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Special Alerts
Sibutramine: Voluntary Withdrawal From U.S. and Canadian Markets
October 2010
Abbott Labs, in conjunction with the U.S. Food and Drug Administration (FDA) and Health Canada, has voluntarily withdrawn sibutramine (Meridia®) from both the U.S. and Canadian markets. This decision comes as a result of postmarketing data from the Sibutramine Cardiovascular OUTcomes (SCOUT) trial, which indicated an increased risk of heart attack and stroke in sibutramine-treated patients with cardiovascular disease.
Healthcare providers are being advised to:
• No longer prescribe/dispense sibutramine
• Discuss alternative weight loss programs with patients
• Monitor/assess patients for signs/symptoms of cardiovascular events
Patients are advised to:
• Discontinue the use of and discard any remaining sibutramine
• Promptly contact their healthcare providers with the onset of adverse cardiovascular events (eg, angina, palpitations, abnormal heart rate, dizziness)
Further information may be found at:
U.S.: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm228812.htm
Canada: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2010/2010_169-eng.php
Pronunciation
(si BYOO tra meen)
Generic Available (U.S.)
No
Index Terms
Controlled Substance
C-IV
Medication Guide
An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/UCM222366.pdf, must be dispensed with this medication.
REMS Components
Medication Guide
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of obesity in patients with an initial body mass index (BMI) ≥30 kg/m2 or ≥27 kg/m2 in the presence of other risk factors (eg, diabetes, hyperlipidemia, hypertension)
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects were not observed in animal studies except at doses also causing maternal toxicity. Weight loss therapy is generally not recommended for pregnant women. Obese and overweight women should be encouraged to participate in weight reduction programs prior to attempting pregnancy; weight gain during pregnancy should be determined by their prepregnancy BMI and current guidelines. Women of childbearing potential should be instructed to use effective contraception while taking sibutramine.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
Weight loss therapy is generally not recommended for lactating women. Weight loss programs which include physical activity and nutrition components should be discussed at the 6-week postpartum visit.
Contraindications
Hypersensitivity to sibutramine or any component of the formulation; patients >65 years of age; during or within 2 weeks of MAO inhibitors or concomitant centrally-acting appetite suppressants; anorexia nervosa, bulimia nervosa; poorly-controlled or uncontrolled hypertension; history of coronary artery disease, heart failure (HF), arrhythmia, stroke, tachycardia, TIA, or peripheral arterial disease
Warnings/Precautions
Concerns related to adverse effects:
• CNS effects: May impair the ability to engage in potentially hazardous activities.
•Cardiovascular effects: May cause increase in blood pressure and/or heart rate; monitor baseline and on-therapy blood pressure and heart rate. For patients experiencing a sustained increase in blood pressure and/or heart rate, discontinuation should be considered. Caution should be used in patients with controlled hypertension; use is contraindicated in patients with poorly-controlled or uncontrolled hypertension.
• Primary pulmonary hypertension (PPH): A rare and frequently fatal pulmonary disease (PPH), has been reported to occur in patients receiving other agents with serotonergic activity which have been used as anorexiants. Although not reported in clinical trials, it is possible that sibutramine may share this potential; patients should be monitored closely.
• Serotonin syndrome (SS)/neuroleptic malignant syndrome (NMS)-like reactions: SS and NMS-like reactions have occurred with serotonin/norepinephrine reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), including sibutramine, when used alone and particularly when used in combination with serotonergic agents (eg, triptans) or antidopaminergic agents (eg, antipsychotics). The diagnosis of SS can be made using the Hunter Serotonin Toxicity Criteria (Dunkley, 2003). Identification and differentiation of SS (eg, tremor, myoclonus, agitation) and more severe NMS-like reactions (eg, hyperthermia, muscle rigidity, autonomic instability, mental status changes) can be complex; monitor patients closely for either syndrome. Discontinue treatment (and any concomitant serotonergic and/or antidopaminergic agents) immediately if signs/symptoms arise.
• Valvular heart disease: The use of some anorexigens has been associated with the development of valvular heart disease. Avoid stimulants in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that could increase the risk of sudden death that these conditions alone carry.
Disease-related concerns:
• Bleeding disorders: Use with caution in patients with bleeding disorders; rare cases of bleeding have occurred.
• Cardiovascular disease (CVD): Use of sibutramine in patients with CVD increased the risk of cardiovascular events in one clinical trial. Use is contraindicated in patients with a history of coronary artery disease, HF, tachycardia, arrhythmia, stroke or TIA, or peripheral arterial disease.
•Diabetes: Use with caution in patients with diabetes mellitus; antidiabetic agent requirements may be altered with anorexigens and concomitant dietary restrictions.
• Gallstones: Use with caution in patients with a history of gallstones; weight loss may precipitate or exacerbate gallstone formation.
• Glaucoma: Use with caution in patients with narrow-angle glaucoma; mydriasis has been reported.
• Hepatic impairment: Use with caution in patients with mild-moderate hepatic impairment; avoid use in severe impairment.
• Renal impairment: Use with caution in patients with mild-moderate renal impairment; avoid use in severe impairment (including patients on dialysis).
• Psychiatric disorders: Use with caution and monitor closely in patients with a history of psychiatric symptoms; rare reports of depression, mania, psychosis, suicide, and suicidal ideation have been documented in patients on sibutramine.
• Seizure disorders: Use with caution in patients with a history of seizure disorder; seizures have been reported with use.
• Tourette's syndrome: Use with caution in patients with Tourette's syndrome; stimulants may unmask tics.
Concurrent drug therapy issues:
• Serotonergic agents: As sibutramine blocks neuronal serotonin uptake, there is a potential for development of serotonin syndrome if used with other serotonergic agents; concurrent use of serotonergic agents (eg, SSRIs, sumatriptan, dihydroergotamine, dextromethorphan, meperidine, pentazocine, fentanyl, lithium) should be avoided.
Other warnings/precautions:
• Appropriate use: Obesity: Pharmacotherapy for weight loss is recommended only for obese patients with a body mass index ≥30 kg/m2, or ≥27 kg/m2 in the presence of other risk factors, such as hypertension, diabetes, and/or dyslipidemia or a high waist circumference; therapy should be used in conjunction with a comprehensive weight management program. Rule out organic causes of obesity (eg, untreated hypothyroidism) prior to use. Discontinue or reevaluate therapy/dose if significant weight loss has not occurred (eg, <4 pounds within the first 4 weeks of treatment).
Adverse Reactions
>10%:
Central nervous system: Headache (30%), insomnia (11%)
Gastrointestinal: Xerostomia (17%), anorexia (13%), constipation (12%)
1% to 10%:
Cardiovascular: Tachycardia (3%), vasodilation (2%), hypertension (2%), palpitation (2%), chest pain (2%), peripheral edema (≥1%)
Central nervous system: Dizziness (7%), nervousness (5%), anxiety (5%), depression (4%), CNS stimulation (2%), migraine (2%), somnolence (2%), emotional lability (1%), agitation (≥1%), fever (≥1%), thinking abnormal (≥1%)
Dermatologic: Rash (4%), pruritus (≥1%)
Endocrine & metabolic: Dysmenorrhea (4%)
Gastrointestinal: Appetite increased (9%), nausea (6%), abdominal pain (5%), dyspepsia (5%), gastritis (2%), taste perversion (2%), vomiting (2%), diarrhea (≥1%), flatulence (≥1%), gastroenteritis (≥1%), tooth disorder (≥1%)
Hepatic: Abnormal LFTs (2%)
Neuromuscular & skeletal: Back pain (8%), weakness (6%), arthralgia (6%), neck pain (2%), myalgia (2%), paresthesia (2%), tenosynovitis (1%), arthritis (≥1%), hypertonia (≥1%), leg cramps (≥1%)
Ocular: Amblyopia (≥1%)
Otic: Ear disorder (2%)
Respiratory: Pharyngitis (10%), rhinitis (10%), sinusitis (5%), cough (4%), bronchitis (≥1%), dyspnea (≥1%)
Miscellaneous: Flu-like syndrome (8%), diaphoresis (3%), allergic reactions (2%), thirst (2%)
<1%, postmarketing, and/or case reports: Abnormal dreams, alopecia, amnesia, anaphylactic shock, anaphylactoid reaction, anemia, angina, angioedema, arthrosis, atrial fibrillation, blurred vision, bradycardia, bruising, bursitis, cardiac arrest, cerebrovascular accident, chest pressure/tightness, CHF, cholecystitis, cholelithiasis, concentration impaired, confusion, depression, dermatitis, dry eye, epistaxis, eructation, eye pain, facial edema, gait abnormal, GI hemorrhage, GI ulcers (duodenal, mouth, stomach), goiter, hematuria, hyper-/hypoglycemia, hyper-/hypothyroidism, hypersensitivity reaction, hypoesthesia, impotence, interstitial nephritis, intestinal obstruction, intraocular pressure increased, leukopenia, libido changes, limb pain, lymphadenopathy, mania, memory loss (short-term), MI, micturition difficult, mood changes, mydriasis, nasal congestion, nightmares, otitis externa/media, petechiae, photosensitivity, psychosis, salivation increased, seizure, serotonin syndrome, stroke, suicidal ideation, supraventricular tachycardia, syncope, thrombocytopenia, tinnitus, tongue edema, torsade de pointes, Tourette's syndrome, transient ischemic attack, tremor, twitch, urinary frequency increased, urinary retention, urticaria, vascular headache, ventricular extrasystoles, ventricular fibrillation, ventricular tachycardia, vertigo, yawn
Metabolism/Transport Effects
Substrate of CYP3A4 (major)
Drug Interactions
Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Management: Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates. Risk D: Consider therapy modification
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ergot Derivatives: Sibutramine may enhance the serotonergic effect of Ergot Derivatives. This may cause serotonin syndrome. Management: Sibutramine should generally be avoided in patients receiving treatment with ergot derivatives due to a theoretical risk of serotonin syndrome. If the combination cannot be avoided, monitor patients for signs/symptoms of serotonin toxicity. Risk D: Consider therapy modification
Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination
Serotonin Modulators: Sibutramine may enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid excess ethanol ingestion.
Food: Administration with a standard breakfast reduced the peak concentrations of the active metabolites, M1 and M2 (27% and 32%, respectively) and delayed the time to peak by ~3 hours; AUC and was not significantly altered.
Herb/Nutraceutical: St John's wort and SAMe may decrease sibutramine levels.
Storage
Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Mechanism of Action
Sibutramine and its two primary metabolites block the neuronal uptake of norepinephrine, serotonin, and (to a lesser extent) dopamine. There is no monoamine-releasing (or depleting) activity.
Pharmacodynamics/Kinetics
Absorption: 77%; rapid
Protein binding, plasma: Parent drug and metabolites: >94%
Metabolism: Hepatic; undergoes first-pass metabolism via CYP3A4; forms two primary metabolites (M1 and M2; active)
Half-life elimination: Sibutramine: 1 hour; Metabolites: M1: 14 hours; M2: 16 hours
Time to peak: Sibutramine: 1.2 hours; Metabolites (M1 and M2): 3-4 hours
Excretion: Primarily urine (77% as inactive metabolites); feces
Dosage
Children ≥16 years and Adults:
Initial: 10 mg once daily; may increase to 15 mg once daily after 4 weeks as needed and tolerated (maximum daily dose: 15 mg); may be used for up to 2 years, per manufacturer labeling
Maintenance: 5-15 mg once daily
Dosage adjustment in renal impairment:
Mild-to-moderate renal impairment: Use with caution.
Severe renal impairment (CLcr ≤30 mL/minute): Use not recommended in this patient population (including patients on dialysis)
Dosage adjustment in hepatic impairment:
Mild-to-moderate hepatic impairment: No adjustment necessary
Severe hepatic impairment: Use not recommended
Administration: Oral
May administer without regard to meals.
Monitoring Parameters
Weight, waist circumference, blood pressure, heart rate. Do initial blood pressure and heart rate evaluation and then monitor regularly during therapy. If patient has sustained increases in either blood pressure or pulse rate, consider discontinuing or reducing the dose of the drug.
Reference Range
Adult classification of weight by BMI (kg/m2):
Underweight: <18.5
Normal: 18.5-24.9
Overweight: 25-29.9
Obese, class I: 30-34.9
Obese, class II: 35-39.9
Extreme obesity (class III): ≥40
Waist circumference: In adults with a BMI of 25-34.9 kg/m2, high-risk waist circumference is defined as:
Men >102 cm (>40 in)
Women >88 cm (>35 in)
Dietary Considerations
Most effective when combined with a low calorie diet and behavior modification counseling. May be taken without regard to meals.
Patient Education
May be taken with meals (do not take at bedtime). Avoid caffeine. You may experience restlessness, dizziness, sleepiness, insomnia, nausea, vomiting, constipation, diarrhea, or altered menstrual periods (reversible when drug is discontinued). Report chest pain, palpitations, or irregular heartbeat; excessive nervousness, excitation, or sleepiness; back pain, muscle weakness, or tremors; CNS changes (acute headache, aggressiveness, restlessness, excitation, sleep disturbances); menstrual pattern changes; rash; blurred vision; runny nose, sinusitis, cough, or respiratory difficulty.
Additional Information
Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (eg, development of tolerance, excessive increases of doses, drug seeking behavior).
Cardiovascular Considerations
Sibutramine may induce a significant blood pressure increase; use is contraindicated in patients with a history of cardiovascular disease. The hypertensive effect of sibutramine may theoretically potentiate the nocturnal hypertension in patients with sleep apnea. Because this drug is used in the management of obesity, it is likely that many of the patients receiving it will have coexisting obstructive sleep apnea.
Unlike dexfenfluramine and fenfluramine, the medication does not cause the release of serotonin from neurons. Tests done on humans show no evidence of valvular heart disease and experiments done on animals show no evidence of the neurotoxicity which was found in similar testing using animals treated with fenfluramine and dexfenfluramine; has minimal potential for abuse.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and taste perversion (see Dental Health Professional Considerations).
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Dental Comment
The mechanism of action is thought to be different from the “fen” drugs. Sibutramine works to suppress the appetite by inhibiting the reuptake of norepinephrine and serotonin. Unlike dexfenfluramine and fenfluramine, it is not a serotonin releaser. Sibutramine is closer chemically to the widely used antidepressants such as fluoxetine (Prozac®). The FDA approved sibutramine over the objections of its own advisory panel, who called the drug too risky. FDA reported that the drug causes blood pressure to increase, generally by a small amount, though in some patients the increases were higher. It is now recommended that patients taking sibutramine have their blood pressure evaluated regularly.
Nursing: Physical Assessment/Monitoring
Monitor vital signs, weight, and adverse reactions at start of therapy, when changing dosage, and at regular intervals during therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Capsule, oral, as hydrochloride:
Meridia®: 5 mg [DSC], 10 mg [DSC], 15 mg [DSC]
Pricing: U.S. (www.drugstore.com)
Capsules (Meridia)
5 mg (10): $45.99
10 mg (10): $45.99
15 mg (10): $56.99
References
Abenhaim L, Moride Y, Brenot F, et al, “Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hypertension. International Primary Pulmonary Hypertension Study Group,” N Engl J Med, 1996, 335(9):609-16.
American College of Obstetricians and Gynecologists, "ACOG Committee Opinion Number 315, September 2005. Obesity in Pregnancy," Obstet Gynecol, 2005, 106(3):671-5.
American Dietetic Association; American Society of Nutrition, Siega-Riz AM, et al, "Position of the American Dietetic Association and American Society for Nutrition: Obesity, Reproduction, and Pregnancy Outcomes," J Am Diet Assoc, 2009, 109(5):918-27.
"Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: Executive Summary. Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults," Am J Clin Nutr, 1998, 68(4):899-917.
Dunkley EJ, Isbister GK, Sibbritt D, et al, “The Hunter Serotonin Toxicity Criteria: Simple and Accurate Diagnostic Decision Rules for Serotonin Toxicity,” QJM, 2003, 96(9):635-42.
IOM (Institute of Medicine) and NRC (National Research Council), "Weight Gain During Pregnancy: Reexamining the Guidelines," Washington, DC: The National Academies Press, 2009. Available at http://www.nap.edu
King DJ and Devaney N, “Clinical Pharmacology of Sibutramine Hydrochloride (BTS 54524), A New Antidepressant, in Healthy Volunteers,” Br J Clin Pharmacol, 1988, 26(5):607-11.
National Heart, Lung, and Blood Institute Obesity Education Initiative, "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. The Evidence Report," NIH Publication No. 98-4083, Bethesda, MD: U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, 1998. Available at http://www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.pdf
Snow V, Barry P, Fitterman N, et al, “Pharmacologic and Surgical Management of Obesity in Primary Care: A Clinical Practice Guideline from the American College of Physicians,” Ann Intern Med, 2005, 142(7):525-31.
“U.S. Preventative Services Task Force. Screening for Obesity in Adults: Recommendations and Rationale,” Ann Intern Med, 2003, 139(11):933-49
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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