TERBUTALINE SULFATE

INDICATIONS AND USAGE Terbutaline Sulfate Injection, USP is 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.

DOSAGE AND ADMINISTRATION Vials should be used only for subcutaneous administration and not intravenous infusion. Sterility and accurate dosing cannot be assured if the vials are not used in accordance with DOSAGE AND ADMINISTRATION . Discard unused portion after single patient use. The usual subcutaneous dose of terbutaline sulfate injection is 0.25 mg injected into the lateral deltoid area. If significant clinical improvement does not occur within 15 to 30 minutes, a second dose of 0.25 mg may be administered. If the patient then fails to respond within another 15 to 30 minutes, other therapeutic measures should be considered. The total dose within 4 hours should not exceed 0.5 mg. Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

CONTRAINDICATIONS 1. Prolonged Tocolysis Terbutaline sulfate has not been approved and should not be used for prolonged tocolysis (beyond 48-72 hours). In particular, terbutaline sulfate should not be used for maintenance tocolysis in the outpatient or home setting (see BOXED WARNING: Prolonged Tocolysis ). 2. Hypersensitivity Terbutaline sulfate injection 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 than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and 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.

Drug Interactions The concomitant use of terbutaline sulfate injection with other sympathomimetic agents is not recommended, since the combined effect on the cardiovascular system may be deleterious to the patient. Monoamine Oxidase Inhibitors or Tricyclic Antidepressants: Terbutaline 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 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 injection, 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 nonpotassium-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 coadministration of beta-agonists with nonpotassium-sparing diuretics.

ADVERSE REACTIONS Adverse reactions observed with terbutaline sulfate injection are similar to those commonly seen with other sympathomimetic agents. All these reactions are transient in nature and usually do not require treatment. The following table compares adverse reactions seen in patients treated with terbutaline sulfate injection (0.25 mg and 0.5 mg), with those seen in patients treated with epinephrine injection (0.25 mg and 0.5 mg), during eight double-blind crossover studies involving a total of 214 patients. Incidence (%) of Adverse Reactions Terbutaline (%) Epinephrine (%) 0.25 mg N = 77 0.5 mg N = 205 0.25 mg N = 153 0.5 mg N = 61 Reaction Central Nervous System Tremor 7.8 38.0 16.3 18.0 Nervousness 16.9 30.7 8.5 31.1 Dizziness 1.3 10.2 7.8 3.3 Headache 7.8 8.8 3.3 9.8 Drowsiness 11.7 9.8 14.4 8.2 Cardiovascular Palpitations 7.8 22.9 7.8 29.5 Tachycardia 1.3 1.5 2.6 0.0 Respiratory Dyspnea 0.0 2.0 2.0 0.0 Chest discomfort 1.3 1.5 2.6 0.0 Gastrointestinal Nausea/vomiting 1.3 3.9 1.3 11.5 Systemic Weakness 1.3 0.5 2.6 1.6 Flushed feeling 0.0 2.4 1.3 0.0 Sweating 0.0 2.4 0.0 0.0 Pain at injection site 2.6 0.5 2.6 1.6 Note: Some patients received more than one dosage strength of terbutaline sulfate and epinephrine. In addition, there were reports of anxiety, muscle cramps, and dry mouth (< 0.5%). There have been rare reports of elevations in liver enzymes and of hypersensitivity vasculitis with terbutaline administration. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc.. at 1-877-233-2001, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Pregnancy -Teratogenic Effects Pregnancy Category C 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 24 to 48 times the common human dose in adults of 2-4 mg/day, on a mg/m 2 basis. Terbutaline sulfate has not been approved and should not be used for prolonged tocolysis (beyond 48-72 hours). In particular, terbutaline sulfate should not be used for maintenance 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: Prolonged Tocolysis and CONTRAINDICATIONS: Prolonged 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 810 and 1,600 times, respectively, the maximum recommended daily subcutaneous dose for adults, on a mg/m 2 basis. Terbutaline sulfate should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.