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Sibutramine - Meridia

MERIDIA (sibutramine hydrochloride monohydrate) is an orally administered agent for the treatment of obesity. Chemically the active ingredient is a racemic mixture of the (+) and (-) enantiomers of cyclobutanemethanamine 1-(4- chlorophenyl)-N , N - dimethyl - alfa - (2-methylpropyl)-, hydrochloride, monohydrate, and has an empirical formula of C17H 29Cl 2NO. Its molecular weight is 334.33. 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

Each MERIDIA capsule contains 5 mg, 10 mg and 15 mg of sibutramine hydrochloride monohydrate. It also contains as 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 USP; gelatin FD&C Blue No.2 (5 and 10 mg capsules only); D&C Yellow No.10 (5 and 15 mg capsules only) and other inactive ingredients.

MERIDIA 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. MERIDIA is recommended for obese patients with an initial body mass index ³ 30 kg/ m2 or 27 kg/ m2 in the presence of other risk factors (e.g., hypertension, diabetes, dyslipidemia).

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 x 0.0254 meters

Physicians should instruct their patients to read the patient package insert before starting therapy with MERIDIA and to reread it each time the prescription is renewed.

Physicians should also discuss with their patients any proof 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 (see DRUG INTERACTIONS).

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.

WARNINGS

Blood Pressure and Pulse

MERIDIA SUBSTANTIALLY INCREASES BLOOD PRESSURE IN SOME PATIENTS. REGULAR MONITORING OF BLOOD PRESSURE IS REQUIRED WHEN PRESCRIBING MERIDIA

In placebo-controlled obesity studies MERIDIA 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 MERIDIA was initiated at the higher doses see table below. In pre-marketing placebo-controlled obesity studies 0.4% of patients treated with MERIDIA 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 MERIDIA were discontinued for tachycardia pulse rate >100 bpm compared with 0.1% in the placebo-group. Blood pressure and pulse should be measured prior to starting therapy with MERIDIA and should be monitored at regular intervals thereafter. For patients who experience a sustained increase in blood pressure or pulse rate while receiving MERIDIA either dose reduction or discontinuation should be considered MERIDIA should be given with caution to those patients with a history of hypertension and should not be given to patients with uncontrolled or poorly controlled hypertension.
Outlier defined as increase from baseline of ³15 mm Hg for three consecutive visits (SBP) ³10 mm Hg for three consecutive visits (DBP) or pulse ³10 bpm for three consecutive visits.

Potential Interaction With Monoamine Oxidase Inhibitors

MERIDIA sibutramine hydrochloride monohydrate is a norepinephrine serotonin and dopamine reuptake inhibitor and should not be used concomitantly with MAOIs (see

PRECAUTIONS
, Drug Interactions subsection). There should be at least a 2-week interval after stopping MAOIs before commencing treatment with MERIDIA. Similarly, there should be at least a 2-week interval after stopping MERIDIA before starting treatment with MAOIs.
Concomitant Cardiovascular Disease

Treatment with MERIDIA has been associated with increases in heart rate and or blood pressure. Therefore MERIDIA should not be used in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, or stroke.

Glaucoma

Because MERIDIA 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 MERIDIA.

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 pre-marketing clinical studies no cases of PPH have been reported with MERIDIA. Because of the low incidence of this disease in the underlying population however it is not known whether or not MERIDIA may cause this disease.

Seizures

During premarketing testing seizures were reported in
Gallstones

Weight loss can precipitate or exacerbate gallstone formation

Renal Hepatic Dysfunction

Patients with severe renal impairment or severe hepatic dysfunction have not been systematically studied. MERIDIA 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 patient package insert before starting therapy with MERIDIA and to reread it each time the prescription is renewed

Physicians should also discuss with their patients any proof 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

Drug Interactions CNS Active Drugs

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

WARNINGS
).

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

The rare but serious constellation of symptoms termed serotonin syndrome has also been reported with the concomitant use of selective serotonin reuptake inhibitors and agents for migraine therapy such as Imitrex (sumatriptan succinate) and dihydroergotamine, certain opioids such as dextramethorphan, 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 MERIDIA inhibits serotonin reuptake it should not be administered with other serotonergic agents such as those listed above.

Drugs That May Raise Blood Pressure and or Heart Rate

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

Drugs That Inhibit Cytochrome P450 3A 4 Metabolism

In vitro studies indicated that the cytochrome P450 (3A 4) mediated metabolism of sibutramine was inhibited by ketoconazole and to a lesser extent by erythromycin. Clinical interaction trials were conducted on these substrates. The data indicate that there is a potential for such interactions but the magnitude appears to be small.

Ketoconazole Concomitant administration of 200 mg doses of ketoconazole twice daily and 20 mg sibutramine once daily for 7 days in 12% uncomplicated obese subjects resulted in moderate increases in AUC and C max of 58% and 36% for M 1 and of 20% and 19% for M 2 respectively.

Erythromycin The steady state pharmacokinetics of sibutramine and metabolites M 1 and M 2 were evaluated in 12 uncomplicated obese subjects following concomitant administration of 500 mg of erythromycin three times daily and 20 mg of sibutramine once daily for 7 days. Concomitant erythromycin resulted in small increases in the AUC (less than 14%) for M 1 and M 2 A small reduction in C max for M 1 (11%) and a slight increase in C max for M 2 (10%) were observed.

Cimetidine

Concomitant administration of cimetidine 400 mg twice daily and sibutramine 15 mg once daily for 7 days in 12 volunteers resulted in small increases in combined M 1 and M 2 plasma C max (3.4%) and AUC (7.3%) these differences are unlikely to be of clinical significance.

Alcohol

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

Oral Contraceptives

The suppression of ovulation by oral contraceptives was not inhibited by MERIDIA. 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.

Drugs Highly Bound to Plasma Proteins

Although sibutramine and its active metabolites M 1 and M 2 are extensively bound to plasma proteins ³94%, 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. In vitro protein binding interaction studies have not been conducted.

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 0.5 and 21 times respectively those following the maximum daily human dose (20 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 43 times those following the maximum human dose (20 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

In rats there was no evidence of teratogenicity at doses of 1, 3 or 10 mg/ kg/ day generating combined plasma AUC's of the two major active metabolites up to approximately 43 times those following the maximum human dose (20 mg). In rabbits dosed at 3, 15, or 75 mg/ kg/ day plasma AUC's greater than approximately 5 times those following the maximum human dose caused maternal toxicity. At markedly toxic doses Dutch Belted rabbits had a slightly higher than control incidence of pigs with a broad short snout short rounded pinnae short tail and in some 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 pigs with cardiovascular anomalies while a second study showed a lower incidence than in the control group.

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

Nursing Mothers

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

Pediatric Use

The safety and effectiveness of MERIDIA in pediatric patients under 16 years of age have not been established.

Geriatric Use

Clinical studies of MERIDIA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general dose selection for an elderly patient should be cautious reflecting the greater frequency of decreased hepatic renal or cardiac function and of concomitant disease or other drug therapy.

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