PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 10 DRUG INTERACTIONS 17 DOSAGE AND ADMINISTRATION 20 OVERDOSAGE 22 ACTION AND CLINICAL PHARMACOLOGY 22 STORAGE AND STABILITY 26 DOSAGE FORMS, COMPOSITION AND PACKAGING 27

PART II: SCIENTIFIC INFORMATION 28

PHARMACEUTICAL INFORMATION 28 CLINICAL TRIALS 29 DETAILED PHARMACOLOGY 31 TOXICOLOGY 35 REFERENCES 39

PART III: CONSUMER INFORMATION. 42

PrMERIDIA(r) (sibutramine hydrochloride monohydrate)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION, AND PACKAGING section of the Product Monograph. MERIDIA(r) (sibutramine hydrochloride monohydrate) is contraindicated in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or cerebrovascular disease (stroke or TIA) (see WARNINGS AND PRECAUTIONS). sibutramine hydrochloride monohydrate is contraindicated in patients with inadequately controlled (>145/90 mm Hg) or unstable hypertension (see WARNINGS AND PRECAUTIONS). sibutramine hydrochloride monohydrate is contraindicated in patients with a history of, or presence of, major eating disorder such as anorexia nervosa or bulimia nervosa. Concomitant use of sibutramine hydrochloride monohydrate with other centrally acting weight-reducing agents is contraindicated (see DRUG INTERACTIONS). Concomitant use of sibutramine hydrochloride monohydrate and MAO inhibitors is contraindicated. At least 14 days should elapse between discontinuation of a MAO inhibitor and initiation of treatment with sibutramine hydrochloride monohydrate (see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS). Concomitant use of sibutramine hydrochloride monohydrate and centrally-acting drugs for the treatment of psychiatric disorders (such as antidepressants, antipsychotics) or herbal remedies (such as St John's Wort) is contraindicated. At least 14 days should elapse between discontinuation of these drugs and initiation of treatment with sibutramine hydrochloride monohydrate. A 5 week discontinuation period is required for fluoxetine (see DRUG INTERACTIONS). sibutramine hydrochloride monohydrate is contraindicated in psychiatric illness. Sibutramine has shown potential antidepressant activity in animal studies and therefore it cannot be excluded that sibutramine could induce a manic episode in bipolar patients.

WARNINGS AND PRECAUTIONS

General

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

Interaction with Monoamine Oxidase Inhibitors

Sibutramine hydrochloride monohydrate is a 5-HT and NE reuptake inhibitor and should not be used concomitantly with MAOIs (see CONTRAINDICATIONS). There should be at least a 2-week interval after stopping MAOIs before commencing treatment with sibutramine hydrochloride monohydrate. Treatment with MAOIs should not be initiated within two weeks of stopping sibutramine hydrochloride monohydrate therapy.

Carcinogenesis and Mutagenesis

For a brief discussion of pre-clinical animal data, see TOXICOLOGY - Carcinogenesis and Mutagenesis

Cardiovascular

Blood Pressure and Pulse Rate

MERIDIA(r) (sibutramine hydrochloride monohydrate) substantially increases blood pressure and heart rate in some patients. Blood pressure and heart rate increases were observed early in treatment with approximately 60% of those patients with significant increases being detected within the first month of therapy and approximately 90% within 4 months. Blood pressure and pulse rate should be measured prior to starting therapy with sibutramine hydrochloride monohydrate and should be monitored at regular intervals thereafter (see DOSAGE AND ADMINISTRATION). In placebo-controlled obesity studies, sibutramine hydrochloride monohydrate 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 of 4 to 5 beats per minute relative to placebo. The percentage of sibutramine-treated patients with sustained and clinically significant increases in SBP relative to placebo varied between 1.7% to 8.4%. The corresponding figures for DBP were 3.8% to 8.0%. The percentage of patients on sibutramine with an increase of 10 bpm or greater at two consecutive visits was greater than on placebo and appeared to be dose dependent (see Table 2). In pre-marketing placebo-controlled obesity studies, 0.4% of patients treated with sibutramine hydrochloride monohydrate were discontinued for hypertension (SBP >=160 mm Hg or DBP >=95 mm Hg), compared with 0.4% in the placebo group, and 0.4% of patients with sibutramine hydrochloride monohydrate were discontinued for tachycardia (pulse rate >=100 bpm) compared with 0.1% in the placebo group. For patients who experience a sustained increase in blood pressure or pulse rate while receiving sibutramine hydrochloride monohydrate, the drug should be discontinued (see DOSAGE AND ADMINISTRATION). Sibutramine hydrochloride monohydrate should be given with caution to patients with well-controlled hypertension, and is contraindicated in patients with inadequately controlled or unstable hypertension.

Concomitant Cardiovascular Disease

Treatment with sibutramine hydrochloride monohydrate has been associated with increases in heart rate and blood pressure. Therefore, sibutramine hydrochloride monohydrate is contraindicated in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or cerebrovascular disease (stroke or TIA) (see CONTRAINDICATIONS).

Pulmonary Hypertension and Cardiac Valvulopathy

Certain centrally-acting weight loss agents that cause both release and re-uptake inhibition of serotonin from nerve terminals have been associated with primary pulmonary hypertension (PPH), a rare but sometimes fatal disease, and cardiac valve dysfunction when used for more than 3 months. It is hypothesized that the mechanism by which these drugs cause PPH and cardiac valvulopathy is the release of serotonin from nerve terminals. MERIDIA(r) (sibutramine hydrochloride monohydrate) is a serotonin and norepinephrine re-uptake inhibitor and not a serotonin releasing agent. The yearly occurrence of PPH in the general population is estimated to be approximately 1-2 cases per 1,000,000 persons. Because of the low background incidence of PPH it is not yet known whether sibutramine hydrochloride monohydrate may cause this condition. The possible occurrence of cardiac valve disease was specifically investigated in clinical studies (see ACTION AND CLINICAL PHARMACOLOGY). The incidence of cardiac valvulopathy in sibutramine hydrochloride monohydrate-treated patients was not different from that in placebo-treated patients. In addition, in extensive postmarketing experience there has been no increase in the incidence of cardiac valve dysfunction. However, due to the limited number of patients studied, it is not yet known whether sibutramine hydrochloride monohydrate may cause this condition. In view of general concerns with anti-obesity drugs, it is important to be on the look out for symptoms such as progressive dyspnea, chest pain and ankle edema in the course of routine check-ups. The patient should be advised to consult a doctor immediately if these symptoms occur.

Dependence/Tolerance

Clinical data and postmarketing experience have not shown any evidence of drug abuse with sibutramine hydrochloride monohydrate.

Hematologic

There have been reports of bleeding abnormalities associated with agents that affect serotonin reuptake. Sibutramine should be used with caution in patients treated concomitantly with drugs known to affect hemostasis or platelet function [e.g., atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, and non-steroidal anti-inflammatory drugs (NSAIDs)]. Caution is also advised in patients with a history of bleeding disorders or those with predisposing conditions.

Hepatic/Biliary/Pancreatic

In patients with mild or moderate hepatic impairment, cautious use of sibutramine hydrochloride monohydrate is advised only where the clinical benefit outweighs the risk. Patients with severe hepatic dysfunction have not been systematically studied; sibutramine hydrochloride monohydrate should therefore not be used in such patients. Weight loss can precipitate or exacerbate gallstone formation.

Neurologic

Seizures/Epilepsy

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

Ophthalmologic

Glaucoma

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

Psychiatric

Cases of depression, suicidal ideation and suicide have been reported rarely in patients on sibutramine treatment. Special attention is therefore required in patients with a history of depression. If signs or symptoms of depression occur during the treatment with sibutramine, the discontinuation of sibutramine and commencement of an appropriate treatment should be considered.

Renal

MERIDIA should be used with caution in patients with mild to moderate renal impairment. MERIDIA should not be used in patients with severe renal impairment, including those with end stage renal disease on dialysis (see ACTION AND CLINICAL PHARMACOLOGY).

Special Populations

Pregnant Women

No adequate and well controlled studies with sibutramine hydrochloride monohydrate have been conducted in pregnant women. The use of sibutramine hydrochloride monohydrate during pregnancy is not recommended. Women of child-bearing potential should employ adequate contraception while taking sibutramine hydrochloride monohydrate. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Labor and Delivery

The effect of sibutramine hydrochloride monohydrate during labor or delivery on the mother and the fetus is unknown. The effects on later growth, development and functional maturation of the child are also unknown.

Nursing Women

It is not known whether sibutramine or its metabolites are excreted in human milk. Since no data are available on the effects of sibutramine hydrochloride monohydrate in the nursing infant, sibutramine hydrochloride monohydrate is not recommended for nursing mothers. Patients should be advised to notify their physician if they are breast-feeding.

Pediatrics (< 18 years of age)

The safety and effectiveness of sibutramine hydrochloride monohydrate in pediatric patients under 18 years old have not been established.

Geriatrics (> 65 years of age)

The safety and effectiveness of sibutramine hydrochloride monohydrate in geriatric patients over 65 years old have not been established.

Monitoring and Laboratory Tests

No specific laboratory tests are recommended.

DRUG INTERACTIONS

Serious Drug Interactions

Concomitant use of sibutramine hydrochloride monohydrate with other centrally acting weight-reducing agents is contraindicated (see CONTRAINDICATIONS).

Concomitant use of sibutramine hydrochloride monohydrate and MAO inhibitors is contraindicated. At least 14 days should elapse between discontinuation of a MAO inhibitor and initiation of treatment with sibutramine hydrochloride monohydrate (see WARNINGS AND PRECAUTIONS and CONTRAINDICATIONS).

Concomitant use of sibutramine hydrochloride monohydrate and centrally-acting drugs for the treatment of psychiatric disorders (such as antidepressants, antipsychotics) or herbal remedies (such as St John's Wort) is contraindicated. At least 14 days should elapse between discontinuation of these drugs and initiation of treatment with sibutramine hydrochloride monohydrate. A 5 week discontinuation period is required for fluoxetine (see CONTRAINDICATIONS).

CNS Active Drugs

The use of sibutramine hydrochloride monohydrate in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of sibutramine hydrochloride monohydrate with other centrally-acting drugs is indicated (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS).

Monoamine oxidase inhibitors (MAOIs)

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 hydrochloride monohydrate inhibits serotonin reuptake, sibutramine hydrochloride monohydrate 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 sibutramine hydrochloride monohydrate. Similarly, at least 2 weeks should elapse between discontinuation of sibutramine hydrochloride monohydrate and initiation of treatment with a MAOI.

Selective serotonin reuptake inhibitors

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(r) (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 hydrochloride monohydrate inhibits serotonin reuptake, co-administration of sibutramine hydrochloride monohydrate with other serotonergic agents is contraindicated (see CONTRAINDICATIONS). At least 5 weeks should elapse between discontinuation of fluoxetine and initiation of treatment with sibutramine hydrochloride monohydrate. Drugs that Inhibit Cytochrome P450(3A4) Metabolism Sibutramine and its active metabolites (M1 and M2) are eliminated primarily via metabolism by the cytochrome P450(3A4) isoenzyme. Caution should be exercised on concomitant administration of sibutramine hydrochloride monohydrate with drugs which effect CYP3A4 enzyme activity. Clinical drug interaction studies were conducted using the cytochrome P450(3A4) inhibitors ketoconazole and erythromycin.

Erythromycin: Co-administration of sibutramine with erythromycin resulted in a 2-fold increase in mean Cmax of unchanged plasma sibutramine, and 10% and 12% increases in Cmax and AUC, respectively, of its active metabolite (M2). Mean systolic and diastolic blood pressure increased by up to 9.6 and mm Hg, respectively, compared to sibutramine treatment alone. Mean pulse rate increased by up to 9.3 bpm compared to sibutramine treatment alone (14.7 bpm above baseline).

Ketoconazole: Co-administration of sibutramine with ketoconazole resulted in a 3-fold increase in mean Cmax of unchanged plasma sibutramine, and 58% and 36% increases in AUC and Cmax, respectively, of its active metabolite (M1). Mean heart rate increased by up to 2.5 beats per minute more than on sibutramine alone (9.5 bpm over baseline).

Drugs That May Raise Blood Pressure and/or Heart Rate

Concomitant use of sibutramine hydrochloride monohydrate 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 phenylpropanolamine (no longer available in Canada), ephedrine, or pseudoephedrine and certain anti-inflammatory agents (e.g. NSAIDs). Caution should be used when prescribing sibutramine hydrochloride monohydrate to patients who use these medications.

Cimetidine

Concomitant administration of cimetidine 400 mg twice daily and sibutramine 15 mg once daily for seven days in 12 volunteers resulted in small increases in combined (M1 and M2) plasma Cmax (3.4%) and AUC (7.3%); these differences are unlikely to be of clinical significance.

Alcohol

At single doses, there was no additional impairment of cognitive or psychomotor performance when sibutramine was administered concomitantly with alcohol. However, the consumption of alcohol is not compatible with the recommended dietary measures as a general rule. The concomitant use of sibutramine with excess alcohol is not recommended.

Oral Contraceptives

The suppression of ovulation by oral contraceptives was not inhibited by sibutramine hydrochloride monohydrate. 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 hydrochloride monohydrate.

Drugs Highly Bound to Plasma Proteins

Although sibutramine and its active metabolites M1 and M2 are extensively bound to plasma proteins (>= 94%), the low therapeutic concentrations and basic characteristics of these compounds make them unlikely to result in clinically significant protein binding interactions with other highly protein bound drugs such as warfarin and phenytoin.

Drug-Food Interactions

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.

Drug-Herb Interactions

Concomitant use of sibutramine hydrochloride monohydrate and St John's Wort is contraindicated. At least 14 days should elapse between discontinuation of these drugs and initiation of treatment with sibutramine hydrochloride monohydrate.

Drug-Laboratory Interactions

There is no evidence that sibutramine and its metabolites interfere with the results of standard laboratory tests.

DOSAGE AND ADMINISTRATION

Treatment with MERIDIA(r) (sibutramine hydrochloride monohydrate) should only be given as part of an integrated therapeutic approach for weight reduction and weight maintenance under the care of a physician with experience in the treatment of obesity.

MERIDIA(r) substantially increases blood pressure and heart rate in some patients. Therefore, regular monitoring of blood pressure and heart rate is required when prescribing MERIDIA(r). In the first three months of treatment, these parameters should be checked at least every 2 weeks, thereafter, regularly at one to three month intervals. Blood pressure and heart rate changes should be taken into account when making decisions regarding monitoring intervals.

Treatment should be discontinued in patients who have an increase, at two consecutive visits, in systolic or diastolic blood pressure of >= 10 mm Hg or in resting heart rate of >= 10 bpm.

In previously well-controlled hypertensive patients, if blood pressure exceeds 145/90 mm Hg at two consecutive readings, treatment should be discontinued

The use of a standardized blood pressure measurement technique as described in the 1999 Canadian recommendations for the management of hypertension from the Canadian Hypertension Society(1) is recommended when assessing blood pressure in order to ensure reliable and accurate results. The guidelines recommend measurement with a mercury manometer using a cuff with an appropriate bladder width:

Recommended Dose and Dosage Adjustment

Adults

The recommended dose is sibutramine hydrochloride monohydrate 10 mg once daily, taken in the morning. The capsule should be swallowed whole and can be taken with or without food. In those patients with an inadequate response to sibutramine hydrochloride monohydrate 10 mg (less than 4 lbs (1.8 kg) weight loss after 4 weeks treatment), the dose may be increased to 1 capsule of sibutramine hydrochloride monohydrate 15 mg once daily, provided that sibutramine hydrochloride monohydrate 10 mg was well tolerated. 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.

Duration of treatment

Physicians should reevaluate the patient's weight management plan and consider discontinuation of sibutramine hydrochloride monohydrate in patients who have not achieved a clinically significant weight loss (at least 5% of initial body weight) within a period of three to six months. Continuation of treatment beyond six months should only be considered for those patients who continue to lose weight or maintain their weight loss. In patients with associated co-morbid conditions, such as Type 2 diabetes or dyslipidemia, it is recommended that treatment with sibutramine hydrochloride monohydrate should only be continued if it can be shown that the weight loss induced is associated with clinical benefits.

Feldman RD, 1999 Canadian recommendations for the management of hypertension. Task force for the development of the 1999 Canadian recommendations for the management of hypertension CMAJ 1999; 161 Suppl 12:S1-S17

The safety and effectiveness of treatment with sibutramine hydrochloride monohydrate beyond one year has not been established.

Missed Dose

If a dose of sibutramine hydrochloride monohydrate is missed, patients should take the next dose the next morning. However, patients should not take an extra capsule to "make up" for the dose that was missed.

OVERDOSAGE

There are a number of reports of overdose in humans (including accidental ingestion by children as young as 18 months) where doses of up to 500 mg MERIDIA(r) (sibutramine hydrochloride monohydrate) were ingested. A heart rate of 160 beats per minute was observed in one patient who took 500 mg sibutramine hydrochloride monohydrate. Except in one case of multiple drug intoxication with alcohol (where the patient died, possibly due to inhalation of vomit), there were no complications and the individuals made a full recovery.

Treatment

There is limited experience of overdose with sibutramine. The most frequently noted adverse events associated with overdose are tachycardia, hypertension, headache and dizziness. Treatment should consist of general measures employed in the management of overdosage: an airway should be established; cardiac and vital sign monitoring is recommended; general symptomatic and supportive measures should be instituted. Early administration of activated charcoal may delay the absorption of sibutramine hydrochloride monohydrate; gastric lavage may be of benefit. Excessive CNS stimulation or seizures may require treatment with an anticonvulsant. Cautious use of b-blockers may be indicated to control elevated blood pressure or tachycardia. In managing overdose, consider the possibility of multiple drug involvement. 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.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

MERIDIA(r) (sibutramine hydrochloride monohydrate) has been shown to reduce body weight by dual actions: reduction of food intake through enhancement of satiety, and increase of energy expenditure by induction of thermogenesis. Sibutramine hydrochloride monohydrate produces its therapeutic effects primarily by serotonin and norepinephrine reuptake inhibition.

Pharmacodynamics

Sibutramine hydrochloride monohydrate exerts its pharmacological actions predominantly via its secondary (M1) and primary (M2) amine metabolites. The parent compound, sibutramine, is a potent inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake in vivo but not in vitro. However, metabolites M1 and M2 inhibit the reuptake of these neurotransmitters both in vitro and in vivo. Sibutramine and its metabolites (M1 and M2) do not cause the release of serotonin, norepinephrine or dopamine (DA). 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 (see Table 4).

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%. Inhibition of dopamine reuptake was not significant. Sibutramine, M1 and M2 exhibit no evidence of anticholinergic or antihistaminergic actions. In addition, receptor binding profiles show that sibutramine, M1 and M 2 have low affinity for 5-HT, (5-HT1, 5-HT1A, 5-HT1D, 5-HT2A, 5-HT2C), NE (b, b1, b3, a1 and a2), DA (D1 and D2), benzodiazepine, and glutamate (NMDA) receptors. These compounds also lack monoamine oxidase inhibitory activity in vitro and in vivo.

Pharmacokinetics

A summary of pharmacokinetic parameters is presented in Table 5.

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. Tissue distribution was unaffected by pregnancy, with relatively low transfer to the fetus. 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.

Special Populations and Conditions

Pediatrics and Geriatrics

Due to insufficient safety and efficacy data, sibutramine hydrochloride monohydrate is not recommended for use in patients <18 or >65 years old.

Gender

Pooled pharmacokinetic parameters from 54 young, healthy volunteers (37 males and 17 females) receiving a 15-mg oral dose of sibutramine showed the mean Cmax and AUC of M1 and M2 to be slightly (19% and 36%, respectively) higher in females than males. Somewhat higher steady-state trough plasma levels were observed in female obese patients from a large clinical efficacy trial. However, these differences are not likely to be of clinical significance. Dosage adjustment based upon the gender of a patient is not necessary (see DOSAGE AND ADMINISTRATION).

Race

The relationship between race and steady-state trough M1 and M2 plasma concentrations was examined in a clinical trial in obese patients. A trend towards higher concentrations in Black patients over Caucasian patients was noted for M1 and M2. However, these differences are not considered to be of clinical significance.

Hepatic Insufficiency

In 12 patients with moderate hepatic impairment receiving a single 15 mg oral dose of sibutramine, the combined AUCs of M1 and M2 were increased by 24% compared to healthy subjects while M5 and M6 plasma concentrations were unchanged. The observed differences in M1 and M2 concentrations do not warrant dosage adjustment in patients with mild to moderate hepatic impairment. Sibutramine hydrochloride monohydrate should not be used in patients with severe hepatic dysfunction.

Renal Insufficiency

The disposition of sibutramine metabolites (M1, M2, M5 and M6) was studied in patients with varying degrees of renal function. Sibutramine itself was not measurable. The AUCs of the active metabolites M1 and M2 were generally not affected by renal impairment, except that the AUC of M2 in end-stage renal disease patients on dialysis was approximately half of that measured in normal subjects (CLcr >= 80 mL/min). The AUCs of inactive metabolites M5 and M6 increased 2-3 fold in patients with moderate impairment (30 mL/min < CLcr <= 60 mL/min), 8-11 fold in patients with severe impairment (CLcr <= 30 mL/min), and 22-33 fold in patients with end-stage renal disease on dialysis as compared to normal subjects. Approximately 1% of the oral dose was recovered in the dialysate as a combination of M5 and M6 during hemodialysis process, while M1 and M2 were not measurable in the dialysate. Sibutramine should not be used in patients with severe renal impairment, including those with end-stage renal disease on dialysis.

STORAGE AND STABILITY

Store between 15 and 25oC, protect from light and high humidity.

DOSAGE FORMS, COMPOSITION AND PACKAGING

MERIDIA(r) (sibutramine hydrochloride monohydrate) capsules contain 10 mg or 15 mg sibutramine hydrochloride monohydrate and are supplied as follows:

• 10 mg, blue/white capsules imprinted with "MERIDIA" on the cap and "-10-" on the body, in PVC-Foil blisters containing 30 capsules and in HDPE bottles containing 100 capsules.

• 15 mg, yellow/white capsules imprinted with "MERIDIA" on the cap and "-15-" on the body, in PVC-Foil blisters containing 30 capsules and in HDPE bottles containing 100 capsules.

Non-medicinal ingredients:

In addition to sibutramine hydrochloride monohydrate, each capsule contains the following inactive ingredients: lactose monohydrate, NF; microcrystalline cellulose, NF; colloidal silicon dioxide, NF; and magnesium stearate, NF in a hard gelatin capsule [which contains titanium dioxide, gelatin, FD&C Blue No. 2 (10 mg capsules only), D&C Yellow No. 10 (15 mg capsules only) and may also contain sodium lauryl sulphate, silicon dioxide and printing ink]. Do not use beyond expiry date indicated on the package.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: sibutramine hydrochloride monohydrate Chemical name: cyclobutanemethanamine, 1-(4-chlorophenyl)-N,N-dimethyl-a-(2- methylpropyl)-, hydrochloride, monohydrate(+-) Molecular formula and molecular mass: C17H26ClN; HCl; H2O 334.33 Structural formula: Physicochemical properties: Sibutramine hydrochloride monohydrate is a white to cream crystalline powder with a solubility of 2.9 mg/mL in pH 5.2 water. Its octanol: water partition coefficient is 30.9 at pH 5.0.

CLINICAL TRIALS

The long-term effects of sibutramine hydrochloride monohydrate on the morbidity and mortality associated with obesity have not been established. Weight loss was examined in 11 double- blind, placebo-controlled obesity trials with study durations of 12 to 52 weeks and doses ranging from 1 to 30 mg once daily. Weight was significantly reduced in a dose-related manner in sibutramine-treated patients compared to placebo over the dose range of 5 to 20 mg once daily. In two 12-month studies, maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months. The amount of placebo-subtracted weight loss achieved on sibutramine hydrochloride monohydrate was consistent across studies. When therapy is stopped, patients experience weight regain. Analysis of the data in three long-term (>=6 months) obesity trials indicates that patients who lose at least 4 pounds (1.8 Kg) in the first 4 weeks of therapy with a given dose of sibutramine hydrochloride monohydrate are most likely to achieve significant long-term weight loss on that dose of sibutramine hydrochloride monohydrate. Approximately 60% of such patients went on to achieve a placebo-subtracted weight loss of >=5% of their initial body weight by month six. Conversely, of those patients on a given dose of sibutramine hydrochloride monohydrate who did not lose at least 4 pounds (1.8 Kg) in the first 4 weeks of therapy, approximately 80% did not go on to achieve a placebo-subtracted weight loss of >=5% of their initial body weight on that dose by month six. Significant dose-related reductions in waist circumference, an indicator of intra-abdominal fat, have also been observed over 6 and 12 months in placebo-controlled clinical trials. In a 12-week placebo-controlled study of non-insulin dependent diabetes mellitus, patients randomized to placebo or 15 mg per day of sibutramine hydrochloride monohydrate, Dual Energy X-Ray Absorptiometry (DEXA) assessment of changes in body composition showed that total body fat mass decreased by 4 lbs (1.8 kg) in the sibutramine hydrochloride monohydrate group versus 0.4 lbs (0.2 kg) in the placebo group (p<0.001). Similarly, truncal (android) fat mass decreased by 1.3 lbs (0.6 kg) in the sibutramine hydrochloride monohydrate group versus 0.2 lbs (0.1 kg) in the placebo group (p<0.01). The changes in lean mass, fasting blood sugar, and HbA1 were not statistically significantly different between the two groups. Eleven double-blind, placebo-controlled obesity trials with study durations of 12 to 52 weeks have provided evidence that sibutramine hydrochloride monohydrate positively affects glycemia, serum lipid profiles, and serum uric acid in obese patients who respond by losing weight. Treatment with sibutramine hydrochloride monohydrate (5 to 20 mg once daily) is associated with mean increases in blood pressure of 1 to 3 mm Hg and with mean increases in pulse rate of 4 to 5 beats per minute relative to placebo. These findings are similar in normotensives and in patients with hypertension controlled with medication. Those patients who lose significant (>=5% weight loss) amounts of weight on sibutramine hydrochloride monohydrate tend to have smaller increases in blood pressure and pulse rate (see WARNINGS AND PRECAUTIONS). In Study 1, a 6-month, double-blind, placebo-controlled study in obese patients, Study 2, a 1-year, double-blind, placebo-controlled study in obese patients, and Study 3, a 1-year, double- blind, placebo-controlled study in obese patients who lost at least 13.2 lbs (6 kg) on a 4-week very low calorie diet (VLCD), sibutramine hydrochloride monohydrate produced significant reductions in weight, as shown in Table 6. In the two 1-year studies, maximal weight loss was achieved by 6 months and statistically significant weight loss was maintained over 12 months.

Weight loss was dose-related, and peaked at 3 to 6 months. The weight loss was essentially maintained with continued sibutramine hydrochloride monohydrate treatment over 12 months. Sibutramine hydrochloride monohydrate induced weight loss has been accompanied by beneficial changes in serum uric acid and lipids that are similar to those seen with nonpharmacologically-mediated weight loss.

Cardiac valve dysfunction

Certain centrally-acting weight loss agents that cause both release and re-uptake inhibition of serotonin from nerve terminals have been associated with cardiac valve dysfunction when used for more than 3 months. It is hypothesized that the mechanism by which these drugs cause cardiac valvulopathy is the release of serotonin from nerve terminals. Sibutramine hydrochloride monohydrate is a serotonin and norepinephrine re-uptake inhibitor and not a releasing agent. The possible occurrence of cardiac valve disease was specifically investigated in clinical studies. In one study 2-D and color Doppler echocardiography were performed on 210 patients (mean age, 54 years) receiving sibutramine hydrochloride monohydrate 15 mg or placebo daily for periods of 2 weeks to 16 months (mean duration of treatment, 7.6 months). In patients without a prior history of valvular heart disease, the incidence of valvular heart disease was 3/132 (2.3%) in the sibutramine treatment group (all three cases were mild aortic insufficiency) and 2/77 (2.6%) in the placebo treatment group (one case of mild aortic insufficiency and one case of severe aortic insufficiency). In a second study, 104 patients received either sibutramine 10 mg or sibutramine 20 mg and 52 patients received placebo daily for 6 months. Echocardiography was performed at baseline and at month 6. In patients with normal valves at baseline, no sibutramine-treated patient compared to one placebo-treated patient (moderate mitral regurgitation) had valvular heart disease at month 6. The incidence of cardiac valvulopathy in sibutramine hydrochloride monohydrate-treated patients was not different from that in placebo-treated patients. In addition, in extensive postmarketing experience there has been no increase in the incidence of cardiac valve dysfunction. However, due to the limited number of patients studied, it is not yet known whether sibutramine hydrochloride monohydrate may cause this condition.

DETAILED PHARMACOLOGY

Monoamine Reuptake Profile

A poor [3H]monoamine uptake inhibitor in vitro, sibutramine's actions are predominantly mediated in vivo by its secondary amine (BTS 54 354, metabolite 1) and primary amine (BTS 54 505, metabolite 2) metabolites, both excellent NE and 5-HT uptake inhibitors, in vitro and in vivo. Sibutramine also gives rise to a range of 4 hydroxylated metabolites in various species (mouse, rat, guinea pig, dog, monkey) including 2 inactive aglycone glucuronide conjugates (metabolites 5 and 6).

In vivo and in vitro, salts of metabolites 3 (maleate) and 6 (hydrochloride) are potent monoamine reuptake inhibitors, whereas 5 (fumarate) is moderately active and 4 (fumarate) is weak. In man, sibutramine exerts its monoamine reuptake inhibition almost exclusively via BTS 54 354 (1) and BTS 54 505 (2), since metabolite 3 has not been identified in human plasma and metabolites 5 and 6 have only been detected as glucuronides.

Effects of Food Intake, Energy Expenditure and Body Weight

Acute sibutramine administration produced a clear dose-dependent food intake reduction in lean growing rats, genetically obese Zucker rats and obese rats fed a high fat diet. Good evidence suggests that this effect was mediated by enhancing natural satiety responses. Sibutramine likely produced these effects (via BTS 54 354 and BTS 54 505), by enhanced central NE and 5-HT function exerted through b1 and 5-HT2A/2C receptors, respectively. 5-HT release is not a mechanism of action. Unlike d-fenfluramine, neither sibutramine nor its active metabolites, at pharmacologically-relevant concentrations, increase [3H]5-HT overflow from brain slices. Furthermore, the sibutramine food intake effect cannot be mediated directly by receptor activation. Sibutramine, BTS 54 354 and BTS 54 505 have no affinity for noradrenergic or 5-hydroxytryptaminergic receptors, including b1 and 5-HT2A/2C. Consistent with the hypothesized NE and 5-HT reuptake mechanism of action, both sibutramine, BTS 54 354 and BTS 54 505 are approximately equipotent in reducing food intake. In addition, the (+)sibutramine enantiomer, a more potent in vivo monoamine reuptake inhibitor, is also about 10 times more potent in reducing food intake than is (-)-enantiomer. Additionally, sibutramine appears to increase energy expenditure. In repeat-dose studies, there was a consistent food intake reduction effect at the treatment start, but its duration was variable. Despite this, reductions in body weight gain were found in all experiments. Corroborating this observation, sibutramine was shown to be thermogenic (increases oxygen consumption and body temperature). At thermoneutral ambient temperatures, in lean and obese rats the effect was both dose-dependent and prolonged (>6h at 10 mg/kg). Moderately selective b1- and b2-adrenoceptors antagonists, (atenolol and ICI 118,55,1 respectively), given at low doses (ie producing b1- and b2 blockade), did not modify sibutramine-induced thermogenesis. High doses (ie. b1-, b2- and b3 blockade) abolished the response. Therefore, in vivo, sibutramine putatively enhances thermogenesis by increasing peripheral b3-mediated noradrenergic activation, via reuptake inhibition. Direct b3-adrenoceptor action can be discounted because sibutramine and its metabolites have no adrenergic receptor affinity, including b3.

Behavioral CNS Effects

Sibutramine is neither sedative nor activating in rats at 6 mg/kg, a dose that potently inhibits food intake and enhances thermogenesis. Increasing the dose to >= 30 mg/kg, however, results in behavioral activation and stereotypy.

Effects on Central Dopaminergic Function

The monoamine uptake inhibition profiles of BTS 54 354 and BTS 54 505 in vitro indicate an overall rank order of potency of NE >5-H[? ]DA whereas ex vivo studies indicate NE>5-HT>DA. This latter ranking has been confirmed using plasma from animals and man after acute or repeated sibutramine treatment to examine the effects of sibutramine's in vivo metabolites on radiolabeled monoamine uptake in vitro. High dose sibutramine is behaviorally activating. However, its pharmacological profile differs from DA activating stimulants such as d-amphetamine and methamphetamine. Sibutramine, BTS 54 354 and BTS 54 505 did not (with one exception) increase [3H]DA release from rat striatal slices, nor elevate 3-methoxytyramine in rat striatum. As for behavioral markers, these compounds did not induce circling in unilateral nigrostriatal lesioned rats at pharmacologically- relevant doses, or generalise in rats trained to discriminate d-amphetamine from saline in a 2-choice lever-pressing model. By comparison, methamphetamine, was potently active, while bupropion, a weak selective DA reuptake inhibitor antidepressant, was active only in the behavioral tests. Psychomotor stimulation, reward and reinforcement effects of stimulants are associated with enhanced limbic DA release. Thus, nucleus accumbens extracellular DA concentrations were determined by intracerebral microdialysis following sibutramine, bupropion and d-amphetamine. Sibutramine produced slow-onset, dose-dependent, moderate increases in limbic DA levels. By contrast, d-amphetamine evoked a rapid flood of DA release (at 3 mg/kg doses about 15 times greater than sibutramine); bupropion (at pharmacologically-relevant doses) also rapidly elevated limbic DA considerably more than sibutramine, but markedly less than d-amphetamine.

Other Effects on CNS Function

Sibutramine, BTS 54 354 and BTS 54 505 are relatively potent anticonvulsants against maximal electroshock seizures in rodents, but are ineffective against bicuculline. Consistent with an NE and 5-HT reuptake inhibitor profile, sibutramine is active in the Porsolt test. Repeated sibutramine administration down-regulates monoamine receptors b1, a2, 5-HT1A. Unaltered receptors are: a1; 5-HT2; 5-HT reuptake sites; D1; D2.

Cardiovascular System Effects

Sibutramine produces less cardiovascular effects than either the tricyclic antidepressants or sympathomimetics. Sibutramine's effects on blood pressure (BP) and heart rate (HR) are consistent with peripheral catecholamine reuptake inhibition. Sibutramine (3 x 10-6 to 10-4 g/mL) inhibited spontaneously-beating and electrically-stimulated guinea-pig atria in vitro. This effect was ~7-fold weaker than that produced by amitriptyline (3 x 10-7 to 10-5 g/mL).

Acute effects on (BP) and (HR), and ECG

In spontaneously hypertensive rats (SHR), sibutramine (1 or 3 mg/kg po) produced small, but significant, BP and HR reductions at 1.5 and 5h; 25% of the rats died at the higher dose. In a second experiment, however, a 3 mg/kg single oral dose of either sibutramine, BTS 54 354 or BTS 54 505 had no effect on BP and HR. 50% of the rats died. In normotensive rats, sibutramine (1 or 3 mg/kg po) produced only transient bradycardia (3 mg/kg). In a second experiment, sibutramine 3 mg/kg po, BTS 54 354 or BTS 54 505 evoked significant bradycardia 1.5 h post-dose. In anaesthetised normotensive rats, sibutramine (3 and 30 mg/kg iv) had no significant effect on BP, but reduced HR by ~25%, prolonged R-R interval and elevated T-waves at the higher dose. Sibutramine only marginally attenuated S-waves depression produced by continuous isoprenaline infusion (1 ug/kg/min iv), unlike amitriptyline which markedly enhanced isoprenaline's effect. In normotensive, pithed rats, sibutramine (1.5 or 5 mg/kg iv) produced a rise in BP and a small increase in HR, with minor variations in the P-Q interval. Sibutramine's pressor effects were qualitatively similar to (but ~10-fold less potent than,) d-amphetamine (0.2 mg/kg iv), but of longer duration. Positive chronotropic effects were less. Reserpine pretreatment markedly attenuated both compounds' effects. In anaesthetized dogs, sibutramine had little effect on mean BP, HR, ECG at 0.03 and 0.1 mg/kg iv. At 0.3 mg/kg iv, there was a slight increase in mean BP and a decrease in HR. At 1 to 10 mg/kg iv, the changes were more marked, with a transient dose-dependent decrease in BP and an increase in HR succeeded by a slight BP increase and a more prolonged fall in HR. The ECG was unaffected at doses < 3 mg/kg. At 3 and 10 mg/kg iv, there were transient decreases in the P-R interval and an increase in the QRS wave height. At 10 mg/kg, P-wave height slightly increased in one of three dogs.

Effects On The Renal System (in Water-loaded Animals)

In mice, doses 10 mg/kg, had no effect on urine volume, sodium and potassium excretion. At 3 and 10 mg/kg chloride excretion was increased. In rats at 1 mg/kg, urine volume was increased 2 and 3 hours after dosing; electrolyte excretion was unaltered. At 3 and 10 mg/kg, urine volume was increased at all time-points; sodium and chloride excretion was enhanced. In dogs, 3 mg/kg sibutramine increased urine volume two hours after dosing; electrolytes were unaltered.

TOXICOLOGY

MULTIDOSE TOXICITY/CARCINOGENICITY STUDIES

GENOTOXICITY STUDIES

BTS 54 345 hydrochloride salt of metabolite 1

BTS 54 505 hydrochloride salt of metabolite 2

BTS 59 482 maleate salt of metabolite 3

BTS 64 472 fumarate salt of the aglycone of metabolite 5 BTS 64 473 fumarate salt of the aglycone of metabolite 4 BTS 65 400 hydrochloride salt of the aglycone of metabolite 6 ND: Not Done

REFERENCES

Study DT 94045. An Investigation of the Extent of Binding of Sibutramine to Plasma Proteins. Data on file with Abbott. Study DT 92038. Investigation of the Enantiomeric Ratios of Sibutramine Metabolites 1, 2, 5 and 6 in the Urine of Depressed Patients After Repeat Oral Administration. Data on file with Abbott. Study SB 2846. Investigation of the Pharmacokinetics of Sibutramine in Young and Elderly Volunteers. Hind ID, Mangham JE, Ghani SP, et al. Sibutramine pharmacokinetics in young and elderly healthy subjects. Eur J Clin Pharmacol 1999; 54 (11): 847-849 Study SB 5823. Investigation of the Pharmacokinetics of Sibutramine in Volunteers with Moderate Liver Impairment and with Normal Liver Function Tests. Data on file with Abbott. Study BPI 852. Multicentre, Double-Blind, 24-week Repeated-Dose, Placebo-Controlled Study of Sibutramine, in Obese Patients. Bray GA, Blackburn GL, Ferguson JM, et al. Sibutramine produces dose-related weight loss. Obesity Res 1999; 7 (2): 189-198. Study SB 1047. Multicentre, Double-Blind, 12 month Repeat-Dose, Placebo-Controlled Study of Sibutramine in Obese Patients. Smith LG. Long-term weight loss with sibutramine (MERIDIA(r)), a once-daily serotonin and norepinephrine reuptake inhibitor (abstract). Obesity Research 1997; 5 (Supp. 1):80 Study BPI 852X. A Multicentre, Open-Label Flexible-Dose Study to Evaluate the Long- Term Effects of Sibutramine Administered for up to an additional 24 Months to Relatively Healthy Obese Patients (extension of Study BPI 852). Data on file with Abbott. Study SB 1049. A Double-Blind Study to Compare the Efficacy and Tolerability of Sibutramine Versus Placebo in the Maintenance Or Improvement of Weight Loss, in Obese Patients, Following a Very Low Calorie Diet. Apfelbaum M, Vague P, Ziegler O et al. Long-term maintenance of weight loss after a very-low-calorie diet: A randomized blinded trial of the efficacy and tolerability of sibutramine. Am J Med 1999; 106 (2): 179-184 Study SB 3051. A Randomized Double-Blind, Study to Compare the Weight Reducing Effects of Sibutramine with Placebo in the Treatment of Obese Type II Diabetes Patients for 12 weeks. Finer N, Bloom SR, Frost GS et al. Sibutramine is effective for weight loss and diabetic control in obesity with type 2 diabetes: a randomised, double-blind, placebo-controlled study. Diabetes, Obesity & Metabolism 2000; 2 (2): 105-112 Study SB 3068. An Open Extension to Study SB 3051: Sibutramine in the Treatment of Obese Subjects with Type II Diabetes for a further 12 Weeks. Data on file with Abbott. Study BPI 863. A Double-Blind, Single-Dose, Placebo-Controlled Study to Evaluate the Potential Abuse Liability of Sibutramine Compared with Dextroamphetamine in Recreational Stimulant Users. Cole JO, Levin A, Beake B, Kaiser PE, and Scheinbaum ML Sibutramine: A new weight loss agent without evidence of the abuse potential associated with amphetamines. J Clin Psychopharmacol 1998; 18 (3): 231-236 Study DT 94043. Investigation of the Cytochrome P450 Enzymes Responsible for In- vitro Metabolism of [14C] Sibutramine in Human Hepatic Microsomes. Data on file with Abbott. Study DT 94088. An Investigation of the Interaction of [14C] Sibutramine with Ketoconazole in Human Hepatic Microsomes. Data on file with Abbott. Study SB 4820. An Investigation of the Pharmacokinetics of Sibutramine when Concomitantly Administered with Cimetidine to Health Volunteers. Data on file with Abbott. Study SB 2822. A Double-Blind, Double-Dummy, 4-way Crossover Study to Compare the Effects of Sibutramine or Placebo with an Alcoholic Drink or Placebo Drink. Data on file with Abbott. Study SB 4819. A Single-Blind Study to Compare the Effects of Sibutramine with Placebo on the Efficacy of Oral Steroid Contraceptives. Back DJ, Fearn R, Oliver S et al. Lack of effect of sibutramine on the efficacy of oral contraceptive steroids in healthy women. Pharm Med 1997; 2/2:71-76 Study DT 86034. Plasma levels and excretion of [14C]BTS 54 524 - equivalents after administration to male volunteers. Data on file with Abbott. Study DT 94034. A comparison of the single dose and steady state pharmacokinetics of sibutramine in obese and normal subjects. Garrett CJ, Hind ID, Haddock RE. Single/repeat dose kinetics of sibutramine metabolites in obese subjects [Abstract]. J Clin Pharmacol 1995; 35: 928. Study BPI 852PK. A multi-centre, double-blind, repeated-dose, placebo- controlled, parallel-group, dose-ranging study to evaluate the weight reducing efficacy, safety and tolerability of sibutramine hydrochloride in obese patients for up to 24 weeks. Kaiser PW, Hinson JL. Sibutramine: Dose response and plasma metabolite concentrations in weight loss [Abstract]. J Clin Pharmacol 1994; 34 (Oct):1019. Study DT 95001. A comparison of the pharmacokinetics of sibutramine and its metabolites in the hepatically impaired subjects and normals. Data on file with Abbott. Study BPI 879. A single-centre, open-label, two-period study of the effect of erythromycin on the steady-state pharmacokinetics and electrocardiographic parameters of 20 mg sibutramine daily in obese patients. Leone MB, Hinson JL, Leese PT, Moult JT, Carter FJ, Faulkner RD. Steady-state interaction study of sibutramine (MERIDIA(r)) and erythromycin in uncomplicated obese subjects. [Abstract] Pharm Res 1996; 13: 116 Freedman DS, Williamson DF, Gunther EW, et al. Relation of serum uric acid to mortality and ischemic heart disease: the NHANES I epidemiologic follow-up study. Am J Epidemiol 1995; 141:637-44. IMPORTANT: PLEASE READ

PART III: CONSUMER INFORMATION

PrMERIDIA(r)

(sibutramine hydrochloride monohydrate)

This leaflet is part III of a three-part "Product Monograph" published when MERIDIA(r) was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about MERIDIA(r). Contact your doctor or pharmacist if you have any questions about the drug.

The manufacturer of MERIDIA(r) offers a free weight management program, myDECISIONTM. To learn more about this program please call 1-877-694-4455 or visit the web site at www.mydecision.ca.

ABOUT THIS MEDICATION

What the medication is used for:

MERIDIA(r) (sibutramine hydrochloride monohydrate) is a once-daily prescription medication for weight loss and weight maintenance. It is to be used as part of a comprehensive weight management program supervised by your doctor, that includes a reduced calorie diet and appropriate physical activity. You will lose more weight if you increase your physical activity, in addition to eating sensibly. MERIDIA(r) can only be prescribed by a medical doctor.

MERIDIA(r) is for patients whose excess weight, in the opinion of their doctor, presents a health risk. MERIDIA(r) may be right for you if you are considerably overweight (a Body Mass Index (BMI) of 30 kg/m2 or greater.) MERIDIA(r) may also be right for you if you are overweight (a BMI of 27 kg/m2 or greater) in the presence of other risk factors (e.g., high blood pressure, diabetes, high cholesterol, large waist measurement). BMI is not a direct measurement of fat and therefore, these guidelines do not apply to athletes and pregnant women.

Your doctor may be equally concerned about where you are carrying your excess weight. Visceral fat, fat stored in your abdomen, is a significant health risk. The best indicator of visceral fat is abdominal circumference. This is measured at a point midway between your waist and below your ribcage. To be a health concern, a woman's abdominal circumference would exceed 88 cm or 35 inches or for men greater than 102 cm or 40 inches.

How to determine your Body Mass Index (BMI):

BMI according to a variety of weights and heights is presented in the Table at the end of this leaflet. The BMI is calculated by dividing your weight in kilograms by your height in meters squared. To use this chart:

Find the weight closest to your weight in the left-hand column.

Then move across the top row to find the height closest to your height. The number where these two meet is your BMI. (For example, a person

who weighs 180 lbs and is 5'5", would have a BMI of 30, as would a person 6'0" and 220 lbs, or a person 5'1" and 160 lbs).

What it does:

MERIDIA(r) works by making you feel full sooner. MERIDIA(r) is not an amphetamine-type drug. Hunger will continue to tell you when to eat, but MERIDIA(r) will help you to be satisfied to eat less food.

MERIDIA(r) is prescribed to help you to be more successful losing and maintaining your weight loss, but you still need to do your part. MERIDIA(r) should be used as part of a comprehensive weight loss program supervised by your doctor, that includes a reduced calorie diet and appropriate physical activity.

Why should MERIDIA(r) be used as part of a weight management program?

Your excess weight is a result of a surplus of energy. The energy that you consume as food has been greater than the energy that you expend such as through physical activity. To lose weight and to maintain a weight loss you need to reverse this imbalance. As you increase your physical activity and decrease the amount of food you eat, you increase the energy deficit and the amount of fat you can lose. MERIDIA(r) makes it easier for you to be successful. You must do your part.

How long does it take for MERIDIA(r) to begin to work?

Every person will respond differently to MERIDIA(r) when used as part of a comprehensive weight-loss program. If you do your part, MERIDIA(r) will help. You may be able to lose 4 or more pounds (1.8 Kg or more) in the first month you take MERIDIA(r). If you find that you do not lose at least 4 pounds (1.8 Kg) during the first month, your doctor may re- evaluate your situation. This may include a review of your entire weight management program, including your menu choices and level of physical activity. Your doctor may advise you to make other food choices or increase your physical activity. Alternatively your doctor may decide that it is appropriate to change your dose of MERIDIA(r) if your blood pressure and heart rate did not increase significantly.

Most people who lose weight on MERIDIA(r) lose it in the first 6 months of treatment. Your doctor may consider discontinuation of MERIDIA(r) if you have not achieved a clinically significant weight loss (at least 5% of initial body weight) within a period of three to six months.

What weight loss results have been observed with MERIDIA(r)?

Patients treated with MERIDIA(r) while on a reduced calorie diet, showed a significant weight loss during the first 6 months of treatment, and significant weight loss was maintained for one year. In one 12-month study, the average weight loss in patients taking MERIDIA(r), 10 mg daily, was about 10 lbs. and in those taking 15 mg daily was about 14 lbs. The average weight loss in persons on only a reduced calorie diet was 3.5 lbs.

In order to achieve long-term maintenance of weight loss, you must change your lifestyle while taking MERIDIA(r) so that you are able to maintain your weight upon cessation of drug treatment. When MERIDIA(r) therapy is stopped, most patients will regain weight unless they have changed their eating habits, as well as increased their level of physical activity. IMPORTANT: PLEASE READ

When it should not be used:

MERIDIA(r) must not be taken by people who:

• Are, in the opinion of their doctor, not medically at risk because of their excess weight.

• Have a diagnosis of coronary artery disease and/or who have angina pectoris (heart-related chest pain).

• Have arrhythmias (irregular heart beats).

• Have had a prior heart attack.

• Have a diagnosis of congestive heart failure.

• Have had a stroke or symptoms of a stroke (transient ischemic attacks [TIAs]).

• Have uncontrolled or poorly controlled high blood pressure because MERIDIA(r) substantially increases blood pressure in some patients.

• Have a diagnosis of depression or any other psychiatric illness.

• Are taking prescription medications for depression or any other psychiatric illnesses

• Are taking prescription medicines called monoamine oxidase inhibitors (MAOIs) for depression, Parkinson's Disease, or any other disorder (for example: Eldepryl(r), Parnate(r), Nardil(r), Manerix(r)).

• Are taking other medications that regulate the neurotransmitter serotonin in the brain (for example: Prozac(r), ZoloftTM, Effexor(r), Luvox(r), or Paxil(r)), including herbal remedies (such as St John's Wort).

• Are taking other weight loss medications that act on the brain (for example: phentermine). This includes prescription and over-the-counter medications and herbal products.

• Are suffering from anorexia nervosa or bulimia nervosa.

• Have had prior allergic reactions to MERIDIA(r) or sibutramine.

• Have severe liver disease

• Have any kidney disease.

• Are pregnant or planning to become pregnant.

• Are breast-feeding their infants.

• Have had seizures (epilepsy or convulsions).

• Have an eye disorder called narrow angle glaucoma.

• Are under 18 years of age.

• Are over 65 years of age.

If you have any concerns or questions about whether or not you should

What dosage forms it comes in:

10 and 15 mg Capsules

WARNINGS AND PRECAUTIONS

BEFORE you use MERIDIA(r) talk to your doctor or pharmacist if:

It is important that you tell your doctor all about your medical history, whether you are taking or have taken weight loss drugs in the past, current medical problems, current symptoms, what other medications you take or have taken (prescription and over-the-counter medicines and herbal products) and any prior allergies to medicines.

It is important to make sure your doctor knows if you have heart disease of any kind, high blood pressure, migraine headaches, glaucoma, seizures, depression, any psychiatric illness, Parkinson's Disease, prior strokes, prior transient ischemic attacks (TIAs), thyroid disorders, osteoporosis, gallstones, liver disease, kidney disease, history of a major eating disorder (anorexia nervosa or bulimia nervosa) or any other medical problem.

What if I am pregnant or nursing?

MERIDIA(r) should not be used by pregnant women or nursing mothers. You should notify your doctor immediately if you become pregnant or plan to become pregnant.

What about pregnancy?

Women of child bearing potential should use an effective birth control method while taking MERIDIA(r). Check with your doctor to make sure you are on a medically safe and effective birth control method while taking MERIDIA(r).

INTERACTIONS WITH THIS MEDICATION

Drugs that may interact with MERIDIA(r) include:

You cannot take MERIDIA(r) if you are taking prescription medicines called monoamine oxidase inhibitors (MAOIs). It is especially important to make sure you tell your doctor if you are taking MAOIs that are sometimes used to treat depression or Parkinson's Disease (for example:

(r) (r) (r) (r)

take MERIDIA(r), talk to your doctor.

IMPORTANT: It is very important that you make sure that your primary care doctor and all your other health care providers know what medications you take and what medical conditions and allergies you have.

What the medicinal ingredient is:

Eldepryl , Nardil , Parnate , Manerix ). This is very important because

serious, sometimes even fatal, reactions can occur if MERIDIA(r) is taken at the same time MAOIs are taken.

If you are currently taking an MAOI, your doctor will want you to stop taking it for at least two (2) full weeks before starting you on MERIDIA(r).

sibutramine hydrochloride monohydrate

What the important non-medicinal ingredients are:

lactose monohydrate, NF; microcrystalline cellulose, NF; colloidal silicon dioxide, NF; and magnesium stearate, NF in a hard gelatin capsule [which contains titanium dioxide, gelatin, FD&C Blue No. 2 (10 mg capsules only), D&C Yellow No. 10 (15 mg capsules only) and may also contain sodium lauryl sulphate, silicon dioxide and printing ink].

If you are currently taking MERIDIA(r), your doctor will want you to stop taking it for at least two (2) full weeks before starting you on an MAOI.

MERIDIA(r) must not be taken if you are taking other weight loss medications that act on the brain (for example: phentermine). This includes both prescription and over-the-counter medications and herbal products.

In addition to the above, a rare, but serious medical syndrome called the "serotonin syndrome" has been reported in patients when medications like MERIDIA(r) are taken along with other drugs that may alter serotonin activity such as: drugs for depression (for example: Desyrel(r), Effexor(r), Eldepryl(r), Serzone(r), Nardil(r), Parnate(r), Paxil(r), Prozac(r), Zoloft(r), IMPORTANT: PLEASE READ

Ludiomil(r), Asendin(r), Elavil(r), Etrafon(r), Norpramin(r), SinequanTM, Surmontil(r), Tofranil(r), Triavil(r), Luvox(r), Anafranil(r), Manerix(r)), drugs for migraine headache therapy (Imitrex(r), Maxalt(r), Zomig(r), Amerge(r)) and dihydroergotamine, certain pain medications such as Demerol(r) (meperidine), Duragesic(tm) (fentanyl), and Talwin(r) (pentazocine); the cough suppressant dextromethorphan found in many cough medicines; lithium; and the amino acid tryptophan. The syndrome requires immediate medical attention and may include one or more of the following symptoms: restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, weakness, tremor, incoordination, fever, shivering, sweating, vomiting and increased heart rate.

MERIDIA(r) must not be taken with medications used to treat depression or other psychiatric illnesses.

Many over-the-counter decongestants, cough, cold and allergy remedies, containing medicines such as phenylpropanolamine (no longer available in Canada), ephedrine, or pseudoephedrine, as well as certain anti- inflammatory drugs (e.g. NSAIDS) may increase blood pressure or heart rate. Before taking these medications on your own, you should check with your doctor to make sure it is all right to take these medicines if you are already taking MERIDIA(r). Your doctor may advise you to take a certain

type of cough, cold, decongestant or allergy medicine that will not interact with MERIDIA(r).

Will MERIDIA(r) change the way I need to take nutritional supplements?

Nutritional supplements, like vitamins, minerals and amino acids (with the exception of tryptophan) can be used along with MERIDIA(r). You should make sure your doctor knows what nutritional supplements you are taking and why you are taking them. You should not take MERIDIA(r) if you are taking tryptophan. You should not use herbal or over-the-counter weight loss products while taking MERIDIA(r).

What about drinking alcoholic beverages?

MERIDIA(r) may increase the sedative effects of alcohol. It is important that you let your doctor know how often, and what type of alcoholic beverages you drink. In addition, alcohol will increase your caloric intake without providing nutritional value, making it more difficult to lose weight.

What about drinking coffee, tea and caffeinated beverages?

MERIDIA(r) can be safely taken with moderate use of coffee, tea or caffeinated beverages. You should check with your doctor to make sure that you do not have a medical condition that can be aggravated by these beverages independent of being on MERIDIA(r). You should check with your doctor if you consume a great deal of caffeinated beverages or use over-the-counter pills that contain caffeine.

Will MERIDIA(r) affect the effectiveness of birth control pills?

No.

How long should I take MERIDIA(r)?

You should continue to take MERIDIA(r) while you are losing weight or continuing to maintain your weight loss. Your doctor will determine how long you should take MERIDIA(r). Follow your doctor's advice.

The safety and effectiveness of MERIDIA(r) when taken for more than one year have not been determined.

Overdose:

In the case of an overdose, immediately speak with your doctor and/or go to the nearest emergency room for immediate medical attention. If you are unable to reach a doctor or emergency room, call your local Poison Information Center (see the front page of your local phone directory).

Missed Dose:

If you forget to take a dose of MERIDIA(r), take the next dose the next morning. Do not take an extra capsule to "make up" for the dose that you missed.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

What are some of the more common side effects of MERIDIA(r)?

MERIDIA(r), like all medications, may cause side effects. In studies the most common side effects were: dry mouth. anorexia, insomnia (inability to fall asleep) and constipation. Other side effects that may occur include: increased sweating, an increase in blood pressure, and an increase in heart rate. These side effects are generally mild, and have usually not caused people to stop taking MERIDIA(r).

Does MERIDIA(r) affect blood pressure or heart rate?

MERIDIA(r) substantially increases blood pressure and heart rate in some patients. Blood pressure increases may be smaller or less likely to occur if you succeed in losing weight.

Because increases in blood pressure are not experienced as a bothersome side effect, you will have to have your blood pressure checked on a regular basis while you are taking MERIDIA(r). Your blood pressure and pulse should be measured prior to starting MERIDIA(r), and you will be required to visit your doctor for follow-up every two weeks during the first three months of therapy and once every 1-3 months thereafter for as long as you are taking MERIDIA(r). If you experience a significant increase in blood pressure or heart rate while taking MERIDIA(r), your doctor may decide to decrease the dose or discontinue MERIDIA(r).

If you have well controlled high blood pressure, before starting to take MERIDIA(r) you will also have to have your blood pressure checked on a regular basis by your doctor. You should not take MERIDIA(r) if you have uncontrolled or poorly controlled high blood pressure.

PROPER USE OF THIS MEDICATION

Usual dose:

The recommended dose, as directed by your physician, should be taken once daily in the morning. MERIDIA(r) should be swallowed whole. You may take MERIDIA(r) on an empty stomach or after a meal. IMPORTANT: PLEASE READ

Does MERIDIA(r) cause damage to the heart valves?

Certain weight loss drugs have been associated with cardiac valve dysfunction (heart valve disease). Patients in two MERIDIA(r) studies were examined by doctors who used cardiac ultrasound testing to carefully look at heart valve structure and function. In one study, 104 patients received MERIDIA(r) for 6 months. None of the patients had heart valve disease at 6 months. In another study, patients who had received either MERIDIA(r) or placebo (sugar pills) for periods of two weeks to 16 months were examined. Three out of 132 patients (2.3%) who had taken MERIDIA(r) and two out of 77 patients (2.6%) who had taken placebo were found to have heart valve disease. In extensive postmarketing experience in other countries, including the U.S.A., there has been no increase in the incidence of cardiac valve disease. However, due to the limited number of patients studied, it is not yet known whether MERIDIA(r) may cause this condition.

When should I call my doctor?

It is important that you call your doctor immediately if you experience any symptoms or feelings that make you concerned about your health or a possible drug side effect. Let your doctor advise you on your concerns. If you experience any of the symptoms in the SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT

THEM Table below, stop taking MERIDIA(r) and notify your doctor

immediately.

What about physician follow-up visits?

You should make sure you see your doctor as directed for regular follow- up visits where your doctor can follow your body weight, and carefully monitor your blood pressure and overall health as you try to lose weight and maintain weight loss. You will be required to visit your doctor once every two weeks for the first three months of MERIDIA(r) therapy and once every 1-3 months thereafter for as long as you are taking this medication.

What about driving a car or dangerous work activities?

Any drug that affects the central nervous system has the potential to impair judgement, thinking, coordination or motor skills. MERIDIA(r) should not interfere with your ability to drive your car. However, you should be on the alert for any signs of fatigue, sedation, or lack of alertness while driving or operating dangerous machinery.

You should check with your doctor if you have any questions with regard to your work and the use of MERIDIA(r).

This is not a complete list of side effects. For any unexpected effects while taking MERIDIA(r), contact your doctor or pharmacist.

What if I develop allergic reactions?

Stop taking MERIDIA(r) and notify your doctor immediately if you develop a skin rash, hives or other allergic reactions.

Does MERIDIA(r) cause primary pulmonary hypertension (PPH)?

Certain other weight loss drugs have been associated with primary pulmonary hypertension (PPH), a rare but sometimes fatal disease. MERIDIA(r) works in a slightly different way from those weight loss medications. In clinical studies, no cases of PPH have been reported with MERIDIA(r). Because this disease is so rare, however, it is not known whether or not MERIDIA(r) may cause this disease.

The first symptom of PPH is usually shortness of breath. If you experience new or worsening shortness of breath, or if you experience chest pain, fainting, or swelling of your feet, ankles, or legs, stop taking MERIDIA(r) and notify your doctor immediately. IMPORTANT: PLEASE READ

HOW TO STORE IT

MERIDIA(r) should be stored at normal room temperature (15E to 25EC). Never leave MERIDIA(r) in hot or moist places.

It is important to keep MERIDIA(r) in a safe area where children cannot get it.

Never take more MERIDIA(r) than prescribed by your doctor. You should never share MERIDIA(r) with a friend.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate

Tunney's Pasture, AL 0701C Ottawa (ON) K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

For more information on this product, please contact the number below, 1-800-361-7852, or visit the website at www.abbott.ca.

This leaflet was prepared by Abbott Laboratories, Limited Saint-Laurent, Quebec, H4S 1Z1

Last revised: May 2005

IMPORTANT: PLEASE READ

Body Mass Index (BMI), kg/m2

WEIGHT, lb (kg)

Patients with BMI values $ 30 may be candidates for MERIDIA(r) therapy.

Patients with BMI values of 27-29 may be candidates for MERIDIA(r) therapy if they also have other risk factors (e.g., high blood pressure, diabetes, high cholesterol, large waist measurement).