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Special Alerts
Terbutaline: Serious Maternal Adverse Reactions When Used for Preterm Labor
February 2011
The U.S. Food and Drug Administration (FDA) is requiring the addition of a boxed warning related to the unlabeled use of terbutaline for the prevention of preterm labor. These labeling changes are due to the potential for maternal death and serious heart problems, including increased heart rate, transient hyperglycemia, hypokalemia, cardiac arrhythmias, pulmonary edema, and myocardial ischemia.
The FDA reviewed postmarketing reports of maternal death and serious cardiovascular adverse events associated with the obstetric use of terbutaline and have identified 16 maternal deaths and 12 maternal cases of serious cardiovascular events reported. These cases involved both inpatient and outpatient use of oral, subcutaneous, and/or intravenous terbutaline. Based on this information, the FDA has concluded that the risk of serious events outweighs any potential benefit to pregnant women receiving prolonged treatment (>48-72 hours) with terbutaline injection. Oral terbutaline should not be used for prevention or any treatment of preterm labor because it has not been shown to be effective and has similar safety concerns. These label changes are consistent with statements from the American College of Obstetricians and Gynecologists (ACOG) on management of preterm labor.
Additional information can be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm243843.htm
Pronunciation
(ter BYOO ta leen)
Generic Available (U.S.)
Yes
Index Terms
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Bronchodilator in reversible airway obstruction and bronchial asthma
Use: Unlabeled/Investigational
Injection: Tocolytic agent (short-term [≤72 hours] prevention or management of preterm labor
Pregnancy Risk Factor
B
Lactation
Enters breast milk/compatible
Contraindications
Hypersensitivity to terbutaline or any component of the formulation; cardiac arrhythmias associated with tachycardia; tachycardia caused by digitalis intoxication
Injection: Additional contraindications: Prolonged (>72 hours) prevention or management of preterm labor
Oral: Additional contraindications: Prevention or treatment of preterm labor
Warnings/Precautions
Concerns related to adverse effects:
• Bronchospasm: Rarely, paradoxical bronchospasm may occur with use of inhaled bronchodilating agents; this should be distinguished from inadequate response.
• Hypersensitivity reactions: Immediate hypersensitivity reactions (urticaria, angioedema, rash, bronchospasm) have been reported.
• Serious effects/fatalities: Do not exceed recommended dose; serious adverse events, including fatalities, have been associated with excessive use of inhaled sympathomimetics.
Disease-related concerns:
• Asthma: Appropriate use: When used as a bronchodilator, optimize anti-inflammatory treatment before initiating maintenance treatment with terbutaline. Do not use as a component of chronic therapy without an anti-inflammatory agent. Only the mildest form of asthma (Step 1 and/or exercise-induced) would not require concurrent use based upon asthma guidelines.
• Cardiovascular disease: Use with caution in patients with cardiovascular disease (arrhythmia or hypertension or HF); beta-agonists may cause elevation in blood pressure, heart rate and result in CNS stimulation/excitation. Beta2-agonists may also increase risk of arrhythmias.
• Diabetes: Use with caution in patients with diabetes mellitus; beta2-agonists may increase serum glucose.
• Glaucoma: Use with caution in patients with glaucoma; may elevate intraocular pressure.
• Hyperthyroidism: Use with caution in hyperthyroidism; may stimulate thyroid activity.
• Hypokalemia: Use with caution in patients with hypokalemia; beta2-agonists may decrease serum potassium.
• Preterm labor: Serious maternal cardiac events (arrhythmias, hypertension, hypokalemia, pulmonary edema, myocardial ischemia, myocardial infarction, tachycardia, death) and transient hyperglycemia have occurred with prolonged (>72 hours) use of oral or injectable; should not administer injectable terbutaline for >72 hours to prevent or treat preterm labor in a hospitalized patient; oral route should not be used acutely or chronically for this indication. Terbutaline should not be used in the outpatient setting to treat preterm labor.
• Seizures: Use with caution in patients with seizure disorders; beta-agonists may result in CNS stimulation/excitation.
Other warnings/precautions:
• Patient information: Patients must be instructed to seek medical attention in cases where acute symptoms are not relieved or a previous level of response is diminished. The need to increase frequency of use may indicate deterioration of asthma, and treatment must not be delayed.
Adverse Reactions
>10%:
Central nervous system: Nervousness, restlessness
Endocrine & metabolic: Serum glucose increased, serum potassium decreased
Neuromuscular & skeletal: Trembling
1% to 10%:
Cardiovascular: Tachycardia, hypertension
Central nervous system: Dizziness, drowsiness, headache, insomnia
Gastrointestinal: Xerostomia, nausea, vomiting, bad taste in mouth
Neuromuscular & skeletal: Muscle cramps, weakness
Miscellaneous: Diaphoresis
<1%: Arrhythmia, cardiac arrest (preterm labor), chest pain, hyperglycemia (preterm labor), hypokalemia (preterm labor), hypotension (preterm labor), paradoxical bronchospasm, myocardial infarction (preterm labor), myocardial ischemia (preterm labor), pulmonary edema (preterm labor)
Drug Interactions
Alpha-/Beta-Blockers: May diminish the therapeutic effect of Beta2-Agonists. Risk D: Consider therapy modification
Atomoxetine: May enhance the tachycardic effect of Beta2-Agonists. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Beta2-Agonists. Of particular concern with nonselective beta-blockers or higher doses of the beta1 selective beta-blockers. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Beta2-Agonists. Risk D: Consider therapy modification
Betahistine: May diminish the therapeutic effect of Beta2-Agonists. Risk C: Monitor therapy
Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination
Loop Diuretics: Beta2-Agonists may enhance the hypokalemic effect of Loop Diuretics. Risk C: Monitor therapy
MAO Inhibitors: May enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Tricyclic Antidepressants: May enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid ephedra, yohimbe (may cause CNS stimulation).
Storage
Store injection at room temperature; do not freeze. Protect from heat and light. Use only clear solutions. Store powder for inhalation (Bricanyl® Turbuhaler [CAN]) at room temperature between 15°C and 30°C (58°F and 86°F).
Compatibility
Stable in D5W, 1/2NS, NS.
Y-site administration: Compatible: Insulin (regular).
Compatibility in syringe: Compatible: Doxapram.
Compatibility when admixed: Compatible: Aminophylline. Incompatible: Bleomycin.
Mechanism of Action
Relaxes bronchial and uterine smooth muscle by action on beta2-receptors with less effect on heart rate
Pharmacodynamics/Kinetics
Onset of action: Oral: 30-45 minutes; SubQ: 6-15 minutes
Protein binding: 25%
Metabolism: Hepatic to inactive sulfate conjugates
Bioavailability: SubQ doses are more bioavailable than oral
Half-life elimination: 11-16 hours
Excretion: Urine
Dosage
Children <12 years: Bronchoconstriction:
Oral: Initial: 0.05 mg/kg/dose 3 times/day, increased gradually as required; maximum: 0.15 mg/kg/dose 3-4 times/day or a total of 5 mg/24 hours
SubQ: 0.005-0.01 mg/kg/dose to a maximum of 0.4 mg/dose; may repeat in 15-20 minutes
Children ≥6 years and Adults: Bronchospasm (acute): Inhalation (Bricanyl® [CAN] MDI: 500 mcg/puff, not labeled for use in the U.S.): One puff as needed; may repeat with 1 inhalation (after 5 minutes); more than 6 inhalations should not be necessary in any 24 hour period. Note: If a previously effective dosage regimen fails to provide the usual relief, or the effects of a dose last for >3 hours, medical advice should be sought immediately; this is a sign of seriously worsening asthma that requires reassessment of therapy.
Children >12 years and Adults: Bronchoconstriction:
Oral:
12-15 years: 2.5 mg every 6 hours 3 times/day; not to exceed 7.5 mg in 24 hours
>15 years: 5 mg/dose every 6 hours 3 times/day; if side effects occur, reduce dose to 2.5 mg every 6 hours; not to exceed 15 mg in 24 hours
SubQ: 0.25 mg/dose; may repeat in 15-30 minutes (maximum: 0.5 mg/4-hour period)
Adults: Premature labor (acute; short-term [≤72 hours] tocolysis; unlabeled use):
I.V.: 2.5-5 mcg/minute; increased gradually every 20-30 minutes by 2.5-5 mcg/minute; effective maximum dosages from 17.5-30 mcg/minute have been used with caution. Duration of infusion is at least 12 hours (Travis, 1993).
SubQ: 0.25 mg every 20 minutes to 3 hours; hold for pulse >120 beats per minute. Terbutaline has not been approved for and should not be used for prolonged tocolysis (beyond 48-72 hours) (ACOG, 2003).
Dosing adjustment/comments in renal impairment:
Clcr 10-50 mL/minute: Administer at 50% of normal dose
Clcr <10 mL/minute: Avoid use
Administration: Oral
Administer around-the-clock to promote less variation in peak and trough serum levels.
Administration: I.V.
Use infusion pump.
Administration: I.V. Detail
pH: 3-5 (adjusted)
Monitoring Parameters
Serum potassium, glucose; intake/output; heart rate, blood pressure, respiratory rate; chest pain, shortness of breath; monitor for signs and symptoms of pulmonary edema (when used as a tocolytic); monitor FEV1, peak flow, and/or other pulmonary function tests (when used as bronchodilator)
Patient Education
You may experience nervousness, dizziness, fatigue, dry mouth, and stomach upset. Report unresolved GI upset; dizziness or fatigue; vision changes; sudden weight gain; swelling of extremities; chest pain, rapid heartbeat, or palpitations; insomnia, nervousness, or hyperactivity; muscle cramping, tremors, or pain; or rash.
Geriatric Considerations
Oral terbutaline should be avoided in the elderly due to the increased incidence of adverse effects as compared to the inhaled form.
Anesthesia and Critical Care Concerns/Other Considerations
Evidence-Based Information: Beta2-selective agents lose much of their receptor selectivity when delivered parenterally or orally. Subcutaneous beta-agonist therapy has a deleterious therapeutic to toxicity ratio when compared with inhalation. There is no proven benefit of systemic therapy over aerosolized (Expert Report Panel 3, 2007).
Cardiovascular Considerations
Beta-agonists will induce increases in heart rate. This should be considered in patients with resting tachycardia. Because of the frequent coexistence of chronic obstructive lung disease and coronary artery disease, many patients are on simultaneous therapy with beta-agonists and beta-blockade.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and bad taste in mouth.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Restlessness and nervousness are common; may cause dizziness, drowsiness, or insomnia
Mental Health: Effects on Psychiatric Treatment
Concurrent use with TCAs or MAO inhibitors may increase toxicity
Nursing: Physical Assessment/Monitoring
Respiratory use: For inpatient care, monitor vital signs and lung sounds prior to and periodically during therapy. Preterm labor use: Inpatient: Monitor maternal vital signs; respiratory, fluid, cardiac, and electrolyte status; frequency, duration, and intensity of contractions; and fetal heart rate.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution, as sulfate: 1 mg/mL (1 mL)
Tablet, oral, as sulfate: 2.5 mg, 5 mg
Pricing: U.S. (www.drugstore.com)
Solution (Terbutaline Sulfate)
1 mg/mL (1): $12.99
Tablets (Terbutaline Sulfate)
2.5 mg (90): $44.99
5 mg (90): $45.99
Extemporaneously Prepared
A 1 mg/mL oral suspension may be made with tablets. Crush twenty-four 5 mg tablets in a mortar and reduce to a fine powder. Add 5 mL purified water USP and mix to a uniform paste; mix while adding simple syrup, NF in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of simple syrup, NF sufficient to make 120 mL. Label "shake well" and "refrigerate". Stable for 30 days.
Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
References
Berkman ND, Thorp JM Jr, Hartmann KE, et al, "Management of Preterm Labor," Evidence Report/Technology Assessment No. 18 (Prepared by Research Triangle Institute under Contract No. 290-97-0011). AHRQ Publication No. 01-E021. Rockville (MD) Agency for Healthcare Research and Quality. December 2000.
Bohn D, Kalloghlian A, Jenkins J, et al, “Intravenous Salbutamol in the Treatment of Status Asthmaticus in Children,” Crit Care Med, 1984, 12(10):892-6.
Canny GJ and Levison H, “Aerosols - Therapeutic Use and Delivery in Childhood Asthma,” Ann Allergy, 1988, 60(1):11-9.
Expert Panel Report 3, “Guidelines for the Diagnosis and Management of Asthma,” Clinical Practice Guidelines, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Publication No. 08-4051, prepublication 2007. Available at http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm
Fuglsang G, Pedersen S, and Borgstrom L, “Dose-Response Relationships of I.V. Administered Terbutaline in Children With Asthma,” J Pediatr, 1989, 114(2):315-20.
Goldenhersh N and Rachelefsky GS, “Childhood Asthma: Management,” Pediatr Rev, 1989, 10(9):259-67.
Kelly HW, McWilliams BC, Katz R, et al, “Safety of Frequent High Dose Nebulized Terbutaline in Children With Acute Severe Asthma,” Ann Allergy, 1990, 64(2 Pt 2):229-33.
Lee DC, “Terbutaline Sulfate Overdose,” Ann Emerg Med, 1995, 26(1):107-8.
“Management of Preterm Labor,” ACOG Practice Bulletin No. 43. American College of Obstetricians and Gynecologists, Obstet Gynecol, 2003, 101(5 Pt 1):1039-47.
Guinn DA, Goepfert AR, Owen J, et al, “Terbutaline Pump Maintenance Therapy for Prevention of Preterm Delivery: A Double-Blind Trial,” Am J Obstet Gynecol, 1998, 179(4):874-8.
Lam F, Gill P, Smith M, et al, “Use of the Subcutaneous Terbutaline Pump for Long-Term Tocolysis,” Obstet Gynecol, 1998, 72(5):810-3.
Rachelefsky GS and Siegel SC, “Asthma in Infants and Children - Treatment of Childhood Asthma: Part II,” J Allergy Clin Immunol, 1985, 76(3):409-25.
Simhav HN and Caritis SN, “Prevention of Preterm Delivery,” N Engl J Med, 2007, 357(5):477-87.
Tipton WR and Nelson HS, “Frequent Parenteral Terbutaline in the Treatment of Status Asthmaticus in Children,” Ann Allergy, 1987, 58(4):252-6.
Travis BE and McCullough JM, “Pharmacotherapy of Preterm Labor,” Pharmacotherapy, 1993, 13(1):28-36.
Zehner WJ Jr, Scott JM, Iannolo PM, et al, “Terbutaline vs Albuterol for Out-of-Hospital Respiratory Distress: Randomized Double-Blind Trial,” Acad Emerg Med, 1995, 2(8):686-91.
International Brand Names
Lexi-Comp.com
Last full review/revision June 2011
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