Zyrolen

Zyrolen UDVs are indicated for treatment of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD).

Zyrolen UDVs are indicated, when used concomitantly with inhaled beta₂-agonists, for treatment of reversible airways obstruction as in acute and chronic asthma.

Zyrolen is indicated for the treatment of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD).

Zyrolen is indicated, when used concomitantly with inhaled beta₂-agonists, for treatment of reversible airways obstruction as in acute and chronic asthma.

Zyrolenasal Spray 0.06% is indicated for the symptomatic relief of rhinorrhea associated with the common cold or seasonal allergic rhinitis for adults and children age 5 years and older. Zyrolenasal Spray 0.06% does not relieve nasal congestion or sneezing associated with the common cold or seasonal allergic rhinitis. The safety and effectiveness of the use of Atrovent® (ipratropium bromide) Nasal Spray 0.06% beyond four days in patients with the common cold or beyond three weeks in patients with seasonal allergic rhinitis has not been established.

The dosage should be adapted to the individual needs of the patient. In children aged 12 years and under, only Zyrolen 250 UDVs, 1 ml should be used. The following doses are recommended:

Adults (including the elderly) and adolescents > 12 years of age:

250 - 500 micrograms (i.e. one vial of 250 micrograms in 1 ml or 1 vial of 500 micrograms in 2 ml) 3 to 4 times daily.

For treatment of acute bronchospasm, 500 micrograms.

Repeated doses can be administered until the patient is stable. The time interval between the doses may be determined by the physician.

It is advisable not to exceed the recommended daily dose during either acute or maintenance treatment. Daily doses exceeding 2 mg in adults and adolescents > 12 years of age should only be given under medical supervision.

Children 6 - 12 years of age:

250 micrograms (i.e. one vial of 250 micrograms in 1ml) up to a total daily dose of 1mg (4 vials).

The time interval between doses may be determined by the physician.

Children 0 - 5 years of age (for treatment of acute asthma only):

125 - 250 micrograms (i.e. half to one vial of 250 micrograms in 1 ml) up to a total daily dose of 1 mg (4 vials).

Ipratropium bromide should be administered no more frequently than 6 hourly in children under 5 years of age.

For acute bronchospasm, repeated doses may be administered until the patient is stable.

If therapy does not produce a significant improvement or if the patient's condition gets worse, medical advice must be sought. The patient should be instructed that in the case of acute or rapidly worsening dyspnoea a physician should be consulted immediately.

Zyrolen UDVs may be combined with a short-acting beta₂-agonist in the same nebuliser chamber, for simultaneous administration where co-administration is required. The solution should be used as soon as possible after mixing and any unused solution should be discarded.

Zyrolen UDVs can be administered using a range of commercially available nebulising devices. The dose of nebuliser solution may need to be diluted in order to obtain a final volume suitable for the particular nebuliser being used (usually 2 - 4 mL); if dilution is necessary use only sterile sodium chloride 0.9% solution.

Zyrolen UDVs and disodium cromoglycate inhalation solutions that contain the preservative benzalkonium chloride should not be administered simultaneously in the same nebuliser as precipitation may occur.

The unit dose vials are intended only for inhalation with suitable nebulising devices and should not be taken orally or administered parenterally.

Please refer to the patient information leaflet for instructions on use with a nebuliser.

This medicinal product is for inhalation use only.

The dosage should be adapted to the individual needs of the patient. In children aged 12 years and under, only Zyrolen Nebuliser Solution 1 ml should be used. The following doses are recommended:

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

250 - 500 micrograms (i.e. one vial of 250 micrograms in 1 ml or one vial of 500 micrograms in 2ml) 3 to 4 times daily. The exact starting dose may vary depending on local guidelines.

For treatment of acute bronchospasm, 500 micrograms.

Repeated doses can be administered until the patient is stable. The time interval between the doses may be determined by the physician.

It is advisable not to exceed the recommended daily dose during either acute or maintenance treatment. Daily doses exceeding 2 mg in adults and children over 12 years of age should only be given under medical supervision.

Children 6 - 12 years of age:

250 micrograms (i.e. one vial of 250 micrograms in 1ml) up to a total daily dose of 1mg (4 vials).

The time interval between doses may be determined by the physician.

Children 0 - 5 years of age (for treatment of acute asthma only):

125 - 250 micrograms (i.e. half to one vial of 250 micrograms in 1ml) up to a total daily dose of 1 mg (4 vials).

Zyrolen should be administered no more frequently than 6 hourly in children under 5 years of age.

For acute bronchospasm, repeated doses may be administered until the patient is stable.

If therapy does not produce a significant improvement or if the patient's condition gets worse, medical advice must be sought. In the case of acute or rapidly worsening dyspnoea (difficulty in breathing) a doctor should be consulted immediately.

Zyrolen may be combined with a short-acting beta₂-agonist in the same nebuliser chamber, for simultaneous administration where co-administration is required, in line with local prescribing guidelines. The solution should be used as soon as possible after mixing and any unused solution should be discarded.

Zyrolen can be administered using a range of commercially available nebulising devices. The dose of nebuliser solution may need to be diluted according to local prescribing guidelines and in order to obtain a final volume suitable for the particular nebuliser being used (usually 2 - 4 ml); if dilution is necessary use only sterile sodium chloride 0.9% solution.

For Symptomatic Relief of Rhinorrhea Associated with the Common Cold

The recommended dose of Zyrolenasal Spray 0.06% is two sprays (84 mcg) per nostril three or four times daily (total dose 504 to 672 mcg/day) in adults and children age 12 years and older. Optimum dosage varies with response of the individual patient. The recommended dose of Zyrolenasal Spray 0.06% for children age 5-11 years is two sprays (84 mcg) per nostril three times daily (total dose of 504 mcg/day).

The safety and effectiveness of the use of Zyrolenasal Spray 0.06% beyond four days in patients with the common cold have not been established.

For Symptomatic Relief of Rhinorrhea Associated with Seasonal Allergic Rhinitis

The recommended dose of Zyrolenasal Spray 0.06% is two sprays (84 mcg) per nostril four times daily (total dose 672 mcg/day) in adults and children age 5 years and older.

The safety and effectiveness of the use of Zyrolenasal Spray 0.06% beyond three weeks in patients with seasonal allergic rhinitis have not been established.

Initial pump priming requires seven sprays of the pump. If used regularly as recommended, no further priming is required. If not used for more than 24 hours, the pump will require two sprays, or if not used for more than seven days, the pump will require seven sprays to reprime. Avoid spraying into eyes.

Zyrolen UDVs are contraindicated in patients with known hypersensitivity to atropine or its derivatives (such as the active substance ipratropium bromide) or to any other component of the product.

Known hypersensitivity to atropine or Zyrolen.

Zyrolenasal Spray 0.06% is contraindicated in patients with a history of hypersensitivity to atropine or its derivatives, or to any of the other ingredients.

Use of the nebuliser solution should be subject to close medical supervision during initial dosing.

Hypersensitivity

Immediate hypersensitivity reactions following the use of Zyrolen have been demonstrated by cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal oedema and anaphylaxis.

Paradoxical bronchospasm

As with other inhalation therapy, inhalation induced bronchoconstriction may occur with an immediate increase in wheezing after dosing. This should be treated straight away with a fast acting inhaled bronchodilator. Zyrolen UDVs should be discontinued immediately, the patient assessed and, if necessary, alternative treatment instituted.

Ocular complications

Caution is advocated in the use of anticholinergic agents in patients predisposed to or with narrow-angle glaucoma.

There have been isolated reports of ocular complications (i.e. mydriasis, increased intra-ocular pressure, narrow-angle glaucoma, eye pain) when aerosolised ipratropium bromide, either alone or in combination with an adrenergic beta₂-agonist, has come into contact with the eyes during nebuliser therapy.

Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately.

Patients must be instructed in the correct administration of Zyrolen UDVs. Care must be taken not to allow the solution or mist to enter the eyes. It is recommended that the nebulised solution is administered via a mouthpiece. If this is not available and a nebuliser mask is used, it must fit properly. Patients who may be predisposed to glaucoma should be warned specifically to protect their eyes.

Renal and urinary effects

Zyrolen UDVs should be used with caution in patients with pre-existing urinary outflow tract obstruction (e.g. prostatic hyperplasia or bladder-outflow obstruction).

Gastro-intestinal motility disturbances

As patients with cystic fibrosis may be prone to gastro-intestinal motility disturbances, Zyrolen, as with other anticholinergics, should be used with caution in these patients.

Use of the nebuliser solution should be subject to close medical supervision during initial dosing.

Caution is advocated in the use of anticholinergic agents in patients with narrow-angle glaucoma, or with prostatic hyperplasia or bladder-outflow obstruction.

As patients with cystic fibrosis may be prone to gastro-intestinal motility disturbances, Zyrolen, as with other anticholinergics, should be used with caution in these patients.

Immediate hypersensitivity reactions following the use of Zyrolen have been demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal oedema and anaphylaxis.

There have been isolated reports of ocular complications (i.e. mydriasis, increased intra-ocular pressure, narrow-angle glaucoma, eye pain) when aerosolised Zyrolen, either alone or in combination with an adrenergic beta₂-agonist, has come into contact with the eyes during nebuliser therapy.

Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal oedema may be signs of acute narrow-angle glaucoma. Should any combination of these symptoms develop, treatment with miotic drops should be initiated and specialist advice sought immediately.

Patients must be instructed in the correct administration of Zyrolen. Care must be taken not to allow the solution or mist to enter the eyes. It is recommended that the nebulised solution is administered via a mouthpiece. If this is not available and a nebuliser mask is used, it must fit properly. Patients who may be predisposed to glaucoma should be warned specifically to protect their eyes.

WARNINGS

Immediate hypersensitivity reactions may occur after administration of ipratropium bromide, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.

PRECAUTIONS

General

1. Effects Seen with Anticholinergic Drugs: Zyrolenasal Spray (ipratropium bromide nasal spray) 0.03% should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder neck obstruction, particularly if they are receiving an anticholinergic by another route.
2. Use in Hepatic or Renal Disease: Zyrolenasal Spray (ipratropium bromide nasal spray) 0.03% has not been studied in patients with hepatic or renal insufficiency. It should be used with caution in those patient populations.

Information for Patients

Patients should be advised that temporary blurring of vision, precipitation or worsening of narrow-angle glaucoma, mydriasis, increased intraocular pressure, acute eye pain or discomfort, visual halos or colored images in association with red eyes from conjunctival and corneal congestion may result if ATROVENT Nasal Spray 0.03% comes into direct contact with the eyes. Patients should be instructed to avoid spraying Zyrolenasal Spray (ipratropium bromide nasal spray) 0.03% in or around their eyes. Patients who experience eye pain, blurred vision, excessive nasal dryness, or episodes of nasal bleeding should be instructed to contact their doctor. To ensure proper dosing, patients should be advised not to alter the size of the nasal spray opening. Patients should be reminded to carefully read and follow the accompanying Patient's Instructions for Use.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to 6 mg/kg. This dose corresponds in rats and mice to approximately 190 and 95 times the maximum recommended daily intranasal dose in adults, respectively, and approximately 110 and 55 times the maximum recommended daily intranasal dose in children, respectively, on a mg/m² basis. Results of various mutagenicity studies (Ames test, mouse dominant lethal test, mouse micronucleus test, and chromosome aberration of bone marrow in Chinese hamsters) were negative.

Fertility of male or female rats at oral doses up to 50 mg/kg (approximately 1,600 times the maximum recommended daily intranasal dose in adults on a mg/m² basis) was unaffected by ipratropium bromide administration. At an oral dose of 500 mg/kg (approximately 16,000 times the maximum recommended daily intranasal dose in adults on a mg/m² basis), ipratropium bromide produced a decrease in the conception rate.

Pregnancy

Teratogenic Effects: Pregnancy Category B.

Oral reproduction studies were performed at doses of 10 mg/kg in mice, 1000 mg/kg in rats and 125 mg/kg in rabbits. These doses correspond, in each species, respectively, to approximately 160, 32,000, and 8,000 times the maximum recommended daily intranasal dose in adults on a mg/m² basis. Inhalation reproduction studies were conducted in rats and rabbits at doses of 1.5 and 1.8 mg/kg, respectively, (approximately 50 and 120 times, respectively, the maximum recommended daily intranasal dose in adults on a mg/m² basis). These studies demonstrated no evidence of teratogenic effects as a result of ipratropium bromide. At oral doses 90 mg/kg and above in rats (approximately 2,900 times the maximum recommended daily intranasal dose in adults on a mg/m² basis) embryotoxicity was observed as increased resorption. This effect is not considered relevant to human use due to the large doses at which it was observed and the difference in route of administration. However, no adequate or well controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, Atrovent® (ipratropium bromide) Nasal Spray 0.03% should be used during pregnancy only if clearly needed.

Nursing Mothers

It is known that some ipratropium bromide is systemically absorbed following nasal administration; however the portion which may be excreted in human milk is unknown. Although lipid-insoluble quaternary cations pass into breast milk, the minimal systemic absorption makes it unlikely that ipratropium bromide would reach the infant in an amount sufficient to cause a clinical effect. However, because many drugs are excreted in human milk, caution should be exercised when Zyrolenasal Spray (ipratropium bromide nasal spray) 0.03% is administered to a nursing mother.

Pediatric Use

The safety of Atrovent® (ipratropium bromide) Nasal Spray 0.03% at a dose of two sprays (42 mcg) per nostril two or three times daily (total dose 168 to 252 mcg/day) has been demonstrated in 77 pediatric patients 6-12 years of age in placebo-controlled, 4-week trials and in 55 pediatric patients in active-controlled, 6 month trials. The effectiveness of Zyrolenasal Spray (ipratropium bromide nasal spray) 0.03% for the treatment of rhinorrhea associated with allergic and nonallergic perennial rhinitis in this pediatric age group is based on an extrapolation of the demonstrated efficacy of Zyrolenasal Spray (ipratropium bromide nasal spray) 0.03% in adults with these conditions and the likelihood that the disease course, pathophysiology, and the drug's effects are substantially similar to that of the adults. The recommended dose for the pediatric population is based on within and cross-study comparisons of the efficacy of Zyrolenasal Spray 0.03% in adults and pediatric patients and on its safety profile in both adults and pediatric patients. The safety and effectiveness of Zyrolenasal Spray 0.03% in patients under 6 years of age have not been established.

No studies on the effects on the ability to drive and use machines have been performed. However, patients should be advised that they may experience undesirable effects such as dizziness, accommodation disorder, mydriasis and blurred vision during treatment with Zyrolen. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

None known.

Many of the listed undesirable effects can be assigned to the anticholinergic properties of Zyrolen. As with all inhalation therapy Zyrolen may show symptoms of local irritation. Adverse drug reactions were identified from data obtained in clinical trials and pharmacovigilance during post approval use of the drug.

The most frequent side effects reported in clinical trials were headache, throat irritation, cough, dry mouth, gastro-intestinal motility disorders (including constipation, diarrhoea and vomiting), nausea, and dizziness.

Frequencies

⁽²⁾ As with other inhalation therapy, inhalation induced bronchoconstriction may occur with an immediate increase in wheezing after dosing. This should be treated straight away with a fast acting inhaled bronchodilator. Zyrolen UDVs should be discontinued immediately, the patient assessed and, if necessary, alterative treatment instituted.

⁽³⁾ the risk of urinary retention may be increased in patients with pre-existing urinary outflow tract obstruction.

Reporting of suspected adverse reactions

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

The most common non-respiratory adverse reactions reported in clinical trials are headache, nausea (with or without vomiting) and dryness of the mouth.

Reporting of suspected adverse reactions

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

Adverse reaction information on Zyrolenasal Spray 0.06% in patients with the common cold was derived from two multicenter, vehicle-controlled clinical trials involving 1,276 patients (195 patients on Zyrolenasal Spray 0.03%, 352 patients on Zyrolenasal Spray 0.06%, 189 patients on Zyrolenasal Spray 0.12%, 351 patients on vehicle and 189 patients receiving no treatment).

Table 1 shows adverse events reported for patients who received Zyrolenasal Spray 0.06% at the recommended dose of 84 mcg per nostril, or vehicle, administered three or four times daily, where the incidence is 1% or greater in the ATROVENT group and higher in the ATROVENT group than in the vehicle group.

Table 1 % of Patients with Common Cold Reporting Events1

Zyrolenasal Spray 0.06% was well tolerated by most patients. The most frequently reported adverse events were transient episodes of nasal dryness or epistaxis. The majority of these adverse events (96%) were mild or moderate in nature, none was considered serious, and none resulted in hospitalization. No patient required treatment for nasal dryness, and only three patients (<1%) required treatment for epistaxis, which consisted of local application of pressure or a moisturizing agent (e.g., petroleum jelly). No patient receiving ATROVENT

Nasal Spray 0.06% was discontinued from the trial due to either nasal dryness or bleeding. Adverse events reported by less than 1% of the patients receiving Zyrolenasal Spray 0.06% during the controlled clinical trials that are potentially related to ATROVENT's local effects or systemic anticholinergic effects include: taste perversion, nasal burning, conjunctivitis, coughing, dizziness, hoarseness, palpitation, pharyngitis, tachycardia, thirst, tinnitus, and blurred vision. No controlled trial was conducted to address the relative incidence of adverse events for three times daily versus four times daily therapy.

Nasal adverse events seen in the clinical trial with seasonal allergic rhinitis (SAR) patients (see Table 2) were similar to those seen in the common cold trials. Additional events were reported at a higher rate in the SAR trial due in part to the longer duration of the trial and the inclusion of Upper Respiratory Tract Infection (URI) as an adverse event. In common cold trials, URI was the disease under study and not an adverse event.

Table 2 % of Patients with SAR Reporting Events¹

There were no reports of allergic-type reactions in the controlled clinical common cold and SAR trials.

Post-Marketing Experience

Allergic-type reactions such as skin rash, angioedema, including that of the throat, tongue, lips and face, generalized urticaria (including giant urticaria), laryngospasm, and anaphylactic reactions have been reported with Zyrolenasal Spray 0.06% and for other ipratropium bromide-containing products, with positive rechallenge in some cases.

Additional side effects identified from the published literature and/or post-marketing surveillance on the use of ipratropium bromide-containing products (singly or in combination with albuterol), include: urinary retention, prostatic disorders, mydriasis, cases of precipitation or worsening of narrow-angle glaucoma, acute eye pain, ocular irritation, wheezing, dryness of the oropharynx, tachycardia, edema, gastrointestinal distress (diarrhea, nausea, vomiting), bowel obstruction, constipation, nasal discomfort, throat irritation, hypersensitivity, accommodation disorder, intraocular pressure increased, glaucoma, halo vision, conjunctival hyperaemia, corneal edema, heart rate increased, bronchospasm, pharyngeal edema, gastrointestinal motility disorder, mouth edema, stomatitis, and pruritus.

After oral inhalation of ipratropium bromide in patients suffering from COPD/Asthma supraventricular tachycardia and atrial fibrillation have been reported.

No symptoms specific to overdosage have been encountered. In view of the wide therapeutic window and topical administration of Zyrolen, no serious anticholinergic symptoms are to be expected. As with other anticholinergics, dry mouth, visual accommodation disturbances and tachycardia would be the expected symptoms and signs of overdose.

Palpitation and increases in heart rate have been produced with inhaled doses of 5 mg. Side effects have not been caused by single inhaled doses of 2 mg in adults and 1 mg in children. Single oral doses of 30 mg of Zyrolen caused anticholinergic side effects, but these did not require treatment.

Severe overdose is characterized by atropine-like symptoms like tachycardia, tachypnea, high fever and central effects like restlessness, confusion and hallucinations. These symptoms should be treated symptomatically. The use of fysostigmine is not recommended because of worsening of cardiotoxic symptoms and induction of convulsions.

Acute overdosage by intranasal administration is unlikely since ipratropium bromide is not well absorbed systemically after intranasal or oral administration. Following administration of a 20 mg oral dose (equivalent to ingesting more than two bottles of Atrovent® (ipratropium bromide) Nasal Spray 0.06%) to 10 male volunteers, no change in heart rate or blood pressure was noted. Following a 2 mg intravenous infusion over 15 minutes to the same 10 male volunteers, plasma ipratropium concentrations of 22-45 ng/mL were observed (>100 times the concentrations observed following intranasal administration). Following intravenous infusion these 10 volunteers had a mean increase of heart rate of 50 bpm and less than 20 mmHg change in systolic or diastolic blood pressure at the time of peak ipratropium levels.

Pharmacotherapeutic group: Anticholinergics

ATC Code: R03BB01

Zyrolen is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In nonclinical studies, it appears to inhibit vagally mediated reflexes by antagonising the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increase in intracellular concentration of Ca++ which is caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle. Ca++ release is mediated by the second messenger system consisting of IP3 (inositol triphosphate) and DAG (diacylglycerol).

The bronchodilation following inhalation of Zyrolen is induced by local drug concentrations sufficient for anticholinergic efficacy at the bronchial smooth muscle and not by systemic drug concentrations.

In clinical trials using metered dose inhalers in patients with reversible bronchospasm associated with chronic obstructive pulmonary disease significant improvements in pulmonary function (FEV₁ increases of 15% or more) occurred within 15 minutes, reached a peak in 1-2 hours, and persisted for approximately 4 hours.

Preclinical and clinical evidence suggest no deleterious effect of Zyrolen on airway mucous secretion, mucociliary clearance or gas exchange.

The bronchodilator effect of Zyrolen in the treatment of acute bronchospasm associated with asthma has been shown in studies in adults and children > 6 years of age. In most of these studies Zyrolen was administered in combination with an inhaled beta₂-agonist.

Pharmacotherapeutic group: Anticholinergics, ATC code: R03BB01

Zyrolen is a competitive antagonist of muscarinic acetylcholine receptors. It exhibits its greatest potency on bronchial receptors, whether given intravenously or inhaled, but causes no tachycardia. No anticholinergic effects have been observed on cardiac function, bladder function or in the eye.

Zyrolen is able to inhibit reflex-induced bronchoconstriction following exercise, inhalation of cold air and the early response to inhaled antigens. It also reverses the bronchoconstriction induced by inhaled cholinergic agonists.

Inhalation of 0.04mg of ipratropium from a metered dose aerosol causes bronchodilation, the maximal effect is seen after 30 - 60 minutes, with a duration of 4 hours. This is a dose related effect and use of a nebuliser produces greater bronchodilation, a dose of 0.5mg producing maximal bronchodilation.

Absorption

The therapeutic effect of Zyrolen is produced by a local action in the airways. Time courses of bronchodilation and systemic pharmacokinetics do not run in parallel.

Following inhalation, 10 to 30% of a dose is generally deposited in the lungs, depending on the formulation, device and inhalation technique. The major part of the dose is swallowed and passes through the gastro-intestinal tract.

The portion of the dose deposited in the lungs reaches the circulation rapidly (within minutes).

Cumulative renal excretion (0-24 hrs) of the parent compound is approximated to 46% of an intravenously administered dose, below 1% of an oral dose and approximately 3 to 13% of an inhaled dose. Based on these data the total systemic bioavailability of oral and inhaled doses of ipratropium bromide is estimated at 2% and 7 to 28% respectively.

Taking this into account, swallowed dose portions of ipratropium bromide do not contribute significantly to systemic exposure.

Distribution

The drug is minimally (less than 20%) bound to plasma proteins. Nonclinical data indicate that the quaternary amine ipratropium does not cross the placental or the blood-brain barrier.

Biotransformation

After intravenous administration approximately 60% of the dose is metabolised, mainly by conjugation (40%), whereas after inhalation about 77% of the systemically available dose is metabolised by ester hydrolysis (41%) and conjugation (36%).

The known metabolites, which are formed by hydrolysis, dehydration or elimination of the hydroxy-methyl group in the tropic acid moiety, show very little or no affinity for the muscarinic receptor and have to be regarded as ineffective

Elimination

Ipratropium has a mean total clearance of 2.3 L/min and a renal clearance of 0.9 L/min.

In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 72.1% after intravenous administration, 9.3% after oral administration and 3.2% after inhalation. Total radioactivity excreted via the faeces was 6.3% following intravenous application, 88.5% following oral dosing and 69.4% after inhalation. Regarding the excretion of drug-related radioactivity after intravenous administration, the main excretion occurs via the kidneys. The half-life for elimination of drug-related radioactivity (parent compound and metabolites) is 3.2 hours.

Depending on the formulation and the inhalation technique, approximately 10-30 % of the inhaled dose reaches the lungs. The major part of the dose is swallowed.

Because of the negligible gastro-intestinal absorption, the bioavailability of the swallowed dose is only about 2 % of the total dose administered. The part of the dose that reaches the lungs has an almost complete systemic bioavailability and reaches the circulation within a few minutes.

From data on renal excretion (0-24 h) the total systemic bioavailability of inhaled Zyrolen is estimated to be 7-28 % (averages from three studies). It can be assumed that this interval is valid for the solution for nebuliser as well.

The kinetic parameters have been calculated from plasma concentrations after intravenous administration. The plasma concentration falls rapidly. The volume of distribution (V_z) is 338 L (approximately 4.6 L/kg). Ipratropium has a low degree of protein binding (<20 %). Because of its ammonium ion structure, ipratropium does not pass the blood-brain barrier. The elimination of ipratropium is biphasic. The half-life of elimination of the drug and metabolites is 3.6 hours. The half-life of the terminal elimination phase is about 1.6 hours.

The average total clearance has been estimated to be 2.3 L/min. About 60 % of the systemic available dose is metabolised, probably in the liver. The main metabolites that are found in the urine have a low affinity for muscarinic receptors and do not possess significant anticholinergic activity.

About 40 % of the systemic available dose is excreted via the kidneys, which corresponds to a renal clearance of 0.9 L/min.

From studies using radioactively labelled ipratropium, less than 10 % of the dose (ipratropium and metabolites) is excreted via bile and faeces. The major part of the radio labelled dose is excreted via the kidneys.

Absorption

Ipratropium bromide is poorly absorbed into the systemic circulation following oral administration (2-3%). Less than 20% of an 84 mcg per nostril dose was absorbed from the nasal mucosa of normal volunteers, induced-cold adult volunteers, naturally acquired common cold pediatric patients, or perennial rhinitis adult patients.

Distribution

Ipratropium bromide is minimally bound (0 to 9% in vitro) to plasma albumin and α1-acid glycoprotein. Its blood/plasma concentration ratio was estimated to be about 0.89. Studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier.

Metabolism

Ipratropium bromide is partially metabolized to ester hydrolysis products, tropic acid, and tropane. These metabolites appear to be inactive based on in vitro receptor affinity studies using rat brain tissue homogenates.

Elimination

After intravenous administration of 2 mg ipratropium bromide to 10 healthy volunteers, the terminal half-life of ipratropium bromide was approximately 1.6 hours. The total body clearance and renal clearance were estimated to be 2,505 and 1,019 mL/min, respectively. The amount of the total dose excreted unchanged in the urine (Ae) within 24 hours was approximately one-half of the administered dose.

Pediatrics

Following administration of 84 mcg of ipratropium bromide per nostril three times a day in patients 5-18 years old (n=42) with a naturally acquired common cold, the mean amount of the total dose excreted unchanged in the urine of 7.8% was comparable to 84 mcg per nostril four times a day in an adult induced common cold population (n=22) of 7.3 to 8.1%. Plasma ipratropium concentrations were relatively low (ranging from undetectable up to 0.62 ng/mL). No correlation of the amount of the total dose excreted unchanged in the urine (Ae) with age or gender was observed in the pediatric population.

The toxicity of ipratropium bromide has been investigated extensively in the following types of studies: acute, subchronic and chronic toxicity, carcinogenicity, reproductive toxicity and mutagenicity via oral, intravenous, subcutaneous, intranasal and/or inhalation routes. Based on these toxicity studies, the probability of systemic anticholinergic side effects decreases in the following order:

intravenous > subcutaneous > oral > inhalation > intranasal.

Pre-clinically, ipratropium bromide was found to be well-tolerated. Two-year carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to approximately 1,200 times the maximum recommended human daily dose for intranasal ipratropium. Results of various mutagenicity tests were negative.

Studies to investigate the possible influence of ipratropium bromide on fertility, embryo-fetotoxicity, and peri-/postnatal development have been performed on mice, rats and rabbits. High oral levels, i.e. 1000 mg/kg/day in the rat and 125 mg/kg/day in the rabbit were maternotoxic for both species and embryo-/fetotoxic in the rat, where the fetal weight was reduced. Treatment-related malformations were not observed. The highest, technically feasible doses for inhalation of the pressurised inhalation, solution, 1.5 mg/kg/day (human equivalent dose of 0.24 mg/kg/day) in rats and 1.8 mg/kg/day (human equivalent dose of 0.576 mg/kg/day) in rabbits, showed no adverse effects on reproduction.

These doses are 6- and 14-fold the maximum recommended human daily dose (MRHDD) of 2 mg or 0.04 mg/kg (based on a body weight of 50 kg).

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction, genotoxicity or carcinogenicity.

Not applicable.

Ipratropium Nebuliser Solution can be diluted only with sterile 0.9% sodium chloride solution.

None.

Zyrolen Nebuliser Solution is for inhalation from an intermittent positive pressure ventilator or from a suitable nebuliser which should be operated according to the manufacturer's instructions.

To open the plastic ampoule, take a strip of ampoules from the foil pack, remove one ampoule, replacing the rest back in the foil pack and replace the foil pack back in the carton. Hold the ampoule upright and open by twisting off the top. Squeeze the liquid into the solution holder of the machine.