Terbutaline Injection (Terbutaline Sulfate Injection) - Description and Clinical Pharmacology

Vials

A sterile aqueous solution for subcutaneous injection

Rx Only

Prescribing Information

DESCRIPTION

Terbutaline sulfate USP, the active ingredient of terbutaline sulfate injection, is a beta-adrenergic agonist bronchodilator available as a sterile, nonpyrogenic, aqueous solution in vials, for subcutaneous administration. Each milliliter of solution contains 1 mg of terbutaline sulfate USP (0.82 mg of the free base), sodium chloride for isotonicity, and hydrochloric acid for adjustment to a target pH of 4. Terbutaline sulfate is (±)-α-[(tert -butylamino)methyl]-3,5-dihydroxybenzyI alcohol sulfate (2:1) (salt). The molecular formula is (C₁₂H₁₉N0₃)₂•H₂SO₄ and the structural formula is:

Terbutaline sulfate USP is a white to gray-white crystalline powder. It is odorless or has a faint odor of acetic acid. It is soluble in water and in 0.1N hydrochloric acid, slightly soluble in methanol, and insoluble in chloroform. Its molecular weight is 548.65.

CLINICAL PHARMACOLOGY

Terbutaline sulfate injection is a beta-adrenergic receptor agonist. In vitro and in vivo pharmacologic studies have demonstrated that terbutaline exerts a preferential effect on beta₂-adrenergic receptors. 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% to 50%. The precise function of these receptors has not been established (see WARNINGS). Controlled clinical studies in patients given terbutaline subcutaneously have not revealed a preferential beta₂-adrenergic effect.

The pharmacologic effects of beta-adrenergic agonists, including terbutaline, are at least in part attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase, the enzyme which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic 3’,5’-adenosine monophosphate (cAMP). Increased cAMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Controlled clinical studies have shown that terbutaline sulfate injection relieves bronchospasm in acute and chronic obstructive pulmonary disease by significantly increasing pulmonary flow rates (e.g., an increase of 15% or more in FEV₁). After subcutaneous administration of 0.25 mg of terbutaline sulfate injection, a measurable change in expiratory flow rate usually occurs within 5 minutes, and a clinically significant increase in FEV₁ occurs within 15 minutes. The maximum effect usually occurs within 30 to 60 minutes, and clinically significant bronchodilator activity may continue for 1.5 to 4 hours. The duration of clinically significant improvement is comparable to that observed with equimilligram doses of epinephrine.

Preclinical

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

Pharmacokinetics

Subcutaneous administration of 0.5 mg of terbutaline sulfate to 17 healthy, adult, male subjects resulted in mean (SD) peak plasma terbutaline concentration of 9.6 (3.6) ng/mL, which was observed at a median (range) time of 0.5 (0.08 to 1.0) hours after dosing. The mean (SD) AUC (0 to 48) and total body clearance values were 29.4 (14.2) hr•ng/mL, and 311 (112) mL/min respectively. The terminal half-life was determined in 9 of the 17 subjects and had a mean (SD) of 5.7 (2.0) hours.

After subcutaneous administration of 0.25 mg of terbutaline sulfate to two male subjects, peak terbutaline serum concentrations of 5.2 and 5.3 ng/mL were observed at about 20 minutes after dosing.

Elimination half-life of the drug in 10 of 14 patients was approximately 2.9 hours after subcutaneous administration, but longer elimination half-lives (between 6 to 14 hours) were found in the other 4 patients. About 90% of the drug was excreted in the urine at 96 hours after subcutaneous administration, with about 60% of this being unchanged drug. It appears that the sulfate conjugate is a major metabolite of terbutaline and urinary excretion is the primary route of elimination.