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 (1-3) and 1.5 (0.5-3.0) hours after dosing. The mean (SD) AUC(0-48) 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%-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 (0.08-1.0) hours after dosing. The mean (SD) AUC(0-48) 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.

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

Seizures

There have been rare reports of seizures in patients receiving terbutaline; seizures did not recur in these patients after the drug was discontinued.

Tocolysis

Terbutaline sulfate has not been approved and should not be used for tocolysis. Serious adverse reactions may occur after administration of terbutaline sulfate to women in labor. In the mother, these 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.

General

Terbutaline, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, including ischemic heart disease, hypertension, and cardiac arrhythmias; hyperthyroidism; diabetes mellitus; hypersensitivity to sympathomimetic amines; and convulsive disorders. 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.

Immediate hypersensitivity reactions and exacerbation of bronchospasm have been reported after terbutaline administration.

Beta-adrenergic agonist medications 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.

Large doses of intravenous terbutaline sulfate have been reported to aggravate preexisting diabetes and ketoacidosis.

Information for Patients

The action of terbutaline sulfate should last up to 6 hours or longer. Terbutaline sulfate should not be used more frequently than recommended. Do not increase the dose or frequency of terbutaline sulfate without consulting your physician. If you find that treatment with terbutaline sulfate becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, you should seek medical attention immediately. While taking terbutaline sulfate, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, tremor or nervousness. If you are pregnant or nursing, contact your physician about use of terbutaline sulfate. Effective and safe use of terbutaline sulfate includes an understanding of the way that it should be administered.

Drug Interactions

The concomitant use of terbutaline sulfate with other sympathomimetic agents is not recommended, since the combined effect on the cardiovascular system may be deleterious to the patient. However, this does not preclude the use of an aerosol bronchodilator of the adrenergic-stimulant type for the relief of an acute bronchospasm in patients receiving chronic oral therapy with terbutaline sulfate.

Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

Terbutaline sulfate 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, since the action of terbutaline sulfate on the vascular system may be potentiated.

Beta-Blockers

Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as terbutaline sulfate, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., 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 non-potassium sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the co-administration of beta-agonists with non-potassium sparing diuretics.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 2-year study in Sprague-Dawley rats, terbutaline sulfate caused a significant and dose-related increase in the incidence of benign leiomyomas of the mesovarium at dietary doses of 50 mg/kg, and above (approximately 25 times the maximum recommended daily oral dose for adults on a mg/m2 basis). In a 21-month study in CD-1 mice, terbutaline sulfate showed no evidence of tumorigenicity at dietary doses up to 200 mg/kg (approximately 55 times the maximum recommended daily oral dose for adults on a mg/m2 basis). The mutagenicity potential of terbutaline sulfate has not been determined.

Reproduction studies in rats using terbutaline sulfate demonstrated no impairment of fertility at oral doses up to 50 mg/kg (approximately 25 times the maximum recommended daily oral dose for adults on a mg/m2 basis).

Pregnancy

Teratogenic Effects

Pregnancy Category B

A reproduction study in Sprague-Dawley rats revealed terbutaline sulfate was not teratogenic when administered at oral doses of 50 mg/kg (approximately 25 times the maximum recommended daily oral dose for adults on a mg/m2 basis). A reproduction study in New Zealand white rabbits revealed terbutaline sulfate was not teratogenic when administered at oral doses up to 50 mg/kg (approximately 55 times the maximum recommended daily oral dose for adults on a mg/m2 basis).

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See PRECAUTIONS, Tocolysis).

Use in Labor and Delivery

Because of the potential for beta-agonist interference with uterine contractility, use of terbutaline sulfate for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Terbutaline crosses the placenta. After single dose IV administration of terbutaline to 22 women in late pregnancy who were delivered by elective Cesarean section due to clinical reasons, umbilical blood levels of terbutaline were found to range from 11% to 48% of the maternal blood levels.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Therefore, terbutaline sulfate should be used during nursing only if the potential benefit justifies the possible risk to the newborn.

Pediatric Use

Terbutaline sulfate is not recommended for patients under the age of 12 years because of insufficient clinical data to establish safety and effectiveness (see DOSAGE AND ADMINISTRATION).

Geriatric Use

Clinical studies of terbutaline sulfate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Adults

The usual oral dose of terbutaline sulfate for adults is 5 mg administered at approximately six-hour intervals, three times daily, during the hours the patient is usually awake. If side effects are particularly disturbing, the dose may be reduced to 2.5 mg three times daily, and still provide a clinically significant improvement in pulmonary function. The total dose within 24 hours should not exceed 15 mg.

Children

Terbutaline sulfate is not recommended for use in children below the age of 12 years. A dosage of 2.5 mg three times daily is recommended for children 12-15 years of age. The total dose within 24 hours should not exceed 7.5 mg.

If a previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately as this is often a sign of seriously worsening asthma that would require reassessment of therapy.

Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature].

Dispense in tight, light-resistant container as defined in the USP.