Atrovent (Ipratropium Bromide Monohydrate) - Description and Clinical Pharmacology

ATTENTION PHARMACISTS: Detach “Patient's Instructions for Use” and dispense with the product.

Bronchodilator Aerosol
For Oral Inhalation Only
Prescribing Information

DESCRIPTION

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. The structural formula is:

Ipratropium bromide is a white to off-white crystalline substance, freely soluble in water and lower alcohols but insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons.

ATROVENT Inhalation Aerosol contains a microcrystalline suspension of ipratropium bromide in a pressurized metered-dose aerosol unit for oral inhalation administration. The net weight is at least 14.7 grams; it yields 200 inhalations. Each actuation meters 21 mcg of ipratropium bromide from the valve and delivers 18 mcg of ipratropium bromide from the mouthpiece. The excipients are dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane as propellants and soya lecithin.

CLINICAL PHARMACOLOGY

Mechanism of Action

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.

Pharmacokinetics

The bronchodilation following inhalation of ipratropium bromide is primarily a local, site-specific effect, not a systemic one. Much of an administered dose is swallowed as shown by fecal excretion studies. Ipratropium bromide is a quaternary amine. It 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. Ipratropium bromide is minimally bound (0 to 9% in vitro) to plasma albumin and α₁-acid glycoprotein. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half of the dose is excreted unchanged in the urine. Autoradiographic studies in rats have shown that ipratropium bromide 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 (FEV₁ 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) Inhalation Aerosol does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions. In studies without a positive control ATROVENT Inhalation Aerosol 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. At recommended doses, ATROVENT Inhalation Aerosol does not produce clinically significant changes in pulse rate or blood pressure.