Terbutaline Sulfate

TERBUTALINE SULFATE- terbutaline sulfate tablet
ANI Pharmaceuticals, Inc.

DESCRIPTION

Terbutaline sulfate USP, the active ingredient of Terbutaline Sulfate Tablets USP, is a beta-adrenergic agonist bronchodilator available as tablets of 2.5 mg (2.05 mg of the free base) and 5 mg (4.1 mg of the free base) for oral administration. Terbutaline sulfate is ±-α-[(tert -butylamino)methyl]-3,5-dihydroxybenzyl alcohol sulfate (2:1) (salt). The empirical formula is (C12 H19 NO3 )2 • H2 SO4 and the structural formula is:

structure
(click image for full-size original)

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.

Inactive Ingredients: Microcrystalline cellulose, lactose monohydrate, magnesium stearate, povidone, and corn starch.

WARNING: TOCOYSIS

Oral terbutaline sulfate has not been approved for and should not be used for acute or maintenance tocolysis. In particular, terbutaline sulfate should not be used for maintenance tocolysis in the outpatient or home setting.

During pregnancy, serious adverse reactions, including death, have been reported after administration of terbutaline sulfate to pregnant women. In the mother, these adverse reactions include increased heart rate, transient hyperglycemia, hypokalemia, cardiac arrhythmias, pulmonary edema and myocardial ischemia. Increased fetal heart rate and neonatal hypoglycemia may occur as a result of maternal administration. [See Contraindications-Tocolysis]

CLINICAL PHARMACOLOGY

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]. In controlled clinical studies in patients given terbutaline sulfate orally, proportionally greater changes occurred in pulmonary function parameters than in heart rate or blood pressure. While this suggests a relative preference for the beta2 -receptors in man, the usual cardiovascular effects commonly associated with other sympathomimetic agents were also observed with terbutaline sulfate.

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 relieves bronchospasm in chronic obstructive pulmonary disease by significantly increasing pulmonary function (e.g., an increase of 15% or more in FEV1 and in FEF25%-75% ). After administration of terbutaline sulfate tablets, a measurable change in flow rate usually occurs within 30 minutes, and a clinically significant improvement in pulmonary function occurs within 60 to 120 minutes. The maximum effect usually occurs within 120 to 180 minutes. Terbutaline sulfate also produces a clinically significant decrease in airway and pulmonary resistance, which persists for 4 hours or longer. Significant bronchodilator action (as measured by airway resistance, FEF25%-75% or PEFR) has also been demonstrated for up to 8 hours in some studies.

In studies comparing the effectiveness of terbutaline sulfate with that of ephedrine for up to 3 months, both drugs maintained a significant improvement in pulmonary function throughout this period of treatment.

Preclinical

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 were administered concurrently. The clinical significance of these findings is unknown.

Pharmacokinetics

Oral administration of 5 mg terbutaline sulfate tablets or 5 mg terbutaline sulfate in solution in 17 healthy, adult, male subjects, resulted in mean (SD) peak plasma terbutaline concentration of 8.3 (3.9) and 8.6 (3.6) ng/mL, which were observed at median (range) times of 2 (1 to 3) and 1.5 (0.5 to 3.0) hours after dosing. The mean (SD) AUC (0 to 48) values were 54.6 (26.8) and 53.1 (23.5) hr•ng/mL, and corresponded to a bioavailability of 103% for the tablet relative to the solution.

After oral administration of terbutaline, 51 to 62 mcg/kg of body weight, to 3 healthy male subjects, peak serum levels of 3.1 to 6.2 ng/mL were observed 1 to 3 hours later. In the same study, after 3 days only 30% to 50% of the dose was recovered from urine and the remainder from the feces, which may indicate poor absorption.

After an oral dose to asthmatic patients, the elimination half-life of terbutaline was approximately 3.4 hours.

In comparison to oral dosing, subcutaneous administration of 0.5 mg of terbutaline sulfate to 17 healthy, adult, male subjects resulted in a 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.

About 90% of the drug was excreted in the urine at 96 hours after subcutaneous administration, with about 60% of this being unchanged drug. The sulfate conjugate is a major metabolite of terbutaline, and urinary excretion is the primary route of elimination.

There are no reports of any clinical pharmacokinetic studies investigating dose proportionality, effect of food, or special population studies with terbutaline.

INDICATIONS AND USAGE

Terbutaline Sulfate Tablets USP are indicated for the prevention and reversal of bronchospasm in patients 12 years of age and older with asthma and reversible bronchospasm associated with bronchitis and emphysema.

CONTRAINDICATIONS

1. Tocolysis

Oral terbutaline sulfate is contraindicated for the treatment of acute or maintenance tocolysis [see Boxed Warning: Tocolysis].

2. Hypersensitivity

Terbutaline sulfate is contraindicated in patients known to be hypersensitive to sympathomimetic amines or any component of this drug product.

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 terbutaline sulfate tablets 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, e.g., 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, e.g., corticosteroids.

Cardiovascular Effects

Terbutaline sulfate, 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 terbutaline sulfate tablets 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, terbutaline sulfate tablets, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

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