Taunus Auqua

Treatment Of Nasal Symptoms Of Allergic Rhinitis

QNASL^® Nasal Aerosol is indicated for the treatment of the nasal symptoms associated with seasonal and perennial allergic rhinitis in patients 4 years of age and older.

Taunus Auqua dipropionate given by inhalation offers preventative treatment for asthma. It provides effective anti-inflammatory action in the lungs with a lower incidence and severity of adverse effects than those observed when corticosteroids are administered systemically. It also offers preventive treatment of asthma.

Easyhaler® Taunus Auqua 200 micrograms/dose is indicated in the following:

Adults Prophylactic management in:

Mild asthma (PEF values greater than 80% predicted at baseline with less than 20% variability):

Patients requiring intermittent symptomatic bronchodilator asthma medication on a regular basis.

Moderate asthma (PEF values 60-80% predicted at baseline with 20-30% variability):

Patients requiring regular asthma medication and patients with unstable or worsening asthma despite prophylactic therapy or bronchodilator alone.

Severe asthma (PEF values less than 60% predicted at baseline with greater than 30% variability):

Patients with severe chronic asthma. On transfer to high dose inhaled Taunus Auqua dipropionate, many patients who are dependent on systemic corticosteroids for adequate control of symptoms may be able to reduce significantly or eliminate their requirement for oral corticosteroids.

Prophylactic management of mild, moderate or severe asthma.

Taunus Auqua Aqueous Nasal Spray is indicated for the prophylaxis and treatment of perennial and seasonal allergic rhinitis including hayfever, and vasomotor rhinitis. Beclometasone dipropionate has a potent anti-inflammatory effect within the respiratory tract, with a lower incidence and severity of adverse events than those observed when corticosteroids are administered systemically.

Administer QNASL Nasal Aerosol by the intranasal route only. QNASL Nasal Aerosol must be primed prior to initial use by actuating four times. To do this, remove the protective dust cap from the device, hold the device upright between your thumb and forefinger (index finger) (the canister should be on top, pointing down), and spray 4 times into the air, away from your eyes and face. After the initial priming, the dose counter should read 120 for QNASL 40 mcg Nasal Aerosol and QNASL 80 mcg Nasal Aerosol 120-actuation products and 60 for QNASL 40 mcg Nasal Aerosol 60-actuation product. If QNASL Nasal Aerosol is not used for 7 consecutive days it should be primed by spraying 2 times. See accompanying illustrated PATIENT INFORMATION and Instructions for Use leaflet for proper use of QNASL Nasal Aerosol.

Allergic Rhinitis

Adults And Adolescents (12 Years Of Age And Older)

The recommended dose of QNASL Nasal Aerosol is 320 mcg per day administered as 2 actuations in each nostril (QNASL 80 mcg Nasal Aerosol) once daily (maximum total daily dose of 4 actuations per day).

Children (4 To 11 Years Of Age)

The recommended dose of QNASL Nasal Aerosol is 80 mcg per day administered as 1 actuation in each nostril (QNASL 40 mcg Nasal Aerosol) once daily (maximum total daily dose of 2 actuations per day).

Easyhaler® Taunus Auqua 200 micrograms/dose is for oral inhalation use only.

Patients should be made aware of the prophylactic nature of therapy with inhaled Taunus Auqua dipropionate and that it should be taken regularly everyday even when they are asymptomatic.

Patients should be given a starting dose of inhaled Taunus Auqua dipropionate appropriate to the severity of their disease. The dose may then be adjusted until control is achieved and should be titrated to the lowest dose at which effective control of asthma is maintained.

Adults

The usual starting dose is 200 micrograms twice a day. In more severe cases the starting dose may need to increase to 600 to 800 micrograms per day which may then be reduced when the patient's asthma has stabilised. The total daily dose may be administered as two, three, or four divided doses.

Paediatric population

Easyhaler® Taunus Auqua 200 micrograms/dose is not recommended for children.

Special Patient Groups

There is no need to adjust the dose in older people or in those with hepatic or renal impairment.

Posology

Qvar is for oral inhalation use only

Patients should be instructed in the proper use of their inhaler, including rinsing out their mouth with water after use.

NOTE: The recommended total daily dose of Qvar is lower than that for current beclometasone dipropionate containing products and should be adjusted to the needs of the individual patient.

ADULT STARTING AND MAINTENANCE DOSE:

It is important to gain control of asthma symptoms and optimise pulmonary function as soon as possible. When patients' symptoms remain under satisfactory control, the dose should be titrated to the lowest dose at which effective control of asthma is maintained.

To be effective, inhaled Qvar must be used on a regular basis even when patients are asymptomatic.

THERAPY IN NEW PATIENTS SHOULD BE INITIATED AT THE FOLLOWING

Patients on budesonide inhalers may be transferred to Qvar as described below

The general approach to switching patients to Qvar involves two steps as detailed below. Specific guidance on switching well-controlled and poorly-controlled (symptomatic) patients is given below the table.

Step 1: Consider the dose of budesonide-containing inhalers appropriate to the patient's current condition.

Step 2: Convert the budesonide inhaler dose to the Qvar dose according to the table below.

Patients with well-controlled asthma using budesonide inhaler products should be switched to Qvar at a dose in accordance with the table above.

For example:

Patients on 2 puffs twice daily of budesonide 100 micrograms would change to 2 puffs twice daily of Qvar 50 micrograms.

Patients with poorly-controlled asthma may be switched from budesonide inhaler products to Qvar at the same microgram for microgram dose up to 800 micrograms daily.

Alternatively the patient's current budesonide inhaler dose can be doubled and this dose can be converted to the Qvar dose according to the table above.

Patients on fluticasone inhalers may be transferred to the same total daily dose of Qvar up to 800 micrograms daily.

Once transferred to Qvar the dose should be adjusted to meet the needs of the individual patient.

The maximum recommended dose is 800 micrograms per day in divided doses.

The same total daily dose in micrograms from either Qvar 50 (a lower strength) or Qvar 100 aerosol provides the same clinical effect.

Paediatric population

There are no data to date on Qvar in children under 12 years of age, hence no definitive dosage recommendation can be made.

Special patient groups

No special dosage recommendations are made for elderly or patients with hepatic or renal impairment.

Method of administration

Taunus Auqua is a breath-actuated inhaler which automatically releases the metered dose of medication during a patient's inhalation through the mouthpiece and overcomes the need for patients to have good manual co-ordination.

The patient should read the instruction leaflet before use.

Before first use of the inhaler, or if the inhaler has not been used for two weeks or more, prime the inhaler by releasing two puffs into the air.

Qvar delivers a consistent dose

- whether or not the canister is shaken by the patient

- without the need for the patient to wait between individual actuations

- regardless of storage orientation or periods without use of up to 14 days

- at temperatures as low as -10°C.

Taunus Auqua Aqueous Nasal Spray is for administration by the intranasal route only.

Adults and children over six years of age:

The recommended dosage is two sprays into each nostril twice daily (400 micrograms/day). Once control has been established it may be possible to maintain control with fewer sprays. A dosage regimen of one spray into each nostril morning and evening has been shown to be efficacious in some patients. However, should symptoms recur, patients should revert to the recommended dosage of two sprays into each nostril morning and evening. The minimum dose should be used at which effective control of symptoms is maintained. Total daily administration should not normally exceed eight sprays.

For full therapeutic benefit regular usage is essential. The co-operation of the patient should be sought to comply with the regular dosage schedule and it should be explained that maximum relief may not be obtained within the first few applications.

For children under six years old, there are insufficient clinical data to recommend use.

QNASL Nasal Aerosol is contraindicated in patients with a history of hypersensitivity to beclomethasone dipropionate and/or any other QNASL Nasal Aerosol ingredients.

Special care is necessary in patients with active or quiescent pulmonary tuberculosis.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Local Nasal Effects

Nasal Discomfort, Epistaxis, And Nasal Ulceration

In clinical trials of 2 to 52 weeks duration, epistaxis and nasal ulcerations were observed more frequently and some epistaxis events were more severe in patients treated with QNASL Nasal Aerosol than those who received placebo. In the 52-week safety trial in patients with perennial allergic rhinitis, nasal erosions were identified in 4 of 415 patients and a nasal ulceration was identified in 1 of 415 patients treated with QNASL Nasal Aerosol. No nasal erosions or ulcerations were reported for patients who received placebo. In clinical trials conducted in pediatric patients ages 4 to 11 years, the local nasal effect was similar to those reported in patients 12 years of age and older. Patients using QNASL Nasal Aerosol over several months or longer should be examined periodically for possible changes in the nasal mucosa. If an adverse reaction (e.g., erosion, ulceration) is noted, discontinue QNASL Nasal Aerosol.

Candida Infection

In previous clinical trials with an aqueous formulation of beclomethasone dipropionate administered intranasally, localized infections of the nose and pharynx with Candida albicans had been reported. There were no instances of similar infections observed in clinical trials with QNASL Nasal Aerosol. If such an infection develops, it may require treatment with appropriate local therapy and discontinuation of QNASL Nasal Aerosol treatment. Thus, patients using QNASL Nasal Aerosol over several months or longer should be examined periodically for evidence of Candida infection.

Nasal Septal Perforation

Instances of nasal septal perforation have been reported in patients following the intranasal application of beclomethasone dipropionate. There were no nasal septal perforations reported during clinical trials in the indicated dose of QNASL 80 mcg Nasal Aerosol administered as 320 mcg once daily in adults and adolescents. There was one report of nasal septal perforation observed in the dose-ranging pediatric clinical trial.

Impaired Wound Healing

Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should not use QNASL Nasal Aerosol until healing has occurred.

Eye Disorders

Use of intranasal and inhaled corticosteroids may result in the development of increased intraocular pressure, blurred vision, glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, blurred vision, glaucoma, and/or cataracts.

Glaucoma and cataract formation was evaluated with ocular assessments that included intraocular pressure measurements and slit lamp examinations in 245 adolescent and adult patients (12 years of age and older) with perennial allergic rhinitis who were treated with QNASL Nasal Aerosol 320 mcg daily (N=197) or placebo (N=48) for up to 52 weeks. In 94% of patients, intraocular pressure (IOP) remained within the normal range (<21 mmHg) during the treatment portion of the trial. There were 10 patients (5%) treated with QNASL Nasal Aerosol and 1 patient (2%) treated with placebo that had intraocular pressure that increased above normal levels (≥21 mmHg) and greater than baseline during the treatment portion of the trial. Two of these occurrences in patients treated with QNASL Nasal Aerosol were reported as adverse reactions, one serious. No instances of cataract formation or other clinically significant ocular incidents were reported in this 52-week safety trial.

Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and rash have been reported following administration of beclomethasone dipropionate nasally administered and inhalationally administered products. Angioedema, urticaria, and rash have been reported following administration of QNASL Nasal Aerosol. Discontinue QNASL Nasal Aerosol if any such reactions occur.

Immunosuppression

Persons who are using drugs that suppress the immune system (e.g., corticosteroids) are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective package inserts for complete VZIG and IG prescribing information). If chickenpox or measles develops, treatment with antiviral agents may be considered.

Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, untreated local or systemic fungal or bacterial infections, systemic viral or parasitic infections, or ocular herpes simplex because of the potential for worsening of these infections.

Hypothalamic-Pituitary-Adrenal Axis Effect

When intranasal steroids are used at higher-than-recommended dosages or in susceptible individuals at recommended dosages, systemic corticosteroid effects such as hypercorticism and adrenal suppression may appear. If such changes occur, the dosage of QNASL Nasal Aerosol should be discontinued slowly, consistent with accepted procedures for discontinuing oral corticosteroid therapy.

The replacement of a systemic corticosteroid with a topical corticosteroid can be accompanied by signs of adrenal insufficiency. In addition, some patients may experience symptoms of corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression). Patients previously treated for prolonged periods with systemic corticosteroids and transferred to topical corticosteroids should be carefully monitored for acute adrenal insufficiency in response to stress. In patients who have asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, rapid decreases in systemic corticosteroid dosages may cause a severe exacerbation of their symptoms.

Effect On Growth

Corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Routinely monitor the growth of pediatric patients receiving QNASL Nasal Aerosol.

Patient Counseling Information

See FDA-Approved Patient Labeling accompanying the product.

Local Nasal Effects

Inform patients that treatment with QNASL Nasal Aerosol may lead to adverse reactions, including epistaxis, nasal ulceration, and nasal discomfort. Candida infection may also occur with treatment with QNASL Nasal Aerosol. In addition, nasal beclomethasone dipropionate products are known to be associated with nasal septal perforation and impaired wound healing. Patients who have experienced recent nasal ulcers, nasal surgery, or nasal trauma should not use QNASL Nasal Aerosol until healing has occurred.

Eye Disorders

Inform patients that blurred vision, glaucoma and cataracts are associated with nasal and inhaled corticosteroid use. Patients should inform their health care providers if a change in vision is noted while using QNASL Nasal Aerosol.

Hypersensitivity Reactions Including Anaphylaxis

Hypersensitivity reactions including anaphylaxis, angioedema, urticaria, and rash have been reported following administration of beclomethasone dipropionate nasally administered and inhalationally administered products. Angioedema, urticaria, and rash have been reported following administration of QNASL Nasal Aerosol. If any such reactions occur, patients should discontinue use of QNASL Nasal Aerosol.

Immunosuppression

Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

Use Daily For Best Effect

Patients should use QNASL Nasal Aerosol on a regular, once-daily basis since its effectiveness depends on its regular use. QNASL Nasal Aerosol may not have an immediate effect on rhinitis symptoms. The patient should not increase the prescribed dosage but should contact their physician if symptoms do not improve or if the condition worsens.

Keep Spray Out Of Eyes Or Mouth

Patients should be informed to avoid spraying QNASL Nasal Aerosol in their eyes or mouth.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

The carcinogenicity of beclomethasone dipropionate was evaluated in rats that were exposed for a total of 95 weeks: 13 weeks at inhalation doses up to 0.4 mg/kg and the remaining 82 weeks at combined oral and inhalation doses up to 2.4 mg/kg. In this trial, there was no evidence of carcinogenicity at the highest dose: approximately 70 and 120 times the maximum recommended human daily intranasal dose (MRHDID) in adults and children, respectively, on a mg/m² basis.

Beclomethasone dipropionate did not induce gene mutation in bacterial cells or mammalian Chinese hamster ovary (CHO) cells in vitro. No significant clastogenic effect was seen in cultured CHO cells in vitro or in the mouse micronucleus test in vivo.

In rats, beclomethasone dipropionate caused decreased conception rates at an oral dose of 16 mg/kg (approximately 490 times the MRHDID in adults on a mg/m² basis). There was no significant effect of beclomethasone dipropionate on fertility in rats at oral doses of 1.6 mg/kg (approximately 50 times the MRHDID in adults on a mg/m² basis). Inhibition of the estrous cycle in dogs was observed following oral doses of 0.5 mg/kg (approximately 50 times the MRHDID in adults on a mg/m² basis). No inhibition of the estrous cycle in dogs was seen following 12 months of exposure at an estimated inhalation dose of 0.33 mg/kg (approximately 35 times the MRHDID in adults on a mg/m² basis).

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C

There are no adequate and well-controlled clinical trials in pregnant women treated with QNASL Nasal Aerosol. Beclomethasone dipropionate was teratogenic and embryocidal in the mouse and rabbit although these effects were not observed in rats. QNASL Nasal Aerosol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Experience with oral corticosteroids since their introduction in pharmacologic, as opposed to physiologic, doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

Beclomethasone dipropionate administered subcutaneously was teratogenic and embryocidal in the mouse and rabbit at doses approximately twice the maximum recommended human daily intranasal dose (MRHDID) in adults (on a mg/m² basis at maternal doses of 0.1 and 0.025 mg/kg/day in mice and rabbits, respectively). No teratogenicity or embryocidal effects were seen in rats at approximately 460 times MRHDID (in adults on a mg/m² basis at a maternal inhalation dose of 15 mg/kg/day).

Non-Teratogenic Effects

Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

Nursing Mothers

It is not known whether beclomethasone dipropionate is excreted in human breast milk. However, other corticosteroids have been detected in human breast milk and thus caution should be exercised when QNASL Nasal Aerosol is administered to a nursing mother.

Pediatric Use

The safety and effectiveness of QNASL Nasal Aerosol in children 4 years and older have been established. The safety and effectiveness of QNASL Nasal Aerosol in children younger than 4 years of age have not been established. Controlled pediatric clinical trials with QNASL Nasal Aerosol included 909 children 4 to 11 years of age and 188 adolescent patients 12 to 17 years of age.

Controlled clinical trials have shown that intranasal corticosteroids may cause a reduction in growth velocity in pediatric patients. This effect has been observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA-axis function. The long-term effects of reduction in growth velocity associated with intranasal corticosteroids, including the impact on final adult height, are unknown. The potential for "catch-up" growth following discontinuation of treatment with intranasal corticosteroids has not been adequately studied. The growth of pediatric patients receiving intranasal corticosteroids, including QNASL Nasal Aerosol, should be monitored routinely (e.g., via stadiometry).

A 12-month, randomized, controlled clinical trial evaluated the effects of QVAR^®, an orally inhaled HFA beclomethasone dipropionate product, without spacer versus chlorofluorocarbon-propelled (CFC) beclomethasone dipropionate with large volume spacer on growth in children with asthma ages 5 to 11 years. A total of 520 patients were enrolled, of whom 394 received HFA-beclomethasone dipropionate (100 to 400 mcg/day ex-valve) and 126 received CFC-beclomethasone dipropionate (200 to 800 mcg/day ex-valve). When comparing results at month 12 to baseline, the mean growth velocity in children treated with HFA-beclomethasone dipropionate was approximately 0.5 cm/year less than that noted with children treated with CFC-beclomethasone dipropionate via large volume spacer. The potential growth effects of prolonged treatment should be weighed against the clinical benefits obtained and the risks/benefits of treatment alternatives.

The potential for QNASL Nasal Aerosol to cause reduction in growth velocity in susceptible patients or when given at higher than recommended dosages cannot be ruled out.

Geriatric Use

Clinical trials of QNASL Nasal Aerosol did not include sufficient numbers of subjects aged 65 years and older to determine whether they responded differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, administration to elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Patients should be instructed in the proper use of the inhaler, and their technique checked, to ensure that the drug reaches the target areas within the lungs. They should also be made aware that Easyhaler® Taunus Auqua 200 micrograms/dose has to be used regularly every day for optimum benefit. Patients should be made aware of the prophylactic nature of therapy with Easyhaler® Taunus Auqua 200 micrograms/dose and that they should be used regularly, even when they are asymptomatic.

Easyhaler® Taunus Auqua 200 micrograms/dose is not designed to relieve acute asthma symptoms for which an inhaled short-acting bronchodilator is required. Patients should be advised to have such rescue medication available.

Severe asthma requires regular medical assessment, including lung-function testing, as patients are at risk of severe attacks and even death.

Increasing use of bronchodilators, in particular short-acting inhaled beta2 agonists to relieve symptoms indicates deterioration of asthma control. If patients find that short acting relief bronchodilator treatment becomes less effective or they need more inhalations than usual, medical attention must be sought.

In this situation, patients should be reassessed and consideration given to the need for increased anti-inflammatory therapy (e.g. higher doses of inhaled corticosteroid or a course of oral corticosteroid) considered. Severe exacerbations of asthma must be treated in the normal way.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur 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 and 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.

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

Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than recommended doses, may result in clinically significant adrenal suppression. Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Lack of response or severe exacerbations of asthma should be treated by increasing the dose of inhaled Taunus Auqua dipropionate and, if necessary, by giving a systemic steroid and/or antibiotic if there is an infection, and by use of beta-agonist therapy.

For the transfer of patients being treated with oral corticosteroids:

The transfer of oral steroid-dependent patients to Easyhaler® Taunus Auqua 200 micrograms/dose and their subsequent management needs special care as recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy, may take a considerable time.

Patients who have been treated with systemic steroids for long periods of time or at a high dose may have adrenocortical suppression. With these patients adrenocortical function should be monitored regularly and their dose of systemic steroid reduced cautiously.

After approximately a week, gradual withdrawal of the systemic steroid is commenced. Decrements in dosages should be appropriate to the level of maintenance systemic steroid, and introduced at not less than weekly intervals. For maintenance doses of prednisolone (or equivalent) of 10mg daily or less, the decrements in dose should not be greater than 1mg per day, at not less than weekly intervals. For maintenance doses of prednisolone in excess of 10mg daily, it may be appropriate to employ cautiously, larger decrements in dose at weekly intervals.

Some patients feel unwell in a non-specific way during the withdrawal phase despite maintenance or even improvement of the respiratory function. They should be encouraged to persevere with Easyhaler® Taunus Auqua 200 micrograms/dose and withdrawal of systemic steroid continued, unless there are objective signs of adrenal insufficiency.

Patients weaned off oral steroids whose adrenocortical function is impaired should carry a steroid warning card indicating that they may need supplementary systemic steroid during periods of stress, e.g. worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc.

Treatment with Easyhaler® Taunus Auqua 200 micrograms/dose should not be stopped abruptly.

As with all inhaled corticosteroids, special care is necessary in patients with active or quiescent pulmonary tuberculosis.

Easyhaler® Taunus Auqua contains approximately 7mg of lactose per dose. This amount does not normally cause problems in lactose intolerant people. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption should not take this medicine.

Patients should be properly instructed on the use of the inhaler to ensure that the drug reaches the target areas within the lungs.To be effective, Qvar must be used by patients on a regular basis, even when patients do not have asthma symptoms. When symptoms are controlled, maintenance Qvar therapy should be reduced in a stepwise manner to the minimum effective dose. Inhaled steroid treatment should not be stopped abruptly.

Patients with asthma are at risk of acute attacks and should have regular assessments of their asthma control including pulmonary function tests.

Qvar is not indicated for the immediate relief of asthma attacks. Patients therefore need to have relief medication (inhaled short-acting bronchodilator) available for such circumstances.

Severe asthma requires regular medical assessment, including lung-function testing, as there is a risk of severe attacks and even death. Patients should be instructed to seek medical attention if short-acting relief bronchodilator treatment becomes less effective, or more inhalations than usual are required as this may indicate deterioration of asthma control. If this occurs, patients should be assessed and the need for increased anti-inflammatory therapy considered (eg. higher doses of inhaled corticosteroid or a course of oral corticosteroid)

Severe asthma exacerbations should be managed in the usual way i.e. by increasing the dose of inhaled beclometasone dipropionate, giving a systemic steroid if necessary, and/or an appropriate antibiotic if there is an infection, together with β-agonist therapy.

Treatment with Qvar should not be stopped abruptly.

However, systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. These effects are much less likely to occur 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, blurred vision, 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.

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

Prolonged treatment with high doses of inhaled corticosteroids, particularly higher than the recommended doses, may result in clinically significant adrenal suppression.

Additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Patients who have received systemic steroids for long periods of time or at high doses, or both, need special care and subsequent management when being transferred to inhaled steroid therapy. Patients should have stable asthma before being given inhaled steroids in addition to the usual maintenance dose of systemic steroid. Withdrawal of systemic steroids should be gradual, starting about seven days after the introduction of Qvar therapy. For daily oral doses of prednisolone of 10mg or less, dose reduction in 1mg steps, at intervals of not less than one week is recommended. For patients on daily maintenance doses of oral prednisolone greater than 10mg, larger weekly reductions in the dose might be acceptable. The dose reduction scheme should be chosen to correlate with the magnitude of the maintenance systemic steroid dose.

As recovery from impaired adrenocortical function, caused by prolonged systemic steroid therapy is slow, adrenocortical function should be monitored regularly.

Patients should be advised that they may feel unwell in a non-specific way during systemic steroid withdrawal despite maintenance of, or even improved respiratory function. Patients should be advised to persevere with their inhaled product and to continue withdrawal of systemic steroids, even if feeling unwell, unless there is evidence of HPA axis suppression.

Patients weaned off oral steroids whose adrenocortical function is impaired should carry a steroid warning card indicating that they may need supplementary systemic steroids during periods of stress, e.g. worsening asthma attacks, chest infections, major intercurrent illness, surgery, trauma, etc.

Discontinuation of systemic steroids may also cause exacerbation of allergic diseases such as atopic eczema and rhinitis. These should be treated as required with topical therapy, including corticosteroids and/or antihistamines.

Like other corticosteroids, caution is necessary in patients with active or latent pulmonary tuberculosis.

Patients should be advised to seek medical attention for review of maintenance Qvar therapy if peak flow falls, symptoms worsen or if the short-acting bronchodilator becomes less effective and increased inhalations are required. This may indicate worsening asthma.

Most patients can be successfully transferred to inhaled steroids with maintenance of good respiratory function, but special care is necessary for the first few months after the transfer, until the hypothalamic-pituitary-adrenal (HPA) system has sufficiently recovered to enable the patient to cope with stressful emergencies such as trauma, surgery or serious infections. Patients should, therefore, carry a steroid warning card to indicate the possible need to re-instate systemic steroid therapy rapidly during periods of stress or where airways obstruction or mucus significantly compromises the inhaled route of administration. In addition, it may be advisable to provide such patients with a supply of corticosteroid tablets to use in these circumstances. The dose of inhaled steroids should be increased at this time and then gradually reduced to the maintenance level after the systemic steroid has been discontinued.

Beclometasone dipropionate, like other inhaled steroids, is absorbed into the systemic circulation from the lungs. Beclometasone dipropionate and its metabolites may exert detectable suppression of adrenal function. Within the dose range 100-800 micrograms daily, clinical studies with Qvar have demonstrated mean values for adrenal function and responsiveness within the normal range.

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.

Patients should be advised that this product contains small amounts of ethanol. At the normal doses, the amounts of ethanol are negligible and do not pose a risk to patients.

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).

Growth retardation has been reported in children receiving nasal corticosteroids at licensed doses. It is recommended that the height of children receiving prolonged treatment with nasal corticosteroids is regularly monitored. If growth is slowed, therapy should be reviewed with the aim of reducing the dose of nasal corticosteroid, if possible to the lowest dose at which effective control of symptoms is maintained. In addition, consideration should be given to referring the patient to a paediatric specialist.

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

Care must be taken while transferring patients from systemic steroid treatment to Taunus Auqua Aqueous Nasal Spray if there is any reason to suppose that their adrenal function is impaired.

Infections of the nasal passages and paranasal sinuses should be appropriately treated but do not constitute a specific contra-indication to treatment with Taunus Auqua Aqueous Nasal Spray.

Although Taunus Auqua Aqueous Nasal Spray will control seasonal allergic rhinitis in most cases, an abnormally heavy challenge of summer allergens may in certain instances necessitate appropriate additional therapy particularly to control eye symptoms.

Taunus Auqua Aqueous Nasal Spray contains Benzalkonium Chloride which may cause bronchospasm.

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.

Systemic and local corticosteroid use may result in the following:

• Epistaxis, nasal discomfort, nasal ulcerations, Candida albicans infection, and impaired wound healing
• Eye Disorders
• Hypercorticism, adrenal suppression, and growth reduction
• Immunosuppression

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.

Adults And Adolescents 12 Years Of Age And Older

The safety data described below for adults and adolescents 12 years of age and older with seasonal or perennial allergic rhinitis are based on 4 placebo-controlled clinical trials of 2 to 6 weeks duration evaluating doses of beclomethasone nasal aerosol from 80 to 320 mcg once daily. These short-term trials included a total of 1394 patients with either seasonal or perennial allergic rhinitis. Of these, 575 (378 female and 197 male) received at least one dose of QNASL Nasal Aerosol, 320 mcg once daily and 578 (360 female and 218 male) received placebo. Patient ages ranged from 12 to 82 years and the racial distribution of patients was 81% white, 16% black, and 4% other.

Short-Term (2–6 Weeks) Trials

Less than 2% of patients in the clinical trials discontinued treatment because of adverse reactions with the rate of withdrawal among patients who received QNASL Nasal Aerosol similar to or lower than the rate among patients who received placebo. Table 1 displays the common adverse reactions (≥ 1% and greater than placebo-treated patients).

Table 1. Adverse Events With ≥ 1% Incidence and Greater than Placebo in QNASL Nasal Aerosol-Treated Adult and Adolescent Patients with Seasonal or Perennial Allergic Rhinitis in Controlled Clinical Trials of 2 to 6 Weeks Duration (Safety Population)

Nasal ulcerations occurred in 2 patients treated with placebo and in 1 patient treated with QNASL Nasal Aerosol. There were no differences in the incidence of adverse reactions based on gender or race. Clinical trials did not have sufficient numbers of patients aged 65 years and older to determine whether they respond differently than younger patients.

Long-Term 52-Week Safety Trial

In a 52-week placebo-controlled long-term safety trial in patients with PAR, 415 patients (128 males and 287 females, aged 12 to 74 years) were treated with QNASL Nasal Aerosol at a dose of 320 mcg once daily and 111 patients (44 males and 67 females, aged 12 to 67 years) were treated with placebo. Of the 415 patients treated with QNASL Nasal Aerosol, 219 patients were treated for 52 weeks and 196 patients were treated for 30 weeks. While most adverse events were similar in type and rate between the treatment groups, epistaxis occurred more frequently in patients who received QNASL Nasal Aerosol (45 out of 415, 11%) than in patients who received placebo (2 out of 111, 2%). Epistaxis also tended to be more severe in patients treated with QNASL Nasal Aerosol. In 45 reports of epistaxis in patients who received QNASL Nasal Aerosol, 27, 13, and 5 cases were of mild, moderate, and severe intensity, respectively, while the reports of epistaxis in patients who received placebo were of mild (1) and moderate (1) intensity. Seventeen patients treated with QNASL Nasal Aerosol experienced adverse reactions that led to withdrawal from the trial compared to 3 patients treated with placebo. There were 4 nasal erosions and 1 nasal septum ulceration which occurred in patients who received QNASL Nasal Aerosol, and no erosions or ulcerations noted in patients who received placebo. No patient experienced a nasal septum perforation during the trial.

Pediatric Patients Aged 4 to 11 Years

The safety data described below for pediatric patients 4 to 11 years of age with seasonal or perennial allergic rhinitis are based on 3 placebo-controlled clinical trials. These trials were 2 to 12 weeks in duration, evaluated doses of beclomethasone nasal aerosol 80 mcg to 160 mcg once daily and included a total of 1360 patients with either seasonal or perennial allergic rhinitis. Of these, 668 (312 female and 356 male) received at least one dose of QNASL Nasal Aerosol, 80 mcg once daily, 241 (116 female and 125 male) received QNASL Nasal Aerosol 160 mcg once daily, and 451 (203 female and 248 male) received placebo. The racial distribution of patients was 73% white, 20% black, and 6% other. Based on the results from the dose ranging trial, 80 mcg once daily was chosen as the dose in pediatric patients.

Less than 1.5% of patients in the clinical trials discontinued treatment because of adverse reactions with the rate of withdrawal among patients who received QNASL Nasal Aerosol 80 mcg once daily similar to or lower than the rate among patients who received placebo. Table 2 displays the common adverse reactions (≥ 2% and greater than placebo-treated patients). Additionally, epistaxis was reported at a rate of 4% for both QNASL Nasal Aerosol 80 mcg once daily and placebo treated patients.

Table 2. Adverse Events With ≥ 2% Incidence and Greater than Placebo in QNASL Nasal Aerosol-Treated Pediatric Patients with Seasonal or Perennial Allergic Rhinitis in Controlled Clinical Trials of 2 to 12 weeks Duration (Safety Population)

Postmarketing Experience

In addition to adverse reactions reported from clinical trials for QNASL Nasal Aerosol, the following adverse events have been reported during postmarketing use of QNASL Nasal Aerosol or other intranasal and inhaled formulations of beclomethasone dipropionate. 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. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to beclomethasone dipropionate or a combination of these factors.

QNASL Nasal Aerosol: sneezing, burning sensation

Intranasal beclomethasone dipropionate: Nasal septal perforation, blurred vision, glaucoma, cataracts, central serous chorioretinopathy (CSC), loss of taste and smell, and hypersensitivity reactions including anaphylaxis, angioedema, rash, and urticaria have been reported following intranasal administration of beclomethasone dipropionate.

Inhaled beclomethasone dipropionate: Hypersensitivity reactions, including anaphylaxis, angioedema, rash, urticaria, and bronchospasm have been reported following the oral inhalation of beclomethasone dipropionate.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common ( 1/10), common ( 1/100 and <1/10), uncommon ( 1/1000 and <1/100), rare ( 1/10,000 and <1/1000), very rare (<1/10,000) including isolated reports and not known (cannot be estimated from the available data). Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo and comparator group has not been taken into account in estimation of these frequencies. Rare and very rare events were generally determined from spontaneous data.

Candidiasis of the mouth and throat (thrush) occurs in some patients, the incidence increasing with doses greater than 400 micrograms of Taunus Auqua dipropionate per day. Patients with high blood levels of Candida precipitins, indicating a previous infection, are most likely to develop this complication. Patients may find it helpful to rinse their mouth thoroughly with water after using the inhaler. Symptomatic candidiasis can be treated with topical anti-fungal therapy whilst still continuing with Easyhaler® Taunus Auqua 200 micrograms/dose treatment.

Systemic effects of inhaled corticosteroids may occur, particularly at high doses prescribed for prolonged periods. Possible systemic effects include Cushing's syndrome, Cushingoid features, adrenal suppression, growth retardation in children and adolescents, decrease in bone mineral density, cataract, glaucoma (see 4.4 Special Warnings and Precautions for Use).

In some patients inhaled Taunus Auqua dipropionate may cause hoarseness, cough, throat irritation and sore throat. It may be helpful to rinse the mouth out with water immediately after inhalation.

As with other inhalation therapy, paradoxical bronchospasm may occur with an immediate increase in wheezing after dosing. This should be treated immediately with a fast-acting inhaled bronchodilator. The Taunus Auqua dipropionate preparation should be discontinued immediately, the patient assessed, and if necessary alternative therapy instituted.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

A serious hypersensitivity reaction including oedema of the eye, face, lips and throat (angioedema) has been reported rarely.

As with other inhaled therapy, paradoxical bronchospasm may occur after dosing. Immediate treatment with a short-acting bronchodilator should be initiated, Qvar should be discontinued immediately and an alternate prophylactic treatment introduced.

Systemic effects of inhaled corticosteroids may occur, particularly with high doses prescribed for prolonged periods. These include adrenal suppression, growth retardation in children, decrease in bone mineral density and the occurrence of cataract and glaucoma.

Commonly, when taking Qvar, hoarseness and candidiasis of the throat and mouth may occur. To reduce the risk of hoarseness and candida infection, patients are advised to rinse their mouth after using their inhaler.

Based on the MedDra system organ class and frequencies, adverse events are listed in the table below according to the following frequency estimate: 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).

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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 at: www.mhra.gov.uk/yellowcard

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Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10,000 and <1/1000) and very rare (<1/10,000) including isolated reports. Very common, common and uncommon reactions were generally determined from clinical trial data. Rare and very rare reactions were generally determined from spontaneous data. In assigning adverse reaction frequencies, the background rates in placebo groups were not taken into account, since these rates were generally comparable to those in the active treatment group.

Systemic effects of nasal corticosteroids may occur particularly when used at high doses 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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Un surdosage chronique peut entraîner des signes / symptômes d'hypercorticisme. Il n'y a pas de données disponibles sur les effets d'un surdosage aigu ou chronique avec QNASL Nasal Aerosol.

Acte: L'inhalation du médicament à des doses supérieures à celles recommandées peut entraîner une suppression temporaire de la fonction surrénale. Cela ne nécessite pas d'action d'urgence. Chez ces patients, le traitement par le diproprionate de Taunus Auqua par inhalation doit être poursuivi à une dose suffisante pour contrôler l'asthme; la fonction surrénale se rétablit en quelques jours et peut être vérifiée en mesurant le cortisol plasmatique.

Chronique: L'utilisation de dipropionate de Taunus Auqua inhalé à des doses quotidiennes supérieures à 1 500 microgrammes sur des périodes prolongées peut entraîner une certaine suppression surrénale. La surveillance de la réserve surrénale peut être indiquée. Le traitement doit être poursuivi à une dose suffisante pour contrôler l'asthme.

Il est peu probable qu'un surdosage aigu cause des problèmes. Le seul effet nocif qui suit l'inhalation de grandes quantités de médicament sur une courte période est la suppression de la fonction HPA. Aucune action d'urgence spécifique n'a besoin d'être prise. Le traitement par Qvar doit être poursuivi à la dose recommandée pour contrôler l'asthme; La fonction HPA se rétablit en un jour ou deux.

Si des doses excessives de dipropionate de béclométasone étaient prises sur une période prolongée, un degré d'atrophie du cortex surrénal pourrait survenir en plus de la suppression de l'HPA. Dans ce cas, le patient doit être traité comme dépendant des stéroïdes et transféré à une dose d'entretien appropriée d'un stéroïde systémique tel que la prednisolone.

Le seul effet nocif qui suit l'inhalation de grandes quantités de médicament sur une courte période est la suppression de la fonction hypothalamo-pituitaire-adrénalienne (HPA). Aucune action d'urgence spéciale ne doit être prise. Le traitement par le spray nasal aqueux Taunus Auqua doit être poursuivi à la dose recommandée. La fonction HPA se rétablit en un jour ou deux.

La gestion doit être conforme aux indications cliniques ou aux recommandations du centre national des poisons, le cas échéant.

Il n'y a pas de traitement spécifique pour une surdose de dipropionate de béclométasone. En cas de surdosage, le patient doit être traité de manière assistée avec une surveillance appropriée si nécessaire

Fonction surrénale: Les effets de l'aérosol nasal QNASL sur l'axe HPA ont été évalués dans deux essais de rhinite allergique pérenne randomisée, en double aveugle et en groupes parallèles - un chez des patients adultes et adolescents âgés de 12 à 45 ans et un autre chez les enfants de 6 à 11 ans. Dans la première étude avec des patients adolescents et adultes âgés de 12 à 45 ans, QNASL Nasal Aerosol 320 mcg, une fois par jour, a été comparé à la fois à un aérosol nasal placebo et à un contrôle positif (un groupe placebo / prednisone qui a reçu de la prednisone 10 mg par voie orale une fois par jour pendant les 7 derniers jours de la période de traitement). Dans la deuxième étude avec des patients pédiatriques âgés de 6 à 11 ans, QNASL Nasal Aerosol 80 mcg une fois par jour a été comparé à un placebo nasal aérosol. La fonction de l'axe HPA a été évaluée par des taux sériques de cortisol sur 24 heures avant la première dose et après 6 semaines de traitement. Les patients ont été domiciliés pour les évaluations de cortisol sérique sur 24 heures. Le changement par rapport à la valeur initiale de la moyenne pondérée en cortisol sérique sur 24 heures pour l'aérosol nasal QNASL et le placebo après 6 semaines de traitement a été comparé.

Dans l'étude sur l'axe HPA chez les patients âgés de 12 à 45 ans, les valeurs moyennes géométriques moyennes pondérées en cortisol sur le sérum étaient similaires dans les groupes de traitement QNASL Nasal Aerosol 320 mcg / jour et placebo (9,04 et 8,45 mcg / dL, respectivement). Après 6 semaines de traitement, les valeurs moyennes géométriques étaient respectivement de 8,18 et 8,01 mcg / dL, avec un changement par rapport à la valeur initiale de la moyenne pondérée en cortisol sérique sur 24 heures pour les groupes QNASL Nasal Aerosol et placebo de 0,86 et 0,44, ce qui entraîne une différence de 0,42. Le rapport moyen géométrique pour QNASL Nasal Aerosol 320 mcg / jour au placebo était de 0,96 (IC à 95%: 0,87, 1,06). À titre de comparaison, dans le groupe de traitement à contrôle positif (prédnisone), le rapport moyen géométrique du placebo au placebo / prednisone 10 mg / jour était de 3,17 (IC à 95%: 2,68, 3,74).

Dans l'étude sur l'axe HPA chez les patients âgés de 6 à 11 ans, les valeurs moyennes géométriques moyennes pondérées en cortisol sur le sérum étaient similaires dans les groupes de traitement QNASL Nasal Aerosol 80 mcg / jour et placebo (5,97 et 6,47 mcg / dL, respectivement). Après 6 semaines de traitement, les valeurs moyennes géométriques étaient respectivement de 6,19 et 7,13 mcg / dL, sans diminution par rapport aux valeurs de référence dans les deux groupes de traitement. Le rapport moyen géométrique pour QNASL Nasal Aerosol 80 mcg / jour au placebo était de 0,91 (IC à 95%; 0,81, 1,03).

Le dipropionate de Taunus Auqua (BDP) est un promédicament à faible activité de liaison des récepteurs glucocorticoïdes. Il est hydrolysé via des enzymes estérases en métabolite actif Taunus Auqua-17-monopropionate (B-17-MP), qui a une activité anti-inflammatoire topique élevée.

Classe pharmacothérapeutique: Glucocorticoïdes, Code ATC: R03B A01

Qvar contient du dipropionate de béclométasone en solution dans le propulseur HFA-134a, ce qui entraîne un aérosol extrafine. Les gouttelettes d'aérosol sont en moyenne beaucoup plus petites que les particules de dipropionate de béclométasone délivrées par les formulations de suspension CFC ou les formulations de poudre sèche de dipropionate de béclométasone. La fraction de particules extrafines sera de 60% ± 20% des particules de médicament «¤ 3,3 microns par coup, ex-actionneur.

Des études de dépôt radiomarquées chez des adultes souffrant d'asthme léger ont démontré que la majorité du médicament (> 55% ex-actionneur) est déposé dans le poumon et une petite quantité (<35% ex-actionneur) est déposée dans l'oropharynx. Ces études ont été réalisées avec Qvar Aerosol. Qvar Aerosol est un inhalateur «presse et respiration», tandis que Taunus Auqua est un inhalateur à respiration.

Le dipropionate de béclométasone inhalé est désormais bien établi dans la gestion de l'asthme. Il s'agit d'un glucocorticoïde synthétique et exerce un effet topique et anti-inflammatoire sur les poumons, avec moins d'effets systémiques que les corticostéroïdes oraux.

Des études cliniques comparatives ont démontré que les patients asthmatiques atteignent une fonction pulmonaire équivalente et contrôlent les symptômes avec Qvar à des doses quotidiennes totales plus faibles que les inhalateurs d'aérosol contenant de la béclométasone dipropionate.

Des études pharmacodynamiques chez des patients souffrant d'asthme léger ayant reçu Qvar pendant 14 jours ont montré qu'il existe une corrélation linéaire entre la suppression urinaire du cortisol libre, la dose administrée et les taux sériques de béclométasone totale obtenus. À une dose quotidienne de 800 microgrammes de Qvar, la suppression du cortisol libre urinaire était comparable à celle observée avec la même dose quotidienne de CFC contenant du dipropionate de béclométasone, indiquant une marge de sécurité plus large, car Qvar est administré à des doses plus faibles que le produit CFC.

Après administration topique, la béclométasone 17,21-dipropionate (BDP) produit de puissants effets anti-inflammatoires et vasoconstricteurs.

Le BDP est un pro-drogue avec une faible affinité de liaison des récepteurs corticostéroïdes. Il est hydrolysé via les enzymes estérases en métabolite hautement actif béclométasone-17-monopropionate (B-17-MP), qui a une activité anti-inflammatoire topique élevée.

Le dipropionate de béclométasone offre un traitement de fond préventif pour la fièvre des foins du foin lorsqu'il est pris avant le défi des allergènes. Après quoi, avec une utilisation régulière, le BDP peut continuer d'empêcher la réapparition des symptômes allergiques.

Absorption

Après administration intranasale, la majeure partie du dipropionate de béclométhasone subit une conversion importante en son métabolite actif, la béclométhasone-17-monopropionate, pendant l'absorption. Les concentrations plasmatiques de dipropionate de béclométhasone et de béclométhasone-17-monopropionate ont été mesurées avec QNASL Nasal Aerosol dans 2 essais cliniques pour adultes et / ou adolescents et 1 essai clinique pédiatrique.

La pharmacocinétique d'une dose unique de QNASL Nasal Aerosol a été évaluée dans un essai randomisé, ouvert, de 3 périodes, sur des volontaires sains pour adultes. Les niveaux systémiques de dipropionate de béclométhasone-17- monopropionate et de béclométhasone après administration intranasale à dose unique de dipropionate de béclométhasone à des doses de 80 et 320 mcg ont été comparés aux niveaux systémiques de béclométhasone-17-monopropionate et de béclométhasone dipropion après administration^® Aérosol par inhalation). Les résultats de cet essai ont démontré que la biodisponibilité systémique de QNASL Nasal Aerosol 320 mcg était d'environ 27,5% (environ 4 fois plus bas) de celui du dipropionate de béclométhasone inhalé par voie orale HFA 320 mcg / jour sur la base des concentrations plasmatiques de béclométhasone-17- monopropionate (AUClast: 1139,7 contre 4140,3 h * pg / mL; GMR: 0,275; IC à 90% pour le GMR: 0,214, 0,354). L'exposition maximale à QNASL Nasal Aerosol 320 mcg / jour était d'environ 19,5% (environ 5 fois plus faible) que celle du dipropionate de béclométhasone inhalé HFA 320 mcg / jour tel que mesuré par la béclométhasone-17-monopropionate (Cmax: 262,7 vs 14 p.

Après administration répétée une fois par jour d'aérosol nasal QNASL, il n'y a eu aucune accumulation ou augmentation de l'exposition plasmatique au dipropionate de béclométhasone-17-monopropionate ou de béclométhasone, probablement en raison de la courte demi-vie plasmatique par rapport à la fréquence de dosage.

Distribution

Le in vitro la liaison aux protéines du béclométhasone-17-monopropionate était de 94% à 96% sur la plage de concentration de 1000 à 5000 pg / ml. Le volume de distribution à l'état d'équilibre du dipropionate de béclométhasone est modéré (20 L) mais plus étendu pour le monopropionate de béclométhasone-17 (424).

Métabolisme

Le dipropionate de béclométhasone subit un métabolisme de premier passage important, formant trois métabolites via le CYP3A4, le béclométhasone-17-monopropionate, la béclométhasone-21-monopropionate et la béclométhasone. Le béclométhasone-17-monopropionate est le métabolite majeur et le plus actif.

Élimination

La principale voie d'élimination du dipropionate de béclométhasone inhalé semble se faire par métabolisme. Plus de 90% du dipropionate de béclométhasone inhalé se trouve sous forme de monopropionate de béclométhasone-17- dans la circulation systémique. La demi-vie d'élimination moyenne du monopropionate de béclométhasone-17 est de 2,8 heures. Les demi-vies d'élimination terminale du dipropionate de béclométhasone et du monopropionate de béclométhasone-17 après administration intranasale avec de l'aérosol nasal QNASL (320 mcg) étaient respectivement d'environ 0,3 heure et 4,5 heures. Quelle que soit la voie d'administration (injection, par voie orale ou par inhalation), le dipropionate de béclométhasone et ses métabolites sont principalement excrétés dans les fèces. Moins de 10% du médicament et de ses métabolites sont excrétés dans l'urine. Il est probable que le dipropionate de béclométhasone intranasal suit une voie d'élimination similaire.

Absorption

Lorsqu'il est administré par inhalation (via un inhalateur-doseur), il y a une conversion importante du BDP au métabolite actif B-17-MP dans les poumons avant l'absorption systémique. L'absorption systémique du B-17-MP provient à la fois du dépôt pulmonaire et de l'absorption orale de la dose avalée. Lorsqu'elle est administrée par voie orale, chez des volontaires sains, la biodisponibilité du BDP est négligeable mais la conversion pré-systémique en B-17-MP se traduit par 41% (IC 95% 27-62%) de la dose disponible en B-17- MP .

Métabolisme

Le BDP est éliminé très rapidement de la circulation systémique, en raison du métabolisme de premier passage important. Le principal produit du métabolisme est le métabolite actif (B-17-MP). Des métabolites inactifs mineurs, le Taunus Auqua-21-monopropionate (B-21-MP) et le Taunus Auqua (BOH), sont également formés mais ils contribuent peu à l'exposition systémique.

Distribution

La distribution tissulaire à l'état d'équilibre pour le BDP est modérée (20L) mais plus étendue pour le B-17-MP (424L). La liaison aux protéines plasmatiques est modérément élevée (87%).

Élimination

L'élimination du BDP et du B-17-MP se caractérise par une clairance plasmatique élevée (150 et 120L / h) avec des demi-vies d'élimination terminale correspondantes de 0,5h et 2,7h. Après administration orale de BDP tritié, environ 60% de la dose a été excrétée dans les fèces en 96 heures, principalement sous forme de métabolites polaires libres et conjugués. Environ 12% de la dose a été excrétée sous forme de métabolites polaires libres et conjugués dans l'urine.

Le profil pharmacocinétique de Qvar montre que la concentration sérique maximale de béclométasone totale (BOH) (total de toute béclométasone OH et dipropionate de béclométasone ou monopropionate hydrolysé en béclométasone OH) après des doses uniques et multiples est atteinte après 30 minutes. La valeur au pic est d'environ 2 nanogrammes / ml après une dose quotidienne totale de 800 microgrammes et les taux sériques après 100, 200 et 400 microgrammes sont proportionnels. La principale voie d'élimination du dipropionate de béclométasone et de ses nombreux métabolites se trouve dans les fèces. Entre 10% et 15% d'une dose administrée par voie orale est excrétée dans l'urine, en tant que métabolites conjugués et libres du médicament.

Dans les études pharmacocinétiques à dose unique et à doses multiples, une dose de 200 microgrammes de Qvar a atteint des niveaux de BOH totaux comparables, en tant que dose de 400 microgrammes de CFC contenant de l'aérosol de dipropionate de béclométasone. Cela a fourni la justification scientifique de l'étude de doses quotidiennes totales plus faibles de Qvar pour obtenir le même effet clinique.

Aucune étude pharmacocinétique avec Qvar n'a été réalisée dans aucune population particulière.

Absorption

Après administration intranasale de BDP chez des hommes en bonne santé, l'absorption systémique a été évaluée en mesurant les concentrations plasmatiques de son métabolite actif B-17-MP, pour lesquelles la biodisponibilité absolue après administration intranasale est de 44% (IC à 95% 28%, 70%) . Après administration intranasale, <1% de la dose est absorbée par la muqueuse nasale. Le reste après avoir été éliminé du nez, soit par drainage, soit par clairance muco-cilaire, est disponible pour l'absorption du tractus gastro-intestinal. Le plasma B-17-MP est presque entièrement dû à la conversion du BDP absorbé par la dose avalée.

Après administration orale de BDP chez des hommes en bonne santé, l'absorption systémique a également été évaluée en mesurant les concentrations plasmatiques de son métabolite actif B-17-MP, pour lesquelles la biodisponibilité absolue après administration orale est de 41% (IC à 95% 27%, 62% ).

Après une dose orale, le B-17-MP est absorbé lentement avec des taux plasmatiques maximaux atteints 3 à 5 heures après l'administration.

Métabolisme

Le BDP est éliminé très rapidement de la circulation et les concentrations plasmatiques sont indétectables (<50pg / ml) après administration orale ou intranasale. Il y a un métabolisme rapide de la majorité de la partie avalée du BDP lors de son premier passage dans le foie. Le principal produit du métabolisme est le métabolite actif (B-17-MP). Des métabolites inactifs mineurs, le béclométasone-21-monopropionate (B-21-MP) et la béclométasone (BOH), sont également formés, mais ils contribuent peu à l'exposition systémique.

Distribution

La distribution tissulaire à l'état d'équilibre pour le BDP est modérée (20l) mais plus étendue pour le B-17-MP (424l). La liaison aux protéines plasmatiques du BDP est modérément élevée (87%).

Élimination

L'élimination du BDP et du B-17-MP se caractérise par une clairance plasmatique élevée (150 et 120l / h) avec des demi-vies d'élimination terminale correspondantes de 0,5h et 2,7h. Après administration orale de BDP tritié, environ 60% de la dose a été excrétée dans les fèces en 96 heures, principalement sous forme de métabolites polaires libres et conjugués. Environ 12% de la dose a été excrétée sous forme de métabolites polaires libres et conjugués dans l'urine.

Les patients doivent être informés de l'inhalation rapide et forcée à travers l'appareil Easyhaler. Les patients doivent être informés de ne pas expirer dans l'appareil. Les instructions d'utilisation de l'utilisateur illustré accompagnent chaque colis.

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