ATROVENT SOLUTION

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Active ingredient:
IPRATROPIUM BROMIDE
Available from:
BOEHRINGER INGELHEIM (CANADA) LTD LTEE
ATC code:
R03BB01
INN (International Name):
IPRATROPIUM BROMIDE
Dosage:
250MCG
Pharmaceutical form:
SOLUTION
Composition:
IPRATROPIUM BROMIDE 250MCG
Administration route:
INHALATION
Units in package:
20ML
Prescription type:
Prescription
Therapeutic area:
ANTIMUSCARINICS ANTISPASMODICS
Product summary:
Active ingredient group (AIG) number: 0115643001; AHFS: 12:08.08
Authorization status:
MARKETED
Authorization number:
00731439
Authorization date:
1988-12-31

Page 1 of 33

PRODUCT MONOGRAPH

Atrovent

(Ipratropium Bromide)

INHALATION SOLUTION

(20 mL bottle, 1 mL and 2 mL Unit Dose Vials)

BRONCHODILATOR

Boehringer Ingelheim (Canada) Ltd.

5180 South Service Road,

Burlington, Ontario

L7L 5H4

Date of Preparation:

September 19, 2003

Date of Revision:

May 16, 2006

Submission Control No:104456

BICL BPI # 0013-05, #0014-06, #0022-05

Page 2 of 33

Table of Contents

[To update, right-click anywhere in the Table of Contents and select “Update Field”, “Update

entire table”, click OK.]

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

SUMMARY PRODUCT INFORMATION ........................................................................3

INDICATIONS AND CLINICAL USE..............................................................................3

CONTRAINDICATIONS ...................................................................................................3

WARNINGS AND PRECAUTIONS..................................................................................4

ADVERSE REACTIONS....................................................................................................5

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

DOSAGE AND ADMINISTRATION..............................................................................10

OVERDOSAGE ................................................................................................................10

ACTION AND CLINICAL PHARMACOLOGY ............................................................11

STORAGE AND STABILITY..........................................................................................13

SPECIAL HANDLING INSTRUCTIONS .......................................................................14

DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................14

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

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

CLINICAL TRIALS..........................................................................................................16

DETAILED PHARMACOLOGY.....................................................................................17

TOXICOLOGY .................................................................................................................18

REFERENCES ..................................................................................................................32

PART III: CONSUMER INFORMATION..............................................................................27

Page 3 of 33

Atrovent

(Ipratropium Bromide)

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

Clinically Relevant Nonmedicinal

Ingredients

oral

Inhalation Solution

20 mL bottle, 1 mL

and 2 mL Unit Dose

Vials

Sodium chloride

For a complete listing see Dosage Forms,

Composition and Packaging section.

INDICATIONS AND CLINICAL USE

ATROVENT (ipratropium bromide) 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 β

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 in children younger than 5 years has not been

established.

CONTRAINDICATIONS

Known hypersensitivity to ATROVENT (ipratropium bromide), to any of the product

ingredients, or to atropinics.

Page 4 of 33

WARNINGS AND PRECAUTIONS

General

ATROVENT (ipratropium bromide) solution in the 20 mL multidose bottle contains

preservatives (benzalkonium chloride and disodium ethylene diamine tetra acetic acid - EDTA-

disodium). It has been reported that these preservatives may cause bronchoconstriction in some

patients with hyper reactive airways.

The unit dose vials do not contain preservatives.

ATROVENT 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 β

agonist.

Immediate hypersensitivity reactions may occur after administration of ATROVENT Inhalation

Solution, as demonstrated by rare cases of utricaria, angioedema, rash, bronchospasm,

oropharyngeal edema and anaphylaxis.

ATROVENT solution (Bottle and UDV's) 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 glaucoma, prostatic hyperplasia, urinary retention and bladder neck obstruction,

ATROVENT (ipratropium bromide) should be used with caution.

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

ATROVENT solution, when administered to patients with acute severe asthma, should be used

with concomitant β

adrenergic stimulant therapy.

Carcinogenesis and Mutagenesis

Please see TOXICOLOGY section.

Ear/Nose/Throat

GLAUCOMA, ANGLE-CLOSURE

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/β

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 β

agonist solution has escaped into the eyes.

Page 5 of 33

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.

Gastrointestinal

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

Special Populations

Pregnant Women:

The safety of ATROVENT inhalation aerosol in pregnancy has not been established. The

benefits of using ATROVENT when pregnancy is present or suspected must be weighed against

possible hazards caused to the fetus. Studies in rats, mice and rabbits showed no embryotoxic nor

teratogenic effects.

Nursing Women:

No specific studies have been conducted on excretion of this drug in breast milk. Benefits of

ATROVENT inhalation aerosol use during lactation should therefore be weighed against

possible effects on the infant.

Pediatrics:

The efficacy and safety of ATROVENT in children younger than 5 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 β

agonist (either fenoterol or saluutmaol)

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.

Page 6 of 33

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

Bad taste

Tremor

Exacerbation of symptoms

Burning eyes

Nausea

Sweating

Cough

Headache

Palpitations

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 β

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 β

agonist (either fenoterol or salbutamol) solution with that of the β

agonist

alone.

Page 7 of 33

ADVERSE REACTION

ATROVENT + β

AGONIST

β

-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

Palpitations

Headache

Cough

Flushing

Dizziness

Numbness in leg

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

Coughing

Dyspnea

Headache

Urinary Retention

Tremor

Nausea

Palpitation

Eye pain

Page 8 of 33

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 + β

agonists (metaproterenol or salbutamol)

versus the β

agonist alone, was as follows:

ADVERSE EFFECT

% OF PATIENTS

ATROVENT + β

AGONIST

(n = 208)

AGONIST

(n = 417)

Headache

Tremor

Nervousness

Dyspnea

Dry mouth

Bronchitis

Dizziness

Coughing

Taste perversion

Insomnia

Dysuria

Nausea

Abnormal vision

Chest pain

Constipation

Dysphonia

Dyspepsia

Bronchospasm aggravated

Micturition frequency

Page 9 of 33

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 β

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 ATROVENT are headache

and dryness of mouth/throat.

Immediate hypersensitivity reactions may occur after administration of ATROVENT. 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.

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.

Page 10 of 33

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 ATROVENT (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 ATROVENT 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 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 (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 accomodation disturbances

and increase of heart rate may occur.

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

considered.

Page 11 of 33

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

ATROVENT (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

again 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 FEV

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 5 years.

A clinical pharmacology study comparing single doses of ATROVENT inhaler

(80 mg) and ATROVENT solution (250 mg) 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.

Page 12 of 33

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:

In man, inhalation of 555 µg by inhaler of radiolabelled ipratropium bromide, about 14 times the

recommended therapeutic dose, produced peak plasma levels (ipratropium and its metabolites) of

0.06 ng/mL after 3 hours. The time to reach peak plasma concentration was similar to that seen

after oral administration, likely reflecting the large fraction of inhaled dose which is deposited on

the pharyngeal mucosae and swallowed.

Direct (non-radioactive) determination of ipratropium bromide revealed that this active

ingredient is absorbed very quickly after oral administration. The peak plasma concentrations

are reached only minutes after inhalation. 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 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).

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 ATROVENT solution in an adult dose finding

study. The following table outlines the doses reaching the patient. The figures for ATROVENT

inhaler are published estimates.

Page 13 of 33

Dose Available (µg)

Amount Reaching

Patient (µg)

Lung Dose (µg)

17.0

40 (ATROVENT Inhaler)

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

C 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.

Renal excretion of the active ingredient is 46% of the dose after intravenous administration and

3% of the dose after oral inhalation. 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 ATROVENT in children younger than 5 years has not

been established.

STORAGE AND STABILITY

Unopened bottles of ATROVENT solution should be stored at controlled room temperature

(between 15ºC and 30ºC). 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 ATROVENT Inhalation Solution, opened

and closed several times, simulating patient use, were stable for up to 28 days when stored at

Page 14 of 33

room temperature (15º - 30ºC).

Controlled laboratory experiments using mixtures of ATROVENT 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:

ATROVENT 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

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

1 mL or 2 mL Unit Dose Vials

Unopened unit dose vials of ATROVENT solution should be stored at controlled room

temperature (between 15ºC and 30ºC) 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 Alupent® (orciprenaline sulfate), Berotec® (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

20 ML BOTTLE

ATROVENT 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.

Page 15 of 33

2 ML UNIT DOSE VIAL

250 mcg/mL

ATROVENT solution 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.

125 mcg/mL

ATROVENT solution 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.

1 ML UNIT DOSE VIAL

ATROVENT solution 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.

Page 16 of 33

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: C

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 (FEV

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.

Page 17 of 33

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 FEV

, FVC and FEF

25-75%

. On

combined therapy, the median duration of 15% improvement in FEV

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. It abolishes acetylcholine-induced

bronchospasm in the guinea pig and dog after intravenous administration at an ED

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 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 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

Page 18 of 33

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 β

sympathomimetic agent (fenoterol hydrobromide). In both the dog and

guinea pig, these agents were additive in antagonizing acetylcholine induced bronchospasm with

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

ACUTE

Acute toxicity has been investigated with observation periods of 14 days in several rodent and

non-rodent species.

SPECIES

ROUTE

(mg/kg)

Mouse

i.v.

13.5

Mouse

i.v.

12.3

Mouse

i.v.

15.0

Mouse

s.c.

Mouse

s.c.

Mouse

oral

2010

Mouse

oral

1038

i.v.

15.8

s.c.

1500

oral

4000

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.

Page 19 of 33

IPRATROPIUM BROMIDE + FENOTEROL HYDROBROMIDE

(RATIO 1:2.5)

SPECIES

ROUTE

(mg/kg)

Mouse

i.v.

23.6

Mouse

i.v.

26.2

Mouse

oral

Mouse

oral

i.v.

32.5

i.v.

32.5

oral

3200

oral

2450

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 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.

Page 20 of 33

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.

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.

Page 21 of 33

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.

Rats were exposed to a combination of fenoterol and ipratropium twice, 4 times and 8 times per

day. Metered dose inhalers containing 50 µg fenoterol and 20 µg ipratropium per actuation were

discharged into the exposure chamber at a rate of 6 doses per minute for 25 minutes over a 7 day

period. No changes apart from a reduction in food consumption in the first 2 days in the high

dose group were noted.

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 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

Page 22 of 33

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.

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. These studies demonstrated that ipratropium bromide

does not have a tumorigenic or carcinogenic effect.

Page 23 of 33

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.

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.

Page 24 of 33

REFERENCES

Beasley GRW, Ratterty P, Holgate ST. Bronchoconstrictor properties of

preservatives in ipratropium bromide (ATROVENT) nebuliser solutions.

Br Med J 1987; 294:1197-8.

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.

Bryant DH. Nebulized ipratropium bromide in the treatment of acute

asthma. Chest 1985;88:24-9.

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.

Chan-Yeung M. The effect of Sch 1000 and disodium cromoglycate on

exercise-induced asthma. Chest 1977;71:320-3.

Cockroft DW, Ruffin RE, Hargreave FE. Effect of Sch 1000 in

allergen-induced asthma, Clin Allergy 1978; 8:361-72.

Cockroft DW, Killian DN, Mellon JJA, Hargreave FE. Protective effect of

drugs on histamine-induced asthma. Thorax 1977;32:429-37.

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.

Douglas NJ, Davidson I, Sudlow MF, Flenley DC. Bronchodilation and

the site of airway resistance in severe chronic bronchitis 1979;34:51-6.

Anonymous. Ipratropium (ATROVENT) for airway obstruction. Drug Ther Bull 1980;

18:59.

Engelhardt A. Pharmacology and toxicology of ATROVENT Scand J Respir Dis 1979;60

(Suppl 103):1l0-5.

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.

Lenney W, Evans NAP. Nebulized salbutamol and ipratropium bromide

Page 25 of 33

in asthmatic children. Br J Dis Chest 1986;80:59-65.

McIntosh D. A comparison between fenoterol/ipratropium bromide

combinations and salbutamol administered as nebulizer solutions

assessing dose-response and duration of action. Pharmacothapeutica

1986;4:416-21.

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.

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.

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.

Rominger KL. Chemistry and pharmacokinetics of ipratropium bromide.

Scand J Respir Dis l979;60(Suppl 103):116-126.

Ruffin RE, Cockcroft DW, Hargreave FE. A comparison of the protective

effect of fenoterol and Sch 1000 on allergen-induced asthma. J Allergy

Clin Immunol 1978;61:42-7.

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.

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.

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.

Ward MJ, Fentem PH, Roderick-Smith WH, Davies D. Ipratropium

bromide in acute asthma. Br Med J 1981;282:598-600.

Page 26 of 33

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).

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 FEV

: The Lung Health Study. JAMA. Nov. 16,

1994, Vol. 272. No. 19: 1471-1556.

IMPORTANT: PLEASE READ

Page 27 of 33

PART III: CONSUMER INFORMATION

Atrovent® (Ipratropium Bromide) InhalationSolution (20 mL

Bottle) (Ipratropium Bromide)

This leaflet is part III of a three-part "Product Monograph"

published when ATROVENT solution was approved for sale in

Canada and is designed specifically for Consumers. This leaflet

is a summary and will not tell you everything about

ATROVENT solution. Contact your doctor or pharmacist if

you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

Atrovent solution is a bronchodilator which relieves the

wheezing and shortness of breath caused by chronic bronchitis

or by asthma. For the treatment of asthma, ATROVENT

solution must be used in conjunction with some other

bronchodilating medication. ATROVENT solution contains

250 mcg/mL (0.025%) ipratropium bromide and the

preservatives benzalkonium chloride and disodium ethylene

diamine tetraacetic acid (EDTA-disodium). It is available only

on prescription.

Before starting treatment with ATROVENT solution, be

certain that you are completely familiar with the use and

proper care of your nebulizer.

What is COPD?

COPD (Chronic Obstructive Pulmonary Disease) is a type of

lung disease in which there is a permanent narrowing of the

airways, leading to breathing difficulties. In many patients,

this narrowing of the airways is a result of many years of

cigarette smoking. Smoking cessation produces symptomatic

benefits and will slow the progression of chronic bronchitis

(which is a form of COPD). COPD can be helped by

medication as well.

What is Asthma?

Asthma is a disease in which the airways can become

temporarily narrowed, leading to breathing difficulties. This

narrowing of the airways is due to inflammation, which causes

swelling and irritation of the airways and tightening of the

muscles around the airways. The narrowed airway can be

relieved with the help of medication.

It is important to know that the treatment of COPD and Asthma

may be different for each patient. Your doctor will most likely

discuss with you the best plan for the treatment of your particular

condition. This plan may include taking other medication(s) in

addition to ATROVENT. It is

necessary that you follow your

doctor's directions for the treatment of your condition. If you

have any questions about how you should treat your condition

at home, you should consult your doctor.

What it does:

ATROVENT solution belongs to a group of medicines known

as “bronchodilators” which make breathing easier by

opening your narrowed airways.

When it should not be used:

ATROVENT solution should not be used by patients with

allergic reactions to ipratropium bromide, atropinics or any

component of the drug.

If you do not get the expected relief from your treatment, you

should contact your doctor.

What the medicinal ingredient is:

Ipratropium bromide

What the important nonmedicinal ingredients are:

benzalkonium chloride, EDTA, sodium chloride..

What dosage forms it comes in:

Inhalation Solution; 20 mL Bottle

WARNINGS AND PRECAUTIONS

BEFORE you use ATROVENT solution talk to your doctor

or pharmacist if:

if you are pregnant or intend to become pregnant;

if you are breast feeding;

if you have any other health problems;

if you are taking any other medications including

those you can buy without a prescription and

including eye drops;

if you have any other medical problems such as

difficult urination or enlarged prostate;

if you have eye problems, such as glaucoma or eye

pain;

if you have any allergies or reactions to foods or

drugs.

INTERACTIONS WITH THIS MEDICATION

Other medications may be affected by ATROVENT solution

or may affect how ATROVENT solution works. Do not take

any other medication, including over-the-counter medications

or herbal products unless your doctor tells you to. Tell any

other doctor, dentist or pharmacist that you talk to that you

are taking ATROVENT solution.

Page 28 of 33

PROPER USE OF THIS MEDICATION

DO NOT exceed the prescribed dose or frequency of

treatments.

Before you start to use ATROVENT solution, read the

following instructions carefully. Care should be taken to

ensure that the nubulizer mask fits the face properly and

that nebulized solution does not escape into the eyes. If you

have any questions about using the nebulizer, check with

your doctor or pharmacist.

Usage Instructions:

Your doctor or pharmacist will tell you how to prepare your

ATROVENT solution for inhalation. If you are told to dilute

ATROVENT solution, you must do so immediately before you

plan to use the solution.

In most cases, dilution of the dose with sterile preservative-free

saline is not necessary. However, volumes of ATROVENT

solution less than 2 mL are not appropriate for nebulization

and must be diluted with saline or another suitable nebulizer

solution to make up for a total fill volume of 2-5 mL.

Immediately before you plan to use the nebulizer, using a

syringe, withdraw the prescribed dose-usually ½ to 2mL

(cc)-of ATROVENT solution form the bottle and add to the

nebulizer chamber. Do not store the prescribed dose in the

syringe for later use.

If your doctor has instructed you to use another inhalation

solution in combination with ATROVENT solution, you

should add the appropriate amount of that solution to the

nebulizer chamber as well.

Add sodium chloride solution to the chamber, if you have

been directed to do so by your physician or pharmacist.

Gently shake the nebulizer chamber and connect it to the

mouthpiece or face mask. Then connect the nebulizer tube

to the air or oxygen pump and begin therapy.

Breathe calmly and deeply through the mask or

mouthpiece until no more mist is formed in the nebulizer

chamber. This usually takes 10-15 minutes. It is very

important to adjust the face mask, if required, to prevent

the mist from getting in your eyes.

Store your recapped bottle of ATROVENT solution and

sodium chloride solution in the refrigerator until the next

treatment.

Follow the instructions provided by the nebulizer and air

pump manufacturers for the proper care and

maintenance of the equipment. Keep the nebulizer,

nebulizer tube and face mask clean to minimize

microbial contamination.

Please Remember

Do not exceed the prescribed dose or frequency of

treatments.

Do not mix this medication with any other medication in

the nebulizer unless instructed to do so by your doctor or

pharmacist.

This medication has been prescribed for you and should

not be given to other people.

Keep out of the reach of children.

The solution is intended for inhalation only. Do not

inject or drink it.

Do not let the nebulized mist get into your eyes. Patients

with glaucoma should use swimming goggles or a

nebulizer with a mouthpiece to prevent nebulized

solution getting into the eyes.

Overdose

If you accidentally take too many puffs, you should get

medical help immediately; either by calling your doctor or by

going to the nearest hospital (do not drive yourself). Always

take the labelled medicine container with you.

Missed Dose:

If you forget to take your dose, don’t worry. Take your next

dose as usual. Do not double your dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like

any drug product, ATROVENT solution may cause

unwanted effects. Do not be alarmed by this list of possible

side effects. You may not experience any of them. If you do

experience any unusual or unwanted effects while you are

using ATROVENT solution you should contact your doctor

or pharmacist immediately.

Undesirable effects include: Headache, dizziness,

constipation, vomiting, diarrhea, nausea, cough, dry mouth,

irritation of mouth and/or throat, hoarseness, increased

wheezing or tightness in the chest or sudden difficulties in

breathing (bronchospasm), rapid or irregular heart beat,

sensation of rapid or irregular heart beat, difficult urination,

retention of urine, pain in the eyes, blurred vision, skin

rash/hives, itchiness, difficulty in swallowing, swelling of the

mouth, lips or face, hypersensitivity reaction.

If you experience a dry mouth or bad taste, sucking on a sour

candy or rinsing your mouth may help. Check with your

IMPORTANT: PLEASE READ

Page 29 of 33

doctor if the dry mouth or bad taste persist or if you experience

constipation for a prolonged period of time.

Remember to tell any other doctor, dentist or pharmacist you

consult that you are taking this medication.

If you have any questions about ATROVENT solution or your

nebulizer, contact your doctor or pharmacist.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Talk with your

doctor or

pharmacist

immediately

Symptom / effect

Only if

severe

In all

cases

Stop taking

drug and

call your

doctor or

pharmacist

Common

Increased

wheezing or

tightness in the

chest or

difficulty in

breathing

(bronchospasm)

Swelling of the

tongue, lips or

face

Difficulty in

swallowing

Fast or

irregular heart

beat

Blurred vision

or pain in the

eyes

Difficult or

painful

urination

Uncommon

Skin rash

This is not a complete list of side effects. For any unexpected

effects while taking ATROVENT Solution contact your doctor or

pharmacist.

HOW TO STORE IT

Keep this medication out of the reach of children.

Unopened bottles of ATROVENT Solution should be stored at

controlled room temperature (between 15

C and 30

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.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects

information on serious and unexpected effects of drugs . If

you suspect you have had a serious or unexpected reaction

to this drug you may notify Health Canada by:

toll-free telephone:

866-234-2345

toll-free fax

866-678-6789

By email: cadrmp@hc-sc.gc.ca

By regular mail:

National AR Centre

Marketed Health Products Safety and Effectiveness

Information Division

Marketed Health Products Directorate

Tunney’s Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should

contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for

health professionals can be found at:

http://www.boehringer-ingelheim.ca

or by contacting the sponsor, Boehringer Ingelheim (Canada)

Ltd., at: 1-800- 263-5103, ext. 4633 (Medical Information).

This leaflet was prepared by Boehringer Ingelheim (Canada) Ltd.

Last revised:.

Page 30 of 33

PART III: CONSUMER INFORMATION

Atrovent® (Ipratropium Bromide) Inhalation Solution (UDV)

(Ipratropium Bromide)

This leaflet is part III of a three-part "Product Monograph"

published when ATROVENT Solution UDV was approved for

sale in Canada and is designed specifically for Consumers. This

leaflet is a summary and will not tell you everything about

ATROVENT Solution UDV. Contact your doctor or

pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

ATROVENT solution is a bronchodilator which relieves the

wheezing and shortness of breath caused by chronic bronchitis

or by asthma. For the treatment of asthma, ATROVENT

solution must be used in conjunction with some other

bronchodilating medication. ATROVENT Solution UDV is

available only on prescription.

Before starting treatment with ATROVENT solution, be

certain that you are completely familiar with the use and

proper care of your nebulizer.

What is COPD?

COPD (Chronic Obstructive Pulmonary Disease) is a type of

lung disease in which there is a permanent narrowing of the

airways, leading to breathing difficulties. In many patients,

this narrowing of the airways is a result of many years of

cigarette smoking. Smoking cessation produces symptomatic

benefits and will slow the progression of chronic bronchitis

(which is a form of COPD). COPD can be helped by

medication as well.

What is Asthma?

Asthma is a disease in which the airways can become

temporarily narrowed, leading to breathing difficulties. This

narrowing of the airways is due to inflammation, which causes

swelling and irritation of the airways and tightening of the

muscles around the airways. The narrowed airway can be

relieved with the help of medication.

It is important to know that the treatment of COPD and Asthma

may be different for each patient. Your doctor will most likely

discuss with you the best plan for the treatment of your particular

condition. This plan may include taking other medication(s) in

addition to ATROVENT. It is

necessary that you follow your

doctor's directions for the treatment of your condition. If you

have any questions about how you should treat your condition at

home, you should consult your doctor.

What it does:

ATROVENT Solution UDV belongs to a group of medicines

known as “bronchodilators” which make breathing easier by

opening your narrowed airways.

When it should not be used:

ATROVENT solution should not be used by patients with

allergic reactions to ipratropium bromide, atropinics or any

component of the drug.

If you do not get the expected relief from your treatment, you

should contact your doctor.

What the medicinal ingredient is:

Ipratropium bromide

What the important nonmedicinal ingredients are:

sodium chloride

What dosage forms it comes in:

Inhalation Solution; 1 mL and 2 mL Unit Dose Vials (UDVs)

WARNINGS AND PRECAUTIONS

BEFORE you use ATROVENT solution talk to your doctor

or pharmacist if:

if you are pregnant or intend to become pregnant;

if you are breast feeding;

if you have any other health problems;

if you are taking any other medications including

those you can buy without a prescription and

including eye drops;

if you have any other medical problems such as

difficult urination or enlarged prostate;

if you have eye problems, such as glaucoma or eye

pain;

if you have any allergies or reactions to foods or

drugs.

INTERACTIONS WITH THIS MEDICATION

Other medications may be affected by ATROVENT solution

or may affect how ATROVENT solution works. Do not take

any other medication, including over-the-counter medications

or herbal products unless your doctor tells you to. Tell any

other doctor, dentist or pharmacist that you talk to that you

are taking ATROVENT solution.

PROPER USE OF THIS MEDICATION

DO NOT exceed the prescribed dose or frequency of

treatments.

Before you start to use ATROVENT solution, read the

following instructions carefully. Care should be taken to

IMPORTANT: PLEASE READ

Page 31 of 33

ensure that the nubulizer mask fits the face properly and

that nebulized solution does not escape into the eyes. If you

have any questions about using the nebulizer, check with

your doctor or pharmacist.

ATROVENT(Ipratropium Bromide) Solution

2 mL Unit Dose Vial

250 mcg/mL

Each plastic vial contains 2 mL of ATROVENT solution. Each

millilitre (mL) of solution contains 250 mcg (0.025%)

ipratropium bromide in a isotonic solution.

125 mcg/mL

Each plastic vial contains 2 mL of ATROVENT solution. Each

millilitre (mL) of solution contains 125 mcg (0.0125%)

ipratropium bromide in an isotonic solution.

1 mL Unit Dose Vial

250 mcg/mL

Each plastic vial contains 1 mL of ATROVENT solution. Each

millilitre (mL) of solution contains 250 mcg (0.025%)

ipratropium bromide in an isotonic solution.

Before starting treatment with ATROVENT solution, be

certain that you are completely familiar with the use and

proper care of your nebulizer.

Usage Instructions:

Your doctor or pharmacist will tell you how to prepare your

ATROVENT solution for inhalation. If you are told to dilute

ATROVENT solution, you must do so immediately before you

plan to use the solution.

In most cases, dilution of the dose with sterile preservative-free

saline is not necessary. However, volumes of ATROVENT

solution less than 2 mL are not appropriate for nebulization

and must be diluted with saline or another suitable nebulizer

solution to make up for a total fill volume of 2-5 mL.

Detach one plastic vial by pulling it firmly from the strip.

Open the vial by twisting off the top. It is important that

you use the contents of the vial as soon as possible after

opening it.

Squeeze the contents of the plastic vial into your nebulizer

chamber. If your doctor has instructed you to use less

than one complete vial, use a syringe to withdraw the

prescribed dose. Any solution left in the plastic vial must

be thrown away.

If you doctor has instructed you to use another inhalation

solution in combination with ATROVENT solution, you

should add the appropriate amount of that solution to the

nebulizer chamber as well.

Use a syringe, add sodium chloride solution to the

chamber if you have directed to do so by your

pharmacist or physician.

Gently shake the nebulizer chamber and connect it to the

mouthpiece or face mask. Then connect the nebulizer

tube to the air or oxygen pump and begin therapy.

Breathe calmly and deeply through the mask or

mouthpiece until no more mist is formed in the nebulizer

chamber. This usually takes 10-15 minutes. It is very

important to adjust the face mask, if required, to prevent

the mist from getting in your eyes.

Follow the instruction provided by the nebulizer and air

pump manufacturers for the proper care and

maintenance of the equipment. Keep the nebulizer,

nebulizer tube and face mask clean to minimize

microbial contamination.

The unit dose vials should be stored at room

temperature. The vials should be protected from heat

and light.

Please Remember

Do not exceed the prescribed dose or frequency of

treatments.

Do not mix this medication with any other medication in

the nebulizer unless instructed to do so by your doctor or

pharmacist.

This medication has been prescribed for you and should

not be given to other people.

Keep out of the reach of children.

The solution is intended for inhalation only. Do not

inject or drink it.

Do not let the nebulized mist get into your eyes. Patients

with glaucoma should use swimming goggles or a

nebulizer with a mouthpiece to prevent nebulized

solution getting into the eyes.

Page 32 of 33

Overdose:

If you accidentally take too many puffs, you should get medical

help immediately; either by calling your doctor or by going to

the nearest hospital (do not drive yourself). Always take the

labelled medicine container with you.

Missed Dose:

If a dose of this medication is missed, it is not necessary to

make up the missed dose. Skip the missed dose and continue

with the next scheduled dose. Do not double doses.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like

any drug product, ATROVENT solution may cause

unwanted effects. Do not be alarmed by this list of possible side

effects. You may not experience any of them. If you do

experience any unusual or unwanted effects while you are using

ATROVENT solution you should contact your doctor or

pharmacist immediately.

Undesirable effects include: Headache, dizziness, constipation,

vomiting, diarrhea, nausea, cough, dry mouth, irritation of

mouth and/or throat, hoarseness, increased wheezing or

tightness in the chest or sudden difficulties in breathing

(bronchospasm), rapid or irregular heat beat, sensation of

rapid or irregular heart beat, difficult urination, retention of

urine, pain in the eyes, blurred vision, skin rash/hives, itchiness,

difficulty in swallowing, swelling of the mouth, lips or face,

hypersensitivity reaction.

If you experience a dry mouth or bad taste, sucking on a sour

candy or rinsing your mouth may help. Check with your

doctor if the dry mouth or bad taste persist or if you experience

constipation for a prolonged period of time.

Remember to tell any other doctor, dentist or pharmacist you

consult that you are taking this medication.

If you have any questions about ATROVENT solution or your

nebulizer, contact your doctor or pharmacist.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY

HAPPEN AND WHAT TO DO ABOUT THEM

Talk with your

doctor or

pharmacist

Symptom / effect

Only if

severe

In all

cases

Stop taking

drug and

call your

doctor or

pharmacist

Common

Increased

wheezing or

tightness in the

chest or

difficulty in

breathing

(bronchospasm)

Uncommon

Swelling of the

tongue, lips or

face

Difficulty in

swallowing

Fast or

irregular heart

beat

Blurred vision

or pain in the

eyes

Difficult or

painful

urination

Skin rash

This is not a complete list of side effects. For any unexpected

effects while taking ATROVENT solution, contact your doctor

or pharmacist.

HOW TO STORE IT

Keep this medication out of the reach of children.

Unopened unit dose vials of ATROVENT solution should be

stored at controlled room temperature (between 15

C and

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.

IMPORTANT: PLEASE READ

Page 33 of 33

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects

information on serious and unexpected effects of drugs . If

you suspect you have had a serious or unexpected reaction

to this drug you may notify Health Canada by:

toll-free telephone:

866-234-2345

toll-free fax

866-678-6789

By email: cadrmp@hc-sc.gc.ca

By regular mail:

National AR Centre

Marketed Health Products Safety and Effectiveness

Information Division

Marketed Health Products Directorate

Tunney’s Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should

contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for

health professionals can be found at:

http://www.boehringer-ingelheim.ca

or by contacting the sponsor, Boehringer Ingelheim (Canada) Ltd.,

at: 1-800- 263-5103, ext. 4633 (Medical Information).

This leaflet was prepared by Boehringer Ingelheim (Canada) Ltd.

Last revised: May 16, 2006

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