposure to people with chicken pox or measles and if exposed, consult a physician. Also, inform patients that they are at increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex and to contact their physician if they develop any symptoms of infection .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.24 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

Mutagenesis

Budesonide showed no evidence of mutagenic potential in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test or the mouse micronucleus test.

Impairment Of Fertility

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg(approximately 0.20 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.05 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No such effects were noted at 5 mcg/kg.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

Risk Summary

There are no adequate and well controlled studies with Abelitan foam in pregnant women. Animal reproduction studies have been conducted with budesonide. In these studies, subcutaneous administration of budesonide to rats and rabbits at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, produced skeletal abnormalities, fetal loss and decreased pup weight. Abelitan foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4 percent for major malformations, and 15 to 20 percent for pregnancy loss.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Hypoadrenalism may occur in neonates exposed to glucocorticosteroids in-utero. Carefully observe these neonates for signs and symptoms of hypoadrenalism.

Animal Data

Budesonide is teratogenic and embryocidal in rabbits and rats. In subcutaneous embryofetal development studies, fetal loss, decreased pup weights, and skeletal abnormalities were observed at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area).

Nursing Mothers

Use of Abelitan foam is likely to result in budesonide in human milk as budesonide delivered by inhalation from a dry powder inhaler is present in human milk at low concentrations. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Abelitan foam and any potential adverse effects on the breastfed child from Abelitan foam or from the underlying maternal condition. Exercise caution when administering UCERIS rectal foam to a nursing woman.

Pediatric Use

The safety and effectiveness of Abelitan foam has not been established in pediatric patients

Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

Geriatric Use

Clinical studies with Abelitan foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

No dosage adjustment is needed for patients with mild (Child-Pugh Class A) hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of Abelitan foam should be considered in these patients if signs of hypercorticism are observed .

Side effects typical of systemic corticosteroids may occur. Potential systemic effects include glaucoma.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Use with caution in patients with infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts or with a family history of diabetes or glaucoma or with any other condition where the use of glucocorticosteroids may have unwanted effects.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

Systemic effects of steroids may occur, particularly when prescribed at high doses and for prolonged periods. Such effects may include Cushing's syndrome, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma and very rarely a wide range of psychiatric/behavioural effects .

Treatment with Abelitan CR Capsules results in lower systemic steroid levels than conventional oral glucocorticosteroid therapy. When patients are transferred from systemic glucocorticosteroid treatment with higher systemic effect to Abelitan CR Capsules, they may have adrenocortical suppression. Therefore, monitoring of adrenocortical function may be considered in these patients and their dose of systemic steroid should be reduced cautiously.

Replacement of high systemic effect glucocorticosteroid treatment with Abelitan CR Capsules, sometimes unmasks allergies, e.g. rhinitis and eczema, which were previously controlled by the systemic drug.

Chicken pox and measles can have a more serious course in patients on oral glucocorticosteroids. Particular care should be taken to avoid exposure in patients who have not previously had these diseases. If patients are infected or suspected of being infected, consider reduction or discontinuation of glucocortiocosteriods treatment and immediately consult a physician. Glucocorticosteroids may cause suppression of the hypothalamus-pituitary-adrenal (HPA) axis and reduce the stress response. Where patients are subject to surgery or other stress situations, supplementary systemic glucocorticoid treatment is recommended.

Reduced liver function may affect the elimination of glucocorticosteroids, causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects. The pharmacokinetics after oral ingestion of budesonide was affected by compromised liver function as evidenced by increased systemic availability in patients with moderately severe hepatic cirrhosis.

When treatment is to be discontinued, the dose should normally be reduced for the last 2 to 4 weeks of therapy. Some patients feel unwell in a non-specific way during the withdrawal phase, e.g. pain in muscles and joints. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of systemic glucocorticosteroids is sometimes necessary.

Co-treatment with CYP3A inhibitors, including ketoconazole and cobicistat-containing products, is expected to increase the risk of systemic side-effects.).

After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times.

When Abelitan CR Capsules are used chronically in excessive doses, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may appear.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

Paediatric population

It is recommended that the height of children receiving prolonged treatment with glucocorticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated. The benefits of the glucocorticosteroid therapy and the possible risks of growth suppression must be carefully weighed. Long-term studies have not been performed in children treated with Abelitan CR Capsules.

Effects on ability to drive and use machines

The information provided in Effects on ability to drive and use machines of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Effects on ability to drive and use machines in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
more... close
Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard

Inhaled Abelitan has no or negligible influence on the ability to drive and use machines.

No studies on the effects on the ability to drive and use machines have been performed.

Abelitan Respules has no or negligible influence on the ability to drive and use machines.

Abelitan has no or negligible influence on the ability to drive and use machines.

No studies on the effects of Abelitan on the ability to drive and use machines have been performed. When driving vehicles or using machines it should be taken into account that occasionally dizziness or tiredness may occur .

This medicine has no or negligible influence on the ability to drive and use machines.

Abelitan CR Capsules have no or negligible influence on the ability to drive and use machines.

Undesirable effects

The information provided in Undesirable effects of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
more... close
Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

Tabulated list of adverse reactions

The following definitions apply to the incidence of undesirable effects: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Infections and infestations

Common

Oropharyngeal candidiasis

Immune system disorders

Rare

Immediate and delayed hypersensitivity reactions* including rash, contact dermatitis, urticaria, angioedema and anaphylactic reaction.

Endocrine disorders

Rare

Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation**

Eye disorders

Uncommon

<)

Not known

Glaucoma

Psychiatric disorders

Uncommon

Anxiety*, depression*

Rare

Restlessness, nervousness, behavioural changes (predominantly in children)

Not known

Sleep disorders, psychomotor activity, aggression

Respiratory, thoracic and mediastinal disorders

Common

Hoarseness, cough, throat irritation

Rare

Bronchospasm, dysphonia

Gastrointestinal disorders

Common

Oral mucosal irritation, difficulty in swallowing

Skin and subcutaneous disorders

Rare

Bruising, skin reactions, pruritus, erythema

Musculoskeletal and connective tissue disorders

Uncommon

Muscle spasms

Rare

Growth retardation

Investigations

Very rare

Bone density decreased

Nervous system disorders

Uncommon

Tremor

* refer to Description of selected adverse reactions: facial skin irritation, cataract, anxiety, depression below

** refer to Paediatric population, below

Description of selected adverse reactions

Facial irritation, as an example of a hypersensitivity reaction, has occurred in some cases when a nebuliser with a face mask has been used. To prevent irritation the facial skin should be washed with water after use of the face mask.

In-placebo controlled studies, cataract was also uncommonly reported in the placebo group.

Clinical trials with 13,119 patients on inhaled Abelitan and 7,278 patients on placebo have been pooled. The frequency of anxiety was 0.52% on inhaled Abelitan and 0.63% on placebo; that of depression was 0.67% on inhaled Abelitan and 1.15% on placebo.

There is an increased risk of pneumonia in patients with newly diagnosed COPD starting treatment with inhaled corticosteroids. However a weighted assessment of 8 pooled clinical trials involving 4643 COPD patients treated with Abelitan and 3,643 patients randomized to non-ICS treatments did not demonstrate an increased risk for pneumonia. The results from the first 7 of these 8 trials have been published as a meta-analysis.

Treatment with inhaled Abelitan may result in candida infection in the oropharynx. Experience has shown that candida infection occurs less often when inhalation is performed before meals and/or when the mouth is rinsed after inhalation. In most cases this condition responds to topical anti-fungal therapy without discontinuing treatment with inhaled Abelitan.

Coughing can usually be prevented by inhaling a beta-2 agonist (e.g. terbutaline) 5-10 minutes before administration of Abelitan 0.5mg Nebuliser Suspension.

Occasionally, signs or symptoms of systemic glucocorticosteroid-side effects may occur with inhaled glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity. These may include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma, and susceptibility to infections. The ability to adapt to stress may be impaired. The systemic effects described, however, are much less likely to occur with inhaled Abelitan than with oral corticosteroids.

Paediatric population

<

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

The following frequency conventions are used in the evaluation of undesirable effects:

very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

System organ class

Frequency according to MedDRA convention

Adverse reaction

Metabolism and nutrition disorders

Common

Cushing's syndrome: e.g. with moon face, truncal obesity, reduced glucose tolerance, diabetes mellitus, hypertension, sodium retention with oedema, increased potassium excretion, inactivity or atrophy of the adrenal cortex, red striae, steroid acne, disturbance of sex hormone secretion (e.g. amenorrhoea, hirsutism, impotence)

Very rare

Growth retardation in children

Eye disorders

Rare

<)

Gastrointestinal disorders

Common

Dyspepsia

Uncommon

Duodenal or gastric ulcer

Rare

Pancreatitis

Very rare

Constipation

Immune system disorders

Common

Increased risk of infection

Musculoskeletal and connective tissue disorders

Common

Muscle and joint pain, muscle weakness and twitching, osteoporosis

Rare

Osteonecrosis

Nervous system disorders

Common

Headache

Very rare

Pseudotumor cerebri including papilloedema in adolescents

Psychiatric disorders

Common

Depression, irritability, euphoria

Uncommon

Psychomotor hyperactivity, anxiety

Rare

Aggression

Skin and subcutaneous tissue disorders

Common

Allergic exanthema, petechiae, delayed wound healing, contact dermatitis

Rare

Ecchymosis

Vascular disorders

Very rare

Increased risk of thrombosis, vasculitis (withdrawal syndrome after long-term therapy)

General disorders and administration site conditions

Common

Burning in the rectum and pain

Very rare

Fatigue, malaise

The following adverse reactions were additionally reported in clinical studies with Abelitan 2mg rectal foam (frequency: uncommon): increased appetite, increase in erythrocyte sedimentation rate, leucocytosis, nausea, abdominal pain, flatulence, paraesthesias in the abdominal region, anal fissure, aphthous stomatitis, frequent urge to defecate, rectal bleeding, increase in transaminases (GOT, GPT), increase in parameters of cholestasis (GGT,AP), increase in amylase, change in cortisol, urinary tract infection, dizziness, disturbances of smell, insomnia, increased sweating, asthenia, increase in body weight.

Most of the adverse events mentioned in this SmPC can also be expected for treatments with other glucocorticosteroids.

Occasionally, adverse events may occur which are typical for systemic glucocorticosteroids. These adverse events depend on the dosage, the period of treatment, concomitant or previous treatment with other glucocorticosteroids and the individual sensitivity.

Some of the adverse events were reported after long-term use of orally administered budesonide.

Due to its local action, the risk of adverse reactions of Abelitan 2mg rectal foam is generally lower than when taking systemically acting glucocorticosteroids.

An exacerbation or the reappearance of extra intestinal manifestations (especially affecting skin and joints) can occur on switching a patient from systemically acting glucocorticosteroids to the locally acting budesonide.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Tabulated list of adverse reactions

The following definitions apply to the incidence of undesirable effects: Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 1 Adverse Drug Reactions (ADR) by System Organ Class (SOC) and Frequency

SOC

Frequency

Adverse Drug Reaction

Infections and infestations

Common

Oropharyngeal candidiasis

Pneumonia (in COPD patients)

Immune system disorders

Rare

Immediate and delayed hypersensitivity reactions* including rash, contact dermatitis, urticaria, angioedema and anaphylactic reaction

Endocrine disorders

Rare

Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation**

Psychiatric disorders

Uncommon

Anxiety

Depression

Rare

Psychomotor hyperactivity

Sleep disorders

Aggression

Behavioural changes (predominantly in children)

Nervous system disorders

Uncommon

Tremor***

Eye disorders

Uncommon

Cataract

<)

Unknown

Glaucoma

Respiratory, thoracic and mediastinal disorders

Common

Cough

Hoarseness

Throat irritation

Rare

Bronchospasm

Dysphonia

Hoarseness****

Skin and subcutaneous tissue disorders

Rare

Bruising

Musculoskeletal and connective tissue disorders

Uncommon

Muscle spasm

* refer to Description of selected adverse reactions; facial skin irritation, below

** refer to Paediatric population, below

*** based on the frequency reported in clinical trials

**** rare in children

Occasionally, signs or symptoms of systemic glucocorticosteroid-side effects may occur with inhaled glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity .

Description of selected adverse reactions

The candida infection in the oropharynx is due to drug deposition. Advising the patient to rinse the mouth out with water after each dosing will minimise the risk.

As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases .

Facial skin irritation, as an example of a hypersensitivity reaction, has occurred in some cases when a nebuliser with a face mask has been used. To prevent irritation, the facial skin should be washed with water after use of the face mask.

In placebo-controlled studies, cataract was also uncommonly reported in the placebo group.

Clinical trials with 13119 patients on inhaled budesonide and 7278 patients on placebo have been pooled. The frequency of anxiety was 0.52% on inhaled budesonide and 0.63% on placebo; that of depression was 0.67% on inhaled budesonide and 1.15% on placebo.

Paediatric population

<

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

Serious and important adverse reactions include:

  • Hypercorticism and adrenal axis suppression
  • Symptoms of steroid withdrawal in those patients transferring from systemic glucocorticosteroid therapy
  • Increased susceptibility to infection
  • Other glucocorticosteroid effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to UCERIS rectal foam in 332 patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The median duration of exposure was 42 days. This included 14 patients exposed for at least 6 months.

UCERIS rectal foam was studied primarily in 2 placebo-controlled, 6-week trials in patients with active disease (Study 1 and Study 2). In these trials, 268 patients received UCERIS rectal foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks .

The most common adverse reactions ( ≥ 2% of the UCERIS rectal foam or Placebo group and at higher frequency in the UCERIS rectal foam group) were decreased blood cortisol, adrenal insufficiency, and nausea (Table 1). Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/dL. Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with adrenocorticotropic hormone (ACTH).

A total of 10% of UCERIS rectal foam-treated patients discontinued treatment due to an adverse reaction compared with 4% of placebo-treated patients.

Table 1: Summary of Adverse Reactions in 2 Placebo Controlled Trials* (Studies 1and 2)

Adverse Reaction UCERIS Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Decreased blood cortisol# 46 (17) 6 (2)
Adrenal insufficiency† 10 (4) 2 (1)
Nausea 6 (2) 2 (1)
* Experienced by ≥ 2% of the UCERIS rectal foam or Placebo group and at higher frequency in the UCERIS rectal foam group
# Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/Dl
† Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH.

Of the 46 UCERIS rectal foam treated patients with decreased blood cortisol (defined as a morning cortisol level of < 5 mcg/dL) reported as an adverse event, none had adrenal insufficiency (defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH) (see Table 2). All cases of adrenal insufficiency resolved.

Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2).

Table 2: Summary of Glucocorticoid Related Effects in Two Placebo- Controlled Trials (Studies 1 and 2)

Adverse Reaction UCERIS Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Overall 60 (22) 10 (4)
Blood cortisol decreased 46 (17)* 6 (2)
Adrenal insufficiency 10 (4) 2 (1)
Insomnia 1 (0.4) 1 (0.4)
Sleep disorder 1 (0.4) 0
Acne 1 (0.4) 0
Depression 1 (0.4) 1 (0.4)
Hyperglycemia 1 (0.4) 0
* Decreases in serum cortisol levels associated with budesonide treatment were seen at Weeks 1 and 2 (twice-daily treatment) in the UCERIS rectal foam group, but gradually returned to baseline levels during the 4 weeks of once daily treatment.

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS rectal foam and placebo after 6 weeks of therapy.

For additional details on morning cortisol levels and the response to the ACTH stimulation test, see CLINICAL PHARMACOLOGY.

Post-Marketing Experience

In addition to adverse reactions reported from clinical trials for UCERIS rectal foam, the following adverse reactions have been identified during post-approval use of other oral and rectal formulations of budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: hypertension

Gastrointestinal disorders: pancreatitis

General disorders and administration site conditions: pyrexia, peripheral edema

Immune System Disorders: anaphylactic reactions

Nervous System Disorders: dizziness, benign intracranial hypertension

Psychiatric Disorders: mood swings

Skin and subcutaneous tissue disorders: pruritus, maculo-papular rash, allergic dermatitis

Tabulated list of adverse reactions

The following definitions apply to the incidence of undesirable effects: Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table 1 Adverse Drug Reactions (ADR) by System Organ Class (SOC) and Frequency

SOC

Frequency

Adverse Drug Reaction

Infections and infestations

Common

Oropharyngeal candidiasis

Pneumonia (in COPD patients)

Immune system disorders

Rare

Immediate and delayed hypersensitivity reactions including rash, contact dermatitis, urticaria, angioedema and anaphylactic reaction

Endocrine disorders

Rare

Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation*

Psychiatric disorders

Uncommon

Anxiety

Depression

Rare

Psychomotor hyperactivity

Sleep disorders

Aggression

Behavioural changes (predominantly in children)

Nervous System Disorders

Uncommon

Tremor**

Eye disorders

Uncommon

Cataract

)

Not known

Glaucoma

Respiratory, thoracic and mediastinal disorders

Common

Cough

Hoarseness

Throat irritation

Rare

Bronchospasm

Dysphonia

Hoarseness***

Skin and subcutaneous tissue disorders

Rare

Bruising

Musculoskeletal and connective tissue disorders

Uncommon

Muscle spasm

* refer to Paediatric population, below

** based on the frequency reported in clinical trials

*** rare in children

Occasionally, signs or symptoms of systemic glucocorticosteroid-side effects may occur with inhaled glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity .

Description of selected adverse reactions

The candida infection in the oropharynx is due to drug deposition. Advising the patient to rinse the mouth out with water after each dosing will minimise the risk.

As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases .

In placebo-controlled studies, cataract was also uncommonly reported in the placebo group.

Clinical trials with 13119 patients on inhaled budesonide and 7278 patients on placebo have been pooled. The frequency of anxiety was 0.52% on inhaled budesonide and 0.63% on placebo; that of depression was 0.67% on inhaled budesonide and 1.15% on placebo.

Paediatric population

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard

Adverse drug reactions reported in clinical trials with Abelitan are presented in Table 1. Adverse drug reactions reported for the therapeutic class are presented in Table 2. In Phase II and III clinical trials, the incidence of adverse events for Abelitan tablets, at the recommended dose of 9 mg/day, was comparable to placebo. Most adverse events were of mild to moderate intensity and of a non-serious nature.

Adverse reactions reported are listed according to the following frequency: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Table 1 Abelitan drug-related adverse reactions reported during clinical trials with more than one case (N=255)

MedDRA System Organ Classification

Preferred Term of Adverse Drug Reaction

Common

Uncommon

Gastrointestinal disorders

Nausea

Abdominal pain upper

Abdominal distension

Abdominal pain

Dry mouth

Dyspepsia

Flatulence

Nervous system disorders

Headache

Dizziness

Psychiatric disorders

Insomnia

Mood altered

Skin and subcutaneous tissue disorders

Acne

General disorders and administration site conditions

Fatigue

Oedema peripheral

Musculoskeletal and connective tissue disorders

Myalgia

Back pain

Muscle spasms

Investigations

Blood cortisol decreased

Infections and infestations

Influenza

Blood and lymphatic system disorders

Leukocytosis

Table 2 Events reported for the therapeutic class (intestinal anti-inflammatory agents, corticosteroids acting locally, budesonide)

MedDRA System Organ Classification

Common

Uncommon

Rare

Very Rare

Cardiac disorders

Palpitations

Endocrine disorders

Cushingoid features

Growth retardation in children*

Eye disorders

Cataract including subcapsular cataract

Glaucoma

)

Gastrointestinal disorders

Dyspepsia

Immune system disorders

Anaphylactic reaction

Metabolism and nutrition disorders

Hypokalemia

Musculoskeletal and connective tissue disorders

Muscle cramps

Nervous system disorders

Tremor

Psychiatric disorders

Behavioural changes such as nervousness, insomnia and mood swings

Depression

Psychomotor hyperactivity

Anxiety

Aggression

Reproductive system and breast disorders

Menstrual disorders

Skin and subcutaneous tissue disorders

Skin reactions (urticaria, exanthema)

Ecchymosis

* Note that Abelitan is not recommended for use in children (see 4.2)

Most of the adverse events mentioned in this SmPC can also be expected for other treatments with glucocorticoids.

Side effects typical of systemic corticosteroids (e.g. cushingoid features and growth retardation) may occur. These side effects are dependent on dose, treatment time, concomitant and previous corticosteroid intake, and individual sensitivity.

Paediatric population

No data available.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

Tabulated list of adverse reactions

Adverse reactions, which have been associated with budesonide, are given below, listed by system organ class and frequency. Frequency is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10 000 to <1/1000), very rare (<1/10,000) and not known (cannot be estimated from available data).

Immune system disorders

Uncommon

Immediate and delayed hypersensitivity reactions including urticaria, rash, dermatitis angioedema and pruritus

Rare

Anaphylactic reaction

Endocrine disorders

Rare

Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation.

Eye disorders

Rare

Vision, blurred

Not known

Raised intraocular pressure or Glaucoma

Cataract

Respiratory, thoracic and mediastinal disorders

Common

Haemorrhagic secretion and epistaxis

Nasal Irritation (sneezing, stinging and dryness)

Rare

Nasal ulcer

Nasal septum perforation

Dysphonia

Very rare

Ulceration of mucous membrane

Musculoskeletal and connective tissue disorders

Uncommon

Muscle spasm

Injury, poisoning and procedural complications

Rare

Contusion*

* based on mechanistic plausibility and extrapolation from other budesonide/corticosteroid formulations.

In rare cases, signs or symptoms of systemic glucocorticosteroid-side effects such as Cushing's syndrome, Cushingoid features, psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children), may occur with nasal glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity .

Paediatric population

Growth retardation has been reported in children receiving intranasal steroids.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

Serious and important adverse reactions include:

  • Hypercorticism and adrenal axis suppression
  • Symptoms of steroid withdrawal in those patients transferring from systemic glucocorticosteroid therapy
  • Increased susceptibility to infection
  • Other glucocorticosteroid effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Abelitan rectal foam in 332 patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The median duration of exposure was 42 days. This included 14 patients exposed for at least 6 months.

Abelitan rectal foam was studied primarily in 2 placebo-controlled, 6-week trials in patients with active disease (Study 1 and Study 2). In these trials, 268 patients received Abelitan rectal foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks .

The most common adverse reactions ( ≥ 2% of the Abelitan rectal foam or Placebo group and at higher frequency in the Abelitan rectal foam group) were decreased blood cortisol, adrenal insufficiency, and nausea (Table 1). Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/dL. Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with adrenocorticotropic hormone (ACTH).

A total of 10% of Abelitan rectal foam-treated patients discontinued treatment due to an adverse reaction compared with 4% of placebo-treated patients.

Table 1: Summary of Adverse Reactions in 2 Placebo Controlled Trials* (Studies 1and 2)

Adverse Reaction Abelitan Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Decreased blood cortisol# 46 (17) 6 (2)
Adrenal insufficiency† 10 (4) 2 (1)
Nausea 6 (2) 2 (1)
* Experienced by ≥ 2% of the Abelitan rectal foam or Placebo group and at higher frequency in the Abelitan rectal foam group
# Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/Dl
† Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH.

Of the 46 Abelitan rectal foam treated patients with decreased blood cortisol (defined as a morning cortisol level of < 5 mcg/dL) reported as an adverse event, none had adrenal insufficiency (defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH) (see Table 2). All cases of adrenal insufficiency resolved.

Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2).

Table 2: Summary of Glucocorticoid Related Effects in Two Placebo- Controlled Trials (Studies 1 and 2)

Adverse Reaction Abelitan Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Overall 60 (22) 10 (4)
Blood cortisol decreased 46 (17)* 6 (2)
Adrenal insufficiency 10 (4) 2 (1)
Insomnia 1 (0.4) 1 (0.4)
Sleep disorder 1 (0.4) 0
Acne 1 (0.4) 0
Depression 1 (0.4) 1 (0.4)
Hyperglycemia 1 (0.4) 0
* Decreases in serum cortisol levels associated with budesonide treatment were seen at Weeks 1 and 2 (twice-daily treatment) in the Abelitan rectal foam group, but gradually returned to baseline levels during the 4 weeks of once daily treatment.

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between Abelitan rectal foam and placebo after 6 weeks of therapy.

For additional details on morning cortisol levels and the response to the ACTH stimulation test, see CLINICAL PHARMACOLOGY.

Post-Marketing Experience

In addition to adverse reactions reported from clinical trials for Abelitan rectal foam, the following adverse reactions have been identified during post-approval use of other oral and rectal formulations of budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: hypertension

Gastrointestinal disorders: pancreatitis

General disorders and administration site conditions: pyrexia, peripheral edema

Immune System Disorders: anaphylactic reactions

Nervous System Disorders: dizziness, benign intracranial hypertension

Psychiatric Disorders: mood swings

Skin and subcutaneous tissue disorders: pruritus, maculo-papular rash, allergic dermatitis

Serious and important adverse reactions include:

  • Hypercorticism and adrenal axis suppression
  • Symptoms of steroid withdrawal in those patients transferring from systemic glucocorticosteroid therapy
  • Increased susceptibility to infection
  • Other glucocorticosteroid effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Abelitan foam in 332 patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The median duration of exposure was 42 days. This included 14 patients exposed for at least 6 months.

Abelitan foam was studied primarily in 2 placebo-controlled, 6-week trials in patients with active disease (Study 1 and Study 2). In these trials, 268 patients received Abelitan foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks .

The most common adverse reactions ( ≥ 2% of the Abelitan foam or Placebo group and at higher frequency in the Abelitan foam group) were decreased blood cortisol, adrenal insufficiency, and nausea (Table 1). Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/dL. Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with adrenocorticotropic hormone (ACTH).

A total of 10% of Abelitan foam-treated patients discontinued treatment due to an adverse reaction compared with 4% of placebo-treated patients.

Table 1: Summary of Adverse Reactions in 2 Placebo Controlled Trials* (Studies 1and 2)

Adverse Reaction UCERIS Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Decreased blood cortisol# 46 (17) 6 (2)
Adrenal insufficiency† 10 (4) 2 (1)
Nausea 6 (2) 2 (1)
* Experienced by ≥ 2% of the UCERIS rectal foam or Placebo group and at higher frequency in the Abelitan foam group
# Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/Dl
† Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH.

Of the 46 Abelitan foam treated patients with decreased blood cortisol (defined as a morning cortisol level of < 5 mcg/dL) reported as an adverse event, none had adrenal insufficiency (defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH) (see Table 2). All cases of adrenal insufficiency resolved.

Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2).

Table 2: Summary of Glucocorticoid Related Effects in Two Placebo- Controlled Trials (Studies 1 and 2)

Adverse Reaction UCERIS Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Overall 60 (22) 10 (4)
Blood cortisol decreased 46 (17)* 6 (2)
Adrenal insufficiency 10 (4) 2 (1)
Insomnia 1 (0.4) 1 (0.4)
Sleep disorder 1 (0.4) 0
Acne 1 (0.4) 0
Depression 1 (0.4) 1 (0.4)
Hyperglycemia 1 (0.4) 0
* Decreases in serum cortisol levels associated with budesonide treatment were seen at Weeks 1 and 2 (twice-daily treatment) in the Abelitan foam group, but gradually returned to baseline levels during the 4 weeks of once daily treatment.

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between Abelitan foam and placebo after 6 weeks of therapy.

For additional details on morning cortisol levels and the response to the ACTH stimulation test, see CLINICAL PHARMACOLOGY.

Post-Marketing Experience

In addition to adverse reactions reported from clinical trials for Abelitan foam, the following adverse reactions have been identified during post-approval use of other oral and rectal formulations of budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: hypertension

Gastrointestinal disorders: pancreatitis

General disorders and administration site conditions: pyrexia, peripheral edema

Immune System Disorders: anaphylactic reactions

Nervous System Disorders: dizziness, benign intracranial hypertension

Psychiatric Disorders: mood swings

Skin and subcutaneous tissue disorders: pruritus, maculo-papular rash, allergic dermatitis

Tabulated list of adverse events

The following definitions apply to the incidence of undesirable effects:

Very Common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very Rare (< 1/10,000); Not Known (cannot estimate from the available data).

Adverse drug reactions by frequency and system organ class (SOC)

SOC

Frequency

Reaction

Immune system disorders

Very Rare

Anaphylactic reaction

Endocrine disorders

Common

Cushingoid features

Very Rare

Growth retardation

Metabolism and nutrition disorders

Common

Hypokalemia

Psychiatric disorders

Common

Behavioural changes such as nervousness, insomnia, mood swings and depression

Uncommon

Anxiety

Rare

Aggression

Nervous system disorders

Uncommon

Tremor, psychomotor hyperactivity

Eye disorders

Rare

<)

Cardiac disorders

Common

Palpitations

Gastrointestinal disorders

Common

Dyspepsia

Skin and subcutaneous tissue disorders

Common

Skin reactions (urticaria, exanthema)

Rare

Ecchymosis

Musculoskeletal and connective tissue disorders

Common

Muscle cramps

Reproductive system and breast disorders

Common

Menstrual disorders

Most of the adverse events mentioned in this SmPC can also be expected for other treatments with glucocorticoids.

Description of selected adverse events

Side effects typical of systemic corticosteroids (e.g. cushingoid features and growth retardation) may occur. These side effects are dependent on dose, treatment time, concomitant and previous corticosteroid intake, and individual sensitivity.

In clinical studies, at recommended doses, the incidence of adverse events was comparable to placebo.

Clinical studies showed the frequency of steroid associated side effects for Abelitan CR Capsules to be approximately half that of conventional prednisolone treatment, at equipotent doses. In studies of patients with active disease, receiving Abelitan 9 mg daily, the incidence of adverse events was comparable to placebo. Very rarely a wide range of psychiatric/ behavioural effects may occur, when systemic steroids are prescribed at high doses and for prolonged periods .

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard.

Overdose

The information provided in Overdose of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
more... close
Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

Symptoms:

Acute overdose with Abelitan usually does not constitute a clinical problem. The only harmful effect after a large amount of sprays during a short period is a suppression of the cortex function.

If it is a matter of chronic use of very high doses, effects such as a degree of cortex atrophy in addition to adrenocortical suppression may occur.

Treatment:

Acute overdosage: There is no need for acute measures. The treatment with Abelitan should be continued with the lowest possible effective maintenance dose, and the adrenocortical function will repair itself automatically within 1-2 days.

Chronic overdosage: The patient should be treated as a steroid dependent and be transferred to a suitable maintenance dose with a systemic steroid, for example prednisolone. When the condition is stabilized, the patient should continue the treatment with the inhalation of Abelitan at the recommended dose.

To date, no cases of overdose with budesonide are known.

Abelitan Respules contains 0.1 mg/ml disodium edetate which has been shown to cause bronchoconstriction at levels above 1.2 mg/ml. Acute overdosage with Abelitan Respules, even in excessive doses, is not expected to be a clinical problem.

Acute overdosage with UCERIS rectal foam is unlikely. However, UCERIS rectal foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism .

Symptoms

Acute overdosage with Abelitan, even in excessive doses, is not expected to be a clinical problem. The only harmful effect that follows inhalation of large amounts of the drug over a short period is suppression of hypothalamic-pituitary-adrenal (HPA) function.

Management

No special emergency action needs to be taken. Treatment with Abelitan should be continued at the recommended dose to control the asthma.

Due to the low systemic availability of Abelitan tablets, acute overdosage even at very high doses is not expected to lead to an acute clinical crisis. In the event of acute overdosage, no specific antidote is available. Treatment consists of supportive and symptomatic therapy.

Acute overdose with this medicine even in excessive doses, is not expected to be a clinical problem.

Inhalation of high doses of corticosteroids may lead to suppression of the hypothalamic-pituitary-adrenal (HPA) axis function.

Acute overdosage with Abelitan rectal foam is unlikely. However, Abelitan rectal foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism .

Acute overdosage with Abelitan foam is unlikely. However, Abelitan foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism .

Reports of acute toxicity or death following overdosage of glucocorticosteroids are rare. Thus, acute overdosage with Abelitan CR Capsules even in excessive doses, is not expected to lead to an acute clinical crisis. In the event of acute overdosage, no specific antidote is available. Treatment consists of supportive and symptomatic therapy.

Chronic overdosage may lead to systemic corticosteroid effects, such as Cushingoid features. If such changes occur, the dose of Abelitan CR Capsules should be gradually reduced until treatment is discontinued, in accordance with normal procedures for the discontinuation of prolonged oral glucocorticosteroid therapy.

Pharmacodynamic properties

The information provided in Pharmacodynamic properties of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
more... close
Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard

Pharmacotherapeutic group: Other drugs for obstructive airways diseases, inhalant, Glucocorticoids

ATC code: R03 BA 02

Abelitan is a glucocorticosteroid with a powerful local anti-inflammatory action.

Mechanism of action

The precise mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory effects (including T-cells, eosinophilic cells and mast cells) such as inhibition of the release of inflammatory mediators and inhibition of cytokine-mediated immune response, are probably important. The strength of Abelitan, measured as affinity for glucocorticoid receptors, is approximately 15 times stronger than that of prednisolone.

Clinical efficacy and safety

A clinical trial with asthma patients in which inhaled and oral Abelitan was compared with placebo, showed statistically significant effects of inhaled Abelitan, but not of oral Abelitan. The therapeutic effect of normally used doses of inhaled Abelitan may therefore chiefly be explained by a direct effect on the airways.

Abelitan has demonstrated an anti-anaphylactic and anti-inflammatory effect in challenge tests in experimental animals and in patients. This effect has manifested itself as reduced bronchial obstruction in both the immediate and the later allergic reaction.

It was also demonstrated that Abelitan reduces the airways' reactivity to histamine and metacholine in hyperreactive patients. Treatment with inhaled Abelitan has been used to effectively prevent exercise-induced asthma.

Influence on plasma cortisol concentration:

Studies in healthy volunteers with inhaled Abelitan have shown dose-related effect on plasma and urinary cortisol. At recommended doses, inhaled Abelitan causes significantly less effect on adrenal function than prednisone 10 mg, as shown by ACTH test. No clinically relevant changes in the plasma cortisol values or response to ACTH stimulation were observed when Abelitan was given in doses up to 1600 µg daily for 3 months to adults and up to 800 µg daily to children. Long-term monitoring for up to 52 weeks confirmed that the HPA axis was not suppressed.

Paediatric population

Clinical – asthma

The efficacy of Abelitan nebuliser suspension has been evaluated in a large number of studies, and it has been shown that Abelitan nebuliser suspension is effective both in adults and children as once- or twice-daily medication for prophylactic treatment of persistent asthma. Some examples of representative studies are given below.

Clinical – croup

A number of studies in children with croup have compared Abelitan nebuliser suspension with placebo. Examples of representative studies evaluating the use of Abelitan for the treatment of children with croup are given below.

Efficacy in children with mild to moderate croup

A randomized, double-blind placebo-controlled trial in 87 children (aged 7 months to 9 years), admitted to hospital with a clinical diagnosis of croup, was conducted to determine whether Abelitan nebuliser suspension improves croup symptom scores or shortens the duration of stay in hospital. An initial dose of Abelitan nebuliser suspension (2 mg) or placebo was given followed by either Abelitan 1 mg or placebo every 12 hours. Abelitan nebuliser suspension statistically significantly improved croup score at 12 and 24 hours and at 2 hours in patients with an initial croup symptom score above 3. There was also a 33% reduction in the length of stay.

Efficacy in children with moderate to severe croup

A randomized, double-blind, placebo-controlled study compared the efficacy of Abelitan nebuliser suspension and placebo in the treatment of croup in 83 infants and children (aged 6 months to 8 years) admitted to hospital for croup. Patients received either Abelitan 2 mg nebuliser suspension or placebo every 12 h for a maximum of 36 h or until discharge from hospital. The total croup symptom score was assessed at 0, 2, 6, 12, 24, 36 and 48 hours after the initial dose. At 2 hours, both the Abelitan nebuliser suspension and placebo groups showed a similar improvement in croup symptom score, with no statistically significant difference between the groups. By 6 hours, the croup symptom score in the Abelitan nebuliser suspension group was statistically significantly improved compared with the placebo group, and this improvement versus placebo was similarly evident at 12 and 24 hours.

Both asthma and inhaled glucocorticosteroids may affect the growth in length. The effect of Abelitan Nebuliser Suspension on the growth in length was studied in 519 children (from 8 months to 9 years) in three prospective, randomised, open, non-blinded studies. The studies did not show any significant difference in the growth in length of children treated either with Abelitan Nebuliser Suspension or with conventional asthma therapy. Two studies (N = 239 and 72 patients, respectively) showed 7 mm and 8 mm greater growth after one year of treatment with Abelitan Nebuliser Suspension compared with traditional asthma therapy (not statistically significant), while one study (N = 208) showed a growth in length that after one year was 8 mm smaller in the Abelitan Nebuliser Suspension group than in the group of conventional asthma treatment (statistically significant difference).

Pharmacotherapeutic group: Intestinal antiinflammatory agents, corticosteroids acting locally

ATC code: A07EA06

The exact mechanism of action of budesonide in the treatment of ulcerative colitis/procto-sigmoiditis is not fully understood. Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of budesonide is predominantly based on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At a dosage of 2 mg budesonide, applied rectally, budesonide leads to practically no suppression of the hypothalamus-hypophysis-adrenal cortex axis.

Abelitan 2mg rectal foam investigated up to the daily dosage of 4 mg budesonide showed virtually no influence on the plasma cortisol level.

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: RO3B A02

Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids.

Topical anti-inflammatory effect

The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important.

A clinical study in asthmatics comparing inhaled and oral budesonide at doses calculated to achieve similar systemic bioavailability demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract.

In a provocation study pre-treatment with budesonide for four weeks has shown decreased bronchial constriction in immediate as well as late asthmatic reactions.

Onset of effect

After a single dose of orally inhaled budesonide, delivered via dry powder inhaler, improvement of the lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment although maximum benefit may not be achieved for up to 4 weeks.

Airway reactivity

Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyperreactive patients.

Exercise-induced asthma

Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma.

Growth

In short term studies a small and generally transient reduction in growth has been observed, which usually occurs within the first year of treatment.

Influence on plasma cortisol concentration

Studies in healthy volunteers with Abelitan Turbohaler have shown dose-related effect on plasma and urinary cortisol. At recommended doses, Abelitan Turbohaler causes significantly less effect on adrenal function than prednisone 10 mg, as shown by ACTH test.

Paediatric population

Clinical – asthma

The efficacy of Abelitan Respules has been evaluated in a large number of studies, and it has been shown that Abelitan Respules is effective both in adults and children as once- or twice-daily medication for prophylactic treatment of persistent asthma. Some examples of representative studies are given below.

Clinical – croup

A number of studies in children with croup have compared Abelitan Respules with placebo. Examples of representative studies evaluating the use of Abelitan Respules for the treatment of children with croup are given below.

Efficacy in children with mild to moderate croup

A randomised, double-blind placebo-controlled trial in 87 children (aged 7 months to 9 years), admitted to hospital with a clinical diagnosis of croup, was conducted to determine whether Abelitan Respules improves croup symptom scores or shortens the duration of stay in hospital. An initial dose of Abelitan Respules (2 mg) or placebo was given followed by either Abelitan Respules 1 mg or placebo every 12 hours. Abelitan Respules statistically significantly improved croup score at 12 and 24 hours and at 2 hours in patients with an initial croup symptom score above 3. There was also a 33% reduction in the length of stay.

Efficacy in children with moderate to severe croup

A randomised, double-blind, placebo-controlled study compared the efficacy of Abelitan Respules and placebo in the treatment of croup in 83 infants and children (aged 6 months to 8 years) admitted to hospital for croup. Patients received either Abelitan Respules 2 mg or placebo every 12 h for a maximum of 36 h or until discharge from hospital. The total croup symptom score was assessed at 0, 2, 6, 12, 24, 36 and 48 hours after the initial dose. At 2 hours, both the Abelitan Respules and placebo groups showed a similar improvement in croup symptom score, with no statistically significant difference between the groups. By 6 hours, the croup symptom score in the Abelitan Respules group was statistically significantly improved compared with the placebo group, and this improvement versus placebo was similarly evident at 12 and 24 hours.

Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids.

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: R03B A02.

Topical anti-inflammatory effect

The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important.

A clinical study in asthmatics comparing inhaled and oral budesonide at doses calculated to achieve similar systemic bioavailability demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract.

In a provocation study pre-treatment with budesonide for four weeks has shown decreased bronchial constriction in immediate as well as late asthmatic reactions.

Onset of effect

After a single dose of orally inhaled budesonide, delivered via dry powder inhaler, improvement of the lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment, although maximum benefit may not be achieved for up to 4 weeks.

Airway reactivity

Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyper-reactive patients.

Exercise-induced asthma

Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma.

Growth

In short term studies a small and generally transient reduction in growth has been observed, which usually occurs within the first year of treatment.

Paediatric Population

Slit lamp examinations were performed in 157 children (5-16 years old), treated with an average daily dose of 504 μg for 3-6 years. Findings were compared with 111 age-matched asthmatic children. Inhaled budesonide was not associated with an increased occurrence of posterior subcapsular cataract.

Influence on plasma cortisol concentration

Studies in healthy volunteers with Abelitan have shown dose-related effects on plasma and urinary cortisol. At recommended doses, Abelitan, causes less effect on the adrenal function than prednisolone 10mg, as shown by ACTH tests.

Pharmacotherapeutic group: Intestinal anti-inflammatory agents, Corticosteroids acting locally

ATC code: A07E A06

Mechanism of action

The exact mechanism of action of budesonide in the treatment of UC is not fully understood. In general, budesonide inhibits many inflammatory processes including cytokine production, inflammatory cell activation and expression of adhesion molecules on endothelial and epithelial cells. At doses clinically equivalent to prednisolone, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.

Data from clinical pharmacology and pharmacokinetic studies indicate that the mode of action of Abelitan tablets is based on a local action in the gut.

Pharmacodynamic effects

MMX extended release technology is characterised by a multi-matrix structure covered by a gastro-resistant coating that dissolves in intestinal fluids having a pH greater than 7.

When the dosage form is administered, the gastro-protective layer protects the dosage form during transit through the stomach and duodenum up to the lower part of the intestine. When the protective layer is lost, the intestinal fluid then comes into contact with the hydrophilic matrix polymers, which start to swell until a viscous gel matrix is formed. The solvent that penetrates into the gel matrix dissolves the active ingredient from the lipophilic matrices. Budesonide is then released into the intestinal tract at a controlled rate throughout the colon.

Budesonide is a glucocorticoid used in the treatment of inflammatory bowel disease. It has a topical anti-inflammatory activity, but does not reduce cortisol levels to the same extent as systemic glucocorticoids.

Clinical efficacy

Two randomised, controlled phase III clinical trials including 1022 patients with mild to moderate active UC have been performed in adult patients. Two hundred fifty five (255) patients were treated for 8 weeks with Abelitan 9 mg per day. Patients included were either treatment naïve (42% ITT) or had failed on 5-ASA (58% ITT). Both studies included a reference arm, mesalazine (Asacol) and budesonide (Entocort), respectively to show assay sensitivity. The definition of remission applied in both studies was UCDAI score of ≤1, with 0 score for rectal bleeding and stool frequency, normal mucosa (no friability) and ≥1 point reduction in endoscopy score.

Effect of Abelitan 9mg tablet on Primary Endpoint:

Study

Abelitan 9 mg

Remission (%)

Placebo

Remission (%)

P=

Study CB-01-02/01

17.9

7.4

0.0143

Study CB-01-02/02

17.4

4.5

0.0047

Statistical difference versus placebo was reached for Abelitan 9 mg for both studies and the difference versus placebo was 10.4% and 12.9% respectively.

5-ASA is the Standard of Care for treatment of mild to moderate disease. Results of a head to head comparison with Abelitan and 5-ASA were not available. Therefore, the place in the therapeutic work-up remains to be established. Some patients may benefit from treatment initially with Abelitan.

Paediatric Population

Abelitan was not studied in the paediatric population.

Pharmacotherapeutic group: Decongestants and other nasal preparations for topical use, corticosteroids. ATC code: R01A D05

Budesonide is a non-halogenated glucocorticosteroid with a high local anti-inflammatory action within the respiratory tract.

Pharmacotherapeutic group: Corticosteroids acting locally.

ATC code: A07EA06

Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect.

The exact mechanism of budesonide in the treatment of Crohn's disease is not fully understood.

Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of Abelitan CR Capsules is based, at least partly, on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At doses clinically equivalent to prednisolone, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.

At recommended doses, Abelitan CR Capsules caused significantly less effect than prednisolone 20–40 mg daily on morning plasma cortisols; on 24 hour plasma cortisol (AUC 0–24 h) and on 24 hour urine cortisol levels.

ACTH tests have shown Abelitan CR Capsules to have significantly less effect than prednisolone on adrenal functions.

Paediatric population

HPA axis function. At recommended doses, Abelitan CR Capsules cause significantly less effect than prednisole 20-40 mg daily on morning plasma cortisol, on 24-hour plasma cortisol (AUC 0-24 h) and on 24-hour urine cortisol. Also ACTH tests have shown that Abelitan CR Capsules, compared with prednisolone, have significantly less impact on the adrenal function. Children with Crohn's disease have a slightly higher systemic exposure and cortisol suppression than adults with Crohn's disease.

Long-term studies have not been performed in children treated with Abelitan CR Capsules. In a study evaluating the effect of Abelitan CR Capsules on cortisol suppression in 8 children (range 9–14 years) and 6 adults , the oral administration of 9 mg Abelitan CR Capsules for 7 days induced a mean cortisol suppression (± SD) of 64% (±18%) in children and 50% (±27%) in adults with respect to baseline values. No clinically relevant findings in terms of safety have been reported. (Study 08-3044)

A study performed in children with mild to moderate Crohn's disease (CDAI ≥ 200) compared the activity of Abelitan CR Capsules at the dose of 9 mg once daily with that of prednisolone, administered at tapering doses, starting from 1 mg/kg. 22 patients were treated with Abelitan CR Capsules and 26 patients were treated with the reference drug prednisolone. After 8 weeks of treatment, 70.8% of patients treated with prednisolone reached the endpoint (CDAI ≤ 150), as compared to 54.5% of subjects treated with Abelitan CR Capsules, the difference was not statistically significant (p = 0.13). In the course of the study, adverse events were observed in 96% of patients treated with prednisolone and 91% of patients treated with Abelitan CR Capsules. The nature of these adverse events was similar in both study arms, but the incidence of glucocorticoid-related side-effects (such as acne and moon face) was lower in patients treated with Abelitan CR Capsules. (Study SD-008-3037)

Study D9422C0001 was an open-label, uncontrolled study designed to evaluate Abelitan in 108 pediatric patients (children and adolescents aged 5 to 17 years) diagnosed with mild to moderate Crohn's disease of the ileum and/or ascending colon. The median duration of treatment exposure of Abelitan of 58 days (range: 5 days to 90 days). Patients were dosed with oral Abelitan once daily according to bodyweight, patients weighing ≤25 kg received 6 mg once daily for 8 weeks; patients weighing >25 kg received 9 mg once daily for 8 weeks. During the 8 weeks of treatment there was a reduction in the mean (±SD) PCDAI score from 19.1 (±10.1) to 9.1 (±8.5), indicating an improvement in disease activity; with an improvement in mean (±SD) IMPACT 3 score from 132.1 (±18.8) to 140.9 (±16.9). AEs were observed at a similar frequency and severity as seen in adults, and were mostly related to Crohn's disease, puberty and possible GCS related side effects.

Study D9422C00002 was an open-label, un-comparative study designed to evaluate Abelitan 6 mg once daily as maintenance treatment in 50 pediatric patients (children and adolescents aged 5 to 17 years) with a diagnosis of mild to moderate Crohn's disease of the ileum and/or ascending colon who were in clinical remission (PCDAI ≤10). Treatment consisted of a 12-week maintenance treatment phase of 6 mg once daily, a 2-week taper phase to 3 mg once daily. The median duration of treatment exposure of Abelitan was 98.5 days (range: 11 days to 135 days). Most patients remained in the clinical remission stage, as there were no major changes in the mean PCDAI composite score or IMPACT 3 score. Mean (SD) PCDAI was 4.85 (3.62) at baseline and 6.89 (8.08) after 12 weeks of maintenance treatment with Abelitan 6 mg daily. At the same points in time the mean IMPACT3 score was 145.62 (12.43) and 146.98 (15.48), respectively. AEs were observed at a similar frequency and severity as seen in adults, and were mostly related to Crohn's disease, puberty and possible GCS related side effects.

Pharmacokinetic properties

The information provided in Pharmacokinetic properties of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard

Absorption

In adults the systemic availability of Abelitan following administration of Abelitan Nebuliser Suspension via a jet nebuliser is approximately 15% of the nominal dose and 40% to 70% of the dose delivered to the patients. A minor fraction of the systemically available drug comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 min after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg.

Distribution

Abelitan has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85 - 90%.

Biotransformation

Abelitan undergoes an extensive degree (~90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxyAbelitan and 16α-hydroxyprednisolone, is less than 1 % of that of Abelitan. The metabolism of Abelitan is primarily mediated by CYP3A, a subfamily of cytochrome P450.

Elimination

The metabolites of Abelitan are excreted as such or in conjugated form mainly via the kidneys. No unchanged Abelitan has been detected in the urine. Abelitan has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of Abelitan after iv dosing averages 2-3 hours.

Linearity

The kinetics of Abelitan are dose-proportional at clinically relevant doses.

Paediatric population

Abelitan has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of Abelitan after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In 4-6 years old asthmatic children, the systemic availability of Abelitan following administration of Abelitan Nebuliser Suspension via a jet nebuliser (Pari LC Jet Plus® with Pari Master® compressor) is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half of that in healthy adults. The maximal plasma concentration, occurring approximately 20 min after start of nebulisation is approximately 2.4 nmol/L in 4-6 years old asthmatic children after a 1 mg dose. The exposure (Cmax and AUC) of Abelitan following administration of a single 1 mg dose by nebulisation to 4-6 year old children is comparable to that in healthy adults given the same delivered dose by the same nebuliser system.

Absorption

After oral application the systemic availability of budesonide is about 10 %. After rectal administration the areas under the concentration time curves are about 1.5-fold higher than in historical controls considering the identical oral budesonide dose. Peak levels are obtained after an average of 2 - 3 hours after administering Abelitan 2mg rectal foam.

Distribution

Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85 - 90 %.

Biotransformation

Budesonide undergoes extensive biotransformation in the liver (approximately 90 %) to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6 β - hydroxybudesonide and 16 α - hydroxyprednisolone, is less than 1 % of that of budesonide.

Elimination

The average elimination half-life is about 3 - 4 hours. The mean clearance rate is about 10 - 15 L/min for budesonide, determined by HPLC-based methods.

Spread

A scintigraphic investigation with technetium-marked Abelitan 2mg rectal foam on patients with ulcerative colitis showed that the foam spreads out over the entire sigmoid.

Specific patient populations (liver diseases)

Dependent on the type and severity of liver diseases the metabolism of budesonide might be decreased.

Absorption

In adults the systemic availability of budesonide following administration of Abelitan Nebuliser Suspension via a jet nebuliser is approximately 15% of the nominal dose and 40% to 70% of the dose delivered to the patients. A minor fraction of the systemically available drug comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 min after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg.

Distribution

Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85 - 90%.

Biotransformation

Budesonide undergoes an extensive degree (≈90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.

Elimination

The metabolites of budesonide are excreted as such or in conjugated form mainly via the kidneys. No unchanged budesonide has been detected in the urine. Budesonide has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of budesonide after iv dosing averages 2 - 3 hours.

Linearity

The kinetics of budesonide are dose-proportional at clinically relevant doses.

In a study, 100 mg ketoconazole taken twice daily, increased plasma levels of concomitantly administered oral budesonide (single dose of 10 mg) on average, by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.

Paediatric population

Budesonide has a systemic clearance of approximately 0.5 L/min in 4 - 6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In 4 - 6 years old asthmatic children, the systemic availability of budesonide following administration of Abelitan Nebuliser Suspension via a jet nebuliser (Pari LC Jet Plus® with Pari Master® compressor) is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half of that in healthy adults.

The maximal plasma concentration, occurring approximately 20 min after start of nebulisation is approximately 2.4 nmol/L in 4 - 6 years old asthmatic children after a 1 mg dose. The exposure (Cmax and AUC) of budesonide following administration of a single 1 mg dose by nebulisation to 4 - 6 year old children is comparable to that in healthy adults given the same delivered dose by the same nebuliser system.

Absorption

Following oral inhalation via Abelitan, peak plasma concentrations of budesonide (4.0 nmol/L after a dose of 800 μg) occur within 30 minutes. Maximum plasma concentration and area under the plasma concentration time profile increase linearly with dose, but are slightly (20-30%) higher following repeated doses (3 weeks treatment) than after a single dose. Lung deposition in healthy subjects was estimated to 34% ±10% of the metered dose (arithmetic mean ± SD), while 22% was retained in the mouthpiece and the rest (approximately 45% of the metered dose) was swallowed.

The maximal plasma concentration after inhalation of 1 milligram budesonide is about 3.5 nmol/L and is reached after about 20 minutes.

Distribution

Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85-90%.

Biotransformation

Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome p450.

Excretion

The metabolites of budesonide are excreted as such or in conjugated form mainly via the kidneys. No unchanged budesonide has been detected in the urine. Budesonide has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of budesonide after iv dosing averages 2-3 hours.

Linearity

The kinetics of budesonide are dose-proportional at clinically relevant doses.

In a study, 100 mg ketoconazole taken twice daily, increased plasma levels of concomitantly administered oral budesonide (single dose of 10 mg) on average, by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.

Paediatric safety data

Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In asthmatic children treated with Abelitan (800 μg single dose), plasma concentration reached Cmax (4.85 nmol/L) at 13.8 minutes after inhalation, and then decreased rapidly; AUC was 10.3 nmol·h/L. The value for AUC is generally comparable to that observed in adults at the same dose, however, the Cmax value tends to be higher in children. Lung deposition in children (31% of the nominal dose) is similar to that measured in healthy adults (34% of nominal dose).

Absorption

After oral dosing of plain micronised compound, absorption seems to be complete. A large proportion of the unformulated drug is absorbed from the ileum and ascending colon.

Systemic availability of Budesonide following a single administration of Abelitan tablets in healthy volunteers was compared to that of Entocort and the result was similar, about 10%, due to first pass metabolism in the liver. Maximum plasma concentrations of budesonide are approximately 1.3-1.8 ng/ml at 13-14 hours post administration. Concomitant administration of Abelitan tablets with food had no clinically relevant effect on absorption. It has been shown that there is no potential for drug accumulation on repeated dosing.

Distribution

Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85–90%.

Biotransformation

Budesonide undergoes extensive biotransformation in the liver to metabolites of low glucocorticoid activity. The glucocorticoid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.

Elimination

Elimination of budesonide is rate limited by absorption. Budesonide has a high systemic clearance (about 1.2 L/min).

Paediatric Population

No data or experience is available with respect to the pharmacokinetics of Abelitan tablets in the paediatric population.

Bioavailablity of oral budesonide in man is low (11-13%) due to an extensive first-pass metabolism in the liver.

The systemic availability of budesonide from this medicine, with reference to the metered dose is 33%. In adults, the maximal plasma concentration after administration of 256 micrograms budesonide from this medicine is 0.64 nM and is reached within 0.7 hours. The AUC after administration of 256 micrograms budesonide from this medicine is 2.7 nmolxh/L in adults.

Absorption

After oral dosing of plain micronised compound, absorption is rapid and seems to be complete. A large proportion of the drug is absorbed from the ileum and ascending colon. Systemic availability in healthy subjects is approximately 9–12% for Abelitan CR Capsules. This is similar to the systemic availability of plain micronised budesonide, indicating complete absorption. In patients with active Crohn's disease systemic availability is approximately 12–20% at the start of treatment.

Distribution

Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85–90%. In healthy volunteers mean maximal plasma concentrations of 5–10 nmol/L were seen at 3–5 hours following a single oral dose of Abelitan CR Capsules 9 mg.

Biotransformation

Budesonide then undergoes extensive biotransformation in the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.

Elimination

Elimination is rate limited by absorption. The average terminal half-life is 4 hours. Budesonide has a high systemic clearance (about 1.2 L/min).

Paediatric population

In a study comparing the pharmacokinetics of Abelitan CR Capsules in 8 children (range 9–14 years) and 6 adults, Abelitan CR Capules 9 mg for 7 days induced a systemic exposure (AUC) that was 17% higher in children than in adults, with maximum concentrations (Cmax) 50% higher in children than in adults (mean AUC ± SD: children 41.3 nmol/L ± 21.2; adults 35.0 nmol/L ± 19.8. Mean Cmax ± SD: children 5.99 nmo/L ± 3.45; adults 3.97 nmo/L ± 2.11.) (Study 08-3044).

Pharmacotherapeutic group

The information provided in Pharmacotherapeutic group of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Pharmacotherapeutic group in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard
Other drugs for obstructive airways diseases, inhalant, Glucocorticoids
Intestinal antiinflammatory agents, corticosteroids acting locally
Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: RO3B A02
Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: R03B A02.
Intestinal anti-inflammatory agents, Corticosteroids acting locally
Decongestants and other nasal preparations for topical use, corticosteroids. ATC code: R01A D05
Corticosteroids acting locally.

Preclinical safety data

The information provided in Preclinical safety data of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
more... close
Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard

Preclinical data revealed no special hazard for humans in the therapeutic dose range based on studies of chronic toxicity, genotoxicity and carcinogenicity.

Glucocorticoids, including Abelitan, have produced teratogenic effects in animals, including cleft palate and skeletal abnormalities. Similar effects are considered unlikely to occur in humans at the recommended dose levels.

Preclinical investigations on dogs have shown that Abelitan 2mg rectal foam is well tolerated locally.

Preclinical data in acute, subchronic and chronic toxicological studies with budesonide showed atrophies of the thymus gland and adrenal cortex and a reduction especially of lymphocytes. These effects were less pronounced or at the same magnitude as observed with other glucocorticosteroids. These steroid effects might also be of relevance in man.

Budesonide had no mutagenic effects in a number of in vitro and in vivo tests.

A slightly increased number of basophilic hepatic foci were observed in chronic rat studies with budesonide, and in carcinogenicity studies there was an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumours (female rats) observed. These tumours are probably due to the specific steroid receptor action, increased metabolic burden on the liver and anabolic effects, effects which are also known from other glucocorticosteroids in rat studies and therefore represent a class effect. No similar effects have ever been observed in man for budesonide, neither in clinical trials nor from spontaneous reports.

In general, preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

<).

The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticosteroids studied (beclomethasone dipropionate, fluocinolone acetonide).

Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.

An increased incidence of brain gliomas in male rats, in a carcinogenicity study, could not be verified in a repeat study in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.

Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.

Available clinical experience shows that there are no indications that budesonide, or other glucocorticosteroids, induce brain gliomas or primary hepatocellular neoplasms in man.

In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not appear to be relevant in humans at the recommended doses.

Animal studies have also identified an involvement of excess prenatal glucocorticosteroids, in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.

The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticosteroids studied (beclomethasone dipropionate, fluocinolone acetonide).

Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of the other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.

An increased incidence of brain gliomas in male rats, in a carcinogenicity study, could not be verified in a repeat study in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.

Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.

Available clinical experience shows no indication that budesonide, or other glucocorticosteroids, induce brain gliomas or primary hepatocellular neoplasms in man.

In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not appear to be relevant in humans at the recommended doses.

Animal studies have also identified an involvement of excess prenatal glucocorticosteroids, in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.

A preclinical toxicology and toxicokinetic bridging study, comparing Abelitan tablets with an existing prolonged release budesonide formulation (Entocort® EC 3 mg capsules, AstraZeneca) in cynomolgous monkeys has confirmed that Abelitan tablets result in a delayed peak exposure and reduced total exposure compared to the existing formulation of budesonide, while maintaining a superimposable toxicological profile.

Preclinical data have shown that budesonide produces effects less severe or similar to other glucocorticoids, such as weight increase, atrophy of the adrenal glands and thymus and effects on the leucocyte count. As with other glucocorticosteroids, and dependent on the dose and duration and the diseases concerned, these steroid effects may also be relevant in man.

Budesonide had no effect on fertility in rats.).

Budesonide had no mutagenic effects in a number of in vitro and in vivo tests. A slightly increased number of basophilic hepatic foci were observed in chronic rat studies with budesonide, and in carcinogenicity studies an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumours (in female rats) were observed. These tumours are probably due to the specific steroid receptor action, increased metabolic burden and anabolic effects on the liver, effects which are also known from rat studies with other glucocorticosteroids and therefore represent a class effect in this species.

The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticoids studied (beclomethasone dipropionate, flucinolone acetonide). Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than or similar to those observed after administration of the other glucocorticosteroids e.g. decreased body weight gain and atrophy of lymphoid tissues and adrenal cortex. An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in a repeat study, in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups. Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.

Available clinical experience shows no indication that budesonide or other glucocorticosteroids induce brain gliomas or primary heptocellular neoplasms in man. Budesonide has been used successfully in the treatment of seasonal allergic rhinitis for several years.

In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However these animal experimental results do not appear to be relevant in humans at the recommended doses.

Animal studies have also identified an involvement of excess prenatal glucocorticosteroids in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behavioural exposures below the teratogenic dose range.

Results from acute, subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe or similar to those observed after administration of other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.

Budesonide, evaluated in six different test systems, did not show any mutagenic or clastogenic effects.

An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in a repeat study, in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.

Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide as well as the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.

Available clinical experience shows that there are no indications that budesonide or other glucocorticosteroids induce brain gliomas or primary hepatocellular neoplasms in man.

The toxicity of Abelitan CR Capsules, with focus on the gastro-intestinal tract, has been studied in cynomolgus monkeys in doses up to 5 mg/kg after repeated oral administration for up to 6 months. No effects were observed in the gastrointestinal tract, neither at gross pathology nor in the histopathological examination.

Incompatibilities

The information provided in Incompatibilities of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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None applicable.

Special precautions for disposal and other handling

The information provided in Special precautions for disposal and other handling of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Special precautions for disposal and other handling in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard

Before using this medicine for the first time the nozzle must be primed (filled with the medicine). To do this the bottle is shaken and the protective cap removed. The bottle is then held upright and the nozzle pumped up and down several times (5-10 times) spraying into the air, until an even mist is seen. The priming effect remains for approximately 24 hours. If a longer period of time passes before the next dose is taken, the nozzle must be loaded with medicine again. This time it is sufficient to spray just once into the air.

a. The patient is then instructed to blow their nose. Next, the bottle needs to be shaken and the protective cap removed.

b. The bottle is then held upright, with one finger held on either side of the nozzle.

c. The tip of the nozzle is inserted into the nostril and the nozzle pressed down once (or more as instructed by the doctor). The spray is then administered into the other nostril in the same way. Note: it is not necessary to inhale at the same time as spraying.

d. The nozzle needs to be wiped with a clean tissue after use and the protective cap replaced. The bottle should be stored in an upright position.

e. Keeping the Abelitan nozzle clean

The plastic nozzle of Abelitan should be cleaned regularly and at any time the spray of medicine is not coming out as it should. If this happens, first the nozzle should be checked to ensure that it is primed with medicine (see earlier). If, after the nozzle is primed again, the pump is still not working, the nozzle should be cleaned by using the following instructions:

The plastic nozzle is removed with a clean tissue and washed in warm, not hot, water. The nozzle is then rinsed thoroughly, dried and then replaced onto the top of the bottle. The nozzle should not be unblocked with a pin or other sharp object. After cleaning, the nozzle must be primed (filled with medicine) again before use.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Name of the medicinal product
Abelitan
Qualitative and quantitative composition
Budesonide
Therapeutic indications
The information provided in Therapeutic indications of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

Treatment of persistent bronchial asthma in patients where use of a pressurised inhaler or dry powder formulation is unsatisfactory or inappropriate.

Very serious pseudocroup (laryngitis subglottica) in which hospitalisation is indicated.

For the treatment of active ulcerative colitis that is limited to the rectum and the sigmoid colon.

Abelitan Respules contain the potent, non-halogenated, corticosteroid, budesonide, for use in bronchial asthma, in patients where use of a pressurised inhaler or dry powder formulation is unsatisfactory or inappropriate.

Abelitan Respules are also recommended for use in infants and children with croup (acute viral upper respiratory tract infection also known as viral laryngotracheobronchitis or laryngitis subglottica), in which hospitalisation is indicated.

UCERIS rectal foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

Pulmicort is recommended in patients with bronchial asthma.

Abelitan is indicated in adults for induction of remission in patients with mild to moderate active ulcerative colitis (UC) where 5-ASA treatment is not sufficient.

Prevention and treatment of seasonal allergic rhinitis (hay fever).

Abelitan rectal foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

Abelitan foam is indicated for the induction of remission in patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge.

Crohn's disease - Induction of remission in patients with mild to moderate active Crohn's disease affecting the ileum and/or the ascending colon.

Microscopic colitis - Induction of remission in patients with active microscopic colitis

Dosage (Posology) and method of administration
The information provided in Dosage (Posology) and method of administration of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

Posology

Asthma

The dose should be given twice daily.

Administration once daily may be considered in cases of mild to moderate stable asthma.

Initial dosage:

The initial dose should be tailored to the severity of the disease and thereafter should be adjusted on an individual basis. The following doses are recommended but the minimum effective dose should always be sought:

Children aged 6 months and above:

0.25 – 1.0mg daily. For patients in maintenance therapy with oral steroids a higher initial dosage up to 2.0 mg daily should be considered.

Adults (including the elderly) and children/adolescents over 12 years of age:

0.5 - 2 mg daily. In very severe cases the dosage may be increased further.

Maintenance dose:

The maintenance dose should be adjusted to meet the requirements of the individual patient taking account of the severity of the disease and the clinical response of the patient. When the desired clinical effect has been obtained, the maintenance dose should be reduced to the minimum required for control of the symptoms.

Children aged 6 months and above:

0.25 - 1.0mg daily.

Adults (including the elderly) and children/adolescents over 12 years of age:

0.5 - 2.0mg daily. In very severe cases the dose may be further increased.

Administration once daily:

Administration once daily should be considered for children and adults with mild to moderate stable asthma and with a maintenance dose between 0.25 mg and 1 mg Abelitan daily. Once-daily administration may be initiated both in patients who are not receiving corticosteroid treatment and in well-controlled patients who are already taking inhaled steroids. The dose may be given in the morning or evening. If a worsening of the asthma occurs, the daily dose should be increased by administering the dose twice daily.

Onset of effect:

An improvement of the asthma following administration of Abelitan may occur within 3 days after initiation of therapy. The maximum effect will only be obtained after 2-4 weeks of treatment.

Patients in maintenance therapy with oral glucocorticosteroids:

Asthma

Abelitan nebuliser suspension may permit replacement or significant reduction in dosage of oral glucocorticosteroids while maintaining asthma control. When transferral from oral steroids to Abelitan nebuliser suspension is started, the patient should be in a relatively stable phase. A high dose of Abelitan nebuliser suspension is then given in combination with the previously used oral steroid dose for about 10 days.

After that, the oral steroid dose should be gradually reduced (by for example 2.5 milligrams prednisolone or the equivalent each month) to the lowest possible level.

When tapering off systemic corticosteroids some patients will experience steroid withdrawal symptoms, e.g. joint and/or muscle pain, lack of energy and depression or even a decreased lung function. Such patients must be advised to continue the inhaled Abelitan therapy, but they should also be examined for any objective signs of adrenocortical insufficiency. If such signs are present, the dose of the systemic corticosteroid should be temporarily increased and then tapered off even more slowly. In periods of stress or severe asthma attacks, patients in the transition phase may require treatment with systemic corticosteroids.

Pseudocroup

In infants and children with pseudocroup, the commonly used dose is 2 mg of nebulised Abelitan. This is given as a single administration, or as two 1 mg doses separated by 30 minutes. Dosing can be repeated every 12 hours for a maximum of 36 hours or until clinical improvement.

Method of administration

For inhalation use only.

Dosage schedule:

Dosage in mg

Volume of Abelitan Nebuliser Suspension

 

0.25

0.5

0.75

1

1.5

2

0.25 mg/ml

1 ml*

2 ml

3 ml

-

-

-

0.5 mg/ml

-

-

-

2 ml

3 ml

4 ml

*) Should be mixed with 0.9 % saline to a volume of 2 ml.

Division of the dose and miscibility:

The contents of the single-dose container may be divided for adjustment of the dose.

Half the ampoule contents should be placed in the nebuliser cup and mixed with an equal volume of 0.9% sodium chloride solution. To ensure accurate dosing the use of a measuring syringe is recommended.

Abelitan Nebuliser Suspension may be mixed with 0.9% sodium chloride solution and with solutions for inhalation containing terbutaline, salbutamol, sodium cromoglycate or ipratropium.

Nebuliser:

Abelitan Nebuliser Suspension must be administered with a jet nebuliser supplied with a mouthpiece or mask. The nebuliser should be connected to an air compressor with adequate air flow (5-8 l/min), and the filling volume should be 2-4 ml.

There can be variation in the performance (dose delivered) between nebulizers, even those of the same make and model.

Note! Ultrasound nebulisers are not suitable for nebulisation of Abelitan Nebuliser Suspension and therefore cannot be recommended.

Instruction for use:

The spray container should be shaken before use.

To minimise the risk of oropharyngeal candida infection, the patient should rinse their mouth out with water after inhaling.

To prevent irritation of the facial skin the face should be washed after using the nebuliser with a mask.

The nebuliser should be cleaned after each use.

Wash the nebuliser container and mouthpiece or face-mask in warm water using a mild detergent in accordance with the manufacturer's instructions. Rinse well and dry it by connecting the nebuliser container to the compressor or the air inlet.

Posology

Adults aged > 18 years

One actuation of 2 mg budesonide daily.

Paediatric population

Abelitan 2mg rectal foam should not be used in children due to insufficient experience in this age group.

Method of administration

Abelitan 2mg rectal foam can be applied in the morning or evening.

The canister is first fitted with an applicator and then shaken for about 15 seconds before the applicator is inserted into the rectum as far as comfortable. Note that the dose is only sufficiently accurate when the pump dome is held downwards as vertically as possible. To administer a dose of Abelitan 2mg rectal foam, the pump dome is fully pushed down and very slowly released. Following the activation the applicator should be held in position for 10 - 15 seconds before being withdrawn from the rectum.

The best results are obtained when the intestine is evacuated prior to administration of Abelitan 2mg rectal foam.

Duration of treatment

The attending physician determines the duration of use. An acute episode generally subsides after 6 to 8 weeks. Abelitan 2mg rectal foam should not be used after this period of time.

Posology

The dosage of Abelitan Respules should be adjusted to the need of the individual.

Dosage schedules: The dose delivered to the patient varies depending on the nebulising equipment used. The nebulisation time and the dose delivered is dependent on flow rate, volume of nebuliser chamber and fill volume. An air-flow rate of 6 - 8 litres per minute through the device should be employed. A suitable fill volume for most nebulisers is 2 - 4 ml. The dosage of Abelitan Respules should be adjusted to the need of the individual. The dose should be reduced to the minimum needed to maintain good asthma control. The highest dose (2 mg per day) for children under 12 years should only be considered in children with severe asthma and during limited periods.

Bronchial asthma

Initiation of therapy

When treatment is started, during periods of severe asthma and while reducing or discontinuing oral glucocorticosteroids, the recommended dose of Abelitan Respules is:

Adults (including the elderly): Usually 1 - 2 mg twice daily. In very severe cases the dosage may be further increased.

Paediatric population

Children 12 years and older: Dosage as for adults.

Children 3 months to 12 years: 0.5 – 1 mg twice daily.

Maintenance

The maintenance dose should be individualised and be the lowest dose which keeps the patient symptom-free.

Adults (including the elderly and children 12 years and older): 0.5 - 1 mg twice daily.

Paediatric population

Children 3 months to 12 years: 0.25 - 0.5 mg twice daily.

Patients maintained on oral glucocorticosteroids

Abelitan Respules may permit replacement or significant reduction in dosage of oral glucocorticosteroids while maintaining asthma control.

Dose division and miscibility

Abelitan Respules can be mixed with 0.9% saline and with solutions for nebulisation of terbutaline, salbutamol, fenoterol, acetylcysteine, sodium cromoglycate or ipratropium bromide. The admixture should be used within 30 minutes.

Recommended Dosage Table

Abelitan Respules 0.5 mg (0.25 mg/ml)

Dose (mg)

Volume (ml)

0.25

1

0.5

2

0.75

3

1.0

4

1.5

6

2.0

8

Where an increased therapeutic effect is desired, especially in those patients without major mucus secretion in the airways, an increased dose of Abelitan Respules is recommended, rather than combined treatment with oral corticosteroids, because of the lower risk of systemic effects.

Croup

In infants and children with croup, the usual dose is 2 mg of nebulised budesonide. This dose is given as a single administration, or as two 1 mg doses separated by 30 minutes. Dosing can be repeated every 12 hour for a maximum of 36 hours or until clinical improvement.

Method of administration

Abelitan respules should be administrated from suitable nebulisers.

Instruction for correct use of Abelitan Respules

The Respule should be detached from the strip, shaken gently and opened by twisting off the wing tab. The contents of the Respule should be gently squeezed into the nebuliser cup. The empty Respule should be thrown away and the top of the nebuliser cup replaced.

Abelitan Respules should be administered via a jet nebuliser equipped with a mouthpiece or suitable face mask. The nebuliser should be connected to an air compressor with an adequate air flow (6-8 L/min), and the fill volume should be 2-4ml.

Note: It is important to instruct the patient

• to carefully read the instructions for use in the patient information leaflet which are packed together with each nebuliser

• that Ultrasonic nebulisers are not suitable for the administration of Abelitan Respules and therefore are not recommended

• Abelitan Respules can be mixed with 0.9% saline and with solutions for nebulisation of terbutaline, salbutamol, fenoterol, acetylcysteine, sodium cromoglycate and ipratropium bromide. The admixture should be used within 30 minutes.

• to minimise the risk of oropharyngeal candida infection, the patient should rinse their mouth out with water after inhaling.

• to wash the facial skin with water after using the face mask to prevent facial skin irritation

• to adequately clean and maintain the nebuliser according to the manufacturer's instructions

Dosage

The recommended dosage regimen is 1 metered dose administered rectally twice daily for 2 weeks followed by 1 metered dose administered rectally once daily for 4 weeks.

Administration Instructions

Advise patients:

  • UCERIS rectal foam is only to be applied rectally. It is not for oral use.
  • Before using UCERIS rectal foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • UCERIS rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply UCERIS rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid concomitant use of CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) during treatment with UCERIS rectal foam.

Posology

When transferring patients to Turbohaler from other devices, treatment should be individualised, whether once or twice daily dosing is being used. The drug and method of delivery should be considered.

Divided doses (twice daily):

The dosage should be individualised.

The dose should always be reduced to the minimum needed to maintain good asthma control.

Adults (including the elderly) and children over 12 years of age: When starting treatment, during periods of severe asthma and while reducing or discontinuing oral glucocorticosteroids, the dosage in adults should be 200 - 1600 micrograms daily, in divided doses.

In less severe cases and children over 12 years of age, 200 - 800 micrograms daily, in divided doses, may be used. During periods of severe asthma, the daily dosage can be increased to up to 1600 micrograms, in divided doses.

Children 5 - 12 years of age: 200 - 800 micrograms daily, in divided doses. During periods of severe asthma, the daily dose can be increased up to 800 micrograms.

Once daily dosage:

The dosage should be individualised.

The dose should always be reduced to the minimum needed to maintain good asthma control.

Adults (including the elderly) and children over 12 years of age: 200 micrograms to 400 micrograms may be used in patients with mild to moderate asthma who have not previously received inhaled glucocorticosteroids.

Up to 800 micrograms may be used by patients with mild to moderate asthma already controlled on inhaled steroids (e.g. budesonide or beclomethasone dipropionate), administered twice daily.

Children 5 - 12 years of age: 200 micrograms to 400 micrograms may be used in children with mild to moderate asthma who have not previously received inhaled glucocorticosteroids, or who are already controlled on inhaled steroids (e.g. budesonide or beclomethasone dipropionate), administered twice daily.

The patient should be transferred to once daily dosing at the same equivalent total daily dose; the drug and method of delivery should be considered. The dose should subsequently be reduced to the minimum needed to maintain good asthma control.

Patients should be instructed to take the once daily dose in the evening. It is important that the dose is taken consistently and at a similar time each evening.

There are insufficient data to make recommendations for the transfer of patients from newer inhaled steroids to once daily Abelitan.

Patients, in particular those receiving once daily treatment, should be advised that if their asthma deteriorates (e.g. increased frequency of bronchodilator use or persistent respiratory symptoms) they should double their steroid dose, by administering it twice daily, and should contact their doctor as soon as possible.

In patients where an increased therapeutic effect is desired, an increased dose of Pulmicort is recommended because of the lower risk of systemic effects as compared with a combined treatment with oral glucocorticosteroids.

Patients maintained on oral glucocorticosteroids

Abelitan may permit replacement or significant reduction in dosage of oral glucocorticosteroids while maintaining asthma control.

Patients should be reminded of the importance of taking prophylactic therapy regularly, even when they are asymptomatic. A short-acting inhaled bronchodilator should be made available for the relief of acute asthma symptoms.

Method of administration

Abelitan is for oral inhalation.

Turbohaler is inspiratory flow-driven which means that, when the patient inhales through the mouthpiece, the substance will follow the inspired air into the airways.

Note: It is important to instruct the patient:

• To carefully read the instructions for use in the patient information leaflet, which is packed with each Turbohaler

• To breathe in forcefully and deeply through the mouthpiece to ensure that an optimal dose is delivered to the lungs

• Never to breathe out through the mouthpiece

• To minimise the risk of oropharyngeal candida infection, the patient should rinse their mouth out with water after inhaling.

The patient may not taste or feel any medication when using Turbohaler due to the small amount of drug dispensed.

Posology

Adults

The recommended daily dose for induction of remission is one 9 mg tablet in the morning, for up to 8 weeks.

When treatment is discontinued, it may be useful to gradually reduce the dose .

Paediatric population

The safety and efficacy of Abelitan tablets in children aged 0-18 years have not yet been established. No data are available, therefore the use in paediatric population is not recommended until further data become available.

Elderly

No special dose adjustment is recommended. However, experience of the use of Abelitan in the elderly is limited.

Hepatic and renal impairment population

Abelitan 9 mg was not studied in patients with hepatic and renal impairment, therefore caution should be exercised in the administration and monitoring of the product in these patients.

Method of administration

One tablet of Abelitan 9 mg is taken orally in the morning, with or without food. The tablet should be swallowed with a glass of water and must not be broken, crushed or chewed as the film coating is intended to ensure a prolonged release.

Posology

Dosage should be individualised.

Rhinitis (Adults including the elderly)

Recommended start dose

Once daily dosing

Twice daily dosing

256 micrograms per day

Two applications of 64 micrograms into each nostril each morning

or

If good effect is achieved, one application of 64 micrograms

One application of 64 micrograms into each nostril morning and evening

The minimum dose should be used at which effective control of symptoms is maintained. The patient should be informed that the full effect of Abelitan is not achieved until after a few days treatment. Treatment of seasonal rhinitis should, if possible, start before exposure to the allergens. If symptoms are not controlled, or persist for longer than 2 weeks of treatment, medical advice must be sought. Concomitant treatment may sometimes be necessary to counteract eye symptoms caused by the allergy. Abelitan should not be used continuously for longer than 3 months without consulting your doctor or pharmacist.

Patients should be reminded of the importance of taking this medicine regularly.

The dose should be titrated to the lowest dose at which effective control of symptoms is achieved.

Paediatric population: This spray should not be used in children and adolescents under 18 years of age. There is insufficient data to recommend the use of Abelitan in children.

Method of administration

For nasal inhalation.

Dosage

The recommended dosage regimen is 1 metered dose administered rectally twice daily for 2 weeks followed by 1 metered dose administered rectally once daily for 4 weeks.

Administration Instructions

Advise patients:

  • Abelitan rectal foam is only to be applied rectally. It is not for oral use.
  • Before using Abelitan rectal foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • Abelitan rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply Abelitan rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid concomitant use of CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) during treatment with Abelitan rectal foam.

Dosage

The recommended dosage regimen is 1 metered dose administered rectally twice daily for 2 weeks followed by 1 metered dose administered rectally once daily for 4 weeks.

Administration Instructions

Advise patients:

  • Abelitan foam is only to be applied rectally. It is not for oral use.
  • Before using Abelitan foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • Abelitan foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply Abelitan foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid concomitant use of CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) during treatment with Abelitan foam.

Posology

Adults

Active Crohn's disease: The recommended daily dose for induction of remission is 9 mg once daily in the morning, for up to eight weeks. The full effect is usually achieved within 2–4 weeks.

When treatment is to be discontinued, the dose should normally be reduced for the last 2 to 4 weeks of therapy.

Active Microscopic colitis: The recommended dose is 9 mg once daily in the morning (corresponding to 3 capsules).

Paediatric population

There are limited data on the use of Abelitan CR Capsules in children . The available data are insufficient to support safety and efficacy in the paediatric population, therefore such use cannot be recommended until further data become available.

Older people

No special dose adjustment is recommended. However, experience with Abelitan CR Capsules in older people is limited.

Method of administration

The capsules should be swallowed whole with water. The capsules must not be chewed.

Contraindications
The information provided in Contraindications of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
more... close
Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

UCERIS rectal foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of UCERIS rectal foam. Reactions have included anaphylaxis .

Hypersensitivity to the active substance.

Abelitan rectal foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of Abelitan rectal foam. Reactions have included anaphylaxis .

Abelitan foam is contraindicated in patients with a history of a known hypersensitivity to budesonide or any of the ingredients of Abelitan foam. Reactions have included anaphylaxis .

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Special warnings and precautions for use
The information provided in Special warnings and precautions for use of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
more... close
Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

Abelitan is not indicated for the treatment of acute dyspnoea or status asthmaticus. These conditions should be treated with short acting β-sympathomimetics and other bronchodilators.

The transfer of patients treated with oral corticosteroids to the inhaled corticosteroid and their subsequent management requires special care. The patients should be in a reasonably stable state before initiating a high dose of inhaled corticosteroid in addition to their usual maintenance dose of systemic corticosteroid. After about 10 days, withdrawal of the systemic corticosteroid is started by reducing the daily dose gradually (by for example 2.5 milligrams prednisolone or the equivalent each month) to the lowest possible level. It may be possible to completely replace the oral corticosteroid with inhaled corticosteroid. Transferred patients whose adrenocortical function is impaired may need supplementary systemic corticosteroid during periods of stress e.g. surgery, infection or worsening asthma attacks.

Patients who have required high dose emergency corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk of impaired adrenal function. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid treatment should be considered during periods of stress or elective surgery.

During transfer from oral therapy to inhaled Abelitan, symptoms may appear that had previously been suppressed by systemic treatment with glucocorticosteroids, for example symptoms of allergic rhinitis, eczema, muscle and joint pain. Specific treatment should be co-administered to treat these conditions.

Some patients may feel unwell in a non-specific way during the withdrawal of systemic corticosteroids despite maintenance or even improvement in respiratory function. Such patients should be encouraged to continue treatment with inhaled Abelitan and withdrawal of oral corticosteroid unless there are clinical signs to indicate the contrary, for example signs which might indicate adrenal insufficiency.

As with other inhalation therapies paradoxical bronchospasm may occur, manifested by an immediate increase in wheezing and shortness of breath after dosing. Paradoxical bronchospasm responds to a rapid-acting inhaled bronchodilator and should be treated straight away. Abelitan should be discontinued immediately, the patient should be assessed and, if necessary, alternative treatment instituted.

When an acute episode of dyspnoea occurs despite a well monitored treatment, a rapid-acting inhaled bronchodilator should be used and medical reassessment should be considered. If despite maximum doses of inhaled corticosteroids, asthma symptoms are not adequately controlled, patients may require short-term treatment with systemic corticosteroids. In such cases, it is necessary to maintain the inhaled corticosteroid therapy in association with treatment by the systemic route.

Systemic effects may occur with any inhaled corticosteroid, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids.

Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Influence on growth

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid. The benefits of the corticosteroid therapy and the possible risks of growth suppression must be carefully weighed. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Patients who have previously been dependent on oral corticosteroids may, as a result of prolonged systemic corticosteroid therapy, experience effects of impaired adrenal function. Recovery may take a considerable amount of time after cessation of oral corticosteroid therapy and hence oral steroid-dependent patients transferred to Abelitan may remain at risk from impaired adrenocortical function for some considerable time. In such circumstances hypothalamic pituitary adrenocortical (HPA) axis function should be monitored regularly.

Oral candidiasis may occur during the therapy with inhaled corticosteroids.).

Exacerbation of clinical symptoms of asthma may be due to acute respiratory tract bacterial infections and treatment with appropriate antibiotics may be required. Such patients may need to increase the dose of inhaled Abelitan and a short course of oral corticosteroids may be required. A rapid-acting inhaled bronchodilator should be used as “rescue” medication to relieve acute asthma symptoms.

Special care and adequate specific therapeutic control of patients with active and quiescent pulmonary tuberculosis is necessary before commencing treatment with inhaled Abelitan. Similarly patients with fungal, viral or other infections of the airways require close observation and special care and should use Abelitan only if they are also receiving adequate treatment for such infections.

In patients with excessive mucous secretion in the respiratory tract, short-term therapy with oral corticosteroids may be necessary.

In patients with severe hepatic dysfunction, treatment with inhaled Abelitan can result in a reduced elimination rate and hence enhanced systemic availability. Possible systemic effects may then result and therefore HPA axis function in these patients should be monitored at regular intervals.

Concomitant treatment with ketoconazole, HIV protease inhibitors or other potent CYP3A4 inhibitors should be avoided . If this is not possible the time interval between administration of the two drugs should be as long as possible.

Recent epidemiological studies show that there is an increased incidence of pneumonia in patients with Chronic Obstructive Pulmonary Disease (COPD) treated with inhaled corticosteroids, with an adjusted odds ratio of 1.7 (Reference). Care should be exercised in prescribing Abelitan for those patients whose respiratory disease might have a component of COPD.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Abelitan Nebuliser Suspension should be used with a jet nebuliser device. An ultrasonic nebuliser should not be used as this is not appropriate for nebuliser suspensions.

Treatment with Abelitan 2mg rectal foam results in lower systemic steroid levels than conventional oral glucocorticosteroid therapy with systemically acting corticoids. Transfer from other glucocorticosteroid therapy may result in reappearance or recurrence of symptoms relating to the change in systemic steroid levels.

Caution is required in patients with tuberculosis, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma, cataracts, family history of diabetes, family history of glaucoma, or any other condition in which glucocorticosteroids may have undesirable effects.

Systemic effects of glucocorticosteroids may occur, particularly when prescribed at high doses and for prolonged periods. Such effects may include Cushing's syndrome, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma and a wide range of psychiatric/behavioural effects .

Infection

Suppression of the inflammatory response and immune function increases the susceptibility to infections and their severity. The risk of deterioration of bacterial, fungal, amoebic and viral infections during glucocorticosteroid treatment should be carefully considered. The clinical presentation may often be atypical and serious infections such as septicaemia and tuberculosis may be masked, and therefore may reach an advanced stage before being recognised.

Chickenpox

Chickenpox is of particular concern since this normally minor illness may be fatal in immunosuppressed patients. Patients without a definite history of chickenpox should be advised to avoid close personal contact with chickenpox or herpes zoster and if exposed they should seek urgent medical attention. If the patient is a child, parents must be given the above advice. Passive immunisation with varicella-zoster immunoglobulin (VZIG) is needed by exposed non-immune patients who are receiving systemic glucocorticosteroids or who have used them within the previous 3 months; this should be given within 10 days of exposure to chickenpox. If a diagnosis of chickenpox is confirmed, the illness warrants specialist care and urgent treatment. Glucocorticosteroids should not be stopped and the dose may need to be increased.

Measles

Patients with compromised immunity who have come into contact with measles should, wherever possible, receive normal immunoglobulin as soon as possible after exposure.

Vaccines

Live vaccines should not be given to individuals with chronic glucocorticosteroid use. The antibody response to other vaccines may be diminished.

Patients with liver function disorders

Based on the experience with patients suffering from late stage primary biliary cirrhosis (PBC) with hepatic cirrhosis an increased systemic availability of budesonide in all patients with severely impaired hepatic function is to be expected. However, in patients with liver disease without hepatic cirrhosis budesonide in daily oral doses of 9 mg was safe and well tolerated. There is no evidence that a specific dose recommendation for patients with non-cirrhotic liver diseases or only slightly impaired liver function is necessary.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Others

Glucocorticosteroids may cause suppression of the hypothalamic-pituitary-adrenal (HPA) axis and reduce the stress response. When patients are subject to surgery or other stresses, supplementary systemic glucocorticosteroid treatment is recommended.

Concomitant treatment with ketoconazole or other CYP3A4 inhibitors should be avoided .

This medicine contains cetyl alcohol and propylene glycol which can cause local skin reactions (e.g. contact dermatitis).

Special caution is necessary in patients with active or quiescent pulmonary tuberculosis and in patients with fungal or viral infections in the airways.

Non steroid-dependent patients: A therapeutic effect is usually reached within 10 days. In patients with excessive mucus secretion in the bronchi, a short (about 2 weeks) additional oral corticosteroid regimen can be given initially. After the course of the oral drug, Abelitan Respules alone should be sufficient therapy.

Steroid-dependent patients: When transfer from oral corticosteroid to treatment with Abelitan Respules is initiated, the patient should be in a relatively stable phase. Abelitan Respules is then given, in combination with the previously used oral steroid dose, for about 10 days.

After that, the oral steroid dose should be gradually reduced (by, for example, 2.5 mg prednisolone or the equivalent each month), to the lowest possible level. In many cases, it is possible to completely substitute Abelitan Respules for the oral corticosteroid.

During transfer from oral therapy to Abelitan Respules, a generally lower systemic corticosteroid action will be experienced, which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary.

As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. If this occurs, treatment with inhaled budesonide should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Patients, who have required high dose emergency corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk of impaired adrenal function. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid treatment should be considered during periods of stress or elective surgery.

Systemic effects may occur with any inhaled corticosteroids, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Abelitan Respules is not intended for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required. If patients find short-acting bronchodilator treatment ineffective, or they need more inhalations than usual, medical attention must be sought. In this situation consideration should be given to the need for or an increase in their regular therapy, e.g., higher doses of inhaled budesonide or the addition of a long-acting beta agonist, or for a course of oral glucocorticosteroid.

Reduced liver function affects the elimination of corticosteroids, causing lower elimination rate and higher systemic exposure. Be aware of possible systemic sides effects.

The plasma clearance following an intravenous dose of budesonide however was similar in cirrhotic patients and in healthy subjects. After oral ingestion systemic availability of budesonide was increased by compromised liver function due to decreased first pass metabolism. The clinical relevance of this to treatment with Abelitan Respules is unknown as no data exist for inhaled budesonide, but increases in plasma levels and hence an increased risk of systemic adverse effects could be expected.

Co-treatment with CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products is expected to increase the risk of systemic corticosteroid side effects. Therefore, the combination should be avoided unless the benefit outweighs this increased risk, in which case patients should be monitored for systemic corticosteroid side effects. This is of limited clinical importance for short-term (1-2 weeks) treatment with itraconazole or ketoconazole or other potent CYP3A inhibitors, but should be taken into consideration during long-term treatment. A reduction in the dose of budesonide should also be considered .

The nebuliser chamber should be cleaned after every administration. Wash the nebuliser chamber and mouthpiece or face-mask in hot water using a mild detergent. Rinse well and dry, by connecting the nebuliser chamber to the compressor or air inlet.

Oral candidiasis may occur during the therapy with inhaled corticosteroids.).

Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Paediatric population

Influence on growth

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. The benefits of the corticosteroid therapy and the possible risks of growth suppression must be carefully weighed. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypercorticism And Adrenal Axis Suppression

When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS rectal foam contains a glucocorticosteroid, general warnings concerning glucocorticoids should be followed .

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis .

Impaired Adrenal Suppression In Patients Transferred From Other Glucocorticoids

Monitor patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS rectal foam, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic glucocorticosteroids with UCERIS rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (See prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered.

Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.

Other Glucocorticosteroid Effects

Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

Flammable Contents

The contents of UCERIS rectal foam include n-butane, isobutane and propane as propellants which are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following administration. Patients should temporarily discontinue use of UCERIS rectal foam before initiation of bowel preparation for colonoscopy and consult their health care provider before resuming therapy.

Patient And Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Administration

Advise patients:

  • UCERIS rectal foam is only to be applied rectally. It is not for oral use.
  • Before using UCERIS rectal foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • UCERIS rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply UCERIS rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid consumption of grapefruit or grapefruit juice during treatment with UCERIS rectal foam.
  • Avoid fire, flame, and smoking during and immediately following administration since UCERIS rectal foam is flammable.
Hypercorticism And Adrenal Suppression

Advise patients that UCERIS rectal foam may cause hypercorticism and adrenal suppression and that they should taper slowly from systemic corticosteroids if transferring to UCERIS rectal foam . Advise patients that replacement of systemic glucocorticosteroids with UCERIS rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Advise patients to avoid exposure to people with chicken pox or measles and if exposed, consult a physician. Also, inform patients that they are at increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex and to contact their physician if they develop any symptoms of infection .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.24 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

Mutagenesis

Budesonide showed no evidence of mutagenic potential in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test or the mouse micronucleus test.

Impairment Of Fertility

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg(approximately 0.20 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.05 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No such effects were noted at 5 mcg/kg.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

Risk Summary

There are no adequate and well controlled studies with UCERIS rectal foam in pregnant women. Animal reproduction studies have been conducted with budesonide. In these studies, subcutaneous administration of budesonide to rats and rabbits at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, produced skeletal abnormalities, fetal loss and decreased pup weight. UCERIS rectal foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4 percent for major malformations, and 15 to 20 percent for pregnancy loss.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Hypoadrenalism may occur in neonates exposed to glucocorticosteroids in-utero. Carefully observe these neonates for signs and symptoms of hypoadrenalism.

Animal Data

Budesonide is teratogenic and embryocidal in rabbits and rats. In subcutaneous embryofetal development studies, fetal loss, decreased pup weights, and skeletal abnormalities were observed at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area).

Nursing Mothers

Use of UCERIS rectal foam is likely to result in budesonide in human milk as budesonide delivered by inhalation from a dry powder inhaler is present in human milk at low concentrations. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for UCERIS rectal foam and any potential adverse effects on the breastfed child from UCERIS rectal foam or from the underlying maternal condition. Exercise caution when administering UCERIS rectal foam to a nursing woman.

Pediatric Use

The safety and effectiveness of UCERIS rectal foam has not been established in pediatric patients

Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

Geriatric Use

Clinical studies with UCERIS rectal foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

No dosage adjustment is needed for patients with mild (Child-Pugh Class A) hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS rectal foam should be considered in these patients if signs of hypercorticism are observed .

Special caution is necessary in patients with active or quiescent pulmonary tuberculosis, and in patients with fungal or viral infections in the airways.

Non steroid-dependent patients: A therapeutic effect is usually reached within 10 days. In patients with excessive mucus secretion in the bronchi, a short (about 2 weeks) additional oral corticosteroid regimen can be given initially.

Steroid-dependent patients: When transferral from oral steroids to Abelitan is started, the patient should be in a relatively stable phase. A high dose of Abelitan is then given in combination with the previously used oral steroid dose for about 10 days.

After that, the oral steroid dose should be gradually reduced (by for example 2.5 milligrams prednisolone or the equivalent each month) to the lowest possible level. In many cases, it is possible to completely substitute Pulmicort for the oral steroid.

During transfer from oral therapy to Pulmicort, a generally lower systemic steroid action will be experienced which may result in the appearance of allergic or arthritic symptoms such as rhinitis, eczema and muscle and joint pain. Specific treatment should be initiated for these conditions. During the withdrawal of oral steroids, patients may feel unwell in a non-specific way, even though respiratory function is maintained or improved. Patients should be encouraged to continue with Pulmicort therapy whilst withdrawing the oral steroid, unless there are clinical signs to indicate the contrary. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of oral glucocorticosteroids is sometimes necessary.

As with other inhalation therapy, paradoxical bronchospasm may occur, with an immediate increase in wheezing after dosing. If this occurs, treatment with inhaled budesonide should be discontinued immediately, the patient assessed and alternative therapy instituted if necessary.

Patients who have previously been dependent on oral steroids may, as a result of prolonged systemic steroid therapy, experience the effects of impaired adrenal function. Recovery may take a considerable amount of time after cessation of oral steroid therapy, hence oral steroid-dependent patients transferred to budesonide may remain at risk from impaired adrenal function for some considerable time. In such circumstances, HPA axis functions should be monitored regularly.

Acute exacerbations of asthma may need an increase in the dose of Pulmicort or additional treatment with a short course of oral corticosteroid and/or an antibiotic, if there is an infection. The patient should be advised to use a short-acting inhaled bronchodilator as rescue medication to relieve acute asthma symptoms.

Pulmicort is not intended for rapid relief of acute episodes of asthma where an inhaled short-acting bronchodilator is required.

If patients find short-acting bronchodilator treatment ineffective or they need more inhalations than usual, medical attention must be sought. In this situation consideration should be given to the need for or an increase in their regular therapy, e.g., higher doses of inhaled budesonide or the addition of a long-acting beta agonist, or for a course of oral glucocorticosteroid.

Patients, who have required high dose emergency corticosteroid therapy or prolonged treatment at the highest recommended dose of inhaled corticosteroids, may also be at risk of impaired adrenal function. These patients may exhibit signs and symptoms of adrenal insufficiency when exposed to severe stress. Additional systemic corticosteroid treatment should be considered during periods of stress or elective surgery. These patients should be instructed to carry a steroid warning card indicating their needs. Treatment with supplementary systemic steroids or Pulmicort should not be stopped abruptly.

Systemic effects may occur with any inhaled corticosteroids, particularly at high doses prescribed for long periods. These effects are much less likely to occur with inhalation treatment than with oral corticosteroids. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children). It is important, therefore, that the dose of inhaled corticosteroid is titrated to the lowest dose at which effective control of asthma is maintained.

Reduced liver function affects the elimination of corticosteroids causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects.

The plasma clearance following an intravenous dose of budesonide however was similar in cirrhotic patients and in healthy subjects. After oral ingestion systemic availability of budesonide was increased by compromised liver function due to decreased first pass metabolism. The clinical relevance of this to treatment with Pulmicort is unknown as no data exist for inhaled budesonide, but increases in plasma levels and hence an increased risk of systemic adverse effects could be expected.

Co-treatment with CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products is expected to increase the risk of systemic corticosteroid side effects. Therefore, the combination should be avoided unless the benefit outweighs this increased risk, in which case patients should be monitored for systemic corticosteroid side effects. This is of limited clinical importance for short-term (1-2 weeks) treatment with itraconazole or ketoconazole or other potent CYP3A inhibitors, but should be taken into consideration during long-term treatment. A reduction in the dose of budesonide should also be considered .

Oral candidiasis may occur during the therapy with inhaled corticosteroids. This infection may require treatment with appropriate antifungal therapy and in some patients discontinuation of treatment may be necessary .

Pneumonia in patients with COPD

An increase in the incidence of pneumonia, including pneumonia requiring hospitalisation, has been observed in patients with COPD receiving inhaled corticosteroids. There is some evidence of an increased risk of pneumonia with increasing steroid dose but this has not been demonstrated conclusively across all studies.

There is no conclusive clinical evidence for intra-class differences in the magnitude of the pneumonia risk among inhaled corticosteroid products.

Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

Risk factors for pneumonia in patients with COPD include current smoking, older age, low body mass index (BMI) and severe COPD.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCS) which have been reported after use of systemic and topical corticosteroids.

Paediatric populations

Influence on growth

It is recommended that the height of children receiving prolonged treatment with inhaled corticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated with the aim of reducing the dose of inhaled corticosteroid, if possible, to the lowest dose at which effective control of asthma is maintained. The benefit of the corticosteroid therapy and the possible risk of growth suppression must be carefully weighed. In addition, consideration should be given to referring the patient to a paediatric respiratory specialist.

Abelitan tablets should be used with caution in patients with infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts or with a family history of diabetes or glaucoma or with any other condition where the use of glucocorticoids may have unwanted effects.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare condition diseases such as Central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Reduced liver function may affect the elimination of glucocorticoids including budesonide, causing higher systemic exposure. Be aware of possible systemic side effects. Potential systemic effects include glaucoma.

When treatment is to be discontinued, it may be useful to gradually reduce the dose at the discretion of the treating physician.

Treatment with Abelitan tablets results in lower systemic steroid levels than conventional oral glucocorticoid therapy. Transfer from other steroid therapy may result in symptoms relating to the change in systemic steroid levels. Some patients may feel unwell in a non-specific way during the withdrawal phase, e.g., pain in muscles and joints. A general insufficient corticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of systemic corticosteroids is sometimes necessary.

As corticosteroids are known to have immunological effects the co-administration of Abelitan tablets is likely to reduce the immune response to vaccines.

Concomitant administration of ketoconazole or other potent CYP3A4 inhibitors should be avoided.).

Abelitan tablets contain lecithin (soya oil). If a patient is hypersensitive to peanut or soya, this medicine should not be used.

Abelitan tablets contain lactose monohydrate and should not be taken by patients with rare hereditary problems such as galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

The following warnings and precautions have been generally identified for corticosteroids:

• Adrenocortical suppression has been observed when patients are transferred from systemic corticosteroid treatment with higher systemic effect.

• Suppression of the inflammatory response and immune system increases the susceptibility to infections.

• Corticosteroids may cause suppression of the HPA axis and reduce the stress response. Where patients are subject to surgery or other stresses, supplementary systemic corticosteroid treatment is recommended.

• Chicken pox and measles may follow a more serious course in patients on oral glucocorticoids. Particular care should be taken to avoid exposure in patients who have not previously had these diseases. If patients are infected or suspected of being infected, consider reduction or discontinuation of glucocorticosteroid treatment at the discretion of the treating physician.

• Systemic effects of steroids may occur, particularly when prescribed at high doses and for prolonged periods. Such effects may include Cushing's syndrome, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma and very rarely a wide range of psychiatric/behavioural effects .

• Particular care is required when considering the use of systemic corticosteroids in patients with current or previous history of severe affective disorders in the patient or any first degree relatives.

• Replacement of high systemic effect corticosteroid treatment sometimes unmasks allergies, e.g. rhinitis and eczema that were previously controlled by the systemic drug.

Treatment should be stopped or the advice of a doctor or pharmacist should be sought if an improvement is not seen within 2 weeks or if symptoms have improved but are not adequately controlled.

This medicine should not be used for more than 3 months continuously without consulting a doctor or pharmacist.

Special care is demanded in treatment of patients transferred from oral steroids to this medicine where disturbances of the hypothalamic-pituitary-adrenal (HPA) axis could be expected.

Special care is needed in patients with fungal and viral infections of the airways and in patients with active or quiescent pulmonary tuberculosis.

Special care is needed where there is an infection in the nasal passages or sinuses, or in the case of recent surgery to the nose, or problems with ulceration in the nose.

Concomitant treatment of seasonal rhinitis may sometimes be necessary to counteract eye symptoms caused by the allergy.

Reduced liver function affects the elimination of corticosteroids, causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects.

Systemic effects of nasal corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur than with oral corticosteroids and may vary in individual patients and between different corticosteroid preparations. Potential systemic effects may include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and more rarely, a range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Paediatric population

The long-term effects of nasal glucocorticosteroids in children are not fully known. Physicians should closely follow the growth of children taking glucocorticosteroids for longer term by any route, and weigh the benefits of the glucocorticosteroid therapy against the possibility of growth suppression.

This medicine should not be used for children or adolescents under 18 years of age.

Treatment with higher than recommended doses may result in clinically significant adrenal suppression. If there is evidence for higher than recommended doses being used, additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Co-treatment with CYP3A inhibitors, e.g. itraconazole, ketoconazole, HIV protease inhibitors and cobicistat-containing products is expected to increase the risk of systemic corticosteroid side effects. Therefore, the combination should be avoided unless the benefit outweighs this increased risk, in which case patients should be monitored for systemic corticosteroid side effects. This is of limited clinical importance for short-term (1-2 weeks) treatment with itraconazole or ketoconazole or other potent CYP3A inhibitors, but should be taken into consideration during long-term treatment. A reduction in the dose of budesonide should also be considered .

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypercorticism And Adrenal Axis Suppression

When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since Abelitan rectal foam contains a glucocorticosteroid, general warnings concerning glucocorticoids should be followed .

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis .

Impaired Adrenal Suppression In Patients Transferred From Other Glucocorticoids

Monitor patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as Abelitan rectal foam, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic glucocorticosteroids with Abelitan rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (See prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered.

Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.

Other Glucocorticosteroid Effects

Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

Flammable Contents

The contents of Abelitan rectal foam include n-butane, isobutane and propane as propellants which are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following administration. Patients should temporarily discontinue use of Abelitan rectal foam before initiation of bowel preparation for colonoscopy and consult their health care provider before resuming therapy.

Patient And Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Administration

Advise patients:

  • Abelitan rectal foam is only to be applied rectally. It is not for oral use.
  • Before using Abelitan rectal foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • Abelitan rectal foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply Abelitan rectal foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid consumption of grapefruit or grapefruit juice during treatment with Abelitan rectal foam.
  • Avoid fire, flame, and smoking during and immediately following administration since Abelitan rectal foam is flammable.
Hypercorticism And Adrenal Suppression

Advise patients that Abelitan rectal foam may cause hypercorticism and adrenal suppression and that they should taper slowly from systemic corticosteroids if transferring to Abelitan rectal foam . Advise patients that replacement of systemic glucocorticosteroids with Abelitan rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Advise patients to avoid exposure to people with chicken pox or measles and if exposed, consult a physician. Also, inform patients that they are at increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex and to contact their physician if they develop any symptoms of infection .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.24 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

Mutagenesis

Budesonide showed no evidence of mutagenic potential in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test or the mouse micronucleus test.

Impairment Of Fertility

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg(approximately 0.20 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.05 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No such effects were noted at 5 mcg/kg.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

Risk Summary

There are no adequate and well controlled studies with Abelitan rectal foam in pregnant women. Animal reproduction studies have been conducted with budesonide. In these studies, subcutaneous administration of budesonide to rats and rabbits at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, produced skeletal abnormalities, fetal loss and decreased pup weight. Abelitan rectal foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4 percent for major malformations, and 15 to 20 percent for pregnancy loss.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Hypoadrenalism may occur in neonates exposed to glucocorticosteroids in-utero. Carefully observe these neonates for signs and symptoms of hypoadrenalism.

Animal Data

Budesonide is teratogenic and embryocidal in rabbits and rats. In subcutaneous embryofetal development studies, fetal loss, decreased pup weights, and skeletal abnormalities were observed at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area).

Nursing Mothers

Use of Abelitan rectal foam is likely to result in budesonide in human milk as budesonide delivered by inhalation from a dry powder inhaler is present in human milk at low concentrations. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Abelitan rectal foam and any potential adverse effects on the breastfed child from Abelitan rectal foam or from the underlying maternal condition. Exercise caution when administering Abelitan rectal foam to a nursing woman.

Pediatric Use

The safety and effectiveness of Abelitan rectal foam has not been established in pediatric patients

Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

Geriatric Use

Clinical studies with Abelitan rectal foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

No dosage adjustment is needed for patients with mild (Child-Pugh Class A) hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of Abelitan rectal foam should be considered in these patients if signs of hypercorticism are observed .

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Hypercorticism And Adrenal Axis Suppression

When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamus-pituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since Abelitan foam contains a glucocorticosteroid, general warnings concerning glucocorticoids should be followed .

Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis .

Impaired Adrenal Suppression In Patients Transferred From Other Glucocorticoids

Monitor patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as Abelitan foam, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously.

Replacement of systemic glucocorticosteroids with UCERIS rectal foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure.

How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (See prescribing information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered.

Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex.

Other Glucocorticosteroid Effects

Monitor patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects.

Flammable Contents

The contents of Abelitan foam include n-butane, isobutane and propane as propellants which are flammable. Instruct the patient to avoid fire, flame, and smoking during and immediately following administration. Patients should temporarily discontinue use of Abelitan foam before initiation of bowel preparation for colonoscopy and consult their health care provider before resuming therapy.

Patient And Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use)

Administration

Advise patients:

  • Abelitan foam is only to be applied rectally. It is not for oral use.
  • Before using Abelitan foam, use the bathroom to empty your bowels.
  • Each applicator is coated with a lubricant. If additional lubrication is needed, petrolatum or petroleum jelly can also be used.
  • Warm the canister in the hands while shaking it vigorously for 10 to 15 seconds prior to use.
  • Abelitan foam can be used in a standing, lying or sitting position (e.g., while using the toilet).
  • Apply Abelitan foam in the morning and the evening for the first 2 weeks of treatment; then once daily in the evening for the next 4 weeks. When applied in the evening, use immediately prior to bedtime. Try not to empty your bowels again until the next morning.
  • Avoid consumption of grapefruit or grapefruit juice during treatment with Abelitan foam.
  • Avoid fire, flame, and smoking during and immediately following administration since Abelitan foam is flammable.
Hypercorticism And Adrenal Suppression

Advise patients that UCERIS rectal foam may cause hypercorticism and adrenal suppression and that they should taper slowly from systemic corticosteroids if transferring to UCERIS rectal foam . Advise patients that replacement of systemic glucocorticosteroids with Abelitan foam may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug.

Increased Risk Of Infection

Advise patients to avoid exposure to people with chicken pox or measles and if exposed, consult a physician. Also, inform patients that they are at increased risk of developing a variety of infections, including worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex and to contact their physician if they develop any symptoms of infection .

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

Carcinogenicity studies with budesonide were conducted in rats and mice. In a 2-year study in Sprague-Dawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.06 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

In an additional 2-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.12 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.24 times the recommended intrarectal dose of 4 mg/day in humans, based on the body surface area).

Mutagenesis

Budesonide showed no evidence of mutagenic potential in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/-) test, the human lymphocyte chromosome aberration test, the Drosophila melanogaster sex-linked recessive lethality test, the rat hepatocyte UDS test or the mouse micronucleus test.

Impairment Of Fertility

In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg(approximately 0.20 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.05 times recommended intrarectal dose of 4 mg/day in humans, based on the body surface area) and above. No such effects were noted at 5 mcg/kg.

Use In Specific Populations

Pregnancy

Pregnancy Category C.

Risk Summary

There are no adequate and well controlled studies with Abelitan foam in pregnant women. Animal reproduction studies have been conducted with budesonide. In these studies, subcutaneous administration of budesonide to rats and rabbits at doses 1.2 times and 0.12 times, respectively, the human intrarectal dose of 4 mg/day, produced skeletal abnormalities, fetal loss and decreased pup weight. Abelitan foam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies, regardless of drug exposure, have a background rate of 2 to 4 percent for major malformations, and 15 to 20 percent for pregnancy loss.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Hypoadrenalism may occur in neonates exposed to glucocorticosteroids in-utero. Carefully observe these neonates for signs and symptoms of hypoadrenalism.

Animal Data

Budesonide is teratogenic and embryocidal in rabbits and rats. In subcutaneous embryofetal development studies, fetal loss, decreased pup weights, and skeletal abnormalities were observed at a subcutaneous dose of 25 mcg/kg in rabbits (approximately 0.12 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area) and 500 mcg/kg in rats (approximately 1.2 times the recommended human intrarectal dose of 4 mg/day, based on the body surface area).

Nursing Mothers

Use of Abelitan foam is likely to result in budesonide in human milk as budesonide delivered by inhalation from a dry powder inhaler is present in human milk at low concentrations. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Abelitan foam and any potential adverse effects on the breastfed child from Abelitan foam or from the underlying maternal condition. Exercise caution when administering UCERIS rectal foam to a nursing woman.

Pediatric Use

The safety and effectiveness of Abelitan foam has not been established in pediatric patients

Children who are treated with corticosteroids by any route may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression. The long-term effects of this reduction in growth velocity associated with corticosteroid treatment, including the impact on final adult height, are unknown. Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in children than some commonly used tests of HPA axis function. The linear growth of children treated with corticosteroids by any route should be monitored (e.g., via stadiometry), and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of other treatment alternatives. In order to minimize the potential growth effects of corticosteroids, children should be titrated to the lowest effective dose.

Geriatric Use

Clinical studies with Abelitan foam did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

No dosage adjustment is needed for patients with mild (Child-Pugh Class A) hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh Class B or C) should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of Abelitan foam should be considered in these patients if signs of hypercorticism are observed .

Side effects typical of systemic corticosteroids may occur. Potential systemic effects include glaucoma.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Use with caution in patients with infections, hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts or with a family history of diabetes or glaucoma or with any other condition where the use of glucocorticosteroids may have unwanted effects.

Particular care is required when considering the use of systemic corticosteroids in patients with existing or previous history of severe affective disorders in themselves or in their first degree relatives. These would include depressive or manic-depressive illness and previous steroid psychosis.

Systemic effects of steroids may occur, particularly when prescribed at high doses and for prolonged periods. Such effects may include Cushing's syndrome, adrenal suppression, growth retardation, decreased bone mineral density, cataract, glaucoma and very rarely a wide range of psychiatric/behavioural effects .

Treatment with Abelitan CR Capsules results in lower systemic steroid levels than conventional oral glucocorticosteroid therapy. When patients are transferred from systemic glucocorticosteroid treatment with higher systemic effect to Abelitan CR Capsules, they may have adrenocortical suppression. Therefore, monitoring of adrenocortical function may be considered in these patients and their dose of systemic steroid should be reduced cautiously.

Replacement of high systemic effect glucocorticosteroid treatment with Abelitan CR Capsules, sometimes unmasks allergies, e.g. rhinitis and eczema, which were previously controlled by the systemic drug.

Chicken pox and measles can have a more serious course in patients on oral glucocorticosteroids. Particular care should be taken to avoid exposure in patients who have not previously had these diseases. If patients are infected or suspected of being infected, consider reduction or discontinuation of glucocortiocosteriods treatment and immediately consult a physician. Glucocorticosteroids may cause suppression of the hypothalamus-pituitary-adrenal (HPA) axis and reduce the stress response. Where patients are subject to surgery or other stress situations, supplementary systemic glucocorticoid treatment is recommended.

Reduced liver function may affect the elimination of glucocorticosteroids, causing lower elimination rate and higher systemic exposure. Be aware of possible systemic side effects. The pharmacokinetics after oral ingestion of budesonide was affected by compromised liver function as evidenced by increased systemic availability in patients with moderately severe hepatic cirrhosis.

When treatment is to be discontinued, the dose should normally be reduced for the last 2 to 4 weeks of therapy. Some patients feel unwell in a non-specific way during the withdrawal phase, e.g. pain in muscles and joints. A general insufficient glucocorticosteroid effect should be suspected if, in rare cases, symptoms such as tiredness, headache, nausea and vomiting should occur. In these cases a temporary increase in the dose of systemic glucocorticosteroids is sometimes necessary.

Co-treatment with CYP3A inhibitors, including ketoconazole and cobicistat-containing products, is expected to increase the risk of systemic side-effects.).

After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times.

When Abelitan CR Capsules are used chronically in excessive doses, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may appear.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine.

Paediatric population

It is recommended that the height of children receiving prolonged treatment with glucocorticosteroids is regularly monitored. If growth is slowed, therapy should be re-evaluated. The benefits of the glucocorticosteroid therapy and the possible risks of growth suppression must be carefully weighed. Long-term studies have not been performed in children treated with Abelitan CR Capsules.

Effects on ability to drive and use machines
The information provided in Effects on ability to drive and use machines of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Effects on ability to drive and use machines in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard

Inhaled Abelitan has no or negligible influence on the ability to drive and use machines.

No studies on the effects on the ability to drive and use machines have been performed.

Abelitan Respules has no or negligible influence on the ability to drive and use machines.

Abelitan has no or negligible influence on the ability to drive and use machines.

No studies on the effects of Abelitan on the ability to drive and use machines have been performed. When driving vehicles or using machines it should be taken into account that occasionally dizziness or tiredness may occur .

This medicine has no or negligible influence on the ability to drive and use machines.

Abelitan CR Capsules have no or negligible influence on the ability to drive and use machines.

Undesirable effects
The information provided in Undesirable effects of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

Tabulated list of adverse reactions

The following definitions apply to the incidence of undesirable effects: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Infections and infestations

Common

Oropharyngeal candidiasis

Immune system disorders

Rare

Immediate and delayed hypersensitivity reactions* including rash, contact dermatitis, urticaria, angioedema and anaphylactic reaction.

Endocrine disorders

Rare

Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation**

Eye disorders

Uncommon

<)

Not known

Glaucoma

Psychiatric disorders

Uncommon

Anxiety*, depression*

Rare

Restlessness, nervousness, behavioural changes (predominantly in children)

Not known

Sleep disorders, psychomotor activity, aggression

Respiratory, thoracic and mediastinal disorders

Common

Hoarseness, cough, throat irritation

Rare

Bronchospasm, dysphonia

Gastrointestinal disorders

Common

Oral mucosal irritation, difficulty in swallowing

Skin and subcutaneous disorders

Rare

Bruising, skin reactions, pruritus, erythema

Musculoskeletal and connective tissue disorders

Uncommon

Muscle spasms

Rare

Growth retardation

Investigations

Very rare

Bone density decreased

Nervous system disorders

Uncommon

Tremor

* refer to Description of selected adverse reactions: facial skin irritation, cataract, anxiety, depression below

** refer to Paediatric population, below

Description of selected adverse reactions

Facial irritation, as an example of a hypersensitivity reaction, has occurred in some cases when a nebuliser with a face mask has been used. To prevent irritation the facial skin should be washed with water after use of the face mask.

In-placebo controlled studies, cataract was also uncommonly reported in the placebo group.

Clinical trials with 13,119 patients on inhaled Abelitan and 7,278 patients on placebo have been pooled. The frequency of anxiety was 0.52% on inhaled Abelitan and 0.63% on placebo; that of depression was 0.67% on inhaled Abelitan and 1.15% on placebo.

There is an increased risk of pneumonia in patients with newly diagnosed COPD starting treatment with inhaled corticosteroids. However a weighted assessment of 8 pooled clinical trials involving 4643 COPD patients treated with Abelitan and 3,643 patients randomized to non-ICS treatments did not demonstrate an increased risk for pneumonia. The results from the first 7 of these 8 trials have been published as a meta-analysis.

Treatment with inhaled Abelitan may result in candida infection in the oropharynx. Experience has shown that candida infection occurs less often when inhalation is performed before meals and/or when the mouth is rinsed after inhalation. In most cases this condition responds to topical anti-fungal therapy without discontinuing treatment with inhaled Abelitan.

Coughing can usually be prevented by inhaling a beta-2 agonist (e.g. terbutaline) 5-10 minutes before administration of Abelitan 0.5mg Nebuliser Suspension.

Occasionally, signs or symptoms of systemic glucocorticosteroid-side effects may occur with inhaled glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity. These may include adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract and glaucoma, and susceptibility to infections. The ability to adapt to stress may be impaired. The systemic effects described, however, are much less likely to occur with inhaled Abelitan than with oral corticosteroids.

Paediatric population

<

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

The following frequency conventions are used in the evaluation of undesirable effects:

very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

System organ class

Frequency according to MedDRA convention

Adverse reaction

Metabolism and nutrition disorders

Common

Cushing's syndrome: e.g. with moon face, truncal obesity, reduced glucose tolerance, diabetes mellitus, hypertension, sodium retention with oedema, increased potassium excretion, inactivity or atrophy of the adrenal cortex, red striae, steroid acne, disturbance of sex hormone secretion (e.g. amenorrhoea, hirsutism, impotence)

Very rare

Growth retardation in children

Eye disorders

Rare

<)

Gastrointestinal disorders

Common

Dyspepsia

Uncommon

Duodenal or gastric ulcer

Rare

Pancreatitis

Very rare

Constipation

Immune system disorders

Common

Increased risk of infection

Musculoskeletal and connective tissue disorders

Common

Muscle and joint pain, muscle weakness and twitching, osteoporosis

Rare

Osteonecrosis

Nervous system disorders

Common

Headache

Very rare

Pseudotumor cerebri including papilloedema in adolescents

Psychiatric disorders

Common

Depression, irritability, euphoria

Uncommon

Psychomotor hyperactivity, anxiety

Rare

Aggression

Skin and subcutaneous tissue disorders

Common

Allergic exanthema, petechiae, delayed wound healing, contact dermatitis

Rare

Ecchymosis

Vascular disorders

Very rare

Increased risk of thrombosis, vasculitis (withdrawal syndrome after long-term therapy)

General disorders and administration site conditions

Common

Burning in the rectum and pain

Very rare

Fatigue, malaise

The following adverse reactions were additionally reported in clinical studies with Abelitan 2mg rectal foam (frequency: uncommon): increased appetite, increase in erythrocyte sedimentation rate, leucocytosis, nausea, abdominal pain, flatulence, paraesthesias in the abdominal region, anal fissure, aphthous stomatitis, frequent urge to defecate, rectal bleeding, increase in transaminases (GOT, GPT), increase in parameters of cholestasis (GGT,AP), increase in amylase, change in cortisol, urinary tract infection, dizziness, disturbances of smell, insomnia, increased sweating, asthenia, increase in body weight.

Most of the adverse events mentioned in this SmPC can also be expected for treatments with other glucocorticosteroids.

Occasionally, adverse events may occur which are typical for systemic glucocorticosteroids. These adverse events depend on the dosage, the period of treatment, concomitant or previous treatment with other glucocorticosteroids and the individual sensitivity.

Some of the adverse events were reported after long-term use of orally administered budesonide.

Due to its local action, the risk of adverse reactions of Abelitan 2mg rectal foam is generally lower than when taking systemically acting glucocorticosteroids.

An exacerbation or the reappearance of extra intestinal manifestations (especially affecting skin and joints) can occur on switching a patient from systemically acting glucocorticosteroids to the locally acting budesonide.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Tabulated list of adverse reactions

The following definitions apply to the incidence of undesirable effects: Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 1 Adverse Drug Reactions (ADR) by System Organ Class (SOC) and Frequency

SOC

Frequency

Adverse Drug Reaction

Infections and infestations

Common

Oropharyngeal candidiasis

Pneumonia (in COPD patients)

Immune system disorders

Rare

Immediate and delayed hypersensitivity reactions* including rash, contact dermatitis, urticaria, angioedema and anaphylactic reaction

Endocrine disorders

Rare

Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation**

Psychiatric disorders

Uncommon

Anxiety

Depression

Rare

Psychomotor hyperactivity

Sleep disorders

Aggression

Behavioural changes (predominantly in children)

Nervous system disorders

Uncommon

Tremor***

Eye disorders

Uncommon

Cataract

<)

Unknown

Glaucoma

Respiratory, thoracic and mediastinal disorders

Common

Cough

Hoarseness

Throat irritation

Rare

Bronchospasm

Dysphonia

Hoarseness****

Skin and subcutaneous tissue disorders

Rare

Bruising

Musculoskeletal and connective tissue disorders

Uncommon

Muscle spasm

* refer to Description of selected adverse reactions; facial skin irritation, below

** refer to Paediatric population, below

*** based on the frequency reported in clinical trials

**** rare in children

Occasionally, signs or symptoms of systemic glucocorticosteroid-side effects may occur with inhaled glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity .

Description of selected adverse reactions

The candida infection in the oropharynx is due to drug deposition. Advising the patient to rinse the mouth out with water after each dosing will minimise the risk.

As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases .

Facial skin irritation, as an example of a hypersensitivity reaction, has occurred in some cases when a nebuliser with a face mask has been used. To prevent irritation, the facial skin should be washed with water after use of the face mask.

In placebo-controlled studies, cataract was also uncommonly reported in the placebo group.

Clinical trials with 13119 patients on inhaled budesonide and 7278 patients on placebo have been pooled. The frequency of anxiety was 0.52% on inhaled budesonide and 0.63% on placebo; that of depression was 0.67% on inhaled budesonide and 1.15% on placebo.

Paediatric population

<

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

Serious and important adverse reactions include:

  • Hypercorticism and adrenal axis suppression
  • Symptoms of steroid withdrawal in those patients transferring from systemic glucocorticosteroid therapy
  • Increased susceptibility to infection
  • Other glucocorticosteroid effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to UCERIS rectal foam in 332 patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The median duration of exposure was 42 days. This included 14 patients exposed for at least 6 months.

UCERIS rectal foam was studied primarily in 2 placebo-controlled, 6-week trials in patients with active disease (Study 1 and Study 2). In these trials, 268 patients received UCERIS rectal foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks .

The most common adverse reactions ( ≥ 2% of the UCERIS rectal foam or Placebo group and at higher frequency in the UCERIS rectal foam group) were decreased blood cortisol, adrenal insufficiency, and nausea (Table 1). Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/dL. Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with adrenocorticotropic hormone (ACTH).

A total of 10% of UCERIS rectal foam-treated patients discontinued treatment due to an adverse reaction compared with 4% of placebo-treated patients.

Table 1: Summary of Adverse Reactions in 2 Placebo Controlled Trials* (Studies 1and 2)

Adverse Reaction UCERIS Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Decreased blood cortisol# 46 (17) 6 (2)
Adrenal insufficiency† 10 (4) 2 (1)
Nausea 6 (2) 2 (1)
* Experienced by ≥ 2% of the UCERIS rectal foam or Placebo group and at higher frequency in the UCERIS rectal foam group
# Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/Dl
† Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH.

Of the 46 UCERIS rectal foam treated patients with decreased blood cortisol (defined as a morning cortisol level of < 5 mcg/dL) reported as an adverse event, none had adrenal insufficiency (defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH) (see Table 2). All cases of adrenal insufficiency resolved.

Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2).

Table 2: Summary of Glucocorticoid Related Effects in Two Placebo- Controlled Trials (Studies 1 and 2)

Adverse Reaction UCERIS Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Overall 60 (22) 10 (4)
Blood cortisol decreased 46 (17)* 6 (2)
Adrenal insufficiency 10 (4) 2 (1)
Insomnia 1 (0.4) 1 (0.4)
Sleep disorder 1 (0.4) 0
Acne 1 (0.4) 0
Depression 1 (0.4) 1 (0.4)
Hyperglycemia 1 (0.4) 0
* Decreases in serum cortisol levels associated with budesonide treatment were seen at Weeks 1 and 2 (twice-daily treatment) in the UCERIS rectal foam group, but gradually returned to baseline levels during the 4 weeks of once daily treatment.

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS rectal foam and placebo after 6 weeks of therapy.

For additional details on morning cortisol levels and the response to the ACTH stimulation test, see CLINICAL PHARMACOLOGY.

Post-Marketing Experience

In addition to adverse reactions reported from clinical trials for UCERIS rectal foam, the following adverse reactions have been identified during post-approval use of other oral and rectal formulations of budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: hypertension

Gastrointestinal disorders: pancreatitis

General disorders and administration site conditions: pyrexia, peripheral edema

Immune System Disorders: anaphylactic reactions

Nervous System Disorders: dizziness, benign intracranial hypertension

Psychiatric Disorders: mood swings

Skin and subcutaneous tissue disorders: pruritus, maculo-papular rash, allergic dermatitis

Tabulated list of adverse reactions

The following definitions apply to the incidence of undesirable effects: Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).

Table 1 Adverse Drug Reactions (ADR) by System Organ Class (SOC) and Frequency

SOC

Frequency

Adverse Drug Reaction

Infections and infestations

Common

Oropharyngeal candidiasis

Pneumonia (in COPD patients)

Immune system disorders

Rare

Immediate and delayed hypersensitivity reactions including rash, contact dermatitis, urticaria, angioedema and anaphylactic reaction

Endocrine disorders

Rare

Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation*

Psychiatric disorders

Uncommon

Anxiety

Depression

Rare

Psychomotor hyperactivity

Sleep disorders

Aggression

Behavioural changes (predominantly in children)

Nervous System Disorders

Uncommon

Tremor**

Eye disorders

Uncommon

Cataract

)

Not known

Glaucoma

Respiratory, thoracic and mediastinal disorders

Common

Cough

Hoarseness

Throat irritation

Rare

Bronchospasm

Dysphonia

Hoarseness***

Skin and subcutaneous tissue disorders

Rare

Bruising

Musculoskeletal and connective tissue disorders

Uncommon

Muscle spasm

* refer to Paediatric population, below

** based on the frequency reported in clinical trials

*** rare in children

Occasionally, signs or symptoms of systemic glucocorticosteroid-side effects may occur with inhaled glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity .

Description of selected adverse reactions

The candida infection in the oropharynx is due to drug deposition. Advising the patient to rinse the mouth out with water after each dosing will minimise the risk.

As with other inhalation therapy, paradoxical bronchospasm may occur in very rare cases .

In placebo-controlled studies, cataract was also uncommonly reported in the placebo group.

Clinical trials with 13119 patients on inhaled budesonide and 7278 patients on placebo have been pooled. The frequency of anxiety was 0.52% on inhaled budesonide and 0.63% on placebo; that of depression was 0.67% on inhaled budesonide and 1.15% on placebo.

Paediatric population

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard

Adverse drug reactions reported in clinical trials with Abelitan are presented in Table 1. Adverse drug reactions reported for the therapeutic class are presented in Table 2. In Phase II and III clinical trials, the incidence of adverse events for Abelitan tablets, at the recommended dose of 9 mg/day, was comparable to placebo. Most adverse events were of mild to moderate intensity and of a non-serious nature.

Adverse reactions reported are listed according to the following frequency: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Table 1 Abelitan drug-related adverse reactions reported during clinical trials with more than one case (N=255)

MedDRA System Organ Classification

Preferred Term of Adverse Drug Reaction

Common

Uncommon

Gastrointestinal disorders

Nausea

Abdominal pain upper

Abdominal distension

Abdominal pain

Dry mouth

Dyspepsia

Flatulence

Nervous system disorders

Headache

Dizziness

Psychiatric disorders

Insomnia

Mood altered

Skin and subcutaneous tissue disorders

Acne

General disorders and administration site conditions

Fatigue

Oedema peripheral

Musculoskeletal and connective tissue disorders

Myalgia

Back pain

Muscle spasms

Investigations

Blood cortisol decreased

Infections and infestations

Influenza

Blood and lymphatic system disorders

Leukocytosis

Table 2 Events reported for the therapeutic class (intestinal anti-inflammatory agents, corticosteroids acting locally, budesonide)

MedDRA System Organ Classification

Common

Uncommon

Rare

Very Rare

Cardiac disorders

Palpitations

Endocrine disorders

Cushingoid features

Growth retardation in children*

Eye disorders

Cataract including subcapsular cataract

Glaucoma

)

Gastrointestinal disorders

Dyspepsia

Immune system disorders

Anaphylactic reaction

Metabolism and nutrition disorders

Hypokalemia

Musculoskeletal and connective tissue disorders

Muscle cramps

Nervous system disorders

Tremor

Psychiatric disorders

Behavioural changes such as nervousness, insomnia and mood swings

Depression

Psychomotor hyperactivity

Anxiety

Aggression

Reproductive system and breast disorders

Menstrual disorders

Skin and subcutaneous tissue disorders

Skin reactions (urticaria, exanthema)

Ecchymosis

* Note that Abelitan is not recommended for use in children (see 4.2)

Most of the adverse events mentioned in this SmPC can also be expected for other treatments with glucocorticoids.

Side effects typical of systemic corticosteroids (e.g. cushingoid features and growth retardation) may occur. These side effects are dependent on dose, treatment time, concomitant and previous corticosteroid intake, and individual sensitivity.

Paediatric population

No data available.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard.

Tabulated list of adverse reactions

Adverse reactions, which have been associated with budesonide, are given below, listed by system organ class and frequency. Frequency is defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10 000 to <1/1000), very rare (<1/10,000) and not known (cannot be estimated from available data).

Immune system disorders

Uncommon

Immediate and delayed hypersensitivity reactions including urticaria, rash, dermatitis angioedema and pruritus

Rare

Anaphylactic reaction

Endocrine disorders

Rare

Signs and symptoms of systemic corticosteroid effects, including adrenal suppression and growth retardation.

Eye disorders

Rare

Vision, blurred

Not known

Raised intraocular pressure or Glaucoma

Cataract

Respiratory, thoracic and mediastinal disorders

Common

Haemorrhagic secretion and epistaxis

Nasal Irritation (sneezing, stinging and dryness)

Rare

Nasal ulcer

Nasal septum perforation

Dysphonia

Very rare

Ulceration of mucous membrane

Musculoskeletal and connective tissue disorders

Uncommon

Muscle spasm

Injury, poisoning and procedural complications

Rare

Contusion*

* based on mechanistic plausibility and extrapolation from other budesonide/corticosteroid formulations.

In rare cases, signs or symptoms of systemic glucocorticosteroid-side effects such as Cushing's syndrome, Cushingoid features, psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children), may occur with nasal glucocorticosteroids, probably depending on dose, exposure time, concomitant and previous corticosteroid exposure, and individual sensitivity .

Paediatric population

Growth retardation has been reported in children receiving intranasal steroids.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard.

Serious and important adverse reactions include:

  • Hypercorticism and adrenal axis suppression
  • Symptoms of steroid withdrawal in those patients transferring from systemic glucocorticosteroid therapy
  • Increased susceptibility to infection
  • Other glucocorticosteroid effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Abelitan rectal foam in 332 patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The median duration of exposure was 42 days. This included 14 patients exposed for at least 6 months.

Abelitan rectal foam was studied primarily in 2 placebo-controlled, 6-week trials in patients with active disease (Study 1 and Study 2). In these trials, 268 patients received Abelitan rectal foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks .

The most common adverse reactions ( ≥ 2% of the Abelitan rectal foam or Placebo group and at higher frequency in the Abelitan rectal foam group) were decreased blood cortisol, adrenal insufficiency, and nausea (Table 1). Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/dL. Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with adrenocorticotropic hormone (ACTH).

A total of 10% of Abelitan rectal foam-treated patients discontinued treatment due to an adverse reaction compared with 4% of placebo-treated patients.

Table 1: Summary of Adverse Reactions in 2 Placebo Controlled Trials* (Studies 1and 2)

Adverse Reaction Abelitan Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Decreased blood cortisol# 46 (17) 6 (2)
Adrenal insufficiency† 10 (4) 2 (1)
Nausea 6 (2) 2 (1)
* Experienced by ≥ 2% of the Abelitan rectal foam or Placebo group and at higher frequency in the Abelitan rectal foam group
# Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/Dl
† Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH.

Of the 46 Abelitan rectal foam treated patients with decreased blood cortisol (defined as a morning cortisol level of < 5 mcg/dL) reported as an adverse event, none had adrenal insufficiency (defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH) (see Table 2). All cases of adrenal insufficiency resolved.

Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2).

Table 2: Summary of Glucocorticoid Related Effects in Two Placebo- Controlled Trials (Studies 1 and 2)

Adverse Reaction Abelitan Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Overall 60 (22) 10 (4)
Blood cortisol decreased 46 (17)* 6 (2)
Adrenal insufficiency 10 (4) 2 (1)
Insomnia 1 (0.4) 1 (0.4)
Sleep disorder 1 (0.4) 0
Acne 1 (0.4) 0
Depression 1 (0.4) 1 (0.4)
Hyperglycemia 1 (0.4) 0
* Decreases in serum cortisol levels associated with budesonide treatment were seen at Weeks 1 and 2 (twice-daily treatment) in the Abelitan rectal foam group, but gradually returned to baseline levels during the 4 weeks of once daily treatment.

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between Abelitan rectal foam and placebo after 6 weeks of therapy.

For additional details on morning cortisol levels and the response to the ACTH stimulation test, see CLINICAL PHARMACOLOGY.

Post-Marketing Experience

In addition to adverse reactions reported from clinical trials for Abelitan rectal foam, the following adverse reactions have been identified during post-approval use of other oral and rectal formulations of budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: hypertension

Gastrointestinal disorders: pancreatitis

General disorders and administration site conditions: pyrexia, peripheral edema

Immune System Disorders: anaphylactic reactions

Nervous System Disorders: dizziness, benign intracranial hypertension

Psychiatric Disorders: mood swings

Skin and subcutaneous tissue disorders: pruritus, maculo-papular rash, allergic dermatitis

Serious and important adverse reactions include:

  • Hypercorticism and adrenal axis suppression
  • Symptoms of steroid withdrawal in those patients transferring from systemic glucocorticosteroid therapy
  • Increased susceptibility to infection
  • Other glucocorticosteroid effects

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to Abelitan foam in 332 patients with active mild to moderate distal ulcerative colitis extending up to 40 cm from the anal verge. The median duration of exposure was 42 days. This included 14 patients exposed for at least 6 months.

Abelitan foam was studied primarily in 2 placebo-controlled, 6-week trials in patients with active disease (Study 1 and Study 2). In these trials, 268 patients received Abelitan foam 2 mg twice a day for 2 weeks followed by 2 mg once a day for 4 weeks .

The most common adverse reactions ( ≥ 2% of the Abelitan foam or Placebo group and at higher frequency in the Abelitan foam group) were decreased blood cortisol, adrenal insufficiency, and nausea (Table 1). Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/dL. Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with adrenocorticotropic hormone (ACTH).

A total of 10% of Abelitan foam-treated patients discontinued treatment due to an adverse reaction compared with 4% of placebo-treated patients.

Table 1: Summary of Adverse Reactions in 2 Placebo Controlled Trials* (Studies 1and 2)

Adverse Reaction UCERIS Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Decreased blood cortisol# 46 (17) 6 (2)
Adrenal insufficiency† 10 (4) 2 (1)
Nausea 6 (2) 2 (1)
* Experienced by ≥ 2% of the UCERIS rectal foam or Placebo group and at higher frequency in the Abelitan foam group
# Decreased blood cortisol was defined as a morning cortisol level of < 5 mcg/Dl
† Adrenal insufficiency was defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH.

Of the 46 Abelitan foam treated patients with decreased blood cortisol (defined as a morning cortisol level of < 5 mcg/dL) reported as an adverse event, none had adrenal insufficiency (defined as a cortisol level of < 18 mcg/dL at 30 minutes post challenge with ACTH) (see Table 2). All cases of adrenal insufficiency resolved.

Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebo-controlled trials (Studies 1 and 2).

Table 2: Summary of Glucocorticoid Related Effects in Two Placebo- Controlled Trials (Studies 1 and 2)

Adverse Reaction UCERIS Rectal Foam 2 mg/25 mL
N = 268
n (%)
Placebo
N = 278
n (%)
Overall 60 (22) 10 (4)
Blood cortisol decreased 46 (17)* 6 (2)
Adrenal insufficiency 10 (4) 2 (1)
Insomnia 1 (0.4) 1 (0.4)
Sleep disorder 1 (0.4) 0
Acne 1 (0.4) 0
Depression 1 (0.4) 1 (0.4)
Hyperglycemia 1 (0.4) 0
* Decreases in serum cortisol levels associated with budesonide treatment were seen at Weeks 1 and 2 (twice-daily treatment) in the Abelitan foam group, but gradually returned to baseline levels during the 4 weeks of once daily treatment.

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between Abelitan foam and placebo after 6 weeks of therapy.

For additional details on morning cortisol levels and the response to the ACTH stimulation test, see CLINICAL PHARMACOLOGY.

Post-Marketing Experience

In addition to adverse reactions reported from clinical trials for Abelitan foam, the following adverse reactions have been identified during post-approval use of other oral and rectal formulations of budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: hypertension

Gastrointestinal disorders: pancreatitis

General disorders and administration site conditions: pyrexia, peripheral edema

Immune System Disorders: anaphylactic reactions

Nervous System Disorders: dizziness, benign intracranial hypertension

Psychiatric Disorders: mood swings

Skin and subcutaneous tissue disorders: pruritus, maculo-papular rash, allergic dermatitis

Tabulated list of adverse events

The following definitions apply to the incidence of undesirable effects:

Very Common (≥ 1/10); Common (≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very Rare (< 1/10,000); Not Known (cannot estimate from the available data).

Adverse drug reactions by frequency and system organ class (SOC)

SOC

Frequency

Reaction

Immune system disorders

Very Rare

Anaphylactic reaction

Endocrine disorders

Common

Cushingoid features

Very Rare

Growth retardation

Metabolism and nutrition disorders

Common

Hypokalemia

Psychiatric disorders

Common

Behavioural changes such as nervousness, insomnia, mood swings and depression

Uncommon

Anxiety

Rare

Aggression

Nervous system disorders

Uncommon

Tremor, psychomotor hyperactivity

Eye disorders

Rare

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Cardiac disorders

Common

Palpitations

Gastrointestinal disorders

Common

Dyspepsia

Skin and subcutaneous tissue disorders

Common

Skin reactions (urticaria, exanthema)

Rare

Ecchymosis

Musculoskeletal and connective tissue disorders

Common

Muscle cramps

Reproductive system and breast disorders

Common

Menstrual disorders

Most of the adverse events mentioned in this SmPC can also be expected for other treatments with glucocorticoids.

Description of selected adverse events

Side effects typical of systemic corticosteroids (e.g. cushingoid features and growth retardation) may occur. These side effects are dependent on dose, treatment time, concomitant and previous corticosteroid intake, and individual sensitivity.

In clinical studies, at recommended doses, the incidence of adverse events was comparable to placebo.

Clinical studies showed the frequency of steroid associated side effects for Abelitan CR Capsules to be approximately half that of conventional prednisolone treatment, at equipotent doses. In studies of patients with active disease, receiving Abelitan 9 mg daily, the incidence of adverse events was comparable to placebo. Very rarely a wide range of psychiatric/ behavioural effects may occur, when systemic steroids are prescribed at high doses and for prolonged periods .

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme.

Website: www.mhra.gov.uk/yellowcard.

Overdose
The information provided in Overdose of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Capsule, Delayed Release; Capsule, Extended Release; Tablet, Extended Release
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Aerosol, Foam
Foam; Kit
Modified-release capsule, hard

Symptoms:

Acute overdose with Abelitan usually does not constitute a clinical problem. The only harmful effect after a large amount of sprays during a short period is a suppression of the cortex function.

If it is a matter of chronic use of very high doses, effects such as a degree of cortex atrophy in addition to adrenocortical suppression may occur.

Treatment:

Acute overdosage: There is no need for acute measures. The treatment with Abelitan should be continued with the lowest possible effective maintenance dose, and the adrenocortical function will repair itself automatically within 1-2 days.

Chronic overdosage: The patient should be treated as a steroid dependent and be transferred to a suitable maintenance dose with a systemic steroid, for example prednisolone. When the condition is stabilized, the patient should continue the treatment with the inhalation of Abelitan at the recommended dose.

To date, no cases of overdose with budesonide are known.

Abelitan Respules contains 0.1 mg/ml disodium edetate which has been shown to cause bronchoconstriction at levels above 1.2 mg/ml. Acute overdosage with Abelitan Respules, even in excessive doses, is not expected to be a clinical problem.

Acute overdosage with UCERIS rectal foam is unlikely. However, UCERIS rectal foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism .

Symptoms

Acute overdosage with Abelitan, even in excessive doses, is not expected to be a clinical problem. The only harmful effect that follows inhalation of large amounts of the drug over a short period is suppression of hypothalamic-pituitary-adrenal (HPA) function.

Management

No special emergency action needs to be taken. Treatment with Abelitan should be continued at the recommended dose to control the asthma.

Due to the low systemic availability of Abelitan tablets, acute overdosage even at very high doses is not expected to lead to an acute clinical crisis. In the event of acute overdosage, no specific antidote is available. Treatment consists of supportive and symptomatic therapy.

Acute overdose with this medicine even in excessive doses, is not expected to be a clinical problem.

Inhalation of high doses of corticosteroids may lead to suppression of the hypothalamic-pituitary-adrenal (HPA) axis function.

Acute overdosage with Abelitan rectal foam is unlikely. However, Abelitan rectal foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism .

Acute overdosage with Abelitan foam is unlikely. However, Abelitan foam is absorbed systemically and chronic overdosage may result in signs/symptoms of hypercorticism .

Reports of acute toxicity or death following overdosage of glucocorticosteroids are rare. Thus, acute overdosage with Abelitan CR Capsules even in excessive doses, is not expected to lead to an acute clinical crisis. In the event of acute overdosage, no specific antidote is available. Treatment consists of supportive and symptomatic therapy.

Chronic overdosage may lead to systemic corticosteroid effects, such as Cushingoid features. If such changes occur, the dose of Abelitan CR Capsules should be gradually reduced until treatment is discontinued, in accordance with normal procedures for the discontinuation of prolonged oral glucocorticosteroid therapy.

Pharmacodynamic properties
The information provided in Pharmacodynamic properties of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard

Pharmacotherapeutic group: Other drugs for obstructive airways diseases, inhalant, Glucocorticoids

ATC code: R03 BA 02

Abelitan is a glucocorticosteroid with a powerful local anti-inflammatory action.

Mechanism of action

The precise mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory effects (including T-cells, eosinophilic cells and mast cells) such as inhibition of the release of inflammatory mediators and inhibition of cytokine-mediated immune response, are probably important. The strength of Abelitan, measured as affinity for glucocorticoid receptors, is approximately 15 times stronger than that of prednisolone.

Clinical efficacy and safety

A clinical trial with asthma patients in which inhaled and oral Abelitan was compared with placebo, showed statistically significant effects of inhaled Abelitan, but not of oral Abelitan. The therapeutic effect of normally used doses of inhaled Abelitan may therefore chiefly be explained by a direct effect on the airways.

Abelitan has demonstrated an anti-anaphylactic and anti-inflammatory effect in challenge tests in experimental animals and in patients. This effect has manifested itself as reduced bronchial obstruction in both the immediate and the later allergic reaction.

It was also demonstrated that Abelitan reduces the airways' reactivity to histamine and metacholine in hyperreactive patients. Treatment with inhaled Abelitan has been used to effectively prevent exercise-induced asthma.

Influence on plasma cortisol concentration:

Studies in healthy volunteers with inhaled Abelitan have shown dose-related effect on plasma and urinary cortisol. At recommended doses, inhaled Abelitan causes significantly less effect on adrenal function than prednisone 10 mg, as shown by ACTH test. No clinically relevant changes in the plasma cortisol values or response to ACTH stimulation were observed when Abelitan was given in doses up to 1600 µg daily for 3 months to adults and up to 800 µg daily to children. Long-term monitoring for up to 52 weeks confirmed that the HPA axis was not suppressed.

Paediatric population

Clinical – asthma

The efficacy of Abelitan nebuliser suspension has been evaluated in a large number of studies, and it has been shown that Abelitan nebuliser suspension is effective both in adults and children as once- or twice-daily medication for prophylactic treatment of persistent asthma. Some examples of representative studies are given below.

Clinical – croup

A number of studies in children with croup have compared Abelitan nebuliser suspension with placebo. Examples of representative studies evaluating the use of Abelitan for the treatment of children with croup are given below.

Efficacy in children with mild to moderate croup

A randomized, double-blind placebo-controlled trial in 87 children (aged 7 months to 9 years), admitted to hospital with a clinical diagnosis of croup, was conducted to determine whether Abelitan nebuliser suspension improves croup symptom scores or shortens the duration of stay in hospital. An initial dose of Abelitan nebuliser suspension (2 mg) or placebo was given followed by either Abelitan 1 mg or placebo every 12 hours. Abelitan nebuliser suspension statistically significantly improved croup score at 12 and 24 hours and at 2 hours in patients with an initial croup symptom score above 3. There was also a 33% reduction in the length of stay.

Efficacy in children with moderate to severe croup

A randomized, double-blind, placebo-controlled study compared the efficacy of Abelitan nebuliser suspension and placebo in the treatment of croup in 83 infants and children (aged 6 months to 8 years) admitted to hospital for croup. Patients received either Abelitan 2 mg nebuliser suspension or placebo every 12 h for a maximum of 36 h or until discharge from hospital. The total croup symptom score was assessed at 0, 2, 6, 12, 24, 36 and 48 hours after the initial dose. At 2 hours, both the Abelitan nebuliser suspension and placebo groups showed a similar improvement in croup symptom score, with no statistically significant difference between the groups. By 6 hours, the croup symptom score in the Abelitan nebuliser suspension group was statistically significantly improved compared with the placebo group, and this improvement versus placebo was similarly evident at 12 and 24 hours.

Both asthma and inhaled glucocorticosteroids may affect the growth in length. The effect of Abelitan Nebuliser Suspension on the growth in length was studied in 519 children (from 8 months to 9 years) in three prospective, randomised, open, non-blinded studies. The studies did not show any significant difference in the growth in length of children treated either with Abelitan Nebuliser Suspension or with conventional asthma therapy. Two studies (N = 239 and 72 patients, respectively) showed 7 mm and 8 mm greater growth after one year of treatment with Abelitan Nebuliser Suspension compared with traditional asthma therapy (not statistically significant), while one study (N = 208) showed a growth in length that after one year was 8 mm smaller in the Abelitan Nebuliser Suspension group than in the group of conventional asthma treatment (statistically significant difference).

Pharmacotherapeutic group: Intestinal antiinflammatory agents, corticosteroids acting locally

ATC code: A07EA06

The exact mechanism of action of budesonide in the treatment of ulcerative colitis/procto-sigmoiditis is not fully understood. Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of budesonide is predominantly based on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At a dosage of 2 mg budesonide, applied rectally, budesonide leads to practically no suppression of the hypothalamus-hypophysis-adrenal cortex axis.

Abelitan 2mg rectal foam investigated up to the daily dosage of 4 mg budesonide showed virtually no influence on the plasma cortisol level.

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: RO3B A02

Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids.

Topical anti-inflammatory effect

The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important.

A clinical study in asthmatics comparing inhaled and oral budesonide at doses calculated to achieve similar systemic bioavailability demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract.

In a provocation study pre-treatment with budesonide for four weeks has shown decreased bronchial constriction in immediate as well as late asthmatic reactions.

Onset of effect

After a single dose of orally inhaled budesonide, delivered via dry powder inhaler, improvement of the lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment although maximum benefit may not be achieved for up to 4 weeks.

Airway reactivity

Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyperreactive patients.

Exercise-induced asthma

Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma.

Growth

In short term studies a small and generally transient reduction in growth has been observed, which usually occurs within the first year of treatment.

Influence on plasma cortisol concentration

Studies in healthy volunteers with Abelitan Turbohaler have shown dose-related effect on plasma and urinary cortisol. At recommended doses, Abelitan Turbohaler causes significantly less effect on adrenal function than prednisone 10 mg, as shown by ACTH test.

Paediatric population

Clinical – asthma

The efficacy of Abelitan Respules has been evaluated in a large number of studies, and it has been shown that Abelitan Respules is effective both in adults and children as once- or twice-daily medication for prophylactic treatment of persistent asthma. Some examples of representative studies are given below.

Clinical – croup

A number of studies in children with croup have compared Abelitan Respules with placebo. Examples of representative studies evaluating the use of Abelitan Respules for the treatment of children with croup are given below.

Efficacy in children with mild to moderate croup

A randomised, double-blind placebo-controlled trial in 87 children (aged 7 months to 9 years), admitted to hospital with a clinical diagnosis of croup, was conducted to determine whether Abelitan Respules improves croup symptom scores or shortens the duration of stay in hospital. An initial dose of Abelitan Respules (2 mg) or placebo was given followed by either Abelitan Respules 1 mg or placebo every 12 hours. Abelitan Respules statistically significantly improved croup score at 12 and 24 hours and at 2 hours in patients with an initial croup symptom score above 3. There was also a 33% reduction in the length of stay.

Efficacy in children with moderate to severe croup

A randomised, double-blind, placebo-controlled study compared the efficacy of Abelitan Respules and placebo in the treatment of croup in 83 infants and children (aged 6 months to 8 years) admitted to hospital for croup. Patients received either Abelitan Respules 2 mg or placebo every 12 h for a maximum of 36 h or until discharge from hospital. The total croup symptom score was assessed at 0, 2, 6, 12, 24, 36 and 48 hours after the initial dose. At 2 hours, both the Abelitan Respules and placebo groups showed a similar improvement in croup symptom score, with no statistically significant difference between the groups. By 6 hours, the croup symptom score in the Abelitan Respules group was statistically significantly improved compared with the placebo group, and this improvement versus placebo was similarly evident at 12 and 24 hours.

Budesonide is a glucocorticosteroid which possesses a high local anti-inflammatory action, with a lower incidence and severity of adverse effects than those seen with oral corticosteroids.

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: R03B A02.

Topical anti-inflammatory effect

The exact mechanism of action of glucocorticosteroids in the treatment of asthma is not fully understood. Anti-inflammatory actions, such as inhibition of inflammatory mediator release and inhibition of cytokine-mediated immune response are probably important.

A clinical study in asthmatics comparing inhaled and oral budesonide at doses calculated to achieve similar systemic bioavailability demonstrated statistically significant evidence of efficacy with inhaled but not oral budesonide compared with placebo. Thus, the therapeutic effect of conventional doses of inhaled budesonide may be largely explained by its direct action on the respiratory tract.

In a provocation study pre-treatment with budesonide for four weeks has shown decreased bronchial constriction in immediate as well as late asthmatic reactions.

Onset of effect

After a single dose of orally inhaled budesonide, delivered via dry powder inhaler, improvement of the lung function is achieved within a few hours. After therapeutic use of orally inhaled budesonide delivered via dry powder inhaler, improvement in lung function has been shown to occur within 2 days of initiation of treatment, although maximum benefit may not be achieved for up to 4 weeks.

Airway reactivity

Budesonide has also been shown to decrease airway reactivity to histamine and methacholine in hyper-reactive patients.

Exercise-induced asthma

Therapy with inhaled budesonide has effectively been used for prevention of exercise-induced asthma.

Growth

In short term studies a small and generally transient reduction in growth has been observed, which usually occurs within the first year of treatment.

Paediatric Population

Slit lamp examinations were performed in 157 children (5-16 years old), treated with an average daily dose of 504 μg for 3-6 years. Findings were compared with 111 age-matched asthmatic children. Inhaled budesonide was not associated with an increased occurrence of posterior subcapsular cataract.

Influence on plasma cortisol concentration

Studies in healthy volunteers with Abelitan have shown dose-related effects on plasma and urinary cortisol. At recommended doses, Abelitan, causes less effect on the adrenal function than prednisolone 10mg, as shown by ACTH tests.

Pharmacotherapeutic group: Intestinal anti-inflammatory agents, Corticosteroids acting locally

ATC code: A07E A06

Mechanism of action

The exact mechanism of action of budesonide in the treatment of UC is not fully understood. In general, budesonide inhibits many inflammatory processes including cytokine production, inflammatory cell activation and expression of adhesion molecules on endothelial and epithelial cells. At doses clinically equivalent to prednisolone, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.

Data from clinical pharmacology and pharmacokinetic studies indicate that the mode of action of Abelitan tablets is based on a local action in the gut.

Pharmacodynamic effects

MMX extended release technology is characterised by a multi-matrix structure covered by a gastro-resistant coating that dissolves in intestinal fluids having a pH greater than 7.

When the dosage form is administered, the gastro-protective layer protects the dosage form during transit through the stomach and duodenum up to the lower part of the intestine. When the protective layer is lost, the intestinal fluid then comes into contact with the hydrophilic matrix polymers, which start to swell until a viscous gel matrix is formed. The solvent that penetrates into the gel matrix dissolves the active ingredient from the lipophilic matrices. Budesonide is then released into the intestinal tract at a controlled rate throughout the colon.

Budesonide is a glucocorticoid used in the treatment of inflammatory bowel disease. It has a topical anti-inflammatory activity, but does not reduce cortisol levels to the same extent as systemic glucocorticoids.

Clinical efficacy

Two randomised, controlled phase III clinical trials including 1022 patients with mild to moderate active UC have been performed in adult patients. Two hundred fifty five (255) patients were treated for 8 weeks with Abelitan 9 mg per day. Patients included were either treatment naïve (42% ITT) or had failed on 5-ASA (58% ITT). Both studies included a reference arm, mesalazine (Asacol) and budesonide (Entocort), respectively to show assay sensitivity. The definition of remission applied in both studies was UCDAI score of ≤1, with 0 score for rectal bleeding and stool frequency, normal mucosa (no friability) and ≥1 point reduction in endoscopy score.

Effect of Abelitan 9mg tablet on Primary Endpoint:

Study

Abelitan 9 mg

Remission (%)

Placebo

Remission (%)

P=

Study CB-01-02/01

17.9

7.4

0.0143

Study CB-01-02/02

17.4

4.5

0.0047

Statistical difference versus placebo was reached for Abelitan 9 mg for both studies and the difference versus placebo was 10.4% and 12.9% respectively.

5-ASA is the Standard of Care for treatment of mild to moderate disease. Results of a head to head comparison with Abelitan and 5-ASA were not available. Therefore, the place in the therapeutic work-up remains to be established. Some patients may benefit from treatment initially with Abelitan.

Paediatric Population

Abelitan was not studied in the paediatric population.

Pharmacotherapeutic group: Decongestants and other nasal preparations for topical use, corticosteroids. ATC code: R01A D05

Budesonide is a non-halogenated glucocorticosteroid with a high local anti-inflammatory action within the respiratory tract.

Pharmacotherapeutic group: Corticosteroids acting locally.

ATC code: A07EA06

Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect.

The exact mechanism of budesonide in the treatment of Crohn's disease is not fully understood.

Data from clinical pharmacology studies and controlled clinical trials strongly indicate that the mode of action of Abelitan CR Capsules is based, at least partly, on a local action in the gut. Budesonide is a glucocorticosteroid with a high local anti-inflammatory effect. At doses clinically equivalent to prednisolone, budesonide gives significantly less HPA axis suppression and has a lower impact on inflammatory markers.

At recommended doses, Abelitan CR Capsules caused significantly less effect than prednisolone 20–40 mg daily on morning plasma cortisols; on 24 hour plasma cortisol (AUC 0–24 h) and on 24 hour urine cortisol levels.

ACTH tests have shown Abelitan CR Capsules to have significantly less effect than prednisolone on adrenal functions.

Paediatric population

HPA axis function. At recommended doses, Abelitan CR Capsules cause significantly less effect than prednisole 20-40 mg daily on morning plasma cortisol, on 24-hour plasma cortisol (AUC 0-24 h) and on 24-hour urine cortisol. Also ACTH tests have shown that Abelitan CR Capsules, compared with prednisolone, have significantly less impact on the adrenal function. Children with Crohn's disease have a slightly higher systemic exposure and cortisol suppression than adults with Crohn's disease.

Long-term studies have not been performed in children treated with Abelitan CR Capsules. In a study evaluating the effect of Abelitan CR Capsules on cortisol suppression in 8 children (range 9–14 years) and 6 adults , the oral administration of 9 mg Abelitan CR Capsules for 7 days induced a mean cortisol suppression (± SD) of 64% (±18%) in children and 50% (±27%) in adults with respect to baseline values. No clinically relevant findings in terms of safety have been reported. (Study 08-3044)

A study performed in children with mild to moderate Crohn's disease (CDAI ≥ 200) compared the activity of Abelitan CR Capsules at the dose of 9 mg once daily with that of prednisolone, administered at tapering doses, starting from 1 mg/kg. 22 patients were treated with Abelitan CR Capsules and 26 patients were treated with the reference drug prednisolone. After 8 weeks of treatment, 70.8% of patients treated with prednisolone reached the endpoint (CDAI ≤ 150), as compared to 54.5% of subjects treated with Abelitan CR Capsules, the difference was not statistically significant (p = 0.13). In the course of the study, adverse events were observed in 96% of patients treated with prednisolone and 91% of patients treated with Abelitan CR Capsules. The nature of these adverse events was similar in both study arms, but the incidence of glucocorticoid-related side-effects (such as acne and moon face) was lower in patients treated with Abelitan CR Capsules. (Study SD-008-3037)

Study D9422C0001 was an open-label, uncontrolled study designed to evaluate Abelitan in 108 pediatric patients (children and adolescents aged 5 to 17 years) diagnosed with mild to moderate Crohn's disease of the ileum and/or ascending colon. The median duration of treatment exposure of Abelitan of 58 days (range: 5 days to 90 days). Patients were dosed with oral Abelitan once daily according to bodyweight, patients weighing ≤25 kg received 6 mg once daily for 8 weeks; patients weighing >25 kg received 9 mg once daily for 8 weeks. During the 8 weeks of treatment there was a reduction in the mean (±SD) PCDAI score from 19.1 (±10.1) to 9.1 (±8.5), indicating an improvement in disease activity; with an improvement in mean (±SD) IMPACT 3 score from 132.1 (±18.8) to 140.9 (±16.9). AEs were observed at a similar frequency and severity as seen in adults, and were mostly related to Crohn's disease, puberty and possible GCS related side effects.

Study D9422C00002 was an open-label, un-comparative study designed to evaluate Abelitan 6 mg once daily as maintenance treatment in 50 pediatric patients (children and adolescents aged 5 to 17 years) with a diagnosis of mild to moderate Crohn's disease of the ileum and/or ascending colon who were in clinical remission (PCDAI ≤10). Treatment consisted of a 12-week maintenance treatment phase of 6 mg once daily, a 2-week taper phase to 3 mg once daily. The median duration of treatment exposure of Abelitan was 98.5 days (range: 11 days to 135 days). Most patients remained in the clinical remission stage, as there were no major changes in the mean PCDAI composite score or IMPACT 3 score. Mean (SD) PCDAI was 4.85 (3.62) at baseline and 6.89 (8.08) after 12 weeks of maintenance treatment with Abelitan 6 mg daily. At the same points in time the mean IMPACT3 score was 145.62 (12.43) and 146.98 (15.48), respectively. AEs were observed at a similar frequency and severity as seen in adults, and were mostly related to Crohn's disease, puberty and possible GCS related side effects.

Pharmacokinetic properties
The information provided in Pharmacokinetic properties of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
more... close
Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard

Absorption

In adults the systemic availability of Abelitan following administration of Abelitan Nebuliser Suspension via a jet nebuliser is approximately 15% of the nominal dose and 40% to 70% of the dose delivered to the patients. A minor fraction of the systemically available drug comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 min after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg.

Distribution

Abelitan has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85 - 90%.

Biotransformation

Abelitan undergoes an extensive degree (~90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxyAbelitan and 16α-hydroxyprednisolone, is less than 1 % of that of Abelitan. The metabolism of Abelitan is primarily mediated by CYP3A, a subfamily of cytochrome P450.

Elimination

The metabolites of Abelitan are excreted as such or in conjugated form mainly via the kidneys. No unchanged Abelitan has been detected in the urine. Abelitan has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of Abelitan after iv dosing averages 2-3 hours.

Linearity

The kinetics of Abelitan are dose-proportional at clinically relevant doses.

Paediatric population

Abelitan has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of Abelitan after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In 4-6 years old asthmatic children, the systemic availability of Abelitan following administration of Abelitan Nebuliser Suspension via a jet nebuliser (Pari LC Jet Plus® with Pari Master® compressor) is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half of that in healthy adults. The maximal plasma concentration, occurring approximately 20 min after start of nebulisation is approximately 2.4 nmol/L in 4-6 years old asthmatic children after a 1 mg dose. The exposure (Cmax and AUC) of Abelitan following administration of a single 1 mg dose by nebulisation to 4-6 year old children is comparable to that in healthy adults given the same delivered dose by the same nebuliser system.

Absorption

After oral application the systemic availability of budesonide is about 10 %. After rectal administration the areas under the concentration time curves are about 1.5-fold higher than in historical controls considering the identical oral budesonide dose. Peak levels are obtained after an average of 2 - 3 hours after administering Abelitan 2mg rectal foam.

Distribution

Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85 - 90 %.

Biotransformation

Budesonide undergoes extensive biotransformation in the liver (approximately 90 %) to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6 β - hydroxybudesonide and 16 α - hydroxyprednisolone, is less than 1 % of that of budesonide.

Elimination

The average elimination half-life is about 3 - 4 hours. The mean clearance rate is about 10 - 15 L/min for budesonide, determined by HPLC-based methods.

Spread

A scintigraphic investigation with technetium-marked Abelitan 2mg rectal foam on patients with ulcerative colitis showed that the foam spreads out over the entire sigmoid.

Specific patient populations (liver diseases)

Dependent on the type and severity of liver diseases the metabolism of budesonide might be decreased.

Absorption

In adults the systemic availability of budesonide following administration of Abelitan Nebuliser Suspension via a jet nebuliser is approximately 15% of the nominal dose and 40% to 70% of the dose delivered to the patients. A minor fraction of the systemically available drug comes from swallowed drug. The maximal plasma concentration, occurring about 10 to 30 min after start of nebulisation is approximately 4 nmol/L after a single dose of 2 mg.

Distribution

Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85 - 90%.

Biotransformation

Budesonide undergoes an extensive degree (≈90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.

Elimination

The metabolites of budesonide are excreted as such or in conjugated form mainly via the kidneys. No unchanged budesonide has been detected in the urine. Budesonide has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of budesonide after iv dosing averages 2 - 3 hours.

Linearity

The kinetics of budesonide are dose-proportional at clinically relevant doses.

In a study, 100 mg ketoconazole taken twice daily, increased plasma levels of concomitantly administered oral budesonide (single dose of 10 mg) on average, by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.

Paediatric population

Budesonide has a systemic clearance of approximately 0.5 L/min in 4 - 6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In 4 - 6 years old asthmatic children, the systemic availability of budesonide following administration of Abelitan Nebuliser Suspension via a jet nebuliser (Pari LC Jet Plus® with Pari Master® compressor) is approximately 6% of the nominal dose and 26% of the dose delivered to the patients. The systemic availability in children is about half of that in healthy adults.

The maximal plasma concentration, occurring approximately 20 min after start of nebulisation is approximately 2.4 nmol/L in 4 - 6 years old asthmatic children after a 1 mg dose. The exposure (Cmax and AUC) of budesonide following administration of a single 1 mg dose by nebulisation to 4 - 6 year old children is comparable to that in healthy adults given the same delivered dose by the same nebuliser system.

Absorption

Following oral inhalation via Abelitan, peak plasma concentrations of budesonide (4.0 nmol/L after a dose of 800 μg) occur within 30 minutes. Maximum plasma concentration and area under the plasma concentration time profile increase linearly with dose, but are slightly (20-30%) higher following repeated doses (3 weeks treatment) than after a single dose. Lung deposition in healthy subjects was estimated to 34% ±10% of the metered dose (arithmetic mean ± SD), while 22% was retained in the mouthpiece and the rest (approximately 45% of the metered dose) was swallowed.

The maximal plasma concentration after inhalation of 1 milligram budesonide is about 3.5 nmol/L and is reached after about 20 minutes.

Distribution

Budesonide has a volume of distribution of approximately 3 L/kg. Plasma protein binding averages 85-90%.

Biotransformation

Budesonide undergoes an extensive degree (approximately 90%) of biotransformation on first passage through the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxyprednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome p450.

Excretion

The metabolites of budesonide are excreted as such or in conjugated form mainly via the kidneys. No unchanged budesonide has been detected in the urine. Budesonide has high systemic clearance (approximately 1.2 L/min) in healthy adults, and the terminal half-life of budesonide after iv dosing averages 2-3 hours.

Linearity

The kinetics of budesonide are dose-proportional at clinically relevant doses.

In a study, 100 mg ketoconazole taken twice daily, increased plasma levels of concomitantly administered oral budesonide (single dose of 10 mg) on average, by 7.8-fold. Information about this interaction is lacking for inhaled budesonide, but marked increases in plasma levels could be expected.

Paediatric safety data

Budesonide has a systemic clearance of approximately 0.5 L/min in 4-6 years old asthmatic children. Per kg body weight children have a clearance which is approximately 50% greater than in adults. The terminal half-life of budesonide after inhalation is approximately 2.3 hours in asthmatic children. This is about the same as in healthy adults. In asthmatic children treated with Abelitan (800 μg single dose), plasma concentration reached Cmax (4.85 nmol/L) at 13.8 minutes after inhalation, and then decreased rapidly; AUC was 10.3 nmol·h/L. The value for AUC is generally comparable to that observed in adults at the same dose, however, the Cmax value tends to be higher in children. Lung deposition in children (31% of the nominal dose) is similar to that measured in healthy adults (34% of nominal dose).

Absorption

After oral dosing of plain micronised compound, absorption seems to be complete. A large proportion of the unformulated drug is absorbed from the ileum and ascending colon.

Systemic availability of Budesonide following a single administration of Abelitan tablets in healthy volunteers was compared to that of Entocort and the result was similar, about 10%, due to first pass metabolism in the liver. Maximum plasma concentrations of budesonide are approximately 1.3-1.8 ng/ml at 13-14 hours post administration. Concomitant administration of Abelitan tablets with food had no clinically relevant effect on absorption. It has been shown that there is no potential for drug accumulation on repeated dosing.

Distribution

Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85–90%.

Biotransformation

Budesonide undergoes extensive biotransformation in the liver to metabolites of low glucocorticoid activity. The glucocorticoid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.

Elimination

Elimination of budesonide is rate limited by absorption. Budesonide has a high systemic clearance (about 1.2 L/min).

Paediatric Population

No data or experience is available with respect to the pharmacokinetics of Abelitan tablets in the paediatric population.

Bioavailablity of oral budesonide in man is low (11-13%) due to an extensive first-pass metabolism in the liver.

The systemic availability of budesonide from this medicine, with reference to the metered dose is 33%. In adults, the maximal plasma concentration after administration of 256 micrograms budesonide from this medicine is 0.64 nM and is reached within 0.7 hours. The AUC after administration of 256 micrograms budesonide from this medicine is 2.7 nmolxh/L in adults.

Absorption

After oral dosing of plain micronised compound, absorption is rapid and seems to be complete. A large proportion of the drug is absorbed from the ileum and ascending colon. Systemic availability in healthy subjects is approximately 9–12% for Abelitan CR Capsules. This is similar to the systemic availability of plain micronised budesonide, indicating complete absorption. In patients with active Crohn's disease systemic availability is approximately 12–20% at the start of treatment.

Distribution

Budesonide has a high volume of distribution (about 3 L/kg). Plasma protein binding averages 85–90%. In healthy volunteers mean maximal plasma concentrations of 5–10 nmol/L were seen at 3–5 hours following a single oral dose of Abelitan CR Capsules 9 mg.

Biotransformation

Budesonide then undergoes extensive biotransformation in the liver to metabolites of low glucocorticosteroid activity. The glucocorticosteroid activity of the major metabolites, 6β-hydroxybudesonide and 16α-hydroxy-prednisolone, is less than 1% of that of budesonide. The metabolism of budesonide is primarily mediated by CYP3A, a subfamily of cytochrome P450.

Elimination

Elimination is rate limited by absorption. The average terminal half-life is 4 hours. Budesonide has a high systemic clearance (about 1.2 L/min).

Paediatric population

In a study comparing the pharmacokinetics of Abelitan CR Capsules in 8 children (range 9–14 years) and 6 adults, Abelitan CR Capules 9 mg for 7 days induced a systemic exposure (AUC) that was 17% higher in children than in adults, with maximum concentrations (Cmax) 50% higher in children than in adults (mean AUC ± SD: children 41.3 nmol/L ± 21.2; adults 35.0 nmol/L ± 19.8. Mean Cmax ± SD: children 5.99 nmo/L ± 3.45; adults 3.97 nmo/L ± 2.11.) (Study 08-3044).

Pharmacotherapeutic group
The information provided in Pharmacotherapeutic group of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Pharmacotherapeutic group in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard
Other drugs for obstructive airways diseases, inhalant, Glucocorticoids
Intestinal antiinflammatory agents, corticosteroids acting locally
Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: RO3B A02
Other drugs for obstructive airway diseases, inhalants, glucocorticoids. ATC Code: R03B A02.
Intestinal anti-inflammatory agents, Corticosteroids acting locally
Decongestants and other nasal preparations for topical use, corticosteroids. ATC code: R01A D05
Corticosteroids acting locally.
Preclinical safety data
The information provided in Preclinical safety data of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Aerosol dosage with maximum dosage / action; Aerosol dosage with minimal dosage / action; Micronized substance-powder; Substance-powder
Capsules; Enteric-coated capsules; Granules intestinal soluble; Rectal Dosed Foam
Nebuliser suspension; Suspension for inhalation dosed; Syrup
Inhalation powder; Nasal powder
Sustained release tablets, film-coated; Tablets enteric-soluble with prolonged release, film-coated
Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard

Preclinical data revealed no special hazard for humans in the therapeutic dose range based on studies of chronic toxicity, genotoxicity and carcinogenicity.

Glucocorticoids, including Abelitan, have produced teratogenic effects in animals, including cleft palate and skeletal abnormalities. Similar effects are considered unlikely to occur in humans at the recommended dose levels.

Preclinical investigations on dogs have shown that Abelitan 2mg rectal foam is well tolerated locally.

Preclinical data in acute, subchronic and chronic toxicological studies with budesonide showed atrophies of the thymus gland and adrenal cortex and a reduction especially of lymphocytes. These effects were less pronounced or at the same magnitude as observed with other glucocorticosteroids. These steroid effects might also be of relevance in man.

Budesonide had no mutagenic effects in a number of in vitro and in vivo tests.

A slightly increased number of basophilic hepatic foci were observed in chronic rat studies with budesonide, and in carcinogenicity studies there was an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumours (female rats) observed. These tumours are probably due to the specific steroid receptor action, increased metabolic burden on the liver and anabolic effects, effects which are also known from other glucocorticosteroids in rat studies and therefore represent a class effect. No similar effects have ever been observed in man for budesonide, neither in clinical trials nor from spontaneous reports.

In general, preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

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The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticosteroids studied (beclomethasone dipropionate, fluocinolone acetonide).

Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.

An increased incidence of brain gliomas in male rats, in a carcinogenicity study, could not be verified in a repeat study in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.

Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.

Available clinical experience shows that there are no indications that budesonide, or other glucocorticosteroids, induce brain gliomas or primary hepatocellular neoplasms in man.

In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not appear to be relevant in humans at the recommended doses.

Animal studies have also identified an involvement of excess prenatal glucocorticosteroids, in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.

The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticosteroids studied (beclomethasone dipropionate, fluocinolone acetonide).

Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than, or similar to, those observed after administration of the other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.

An increased incidence of brain gliomas in male rats, in a carcinogenicity study, could not be verified in a repeat study in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.

Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.

Available clinical experience shows no indication that budesonide, or other glucocorticosteroids, induce brain gliomas or primary hepatocellular neoplasms in man.

In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However, these animal experimental results do not appear to be relevant in humans at the recommended doses.

Animal studies have also identified an involvement of excess prenatal glucocorticosteroids, in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behaviour at exposures below the teratogenic dose range.

A preclinical toxicology and toxicokinetic bridging study, comparing Abelitan tablets with an existing prolonged release budesonide formulation (Entocort® EC 3 mg capsules, AstraZeneca) in cynomolgous monkeys has confirmed that Abelitan tablets result in a delayed peak exposure and reduced total exposure compared to the existing formulation of budesonide, while maintaining a superimposable toxicological profile.

Preclinical data have shown that budesonide produces effects less severe or similar to other glucocorticoids, such as weight increase, atrophy of the adrenal glands and thymus and effects on the leucocyte count. As with other glucocorticosteroids, and dependent on the dose and duration and the diseases concerned, these steroid effects may also be relevant in man.

Budesonide had no effect on fertility in rats.).

Budesonide had no mutagenic effects in a number of in vitro and in vivo tests. A slightly increased number of basophilic hepatic foci were observed in chronic rat studies with budesonide, and in carcinogenicity studies an increased incidence of primary hepatocellular neoplasms, astrocytomas (in male rats) and mammary tumours (in female rats) were observed. These tumours are probably due to the specific steroid receptor action, increased metabolic burden and anabolic effects on the liver, effects which are also known from rat studies with other glucocorticosteroids and therefore represent a class effect in this species.

The acute toxicity of budesonide is low and of the same order of magnitude and type as that of the reference glucocorticoids studied (beclomethasone dipropionate, flucinolone acetonide). Results from subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe than or similar to those observed after administration of the other glucocorticosteroids e.g. decreased body weight gain and atrophy of lymphoid tissues and adrenal cortex. An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in a repeat study, in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups. Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide, as well as with the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.

Available clinical experience shows no indication that budesonide or other glucocorticosteroids induce brain gliomas or primary heptocellular neoplasms in man. Budesonide has been used successfully in the treatment of seasonal allergic rhinitis for several years.

In animal reproduction studies, corticosteroids such as budesonide have been shown to induce malformations (cleft palate, skeletal malformations). However these animal experimental results do not appear to be relevant in humans at the recommended doses.

Animal studies have also identified an involvement of excess prenatal glucocorticosteroids in increased risk for intrauterine growth retardation, adult cardiovascular disease and permanent changes in glucocorticoid receptor density, neurotransmitter turnover and behavioural exposures below the teratogenic dose range.

Results from acute, subacute and chronic toxicity studies show that the systemic effects of budesonide are less severe or similar to those observed after administration of other glucocorticosteroids, e.g. decreased body-weight gain and atrophy of lymphoid tissues and adrenal cortex.

Budesonide, evaluated in six different test systems, did not show any mutagenic or clastogenic effects.

An increased incidence of brain gliomas in male rats in a carcinogenicity study could not be verified in a repeat study, in which the incidence of gliomas did not differ between any of the groups on active treatment (budesonide, prednisolone, triamcinolone acetonide) and the control groups.

Liver changes (primary hepatocellular neoplasms) found in male rats in the original carcinogenicity study were noted again in the repeat study with budesonide as well as the reference glucocorticosteroids. These effects are most probably related to a receptor effect and thus represent a class effect.

Available clinical experience shows that there are no indications that budesonide or other glucocorticosteroids induce brain gliomas or primary hepatocellular neoplasms in man.

The toxicity of Abelitan CR Capsules, with focus on the gastro-intestinal tract, has been studied in cynomolgus monkeys in doses up to 5 mg/kg after repeated oral administration for up to 6 months. No effects were observed in the gastrointestinal tract, neither at gross pathology nor in the histopathological examination.

Incompatibilities
The information provided in Incompatibilities of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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None applicable.

Special precautions for disposal and other handling
The information provided in Special precautions for disposal and other handling of Abelitan is based on data of another medicine with exactly the same composition as the Abelitan of the medicine (Budesonide). Be careful and be sure to specify the information on the section Special precautions for disposal and other handling in the instructions to the drug Abelitan directly from the package or from the pharmacist at the pharmacy.
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Inhalation solution; Powder for inhalation dosed
Modified-release capsule, hard

Before using this medicine for the first time the nozzle must be primed (filled with the medicine). To do this the bottle is shaken and the protective cap removed. The bottle is then held upright and the nozzle pumped up and down several times (5-10 times) spraying into the air, until an even mist is seen. The priming effect remains for approximately 24 hours. If a longer period of time passes before the next dose is taken, the nozzle must be loaded with medicine again. This time it is sufficient to spray just once into the air.

a. The patient is then instructed to blow their nose. Next, the bottle needs to be shaken and the protective cap removed.

b. The bottle is then held upright, with one finger held on either side of the nozzle.

c. The tip of the nozzle is inserted into the nostril and the nozzle pressed down once (or more as instructed by the doctor). The spray is then administered into the other nostril in the same way. Note: it is not necessary to inhale at the same time as spraying.

d. The nozzle needs to be wiped with a clean tissue after use and the protective cap replaced. The bottle should be stored in an upright position.

e. Keeping the Abelitan nozzle clean

The plastic nozzle of Abelitan should be cleaned regularly and at any time the spray of medicine is not coming out as it should. If this happens, first the nozzle should be checked to ensure that it is primed with medicine (see earlier). If, after the nozzle is primed again, the pump is still not working, the nozzle should be cleaned by using the following instructions:

The plastic nozzle is removed with a clean tissue and washed in warm, not hot, water. The nozzle is then rinsed thoroughly, dried and then replaced onto the top of the bottle. The nozzle should not be unblocked with a pin or other sharp object. After cleaning, the nozzle must be primed (filled with medicine) again before use.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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