Atrovent Inhalation Solution

ATROVENT® Inhalation Solution

Boehringer Ingelheim

Ipratropium Bromide

Bronchodilator

Action And Clinical Pharmacology: Ipratropium, a quaternary ammonium derivative of atropine, is an anticholinergic drug which has 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 from the peak. Bronchodilation is still evident 8 hours after inhalation.

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

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 FEF25-75% in increases of 15% or more) occurred within 15 minutes, reached a peak in 1 to 2 hours, and persisted for periods of 4 to 5 hours in the majority of patients, with 25 to 38% of the patients demonstrating increases of at least 15% at 7 to 8 hours. Continued effectiveness of ipratropium solution was demonstrated throughout the 12-week period. In addition, significant changes in forced vital capacity (FVC) have been demonstrated.

Additional controlled 12-week studies were conducted to evaluate the safety and efficacy of ipratropium 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 FEF25-75%. On combined therapy, the median duration of 15% improvement in FEV1 was 5 to 7 hours, compared with 3 to 4 hours in patients receiving a beta agonist alone.

Significant alterations in mucociliary clearance of tracheobronchial secretions (sputum) were not observed in short-term clinical trials. Systemic absorption of ipratropium is poor and the blood levels reached are very low. Metabolic studies with ipratropium in healthy volunteers show an average elimination half-life of 3.5 hours (range 1.5 to 4 hours). The drug is transformed to some 8 metabolites with little or no anticholinergic activity.

Indications And Clinical Uses: Ipratropium solution administered either alone or with a B2-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. Ipratropium solution, when used in conjunction with a b2-adrenergic stimulant solution such as fenoterol or salbutamol, is indicated for acute asthmatic attacks. Ipratropium solution is to be administered by compressed air or oxygen driven nebulizers.

Contra-Indications: Known hypersensitivity to ipratropium, to any of the product’s ingredients or to atropinics.

Manufacturers’ Warnings In Clinical States: Ipratropium solution in the 20 mL multidose bottle contains preservatives (benzalkonium chloride and disodium ethylene diamine tetraacetic acid – EDTA-disodium). It has been reported that these preservatives may cause bronchoconstriction in some patients with hyperreactive airways.

The unit dose vials do not contain preservatives.

Ipratropium 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 b2 agonist.

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

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 ipratropium/B2-agonist solution should be avoided unless measures (e.g., use of swimming goggles or use of a nebulizer with a mouth piece) are taken to ensure that nebulized solution does not reach the eye. There have been isolated reports of ocular complications (i.e., mydriasis, increased intraocular pressure, angle closure glaucoma) when nebulized ipratropium either alone or in combination with an adrenergic b2 agonist solution has escaped into the eyes. In the event that glaucoma is precipitated or worsened, treatment should include standard measures for this condition.

Pregnancy: The safety of ipratropium in pregnancy has not been established. The benefits of using ipratropium when pregnancy is confirmed or suspected must be weighed against possible hazards to the fetus. Studies in rats, mice and rabbits showed no embryotoxic nor teratogenic effects.

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

Children: The efficacy and safety in children younger than 5 years has not been established.

Precautions: Ipratropium solution 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 hypertrophy or urinary retention, ipratropium should be used with caution.

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

Ipratropium solution, when administered to patients with acute severe asthma, should be used with concomitant b2-adrenergic stimulant therapy.

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

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

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

Adverse Reactions: Because of the low systemic absorption of ipratropium, anticholinergic side effects, such as tachycardia and palpitations, ocular accommodation disturbances, gastro-intestinal motility disturbances and urinary retention, are rare and reversible, although the risk of urinary retention may be increased in patients with pre-existing outflow tract obstruction.

Acute Administration: The frequency of adverse reactions recorded in 214 patients receiving ipratropium solution was as follows: 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 effect judged to be most severe was exacerbation of bronchospasm. This occurred in 8 patients treated with ipratropium solution alone, 6 of whom withdrew from the clinical studies.

Bronchospasm occurred in 3 patients with acute severe asthma who received ipratropium solution alone. In 2 patients, this was reversed after therapy with a b2 sympathomimetic solution. The third patient received no other therapy.

Table I compares the incidence of adverse effects of the combination of Atrovent and a b2 agonist (either fenoterol or salbutamol) solution with that of the b2 agonist alone.

Chronic Administration: The frequency of adverse reactions reported as possibly related to ipratropium treatment in 219 COPD patients participating in long-term (12-week) controlled clinical trials was as follows: 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%, sputum increased 0.9%, rhinitis 0.9%, eye pain 0.9%.

The following other adverse events were reported as possibly related to drug treatment in 1 patient each: bronchitis, bronchospasm, chest pain, depression, fatigue, flu-symptoms, hypoesthesia, increased saliva, insomnia, nervousness, pain, paresthesia, pharyngitis, somnolence, tachycardia and urticaria.

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+B2-agonists (metaproterenol or salbutamol) versus the B2-agonist alone, was as follows: see Table II.

There have been isolated reports of ocular effects such as mydriasis, increased intraocular pressure, and acute glaucoma associated with the escape of nebulized ipratropium alone or in combination with a b2-agonist solution into the eyes.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Doses of ipratropium up to 1.2 mg (approximately 30 times the therapeutic dose) have been administered by ipratropium inhaler without the appearance of serious systemic anticholinergic effects.

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

Dosage And Administration: 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.

Adults: The average single dose is 250 to 500 µg of ipratropium. Children 5 to 12 years: The recommended dose is 125 to 250 µg of ipratropium. In most cases, dilution of the dose with sterile preservative-free saline is not necessary. However, volumes of ipratropium solution less than 2 mL are not appropriate for nebulization and must be diluted with saline or another suitable nebulizer solution to make up a total fill volume of 2 to 5 mL (see Stability and Storage).

Nebulization should take place using a gas flow (oxygen or compressed air) of 6 to 10 L/minute and the solution nebulized to dryness over a 10 to 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 manufacturer’s instructions concerning cleaning and maintenance of the nebulizer should be strictly followed.

Treatment with ipratropium solution may be repeated every 4 to 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 µg of ipratropium solution given 3 to 4 times/day.

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

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

Controlled laboratory experiments using mixtures of the solution with Alupent, Berotec 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.

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

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

The solution is physically compatible with Alupent, Berotec 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.

Availability And Storage: Bottles: Each mL of clear, colorless or almost colorless solution contains: ipratropium bromide 250 µg (0.025%). Nonmedicinal ingredients: benzalkonium chloride, edetate disodium, purified water and sodium chloride. Amber glass bottles of 20 mL with screwcap.

Unit Dose Vials: 125 µg/mL: Each mL of clear, colorless solution contains: ipratropium bromide 125 µg (0.0125%). Nonmedicinal ingredients: hydrochloric acid, purified water and sodium chloride. Plastic single use vials of 2 mL.

250 µg/mL: Each mL of clear, colorless solution contains: ipratropium bromide 250 µg (0.025%). Nonmedicinal ingredients: hydrochloric acid, purified water and sodium chloride. Plastic single use vials of 1 and 2 mL.

ATROVENT® Inhalation Solution Boehringer Ingelheim Ipratropium Bromide Bronchodilator

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