Sibutramine

What is Sibutramine?

Sibutramine is a chemical substance of the amphetamine type with strong fatburning properties. Proofen effective by thousands of people worldwide, sibutramine is here to slim trim and make obesity a thing of the past. Also known under tradenames like Reductil, Meridia, Reduce and many more it revolutionized the world of fatb...

What is Sibutramine?

Sibutramine is a chemical substance of the amphetamine type with strong fatburning properties. Proofen effective by thousands of people worldwide, sibutramine is here to slim trim and make obesity a thing of the past. Also known under tradenames like Reductil, Meridia, Reduce and many more it revolutionized the world of fatburning and started another level of targeted fatrburning of typical problem zones of the human body.

Reductil (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-
α-(2-methylpropyl)-, hydrochloride, monohydrate, and has an empirical formula of
C
17H29CI2NO. 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.

Mechanism of action

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

Sibutramine exerts its pharmacological actions predominantly via its secondary (M1)
and primary (M
2) 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, M
1 and M2 also inhibit dopamine reuptake in vitro, but with
about 3-fold lower potency than for the reuptake inhibition of serotonin or
norepinephrine.

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 (M
1 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, M
1 and M2 exhibit no evidence of anticholinergic or antihistaminergic
actions. In addition, receptor binding profiles show that sibutramine, M
1 and M2 have
low affinity for serotonin (5-HT
1, 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C), norepinephrine (β, β1,
β3, α1 and α2), dopamine (D1 and D2), benzodiazepine, and glutamate (NMDA)
receptors. These compounds also lack monoamine oxidase inhibitory activity
in vitro
and in vivo.

Pharmacokinetics

Absorption
Sibutramine is rapidly absorbed from the gastrointestinal [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 M
1 and M2. Peak plasma concentrations of M1 and
M
2 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.

Effect of Food


Administration of a single 20 mg dose of sibutramine with a standard breakfast
resulted in reduced peak M
1 and M2 concentrations (by 27% and 32%, respectively)
and delayed the time to peak by approximately 3 hours. However, the AUCs of M
1 and
M
2 were not significantly altered.

Special Population


Geriatrics

Plasma concentration 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 M
5 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 sibutramine 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.

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 was noted for M
1 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 M
1 and M2 were increased by 24% compared to
healthy subjects, while M
5 and M6 plasma concentrations were unchanged. The
observed differences in M
1 and M2 concentrations do not warrant dosage adjustment in
patients with mild to moderate hepatic impairment.
Sibutramine should not be used in patients with severe hepatic dysfunction.

Renal Insufficiency
The effect of renal disease has not been studied. However, since sibutramine and its
active metabolites M
1 and M2 are eliminated by hepatic metabolism, renal disease is
unlikely to have a significant effect on their disposition. Elimination of the inactive
metabolites M
5 and M6, which are renally excreted, may be affected in this population.
Sibutramine should not be used in patients with severe renal impairment.

Clinical Studies
Observational epidermiologic 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 sibutramine 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 weight loss was maintained over 12 months. The amount of
placebo-substracted weight loss achieved on sibutramine was consistent across
studies.
Analysis of the data in 3 long term (>6 months) obesity trial indicates that patients
who lose at least 4 pounds in the first 4 weeks of therapy with a given dose of
sibutramine are most likely to achieve significant long-term weight loss on that dose of sibutramine.

Approximately 60% of such patients went on to achieve a placebosubtracted weight loss of > 5% of their initial body weight by month 6. Conversely, of those patients on a given dose of sibutramine 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 substracted weight loss of > 5% of their initial body weight on that dose by month 6.
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, Dual Energy
X-Ray Asorptiometry (DEXA) assessment of changes in body composition showed that
total body fat mass decreased by 1.8 kg in the sibutramine group versus 0.2 in the
placebo group (p<0.001). Similarly, truncal (android) fat mass decreased by 0.6 kg in
the sibutramine group versus 0.1 kg in the placebo group (p<0.01). The changes in
lean mass, fasting blood sugar, and HbA
1 were not statistically 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 does not adversely affect glycemia,
serum lipid profiles, or serum uric acid in obese patients. Treatment with sibutramine
(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 tend to have smaller increases in blood pressure
and pulse rate.


In all Studies, sibutramine produced significant reductions in weight.                                              In two 1-year studies, maximal weight loss was achieved by 6 months and                                       statistically significant weight loss was maintained over 12 months.

Sibutramine- induced weight loss has been accompanied by beneficial changes in
serum lipids that are similar to those seen with nonpharmacologically-mediated weight
loss.

Sibutramine induced weight loss has been accompanied by reductions in serum uric
acid. In one study, serum uric acid has been identified as an independent risk factor for
death from coronary artery disease.

Contraindications

Reductil is contraindicated in patients with hypersensitivity to sibutramine or to any
other ingredient of the preparation.
Reductil is contraindicated in patients receiving monoamine oxidase inhibitors
(MAOIs).
Reductil is contraindicated in patients who have anorexia nervosa.
Reductil is contraindicated in patients taking other centrally acting appetite
suppressant drugs.

The duration of treatment is limited to one year.
Treatment with sibutramine should only be given as part of an integrated therapeutic
approach for weight reduction under care of a physician experienced in the treatment
of obesity. An appropriate approach to obesity management should include dietary and
behavioral modifications as well as increased physical activity. This integrated
approach is essential for a lasting change in eating habits and behavior which is
fundamental to the long-term maintenance of the reduced weight level once therapy is
complete.


Blood Pressure and Pulse

SIBUTRAMINE SUBSTANTIALLY INCREASES BLOOD PRESSURE. REGULAR MONITORING OF BLOOD PRESSURE IS REQUIRED WHEN USING SIBUTRAMINE.

Dosage and Administration

The recommended starting dose of Reductil is 10 mg administered once daily in the
morning swallowed whole with a glass of water. The capsule can be taken with or
without food. If there is inadequate weight loss, the dose may be titrated after 4 weeks
to a total of 15 mg once daily.

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