Reductil (Meridia) for obesity management

Reductil is the brand name of an oral drug indicated for the treatment of obesity, including weight loss and maintenance of weight loss, and should be used in conjunction with a reduced calorie diet. Reductil can help people eat less, and still eat the foods they like. You can buy it in our online pharmacy. No prescription required.

Reductil is a systematic agent that affects the brain's appetite control centers without completely suppressing appetite. Reductil blocks serotonin and norepinephrine reuptake, and does not cause neurotransmitter release. Reductil promotes gradual, sustained weight loss and works without inducing feelings of euphoria.

MERIDIA® (sibutramine hydrochloride monohydrate)

DESCRIPTION

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,Ndimethyl-a-(2-methylpropyl)-, hydrochloride, monohydrate, and has an empirical formula of C₁₇H₂₉Cl₂NO. Its molecular weight is 334.33. The structural formula is shown below:

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].

CLINICAL PHARMACOLOGY
Mode of Action
Sibutramine produces its therapeutic effects by norepinephrine, serotonin and dopamine reuptake inhibition. Sibutramine and its major pharmacologically active metabolites (M₁ and M₂) do not act via release of monoamines.

Pharmacodynamics
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 (5-hydroxytryptamine, 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 (K_i;nM)

	Serotonin	Norepinephrine	Dopamine
Sibutramine	298	5451	943
M1	15	20	49
M2	20	15	45

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, 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT_2C), norepinephrine (ß, ß₁, ß₃, a₁ and a₂), dopamine (D₁ and D₂), benzodiazepine, and glutamate (NMDA) receptors. These compounds also lack monoamine oxidase inhibitory activity in vitro and in vivo.

Pharmacokinetics
Absorption
Sibutramine is rapidly absorbed from the GI tract (T_max 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 = 15 mg)

Study Population	Cmax (ng/mL)	Tmax (h)	AUC** (ng*h/mL)	T1/2 (h)
Metabolite M1 Target Population:
Obese Subjects	4.0 (42)	3.6 (28)	25.2 (63)	--
(n=18)	3.2 - 4.8	3.1 - 4.1	18.1 - 32.9
Special Population:
Moderate Hepatic	2.2 (36)	3.3 (33)	18.7 (65)	--
Impairment (n=12)	1.8 - 2.7	2.7 - 3.9	11.9 - 25.5
Metabolite M2 Target Population:
Obese Subjects	6.4 (28)	3.5 (17)	92.1 (26)	17.2 (58)
(n=18)	5.6 - 7.2	3.2 - 3.8	81.2 - 103	12.5 - 21.8
Special Population:
Moderate Hepatic	4.3 (37)	3.8 (34)	90.5 (27)	22.7 (30)
Impairment (n=12)	3.4 - 5.2	3.1 - 4.5	76.9 - 104	18.9 - 26.5
**Calculated only up to 24 hr for M1

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.
Special Populations
Geriatric: Plasma concentrations of M₁ and M₂ were similar between elderly (ages 61 to 77 yr) and young (ages 19 to 30 yr) subjects following a single 15-mg oral sibutramine dose. Plasma concentrations of the inactive metabolites M₅ and M₆ were higher in the elderly; these differences are not likely to be of clinical significance. 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.
Pediatric: The safety and effectiveness of MERIDIA in pediatric patients under 16 years old have not been established.
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 C_max 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.
Renal Insufficiency: The effect of renal disease has not been studied. However, since sibutramine and its active metabolites M₁ and M₂ are eliminated by hepatic metabolism, renal disease is unlikely to have a significant effect on their disposition.
Elimination of the inactive metabolites M₅ and M₆, which are renally excreted, may be affected in this population. MERIDIA should not be used in patients with severe renal impairment.
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. MERIDIA should not be used in patients with severe hepatic dysfunction.

CLINICAL STUDIES
Observational epidemiologic studies have established a relationship between obesity and the risks for cardiovascular disease, non-insulin dependent diabetes mellitus (NIDDM), certain forms of cancer, gallstones, certain respiratory disorders, and an increase in overall mortality. These studies suggest that weight loss, if maintained, may produce health benefits for some patients with chronic obesity who may also be at risk for other diseases.
The long-term effects of MERIDIA Capsules on the morbidity and mortality associated with obesity have not been established. Weight loss was examined in 11 double-blind, placebo-controlled obesity trials (BMI range across all studies 27-43) 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 MERIDIA was consistent across studies.
Analysis of the data in three long-term (=6 months) obesity trials indicates that patients who lose at least 4 pounds in the first 4 weeks of therapy with a given dose of MERIDIA are most likely to achieve significant long-term weight loss on that dose of MERIDIA. Approximately 60% of such patients went on to achieve a placebo-subtracted weight loss of =5% of their initial body weight by month 6. Conversely, of those patients on a given dose of MERIDIA who did not lose at least 4 pounds 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 6.

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