In placebo-controlled studies, 9% of patients treated with sibutramine (n = 2068) and 7% of patients treated with placebo (n = 884) withdrew for adverse events.

In placebo-controlled studies, the most common events were dry mouth, anorexia, insomnia, constipation and headache. Adverse events in these studies occurring in ≥ 1% of sibutramine treated patients and more frequently than in the placebo group are shown in the following table.

Obese Patients in Placebo-Controlled Studies

The following additional adverse events were reported in ≥ 1% of all patients who received sibutramine in controlled and uncontrolled pre-marketing studies.

Body as a Whole

fever.

Digestive System

diarrhea, flatulence, gastroenteritis, tooth disorder.

Metabolic and Nutritional

peripheral edema.

Musculoskeletal System

arthritis.

Nervous System

agitation, leg cramps, hypertonia, thinking abnormal.

Respiratory System

bronchitis, dyspnea.

Skin and Appendages

pruritus.

Special Senses

amblyopia.

Urogenital System

menstrual disorders.

Other Adverse Events

Clinical Studies

Seizures

Convulsions were reported as an adverse event in three of 2068 (0.1%) sibutramine treated patients and in none of 884 placebo-treated patients in placebo-controlled premarketing obesity studies. Two of the three patients with seizures had potentially predisposing factors (one had a prior history of epilepsy; one had a subsequent diagnosis of brain tumor). The incidence in all subjects who received sibutramine (three of 4,588 subjects) was less than 0.1%.

Ecchymosis/Bleeding Disorders

Ecchymosis (bruising) was observed in 0.7% of sibutramine treated patients and in 0.2% of placebo-treated patients in pre-marketing placebo-controlled obesity studies. One patient had prolonged bleeding of a small amount which occurred during minor facial surgery. Sibutramine may have an effect on platelet function due to its effect on serotonin uptake.

Interstitial Nephritis

Acute interstitial nephritis (confirmed by biopsy) was reported in one obese patient receiving sibutramine during pre-marketing studies. After discontinuation of the medication, dialysis and oral corticosteroids were administered; renal function normalized. The patient made a full recovery.

Altered Laboratory Findings

Abnormal liver function tests, including increases in AST, ALT, GGT, LDH, alkaline phosphatase and bilirubin, were reported as adverse events in 1.6% of sibutramine-treated obese patients in placebo-controlled trials compared with 0.8% of placebo patients. In these studies, potentially clinically significant values (total bilirubin ≥ 2 mg/dL; ALT, AST, GGT, LDH, or alkaline phosphatase ≥ 3 × upper limit of normal) occurred in 0% (alkaline phosphatase) to 0.6% (ALT) of the sibutramine treated patients and in none of the placebo-treated patients. Abnormal values tended to be sporadic, often diminished with continued treatment, and did not show a clear dose-response relationship.

Postmarketing Reports

Voluntary reports of adverse events temporally associated with the use of sibutramine are listed below. It is important to emphasize that although these events occurred during treatment with sibutramine, they may have no causal relationship with the drug. Obesity itself, concurrent disease states/risk factors, or weight reduction may be associated with an increased risk for some of these events.

Psychiatric

Cases of depression, suicidal ideation and suicide have been reported rarely in patients on sibutramine treatment. However, a relationship has not been established between the occurrence of depression and/or suicidal ideation and the use of sibutramine. If depression occurs during treatment with sibutramine, further evaluation may be necessary.

Hypersensitivity

Allergic hypersensitivity reactions ranging from mild skin eruptions and urticaria to angioedema and anaphylaxis have been reported (see CONTRAINDICATIONS and PRECAUTIONS-Information For Patients, and other reports of allergic reactions listed below).

Other Postmarketing Reported Events:

Body as a Whole

anaphylactic shock, anaphylactoid reaction, chest pressure, chest tightness, facial edema, limb pain, sudden unexplained death.

Cardiovascular System

angina pectoris, atrial fibrillation, congestive heart failure, heart arrest, heart rate decreased, myocardial infarction, supraventricular tachycardia, syncope, torsade de pointes, vascular headache, ventricular tachycardia, ventricular extrasystoles, ventricular fibrillation.

Digestive System

cholecystitis, cholelithiasis, duodenal ulcer, eructation, gastrointestinal hemorrhage, increased salivation, intestinal obstruction, mouth ulcer, stomach ulcer, tongue edema.

Endocrine System

goiter, hyperthyroidism, hypothyroidism.

Hemic and Lymphatic System

anemia, leukopenia, lymphadenopathy, petechiae, thrombocytopenia.

Metabolic and Nutritional

hyperglycemia, hypoglycemia.

Musculoskeletal System

arthrosis, bursitis.

Nervous System

abnormal dreams, abnormal gait, amnesia, anger, cerebrovascular accident, concentration impaired, confusion, depression aggravated, Gilles de la Tourette's syndrome, hypesthesia, libido decreased, libido increased, manic reaction, mood changes, nightmares, serotonin syndrome, short term memory loss, speech disorder, transient ischemic attack, tremor, twitch, vertigo.

Respiratory System

epistaxis, nasal congestion, respiratory disorder, yawn.

Skin and Appendages

alopecia, dermatitis, photosensitivity (skin), urticaria.

Special Senses

abnormal vision, blurred vision, dry eye, eye pain, increased intraocular pressure, otitis externa, otitis media, photosensitivity (eyes), tinnitus.

Urogenital System

abnormal ejaculation, hematuria, impotence, increased urinary frequency, micturition difficulty, urinary retention.

Drug Abuse And Dependence

Controlled Substance

MERIDIA is controlled in Schedule IV of the Controlled Substances Act (CSA).

Abuse and Physical and Psychological Dependence

Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., drug development of tolerance, incrementation of doses, drug seeking behavior).

CNS Active Drugs:

The use of MERIDIA in combination with other CNS-active drugs, particularly serotonergic agents, has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of MERIDIA with other centrally-acting drugs is indicated (see CONTRAINDICATIONS and WARNINGS).

In patients receiving monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine, selegiline) in combination with serotonergic agents (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine), there have been reports of serious, sometimes fatal, reactions ("serotonin syndrome;" see below). Because sibutramine inhibits serotonin reuptake, MERIDIA should not be used concomitantly with a MAOI (see CONTRAINDICATIONS). At least 2 weeks should elapse between discontinuation of a MAOI and initiation of treatment with MERIDIA. Similarly, at least 2 weeks should elapse between discontinuation of MERIDIA and initiation of treatment with a MAOI.

The rare, but serious, constellation of symptoms termed "serotonin syndrome" has also been reported with the concomitant use of selective serotonin reuptake inhibitors and agents for migraine therapy, such as Imitrex® (sumatriptan succinate) and dihydroergotamine, certain opioids, such as dextromethorphan, meperidine, pentazocine and fentanyl, lithium, or tryptophan. Serotonin syndrome has also been reported with the concomitant use of two serotonin reuptake inhibitors. The syndrome requires immediate medical attention and may include one or more of the following symptoms: excitement, hypomania, restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, motor weakness, myoclonus, tremor, hemiballismus, hyperreflexia, ataxia, dysarthria, incoordination, hyperthermia, shivering, pupillary dilation, diaphoresis, emesis, and tachycardia.

Because sibutramine inhibits serotonin reuptake, in general, it should not be administered with other serotonergic agents such as those listed above. However, if such a combination is clinically indicated, appropriate observation of the patient is warranted.

Drugs That May Raise Blood Pressure and/or Heart Rate

Concomitant use of MERIDIA and other agents that may raise blood pressure or heart rate have not been evaluated. These include certain decongestants, cough, cold, and allergy medications that contain agents such as ephedrine, or pseudoephedrine. Caution should be used when prescribing MERIDIA to patients who use these medications.

Alcohol

In a double-blind, placebo-controlled, crossover study in 19 volunteers, administration of a single dose of ethanol (0.5 mL/kg) together with 20 mg of sibutramine resulted in no psychomotor interactions of clinical significance between alcohol and sibutramine. However, the concomitant use of MERIDIA and excess alcohol is not recommended.

Oral Contraceptives

The suppression of ovulation by oral contraceptives was not inhibited by sibutramine. In a crossover study, 12 healthy female volunteers on oral steroid contraceptives received placebo in one period and 15 mg sibutramine in another period over the course of 8 weeks. No clinically significant systemic interaction was observed; therefore, no requirement for alternative contraceptive precautions are needed when patients taking oral contraceptives are concurrently prescribed sibutramine.

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