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The active ingredient in Atrovent® (ipratropium bromide) Inhalation Aerosol is ipratropium bromide. It is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo (3.2.1)-octane,3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-, bromide, monohydrate (endo, syn)-, (±)-: a synthetic quaternary ammonium compound, chemically related to atropine.
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Ipratropium bromide is a white crystalline substance, freely soluble in water and lower alcohols but insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons.
Atrovent Inhalation Aerosol is an inhalation aerosol for oral administration. The net weight is 14 grams; it yields 200 inhalations. Each actuation of the valve delivers 18 mcg of ipratropium bromide from the mouthpiece. The inert ingredients are dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane as propellants and soya lecithin.
Atrovent® (ipratropium bromide) is an anticholinergic (parasympatholytic) agent which, based on animal studies, appears to inhibit vagally mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increases in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) which are caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.
The bronchodilation following inhalation of Atrovent is primarily a local, site-specific effect, not a systemic one. Much of an inhaled dose is swallowed as shown by fecal excretion studies. Atrovent is not readily absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract as confirmed by blood level and renal excretion studies.
The half-life of elimination is about 2 hours after inhalation or intravenous administration. Autoradiographic studies in rats have shown that Atrovent does not penetrate the blood-brain barrier.
In controlled 90 day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema) significant improvements in pulmonary function (FEV 1 and FEF 25 - 75% increases of 15% or more) occurred within 15 minutes, reached a peak in 1-2 hours, and persisted for periods of 3 to 4 hours in the majority of patients and up to 6 hours in some patients. In addition, significant increases in Forced Vital Capacity (FVC) have been demonstrated.
Controlled clinical studies have demonstrated that Atrovent® (ipratropium bromide) does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions. In studies without a positive control Atrovent did not alter pupil size, accommodation or visual acuity (See ADVERSE REACTIONS ).
Ventilation/perfusion studies have shown no clinically significant effects on pulmonary gas exchange or arterial oxygen tension. Atrovent does not produce clinically significant changes in pulse rate or blood pressure.
Atrovent® (ipratropium bromide) Inhalation Aerosol is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema.
Atrovent® (ipratropium bromide) Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to soya lecithin or related food products such as soybean and peanut. Atrovent should also not be taken by patients hypersensitive to any other components of the drug product or to atropine or its derivatives.
Atrovent® (ipratropium bromide) is not indicated for the initial treatment of acute episodes of bronchospasm where rapid response is required. Immediate hypersensitivity reactions may occur after administration of ipratropium bromide, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm and oropharyngeal edema.
General Atrovent® (ipratropium bromide) should be used with caution in patients with narrow-angle glaucoma, prostatic hypertrophy or bladder-neck obstruction.
Information for Patients Patients should be advised that temporary blurring of vision, precipitation or worsening of narrow-angle glaucoma or eye pain may result if the aerosol is sprayed into the eyes. If recommended dosage does not provide relief or symptoms become worse, patients should seek immediate medical attention. While taking Atrovent® Inhalation Aerosol, other inhaled drugs should not be used unless prescribed. (See illustrated Patient' Instructions for Use).
Drug Interactions Atrovent has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, steroids and cromolyn sodium, commonly used in the treatment of chronic obstructive pulmonary disease, without adverse drug reactions. There are no formal studies fully evaluating the interaction effects of Atrovent and these drugs with respect to effectiveness.
Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year oral carcinogenicity studies in rats and mice have revealed no carcinogenic potential at doses up to 1,250 times the maximum recommended human daily dose for Atrovent. Results of various mutagenicity studies were negative.
Fertility of male or female rats at oral doses up to approximately 10,000 times the maximum recommended human daily dose was unaffected by Atrovent administration. At doses above 18,000 times the maximum recommended human daily dose, increased resorption and decreased conception rates were observed.
Pregnancy TERATOGENIC EFFECTS Pregnancy Category B: Oral reproduction studies performed in mice, rats and rabbits (at doses approximately 2,000, 200,000 and 26,000 times the maximum recommended human daily dose, respectively) and inhalation reproduction studies in rats and rabbits (at doses approximately 312 and 375 times the maximum recommended human daily dose, respectively) have demonstrated no evidence of teratogenic effects as a result of Atrovent® (ipratropium bromide). However, no adequate or well controlled studies have been conducted in pregnant women. Because animal reproduction studies are not always predictive of human response, Atrovent® (ipratropium bromide) should be used during pregnancy only if clearly needed.
Nursing Mothers It is not known whether Atrovent is excreted in human milk. Although lipid-insoluble quaternary bases pass into breast milk, it is unlikely that Atrovent would reach the infant to an important extent, especially when taken by aerosol. However, because many drugs are excreted in human milk, caution should be exercised when Atrovent is administered to a nursing woman.
Pediatric Use Safety and effectiveness in the pediatric population below the age of 12 have not been established.
Adverse reaction information concerning Atrovent® (ipratropium bromide) is derived from 90 day controlled clinical trials (N=254), other controlled clinical trials using recommended doses of Atrovent (N=377) and an uncontrolled study (N=1924). Additional information is derived from the foreign post-marketing experience and the published literature.
Adverse reactions occurring in greater than one percent of patients in the 90 day controlled clinical trials appear in the following table:
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Additional adverse reactions reported in less than one percent of the patients considered possibly due to Atrovent include urinary difficulty, fatigue, insomnia and hoarseness.
The large uncontrolled, open-label study included seriously ill patients. About 7% of patients treated discontinued the program because of adverse events.
Of the 2301 patients treated in the large uncontrolled study and in clinical trials other than the 90 day studies, the most common adverse reactions reported were: dryness of the oropharynx, about 5 in 100; cough, exacerbation of symptoms and irritation from aerosol, each about 3 in 100; headache, about 2 in 100; nausea, dizziness, blurred vision/difficulty in accommodation, and drying of secretions, each about 1 in 100. Less frequently reported adverse reactions that were possibly due to Atrovent® (ipratropium bromide) include tachycardia, paresthesias, drowsiness, coordination difficulty, itching, hives, flushing, alopecia, constipation, tremor, and mucosal ulcers.
Cases of precipitation or worsening of narrow-angle glaucoma, acute eye pain and hypotension have been reported.
Allergic-type reactions such as skin rash, angioedema of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reaction have been reported, with positive rechallenge in some cases. Many of the patients had a history of allergies to other drugs and/or foods, including soybean. (See CONTRAINDICATIONS .)
Acute overdosage by inhalation is unlikely since Atrovent® (ipratropium bromide) is not well absorbed systemically after aerosol or oral administration. The oral LD 50 of Atrovent ranged between 1001 and 2010 mg/kg in mice; between 1667 and more than 4000 mg/kg in rats; and between 400 and 1300 mg/kg in dogs.
The usual starting dose of Atrovent® (ipratropium bromide) is two inhalations (36 mcg) four times a day. Patients may take additional inhalations as required; however, the total number of inhalations should not exceed 12 in 24 hours.
Atrovent® (ipratropium bromide) Inhalation Aerosol is supplied as a metered dose inhaler with a white mouthpiece which has a clear, colorless sleeve and a green protective cap.
Atrovent® Inhalation Aerosol with Mouthpiece (NDC 0597-0082-14), net contents 14 g. Atrovent® Inhalation Aerosol Refill (NDC 0597-0082-18), net contents 14 g. Each 14 gram vial provides sufficient medication for 200 inhalations. Each actuation delivers 18 mcg of ipratropium bromide from the mouthpiece.
Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs):
WARNING
Contains trichloromonofluoromethane (CFC-11), dichlorodifluoromethane (CFC-12) and dichlorotetrafluoroethane (CFC-114), substances which harm public health and the environment by destroying ozone in the upper atmosphere.
A notice similar to the above WARNING has been placed in the information for the patient of this product under the Environmental Protection Agency's (EPA's) regulations. The patient' warning states that the patient should consult his or her physician if there are questions or alternatives.
Store between 59°F (15°C) and 86°F (30°C). Avoid excessive humidity.
Keep out of children's reach. Shake well before using. Patients should be reminded to read and follow the accompanying "Instructions for Use," which should be dispensed with the product. As with most inhaled medications in aerosol canisters, the therapeutic effect of this medication may decrease when the canister is cold.
Warning: Discard the canister after you have used the labeled number of inhalations. The correct amount of medication in each inhalation cannot be assured after this point.
Rx only
AT-PI-4042170 039(3/99)
Manufactured by: 3M Pharmaceuticals, St. Paul, MN 55144
Pharmaceuticals, Inc., Ridgefield, CT 06877
Licensed from: Boehringer Ingelheim
International GmbH
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