Teva-Ipratropium Sterinebs Product Monograph

RECENT MAJOR LABEL CHANGES

7 Warnings and Precautions 02/2022

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES .............................................................................................................. 2

PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................................... 3

1 INDICATIONS ............................................................................................................................................. 3

1.1 Pediatrics: ...................................................................................................................................... 3

1.2 Geriatrics: ....................................................................................................................................... 3

2 CONTRAINDICATIONS .............................................................................................................................. 3

4 DOSAGE AND ADMINISTRATION ............................................................................................................. 3

4.1 Dosing Considerations ......................................................................................................................... 3

4.2 Recommended Dose and Dosage Adjustment ..................................................................................... 4

4.4 Administration ...................................................................................................................................... 4

4.5 Missed Dose ........................................................................................................................................ 5

5 OVERDOSAGE .......................................................................................................................................... 5

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ...................................................... 5

7 WARNINGS AND PRECAUTIONS ............................................................................................................. 6

7.1 Special Populations ............................................................................................................................. 7

7.1.1 Pregnant Women .............................................................................................................................. 7

7.1.2 Breast-feeding................................................................................................................................... 7

7.1.3 Pediatrics .......................................................................................................................................... 7

8 ADVERSE REACTIONS ............................................................................................................................. 7

8.1 Adverse Reaction Overview ................................................................................................................. 7

8.2 Clinical Trial Adverse Reactions ........................................................................................................... 8

8.3 Less Common Clinical Trial Adverse Drug Reactions (<1%) .............................................................. 10

8.5 Post-Market Adverse Reactions ......................................................................................................... 10

9 DRUG INTERACTIONS ............................................................................................................................ 11

9.4 Drug-Drug Interactions ....................................................................................................................... 11

9.5 Drug-Food Interactions ...................................................................................................................... 11

9.6 Drug-Herb Interactions ....................................................................................................................... 11

9.7 Drug-Laboratory Test Interactions ...................................................................................................... 11

10 CLINICAL PHARMACOLOGY ................................................................................................................. 11

10.1 Mechanism of Action ........................................................................................................................ 11

10.2 Pharmacodynamics ......................................................................................................................... 12

10.3 Pharmacokinetics ............................................................................................................................. 13

11 STORAGE, STABILITY AND DISPOSAL ................................................................................................ 14

12 SPECIAL HANDLING INSTRUCTIONS .................................................................................................. 15

PART II: SCIENTIFIC INFORMATION ........................................................................................................... 16

13 PHARMACEUTICAL INFORMATION ..................................................................................................... 16

14 CLINICAL TRIALS .................................................................................................................................. 17

14.1 Clinical Trials by Indication ............................................................................................................... 17

15 MICROBIOLOGY .................................................................................................................................... 17

16 NON-CLINICAL TOXICOLOGY .............................................................................................................. 17

PATIENT MEDICATION INFORMATION ........................................................................................................ 22

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

TEVA-IPRATROPIUM STERINEBS (ipratropium bromide) solution administered either alone or with an adrenergic stimulant solution is indicated:

• As a bronchodilator for the maintenance treatment of bronchospasm associated with acute exacerbations of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema in adults.
• As a bronchodilator for the treatment of acute exacerbations of COPD in adults.
• When used concomitantly with an inhaled beta₂-adrenergic agonist, such as salbutamol, for the treatment of acute bronchospasm due to asthma in patients 5 years and older.

1.1 Pediatrics:

Pediatrics (less than 5 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of TEVA-IPRATROPIUM STERINEBS in pediatric patients younger than 5 years has not been established; therefore, Health Canada has not authorized an indication for use in patients younger than 5 years.

1.2 Geriatrics:

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use.

2 CONTRAINDICATIONS

TEVA-IPRATROPIUM STERINEBS is contraindicated in patients who are hypersensitive to ipratropium bromide or atropine or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

General

The dose of TEVA-IPRATROPIUM STERINEBS should be determined individually and patients should be kept under supervision by a healthcare professional during treatment.

Patients should be instructed to consult a healthcare professional immediately in the case of acute or rapidy worsening dyspnea.

COPD

Counselling by healthcare professionals on smoking cessation should be the first step in treating patients with chronic obstructive pulmonary disease (COPD), who smoke, independent of the clinical presentation i.e. chronic bronchitis (with or without airflow limitation) or emphysema.

Cessation of smoking produces dramatic symptomatic benefits and has been shown to confer a survival advantage.

Asthma

TEVA-IPRATROPIUM STERINEBS when administered to patients with acute severe asthma, should only be used with a concomitant β₂-adrenergic agonist.

Only specialists in respiratory medicine should initiate and clinically manage use of nebulisers and associated nebulised medicines at home for acute treatment of asthma in children and adolescents.

Urgent medical assistance should be sought if worsening asthma symptoms are not relieved by rescue medicines, even if there is short-term recovery following use of nebulised medication.

4.2 Recommended Dose and Dosage Adjustment

Adults and children 12 years of age and older

The recommended single dose of TEVA-IPRATROPIUM STERINEBS solution is 250-500 mcg (1 or 2 vials of 250 mcg/1 mL or 1 vial of 500 mcg/2 mL).

For the maintenance treatment of bronchospasm associated with COPD, the recommended dose is 500 mcg of TEVA-IPRATROPIUM STERINEBS given 3-4 times per day.

The maximum recommended daily dose is 2 mg per day in patients 12 years and older.

Daily doses exceeding 2 mg in adults should only be given under medical supervision.

Children 5 to 12 years of age

The recommended single dose of TEVA-IPRATROPIUM STERINEBS is 125-250 mcg.

Treatment with TEVA-IPRATROPIUM STERINEBS may be repeated every 4-6 hours as necessary.

The maximum recommended daily dose in children is 1 mg per day.

4.4 Administration

TEVA-IPRATROPIUM STERINEBS is for oral inhalation only with suitable nebulizing devices and must not be taken orally or administered parenterally.

Patients should be instructed in the proper use of the nebulizer. Patients should be cautioned against accidental release of the solution into the eyes.

TEVA-IPRATROPIUM STERINEBS is to be administered by compressed air or oxygen driven nebulizers. Nebulization should take place using a gas flow (oxygen or compressed air) of 6-10 L/minute and the solution nebulized to dryness over a 10-15 minute period. The Hudson Updraft^TM, Bennett Twin Jet^®, DeVilbiss, Pari Compressors and Inspiron Mini-Neb^® nebulizers, with facemask or mouthpiece have been used. The manufacturers' instructions concerning cleaning and maintenance of the nebulizer should be strictly followed.

Ipratropium bromide may be combined with a short-acting beta2-agonist (such as salbutamol) in the same nebuliser chamber, for simultaneous administration. The solution should be used as soon as possible after mixing and any unused solution should be discarded.

In most cases, dilution of the dose with sterile preservative-free saline is not necessary.

4.5 Missed Dose

If a dose is missed, the next scheduled dose should be taken. An extra dose must not be taken.

5 OVERDOSAGE

Doses of ipratropium bromide solution up to 1.2 mg (60 puffs) have been administered by inhalation without the appearance of serious systemic anticholinergic effects. Minor systemic manifestations of anticholinergic action, including dry mouth, visual accomodation disturbances and increased heart rate may occur.

Should signs of serious anticholinergic toxicity appear, cholinesterase inhibitors may be considered.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

TEVA-IPRATROPIUM STERINEBS is available as unit dose vials (UDV) containing ipratropium bromide 0.025% in Normal Saline (9 mg/mL (0.9%) sodium chloride solution). Also contains hydrochloric acid. The unit dose vials do not contain preservatives.

500 mcg /2 mL

TEVA-IPRATROPIUM STERINEBS 500 mcg /2 mL is provided as 2 mL of clear, colourless solution containing 0.025% ipratropium bromide in isotonic solution, presented in a plastic single use vial. Each vial contains a total of 500 mcg of ipratropium bromide. Available in cartons of 10 vials.

250 mcg/mL

TEVA-IPRATROPIUM STERINEBS 250 mcg /mL is provided as 1 mL of clear, colourless solution containing 0.025% ipratropium bromide in isotonic solution, presented in a plastic single use vial. Each vial contains a total of 250 mcg of ipratropium bromide. Available in cartons of 20 vials.

7 WARNINGS AND PRECAUTIONS

General

TEVA-IPRATROPIUM STERINEBS should not be used alone for the abatement of an acute asthmatic attack since the drug has a slower onset of effect than that of a β₂-adrenergic agonist.

If a reduced response to TEVA-IPRATROPIUM STERINEBS becomes apparent, the patient should seek medical advice.

Excessive Use and Use with other Muscarinic Antagonists:

TEVA-IPRATROPIUM STERINEBS should not be used more frequently or at higher doses than recommended.

TEVA-IPRATROPIUM STERINEBS should not be administered concomitantly with other medications that contain a short- or long-acting muscarinic antagonist (e.g. ipratropium, tiotropium, glycopyrronium, aclidinium or umeclidinium)

Anticholinergic Effects

Like other anticholinergic drugs, TEVA-IPRATROPIUM STERINEBS should be used with caution in patients with narrow-angle glaucoma (see Ophthalmologic) or urinary retention (see Renal).

Cardiovascular

Cardiovascular effects, such as cardiac arrhythmias (e.g. atrial fibrillation and tachycardia), may be seen after the administration of muscarinic receptor antagonists.

Gastrointestinal

Patients with cystic fibrosis may be more prone to gastro-intestinal motility disturbances, therefore, ipratropium bromide should be used with caution in these patients.

Immune

Hypersensitivity:

Immediate hypersensitivity reactions may occur after administration of TEVA-IPRATROPIUM STERINEBS, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal edema and anaphylaxis.

Ophthalmologic

Worsening of narrow-angle glaucoma:

Like other anticholinergic drugs, TEVA-IPRATROPIUM STERINEBS should be used with caution in patients with narrow-angle glaucoma.

Care should be taken to ensure that the nebulizer mask fits the patient's face properly and that nebulized solution does not escape into the eyes. In patients with glaucoma or narrow anterior chambers, the administration by nebulizer of an ipratropium solution or a combined ipratropium/β₂-agonist solution should be avoided unless measures (e.g. use of swimming goggles or use of a nebulizer with a mouth piece) are taken to ensure that nebulized solution does not reach the eye.

There have been isolated reports of ocular complications (i.e., mydriasis, increased intraocular pressure, angle closure glaucoma) when nebulized ipratropium bromide either alone or in combination with an β₂-adrenergic agonist solution has escaped into the eyes.

Eye pain or discomfort, blurred vision, visual halos or coloured images in association with red eyes from conjunctival congestion and corneal edema may be signs or acute narrow-angle glaucoma. In the event that glaucoma is precipitated or worsened, treatment should include standard measures for this condition. Miotic drops alone are not considered to be effective treatment.

Renal

Worsening of urinary retention:

TEVA-IPRATROPIUM STERINEBS should be used with caution in patients with urinary retention, prostatic hyperplasia or bladder neck obstruction. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Patients should be instructed to consult a health professional immediately should any of these signs or symptoms develop.

Respiratory

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. Ipratropium bromide should be discontinued immediately, the patient assessed and, if necessary, alternative treatment instituted.

7.1 Special Populations

7.1.1 Pregnant Women

The safety of TEVA-IPRATROPIUM STERINEBS in pregnancy has not been established. The benefits of using ipratropium bromide during confirmed or suspected must be weighed against possible harms to the fetus. Studies in rats, mice and rabbits showed no embryotoxic nor teratogenic effects (See 16 NON-CLINICAL TOXICOLOGY).

7.1.2 Breast-feeding

No specific studies have been conducted on excretion of ipratropium bromide in breast milk. It is not known whether ipratropium bromide is excreted into human breast milk. TEVA-IPRATROPIUM STERINEBS should be used during breastfeeding only if the potential benefit outweighs the potential risks to the infant.

7.1.3 Pediatrics

The efficacy and safety of TEVA-IPRATROPIUM STERINEBS in children younger than 5 years have not been established.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Side effects observed with inhaled ipratroprium bromide solution are consistent with other inhalation therapies and include cough, local irritation and inhalation induced bronchospasm, and in very rare instances exacerbation of symptoms has been observed.

The most frequent non-respiratory adverse events reported in clinical trials were headache, gastro-intestinal motility disturbances (constipation, diarrhea and vomiting), dizziness and dryness of the mouth/throat.

8.2 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful for identifying and approximating rates of adverse drug reactions in real-world use.

The adverse event profile was examined in a total of 214 patients receiving ipratropium bromide solution and 94 patients receiving ipratropium bromide plus a β₂-adrenergic agonist. Furthermore the frequency of adverse reactions reported as possibly related to ipratropium bromide treatment was studied in a 12-week controlled clinical trial in 219 COPD patients.

ACUTE ADMINISTRATION

The frequency of adverse reactions (≥1%) recorded in 214 patients receiving ipratropium bromide solution was as follows:

Table 2 -

The adverse reaction judged to be most severe was exacerbation of bronchospasm. This occurred in 8 patients treated with ipratropium bromide solution alone, 6 of whom withdrew from the clinical studies.

Bronchospasm occurred in 3 patients with acute severe asthma who received ipratropium bromide solution alone. In two patients, this was reversed after therapy with a β₂ sympathomimetic solution. The third patient received no other therapy.

The following table compares the incidence of adverse reactions (≥1%) of the combination of ipratropium bromide and a β₂-adrenergic agonist (fenoterol or salbutamol) solution with that of the β₂–adrenergic agonist alone.

Table 3-

CHRONIC ADMINISTRATION

The frequency of adverse reactions reported as possibly related to ipratropium treatment in 219 COPD patients participating in 12-week controlled clinical trials was as follows:

Table 4-

Observed adverse events occurring in at least 1% of subjects include rhinitis (0.9) and sputum increase (0.9%).

The following other adverse reactions were reported in one patient each: bronchospasm, tachycardia and urticaria.

In addition, the following adverse events were observed in one patient each: bronchitis, chest pain, depression, fatigue, flu-symptoms, hypoaesthesia, increased saliva, insomnia, nervousness, pain, paraesthesia, pharyngitis, somnolence.

The frequency of adverse reactions reported as possibly related to drug treatment in greater than 1% of COPD patients participating in long-term (12-week) controlled clinical trials that compared the efficacy and safety of ipratropium bromide solution + β₂ agonists (metaproterenol or salbutamol) versus the β₂ agonist alone, was as follows:

Table 5-

8.3 Less Common Clinical Trial Adverse Drug Reactions (<1%)

In the acute administration trial in 214 patients treated with ipratropium bromide solution the following less common adverse reactions were reported: burning eyes, cough, headache, nausea, palpitations and sweating.

There have been isolated reports of ocular effects such as mydriasis, increased intraocular pressure, and acute glaucoma associated with the escape of nebulized ipratropium bromide, alone or in combination with a β₂ agonist solution into the eyes.

Side effects such as tachycardia and palpitations, supraventricular tachycardia and atrial fibrillation, ocular accommodation disturbances, nausea and urinary retention have been reversible, although the risk of urinary retention may be increased in patients with pre-existing outflow tract obstruction.

Ocular side effects have been reported (see 7 WARNINGS AND PRECAUTIONS, Ophthalmologic).

8.5 Post-Market Adverse Reactions

World-wide safety data, which includes post-marketing data, spontaneous reports and literature reports indicates that the most frequent non-respiratory side effects of ipratropium bromide are headache and dryness of mouth/throat.

Immediate hypersensitivity reactions may occur after administration of ipratropium bromide. Allergic type reactions such as skin rash, pruritus, angioedema of the tongue, lips and face, urticaria (including giant uritcaria), laryngospasm, oropharyngeal edema, bronchospasm, and anaphylactic reactions, may occur.

Dizziness has been reported.

9 DRUG INTERACTIONS

9.4 Drug-Drug Interactions

The chronic co-administration of ipratropium bromide inhalation with other anticholinergic drugs has not been studied. There is potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, TEVA-IPRATROPIUM STERINEBS should not be administered concomitantly with other medications that contain a short- or long-acting muscarinic antagonist (e.g. ipratropium, tiotropium, glycopyrronium, aclidinium, umeclidinium) as this may lead to an increase in anticholinergic adverse effects (see 7 WARNINGS AND PRECAUTIONS).

There is evidence that the administration of ipratropium bromide with beta-adrenergic drugs and xanthine preparations may produce an additive bronchodilatory effect.

The risk of acute glaucoma in patients with a history of narrow-angle glaucoma may be increased when nebulised ipratropium bromide and beta₂-adrenergic agonists are administered simultaneously (See 7 WARNINGS AND PRECAUTIONS).

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Ipratropium bromide, a quaternary ammonium derivative of atropine, is an anticholinergic drug having bronchodilator properties. In nonclinical studies, it appears to inhibit vagally mediated reflexes by antagonizing 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 ipratropium bromide is primarily local and site specific to the lung and not systemic in nature.

On inhalation the onset of action is noted within 5 to 15 minutes with a peak response between 1 and 2 hours, lasting about 2 additional hours with subsequent decline. Bronchodilation is still evident 8 hours after inhalation.

10.2 Pharmacodynamics

Large, single inhaled doses of ipratropium bromide have been given to man without any signs of toxicity. After the administration of 400 mcg by inhaler (10 times the recommended single dose) to 10 normal subjects, no changes were detected in pulse rate, blood pressure, intraocular pressure, salivary secretion, visual accommodation or electrocardiograms. Likewise, in another study, no changes in pulse rate or salivary secretion were seen when cumulative doses up to 1.2 mg were administered by inhaler to 12 normal volunteers.

Special studies utilizing normal therapeutic doses in asthmatic and chronic bronchitic patients again have not revealed any systemic anticholinergic effects. In one study, 14 patients were treated for 45 days with either ipratropium bromide inhaler 40 mcg q.i.d. or ipratropium bromide inhaler 40 mcg q.i.d. plus oral fenoterol hydrobromide 5 mg q.i.d. No changes in visual acuity intraocular pressure, pupil size or accommodation of vision occurred. Micturition function studies in 20 male patients showed no differences in urinary flow, total flow time and time until maximum flow between placebo and ipratropium bromide inhaler 40 mcg t.i.d. administered for 3 days.

Deterioration in pulmonary function in patients treated in all clinical trials with therapeutic doses of ipratropium bromide solution was examined. The following table shows the number of patients who showed a 15% or greater fall in FEV₁ at any time within 2 hours following the administration of the drug. Also shown are the figures for comparative agents used.

Table 6-

Dose titration studies in stable asthmatic patients with ipratropium bromide solution have indicated that maximal improvement in pulmonary function occurs at approximately 250 mcg for adults and 125 mcg for children over 5 years.

A clinical pharmacology study comparing single doses of ipratropium bromide inhaler (80 mcg) and ipratropium bromide solution (250 mcg) in 16 stable adult asthmatics was performed. No difference between the regimens was found, based on an improvement in pulmonary function over a 2 hour period.

A wide variety of challenge studies have been conducted utilizing ipratropium bromide as a protective agent. In pharmacologically induced bronchospasm, ipratropium bromide in clinical doses, was very effective against methacholine and acetylcholine, moderately effective against propranolol but had little or no effect against histamine or serotonin.

Antigen challenge studies have demonstrated that ipratropium bromide offers some protection against the “early” allergic asthma response, but has no effect on the “late” response.

Non-clinical pharmacology

Ipratropium bromide was shown to abolish acetylcholine-induced bronchospasm in the guinea pig and dog after intravenous (i.v) administration at an ED₅₀ of 0.15-0.40 mcg /kg with a transient effect on blood pressure. By inhalation, approximately 25 mcg of ipratropium bromide produced a 50% inhibition of acetylcholine-induced bronchospasm in the dog with no detectable effect on blood pressure but with an increased duration of action compared to i.v. administration.

The anticholinergic effects of ipratropium bromide were evaluated in several other organ systems following oral, subcutaneous, intravenous and inhalation administration. In dogs, a 50% increase in heart rate resulted from a subcutaneous dose of about 0.011 mg/kg, equipotent to atropine, but the equi-effective oral dose of ipratropium was 58 times greater. When given by inhalation, no increase in heart rate or pathological changes in ECG pattern were recorded at doses up to 8 mg.

Salivary secretion in rat, mouse and dog was effectively inhibited by low parenteral doses of ipratropium bromide (0.001 to 0.032 mg/kg) but when given by the oral route, the effective dose increased over 100-fold. Aerosol administration in dogs of about 65 puffs (0.04 mg/puff) produced a 50% inhibition of salivary flow. Similarly, effects on gastric secretion in the rat showed at least a 100-fold difference between effective enteral and subcutaneous doses.

Mydriatic effects of ipratropium bromide in mice were approximately equipotent to atropine after subcutaneous (s.c.) doses but were 10-20 times less after oral administration. Tests of doses of ipratropium bromide up to 100 mg/kg in the rabbit showed no effect on the central nervous system.

Ipratropium bromide administered by inhalation in combination with a β₂ sympathomimetic agent (fenoterol hydrobromide) showed additive effects in antagonizing acetylcholine induced bronchospasm in the dog and guinea pig. In the dog, 50 mcg of fenoterol by inhalation produced an 8% increase in heart rate and a 16% increase in left ventricular dp/dt. When 20 mcg ipratropium was added the corresponding increases were 8% and 9%.

10.3 Pharmacokinetics

Absorption:

Ipratropium bromide is absorbed quickly after oral inhalation of a nominal dose of 40 mcg administered from a pressurized metered dose inhaler. The peak plasma concentration (mean C_max = 32 pg/mL) is reached within 5 minutes after inhalation. The therapeutic effect of ipratropium bromide is produced by a local action in the airways. Therefore time courses of bronchodilation and systemic pharmacokinetics do not run in parallel. The systemic bioavailability after inhalation of 2 mg ipratropium bromide, via an ultrasonic Mizer inhaler, over 20 minutes is estimated to be 7% of the dose. The bioavailability of the swallowed portion of the dose is approximately 2%.

Distribution:

Intravenous administration of 1.0 mg showed a rapid distribution into tissues (half-life of an alpha phase approximately 5 minutes), and a terminal half-life (beta phase) of 3-4 hours. Plasma concentrations after inhaled ipratropium bromide were about 1000 times lower than equipotent oral or intravenous doses (15 and 0.15 mg, respectively).

Parameters describing the disposition of ipratropium bromide were calculated from the plasma concentrations after i.v. administration. A rapid biphasic decline in plasma is noted for ipratropium. The half-life of the terminal elimination phase is about 1.6 hours. The total clearance of the active ingredient is 2.3 L/min. Approximately 40% of the clearance is renal (0.9 L /min) and

60% non-renal i.e. mainly hepato-metabolic. The volume of distribution is 338 L (corresponding to approximately 4.6 L /kg).

Radio-labelled technetium was administered with ipratropium bromide solution in an adult dose finding study. The following table outlines the doses reaching the patient.

The drug is minimally (less than 20%) bound to plasma proteins. The ipratropium ion does not cross the blood-brain barrier, consistent with the quaternary amine structure of the molecule.

Metabolism:

Up to 8 metabolites of ipratropium bromide have been detected in man, rat and dog. However, the main metabolites bind poorly to the muscarinic receptor.

Excretion:

In man, about 70% of the ¹⁴C labelled drug is excreted unchanged after i.v. administration and only one metabolite exceeds 10% of the total radioactivity. The elimination of ipratropium and its metabolites occurs primarily via the kidney with less than 10% of the total intravenous dose excreted via the biliary or fecal route. After oral or inhaled doses, however, up to 90% of the radiolabelled dose is detectable in the feces, suggesting relatively low lung deposition and poor absorption of the swallowed portion.

Thirty-nine percent of the active ingredient is excreted renally after intravenous administration, 4.4% - 13.1% after inhalation from a metered dose inhaler is excreted as unchanged compound in urine. Depending on the formulation and inhalation technique, renal excretion may increase up to 13% of the dose (40 or 80 μg dose), reflecting a higher deposition in the airways and a higher bioavailability.

Special Populations and Conditions

Pediatrics: The efficacy and safety of ipratropium bromide in children younger than 5 years have not been established.

11 STORAGE, STABILITY AND DISPOSAL

1 mL or 2 mL Unit Dose Vials:

Unopened unit dose vials of TEVA-IPRATROPIUM STERINEBS should be stored at controlled room temperature (15°C – 30°C) and protected from light. If required, the solution should be diluted with a preservative free sterile sodium chloride solution 0.9% and used immediately. Any solution remaining in the vial must be discarded.

The solution is physically compatible with orciprenaline sulfate, or salbutamol sulfate (6 mg/mL) solutions. If such mixtures are prepared, they should be diluted with preservative free 0.9% sterile sodium chloride solution and used immediately. Any unused portion of such combined solutions must be discarded.

12 SPECIAL HANDLING INSTRUCTIONS

No special handling instructions are required for this product.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: ipratropium bromide

Chemical Name: 8-azoniabicyclo [3.2.1] octane, 3-(3-hydroxy-1-oxo-2-

phenylpropoxy)-8-methyl-8-(1- methylethyl)-,bromide, monohydrate(endo,syn)-,(±)-.

Molecular Formula: C₂₀H₃₀BrNO₃•H₂O

Molecular Weight: 430.4

Structural Formula:

Description: White crystalline substance with a bitter taste. Freely soluble in water and alcohol; insoluble in chloroform and ether. In neutral and acid solutions the substance is rather stable; in alkaline solutions the ester bond is rapidly hydrolyzed.

Melting point: 230°C with decomposition.

pH: Between 5.0 to 7.5 of 1% solution in water.

14 CLINICAL TRIALS

14.1 Clinical Trials by Indication

Chronic Obstructive Pulmonary Disease (COPD)

In controlled 12-week studies in patients with bronchospasm associated with COPD (chronic bronchitis and emphysema), treatment with ipratropium bromide solution resulted in significant improvements in pulmonary function (FEV₁ and FEF_25-75% increases of 15% or more) occurred within 15 minutes, and reached a peak in 1 - 2 hours. The improvements persisted for periods of 4 - 5 hours in the majority of patients, with 25 to 38% of the patients demonstrating increases of at least 15% at 7 - 8 hours. Continued effectiveness of ipratropium bromide solution was demonstrated throughout the 12-week period. In addition, significant changes in forced vital capacity (FVC) have been demonstrated.

Asthma

Controlled 12-week studies were conducted to evaluate the safety and efficacy of ipratropium bromide solution administered concomitantly with bronchodilator solutions of orciprenaline or salbutamol, compared with the administration of each of the beta₂-adrenergic agonists alone in patients with asthma.

Combined therapy produced significant additional responses in FEV₁, FVC and FEF_25-75%. On combined therapy, the median duration of 15% improvement in FEV₁ was 5 - 7 hours, compared with 3 - 4 hours in patients receiving a beta agonist alone.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Acute

Acute toxicity has been investigated with observation periods of 14 days in several rodent and non-rodent species.

Table 7-

The signs of toxicity were apathy, reduced mobility, ataxia, paralysis of skeletal muscle, clonic convulsions and death from respiratory failure. Toxic signs persisted for 3 hours after intravenous (i.v.) and 8 days after oral administration.

Table 8-IPRATROPIUM BROMIDE + FENOTEROL HYDROBROMIDE

(RATIO 1:2.5)

The signs of toxicity were spasmodic breathing, tonic, clonic and saltatory convulsions, sedation, ataxia, spasms, exophthalmus, chromolacryorrhoea, reduced motility, tremor and positive sliding test. Late mortality occurred only after oral administration.

Acute dose tolerance studies were performed in dogs. No deaths occurred up to doses of 400 mg/kg oral or 50 mg/kg subcutaneous (s.c). Signs of toxicity were mydriasis, dryness of oral, nasal and optic mucosa, vomiting, ataxia, increased heart rate, decreased body temperature, and death from respiratory failure.

An acute inhalation toxicity study of ipratropium bromide administered as 4% and 8% solution to guinea pigs was performed. No toxic signs were observed with the 4% solution and death occurred after 5 hours of administration with the 8% solution (approximately 200 mg/kg).

Anesthetized normal and hypoventilated dogs tolerated doses up to 200 puffs (4 mg) of ipratropium bromide without EGG changes or heart failure. Reductions in heart rate were observed. Similar findings were seen in dogs given i.v. infusions up to 1550 mg/kg or 1000 mg/kg plus 200 puffs from a placebo inhaler. Blood pressure reductions were also observed.

No deaths occurred in an acute inhalation dose tolerance study in rats using doses up to 160 puffs (3.2 mg) from an ipratropium bromide inhaler was performed or with a combination of ipratropium bromide (up to 3.2 mg/kg) and fenoterol hydrobromide (up to 8 mg/kg) administered by inhalation (up to 320 puffs) to rats.

SUBACUTE

Oral:

A study of 9 weeks duration in rats utilizing doses of 10, 100 and 500 mg/kg revealed no pathological findings apart from a dose related decrease in food consumption and growth rate.

A 4 week study in dogs using doses of 3, 30 and 150 (for 3 weeks) increased to 300 mg/kg showed mydriasis, inhibition of lacrimal and salivary secretion, tracheal and ocular inflammation, decreased food intake and weight loss at the medium and high doses. Three of 6 dogs died when the dose was increased from 150 to 300 mg/kg.

A supplementary study in dogs of 13 weeks duration, using doses of 1.5, 3.0 and 15 mg/kg revealed no pathological changes apart from a dose related inhibition of lacrimal secretions and associated keratoconjunctivitis and dryness of the mouth.

Intravenous:

A 32 day study in rats was conducted with the combination of ipratropium bromide and fenoterol hydrobromide at doses of 1.32 + 3.32 μg/kg (Group 1) 8 + 20 μg /kg (Group 2) and 24 + 60 μg /kg (Group 3), respectively. Fenoterol 60 μg /kg (Group 4) and ipratropium 24 μg /kg (Group 5) were also administered. Increases in heart rate (dose related in all treated animals) and dry mouth and nose (Groups 3 and 5) were seen. Increases in LDH (Groups 3 and 4), creatine kinase (all treated Groups), potassium (Groups 2, 3 and 4) and cholesterol (Groups 3 and 4) were observed. Myocardial scars were seen in one animal in Group 3 and fatty changes in the liver were noted in one animal in Group 4.

Subcutaneous:

Rats were treated with subcutaneous injections of 1, 10 and 100 mg/kg. One death occurred in the 10 mg/kg dose group from paralytic ileus. Inflammatory changes were noted at the injection site.

A 4 week study in dogs using doses of 10, 20 and 30 mg/kg (increased to 40 mg/kg on the last 5 days) was conducted. Dryness of the oral and nasal mucous membranes and mydriasis were noted along with conjunctivitis and keratitis associated with decreased lacrimal secretions. A decrease in food intake and body weight also occurred. One dog died in the high dose group. Signs of liver damage were noted in 2 high dose dogs. Low testicular weights, which have not been observed in other subsequent studies, were also observed.

Inhalation:

Twelve rats were exposed to aerosolized ipratropium bromide in a concentration of 11.5 mcg /L for 1 hour, 4 times per day for 7 days. No drug toxicity was found.

Aerosolized ipratropium bromide of 11.5 mcg/L for 1 hour 4 times daily for 7 days administered to rats demonstrated no toxicity. Administration of ipratropium bromide in doses of 128, 256 and 384 mcg per rat per day for 30 days showed no signs of toxicity apart from a low grade inflammatory response and areas of fibrosis and hemorrhage in the parametrium of 2/9 females in the high dose group. This finding has not been observed in subsequent studies.

No signs of toxicity were observed in rhesus monkeys following inhalation of 500 mcg iptratropium twice daily for 7 days or following inhaled doses of 200, 400 and 800 mcg/day for 6 weeks.

No changes apart from a reduction in food consumption were observed in rats following inhalation exposure to a combination of ipratropium bromide and fenoterol.

A 28 day study in dogs was conducted using fenoterol and ipratropium in the following doses respectively: 350 + 140 μg (Group 3); 1050 + 420 μg (Group 4); 3150 + 1260 μg (Group 5). Vasodilation occurred in Groups 4 and 5 and heart rate was increased in the treated animals. Potassium levels were raised in Group 5. Liver glycogen content was raised in 4 (of 6) animals in Group 5 and 2 in Group 4.

A further 13 week combination study was done in dogs using doses of 23 + 9 μg (Group 1), 160 + 64 μg (Group 2) and 1100 + 440 (Group 3) fenoterol + ipratropium bromide respectively. Peripheral hyperaemia and dry mucous membranes were observed in all treated animals. Increases in heart rate were seen in Groups 1 to 3, and 5 of 6 dogs in Group 3 had disturbances of impulse formation and conduction. Slight increases in GPT in Groups 2 and 3, as well as increases in AP in individual animals of Groups 1 to 3 were noted. Histological findings consisted of a scar in the papillary muscle of the left ventricle of one dog in Group 3 as well as centrolobular fatty infiltration of hepatocytes in dogs of Groups 2 and 3.

CHRONIC

Oral:

A 6 month and a 1 year study in rats using doses of 6, 30 and 150 mg/kg were performed. The high dose was increased to 200 mg/kg after 14 weeks. Reductions in food consumption and growth rates were observed in the highest dose group. A dose dependent constipation which caused severe coprostasis and dilatation of the intestines was observed in the highest dose groups. A toxic hepatosis was observed in some animals of the highest dose group.

Ipratropium bromide was administered to dogs in doses of 1.5, 3.0, 15.0 and 75.0 mg/kg for 1 year. A decrease in body weight was seen in the highest dose group and food consumption was reduced in the dogs receiving 3 mg/kg and above. Emesis was seen in all treated groups. A dose dependent decrease (3 mg/kg and above) in nasal, oral and lacrimal secretions - the latter leading to keratoconjunctivitis - was observed. Increases in SGPT and SGOT (15 and 75 mg/kg) and alkaline phosphatase (75 mg/kg) were noted. Localized gastric necrosis was found in 2 dogs at the highest dose and a non dose-dependent fatty degeneration of the liver, which varied from animal to animal, was also seen.

Inhalation:

In a 6 month study in rats using inhaled doses of 128, 256 and 384 mcg per rat per day the only finding was a dose related decrease in growth rate of the male animals.

No findings were observed in a 6 month inhalation toxicity study in rhesus monkeys administered daily doses of 20, 800 and 1600 mcg.

MUTAGENICITY:

Three Ames tests, a micronucleus test in mice, a cytogenetic study in Chinese hamsters, and a dominant lethal test in mice were performed to assess the mutagenic potential of ipratropium bromide. Two positive tests (one Ames and the micronucleus study) were apparently spurious as they could not be reproduced with subsequent exhaustive experimentation. In the cytogenetic study, a dose related increase in the number of chromatid gaps, but not of other aberrations, was seen. The significance of this finding is not known. All other test results were negative.

CARCINOGENICITY:

Carcinogenicity studies in mice (107 weeks duration) and rats (114 weeks duration) utilizing oral doses of up to 6 mg/kg were performed. No tumorigenic or carcinogenic effects were observed.

REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY:

Three teratological studies, one in mice using oral doses of 2 and 10 mg/kg, and two in rats (oral doses of 2 and 10 mg/kg and 10 and 20 mg/kg), were performed. No drug induced fetal abnormalities were observed.

An oral study in rabbits utilizing doses of 2 and 10 mg/kg again showed no teratogenic or embryotoxic effects of ipratropium bromide.

An inhalation teratology study in rabbits using doses of 0.3, 0.9 and 1.8 mg/kg demonstrated no effect on litter parameters, and no embryotoxic or teratogenic effects.

Two inhalation teratology studies with the combination of fenoterol and ipratropium in rats (doses up to 8 x 25 minute exposures of 7.5 mg fenoterol + 3.0 mg ipratropium per day) and rabbits (doses up to 3.0 mg fenoterol + 1.2 mg ipratropium) revealed no embryotoxic or teratogenic effects.

A fertility study in rats with oral doses of 5, 50 and 500 mg/kg being given 60 days prior to and during early gestation was performed. Fertility was delayed in 8 of 20 couples at 500 mg/kg and spurious pregnancy in 5 of 20 females occurred at this dose. In addition, the conception rate was decreased in 75% of females at this dose. No embryotoxic or teratogenic effects were observed.