The following prescribing information is based on official labeling in effect July 2000.
Terbutaline sulfate USP, the active ingredient of Brethine, is a beta-adrenergic agonist bronchodilator available as a sterile, nonpyrogenic, aqueous solution in ampuls, 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 (±)-(alpha)-[( tert -butylamino)methyl]-3,5-dihydroxybenzyl alcohol sulfate (2:1) (salt). The empirical formula is (C 12 H 19 NO 3 ) 2 · H 2 SO 4 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.
Brethine is a beta-adrenergic receptor agonist. In vitro and in vivo pharmacologic studies have demonstrated that terbutaline exerts a preferential effect on beta 2 -adrenergic receptors. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta 2 -receptors in the human heart, existing in a concentration between 10%-50%. The precise function of these receptors has not been established (see ). Controlled clinical studies in patients given terbutaline subcutaneously have not revealed a preferential beta 2 -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 Brethine relieves bronchospasm in acute and chronic obstructive pulmonary disease by significantly increasing pulmonary flow rates (e.g., an increase of 15% or more in FEV 1 ). After subcutaneous administration of 0.25 mg of Brethine, a measurable change in expiratory flow rate usually occurs within 5 minutes, and a clinically significant increase in FEV 1 occurs within 15 minutes. The maximum effect usually occurs within 30-60 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.
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.
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 (0.08-1.0) 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.
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 6-14 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.
Brethine 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.
Brethine is contraindicated in patients known to be hypersensitive to sympathomimetic amines or any component of this drug product.
Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of Brethine than usual, this may be a marker of destabilization of asthma and requires re-evaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.
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.
Brethine, 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 Brethine 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, Brethine, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
There have been rare reports of seizures in patients receiving terbutaline; seizures did not recur in these patients after the drug was discontinued.
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.
Terbutaline, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, including ischemic heart disease, hypertension, and cardiac arrhythmias; in patients with hyperthyroidism or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines or who have 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 exacerbations 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 have been reported to aggravate pre-existing diabetes mellitus and keto-acidosis.
The concomitant use of Brethine 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 Brethine, 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.
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 810 times the maximum recommended daily subcutaneous (sc) 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 1,600 times the maximum recommended daily sc 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 810 times the maximum recommended daily sc dose for adults on a mg/m 2 basis
A reproduction study in Sprague-Dawley rats revealed terbutaline sulfate was not teratogenic when administered orally at doses up to 50 mg/kg (approximately 810 times the maximum recommended daily sc dose for adults on a mg/m 2 basis). A reproduction study in New Zealand white rabbits revealed terbutaline sulfate was not teratogenic when administered orally at doses up to 50 mg/kg (approximately 1,600 times the maximum recommended daily sc dose for adults on a mg/m 2 basis
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human responses, Brethine should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.
Because of the potential for beta-agonist interference with uterine contractility, use of Brethine 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.
It is not known whether this drug is excreted in human milk. Therefore, Brethine should be used during nursing only if the potential benefit justifies the possible risk to the newborn.
Brethine is not recommended for patients under the age of 12 years because of insufficient clinical data to establish safety and effectiveness.
Adverse reactions observed with Brethine 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.
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.
The median sc lethal dose of terbutaline sulfate in mature rats was approximately 165 mg/kg (approximately 2,700 times the maximum recommended daily sc dose for adults on a mg/m 2 basis). The median sc lethal dose of terbutaline sulfate in young rats was approximately 2,000 mg/kg (approximately 32,000 times the maximum recommended daily sc dose for adults on a mg/m 2 basis
The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS , e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Hypokalemia may also occur. There is no specific antidote. Treatment consists of discontinuation of Brethine together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of Brethine.
Ampuls should be used only for subcutaneous administration and not intravenous infusion. Sterility and accurate dosing cannot be assured if the ampuls are not used in accordance with DOSAGE AND ADMINISTRATION.
Discard unused portion after single patient use.
The usual subcutaneous dose of Brethine is 0.25 mg injected into the lateral deltoid area. If significant clinical improvement does not occur within 15-30 minutes, a second dose of 0.25 mg may be administered. If the patient then fails to respond within another 15-30 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.
Ampuls 1 mg/mL -- The drug is supplied at a volume of 1 mL contained in a 2 mL clear glass ampul. Each ampul contains 1 mg of Brethine per 1 mL of solution; 0.25 mL of solution will provide the usual clinical dose of 0.25 mg. Ampuls are expiration-dated.
Box of 10 ampuls ......................... NDC 0028-7507-23
Box of 100 ampuls ....................... NDC 0028-7507-01
Keep at controlled room temperature 15°C-30°C (59°F-86°F).
Protect from light by storing ampuls in original carton until dispensed. Do not use if solution is discolored.
REV: APRIL 2000 T2000-13
Novartis Pharma AG
Basle, Switzerland for
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936