Terbutaline Sulfate

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.

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.

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

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 tablets should last up to 6 hours or longer. Terbutaline sulfate tablets should not be used more frequently than recommended. Do not increase the dose or frequency of terbutaline sulfate tablets without consulting your physician. If you find that treatment with terbutaline sulfate tablets 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 tablets, 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 tablets. Effective and safe use of terbutaline sulfate tablets includes an understanding of the way that it should be administered. Drug Interactions The concomitant use of terbutaline sulfate tablets 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 tablets. 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, and 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/m 2 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/m 2 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/m 2 basis). Teratogenic Effects There are no adequate and well-controlled studies of terbutaline sulfate in pregnant women. Published animal studies show that rat offspring exhibit alterations in behavior and brain development, including decreased cellular proliferation and differentiation when dams were treated subcutaneously with terbutaline during the late stage of pregnancy and lactation period. Terbutaline exposures in rat dams were approximately 6.5 times the common human dose in adults of 15 mg/day, on a mg/m 2 basis. 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 tocolysis in the outpatient or home setting. 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 Boxed Warning: Tocolysis and Contraindications-Tocolysis ] In animal embryofetal developmental studies, no teratogenic effects were observed in offspring when pregnant rats and rabbits received terbutaline sulfate at oral doses up to 50 mg/kg/day, approximately 32 and 65 times, respectively, the maximum recommended daily oral dose for adults, on a mg/m 2 basis. Terbutaline sulfate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Use in Labor and Delivery Because of the potential for beta-agonist interference with uterine contractility, use of terbutaline sulfate tablets 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 tablets should be used during nursing only if the potential benefit justifies the possible risk to the newborn. Pediatric Use Terbutaline sulfate tablets are 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.

Adverse reactions observed with terbutaline sulfate are similar to those commonly seen with other sympathomimetic amines. All of these reactions are generally transient in nature and usually do not require treatment. The frequency of these side effects appears to diminish with continued therapy. The following table lists the adverse reactions seen in 199 patients treated with terbutaline sulfate tablets during six double-blind crossover studies and four double-blind parallel studies (short- and long-term) performed in the United States. Percent Incidence of Adverse Reactions (Total Daily Dosage Range 5 to 15 mg) Terbutaline N=199 Reaction % Nervous System Nervousness

35.0 Tremor

15.0 Somnolence

5.5 Dizziness

3.5 Anxiety

1.0 Insomnia

1.5 Cardiovascular Palpitations

5.0 Tachycardia

3.5 Extrasystoles ventricular

1.5 Vasodilations

1.0 Digestive Nausea

3.0 Dry mouth

1.5 Body as a Whole Headache

7.5 Asthenia

2.0 Skin and Appendages Sweating

1.0 The following adverse reactions each occurred in fewer than 1% of patients: hallucinations, rash, paresthesia, hypertonia, (muscle cramps), vomiting. There have been rare reports of elevations in liver enzymes and of hypersensitivity vasculitis. To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The concomitant use of terbutaline sulfate tablets 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 tablets.

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

Terbutaline sulfate tablets are not recommended for patients under the age of 12 years because of insufficient clinical data to establish safety and effectiveness [see Dosage and Administration ] .

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.