PROVENTIL

PROVENTIL- albuterol aerosol, spray
Schering Corporation

DESCRIPTION

The active component of PROVENTIL Inhalation Aerosol is albuterol, USP racemic α1 -[(tert -butylamino)methyl]-4-hydroxy-m -xylene-α,α’-diol), a relatively selective beta2 -adrenergic bronchodilator, having the chemical structure:

Image from Drug Label Content

The molecular weight of albuterol is 239.3, and the empirical formula is C13 H21 NO3 . Albuterol is a white to off-white crystalline solid. It is soluble in ethanol, sparingly soluble in water, and very soluble in chloroform. The World Health Organization recommended name for albuterol base is salbutamol.

PROVENTIL Inhalation Aerosol is a pressurized metered-dose aerosol unit for oral inhalation. It contains a microcrystalline suspension of albuterol in propellants (trichloromonofluoromethane and dichlorodifluoromethane) with oleic acid. Each actuation delivers 100 mcg albuterol, USP from the valve and 90 mcg of albuterol, USP from the mouthpiece. Each 17.0 g canister provides 200 oral inhalations.

PROVENTIL Inhalation aerosol should be primed by actuating into air, away from the eyes and face, 4 times before using for the first time and 2 times when the aerosol has not been used for a period of at least 4 days.

CLINICAL PHARMACOLOGY

The primary action of beta-adrenergic drugs, including albuterol, is to stimulate adenyl cyclase, the enzyme which catalyzes the formation of cyclic-3′,5′-adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP) in beta-adrenergic cells. The cyclic AMP thus formed mediates the cellular responses. Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta2 -adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta2 -receptors in the human heart existing in a concentration between 10% and 50%. The precise function of these receptors has not been established.

In controlled clinical trials, albuterol has been shown to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or ECG changes.

Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not a substrate for the cellular uptake processes for catecholamines nor for catechol-O -methyl transferase.

The effects of rising doses of albuterol and isoproterenol aerosols were studied in volunteers and asthmatic patients. Results in normal volunteers indicated that the propensity for increase in heart rate for albuterol is ½ to ¼ that of isoproterenol. In asthmatic patients similar cardiovascular differentiation between the two drugs was also seen.

Preclinical

Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations that are amounting to approximately 5.0% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those in the whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.

Pharmacokinetics

Because of its gradual absorption from the bronchi, systemic levels of albuterol are low after inhalation at recommended doses.

Administration of tritiated albuterol by inhalation to four subjects resulted in maximum plasma concentrations within 2 to 4 hours. Due to the insensitivity of the assay method, the metabolic rate and half-life of elimination of albuterol in plasma could not be determined. However, data from urinary excretion studies indicated that albuterol has an elimination half-life of 3.8 hours. Approximately 72% of the inhaled dose is excreted in the urine within 24 hours, 28% as unchanged drug and 44% as metabolite.

Clinical Trials

In controlled clinical trials the onset of improvement in pulmonary function was within 15 minutes, as determined by both maximal midexpiratory flow rate (MMEF) and FEV1 . MMEF measurements also showed that near maximum improvement in pulmonary function generally occurs within 60 to 90 minutes, following 2 inhalations of albuterol and that clinically significant improvement generally continues for 3 to 4 hours in most patients. In clinical trials, some patients with asthma showed a therapeutic response (defined by maintaining FEV1 values 15% or more above baseline) which was still apparent at 6 hours. Continued effectiveness of albuterol was demonstrated over a 13-week period in these same trials.

In clinical studies, 2 inhalations of albuterol taken approximately 15 minutes prior to exercise prevented exercise-induced bronchospasm, as demonstrated by the maintenance of FEV1 within 80% of baseline values in the majority of patients. One of these studies also evaluated the duration of the prophylactic effect to repeated exercise challenges, which was evident at 4 hours in the majority of patients, and at 6 hours in approximately one third of the patients.

PROVENTIL Indications and Usage

PROVENTIL Inhalation Aerosol is indicated in patients 12 years of age and older, for the prevention and relief of bronchospasm in patients with reversible obstructive airway disease, and for the prevention of exercise-induced bronchospasm.

CONTRAINDICATIONS

PROVENTIL Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to albuterol or any of its components.

WARNINGS

Deterioration of Asthma

Asthma may deteriorate acutely over a period of hours, or chronically over several days or longer. If the patient needs more doses of PROVENTIL Inhalation Aerosol than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, eg, corticosteroids.

Use of Anti-inflammatory Agents

The use of beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, eg, corticosteroids.

Paradoxical Bronchospasm

PROVENTIL Inhalation Aerosol can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, PROVENTIL Inhalation Aerosol should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial.

Cardiovascular Effects

PROVENTIL Inhalation Aerosol, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of PROVENTIL Inhalation Aerosol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, PROVENTIL Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Immediate Hypersensitivity Reactions

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

PRECAUTIONS

General

Albuterol, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator.

Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-agonists, albuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.

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