Atrovent Udv Sol Inh 250mcg/mL Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

ATROVENT UDV (ipratropium bromide) Inhalation Solution administered either alone or with a adrenergic stimulant solution is indicated:

• As a bronchodilator for the maintenance treatment of bronchospasm associated with, or for the therapy of, acute exacerbations of chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. ATROVENT solution, when used in conjunction with a β₂ adrenergic stimulant solution such as fenoterol or salbutamol, is indicated for acute asthmatic attacks. It is to be administered by compressed air or oxygen driven nebulizers.

Pediatrics:

The efficacy and safety of ATROVENT UDV in children younger than 6 years has not been established.

CONTRAINDICATIONS

• Known hypersensitivity to ATROVENT UDV (ipratropium bromide), to any of the product ingredients, or to atropinics. For a complete listing see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.

WARNINGS AND PRECAUTIONS

General

ATROVENT UDV 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 β₂ agonist.

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

ATROVENT UDV is intended only for inhalation with suitable nebulizing devices and should not be taken orally or administered parenterally.

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 pre-existing urinary outflow tract obstruction (e.g. prostatic hyperplasia, urinary retention or bladder neck obstruction,) ATROVENT should be used with caution.

If a reduced response to ATROVENT UDV comes apparent, the patient should seek medical advice.

ATROVENT UDV solution, when administered to patients with acute severe asthma, should be used with concomitant β₂ adrenergic stimulant therapy.

Carcinogenesis and Mutagenesis

Please see TOXICOLOGY section.

Ophthalmic

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 a combined ATROVENT/β₂ agonist solution should be avoided unless measures (eg., 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 adrenergic β₂ 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 of acute narrow-angle glaucoma. In the event that glaucoma is precipitated or worsened, treatment should include standard measures for this condition.

In patients with a predisposition to narrow-angle glaucoma, ATROVENT should be used with caution.

Gastrointestinal

Patients with cystic fibrosis may be more prone to gastro-intestinal motility disturbances.

Special Populations

Fertility: Preclinical studies performed with ipratropium bromide showed no adverse effect on fertility (see Toxicology Section). Clinical data on fertility are not available for ipratropium bromide.

Pregnant Women:

The safety of ATROVENT UDV in pregnancy has not been established. The benefits of using ATROVENT UDV when pregnancy is present or suspected must be weighed against possible hazards caused to the fetus. Studies in rats, mice and rabbits showed nor embryotoxic or teratogenic effects.

Nursing Women:

No specific studies have been conducted on excretion of this drug in breast milk. Benefits of ATROVENT UDV use during lactation should therefore be weighed against possible effects on the infant.

Pediatrics:

The efficacy and safety of ATROVENT UDV in children younger than 6 years has not been established.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Side effects noted as with the use of other inhalation therapy are 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 (constipation, diarrhoea and vomiting), dizziness and dryness of the mouth/throat.

The adverse event profile was examined in a total of 214 patients receiving ATROVENT solution, 94 patients receiving ATROVENT plus a β₂ agonist (either fenoterol or salbutmaol)

solution and in 96 patients receiving a β2 agonist alone. Furthermore the frequency of adverse reactions reported as possibly related to ATROVENT treatment was studied in a 12-week controlled clinical trial in 219 COPD patients.

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 ATROVENT (ipratropium bromide) solution was as follows:

ADVERSE REACTION % OF PATIENTS

Dry mouth or throat 9.3

Bad taste 5.1

Tremor 4.2

Exacerbation of symptoms 4.2

Burning eyes 0.9

Nausea 0.9

Sweating 0.9

Cough 0.9

Headache 0.5

Palpitations 0.5

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

Bronchospasm occurred in 3 patients with acute severe asthma who received ATROVENT 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 of the combination of ATROVENT and a β₂ agonist (either fenoterol or salbutamol) solution with that of the β₂ agonist alone.

ADVERSE REACTION ATROVENT + β₂ AGONIST β₂-AGONIST

(% of 94 patients) (% of 96 patients)

Tremor 31.9 26.0

Dry Mouth 16.0 28.1

Bad Taste 16.0 13.5

Vomiting 2.1 2.1

Palpitations 2.1 1.0

Headache 1.1 2.1

Cough 1.1 0.0

Flushing 1.1 0.0

Dizziness 0.0 1.0

Numbness in leg 0.0 1.0

CHRONIC ADMINISTRATION

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

ADVERSE REACTIONS % OF PATIENTS

Dry Mouth 2.7

Coughing 1.8

Dyspnea 1.8

Headache 1.8

Urinary Retention 1.4

Tremor 0.9

Nausea 0.9

Palpitation 0.9

Eye pain 0.9

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 ATROVENT + β₂ agonists (metaproterenol or salbutamol) versus the β₂ agonist alone, was as follows:

ADVERSE EFFECT % OF PATIENTS

ATROVENT + β₂ AGONIST

(n = 208)

β₂ AGONIST (n = 417)

Headache 4.3 1.7

Tremor 3.8 3.4

Nervousness 3.8 1.9

Dyspnea 2.4 3.4

Dry mouth 2.4 1.0

Bronchitis 2.9 2.9

Dizziness 1.4 1.9

Coughing 1.4 1.0

Taste perversion 1.9 1.2

Insomnia 1.9 0.2

Dysuria 1.0 0.2

Nausea 1.0 1.7

Abnormal vision 0.5 1.2

Chest pain 1.4 0.7

Constipation 1.4 0.0

Dysphonia 1.0 0.2

Dyspepsia 1.0 0.0

Bronchospasm aggravated 1.0 0.7

Micturition frequency 1.0 0.2

Many of the listed undesirable effects can be assigned to the anticholinergic properties of ATROVENT^®. As with all inhalation therapy ATROVENT^® 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 adverse events reported in clinical trials were headache, throat irritation, cough, dry mouth, gastrointestinal motility disorders (constipation, diarrhea, vomiting), dizziness and nausea.

As with other inhaled therapy including bronchodilators, cough, local irritation, paradoxical bronchospasm and in very rare instances, exacerbation of symptoms have been observed.

Post-Market Adverse Drug Reactions World-wide safety data, including post-marketing data, spontaneous reports, literature reports, and reports from clinical trials list below the most frequent undesirable effects of ATROVENT according to system organ class.

Immune system disorders

• hypersensitivity
• anaphylactic reaction
• angioedema

Nervous system disorders

• headache
• dizziness

Eye disorders

• vision blurred
• mydriasis
• intraocular pressure increased
• glaucoma
• eye pain
• halo vision
• conjunctival hyperaemia
• corneal oedema
• accommodation disorder

Cardiac disorders

• palpitations
• supraventricular tachycardia
• atrial fibrillation
• heart rate increased

Respiratory, thoracic and mediastinal disorders

• throat irritation
• cough
• bronchospasm
• bronchospasm paradoxical
• laryngospasm
• pharyngeal oedema
• dry throat

Gastrointestinal disorders

• dry mouth
• nausea
• gastrointestinal motility disorder
• diarrhoea
• constipation
• vomiting
• stomatitis
• oedema mouth

Skin and subcutaneous tissue disorders

• rash
• pruritus
• urticaria

Renal and urinary disorders

• urinary retention

DRUG INTERACTIONS

Overview

In patients receiving other anticholinergic drugs, ATROVENT should be used with caution because of possible additive effects.

ATROVENT 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 ATROVENT solution without preservatives (i.e., from the unit dose vial).

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

Drug-Lifestyle Interactions

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 ATROVENT^®. 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.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

In adults, the average single dose of ATROVENT (ipratropium bromide) UDV solution is 250-500 mcg of ipratropium bromide. In children, aged 6 - 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 ATROVENT UDV solution less than 2 mLs 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 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.

Treatment with ATROVENT UDV 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 ATROVENT UDV(ipratropium bromide) 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 ATROVENT (ipratropium bromide) 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 accommodation disorder and increase of heart rate may occur.

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

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

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

ATROVENT UDV (ipratropium bromide), a quaternary ammonium derivative of atropine is an anticholinergic drug having bronchodilator properties. 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.

Pharmacodynamics

Large, single inhaled doses of ATROVENT have been given to man without any signs of toxicity. After the administration of 400 μg 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 have not revealed any systemic anticholinergic effects. In one study, 14 patients were treated for 45 days with either ATROVENT inhaler 40 μg q.i.d. or ATROVENT inhaler 40 μg q.i.d. plus oral Berotec 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 ATROVENT inhaler 40 μg t.i.d administered for 3 days.

Deterioration in pulmonary function in patients treated in all clinical trials with therapeutic doses of ATROVENT 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.

Treatment Incidence

Normal saline 15/90 (16.7%)

ATROVENT Solution 14/214 (6.5%)

ATROVENT Inhaler 4/78 (5.1%)

Berotec Solution 4/83 (4.8%)

ATROVENT Solution + Berotec Solution 1/81 (1.2%)

Dose titration studies in stable asthmatic patients with ATROVENT solution have indicated that maximal improvement in pulmonary function occurs at approximately 250 μg for adults and 125 μg for children over 6 years.

A clinical pharmacology study comparing single doses of ATROVENT inhaler (80 mcg) and ATROVENT 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 ATROVENT as a protective agent. In pharmacologically induced bronchospasm, ATROVENT, in clinical doses, was very effective against methacholine and acetylcholine, moderately effective against propranolol but had little or no effect against histamine or serotonin. Studies in exercise induced bronchospasm have yielded variable results. Some investigations have indicated that ATROVENT has little or no effect but other studies have shown that some patients are protected against bronchospasm induced by exercise. Likewise, the protective effects of ATROVENT against cold air induced bronchospasm have been variable.

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

Pharmacokinetics

Absorption:

Ipratropium bromide is absorbed quickly after oral inhalation of a nominal dose of 40 µg 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. Time courses of bronchodilation and systemic pharmacokinetics do not run in parallel.

Following inhalation 10 to 30% of a dose is generally deposited in lungs, depending on the formulation and inhalation technique. The major part of the dose is swallowed and passes 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 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 relevantly

contribute to systemic exposure.

Distribution:

Intravenous administration of 1.0 mg in man 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).

The basic pharmacokinetic parameters describing the disposition of ipratropium were calculated from the plasma concentrations after i.v. administration. A rapid biphasic decline in plasma was noted for ipratropium. The half-life of the terminal elimination phase was approximately 1.6 hours. The total clearance of the active ingredient is 2.3 L/minute with a renal clearance of 0.9 L/min. 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. The quaternary amine ipratropium does not cross the blood-brain barrier.

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.

After intravenous administration approximately 60% of a dose is metabolised, the major portion probably in the liver by oxidation.

Excretion:

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.

Special Populations and Conditions

Pediatrics: The efficacy and safety of ATROVENT UDV in children younger than 6 years has not been established.

STORAGE AND STABILITY

1 mL or 2 mL Unit Dose Vials

1 mL Unit Dose Vials

Store at 15- 25ºC. Protect from heat and light.

2mL Unit Dose Vials

Store at 15-30ºC. Protect from heat and light.

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

DOSAGE FORMS, COMPOSITION AND PACKAGING

2 ML UNIT DOSE VIAL

250 mcg/mL

ATROVENT UDV is also provided as 2 mL of clear, colourless solution containing 250 mcg/mL (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. Each UDV strip is packaged in an aluminum/low density polyethylene (LDPE) pouch.

Non-medicinal ingredients include sodium chloride, hydrochloric acid and purified water.

125 mcg/mL

ATROVENT UDV is also provided as 2 mL of clear, colourless solution containing 125 mcg/mL (0.0125%) ipratropium bromide in isotonic solution, presented in a plastic single use vial. Each vial contains a total of 250 mcg of ipratropium bromide. Each UDV strip is packaged in an aluminum/low density polyethylene (LDPE) pouch.

Non-medicinal ingredients include sodium chloride, hydrochloric acid and purified water.

1 ML UNIT DOSE VIAL

ATROVENT UDV is also provided as 1 mL of clear, colourless solution containing 250 mcg/mL (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. Each UDV strip is packaged in an aluminum/low density polyethylene (LDPE) pouch.

Non-medicinal ingredients include sodium chloride, hydrochloric acid and purified water.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: ipratropium bromide

Chemical name: (8r)-8-Isopropyl-3-(+)-tropoyloxylαH, 5αH-

tropanium bromide

Molecular formula and molecular mass: C₂₀H₃₀NO₃Br

412.37

Structural formula:

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.

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 1-2 hours, and persisted for periods of 4-5 hours in the majority of patients, with 25-38% of the patients demonstrating increases of at least 15% at 7-8 hours. Continued effectiveness of ATROVENT (ipratropium bromide) 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 ATROVENT (ipratropium bromide) 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 5-7 hours, compared with 3-4 hours in patients receiving a beta agonist alone.

DETAILED PHARMACOLOGY

Ipratropium bromide (ATROVENT) is an anticholinergic agent which, when delivered by aerosol, exerts its effects primarily in the bronchial tree. . In preclinical 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 ATROVENT^® (ipratropium bromide) is primarily local and site specific to the lung and not systemic in nature.

It abolishes acetylcholine-induced bronchospasm in the guinea pig and dog after intravenous administration at an ED₅₀ of 0.15-0.40 μg/kg with a transient effect on blood pressure. By inhalation, approximately 25 μg 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 i.v. administration. Histological evaluation of human bronchial mucosa 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 μg 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 an s.c. 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. In another experiment, blood pressure and heart rate in the dog could be modulated after i.v. administration of low doses of ipratropium bromide, but metered aerosol administration of 100 puffs (40 μg/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% 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 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, subcutaneously, inhibited the secretory effects of the cholinergic agonist, oxtremorine, in mice. It also exhibited spasmolytic effects equivalent to or greater than atropine in isolated guinea pig gut. In vitro tests with the 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. Ipratropium bromide was administered by inhalation in combination with a β₂ sympathomimetic agent (fenoterol hydrobromide). In both the dog and guinea pig, these agents were additive in antagonizing acetylcholine induced bronchospasm with ED₅₀ being 19.8 μg (ipratropium), 49.25 μg (fenoterol) and 11.05 μg + 27.63 μg (ipratropium + fenoterol). In the dog, 50 μg of fenoterol by inhalation produced an 8% increase in heart rate and a 16% increase in left ventricular dp/dt. When 20 μg ipratropium was added to the above, the corresponding increases were 8% and 9%.

TOXICOLOGY

Local and systemic tolerability of ipratropium bromide have comprehensively been investigated in several animal species using various administration routes.

ACUTE

The acute inhalation, oral and intravenous toxicity has been assessed in several rodent and non-rodent species. When administered by inhalation, the minimum lethal dose in male Guinea pigs was 199 mg/kg . In rats, no mortality was observed up to the highest technically feasible dosages (.i.e. 0.05 mg/kg after 4 h of administration or 160 puffs of ipratropium bromide, 0.02 mg/puff).

The oral LD₅₀ values for the mouse, rat and rabbit were 1585, 1925 and 1920 mg/kg, respectively. The intravenous LD₅₀ for the mouse, rat and dog was, respectively, 13.6, 15.8 and about 18.2 mg/kg. Clinical signs included mydriasis, dry oral mucosa, dyspnoea, tremor, spasms and/or tachycardia.

SPECIES SEX ROUTE LD₅₀ (mg/kg)

Mouse i.v. 13.5

Mouse M i.v. 12.3

Mouse F i.v. 15.0

Mouse s.c. 322

Mouse s.c. 300

Mouse oral 2010

Mouse oral 1038

Rat i.v. 15.8

Rat s.c. 1500

Rat oral 4000

Rat oral 1722

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 i.v. and 8 days 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 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).

An acute 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 EGG changes or heart failure. Reductions in heart rate were observed. Similar findings were seen in dogs given i.v. 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.

An acute inhalation dose tolerance study in rats using doses of up to 160 puffs (3.2 mg) from an ATROVENT inhaler was performed. No deaths occurred. A combination of ipratropium bromide (up to 3.2 mg/kg) with fenoterol hydrobromide (up to 8 mg/kg) was administered by inhaler (up to 320 puffs) to rats. There were no deaths or clinical signs observed.

SUBACUTE

Oral:

A subacute toxicity 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.

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 μg/L for 1 hour, 4 times per day for 7 days. No drug toxicity was found.

In another study, administration of ipratropium bromide in doses of 128, 256 and 384 μg 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.

Four rhesus monkeys inhaled 500 μg of ipratropium bromide twice a day (total dose 1 mg/day) for 7 days without the appearance of any drug induced toxicity.

In another study rhesus monkeys were given ipratropium bromide in doses of 200, 400 and 800 μg/day by inhalation for 6 weeks. Included in the tests were measurements of mucociliary transport rate and ciliary beat frequency. No signs of drug toxicity were found.

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 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 2 dogs at the highest dose and a nondose-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 μg 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 μg. All findings were negative including measurements of lung mechanics, ciliary beat frequency and blood gases.

Repeat-dose toxicity studies have been performed in rats, rabbits, dogs and Rhesus monkeys. In inhalation studies up to 6 months in rats, dogs and Rhesus monkeys, the No Observed Adverse Effect Level (NOAEL) was 0.38 mg/kg/day, 0.18 mg/kg/day and 0.8 mg/kg/day, respectively. Dry oral mucosa and tachycardia were noted in the dogs. No substance-related histopathological lesions were observed in the broncho-pulmonary system or in any other organs. In the rat, the NOAEL after 18 months of oral administration was 0.5 mg/kg/day.

Repeated-dose inhalation toxicity studies in rats for up to 6 months and in dogs for up to 3 months with other formulations (intranasal formulation, alternative propellant HFA 134a and lactose powder formulation) revealed no additional information on the general toxicity profile of ipratropium bromide .

Intranasal administration for up to 6 months revealed No Effect Level (NOEL) > 0.20 mg/kg/day in dogs and confirmed earlier studies with intranasal administration for up to 13 weeks. Repeat-dose toxicity studies of ipratropium bromide have shown the toxicological profiles of the HFA formulation and the conventional CFC formulation to be similar.

An aqueous solution of ipratropium bromide, (0.05 mg/kg) was locally well tolerated when administered to rats by inhalation by inhalation (single administration over 4 h). In the repeated dose toxicity studies, ipratropium bromide, was locally well tolerated.

Neither active anaphylaxis nor passive cutaneous anaphylactic reactions were demonstrated in Guinea pigs.

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.

There was no evidence of genotoxicity in vitro (Ames test) and in vivo (micronucleus test, dominant lethal test in mice, cytogenetic assay on bone marrow cells of Chinese hamsters).

CARCINOGENICITY:

Carcinogenicity studies in mice (107 weeks duration) and rats (114 weeks duration) utilizing oral doses of up to 6 mg/kg were performed. These studies demonstrated that ipratropium bromide does not have a tumorigenic or carcinogenic effect.

REPRODUCTIVE STUDIES

Three teratological studies, one in mice using oral doses of 2 and 10 mg/kg, and two in rats, were performed. The first study used the same doses and the second employed 10 and 20 mg/kg and revealed no drug induced fetal abnormalities.

A similar 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.

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.

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 dose 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 metered dose aerosol, 1.5 mg/kg/day in rats and 1.8 mg/kg/day in rabbits, showed no adverse effects on reproduction.

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