Controlex

Controlex (sibutramine hydrochloride monohydrate) is indicated for the management of obesity, including weight loss and maintenance of weight loss, and should be used in conjunction with a reduced calorie diet. Controlex (sibutramine hydrochloride monohydrate) is recommended for obese patients with an initial body mass index ≥ 30 kg/m², or ≥ 27 kg/m² in the presence of other risk factors (e.g., diabetes, dyslipidemia, controlled hypertension).

Below is a chart of Body Mass Index (BMI) based on various heights and weights.

BMI is calculated by taking the patient's weight, in kg, and dividing by the patient's height, in meters, squared. Metric conversions are as follows: pounds ÷ 2.2 = kg; inches × 0.0254 = meters.

The recommended starting dose of Controlex (sibutramine hydrochloride monohydrate) is 10 mg administered once daily with or without food. If there is inadequate weight loss, the dose may be titrated after four weeks to a total of 15 mg once daily. The 5 mg dose should be reserved for patients who do not tolerate the 10 mg dose. Blood pressure and heart rate changes should be taken into account when making decisions regarding dose titration (see WARNINGS and PRECAUTIONS).

Doses above 15 mg daily are not recommended. In most of the clinical trials, Controlex (sibutramine hydrochloride monohydrate) was given in the morning.

Analysis of numerous variable s has indicated that approximately 60% of patients who lose at least 4 pounds in the first 4 weeks of treatment with a given dose of Controlex (sibutramine hydrochloride monohydrate) in combination with a reduced-calorie diet lose at least 5% (placebo-subtracted) of their initial body weight by the end of 6 months to 1 year of treatment on that dose of Controlex (sibutramine hydrochloride monohydrate). Conversely , approximately 80% of patients who do not lose at least 4 pounds in the first 4 weeks of treatment with a given dose of Controlex (sibutramine hydrochloride monohydrate) do not lose at least 5% (placebo-subtracted) of their initial body weight by the end of 6 months to 1 year of treatment on that dose. If a patient has not lost at least 4 pounds in the first 4 weeks of treatment, the physician should consider reevaluation of therapy which may include increasing the dose or discontinuation of Controlex (sibutramine hydrochloride monohydrate).

The safety and effectiveness of Controlex (sibutramine hydrochloride monohydrate) , as demonstrated in double-blind, placebo-controlled trials, have not been determined beyond 2 years at this time.

Controlex (sibutramine hydrochloride monohydrate) is contraindicated in patients:

• with a history of coronary artery disease (e.g., angina, history of myocardial infarction), congestive heart failure, tachycardia, peripheral arterial occlusive disease, arrhythmia or cerebrovascular disease (stroke or transient ischemic attack (TIA)) (see WARNINGS).
• with inadequately controlled hypertension > 145/90 mm Hg (see WARNINGS).
• over 65 years of age.
• receiving monoamine oxidase inhibitors (MAOIs) (see WARNINGS).
• with hypersensitivity to sibutramine or any of the inactive ingredients of Controlex (sibutramine hydrochloride monohydrate).
• who have a major eating disorder (anorexia nervosa or bulimia nervosa).
• taking other centrally acting weight loss drugs.

WARNINGS

Concomitant Cardiovascular Disease

Due to an increased risk of heart attack and stroke in patients with cardiovascular disease, Controlex (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

Controlex (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 Controlex (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 Controlex (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 Controlex (sibutramine hydrochloride monohydrate) , either dose reduction or discontinuation should be considered. Controlex (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

Potential Interaction With Monoamine Oxidase Inhibitors

Controlex (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 Controlex (sibutramine hydrochloride monohydrate). Similarly, there should be at least a 2-week interval after stopping Controlex (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 Controlex (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.

Glaucoma

Because Controlex (sibutramine hydrochloride monohydrate) can cause mydriasis, it should be used with caution in patients with narrow angle glaucoma.

Miscellaneous

Organic causes of obesity (e.g., untreated hypothyroidism) should be excluded before prescribing Controlex (sibutramine hydrochloride monohydrate).

PRECAUTIONS

Pulmonary Hypertension

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 Controlex (sibutramine hydrochloride monohydrate) may cause this disease.

Seizures

During premarketing testing, seizures were reported in < 0.1% of sibutramine treated patients. Controlex (sibutramine hydrochloride monohydrate) should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.

Bleeding

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.

Gallstones

Weight loss can precipitate or exacerbate gallstone formation.

Renal Impairment

Controlex (sibutramine hydrochloride monohydrate) should be used with caution in patients with mild to moderate renal impairment. Controlex (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).

Hepatic Dysfunction

Patients with severe hepatic dysfunction have not been systematically studied; Controlex (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 Controlex (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 notify their physician if they develop a rash, hives, or other allergic reactions.

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

Carcinogenicity

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.

Mutagenicity

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

Teratogenic Effects

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 Controlex (sibutramine hydrochloride monohydrate) during pregnancy is not recommended. Women of childbearing potential should employ adequate contraception while taking Controlex (sibutramine hydrochloride monohydrate). Patients should be advised to n otify their physician if they become pregnant or intend to become p regnant while taking Controlex (sibutramine hydrochloride monohydrate).

Nursing Mothers

It is not known whether sibutramine or its metabolites are excreted in human milk. Controlex (sibutramine hydrochloride monohydrate) is not recommended for use in nursing mothers. Patients should be advised to notify their physician if they are breast-feeding.

Pediatric Use

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.

Geriatric Use

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.”

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 premarketing 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-cont rolled 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 trea ted patients and in 0.2% of placebo-treated patients in premarketing 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 premarketing 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, psychosis, mania, suicidal ideation and suicide have been reported rarely in patients on sibutramine treatment. However, a relationship has not been established between these events and the use of sibutramine. If any of these events should occur during treatment with sibutramine, discontinuation should be considered.

Hypersensitivity

Allergic hypersensitivity reactions ranging from mild skin eruptions and urticaria to angioedema and anaphylaxis have been reported (see CONTRAINDICATIONS and PATIENT INFORMATION, 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, mood changes, nightmares, 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, otitisexterna, otitis media, photosensitivity (eyes), tinnitus.

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

Drug Abuse And Dependence

Controlled Substance

Controlex (sibutramine hydrochloride monohydrate) 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).

Overdose Management

There is limited experience of overdose with sibutramine. The most frequently noted adverse events associated with overdose are tachycardia, hypertension, headache and dizziness. Tre atment should consist of general measures employed in the management of overdosage: an airway should be established as needed; cardiac and vital sign monitoring is recommended; general symptomatic and supportive measures should be instituted. Cautious use of β-blockers may be indicated to control elevated blood pressure or tachycardia. The results from a study in patients with end-stage renal disease on dialysis showed that sibutramine metabolites were not eliminated to a significant degree with hemodialysis. (see Pharmacokinetics - Special Populations - Renal Insufficiency).

Sibutramine exerts its pharmacological actions predominantly via its secondary (M₁) and primary (M₂) amine metabolites. The parent compound, sibutramine, is a potent inhibitor of serotonin (5­hydroxytryptamine, 5-HT) and norepinephrine reuptake in vivo, but not in vitro . However, metabolites M₁ and M₂ inhibit the reuptake of these neurotransmitters both in vitro and in vivo.

In human brain tissue, M₁ and M₂ also inhibit dopamine reuptake in vitro , but with ~3-fold lower potency than for the reuptake inhibition of serotonin or norepinephrine.

Potencies of Sibutramine, M₁ and M₂ as In Vitro Inhibitors of Monoamine Reuptake in Human Brain Potency to Inhibit Monoamine Reuptake (Ki;nM)

A study using plasma samples taken from sibutramine-treated volunteers showed monoamine reuptake inhibition of norepinephrine > serotonin > dopamine; maximum inhibitions were norepinephrine = 73%, serotonin = 54% and dopamine = 16%.

Sibutramine and its metabolites (M₁ and M₂) are not serotonin, norepinephrine or dopamine releasing agents. Following chronic administration of sibutramine to rats, no depletion of brain monoamines has been observed.

Sibutramine, M₁ and M₂ exhibit no evidence of anticholinergic or antihistaminergic actions. In addition, receptor binding profiles show that sibutramine, M₁ and M₂ have low affinity for serotonin (5-HT₁, 5­HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C), norepinephrine (β, β1, β3, α1 and α2), dopamine (D1 and D2), benzodiazepine, and glutamate (NMDA) receptors. These compounds also lack monoamine oxidase inhibitory activity in vitro and in vivo.

Absorption

Sibutramine is rapidly absorbed from the GI tract (Tmax of 1.2 hours) following oral administration and undergoes extensive first-pass metabolism in the liver (oral clearance of 1750 L/h and half-life of 1.1 h) to form the pharmacologically active mono- and di-desmethyl metabolites M₁ and M₂. Peak plasma concentrations of M₁ and M₂ are reached within 3 to 4 hours. On the basis of mass balance studies, on average, at least 77% of a single oral dose of sibutramine is absorbed. The absolute bioavailability of sibutramine has not been determined.

Distribution

Radiolabeled studies in animals indicated rapid and extensive distribution into tissues: highest concentrations of radiolabeled material were found in the eliminating organs, liver and kidney. In vitro, sibutramine, M₁ and M₂ are extensively bound (97%, 94% and 94%, respectively) to human plasma proteins at plasma concentrations seen following therapeutic doses.

Metabolism

Sibutramine is metabolized in the liver principally by the cytochrome P450 (3A4) isoenzyme, to desmethyl metabolites, M₁ and M₂. These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M₅ and M₆. Following oral administration of radiolabeled sibutramine, essentially all of the peak radiolabeled material in plasma was accounted for by unchanged sibutramine (3%), M₁ (6%), M₂ (12%), M₅ (52%), and M₆ (27%).

M₁ and M₂ plasma concentrations reached steady-state within four days of dosing and were approximately two-fold higher than following a single dose. The elimination half-lives of M₁ and M₂, 14 and 16 hours, respectively, were unchanged following repeated dosing.

Excretion

Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and feces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. Major metabolites in urine were M₅ and M₆; unchanged sibutramine, M₁, and M₂ were not detected. The primary route of excretion for M₁ and M₂ is hepatic metabolism and for M₅ and M₆ is renal excretion.

Summary of Pharmacokinetic Parameters
Mean (% CV) and 95% Confidence Intervals of Pharmacokinetic Parameters (Dose = 15mg)

Effect of Food

Administration of a single 20 mg dose of sibutramine with a standard breakfast resulted in reduced peak M₁ and M₂ concentrations (by 27% and 32%, respectively) and delayed the time to peak by approximately three hours. However, the AUCs of M₁ and M₂ were not significantly altered.