PMS-Ipratropium (Pharmascience, 250 mcg) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

pms-IPRATROPIUM (ipratropium bromide) nebulizer solution is indicated for:

• the treatment of bronchospasm associated with acute exacerbations of chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.
• the treatment of bronchospasm associated with acute severe exacerbations of bronchial asthma when used in conjunction with a beta₂ adrenergic agonist such as salbutamol.

pms-IPRATROPIUM nebulizer solution must be administered by means of nebulizer using gas flow (oxygen or compressed air).

Pediatrics

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

CONTRAINDICATIONS

pms-IPRATROPIUM is contraindicated in:

• Patients with a history of hypersensitivity to any of its components or to atropine or its derivatives. For a complete listing, see DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

WARNINGS AND PRECAUTIONS

General

Ipratropium bromide nebulizer solution is intended only for inhalation with suitable nebulizing devices and must not be taken orally or administered parenterally.

It is recommended that the nebulized ipratropium bromide solution be administered via a mouth piece. If this is not available and a nebulizer mask is used, it must fit properly.

Ipratropium bromide nebulizer solution in the 20 mL multidose bottle contains preservatives (Benzalkonium Chloride and disodium ethylenediamine tetraacetic acid- EDTA-disodium). It has been reported that these preservatives may cause bronchoconstriction in some patients with hyper reactive airways.

Ipratropium bromide nebulizer solution 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 an adrenergic beta₂-agonist.

Patients should be instructed in the proper use of the nebulizer.

Caution is advised against accidental release of the solution into the eyes.

In patients with glaucoma, prostatic hyperplasia, urinary retention and bladder neck obstruction, ipratropium bromide nebulizer solution should be used with caution.

If a reduced response to ipratropium bromide nebulizer solution becomes apparent, the patient should seek medical advice.

Ipratropium bromide nebulizer solution, when administered to patients with acute severe asthma, should be used with concomitant beta₂ adrenergic agonist therapy.

Anticholinergic Effects

Like other anticholinergic drugs, ipratropium bromide nebulizer solution should be used with caution in patients with narrow-angle glaucoma or urinary retention.

Worsening of Narrow-Angle Glaucoma

Ipratropium bromide nebulizer solution 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 has not come in contact with the eyes. Patients should be advised that this may result in precipitation or worsening of narrow-angle glaucoma. There have been isolated cases of ocular complications (i.e., mydriasis, increased intraocular pressure, narrow angle closure glaucoma, eye pain) when nebulized ipratropium bromide either alone or in combination with an adrenergic beta2-agonist solution has come in contact with the eyes.

In patients with glaucoma or narrow anterior chambers, the administration by nebulizer of a combined ipratropium/beta₂-agonist solution should be avoided unless measures (e.g., use of swimming goggles or use of a nebulizer with a mouthpiece) are taken to ensure that nebulized solution does not reach the eye. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. Miotic drops alone are not considered to be effective treatment.

Worsening of Urinary Retention

Ipratropium bromide nebulizer solution should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

Carcinogenesis and Mutagenesis

Please see TOXICOLOGY section.

Gastrointestinal

Patients with cystic fibrosis may be more prone to gastrointestinal motility disturbances.

Immune

Hypersensitivity reactions including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema may occur after administration of ipratropium bromide. In clinical trials and post-marketing experience with ipratropium containing products, hypersensitivity reactions such as skin rash, pruritus, angioedema of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported (see ADVERSE REACTIONS). If such a reaction occurs, therapy with ipratropium bromide nebulizer solution should be stopped at once and alternative treatment should be considered (see CONTRAINDICATIONS).

Ophthalmologic

Worsening of Narrow-Angle Glaucoma (see WARNINGS AND PRECAUTIONS, Anticholinergic Effects).

Renal

Worsening of Urinary Retention (see WARNINGS AND PRECAUTIONS, Anticholinergic Effects).

Respiratory

Paradoxical Bronchospasm

Severe life threatening paradoxical bronchospasm has been reported in patients receiving beta₂-agonists. If it occurs, therapy with ipratropium bromide nebulizer solution should be discontinued immediately and alternative therapy instituted.

Dyspnea

The patient should be instructed to consult a doctor immediately in the event of acute, rapidly worsening dyspnea. In addition, the patient should be warned to seek medical advice should a reduced response become apparent.

Special Populations

Pregnant Women

The safety of ipratropium bromide nebulizer solution in pregnancy has not been established. There are no adequate and well-controlled studies of ipratropium bromide nebulizer solution in pregnant women.

Nonclinical studies have shown no embryotoxic or teratogenic effects following inhalation or intranasal application at doses considerably higher than those recommended in man.

Because animal reproduction studies are not always predictive of human response, ipratropium bromide nebulizer solution should be used during pregnancy only if the potential benefit justifies the potential risk to the unborn child.

Nursing Women

No specific studies have been conducted on the excretion of ipratropium bromide in breast milk. It is considered unlikely that ipratropium bromide would reach the infant to an important extent, especially when administered by inhalation. However, caution should be exercised when ipratropium bromide nebulizer solution is administered to nursing mothers. The benefits of ipratropium bromide nebulizer solution use during lactation should therefore be weighed against possible effects on the infant.

Pediatrics

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

Effects on Ability to Drive and Use Machines

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 ipratropium bromide nebulizer solution. Therefore, caution should be recommended when driving a car or operating machinery. If patients experience the above mentioned side effects they should avoid potentially hazardous tasks such as driving or operating machinery.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Use of ipratropium bromide may result in:

• Ocular effects (see WARNINGS AND PRECAUTIONS, General and Ophthalmologic)
• Urinary retention (see WARNINGS AND PRECAUTIONS)

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Acute Administration

The frequency of adverse reactions recorded in 214 patients receiving ipratropium bromide nebulizer solution was as follows:

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

Bronchospasm occurred in 3 patients with acute severe asthma who received ipratropium bromide nebulizer solution alone. In two patients, this was reversed after therapy with a beta₂- sympathomimetic solution. The third patient received no other therapy.

The following table compares the incidence of adverse reactions of the combination of ipratropium bromide and a beta₂-agonist (either fenoterol or salbutamol) solution with that of the beta₂- agonist alone.

Chronic Administration

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

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 and 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 + beta_2-agonists (metaproterenol or salbutamol) versus the beta₂-agonist alone, was as follows:

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

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 beta₂-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 WARNINGS AND PRECAUTIONS).

Post-Market Adverse Drug 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 nebulizer solution are headache and dryness of mouth/throat.

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

Dizziness has been reported.

DRUG INTERACTIONS

Overview

In patients receiving other anticholinergic drugs, ipratropium bromide nebulizer solution should be used with caution because of possible additive effects.

Ipratropium bromide nebulizer solution with preservatives (i.e., from the 20 mL multidose bottle) should not be mixed with sodium cromoglycate, as this produces a cloudy solution caused by complexation between the preservatives and sodium cromoglycate. If the patient's condition requires the administration of sodium cromoglycate, it should be given in combination with ipratropium bromide nebulizer solution without preservatives.

In acute and maintenance therapy of chronic reversible airways obstruction, ipratropium bromide has been shown to provide additive bronchodilating effects to theophylline and beta-adrenoceptor agonists (sympathomimetic amines). Repeated inhalation of ipratropium bromide has not been linked to tolerance towards bronchodilating effects.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Counselling by physicians 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.

In adults, the average single dose of pms-IPRATROPIUM (ipratropium bromide) solution is 250 - 500 mcg of ipratropium bromide. In children, aged 5 - 12 years, the recommended dose is 125 - 250 mcg of ipratropium bromide. In most cases, dilution of the dose with sterile preservative-free saline is not necessary. However, volumes of pms-IPRATROPIUM solution less than 2 mL are not appropriate for nebulization and must be diluted with saline or another suitable nebulizer solution to make up a total fill volume of 2 - 5 mL (see PHARMACEUTICAL INFORMATION).

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™,

Bennett Twin Jet^®, DeVilbiss, Pari Compressors and lnspiron Mini-Neb^® nebulizers, with facemask or mouthpiece have been used. The manufacturers' instructions concerning cleaning and maintenance of the nebulizer should be strictly followed.

Treatment with pms-IPRATROPIUM solution may be repeated every 4 - 6 hours as necessary.

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

For the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, the recommended dose is 500 mcg of pms-IPRATROPIUM (ipratropium bromide) nebulizer solution given 3 - 4 times per day.

Missed Dose

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

OVERDOSAGE

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

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

For management of a suspected overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) 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 from the peak. Bronchodilation is still evident 8 hours after inhalation.

Pharmacodynamics

Large, single inhaled doses of ipratropium bromide have been given to man without any signs of toxicity. After the administration of 400 mcg to 10 healthy subjects, no changes were detected in pulse rate, blood pressure, intraocular pressure, salivary secretion, visual accommodation or electrocardiograms. Likewise, in a similar study no change in pulse rate or salivary secretion were seen when cumulative doses up to 1.2 mg were administered by inhalation to healthy volunteers.

Special studies utilizing normal therapeutic doses in asthmatic and chronic bronchitic patients have not revealed any systemic anticholinergic effects.

In one study, 14 patients were treated for 45 days with ipratropium bromide 40 mcg q.i.d. or ipratropium bromide 40 mcg q.i.d. plus oral fenoterol 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 40 mcg t.i.d. administered for 3 days.

A wide variety of challenge studies have been conducted using 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 no effect against histamine or serotonin. Studies in exercise induced bronchospasm have yielded variable results. Some investigations have indicated that ipratropium bromide has little or no effect but other studies have shown that some patients, at least, were protected against bronchospasm induced by exercise. Likewise, the protection against cold air induced bronchospasm has been variable.

The Lung Health Study

The Lung Health Study was a randomized multi-centre clinical trial carried out from October 1986 to April 1994 in North America. It was designed to test the effectiveness of intervention-smoking cessation and bronchodilator administration in smokers aged 35 - 60 years who have mild obstructive pulmonary disease. The main outcome or end point was the rate of change and cumulative change in FEV₁ over a 5-year period.

A total of 5887 male and female smokers, aged 35 to 60 years, with spirometric signs of early chronic obstructive pulmonary disease were recruited. Participants were randomized to one of the following groups: (1) smoking intervention plus bronchodilator, (2) smoking intervention plus placebo, or (3) no intervention.

Smoking intervention consisted of an intensive 12-session smoking cessation program combining behaviour modification and use of nicotine gum, with continuing 5-year maintenance program to minimize relapse. Two puffs ipratropium bromide was prescribed three times daily from a metered-dose-inhaler.

The results showed that participants in the two smoking intervention groups showed significantly smaller declines in FEV₁ than did those in the control group. Most of this difference occurred during the first year following entry into the study and was attributable to smoking cessation, with those who achieved sustained smoking cessation experiencing the largest benefit. The benefit associated with the use of the ipratropium bromide vanished after the ipratropium bromide was discontinued at the end of the study.

In summary, the results showed that smoking intervention reduced the rate of decline in FEV₁ in middle aged smokers with mild airways obstruction who remained non-smokers throughout the 5 years. The other intervention, administration of ipratropium bromide, did not alter the rate of decline in lung function. There was a small one time improvement in lung function associated with the onset of ipratropium use, but this disappeared rapidly when ipratropium use was discontinued at the end of the study. Otherwise, the regular use of ipratropium bromide had no effect on the rate of decline of lung function over 5 years in patients studied.

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 plasma concentration-versus-time curve was similar to that seen after oral administration, likely reflecting the large fraction of inhaled dose which is deposited on the pharyngeal mucosa and swallowed.

Intravenous administration of 1.0 mg in man showed a rapid distribution into tissues (half-life of an alpha phase approximately five 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).

Cumulative renal excretion (0 - 24 hrs) of ipratropium (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 apparent 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 relevantly contribute to systemic exposure.

Distribution

Kinetic parameters describing the disposition of ipratropium were calculated from plasma concentrations after IV administration. A rapid biphasic decline in plasma concentrations is observed. The apparent volume of distribution at steady-state (Vdss) is approximately 176 L (≈ 2.4 L/kg).

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.

Metabolism

The half-life of the terminal elimination phase is approximately 1.6 hours. Ipratropium has a total clearance of 2.3 L/min and a renal clearance of 0.9 L/min. After intravenous administration approximately 60% of a dose is metabolised, the major portion probably in the liver by oxidation.

Elimination

Up to 8 metabolites of ipratropium bromide have been detected in man, dog and rat. 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 3.6 hours. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective.

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.

Special Populations and Conditions

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

STORAGE AND STABILITY

Unopened bottles of pms-IPRATROPIUM solution should be stored at controlled room temperature (between 15°C and 30°C). Solutions diluted with preservative free sterile Sodium Chloride Inhalation Solution, USP 0.9% should be used within 24 hours from time of dilution when stored at room temperature and within 48 hours when stored in the refrigerator.

A controlled Preservative Challenge test, done in accordance with the current USP guideline for Preservative Efficacy Testing, indicated that bottles of ipratropium bromide nebulizer solution, opened and closed several times, simulating patient use, were stable for up to 28 days when stored at room temperature (15º - 30ºC).

Controlled laboratory experiments using mixtures of ipratropium bromide solution with ALUPENT^® (orciprenaline sulfate), BEROTEC^® (fenoterol hydrobromide) or salbutamol sulfate (6 mg/mL preserved with benzalkonium chloride) solutions and diluted with a sterile bacteriostatic sodium chloride solution 0.9% (i.e., normal saline), preserved with benzalkonium chloride, indicated that such mixtures were stable for 7 days at room temperature. For the preparation of such mixtures, it is recommended that only sterile solutions of bacteriostatic sodium chloride 0.9% preserved with 0.01% Benzalkonium Chloride be used to maintain the level of preservative in the mixture.

The safety of preservatives other than Benzalkonium Chloride has not been established.

SPECIAL HANDLING INSTRUCTIONS

Incompatibilities

pms-IPRATROPIUM solution with preservatives (i.e., from the 20 mL multidose bottle) should not be mixed with sodium cromoglycate solution, as this produces a cloudy solution caused by complexation between the preservatives and sodium cromoglycate. If the patient's condition requires the administration of sodium cromoglycate, it should be given in combination with ipratropium bromide solution without preservatives.

DOSAGE FORMS, COMPOSITION AND PACKAGING

pms-IPRATROPIUM solution is provided as 20 mL of clear, colourless or almost colourless solution containing 250 mcg/mL (0.025%) ipratropium bromide in isotonic solution. This solution is preserved with Benzalkonium Chloride (250 mcg/mL) and EDTA-disodium (500 mcg/mL) at a pH of 3.4, and is presented in an amber glass bottle with screwcap.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Common Name: Ipratropium bromide monohydrate

Chemical Name: (8r)-3α-hydroxy-8-isopropyl-1αH, 5αH-tropanium bromide (±)-tropate monohydrate

Structural Formula:

Molecular Formula: C₂₀H₃₀NO₃Br•H₂O

Molecular Weight: 430.4 g/mol

Physicochemical Properties: 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. The melting point is 229 - 231°C with decomposition. [α] 20=0°

CLINICAL TRIALS

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

Additional controlled 12-week studies were conducted to evaluate the safety and efficacy of ipratropium bromide nebulizer solution administered concomitantly with bronchodilator solutions of orciprenaline or salbutamol, compared with the administration of each of the beta agonists alone.

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 to 7 hours, compared with 3 to 4 hours in patients receiving a beta agonist alone.

DETAILED PHARMACOLOGY

Mechanism of Action

Ipratropium bromide is an anticholinergic agent which, when delivered by aerosol, exerts its effects primarily in the bronchial tree. It abolishes acetylcholine-induced bronchospasm in the guinea pig and dog after intravenous administration of ED₅₀ of 0.15 and 0.40 mcg/kg with a transient effect on blood pressure. By inhalation, approximately 25 mcg of ipratropium bromide produces 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 IV administration. Histological evaluation of human bronchial mucosae following chronic inhalation of ipratropium bromide showed no alterations of epithelial, ciliated or goblet cells. Short term mucociliary clearance in normal and bronchitic subjects was not adversely affected by 200 mcg of inhaled ipratropium bromide.

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 s.c. dose of about 0.011 mg/kg, equipotent to atropine, but the equi-effective oral dose of ipratropium was 58 times greater. By inhalation, no increase in heart rate or pathological changes in ECG pattern were recorded at doses up to 8 mg. In another study, blood pressure and heart rate in the dog could be modulated after intravenous (IV) administration of low doses of ipratropium but metered aerosol administration of 100 puffs (40 mcg/puff) was required to produce an 11% increase in heart rate.

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% decrease in 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 s.c. doses but were 10 - 20 times less after oral administration. Tests in the rabbit indicated that doses up to 100 mg/kg had no effect on the central nervous system.

Ipratropium bromide administered s.c. inhibited the secretory effects of the cholinergic agonist, oxitropium, in mice. It also inhibited spasmolytic effects equivalent to or greater than atropine in isolated guinea pig gut. In vitro tests with isolated rectum of the guinea pig demonstrated the effectiveness of ipratropium bromide in suppressing the spasmogenic effects of acetylcholine and pilocarpine. It was ineffective against histamine or barium chloride induced spasm. Ipratropium bromide exerted anticholinergic effects on the in situ bladder and intestine preparations of the dog. Intravenous doses were 500 times more potent than oral or intraduodenal administration.

TOXICOLOGY

Single Dose Studies

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

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 IV and 8 days after oral administration.

Single dose tolerance studies were performed in dogs. No deaths occurred at doses of up to 400 mg/kg oral or 50 mg/kg 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.

A single dose inhalation toxicity study of ipratropium bromide administered as a 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).

A single dose inhalation tolerance study in rats with Benzalkonium Chloride (0.025%) or Benzalkonium Chloride (0.025%) plus ipratropium bromide (0.025%) administered over 8 hours was performed. No clinical signs of intolerance were observed. Necropsy and histological findings (16 hours and 14 days after administration) were also negative.

Anesthetized normal and hypoventilated dogs tolerated doses up to 200 puffs (4 mg) of ipratropium bromide without ECG changes or heart failure. Reductions in heart rate were observed. Similar findings were seen in dogs given IV infusions (10 mg/kg/min) up to 1550 mg/kg or 1000 mg/kg plus 200 puffs from a placebo inhaler. Blood pressure reductions were also seen in these experiments.

A single dose inhalation, dose tolerance study in rats using doses of up to 160 puffs (3.2 mg) from an ipratropium bromide inhaler was performed. No deaths occurred.

Multiple Dose Studies

Oral

A multiple dose toxicity study of nine 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 four week study in dogs using doses of 3, 30 and 150 (for three 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 six dogs died when the dose was increased from 150 to 300 mg/kg.

A supplementary study of 13 weeks 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.

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 four week study in dogs using doses of 10, 20 and 30 mg/kg (increased to 40 mg/kg on the last five 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 two 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.

In another study, administration of ipratropium bromide at concentrations 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 of 9 females in the high dose group. This finding has not been observed in subsequent studies.

Four rhesus monkeys inhaled 500 mcg of ipratropium bromide twice a day (total dose 1 mg/day) for seven days without the appearance of any drug induced toxicity.

In another rhesus monkey study, the animals were given ipratropium bromide at doses of 200, 400 and 800 mcg/day by inhalation for six weeks. Included in the tests were measurements of mucociliary transport rate and ciliary beat frequency. No signs of drug toxicity were found.

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 at doses of 1.5, 3.0, 15.0 and 75.0 mg/kg for 1 year. A decrease in body weight development 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 two 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

A 6 month study in rats was performed using doses of 128, 256 and 384 mcg per rat per day. Measurements included ciliary beat frequency, lung mechanics and blood gas. The only finding was a dose related decrease in growth rate of the male animals.

A 6 month inhalation toxicity study was performed in rhesus monkeys utilizing daily doses of 20, 800 and 1600 mcg. All findings were negative including measurements of lung mechanics, ciliary beat frequency and blood gases.

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

Ipratropium bromide was tested individually for neoplastic properties in several carcinogenicity studies. Carcinogenicity studies in mice (107 weeks duration) and rats (114 weeks duration) utilizing oral doses of up to 6 mg/kg were performed. Ipratropium bromide revealed no carcinogenic potential when tested orally in mice and rats.

Genotoxicity

Ipratropium bromide was tested in numerous in-vivo and in-vitro genotoxicity tests and showed no evidence of mutagenic properties.

Reproductive Studies

Three teratology studies, one in mice using oral doses of 2 and 10 mg/kg and two in rats have been conducted. The first rat study used the same dosages while the second employed 10 and 20 mg/kg. None of these studies revealed any drug induced fetal abnormalities.

A similar oral study in rabbits utilizing doses of 2 and 10 mg/kg again demonstrated 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.

A fertility study in rats with oral doses of 5, 10 and 500 mg/kg given 60 days prior to and during early gestation was performed. Fertility was delayed in eight of 20 couples at 500 mg/kg dose and spurious pregnancy in five 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.

Apart from these findings, the studies performed with ipratropium bromide revealed only marginal effects, if any, on embryos, foetuses and pups and these only in the range of maternal toxicity. Ipratropium bromide did not affect fertility of male or female rats at oral doses up to 50 mg/kg (approximately 3,400 times the MRHDD on a mg/m² basis).

REFERENCES

1. 1) Beasley GRW, Ratterty P, Holgate ST. Bronchoconstrictor properties of preservatives in ipratropium bromide (ATROVENT) nebuliser solutions. Br Med J 1987; 294:1197-8.
2. 2) Beck R, Robertson C, Galdes-Sebaldt M, Levison H. Combined salbutamol and ipratropium bromide by inhalation in the treatment of severe acute asthma. J Pediatr 1985; 107:605-8.
3. 3) Brown I.G., Chan C.S., Kelly C.A., et al. Assessment of the Clinical Usefulness of Nebulised Ipratropium Bromide in Patients with Chronic Airflow Limitation. Thorax 1984; 39:4:272-276
4. 4) Bryant DH. Nebulized ipratropium bromide in the treatment of acute asthma. Chest 1985; 88:24-9.
5. 5) Chan CS, Brown IG, Kelly GA, Dent AG, Zimmerman PV. Bronchodilator responses to nebulized ipratropium and salbutamol singly and in combination in chronic bronchitis. Br J Clin Pharmacol 1984; 17:103-5.
6. 6) Chan-Yeung M. The effect of Sch 1000 and disodium cromoglycate on exercise-induced asthma. Chest 1977; 71:320-3.
7. 7) Cockroft DW, Ruffin RE, Hargreave FE. Effect of Sch 1000 in allergen-induced asthma. Clin Allergy 1978; 8:361-72.
8. 8) Cockroft DW, Killian DN, Mellon JJA, Hargreave FE. Protective effect of drugs on histamine-induced asthma. Thorax 1977; 32:429-37.
9. 9) Davis A, Vickerson F, Worsley G, Mindorff G, Kazim F, Levison H. Determination of the dose response relationship for nebulized ipratropium in asthmatic children. J Pediatr 1984; 105:1002-5.
10. 10) Douglas NJ, Davidson I, Sudlow MF, Flenley DC. Bronchodilation and the site of airway resistance in severe chronic bronchitis 1979; 34:51-6.
11. 11) Anonymous. Ipratropium (ATROVENT) for airway obstruction. Drug Ther Bull 1980; 18:59.
12. 12) Engelhardt A. Pharmacology and toxicology of ATROVENT. Scand J Respir Dis 1979; 60 (Suppl 103):110-5.
13. 13) Ensing K, Zeeuw RA de, Nossent GD, Koeter GH, Cornelissen PJG. Pharmacokinetics of ipratropium bromide after single dose inhalation and oral and intravenous administration.. Eur J Clin Pharmacol 1989; 36(2):189-194.
14. 14) Ensinger HA, Wahl D, Brantl V. Radioreceptor assay for determination of the antimuscarinic drug ipratropium bromide in man. Eur J Clin Pharmacol 33, 459 - 462 (1987).
15. 15) Jenkins CR, Chow GM, Fisher BL, Martin GE. Comparison of ipratropium bromide and salbutamol by aerosolized solution. Aust NZ J Med 1981; 11:513-6.
16. 16) Lenney W, Evans NAP. Nebulized salbutamol and ipratropium bromide in asthmatic children. Br J Dis Chest 1986; 80:59-65.
17. 17) McIntosh D. A comparison between fenoterol/ipratropium bromide combinations and salbutamol administered as nebulizer solutions assessing dose-response and duration of action. Pharmatherapeutica 1986; 4:416-21.
18. 18) Molkenboer JFWM, Lardenoye JG. The effect of ATROVENT in micturition function, double-blind cross-over study. Scand J Respir Dis 1979; 60 (Suppl 103):154-8.
19. 19) Pavia, Bateman JRM, Sheahan NF, Clarke SW. Effect of ipratropium bromide on mucociliary clearance and pulmonary function in reversible airways obstruction. Thorax 1979; 34: 501-7.
20. 20) Ipratropium bromide. In: Martindale: the complete drug reference. 34th ed. London: Pharmaceutical Press, 787 (2005).
21. 21) Rebuck AS, Abboud R, Pare PD, et al. Nebulized anticholinergic and sympathomimetic treatment of obstructive airways disease in the emergency room. Am J Med 1987; 82:59-64.
22. 22) Rominger KL. Chemistry and pharmacokinetics of ipratropium bromide. Scand J Respir Dis 1979; 60 (Suppl 103):116-126.
23. 23) Ruffin RE, Cockcroft DW, Hargreave FE. A comparison of the protective effect of fenoterol and Sch 1000 on allergen-induced asthma. J Allergy Clin lmmunol 1978; 61:42-7.
24. 24) Ruffin RE, Wolff RD, Dolovich MB, Rossman CM, Fitzgerald MB, Newhouse MT. Aerosol therapy with Sch 1000: Short-term mucociliary clearance in normal and bronchitic subjects and toxicology in normal subjects. Chest 1978; 73:501-6.
25. 25) Sackner MA, Friedman M, Silva G, Fernandez R. The pulmonary hemodynamic effects of aerosols of isoproterenol and ipratropium in normal subjects and patients with reversible airway obstruction. Am Rev Respir Dis 1977; 116:1013-22.
26. 26) Ward MJ, Macfarlane JH, Davies D. A place for ipratropium bromide in the treatment of severe asthma. Br J Dis Chest 1985; 79:374-8.
27. 27) Ward MJ, Fentem PH, Roderick-Smith WH, Davies D. lpratropium bromide in acute asthma. Br Med J 1981; 282:598-600.
28. 28) Proceedings from the Canadian Bronchitis Symposium. February 18-19, 1994. Recommendations on the Management of Chronic Bronchitis. CMAJ, suppl. Nov. 15, 1994; Vol. 151 (10).
29. 29) Anthonisen NR, Connett JE, Kiley JP, et al. Effects of Smoking Intervention and the use of an Inhaled Anticholinergic Bronchodilator on the Rate of Decline of FEV₁: The Lung Health Study. JAMA. Nov.16, 1994, Vol. 272 (19):1471-1556.
30. 30) Product Monograph. ATROVENT^® (Ipratropium Bromide) Inhalation Solution. Boehringer Ingelheim (Canada) Ltd., Burlington, Ontario (Revised May 16, 2006).
31. 31) Product Monograph. COMBIVENT^® UDV, lpratropium Bromide (as Monohydrate) and Salbutamol (as Salbutamol Sulfate) Nebulizer Solution. Boehringer lngelheim (Canada) Ltd., Burlington, Ontario (Revised November 25, 2015).