Proventil inhalation solution 0.083%

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 beta 2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta- 2 -adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta- 2 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 1 / 2 to 1 / 4 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:   After either IPPB or nebulizer administration in asthmatic patients, less than 20% of a single albuterol dose was absorbed; the remaining amount was recovered from the nebulizer and apparatus and expired air. Most of the absorbed dose was recovered in the urine 24 hours after drug administration. Following a 3.0-mg dose of nebulized albuterol, the maximum albuterol plasma level at 0.5 hour was 2.1 ng/mL (range 1.4-3.2 ng/mL). It has been demonstrated that following oral administration of 4 mg of albuterol, the elimination half-life was 5 to 6 hours.

Clinical Trials:   In controlled clinical trials, most patients exhibited an onset of improvement in pulmonary function within 5 minutes as determined by FEV 1 . FEV 1 measurements also showed that the maximum average improvement in pulmonary function usually occurred at approximately 1 hour following inhalation of 2.5 mg of albuterol by compressor-nebulizer, and remained close to peak for 2 hours. Clinically significant improvement in pulmonary function (defined as maintenance of a 15% or more increase in FEV 1 over baseline values) continued for 3 to 4 hours in most patients and in some patients continued up to 6 hours.

PROVENTIL Inhalation Solution is indicated for the relief of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease and acute attacks of bronchospasm.

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

Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should not be used concomitantly with albuterol.

Beta Blockers:   Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as PROVENTIL Inhalation Solution, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta blockers. However, under certain circumstances, eg, as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta blockers could be considered, although they should be administered with caution.

Diuretics:   The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics.

Digoxin:   Mean decreases of 16% to 22% in serum digoxin levels were demonstrated after single dose intravenous and oral administration of albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of this finding for patients with obstructive airway disease who are receiving albuterol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and albuterol.

Monoamine Oxidase Inhibitors or Tricyclic Antidepressants: Albuterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of albuterol on the vascular system may be potentiated.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:   In a 2-year study in Sprague-Dawley rats, albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at the above dietary doses of 2 mg/kg (approximately two times the maximum recommended daily inhalation dose for adults on an mg/m 2 basis). In another study, this effect was blocked by the coadministration of a propranolol, a nonselective beta-adrenergic antagonist.

In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 500 mg/kg (approximately 200 times the maximum recommended daily inhalation dose for adults on an mg/m 2 basis). In a 22-month study in the Golden Hamster, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 25 times the maximum recommended daily inhalation dose for adults on an mg/m 2 basis).

Albuterol sulfate was not mutagenic in the Ames test with or without metabolic activation using tester strains S. typhimurium TA1537, TA1538, and TA98 or E. coli WP2, WP2uvrA, and WP67. No forward mutation was seen in yeast strain S. cerevisiae S9 nor any mitotic gene conversion in yeast strain S. cerevisiae JD1 with or without metabolic activation. Fluctuation assays in S. typhimurium TA98 and E. coli WP2, both with metabolic activation, were negative. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of albuterol sulfate up to 50 mg/kg (approximately 40 times the maximum recommended daily inhalation dose for adults on an mg/m 2 basis).

Teratogenic Effects--Pregnancy Category C:   Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses at and above 0.25 mg/kg (corresponding to less than the maximum recommended daily inhalation dose for adults on an mg/m 2 basis), induced cleft palate formation in 5 of 111 (4.5%) fetuses. At an sc dose of 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on an mg/m 2 basis) albuterol sulfate induced cleft palate formation in 10 of 108 (9.3%) fetuses. The drug did not induce cleft palate formation when administered at an sc dose of 0.025 mg/kg (corresponding to less than the maximum recommended daily inhalation dose for adults on an mg/m 2 basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg isoproterenol (positive control) administered subcutaneously.

A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol was administered orally at a dose of 50 mg/kg (approximately 80 times the maximum recommended daily inhalation dose for adults on an mg/m 2 basis).

Studies in pregnant rats with tritiated albuterol demonstrated that approximately 10% of the circulating maternal drug is transferred to the fetus. Disposition in the fetal lungs is comparable to maternal lungs, but fetal liver disposition is 1% of the maternal liver levels.

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, albuterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. Because no consistent pattern of defects can be discerned, a relationship between albuterol use and congenital anomalies has not been established.

Use in Labor and Delivery--Use in Labor:   Because of the potential for beta-agonist interference with uterine contractility, use of PROVENTIL Inhalation Solution for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Tocolysis:   Albuterol has not been approved for the management of preterm labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta-agonists, including albuterol.

Nursing Mothers:   It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for albuterol in some animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:   Safety and effectiveness of albuterol inhalation solution and solution for inhalation in children below the age of 12 years have not been established.

The results of clinical trials with PROVENTIL Inhalation Solution in 135 patients showed the following side effects which were considered probably or possibly drug related:

No clinically relevant laboratory abnormalities related to PROVENTIL Inhalation Solution were determined in these studies.

Cases of urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, and extrasystoles) have also been reported after the use of inhaled albuterol.