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Concomitant Cardiovascular Disease
Due to an increased risk of heart attack and stroke in patients with cardiovascular disease, MERIDIA (sibutramine hydrochloride monohydrate) should not be used in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke.
Blood Pressure and Pulse
MERIDIA (sibutramine hydrochloride monohydrate) SUBSTANTIALLY INCREASES BLOOD PRESSURE AND/OR PULSE RATE IN SOME PATIENTS. REGULAR MONITORING OF BLOOD PRESSURE AND PULSE RATE IS REQ UIRED WHEN PRESCRIBING MERIDIA (sibutramine hydrochloride monohydrate) .
In placebo-controlled obesity studies, sibutramine 5 to 20 mg once daily was associated with mean increases in systolic and diastolic blood pressure of approximately 1 to 3 mm Hg relative to placebo, and with mean increases in pulse rate relative to placebo of approximately 4 to 5 beats per minute. Larger increases were seen in some patients, particularly when therapy with sibutramine was initiated at the higher doses (see table below). In premarketing placebo-controlled obesity studies, 0.4% of patients treated with sibutramine were discontinued f or hypertension (SBP ≥ 160 mm Hg or DBP ≥ 95 mm Hg), compared with 0.4% in the placebo group, and 0.4 % of patients treated with sibutramine were discontinued for tachycardia (pulse rate ≥ 100bpm), compared with 0.1% in the placebo group. Blood pressure and pulse should be measured prior to starting therapy with MERIDIA (sibutramine hydrochloride monohydrate) and should be monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate while receiving MERIDIA (sibutramine hydrochloride monohydrate) , either dose reduction or discontinuation should be considered. MERIDIA (sibutramine hydrochloride monohydrate) should be given with caution to those patients with a history of hypertension (see DOSAGE AND ADMINISTRATION), and should not be given to patients with uncontrolled or poorly controlled hypertension.
Percent Outliers in Studies 1 and 2
|Dose (mg)||SBP||% Outliers*|
|* Outlier defined as increase from baseline of ≥ 15 mm Hg for three consecutive visits (SBP), ≥ 10 mm Hg for three consecutive visits (DBP), or pulse ≥ 10 bpm for three consecutive visits.|
Potential Interaction With Monoamine Oxidase Inhibitors
MERIDIA (sibutramine hydrochloride monohydrate) is a norepinephrine, serotonin and dopamine reuptake inhibitor and should not be used concomitantly with MAOIs (see PRECAUTIONS: DRUG INTERACTIONS subsection). There should be at least a 2-week interval after stopping MAOIs before commencing treatment with MERIDIA (sibutramine hydrochloride monohydrate) . Similarly, there should be at least a 2-week interval after stopping MERIDIA (sibutramine hydrochloride monohydrate) before starting treatment with MAOIs.
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions
The development of a potentially life-threatening serotonin syndrome, or Neuroleptic Malignant Syndrome (NMS)-like reactions, has been reported with SNRIs and SSRIs alone, including MERIDIA (sibutramine hydrochloride monohydrate) treatment, but particularly with concomitant use of serotonergic drugs (including triptans), with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms [e.g., nausea, vomiting, diarrhea] (seePRECAUTIONS: DRUG INTERACTIONS). Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.
Because MERIDIA (sibutramine hydrochloride monohydrate) can cause mydriasis, it should be used with caution in patients with narrow angle glaucoma.
Organic causes of obesity (e.g., untreated hypothyroidism) should be excluded before prescribing MERIDIA (sibutramine hydrochloride monohydrate) .
Certain centrally-acting weight loss agents that cause release of serotonin from nerve terminals have been associated with pulmonary hypertension (PPH), a rare but lethal disease. In premarketing clinical studies, no cases of PPH have been reported with sibutramine capsules. Because of the low incidence of this disease in the underlying population, however, it is not known whether or not MERIDIA (sibutramine hydrochloride monohydrate) may cause this disease.
During premarketing testing, seizures were reported in < 0.1% of sibutramine treated patients. MERIDIA (sibutramine hydrochloride monohydrate) should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.
There have been reports of bleeding in patients taking sibutramine. While a causal relationship is unclear, caution is advised in patients predisposed to bleeding events and those taking concomitant medications known to affect hemostasis or platelet function.
Weight loss can precipitate or exacerbate gallstone formation.
MERIDIA (sibutramine hydrochloride monohydrate) should be used with caution in patients with mild to moderate renal impairment. MERIDIA (sibutramine hydrochloride monohydrate) should not be used in patients with severe renal impairment, including those with end stage renal disease on dialysis (see Pharmacokinetics - Special Populations - Renal Insufficiency).
Patients with severe hepatic dysfunction have not been systematically studied; MERIDIA (sibutramine hydrochloride monohydrate) should therefore not be used in such patients.
Interference With Cognitive and Motor Performance
Although sibutramine did not affect psychomotor or cognitive performance in healthy volunteers, any CNS active drug has the potential to impair judgment, thinking or motor skills.
Information For Patients
Physicians should instruct their patients to read the Medication Guide before starting therapy with MERIDIA (sibutramine hydrochloride monohydrate) and to reread it each time the prescription is renewed.
Physicians should also discuss with their patients any part of the package insert that is relevant to them. In particular, the importance of keeping appointments for follow-up visits should be emphasized.
Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, especially weight-reducing agents, decongestants, antidepressants, cough suppressants, lithium, dihydroergotamine, sumatriptan (Imitrex®), or tryptophan, since there is a potential for interactions.
Patients should be reminded of the importance of having their blood pressure and pulse monitored at regular intervals.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Sibutramine was administered in the diet to mice (1.25, 5 or 20 mg/kg/day) and rats (1, 3, or 9 mg/kg/day) for two years generating combined maximum plasma AUC's of the two major active metabolites equivalent to 0.4 and 16 times, respectively, those following a daily human dose of 15 mg. There was no evidence of carcinogenicity in mice or in female rats. In male rats there was a higher incidence of benign tumors of the testicular interstitial cells; such tumors are commonly seen in rats and are hormonally mediated. The relevance of these tumors to humans is not known.
Sibutramine was not mutagenic in the Ames test, in vitro Chinese hamster V79 cell mutation assay, in vitro clastogenicity assay in human lymphocytes or micronucleus assay in mice. Its two major active metabolites were found to have equivocal bacterial mutagenic activity in the Ames test. However, both metabolites gave consistently negative results in the in vitro Chinese hamster V79 cell mutation assay, in vitro clastogenicity assay in human lymphocytes, in vitro DNA-repair assay in HeLa cells, micronucleus assay in mice and in vivo unscheduled DNA-synthesis assay in rat hepatocytes.
Impairment of Fertility
In rats, there were no effects on fertility at doses generating combined plasma AUC's of the two major active metabolites up to 32 times those following a human dose of 15 mg. At 13 times the human combined AUC, there was maternal toxicity, and the dams' nest-building behavior was impaired, leading to a higher incidence of perinatal mortality; there was no effect at approximately 4 times the human combined AUC.
Pregnancy Category C
Radiolabeled studies in animals indicated that tissue distribution was unaffected by pregnancy, with relatively low transfer to the fetus. In rats, there was no evidence of teratogenicity at doses of 1, 3, o r 10 mg/kg/day generating combined plasma AUC's of the two major active metabolites up to approximately 32 times those following the human dose of 15 mg. In rabbits dosed at 3, 15, or 75 mg/kg/day, plasma AUC's greater than approximately 5 times those following the human dose of 15 mg caused maternal toxicity. At markedly toxic doses, Dutch Belted rabbits had a slightly higher than control incidence of pups with a broad short snout, short rounded pinnae, short tail and, in so me, shorter thickened long bones in the limbs; at comparably high doses in New Zealand White rabbits, one study showed a slightly higher than control incidence of pups with cardiovascular anomalies while a second study showed a lower incidence than in the control group.
No adequate and well controlled studies with sibutramine have been conducted in pregnant women. The use of MERIDIA (sibutramine hydrochloride monohydrate) during pregnancy is not recommended. Women of childbearing potential should employ adequate contraception while taking MERIDIA (sibutramine hydrochloride monohydrate) . Patients should be advised to n otify their physician if they become pregnant or intend to become p regnant while taking MERIDIA (sibutramine hydrochloride monohydrate) .
It is not known whether sibutramine or its metabolites are excreted in human milk. MERIDIA (sibutramine hydrochloride monohydrate) is not recommended for use in nursing mothers. Patients should be advised to notify their physician if they are breast-feeding.
The efficacy of sibutramine in adolescents who are obese has not been adequately studied.
Sibutramine's mechanism of action inhibiting the reuptake of serotonin and norepinephrine is similar to the mechanism of action of some antidepressants. Pooled analyses of short-term placebo-controlled trials of antidepressants in children and adolescents with major depressive disorder (MD D), obsessive compulsive disorder (OCD), and other psychiatric disorders have revealed a greater risk of adverse events representing suicidal behavior or thinking during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%.
No placebo-controlled trials of sibutramine have been conducted in children or adolescents with MDD, OCD, or other psychiatric disorders. In a study of adole scents with obesity in which 368 patients were treated with sibutramine and 130 patients with placebo, one patient in the sibutr amine group and one patient in the placebo group attempted suicide. Suicidal ideation was reported by 2 sibutramine-treated patients and none of the placebo patients. It is unknown if sibutramine increases the risk of suicidal behavior or thinking in pediatric patients.
The data are inadequate to recommend the use of sibutramine for the treatment of obesity in pediatric patients.
Clinical studies of sibutramine did not include sufficient numbers of patients over 65 years of age. Sibutramine is contraindicated in this group of patients (see CONTRAINDICATIONS). Pharmacokinetics in elderly patients are discussed in “CLINICAL PHARMACOLOGY.”This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 1/31/2011
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