Components:
Mannitol
Mannitol
Method of action:
Cough And Cold Preparations, Decongestant, Diuretic
Cough And Cold Preparations, Decongestant, Diuretic
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Name of the medicinal product

20% Mannitol YD

Qualitative and quantitative composition

Mannitol

Therapeutic indications

The information provided in Therapeutic indications of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

20% Mannitol YDol 10% Solution for infusion is indicated for use as an osmotic diuretic in the following situations:

• Promotion of diuresis in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established.

• Reduction of intracranial pressure and cerebral oedema, when blood-barrier is intact.

• Reduction of elevated intraocular pressure when it cannot be lowered by other means.

• Promotion of elimination of renally excreted toxic substances in poisoning.

20% Mannitol YD is indicated for the treatment of cystic fibrosis (CF) in adults aged 18 years and above as an add-on therapy to best standard of care.

Dosage (Posology) and method of administration

The information provided in Dosage (Posology) and method of administration of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Posology:

The choice of the specific 20% Mannitol YDol concentration, dosage and rate of administration depends on the age, weight, clinical and biological condition of the patient and concomitant therapy.

Adults and adolescents:

Acute renal failure

The general dose range is 50 to 200 g 20% Mannitol YDol (500 ml to 2000 ml/day) in a 24 hour period, with a dosage limit of 50 g (500ml 20% Mannitol YDol) on any one occasion. In most instances, adequate response will be achieved at a dosage of 50 to 100 g 20% Mannitol YDol/day (500 ml to 1000 ml /day).

The rate of administration is usually adjusted to maintain a urine flow of at least 30-50 ml/hour.

Only in emergency situations, the maximum infusion rate can be as high as 200 mg/kg infused over 5 minutes (see also test dose). After 5 minutes, the infusion rate should be readjusted to maintain a urine flow of at least 30-50 ml/hour, with a maximal dose of 200 g/24h.

Use in patients with oliguria or renal impairment

Patients with marked oliguria or suspected inadequate renal function should first receive a test dose of approximately 200 mg 20% Mannitol YDol/kg bw (body weight) (2ml/kg bw) over a period of 3 to 5 minutes. For example: in an adult patient with a body weight of 70 kg: approximately 75 ml of a 20% solution or 100 ml of a 15% solution. The response to the test dose is considered adequate if at least 30-50 ml/hour of urine is excreted for 2-3 hours. If an adequate response is not attained, a further test dose may be given. If an adequate response to the second test dose is not attained, treatment with 20% Mannitol YDol should be discontinued and the patient reassessed as established renal failure may be present.

Reduction of intracranial pressure, cerebral volume and intraocular pressure

The usual dose is 1.5 to 2g/kg bw (15 to 20 ml/kg bw), infused over 30 to 60 minutes. When used preoperatively, the dose should be administered 1 to 1.5 hours before surgery to obtain the maximum effect.

Promotion of elimination of renally excreted toxic substances in poisoning

In forced diuresis, the dose of 20% Mannitol YDol should be adjusted to maintain urinary output of at least 100ml/hour and positive fluid balance of 1-2 litres. An initial loading dose of approximately 25 g (250 ml) may be given.

Paediatric population:

In renal insufficiency, the test dose should be 200 mg 20% Mannitol YDol/kg bw (2 ml/kg bw) over 3-5 minutes. The treatment dose ranges from 0.5 to 1.5 g/kg bw (5 ml/kg bw to 15 ml/kg bw). This dose may be repeated once or twice, after an interval of 4 to 8 hours, if necessary.

For cerebral and ocular oedema, this dose may be given over 30 to 60 minutes as for adults.

Elderly population:

As for adults, the dosage depends on the weight, clinical and biological condition of the patient and concomitant therapy. The general dose range is the same as for adults, 50 to 200 g in a 24 hour period (500 ml to 2000ml/day), with a dosage limit of 50 g 20% Mannitol YDol (500 ml) on any one occasion. Since incipient renal insufficiency may be present, caution should be used when reviewing patient's status prior to dose selection.

Method of administration:

The solution is for intravenous administration through sterile and non-pyrogenic equipment.

Hyperosmolar 20% Mannitol YDol solutions may cause vein damage. Check product's osmolarity before administration.

Use administration set which includes a final in-line filter because of the potential for 20% Mannitol YDol crystals to form and using an aseptic technique. The equipment should be primed with the solution in order to prevent air entering the system.

Do not remove unit from overwrap until ready for use. The inner bag maintains the sterility of the product.

Use only if the solution is clear, without visible particles or discoloration and the seal is intact. Confirm the integrity of the bag. Use only if the container is undamaged. Administer immediately following insertion of the infusion set.

This hypertonic solution should be administered via a large peripheral or preferably a central vein. Rapid infusion in peripheral veins may be harmful.

20% Mannitol YDol solutions may crystallize when exposed to low temperature.6.

<6.

The patient's initiation dose of 20% Mannitol YD must be used under the supervision and monitoring of an experienced physician or another health care professional appropriately trained and equipped to perform spirometry, monitor oxygen saturation (SpO2), and manage acute bronchospasm including appropriate use of resuscitation equipment.

Posology

Initiation dose assessment

Before commencing treatment with 20% Mannitol YD, all patients should be assessed for bronchial hyperresponsiveness to inhaled mannitol during administration of their initiation dose .

The patient should be pre-medicated with a bronchodilator 5-15 minutes prior to the initiation dose but after the baseline FEV1 and SpO2 (Oxygen saturation in the blood) measurement. All FEV1 measurements and SpO2 monitoring should be performed 60 seconds after dose inhalation.

Training the patient to practice correct inhaler technique during the initiation dose assessment is important.

The initiation dose assessment must be performed according to the following steps:

Step 1: Patients baseline FEV1 and SpO2 is measured prior to the initiation dose

Step 2: Patient inhales 40 mg (1x40 mg capsules) and SpO2 is monitored

Step 3: Patient inhales 80 mg (2x40 mg capsules) and SpO2 is monitored

Step 4: Patient inhales 120 mg (3x40 mg capsules), FEV1 is measured and SpO2 is monitored

Step 5: Patient inhales 160 mg (4x40 mg capsules), FEV1 is measured and SpO2 is monitored

Step 6: Patients FEV1 is measured 15 minutes post initiation dose.

Patients with asthma may experience reversible temporary mild bronchospasm after passing the initiation dose assessment and therefore all patients should be monitored until their FEV1 has returned to baseline levels.

Therapeutic dose regimen

The therapeutic dose regimen should not be prescribed until the initiation dose assessment has been performed. The patient must complete and pass the initiation dose assessment before starting treatment with 20% Mannitol YD.

A bronchodilator must be administered 5-15 minutes before each dose of 20% Mannitol YD.

The recommended dose of 20% Mannitol YD is 400 mg twice a day. This requires the inhalation of the contents of ten capsules via the inhaler device twice a day.

The doses should be taken morning and night with the evening dose taken 2-3 hours before bedtime.

For patients receiving several respiratory therapies, the recommended order is:

1. Bronchodilator

2. 20% Mannitol YD

3. Physiotherapy/exercise

4. Dornase alfa (if applicable)

5. Inhaled antibiotics (if applicable)

Special populations

Elderly patients (≥65 years)

There are insufficient data in this population to support a recommendation for or against dose adjustment.

Renal or hepatic impairment

20% Mannitol YD has not specifically been studied in patients with impaired renal and hepatic function. Available data from studies DPM-CF-301 and 302 suggest that no dose adjustments are required for these patient populations.

Paediatric population

The safety and efficacy of 20% Mannitol YD in children and adolescents aged 6 to 18 years has not yet been established.1 and 5.2 but no recommendation on a posology can be made.

The safety and efficacy of 20% Mannitol YD in children aged less than 6 years has not been established. No data are available.

Method of administration

20% Mannitol YD is for inhalation use, using the inhaler provided in the pack. It must not be administered by any other route or using any other inhaler. The capsules must not be swallowed.

Each of the capsules is loaded into the device separately. The contents of the capsules are inhaled via the inhaler device with one or two breaths. After inhalation, each empty capsule is discarded before inserting the next capsule into the inhaler device with as little delay as possible between capsules.

The inhaler device is to be replaced after one week of use. If the inhaler does require cleaning, it must be ensured that the device is empty, then it should be washed in warm water and before re use, the inhaler should be allowed to thoroughly air dry.

Detailed instructions on how to use the inhaler can be found in the patient information leaflet. Patients should be advised to carefully read them.

Contraindications

The information provided in Contraindications of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

20% Mannitol YDol 10% Solution for Infusion is contra-indicated in patients presenting with:

• Pre-existing plasma hyperosmolarity.

• Severe dehydration.

• Well established anuria.

• Severe heart failure.

• Severe pulmonary congestion or pulmonary oedema.

• Active intracranial bleeding, except during craniotomy.

• Disturbance of the blood-brain barrier.

• Hypersensitivity to 20% Mannitol YDol.

Hypersensitivity to the active substance.

Bronchial hyperresponsiveness to inhaled mannitol .

Special warnings and precautions for use

The information provided in Special warnings and precautions for use of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Hypersensitivity

Anaphylactic/anaphylactoid reactions, including anaphylaxis, as well as other hypersensitivity/infusion reactions have been reported with 20% Mannitol YDol. Fatal outcome has been reported .

The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated.

20% Mannitol YDol occurs in nature (e.g., in some fruits and vegetables) and is widely used as excipient in drugs and cosmetics. Therefore, patients may be sensitized without having received intravenous treatment with 20% Mannitol YDol.

CNS toxicity

CNS toxicity manifested by, e.g. confusion, lethargy, and coma has been reported in patients treated with 20% Mannitol YDol, in particular in the presence of impaired renal function. Fatal outcomes have been reported.

CNS toxicity may result from:

- High serum 20% Mannitol YDol concentrations.

- Serum hyperosmolarity resulting in intracellular dehydration within the CNS.

- Hyponatraemia or other disturbances of electrolyte and acid/base balance secondary to 20% Mannitol YDol administration.

At high concentrations, 20% Mannitol YDol may cross the blood brain barrier and interfere with the ability of the brain to maintain the pH of the cerebrospinal fluid especially in the presence of acidosis.

In patients with pre-existing compromised blood brain barrier, the risk of increasing cerebral oedema (general or focal) associated with repeated or continued use of 20% Mannitol YDol must be individually weighed against the expected benefits.

A rebound increase of intracranial pressure may occur several hours after the use of 20% Mannitol YDol. Patients with compromised blood brain barrier are at increased risk.

Risk of renal complications

Reversible, acute oligoanuric renal failure has occurred in patients with normal pre-treatment renal function, who received large intravenous doses of 20% Mannitol YDol.

Progressive renal damage or dysfunction, after institution of 20% Mannitol YDol therapy, including increasing oliguria and azotemia, has also been described.

Although the osmotic nephrosis associated with 20% Mannitol YDol administration is, in principle, reversible, osmotic nephrosis in general is known to potentially proceed to chronic or even end-stage renal failure.

Patients with pre-existing renal disease, or those receiving potentially nephrotoxic drugs, are at increased risk of renal failure following administration of 20% Mannitol YDol. Serum osmolar gap and renal function should be closely monitored and appropriate action initiated, should signs of worsening renal function appear.

20% Mannitol YDol should be administered with caution to patients with severely impaired renal function. A test dose should be employed and therapy with 20% Mannitol YDol continued only if an adequate urine flow is achieved .

If the urine output declines during 20% Mannitol YDol infusion, the patient's clinical status should be closely reviewed for developing renal impairment, and the 20% Mannitol YDol infusion suspended, if necessary.

Risk of hypervolaemia

The cardiovascular status of the patient should be carefully evaluated before rapidly administering 20% Mannitol YDol 10% Solution for Infusion.

High doses and/or high rates of infusion as well as accumulation of 20% Mannitol YDol (due to insufficient renal excretion of 20% Mannitol YDol), may result in hypervolaemia, overexpansion of the extracellular fluid, which may lead to or exacerbate existing congestive heart failure.

Accumulation of 20% Mannitol YDol may result if urine output continues to decline during administration and this may intensify existing or latent congestive heart failure.

If the patient's cardiac or pulmonary function deteriorates, treatment should be discontinued.

Risk of water and electrolyte imbalances, hyperosmolarity

20% Mannitol YDol-induced osmotic diuresis may cause or worsen dehydration/hypovolaemia and hemoconcentration. Administration of 20% Mannitol YDol may also cause hyperosmolarity.

In addition, depending on dosage and duration of administration, electrolyte and acid/base imbalances may result from transcellular shifts of water and electrolytes, osmotic diuresis and/or other mechanisms. Such imbalances may be severe and potentially fatal.

Imbalances that may result from 20% Mannitol YDol treatment include:

• Hypernatraemia, dehydration and hemoconcentration (resulting from excessive water loss).

• Hyponatraemia (Shift of sodium-free intracellular fluid into the extra cellular compartment following 20% Mannitol YDol infusion may lower serum sodium concentration and aggravate pre-existing hyponatraemia. Sodium may be lost in the urine).

Hyponatraemia can lead to headache, nausea, seizures, lethargy, coma, cerebral oedema, and death. Acute symptomatic hyponatraemic encephalopathy is considered a medical emergency.

The risk for developing hyponatraemia is increased, for example:

• In children.

• In elderly patients.

• In women.

• Postoperatively.

• In persons with psychogenic polydipsia.

The risk for developing encephalopathy as a complication of hyponatraemia is increased, for example:

• In paediatric patients (≤16 years of age).

• In women (in particular, premenopausal women).

• In patients with hypoxaemia.

• In patients with underlying central nervous system disease.

Hypokalaemia, hyperkalaemia, other electrolytes imbalances, metabolic acidosis and metabolic alkalosis.

20% Mannitol YDol may obscure and intensify inadequate hydration and hypovolaemia.

Infusion reactions

Infusion site reactions have occurred with the use of 20% Mannitol YDol.

Adding other medications or using an incorrect administration technique may cause febrile reactions due to possible introduction of pyrogens.6.

Volume and electrolyte replacement before use

In patients with shock and renal dysfunction, 20% Mannitol YDol should not be administered until volume (fluid, blood) and electrolytes have been replaced.

Monitoring

The acid base balance, renal function and serum osmolarity must be monitored carefully when 20% Mannitol YDol is used.

Patients receiving 20% Mannitol YDol should be monitored for any deterioration in renal, cardiac or pulmonary function and treatment discontinued in the case of adverse events.

Urinary output, fluid balance, central venous pressure and electrolyte balance (in particular serum sodium and potassium levels) should be carefully monitored.

Incompatibility with blood

20% Mannitol YDol should not be given concomitantly with blood because it may cause agglutination and crenation of blood cells.

Crystallization

When exposed to low temperatures, solutions of 20% Mannitol YDol may crystallize.

Laboratory test interferences

20% Mannitol YDol can cause false low results in some tests systems for inorganic phosphorus blood concentrations.

20% Mannitol YDol produces false positive results in tests for blood ethylene glycol concentrations in which 20% Mannitol YDol is initially oxidized to an aldehyde.

Paediatric use

Safety and effectiveness in the paediatric population have not been established in clinical studies.

Geriatric use

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.

Risk of air embolism

Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is completed.

Pressurizing intravenous solutions, contained in flexible plastic containers, in order to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration.

Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers.

Hyperresponsiveness to mannitol

Patients must be monitored for bronchial hyperresponsiveness to inhaled mannitol during their initiation dose assessment before commencing the therapeutic dose regimen of 20% Mannitol YD.If the patient is unable to perform spirometry or complete the initiation dose assessment, they must not be prescribed 20% Mannitol YD. Hyperresponsive patients should not be prescribed the therapeutic dose regimen of 20% Mannitol YD .The usual precautions regarding bronchial hyperresponsiveness monitoring apply .

A patient is defined as hyperresponsive to inhaled mannitol and must not be prescribed the therapeutic dose regimen if they experience any of the following during the initiation dose assessment:

- ≥10% fall from baseline in SpO2 at any point of the assessment;

- FEV1 fall from baseline is ≥20% at 240 mg cumulative dose;

- FEV1 has fallen 20-<50% (from baseline) at the end of the assessment and does not return to <20% within 15 minutes;

- FEV1 has fallen ≥50% (from baseline) at the end of the assessment.

If a therapy induced hyperresponsive reaction is suspected, 20% Mannitol YD should be discontinued.

Bronchospasm

Bronchospasm can occur with inhalation of medicinal product and has been reported with 20% Mannitol YD in clinical studies, even in patients who were not hyperresponsive to the initiation dose of inhaled mannitol . Bronchospasm should be treated with a bronchodilator or as medically appropriate.

If there is evidence of therapy induced bronchospasm, the physician should carefully evaluate whether the benefits of continued use of 20% Mannitol YD outweigh the risks to the patient.

All patients should be formally reviewed after approximately six weeks of 20% Mannitol YD treatment to assess for signs and symptoms suggestive of active substance induced bronchospasm.

Asthma

The safety/efficacy of mannitol in patients with asthma has not been properly studied. Patients with asthma must be carefully monitored for worsening signs and symptoms of asthma after the initiation dose of 20% Mannitol YD.

Patients must be advised to report worsening signs and symptoms of asthma during therapeutic use to their physician. If there is evidence of therapy induced bronchospasm, the physician should carefully evaluate whether the benefits of continued use of 20% Mannitol YD outweigh the risks to the patient. Bronchospasm should be treated with a bronchodilator or as medically appropriate.

Haemoptysis

Haemoptysis has been commonly reported with 20% Mannitol YD in clinical studies. 20% Mannitol YD has not been studied in patients with a history of significant episodes of haemoptysis (>60 ml) in the previous three months. As a consequence, these patients should be carefully monitored, and 20% Mannitol YD should be withheld in the event of massive haemoptysis. A massive/serious haemoptysis is considered to be:

• acute bleeding ≥240 ml in a 24-hour period

• recurrent bleeding ≥100 ml/day over several days

The reinstitution or withholding of 20% Mannitol YD following smaller episodes of haemoptysis should be based on clinical judgement.

Cough

Cough was very commonly reported with use of 20% Mannitol YD in clinical studies . Patients should be trained to practice correct inhaler technique during treatment and advised to report persistent cough with the use of 20% Mannitol YD to their physician.

Impaired lung function

Safety and efficacy have not been demonstrated in patients with a FEV1 of less than 30% of predicted . The use of 20% Mannitol YD is not recommended in these patients.

Non-CF Bronchiectasis

Efficacy and safety have not been established in non-CF bronchiectasis patients. Therefore, treatment with 20% Mannitol YD is not recommended.

Effects on ability to drive and use machines

The information provided in Effects on ability to drive and use machines of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). 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 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Not relevant.

20% Mannitol YD has no or negligible influence on the ability to drive and use machines.

Undesirable effects

The information provided in Undesirable effects of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

The following adverse reactions have been reported in post-marketing experience. The frequency of the adverse drug reactions listed in this section cannot be estimated from the available data.

MedDRA System Organ Class

Adverse reaction (MedDRA Preferred Term)

Frequency

Immune system disorders

Allergic reaction

Anaphylactic reaction including anaphylactic shock that can be manifested with skin, gastrointestinal, and severe circulatory (hypotension) and respiratory manifestations (e.g. dyspnea).

Other hypersensitivity/infusion reactions, include

• hypertension

• pyrexia

• chills

• sweating

• cough

• musculoskeletal stiffness and myalgia

• urticaria/rash

• pruritus

• generalized pain

• discomfort

• nausea

• vomiting

• headache

Not known

Metabolism and nutrition disorders

Fluid and electrolytes imbalance including

• hypervolaemia

• peripheral oedema

• dehydration

• hyponatraemia

• hypernatraemia

• hyperkalaemia

• hypokalaemia

Metabolic acidosis

Not known

Nervous system disorders

Headache

Dizziness

Rebound intracranial pressure increase

CNS toxicity manifested by

• Convulsions

• Coma

• Confusion

• Lethargy

Not known

Eye disorders

Blurred vision

Not known

Cardiac disorders

Cardiac arrhythmia

Congestive heart failure

Not known

Respiratory, thoracic and mediastinal disorders

Pulmonary oedema

Rhinitis

Not known

Gastrointestinal disorders

Mouth dry

Thirst

Nausea

Vomiting

Not known

Skin and subcutaneous tissue disorders

Skin necrosis

Urticaria

Not known

Musculoskeletal and connective tissue disorders

Cramps

Not known

Renal and urinary disorders

Excessive diuresis

Nephrosis osmotic

Urinary retention

Acute renal failure

Azotemia

Anuria

Oliguria

Polyuria

Not known

General disorders and administration site conditions

Chills

Chest pain (angina-like chest pain)

Fever

Asthenia

Malaise

Infusion site reactions including

• infusion thrombophlebitis

• infusion site inflammation

• infusion site pain

• infusion site rash

• infusion site erythema, infusion site pruritus

• infusion site pruritus

Compartment syndrome (associated with extravasation and swelling at the injection site)

Not known

Not known

Other adverse reactions

Severe anaphylaxis with cardiac arrest, and fatal outcome.

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

Summary of the safety profile

Initiation dose assessment

The most commonly observed adverse reaction associated with the use of 20% Mannitol YD during the initiation dose assessment is cough (3.6% of patients), .

The most important adverse reaction associated with the use of 20% Mannitol YD during the initiation dose assessment is bronchospasm .

Therapeutic dose regimen

The most commonly observed adverse reaction associated with the use of 20% Mannitol YD is cough . This was observed in 10.2% of patients compared to 5.0% of patients in the control arm. Cough which led to cessation of treatment was also commonly experienced and was observed in 4.7% of patients in the 20% Mannitol YD treatment arm.

The most important adverse reaction associated with the use of 20% Mannitol YD is haemoptysis. The proportion of patients who experienced haemoptysis as an adverse reaction was 7.3% and 2.9% in the 20% Mannitol YD arms for studies 301 and 302, respectively vs. 3.4% and 0% in the control arms. Total haemoptysis incidence including during exacerbation was 15.8% in the mannitol arm and 14.6% in the control arm .

Tabulated list of adverse reactions

Frequencies provided in Table 1 and 2 are based on the observations on the day of screening and during two pivotal comparative clinical studies investigating the effect of 20% Mannitol YD (safety population, 361 patients on 20% Mannitol YD).

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

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Frequency of adverse reactions with 20% Mannitol YD during the treatment phase and on the day of screening

System organ class

Very common

Common

Uncommon

Infections and infestations

Bacterial disease carrier

Oral candidiasis

Staphylococcal infection

Metabolism and nutrition disorders

Decreased appetite

CF related diabetes

Dehydration1

Psychiatric disorders

Initial insomnia

Morbid thoughts

Nervous system disorders

Headache

Dizziness2

Ear and labyrinth disorders

Ear pain

Respiratory, thoracic and mediastinal disorders

Cough

Haemoptysis

Condition aggravated2

Pharyngolaryngeal pain

Cough1

Chest discomfort2

Wheezing

Productive cough

Throat irritation

Wheezing1

Bacteria sputum identified

Asthma

Rhinorrhoea

Bronchospasm2

Fungus sputum test positive

Dysphonia

Dyspnoea

Hyperventilation

Obstructive airways disorder

Respiratory tract congestion

Sputum discoloured

Bronchitis

Bronchopneumonia

Lung infection

Pharyngitis

Upper respiratory tract infection

Hypoxia1

Productive cough1

Forced expiratory volume decreased1

Chest pain1

Throat irritation1

Gastrointestinal disorders

Post-tussive vomiting

Vomiting

Nausea2

Vomiting1

Diarrhoea1

Eructation

Flatulence

Gastrooesophageal reflux disease

Glossodynia

Retching2

Stomatitis

Abdominal pain upper1

Apthous Stomatitis1

Odynophagia1

Post-tussive vomiting1

Skin and subcutaneous tissue disorders

Acne

Cold sweat

Pruritus

Rash

Rash pruritic

Musculoskeletal and connective tissue disorders

Musculoskeletal chest pain

Arthralgia

Back pain

Joint stiffness

Musculoskeletal pain

Renal and urinary disorders

Urinary incontinence

General disorders and administration site conditions

Influenza like illness

Fatigue2

Hernia pain

Malaise

Pyrexia

Investigations

Blood alkaline phosphatase increased1

1Adverse reaction occurred on the day of screening

2Adverse reaction occurred both during the treatment phase and on the day of screening

Description of selected adverse reactions

Twenty seven (7%) out of 389 patients enrolled in study 301 and 14 (4.1%) out of 342 enrolled in study 302 were not randomised due to a positive mannitol tolerance test (MTT). In study 301, overall the most frequently reported events during the MTT were cough in 18 (4.8%) subjects, wheezing/bronchospasm in eight (2.1%) subjects and chest discomfort in six (1.6%) subjects. In study 302 the most frequent clinical sign or symptom reported during the MTT was cough (7.9%).

Paediatric population (6 to 17 years of age)

Frequency, type and severity of adverse reactions in children are similar to those observed in adults.

Initiation dose (6 to 17 years of age)

The most commonly observed adverse reaction associated with the use of 20% Mannitol YD during the initiation dose assessment with the paediatric population is cough (4.8% of patients).

The most important adverse reaction associated with the use of 20% Mannitol YD during the initiation dose assessment with the paediatric population is bronchospasm.

Therapeutic dose regimen(6 to 17 years of age)

The most commonly observed adverse reaction associated with the use of 20% Mannitol YD is cough. This was observed in 7.8% of patients compared to 3.8% of patients in the control arm. The most important adverse reaction associated with the use of 20% Mannitol YD is haemoptysis.

Table 2: Frequency of adverse reactions with 20% Mannitol YD during the treatment phase and on the day of screening-paediatric population (6 to 17 years of age)

System organ class

Very common

Common

Uncommon

Psychiatric disorders

Initial insomnia

Nervous system disorders

Headache

Dizziness2

Ear and labyrinth disorders

Ear Pain

Respiratory, thoracic and mediastinal disorders

Cough2

Condition aggravated

Haemoptysis

Pharyngolaryngeal pain

Bacteria sputum identified

Chest discomfort

Wheezing

Asthma

Productive cough

Bronchitis

Bronchopneumonia

Dysphonia

Hyperventilation

Sputum Discoloured

Throat irritation Pharyngitis

Upper respiratory tract infection

Bronchospasm1

Dyspnoea

Chest discomfort1

Chest pain1

Gastrointestinal disorders

Vomiting

Post-tussive vomiting

Nausea2

Vomiting1

Odynophagia1

Post-tussive vomiting1

Retching1

Skin and subcutaneous tissue disorders

Pruritus

Pruritic rash

Musculoskeletal and connective tissue disorders

Musculoskeletal chest pain

Renal and urinary disorders

Urinary incontinence

General disorders and administration site conditions

Pyrexia

1Adverse reaction occurred on the day of screening

2Adverse reaction occurred both during the treatment phase and on the day of screening

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 in the UK, Website: www.mhra.gov.uk/yellowcard or in Ireland to HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: [email protected]

Overdose

The information provided in Overdose of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Signs and symptoms of overdose with 20% Mannitol YDol may include acute renal failure, electrolytes imbalance, hypervolaemia, CNS toxicity.

Prolonged administration or rapid infusion of large volumes of hyperosmotic solutions may results in circulatory overload and acidosis. Headache, nausea and shivering without temperature change may represent initial signs/symptoms. Confusion, lethargy, convulsions, stupor and coma may follow.

In case of suspected overdose, treatment with 20% Mannitol YDol should be stopped immediately.

Management is symptomatic and supportive, with monitoring of fluid and electrolyte balance. 20% Mannitol YDol is dialyzable. Haemodialysis may be helpful.

Susceptible persons may suffer bronchoconstriction in the event of an inhaled overdose. If excessive coughing and bronchoconstriction occurs, a beta2 agonist should be given, and oxygen if necessary.

Pharmacodynamic properties

The information provided in Pharmacodynamic properties of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Pharmacotherapeutic group: “Solutions producing osmotic diuresis”, ATC code: “B05BC01”

20% Mannitol YDol, a carbohydrate, is confined to the extracellular compartment. It has an osmotic effect which causes fluid to pass from the intracellular to the extracellular compartment.

20% Mannitol YDol is freely filterable at the kidney glomerulus and less than 10% is reabsorbed back from the kidney tubule. Confined to the kidney tubules, 20% Mannitol YDol exerts an osmotic effect which prevents fluid reabsorption from the glomerular filtrate and produces diuresis. It thereby promotes urine flow in oliguria/anuria or in situations where the patient is at risk of onset of acute renal failure. 20% Mannitol YDol also increases electrolyte excretion, especially sodium, potassium and chloride. Excretion of renally excreted toxic substances such as aspirin and barbiturates is also increased.

20% Mannitol YDol does not penetrate the blood-brain barrier under usual circumstances. Confined to the plasma, 20% Mannitol YDol exerts an osmotic pressure, causing fluid to leave the brain tissue, and brain volume and intracranial pressure to be reduced.

20% Mannitol YDol does not penetrate the eye. 20% Mannitol YDol promotes excretion of aqueous humour and thereby reduces intraocular pressure.

Pharmacotherapeutic group: Cough and cold preparations, Mucolytic. ATC code: R05CB16

Mechanism of action

20% Mannitol YD is an inhaled hyperosmotic medicinal product. While the exact mechanism of action is unknown, inhaled mannitol may change the viscoelastic properties of mucus, increase the hydration of the periciliary fluid layer and contribute to increased mucus clearance of the retained secretions through mucociliary activity. Productive cough can contribute to sputum clearance.

Pharmacodynamic effects

In the ITT population of an open label dose response study, DPM-CF-202, the mean (SD) percent change in FEV1 for the 400 mg dose was 8.75 (SD: 12.4) and -1.569 (SD: 9.0) for 40 mg dose (p < 0.0001).

Clinical efficacy and safety

Two Phase 3, 26-week double blind, randomised, parallel arm, controlled, intervention studies (DPM-CF-301 and DPM-CF-302) have been performed in which 324 (DPM-CF-301) and 318 (DPM-CF-302) patients aged 6 years and above were randomised in a 3:2 ratio to inhaled mannitol 400 mg twice daily or to control (inhaled mannitol 50 mg twice daily). Twenty seven (7%) out of 389 patients enrolled in study 301 and 14 (4.1%) out of 342 enrolled in study 302 were not randomised due to a positive mannitol tolerance test (MTT) defined as either 1) a fall in FEV1 >20% from baseline at midpoint (step 4) or 2) fall from baseline > 20 % at end of test that did not recover to < 20% within 15 minutes or 3) who had a fall in FEV1 > 50% from baseline at end of test (step 6) or 4) who had a fall in Sp02 to < 89% during the procedure. An additional 4% (n=27) of patients from the two studies had incomplete MTTs and were not randomised.

Mean (SD) baseline FEV1 percent predicted in study DPM-CF-301 (safety population, N= 295) was 62.4 (SD:16.45) and 61.4 (SD:16.13) in the mannitol and control groups, respectively. These figures for study DPM-CF-302 (N=305) are as follows: 65.24 (SD:13.90) and 64.35 (SD:15.29). In study DPM-CF-301 64.4 % of the patient population were adults while in study DPM-CF-302 this figure was 49.5%. Fifty five % of patients were receiving rhDNase in study DPM-CF-301 while in study DPM-CF-302 this number was 75%. The percentage of patients receiving inhaled antibiotics was 55% in study DPM-CF-301 and 56% in study DPM-CF-302. Concomitant administration with hypertonic saline was not permitted in these trials.

The primary pre-specified endpoint i.e. the change from baseline in FEV1 (ml) in the modified ITT (mITT) population (n=269 and 297 in studies DPM-CF-301 and DPM-CF-302, respectively) compared to control over the 26 weeks period is provided in Table 1 alongside FEV1 presented as absolute and relative change % predicted.

Table 1 – Change in FEV1 from baseline over 26 weeks in the mITT and adult populations

Effect size estimate

DPM-CF-301

DPM-CF-302

FEV1

(95% CI)

p value

FEV1

(95% CI)

p value

Overall Population

N=269

N=297

Absolute mL

94.5

(46.2, 142.7)

<0.001

54.1

(-1.97, 110.3)

0.059

Absolute % predicted

2.4

(0.9, 3.9)

0.001

1.9

(-0.02, 3.8)

0.052

Relative % predicted

3.5

(1.0, 6.1)

0.007

3.6

(0.3, 6.9)

0.033

Adult Population

N=171

N=144

Absolute mL

108.5

(47.6, 169.4)

<0.001

85.9

(4.6, 167.3)

0.038

Absolute % predicted

2.7

(0.9, 4.5)

0.004

2.3

(-0.4, 5.1)

0.095

Relative % predicted

4.3

(1.1, 7.5)

0.008

5.0

(0.2, 9.8)

0.040

In rhDNase users in study 301 the relative change in FEV1 % predicted from baseline across 26 weeks of treatment was 2.83 (95% CI -0.62, 6.27). For non-users the relative change was 4.30 (95% CI 0.53, 8.07). In study 302 the relative change (95% CI) for rhDNase users and non-users was 3.21 (-0.61, 7.03) and 4.73 (-1.93, 11.40), respectively.

The number of subjects with at least one protocol defined pulmonary exacerbation (PDPE, defined by the presence of at least 4 symptoms and signs plus the use of intravenous antibiotics) was 18.1% in the mannitol arm and 28% in the control arm in study 301 (ITT population). In study 302 15.2% subjects in the mannitol arm and 19% in the control had a PDPE.

The estimated effect of treatment (mean change and 95% CI from baseline over 26 weeks, mITT population) on FVC was 108.78 ml (95% CI: 49.21, 168.35) in study 301 and 71.4 ml (95% CI: 10.57, 132.13) in study 302.

Paediatric population

The safety and efficacy of 20% Mannitol YD in children and adolescents aged less than 18 years has not been established .

In studies DPM-CF-301 and 302 relative % predicted FEV1 compared to control in children (6-11 years) was improved by 0.44% (95% CI -5.90, 6.77, N=43) and 6.1% (95% CI -1.28, 13.54, N=59) over 26 weeks (p=0.892 and 0.104) respectively.

In adolescents (12-17 years) relative change in % predicted FEV1 compared to control improved by 3.31% (95% CI -2.29, 8.90, N=55) and 0.42% (95% CI -5.45, 6.29, N=94) over 26 weeks (p=0.245 and 0.888) respectively.

Pharmacokinetic properties

The information provided in Pharmacokinetic properties of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

When administered intravenously, 20% Mannitol YDol is eliminated largely unmetabolised through the glomeruli. It is freely filtered by the glomeruli, with less than 10% tubular reabsorption and is not secreted by tubular cells. The elimination half-life in adults is approximately 2 hours, longer where renal failure is present. 80% of an intravenous dose is excreted unchanged within 3 hours.

Absorption

In a study of 18 healthy male adult volunteers, the absolute bioavailability of mannitol powder for inhalation by comparison to mannitol administered intravenously was 0.59% ± 0.15.

The rate and extent of absorption of mannitol after inhaled administration was very similar to that observed after oral administration. The Tmax after inhaled administration was 1.5 ± 0.5 hours.

In a study of 9 cystic fibrosis patients (6 adults, 3 adolescents), using 400 mg inhaled mannitol as a single dose (Day 1) then twice a day for 7 days (Days 2 - 7), pharmacokinetic parameters were similar for adults and adolescents, except for a longer average apparent terminal half life for adolescents (Day 1 = 7.29 hours, Day 7 = 6.52 hours) compared with adults (Day 1 = 6.10 hours, Day 7 = 5.42 hours). Overall, the comparison of AUCs between Day 1 and Day 7 showed a time independence of pharmacokinetics, indicating linearity at the dose level administered in this study.

Biotransformation

A small percentage of systemically absorbed mannitol undergoes hepatic metabolism to glycogen and carbon dioxide. Studies in rats, mice and humans have demonstrated that mannitol has no toxic metabolites. The metabolic pathway of inhaled mannitol was not examined in pharmacokinetic studies.

Distribution

Lung deposition studies have demonstrated a 24.7% deposition of inhaled mannitol confirming its distribution to the target organ. Nonclinical toxicology studies indicate that mannitol inhaled into the lungs is absorbed into the bloodstream, with the maximum serum concentration being achieved occurring at 1 hour. There is no evidence that mannitol is accumulated in the body, therefore distribution of inhaled mannitol was not examined in PK studies.

Elimination

The cumulative amount of mannitol filtered into the urine over the 24 hour collection period was similar for inhaled (55%) and oral (54%) mannitol. When administered intravenously, mannitol is eliminated largely unchanged by glomerular filtration and 87% of the dose is excreted in the urine within 24 hours. The mean terminal half-life in adults was approximately 4 to 5 hours from serum and approximately 3.66 hours from urine.

Paediatric population

The safety and efficacy of 20% Mannitol YD in children and adolescents aged 6 to 18 years has not yet been established.

The limited data available in adolescents aged 12 to 17 years indicate the pharmacokinetic parameters of inhaled mannitol are similar to the adult population.

There are no data available for children under 12 years of age.

Pharmacotherapeutic group

The information provided in Pharmacotherapeutic group of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Pharmacotherapeutic group in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution
“Solutions producing osmotic diuresis”, ATC code: “B05BC01”
Cough and cold preparations, Mucolytic. ATC code: R05CB16

Preclinical safety data

The information provided in Preclinical safety data of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

The preclinical safety assessment of 20% Mannitol YDol 10% in animals is not relevant as 20% Mannitol YDol is a substance with well-established use in patients and is covered by appropriate pharmacopoeial references.

In male rats after 13 weeks of inhaled mannitol dosing, elevated circulating lymphocyte numbers and mandibular lymph node plasmacytosis was observed at doses greater than 9.3 fold the maximal dose. The elevated lymphocyte count was within historical control values, did not progress and was essentially resolved by the end of the in life phase of the study and following withdrawal of treatment. This effect was not noted in any other species and did not result in clinical signs.

In dogs an increased occurrence of coughing was observed both during and immediately post dose for low and high dose inhaled mannitol administration. No treatment-related adverse effect occurred greater than 13 fold the maximal therapeutic dose.

No mutagenic or genotoxic effect has been revealed when mannitol was assayed in a standard battery of genotoxicity tests.

Mannitol was shown not to be an irritant in an isolated bovine eye assay or when introduced into rabbit eyes.

No evidence of carcinogenicity was observed when dietary mannitol (≤5%) was administered to mice and rats for 2 years. Carcinogenicity studies have not been carried out with inhaled mannitol.

Reproduction and developmental toxicity studies have not been carried out with inhaled mannitol. However, studies conducted with mannitol administered via other routes indicated no effect on foetal survival in mice, rats and hamsters and on embryo and foetal development in rats and rabbits.

Animal reproduction studies have not been carried out with inhaled mannitol. However, studies conducted with orally administered mannitol indicated no teratogenic effects in mice or rats, at doses of up to 1.6 g/kg, or in hamsters at 1.2 g/kg.

Incompatibilities

The information provided in Incompatibilities of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Additives may be incompatible with 20% Mannitol YDol 10% Solution for infusion.

Incompatibility of the medicinal product to be added with the solution in the Viaflo container must be assessed before addition.

Before adding a medicinal product, verify it is soluble and stable in water at the pH of the 20% Mannitol YDol solution (4.5 to 7.0)

20% Mannitol YDol 10% Solution for Infusion should not be administered simultaneously with, before, or after administration of blood through the same infusion equipment, due to risk of pseudoagglutination.

The Instructions for Use of the medicinal product to be added must be consulted.

As an example cefepime, imipenem, cilastin and filgrastim are incompatible with 20% Mannitol YDol solutions, but this list is not exhaustive. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

The addition of Potassium or Sodium Chloride to 20% Mannitol YDol 10% may cause precipitation of 20% Mannitol YDol.

Not applicable.

Special precautions for disposal and other handling

The information provided in Special precautions for disposal and other handling of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). 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 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Use administration sets with a final in-line filter because of the potential for 20% Mannitol YDol crystals to form.

Additives may be introduced before infusion or during infusion through the re-sealable medication port.

Thorough and careful aseptic mixing of any additive is mandatory. Solutions containing additives should be used immediately and not stored.

Before adding a medicinal product, verify it is soluble in water at the pH of 20% Mannitol YDol solution.

Discard after single use.

Discard any unused portion.

Do not reconnect partially used bags.

Opening

• Remove the Viaflo container from the overpouch just before use.

• Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution, as sterility may be impaired.

• Check solution for limpidity and absence of foreign matter. If solution is not clear or contains foreign matter, discard the solution.

Preparation for administration

Use sterile material for preparation and administration.

• Suspend container from eyelet support. Remove plastic protector from outlet port at bottom of container:

• grip the small wing on the neck of the port with one hand

• grip the large wing on the cap with the other hand and twist,

• the cap will pop off.

• Use an aseptic method to set up the infusion. Attach administration set. Refer to complete directions accompanying set.

Techniques for injection of additive medicinal products

Warning: Additives may be incompatible. Check additive compatibility with both the solution and container prior to use.

To add medicinal products before administration:

• Disinfect medication site. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.

Mix solution and medication thoroughly. For high-density medication such as potassium chloride, tap the ports gently while ports are upright and mix.

Caution: Do not store bags containing added medications.

To add medicinal products during administration:

1. Close clamp on the set

2. Disinfect medication site.

3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.

4. Remove container from intravenous pole and/or turn to an upright position.

5. Evacuate both ports by tapping gently while the container is in an upright position.

6. Mix solution and medication thoroughly.

7. Return container to in use position, re-open the clamp and continue administration.

No special requirements.

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

Name of the medicinal product
20% Mannitol YD
Qualitative and quantitative composition
Mannitol
Therapeutic indications
The information provided in Therapeutic indications of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

20% Mannitol YDol 10% Solution for infusion is indicated for use as an osmotic diuretic in the following situations:

• Promotion of diuresis in the prevention and/or treatment of the oliguric phase of acute renal failure before irreversible renal failure becomes established.

• Reduction of intracranial pressure and cerebral oedema, when blood-barrier is intact.

• Reduction of elevated intraocular pressure when it cannot be lowered by other means.

• Promotion of elimination of renally excreted toxic substances in poisoning.

20% Mannitol YD is indicated for the treatment of cystic fibrosis (CF) in adults aged 18 years and above as an add-on therapy to best standard of care.

Dosage (Posology) and method of administration
The information provided in Dosage (Posology) and method of administration of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Posology:

The choice of the specific 20% Mannitol YDol concentration, dosage and rate of administration depends on the age, weight, clinical and biological condition of the patient and concomitant therapy.

Adults and adolescents:

Acute renal failure

The general dose range is 50 to 200 g 20% Mannitol YDol (500 ml to 2000 ml/day) in a 24 hour period, with a dosage limit of 50 g (500ml 20% Mannitol YDol) on any one occasion. In most instances, adequate response will be achieved at a dosage of 50 to 100 g 20% Mannitol YDol/day (500 ml to 1000 ml /day).

The rate of administration is usually adjusted to maintain a urine flow of at least 30-50 ml/hour.

Only in emergency situations, the maximum infusion rate can be as high as 200 mg/kg infused over 5 minutes (see also test dose). After 5 minutes, the infusion rate should be readjusted to maintain a urine flow of at least 30-50 ml/hour, with a maximal dose of 200 g/24h.

Use in patients with oliguria or renal impairment

Patients with marked oliguria or suspected inadequate renal function should first receive a test dose of approximately 200 mg 20% Mannitol YDol/kg bw (body weight) (2ml/kg bw) over a period of 3 to 5 minutes. For example: in an adult patient with a body weight of 70 kg: approximately 75 ml of a 20% solution or 100 ml of a 15% solution. The response to the test dose is considered adequate if at least 30-50 ml/hour of urine is excreted for 2-3 hours. If an adequate response is not attained, a further test dose may be given. If an adequate response to the second test dose is not attained, treatment with 20% Mannitol YDol should be discontinued and the patient reassessed as established renal failure may be present.

Reduction of intracranial pressure, cerebral volume and intraocular pressure

The usual dose is 1.5 to 2g/kg bw (15 to 20 ml/kg bw), infused over 30 to 60 minutes. When used preoperatively, the dose should be administered 1 to 1.5 hours before surgery to obtain the maximum effect.

Promotion of elimination of renally excreted toxic substances in poisoning

In forced diuresis, the dose of 20% Mannitol YDol should be adjusted to maintain urinary output of at least 100ml/hour and positive fluid balance of 1-2 litres. An initial loading dose of approximately 25 g (250 ml) may be given.

Paediatric population:

In renal insufficiency, the test dose should be 200 mg 20% Mannitol YDol/kg bw (2 ml/kg bw) over 3-5 minutes. The treatment dose ranges from 0.5 to 1.5 g/kg bw (5 ml/kg bw to 15 ml/kg bw). This dose may be repeated once or twice, after an interval of 4 to 8 hours, if necessary.

For cerebral and ocular oedema, this dose may be given over 30 to 60 minutes as for adults.

Elderly population:

As for adults, the dosage depends on the weight, clinical and biological condition of the patient and concomitant therapy. The general dose range is the same as for adults, 50 to 200 g in a 24 hour period (500 ml to 2000ml/day), with a dosage limit of 50 g 20% Mannitol YDol (500 ml) on any one occasion. Since incipient renal insufficiency may be present, caution should be used when reviewing patient's status prior to dose selection.

Method of administration:

The solution is for intravenous administration through sterile and non-pyrogenic equipment.

Hyperosmolar 20% Mannitol YDol solutions may cause vein damage. Check product's osmolarity before administration.

Use administration set which includes a final in-line filter because of the potential for 20% Mannitol YDol crystals to form and using an aseptic technique. The equipment should be primed with the solution in order to prevent air entering the system.

Do not remove unit from overwrap until ready for use. The inner bag maintains the sterility of the product.

Use only if the solution is clear, without visible particles or discoloration and the seal is intact. Confirm the integrity of the bag. Use only if the container is undamaged. Administer immediately following insertion of the infusion set.

This hypertonic solution should be administered via a large peripheral or preferably a central vein. Rapid infusion in peripheral veins may be harmful.

20% Mannitol YDol solutions may crystallize when exposed to low temperature.6.

<6.

The patient's initiation dose of 20% Mannitol YD must be used under the supervision and monitoring of an experienced physician or another health care professional appropriately trained and equipped to perform spirometry, monitor oxygen saturation (SpO2), and manage acute bronchospasm including appropriate use of resuscitation equipment.

Posology

Initiation dose assessment

Before commencing treatment with 20% Mannitol YD, all patients should be assessed for bronchial hyperresponsiveness to inhaled mannitol during administration of their initiation dose .

The patient should be pre-medicated with a bronchodilator 5-15 minutes prior to the initiation dose but after the baseline FEV1 and SpO2 (Oxygen saturation in the blood) measurement. All FEV1 measurements and SpO2 monitoring should be performed 60 seconds after dose inhalation.

Training the patient to practice correct inhaler technique during the initiation dose assessment is important.

The initiation dose assessment must be performed according to the following steps:

Step 1: Patients baseline FEV1 and SpO2 is measured prior to the initiation dose

Step 2: Patient inhales 40 mg (1x40 mg capsules) and SpO2 is monitored

Step 3: Patient inhales 80 mg (2x40 mg capsules) and SpO2 is monitored

Step 4: Patient inhales 120 mg (3x40 mg capsules), FEV1 is measured and SpO2 is monitored

Step 5: Patient inhales 160 mg (4x40 mg capsules), FEV1 is measured and SpO2 is monitored

Step 6: Patients FEV1 is measured 15 minutes post initiation dose.

Patients with asthma may experience reversible temporary mild bronchospasm after passing the initiation dose assessment and therefore all patients should be monitored until their FEV1 has returned to baseline levels.

Therapeutic dose regimen

The therapeutic dose regimen should not be prescribed until the initiation dose assessment has been performed. The patient must complete and pass the initiation dose assessment before starting treatment with 20% Mannitol YD.

A bronchodilator must be administered 5-15 minutes before each dose of 20% Mannitol YD.

The recommended dose of 20% Mannitol YD is 400 mg twice a day. This requires the inhalation of the contents of ten capsules via the inhaler device twice a day.

The doses should be taken morning and night with the evening dose taken 2-3 hours before bedtime.

For patients receiving several respiratory therapies, the recommended order is:

1. Bronchodilator

2. 20% Mannitol YD

3. Physiotherapy/exercise

4. Dornase alfa (if applicable)

5. Inhaled antibiotics (if applicable)

Special populations

Elderly patients (≥65 years)

There are insufficient data in this population to support a recommendation for or against dose adjustment.

Renal or hepatic impairment

20% Mannitol YD has not specifically been studied in patients with impaired renal and hepatic function. Available data from studies DPM-CF-301 and 302 suggest that no dose adjustments are required for these patient populations.

Paediatric population

The safety and efficacy of 20% Mannitol YD in children and adolescents aged 6 to 18 years has not yet been established.1 and 5.2 but no recommendation on a posology can be made.

The safety and efficacy of 20% Mannitol YD in children aged less than 6 years has not been established. No data are available.

Method of administration

20% Mannitol YD is for inhalation use, using the inhaler provided in the pack. It must not be administered by any other route or using any other inhaler. The capsules must not be swallowed.

Each of the capsules is loaded into the device separately. The contents of the capsules are inhaled via the inhaler device with one or two breaths. After inhalation, each empty capsule is discarded before inserting the next capsule into the inhaler device with as little delay as possible between capsules.

The inhaler device is to be replaced after one week of use. If the inhaler does require cleaning, it must be ensured that the device is empty, then it should be washed in warm water and before re use, the inhaler should be allowed to thoroughly air dry.

Detailed instructions on how to use the inhaler can be found in the patient information leaflet. Patients should be advised to carefully read them.

Contraindications
The information provided in Contraindications of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

20% Mannitol YDol 10% Solution for Infusion is contra-indicated in patients presenting with:

• Pre-existing plasma hyperosmolarity.

• Severe dehydration.

• Well established anuria.

• Severe heart failure.

• Severe pulmonary congestion or pulmonary oedema.

• Active intracranial bleeding, except during craniotomy.

• Disturbance of the blood-brain barrier.

• Hypersensitivity to 20% Mannitol YDol.

Hypersensitivity to the active substance.

Bronchial hyperresponsiveness to inhaled mannitol .

Special warnings and precautions for use
The information provided in Special warnings and precautions for use of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Hypersensitivity

Anaphylactic/anaphylactoid reactions, including anaphylaxis, as well as other hypersensitivity/infusion reactions have been reported with 20% Mannitol YDol. Fatal outcome has been reported .

The infusion must be stopped immediately if any signs or symptoms of a suspected hypersensitivity reaction develop. Appropriate therapeutic countermeasures must be instituted as clinically indicated.

20% Mannitol YDol occurs in nature (e.g., in some fruits and vegetables) and is widely used as excipient in drugs and cosmetics. Therefore, patients may be sensitized without having received intravenous treatment with 20% Mannitol YDol.

CNS toxicity

CNS toxicity manifested by, e.g. confusion, lethargy, and coma has been reported in patients treated with 20% Mannitol YDol, in particular in the presence of impaired renal function. Fatal outcomes have been reported.

CNS toxicity may result from:

- High serum 20% Mannitol YDol concentrations.

- Serum hyperosmolarity resulting in intracellular dehydration within the CNS.

- Hyponatraemia or other disturbances of electrolyte and acid/base balance secondary to 20% Mannitol YDol administration.

At high concentrations, 20% Mannitol YDol may cross the blood brain barrier and interfere with the ability of the brain to maintain the pH of the cerebrospinal fluid especially in the presence of acidosis.

In patients with pre-existing compromised blood brain barrier, the risk of increasing cerebral oedema (general or focal) associated with repeated or continued use of 20% Mannitol YDol must be individually weighed against the expected benefits.

A rebound increase of intracranial pressure may occur several hours after the use of 20% Mannitol YDol. Patients with compromised blood brain barrier are at increased risk.

Risk of renal complications

Reversible, acute oligoanuric renal failure has occurred in patients with normal pre-treatment renal function, who received large intravenous doses of 20% Mannitol YDol.

Progressive renal damage or dysfunction, after institution of 20% Mannitol YDol therapy, including increasing oliguria and azotemia, has also been described.

Although the osmotic nephrosis associated with 20% Mannitol YDol administration is, in principle, reversible, osmotic nephrosis in general is known to potentially proceed to chronic or even end-stage renal failure.

Patients with pre-existing renal disease, or those receiving potentially nephrotoxic drugs, are at increased risk of renal failure following administration of 20% Mannitol YDol. Serum osmolar gap and renal function should be closely monitored and appropriate action initiated, should signs of worsening renal function appear.

20% Mannitol YDol should be administered with caution to patients with severely impaired renal function. A test dose should be employed and therapy with 20% Mannitol YDol continued only if an adequate urine flow is achieved .

If the urine output declines during 20% Mannitol YDol infusion, the patient's clinical status should be closely reviewed for developing renal impairment, and the 20% Mannitol YDol infusion suspended, if necessary.

Risk of hypervolaemia

The cardiovascular status of the patient should be carefully evaluated before rapidly administering 20% Mannitol YDol 10% Solution for Infusion.

High doses and/or high rates of infusion as well as accumulation of 20% Mannitol YDol (due to insufficient renal excretion of 20% Mannitol YDol), may result in hypervolaemia, overexpansion of the extracellular fluid, which may lead to or exacerbate existing congestive heart failure.

Accumulation of 20% Mannitol YDol may result if urine output continues to decline during administration and this may intensify existing or latent congestive heart failure.

If the patient's cardiac or pulmonary function deteriorates, treatment should be discontinued.

Risk of water and electrolyte imbalances, hyperosmolarity

20% Mannitol YDol-induced osmotic diuresis may cause or worsen dehydration/hypovolaemia and hemoconcentration. Administration of 20% Mannitol YDol may also cause hyperosmolarity.

In addition, depending on dosage and duration of administration, electrolyte and acid/base imbalances may result from transcellular shifts of water and electrolytes, osmotic diuresis and/or other mechanisms. Such imbalances may be severe and potentially fatal.

Imbalances that may result from 20% Mannitol YDol treatment include:

• Hypernatraemia, dehydration and hemoconcentration (resulting from excessive water loss).

• Hyponatraemia (Shift of sodium-free intracellular fluid into the extra cellular compartment following 20% Mannitol YDol infusion may lower serum sodium concentration and aggravate pre-existing hyponatraemia. Sodium may be lost in the urine).

Hyponatraemia can lead to headache, nausea, seizures, lethargy, coma, cerebral oedema, and death. Acute symptomatic hyponatraemic encephalopathy is considered a medical emergency.

The risk for developing hyponatraemia is increased, for example:

• In children.

• In elderly patients.

• In women.

• Postoperatively.

• In persons with psychogenic polydipsia.

The risk for developing encephalopathy as a complication of hyponatraemia is increased, for example:

• In paediatric patients (≤16 years of age).

• In women (in particular, premenopausal women).

• In patients with hypoxaemia.

• In patients with underlying central nervous system disease.

Hypokalaemia, hyperkalaemia, other electrolytes imbalances, metabolic acidosis and metabolic alkalosis.

20% Mannitol YDol may obscure and intensify inadequate hydration and hypovolaemia.

Infusion reactions

Infusion site reactions have occurred with the use of 20% Mannitol YDol.

Adding other medications or using an incorrect administration technique may cause febrile reactions due to possible introduction of pyrogens.6.

Volume and electrolyte replacement before use

In patients with shock and renal dysfunction, 20% Mannitol YDol should not be administered until volume (fluid, blood) and electrolytes have been replaced.

Monitoring

The acid base balance, renal function and serum osmolarity must be monitored carefully when 20% Mannitol YDol is used.

Patients receiving 20% Mannitol YDol should be monitored for any deterioration in renal, cardiac or pulmonary function and treatment discontinued in the case of adverse events.

Urinary output, fluid balance, central venous pressure and electrolyte balance (in particular serum sodium and potassium levels) should be carefully monitored.

Incompatibility with blood

20% Mannitol YDol should not be given concomitantly with blood because it may cause agglutination and crenation of blood cells.

Crystallization

When exposed to low temperatures, solutions of 20% Mannitol YDol may crystallize.

Laboratory test interferences

20% Mannitol YDol can cause false low results in some tests systems for inorganic phosphorus blood concentrations.

20% Mannitol YDol produces false positive results in tests for blood ethylene glycol concentrations in which 20% Mannitol YDol is initially oxidized to an aldehyde.

Paediatric use

Safety and effectiveness in the paediatric population have not been established in clinical studies.

Geriatric use

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.

Risk of air embolism

Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before the administration of the fluid from the secondary container is completed.

Pressurizing intravenous solutions, contained in flexible plastic containers, in order to increase flow rates can result in air embolism if the residual air in the container is not fully evacuated prior to administration.

Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Vented intravenous administration sets with the vent in the open position should not be used with flexible plastic containers.

Hyperresponsiveness to mannitol

Patients must be monitored for bronchial hyperresponsiveness to inhaled mannitol during their initiation dose assessment before commencing the therapeutic dose regimen of 20% Mannitol YD.If the patient is unable to perform spirometry or complete the initiation dose assessment, they must not be prescribed 20% Mannitol YD. Hyperresponsive patients should not be prescribed the therapeutic dose regimen of 20% Mannitol YD .The usual precautions regarding bronchial hyperresponsiveness monitoring apply .

A patient is defined as hyperresponsive to inhaled mannitol and must not be prescribed the therapeutic dose regimen if they experience any of the following during the initiation dose assessment:

- ≥10% fall from baseline in SpO2 at any point of the assessment;

- FEV1 fall from baseline is ≥20% at 240 mg cumulative dose;

- FEV1 has fallen 20-<50% (from baseline) at the end of the assessment and does not return to <20% within 15 minutes;

- FEV1 has fallen ≥50% (from baseline) at the end of the assessment.

If a therapy induced hyperresponsive reaction is suspected, 20% Mannitol YD should be discontinued.

Bronchospasm

Bronchospasm can occur with inhalation of medicinal product and has been reported with 20% Mannitol YD in clinical studies, even in patients who were not hyperresponsive to the initiation dose of inhaled mannitol . Bronchospasm should be treated with a bronchodilator or as medically appropriate.

If there is evidence of therapy induced bronchospasm, the physician should carefully evaluate whether the benefits of continued use of 20% Mannitol YD outweigh the risks to the patient.

All patients should be formally reviewed after approximately six weeks of 20% Mannitol YD treatment to assess for signs and symptoms suggestive of active substance induced bronchospasm.

Asthma

The safety/efficacy of mannitol in patients with asthma has not been properly studied. Patients with asthma must be carefully monitored for worsening signs and symptoms of asthma after the initiation dose of 20% Mannitol YD.

Patients must be advised to report worsening signs and symptoms of asthma during therapeutic use to their physician. If there is evidence of therapy induced bronchospasm, the physician should carefully evaluate whether the benefits of continued use of 20% Mannitol YD outweigh the risks to the patient. Bronchospasm should be treated with a bronchodilator or as medically appropriate.

Haemoptysis

Haemoptysis has been commonly reported with 20% Mannitol YD in clinical studies. 20% Mannitol YD has not been studied in patients with a history of significant episodes of haemoptysis (>60 ml) in the previous three months. As a consequence, these patients should be carefully monitored, and 20% Mannitol YD should be withheld in the event of massive haemoptysis. A massive/serious haemoptysis is considered to be:

• acute bleeding ≥240 ml in a 24-hour period

• recurrent bleeding ≥100 ml/day over several days

The reinstitution or withholding of 20% Mannitol YD following smaller episodes of haemoptysis should be based on clinical judgement.

Cough

Cough was very commonly reported with use of 20% Mannitol YD in clinical studies . Patients should be trained to practice correct inhaler technique during treatment and advised to report persistent cough with the use of 20% Mannitol YD to their physician.

Impaired lung function

Safety and efficacy have not been demonstrated in patients with a FEV1 of less than 30% of predicted . The use of 20% Mannitol YD is not recommended in these patients.

Non-CF Bronchiectasis

Efficacy and safety have not been established in non-CF bronchiectasis patients. Therefore, treatment with 20% Mannitol YD is not recommended.

Effects on ability to drive and use machines
The information provided in Effects on ability to drive and use machines of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). 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 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Not relevant.

20% Mannitol YD has no or negligible influence on the ability to drive and use machines.

Undesirable effects
The information provided in Undesirable effects of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

The following adverse reactions have been reported in post-marketing experience. The frequency of the adverse drug reactions listed in this section cannot be estimated from the available data.

MedDRA System Organ Class

Adverse reaction (MedDRA Preferred Term)

Frequency

Immune system disorders

Allergic reaction

Anaphylactic reaction including anaphylactic shock that can be manifested with skin, gastrointestinal, and severe circulatory (hypotension) and respiratory manifestations (e.g. dyspnea).

Other hypersensitivity/infusion reactions, include

• hypertension

• pyrexia

• chills

• sweating

• cough

• musculoskeletal stiffness and myalgia

• urticaria/rash

• pruritus

• generalized pain

• discomfort

• nausea

• vomiting

• headache

Not known

Metabolism and nutrition disorders

Fluid and electrolytes imbalance including

• hypervolaemia

• peripheral oedema

• dehydration

• hyponatraemia

• hypernatraemia

• hyperkalaemia

• hypokalaemia

Metabolic acidosis

Not known

Nervous system disorders

Headache

Dizziness

Rebound intracranial pressure increase

CNS toxicity manifested by

• Convulsions

• Coma

• Confusion

• Lethargy

Not known

Eye disorders

Blurred vision

Not known

Cardiac disorders

Cardiac arrhythmia

Congestive heart failure

Not known

Respiratory, thoracic and mediastinal disorders

Pulmonary oedema

Rhinitis

Not known

Gastrointestinal disorders

Mouth dry

Thirst

Nausea

Vomiting

Not known

Skin and subcutaneous tissue disorders

Skin necrosis

Urticaria

Not known

Musculoskeletal and connective tissue disorders

Cramps

Not known

Renal and urinary disorders

Excessive diuresis

Nephrosis osmotic

Urinary retention

Acute renal failure

Azotemia

Anuria

Oliguria

Polyuria

Not known

General disorders and administration site conditions

Chills

Chest pain (angina-like chest pain)

Fever

Asthenia

Malaise

Infusion site reactions including

• infusion thrombophlebitis

• infusion site inflammation

• infusion site pain

• infusion site rash

• infusion site erythema, infusion site pruritus

• infusion site pruritus

Compartment syndrome (associated with extravasation and swelling at the injection site)

Not known

Not known

Other adverse reactions

Severe anaphylaxis with cardiac arrest, and fatal outcome.

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

Summary of the safety profile

Initiation dose assessment

The most commonly observed adverse reaction associated with the use of 20% Mannitol YD during the initiation dose assessment is cough (3.6% of patients), .

The most important adverse reaction associated with the use of 20% Mannitol YD during the initiation dose assessment is bronchospasm .

Therapeutic dose regimen

The most commonly observed adverse reaction associated with the use of 20% Mannitol YD is cough . This was observed in 10.2% of patients compared to 5.0% of patients in the control arm. Cough which led to cessation of treatment was also commonly experienced and was observed in 4.7% of patients in the 20% Mannitol YD treatment arm.

The most important adverse reaction associated with the use of 20% Mannitol YD is haemoptysis. The proportion of patients who experienced haemoptysis as an adverse reaction was 7.3% and 2.9% in the 20% Mannitol YD arms for studies 301 and 302, respectively vs. 3.4% and 0% in the control arms. Total haemoptysis incidence including during exacerbation was 15.8% in the mannitol arm and 14.6% in the control arm .

Tabulated list of adverse reactions

Frequencies provided in Table 1 and 2 are based on the observations on the day of screening and during two pivotal comparative clinical studies investigating the effect of 20% Mannitol YD (safety population, 361 patients on 20% Mannitol YD).

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

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Frequency of adverse reactions with 20% Mannitol YD during the treatment phase and on the day of screening

System organ class

Very common

Common

Uncommon

Infections and infestations

Bacterial disease carrier

Oral candidiasis

Staphylococcal infection

Metabolism and nutrition disorders

Decreased appetite

CF related diabetes

Dehydration1

Psychiatric disorders

Initial insomnia

Morbid thoughts

Nervous system disorders

Headache

Dizziness2

Ear and labyrinth disorders

Ear pain

Respiratory, thoracic and mediastinal disorders

Cough

Haemoptysis

Condition aggravated2

Pharyngolaryngeal pain

Cough1

Chest discomfort2

Wheezing

Productive cough

Throat irritation

Wheezing1

Bacteria sputum identified

Asthma

Rhinorrhoea

Bronchospasm2

Fungus sputum test positive

Dysphonia

Dyspnoea

Hyperventilation

Obstructive airways disorder

Respiratory tract congestion

Sputum discoloured

Bronchitis

Bronchopneumonia

Lung infection

Pharyngitis

Upper respiratory tract infection

Hypoxia1

Productive cough1

Forced expiratory volume decreased1

Chest pain1

Throat irritation1

Gastrointestinal disorders

Post-tussive vomiting

Vomiting

Nausea2

Vomiting1

Diarrhoea1

Eructation

Flatulence

Gastrooesophageal reflux disease

Glossodynia

Retching2

Stomatitis

Abdominal pain upper1

Apthous Stomatitis1

Odynophagia1

Post-tussive vomiting1

Skin and subcutaneous tissue disorders

Acne

Cold sweat

Pruritus

Rash

Rash pruritic

Musculoskeletal and connective tissue disorders

Musculoskeletal chest pain

Arthralgia

Back pain

Joint stiffness

Musculoskeletal pain

Renal and urinary disorders

Urinary incontinence

General disorders and administration site conditions

Influenza like illness

Fatigue2

Hernia pain

Malaise

Pyrexia

Investigations

Blood alkaline phosphatase increased1

1Adverse reaction occurred on the day of screening

2Adverse reaction occurred both during the treatment phase and on the day of screening

Description of selected adverse reactions

Twenty seven (7%) out of 389 patients enrolled in study 301 and 14 (4.1%) out of 342 enrolled in study 302 were not randomised due to a positive mannitol tolerance test (MTT). In study 301, overall the most frequently reported events during the MTT were cough in 18 (4.8%) subjects, wheezing/bronchospasm in eight (2.1%) subjects and chest discomfort in six (1.6%) subjects. In study 302 the most frequent clinical sign or symptom reported during the MTT was cough (7.9%).

Paediatric population (6 to 17 years of age)

Frequency, type and severity of adverse reactions in children are similar to those observed in adults.

Initiation dose (6 to 17 years of age)

The most commonly observed adverse reaction associated with the use of 20% Mannitol YD during the initiation dose assessment with the paediatric population is cough (4.8% of patients).

The most important adverse reaction associated with the use of 20% Mannitol YD during the initiation dose assessment with the paediatric population is bronchospasm.

Therapeutic dose regimen(6 to 17 years of age)

The most commonly observed adverse reaction associated with the use of 20% Mannitol YD is cough. This was observed in 7.8% of patients compared to 3.8% of patients in the control arm. The most important adverse reaction associated with the use of 20% Mannitol YD is haemoptysis.

Table 2: Frequency of adverse reactions with 20% Mannitol YD during the treatment phase and on the day of screening-paediatric population (6 to 17 years of age)

System organ class

Very common

Common

Uncommon

Psychiatric disorders

Initial insomnia

Nervous system disorders

Headache

Dizziness2

Ear and labyrinth disorders

Ear Pain

Respiratory, thoracic and mediastinal disorders

Cough2

Condition aggravated

Haemoptysis

Pharyngolaryngeal pain

Bacteria sputum identified

Chest discomfort

Wheezing

Asthma

Productive cough

Bronchitis

Bronchopneumonia

Dysphonia

Hyperventilation

Sputum Discoloured

Throat irritation Pharyngitis

Upper respiratory tract infection

Bronchospasm1

Dyspnoea

Chest discomfort1

Chest pain1

Gastrointestinal disorders

Vomiting

Post-tussive vomiting

Nausea2

Vomiting1

Odynophagia1

Post-tussive vomiting1

Retching1

Skin and subcutaneous tissue disorders

Pruritus

Pruritic rash

Musculoskeletal and connective tissue disorders

Musculoskeletal chest pain

Renal and urinary disorders

Urinary incontinence

General disorders and administration site conditions

Pyrexia

1Adverse reaction occurred on the day of screening

2Adverse reaction occurred both during the treatment phase and on the day of screening

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 in the UK, Website: www.mhra.gov.uk/yellowcard or in Ireland to HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: [email protected]

Overdose
The information provided in Overdose of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Signs and symptoms of overdose with 20% Mannitol YDol may include acute renal failure, electrolytes imbalance, hypervolaemia, CNS toxicity.

Prolonged administration or rapid infusion of large volumes of hyperosmotic solutions may results in circulatory overload and acidosis. Headache, nausea and shivering without temperature change may represent initial signs/symptoms. Confusion, lethargy, convulsions, stupor and coma may follow.

In case of suspected overdose, treatment with 20% Mannitol YDol should be stopped immediately.

Management is symptomatic and supportive, with monitoring of fluid and electrolyte balance. 20% Mannitol YDol is dialyzable. Haemodialysis may be helpful.

Susceptible persons may suffer bronchoconstriction in the event of an inhaled overdose. If excessive coughing and bronchoconstriction occurs, a beta2 agonist should be given, and oxygen if necessary.

Pharmacodynamic properties
The information provided in Pharmacodynamic properties of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Pharmacodynamic properties in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Pharmacotherapeutic group: “Solutions producing osmotic diuresis”, ATC code: “B05BC01”

20% Mannitol YDol, a carbohydrate, is confined to the extracellular compartment. It has an osmotic effect which causes fluid to pass from the intracellular to the extracellular compartment.

20% Mannitol YDol is freely filterable at the kidney glomerulus and less than 10% is reabsorbed back from the kidney tubule. Confined to the kidney tubules, 20% Mannitol YDol exerts an osmotic effect which prevents fluid reabsorption from the glomerular filtrate and produces diuresis. It thereby promotes urine flow in oliguria/anuria or in situations where the patient is at risk of onset of acute renal failure. 20% Mannitol YDol also increases electrolyte excretion, especially sodium, potassium and chloride. Excretion of renally excreted toxic substances such as aspirin and barbiturates is also increased.

20% Mannitol YDol does not penetrate the blood-brain barrier under usual circumstances. Confined to the plasma, 20% Mannitol YDol exerts an osmotic pressure, causing fluid to leave the brain tissue, and brain volume and intracranial pressure to be reduced.

20% Mannitol YDol does not penetrate the eye. 20% Mannitol YDol promotes excretion of aqueous humour and thereby reduces intraocular pressure.

Pharmacotherapeutic group: Cough and cold preparations, Mucolytic. ATC code: R05CB16

Mechanism of action

20% Mannitol YD is an inhaled hyperosmotic medicinal product. While the exact mechanism of action is unknown, inhaled mannitol may change the viscoelastic properties of mucus, increase the hydration of the periciliary fluid layer and contribute to increased mucus clearance of the retained secretions through mucociliary activity. Productive cough can contribute to sputum clearance.

Pharmacodynamic effects

In the ITT population of an open label dose response study, DPM-CF-202, the mean (SD) percent change in FEV1 for the 400 mg dose was 8.75 (SD: 12.4) and -1.569 (SD: 9.0) for 40 mg dose (p < 0.0001).

Clinical efficacy and safety

Two Phase 3, 26-week double blind, randomised, parallel arm, controlled, intervention studies (DPM-CF-301 and DPM-CF-302) have been performed in which 324 (DPM-CF-301) and 318 (DPM-CF-302) patients aged 6 years and above were randomised in a 3:2 ratio to inhaled mannitol 400 mg twice daily or to control (inhaled mannitol 50 mg twice daily). Twenty seven (7%) out of 389 patients enrolled in study 301 and 14 (4.1%) out of 342 enrolled in study 302 were not randomised due to a positive mannitol tolerance test (MTT) defined as either 1) a fall in FEV1 >20% from baseline at midpoint (step 4) or 2) fall from baseline > 20 % at end of test that did not recover to < 20% within 15 minutes or 3) who had a fall in FEV1 > 50% from baseline at end of test (step 6) or 4) who had a fall in Sp02 to < 89% during the procedure. An additional 4% (n=27) of patients from the two studies had incomplete MTTs and were not randomised.

Mean (SD) baseline FEV1 percent predicted in study DPM-CF-301 (safety population, N= 295) was 62.4 (SD:16.45) and 61.4 (SD:16.13) in the mannitol and control groups, respectively. These figures for study DPM-CF-302 (N=305) are as follows: 65.24 (SD:13.90) and 64.35 (SD:15.29). In study DPM-CF-301 64.4 % of the patient population were adults while in study DPM-CF-302 this figure was 49.5%. Fifty five % of patients were receiving rhDNase in study DPM-CF-301 while in study DPM-CF-302 this number was 75%. The percentage of patients receiving inhaled antibiotics was 55% in study DPM-CF-301 and 56% in study DPM-CF-302. Concomitant administration with hypertonic saline was not permitted in these trials.

The primary pre-specified endpoint i.e. the change from baseline in FEV1 (ml) in the modified ITT (mITT) population (n=269 and 297 in studies DPM-CF-301 and DPM-CF-302, respectively) compared to control over the 26 weeks period is provided in Table 1 alongside FEV1 presented as absolute and relative change % predicted.

Table 1 – Change in FEV1 from baseline over 26 weeks in the mITT and adult populations

Effect size estimate

DPM-CF-301

DPM-CF-302

FEV1

(95% CI)

p value

FEV1

(95% CI)

p value

Overall Population

N=269

N=297

Absolute mL

94.5

(46.2, 142.7)

<0.001

54.1

(-1.97, 110.3)

0.059

Absolute % predicted

2.4

(0.9, 3.9)

0.001

1.9

(-0.02, 3.8)

0.052

Relative % predicted

3.5

(1.0, 6.1)

0.007

3.6

(0.3, 6.9)

0.033

Adult Population

N=171

N=144

Absolute mL

108.5

(47.6, 169.4)

<0.001

85.9

(4.6, 167.3)

0.038

Absolute % predicted

2.7

(0.9, 4.5)

0.004

2.3

(-0.4, 5.1)

0.095

Relative % predicted

4.3

(1.1, 7.5)

0.008

5.0

(0.2, 9.8)

0.040

In rhDNase users in study 301 the relative change in FEV1 % predicted from baseline across 26 weeks of treatment was 2.83 (95% CI -0.62, 6.27). For non-users the relative change was 4.30 (95% CI 0.53, 8.07). In study 302 the relative change (95% CI) for rhDNase users and non-users was 3.21 (-0.61, 7.03) and 4.73 (-1.93, 11.40), respectively.

The number of subjects with at least one protocol defined pulmonary exacerbation (PDPE, defined by the presence of at least 4 symptoms and signs plus the use of intravenous antibiotics) was 18.1% in the mannitol arm and 28% in the control arm in study 301 (ITT population). In study 302 15.2% subjects in the mannitol arm and 19% in the control had a PDPE.

The estimated effect of treatment (mean change and 95% CI from baseline over 26 weeks, mITT population) on FVC was 108.78 ml (95% CI: 49.21, 168.35) in study 301 and 71.4 ml (95% CI: 10.57, 132.13) in study 302.

Paediatric population

The safety and efficacy of 20% Mannitol YD in children and adolescents aged less than 18 years has not been established .

In studies DPM-CF-301 and 302 relative % predicted FEV1 compared to control in children (6-11 years) was improved by 0.44% (95% CI -5.90, 6.77, N=43) and 6.1% (95% CI -1.28, 13.54, N=59) over 26 weeks (p=0.892 and 0.104) respectively.

In adolescents (12-17 years) relative change in % predicted FEV1 compared to control improved by 3.31% (95% CI -2.29, 8.90, N=55) and 0.42% (95% CI -5.45, 6.29, N=94) over 26 weeks (p=0.245 and 0.888) respectively.

Pharmacokinetic properties
The information provided in Pharmacokinetic properties of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

When administered intravenously, 20% Mannitol YDol is eliminated largely unmetabolised through the glomeruli. It is freely filtered by the glomeruli, with less than 10% tubular reabsorption and is not secreted by tubular cells. The elimination half-life in adults is approximately 2 hours, longer where renal failure is present. 80% of an intravenous dose is excreted unchanged within 3 hours.

Absorption

In a study of 18 healthy male adult volunteers, the absolute bioavailability of mannitol powder for inhalation by comparison to mannitol administered intravenously was 0.59% ± 0.15.

The rate and extent of absorption of mannitol after inhaled administration was very similar to that observed after oral administration. The Tmax after inhaled administration was 1.5 ± 0.5 hours.

In a study of 9 cystic fibrosis patients (6 adults, 3 adolescents), using 400 mg inhaled mannitol as a single dose (Day 1) then twice a day for 7 days (Days 2 - 7), pharmacokinetic parameters were similar for adults and adolescents, except for a longer average apparent terminal half life for adolescents (Day 1 = 7.29 hours, Day 7 = 6.52 hours) compared with adults (Day 1 = 6.10 hours, Day 7 = 5.42 hours). Overall, the comparison of AUCs between Day 1 and Day 7 showed a time independence of pharmacokinetics, indicating linearity at the dose level administered in this study.

Biotransformation

A small percentage of systemically absorbed mannitol undergoes hepatic metabolism to glycogen and carbon dioxide. Studies in rats, mice and humans have demonstrated that mannitol has no toxic metabolites. The metabolic pathway of inhaled mannitol was not examined in pharmacokinetic studies.

Distribution

Lung deposition studies have demonstrated a 24.7% deposition of inhaled mannitol confirming its distribution to the target organ. Nonclinical toxicology studies indicate that mannitol inhaled into the lungs is absorbed into the bloodstream, with the maximum serum concentration being achieved occurring at 1 hour. There is no evidence that mannitol is accumulated in the body, therefore distribution of inhaled mannitol was not examined in PK studies.

Elimination

The cumulative amount of mannitol filtered into the urine over the 24 hour collection period was similar for inhaled (55%) and oral (54%) mannitol. When administered intravenously, mannitol is eliminated largely unchanged by glomerular filtration and 87% of the dose is excreted in the urine within 24 hours. The mean terminal half-life in adults was approximately 4 to 5 hours from serum and approximately 3.66 hours from urine.

Paediatric population

The safety and efficacy of 20% Mannitol YD in children and adolescents aged 6 to 18 years has not yet been established.

The limited data available in adolescents aged 12 to 17 years indicate the pharmacokinetic parameters of inhaled mannitol are similar to the adult population.

There are no data available for children under 12 years of age.

Pharmacotherapeutic group
The information provided in Pharmacotherapeutic group of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Pharmacotherapeutic group in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution
“Solutions producing osmotic diuresis”, ATC code: “B05BC01”
Cough and cold preparations, Mucolytic. ATC code: R05CB16
Preclinical safety data
The information provided in Preclinical safety data of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Preclinical safety data in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

The preclinical safety assessment of 20% Mannitol YDol 10% in animals is not relevant as 20% Mannitol YDol is a substance with well-established use in patients and is covered by appropriate pharmacopoeial references.

In male rats after 13 weeks of inhaled mannitol dosing, elevated circulating lymphocyte numbers and mandibular lymph node plasmacytosis was observed at doses greater than 9.3 fold the maximal dose. The elevated lymphocyte count was within historical control values, did not progress and was essentially resolved by the end of the in life phase of the study and following withdrawal of treatment. This effect was not noted in any other species and did not result in clinical signs.

In dogs an increased occurrence of coughing was observed both during and immediately post dose for low and high dose inhaled mannitol administration. No treatment-related adverse effect occurred greater than 13 fold the maximal therapeutic dose.

No mutagenic or genotoxic effect has been revealed when mannitol was assayed in a standard battery of genotoxicity tests.

Mannitol was shown not to be an irritant in an isolated bovine eye assay or when introduced into rabbit eyes.

No evidence of carcinogenicity was observed when dietary mannitol (≤5%) was administered to mice and rats for 2 years. Carcinogenicity studies have not been carried out with inhaled mannitol.

Reproduction and developmental toxicity studies have not been carried out with inhaled mannitol. However, studies conducted with mannitol administered via other routes indicated no effect on foetal survival in mice, rats and hamsters and on embryo and foetal development in rats and rabbits.

Animal reproduction studies have not been carried out with inhaled mannitol. However, studies conducted with orally administered mannitol indicated no teratogenic effects in mice or rats, at doses of up to 1.6 g/kg, or in hamsters at 1.2 g/kg.

Incompatibilities
The information provided in Incompatibilities of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). Be careful and be sure to specify the information on the section Incompatibilities in the instructions to the drug 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Additives may be incompatible with 20% Mannitol YDol 10% Solution for infusion.

Incompatibility of the medicinal product to be added with the solution in the Viaflo container must be assessed before addition.

Before adding a medicinal product, verify it is soluble and stable in water at the pH of the 20% Mannitol YDol solution (4.5 to 7.0)

20% Mannitol YDol 10% Solution for Infusion should not be administered simultaneously with, before, or after administration of blood through the same infusion equipment, due to risk of pseudoagglutination.

The Instructions for Use of the medicinal product to be added must be consulted.

As an example cefepime, imipenem, cilastin and filgrastim are incompatible with 20% Mannitol YDol solutions, but this list is not exhaustive. In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

The addition of Potassium or Sodium Chloride to 20% Mannitol YDol 10% may cause precipitation of 20% Mannitol YDol.

Not applicable.

Special precautions for disposal and other handling
The information provided in Special precautions for disposal and other handling of 20% Mannitol YD is based on data of another medicine with exactly the same composition as the 20% Mannitol YD of the medicine (Mannitol). 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 20% Mannitol YD directly from the package or from the pharmacist at the pharmacy.
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Solution for infusion; Substance-powder
Nebuliser solution

Use administration sets with a final in-line filter because of the potential for 20% Mannitol YDol crystals to form.

Additives may be introduced before infusion or during infusion through the re-sealable medication port.

Thorough and careful aseptic mixing of any additive is mandatory. Solutions containing additives should be used immediately and not stored.

Before adding a medicinal product, verify it is soluble in water at the pH of 20% Mannitol YDol solution.

Discard after single use.

Discard any unused portion.

Do not reconnect partially used bags.

Opening

• Remove the Viaflo container from the overpouch just before use.

• Check for minute leaks by squeezing inner bag firmly. If leaks are found, discard solution, as sterility may be impaired.

• Check solution for limpidity and absence of foreign matter. If solution is not clear or contains foreign matter, discard the solution.

Preparation for administration

Use sterile material for preparation and administration.

• Suspend container from eyelet support. Remove plastic protector from outlet port at bottom of container:

• grip the small wing on the neck of the port with one hand

• grip the large wing on the cap with the other hand and twist,

• the cap will pop off.

• Use an aseptic method to set up the infusion. Attach administration set. Refer to complete directions accompanying set.

Techniques for injection of additive medicinal products

Warning: Additives may be incompatible. Check additive compatibility with both the solution and container prior to use.

To add medicinal products before administration:

• Disinfect medication site. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.

Mix solution and medication thoroughly. For high-density medication such as potassium chloride, tap the ports gently while ports are upright and mix.

Caution: Do not store bags containing added medications.

To add medicinal products during administration:

1. Close clamp on the set

2. Disinfect medication site.

3. Using syringe with 19 to 22 gauge needle, puncture resealable medication port and inject.

4. Remove container from intravenous pole and/or turn to an upright position.

5. Evacuate both ports by tapping gently while the container is in an upright position.

6. Mix solution and medication thoroughly.

7. Return container to in use position, re-open the clamp and continue administration.

No special requirements.

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

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