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Meridia Product Information

In human brain tissue, M1 and M2 also inhibit dopamine reuptake in vitro, but with
~3-fold lower potency than for the reuptake inhibition of serotonin or
norepinephrine.
Potencies of Sibutramine, M1 and M2 as In Vitro Inhibitors
of Monoamine Reuptake in Human Brain
Potency to Inhibit Monoamine Reuptake (Ki; nM)
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-HT1A, 5-HT1B, 5-HT2A, 5-HT2C),
norepinephrine (, 1, 3, 1 and 2), 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 (Tmax of 1.2 hours) following oral
administration and undergoes extensive first-pass metabolism in the liver (oral
clearance of 1750 L/h and half-life of 1.1 h) to form the pharmacologically active
mono- and di-desmethyl metabolites M1 and M2. Peak plasma concentrations of M1
and M2 are reached within 3 to 4 hours. On the basis of mass balance studies, on
average, at least 77% of a single oral dose of sibutramine is absorbed. The absolute
bioavailability of sibutramine has not been determined.

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

Metabolism
Sibutramine is metabolized in the liver principally by the cytochrome P450(3A4)
isoenzyme, to desmethyl metabolites, M1 and M2. These active metabolites are
further metabolized by hydroxylation and conjugation to pharmacologically inactive
metabolites, M5 and M6. Following oral administration of radiolabeled sibutramine,
essentially all of the peak radiolabeled material in plasma was accounted for by
unchanged sibutramine (3%), M1 (6%), M2 (12%), M5 (52%), and M6 (27%).
M1 and M2 plasma concentrations reached steady-state within four days of dosing
and were approximately two-fold higher than following a single dose. The
elimination half-lives of M1 and M2 , 14 and 16 hours, respectively, were
unchanged following repeated dosing.

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

Summary of Pharmacokinetic Parameters
Mean (%CV) and 95% Confidence Intervals of Pharmacokinetic Parameters
(Dose = 15 mg)
Study
Population
Cmax
(ng/mL)
Tmax
(h)
AUC†
(ng*h/mL)
T½
(h)
Metabolite M1
Target Population:
Obese Subjects (n=18) 4.0 (42)
3.2 - 4.8
3.6 (28)
3.1 - 4.1
25.5 (63)
18.1 - 32.9
--

Special Population:
Moderate Hepatic
Impairment (n=12)
2.2 (36)
1.8 - 2.7
3.3 (33)
2.7 - 3.9
18.7 (65)
11.9 - 25.5
--
Metabolite M2

Target Population:
Obese Subjects (n=18) 6.4 (28)
5.6 - 7.2
3.5 (17)
3.2 - 3.8
92.1 (26)
81.2 - 103
17.2 (58)
12.5 - 21.8

Special Population:
Moderate Hepatic
Impairment (n=12)
4.3 (37)
3.4 - 5.2
3.8 (34)
3.1 - 4.5
90.5 (27)
76.9 - 104
22.7 (30)
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® (sibutramine hydrochloride
monohydrate) Capsules 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
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

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® (sibutramine hydrochloride monohydrate)
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.

Significant dose-related reductions in waist circumference, an indicator of intraabdominal
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 MERIDIA,
Dual Energy X-Ray Absorptiometry (DEXA) assessment of changes in body
composition showed that total body fat mass decreased by 1.8 kg in the MERIDIA
group versus 0.2 kg in the placebo group (p<0.001). Similarly, truncal (android) fat
mass decreased by 0.6 kg in the MERIDIA group versus 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 MERIDIA does not adversely affect
glycemia, serum lipid profiles, or serum uric acid in obese patients. Treatment with
MERIDIA (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 MERIDIA tend to have smaller
increases in blood pressure and pulse rate
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 6 kg on a 4-week very low calorie diet (VLCD), MERIDIA produced
significant reductions in weight, as shown below. In the two 1-year studies, maximal
weight loss was achieved by 6 months and statistically significant weight loss was
maintained over 12 months.
Mean Weight Loss (lbs) in the Six-Month and One-Year Trials
Study/Patient Group Placebo
(n)
MERIDIA (mg)
5
(n)
10
(n)
15
(n)
20
(n)
Study 1
All patients* 2.0
(142)
6.6
(148)
9.7
(148)
12.1
(150)
13.6
(145)
Completers** 2.9
(84)
8.1
(103)
12.1
(95)
15.4
(94)
18.0
(89)
Early responders*** 8.5
(17)
13.0
(60)
16.0
(64)
18.2
(73)
20.1
(76)
Study 2
All patients* 3.5
(157)
9.8
(154)
14.0
(152)

Completers** 4.8
(76)
13.6
(80)
15.2
(93)
Early responders*** 10.7
(24)
18.2
(57)
18.8
(76)
Study 3****
All patients* 15.2
(78)
28.4
(81)
Completers** 16.7
(48)
29.7
(60)
Early responders*** 21.5
(22)
33.0
(46)
* Data for all patients who received study drug and who had any postbaseline
measurement (last observation carried forward analysis).
** Data for patients who completed the entire 6-month (Study 1) or one-year
period of dosing and have data recorded for the month 6 (Study 1) or month 12 visit.
*** Data for patients who lost at least 4 lbs in the first 4 weeks of treatment and
completed the study.
**** Weight loss data shown describe changes in weight from the pre-VLCD;
mean weight loss during the 4-week VLCD was 16.9 lbs for sibutramine and 16.3
lbs for placebo.
Maintenance of weight loss with sibutramine was examined in a 2-year, doubleblind,
placebo-controlled trial. After a 6-month run-in phase in which all patients
received sibutramine 10 mg (mean weight loss, 26 lbs.), patients were randomized to
sibutramine (10 to 20 mg, 352 patients) or placebo (115 patients). The mean weight
loss from initial body weight to endpoint was 21 lbs. and 12 lbs. for sibutramine and
placebo patients, respectively.1 A statistically significantly (p<0.001) greater
proportion of sibutramine treated patients, 75%, 62%, and 43%, maintained at least
80% of their initial weight loss at 12, 18, and 24 months, respectively, compared
with the placebo group (38%, 23%, and 16%). Also 67%, 37%, 17%, and 9% of
sibutramine treated patients compared with 49%, 19%, 5%, and 3% of placebo
patients lost 5%, 10%, 15%, and 20%, respectively, of their initial body weight at
endpoint.2 From endpoint to the post-study follow-up visit (about 1 month), weight
regain was approximately 4 lbs for the sibutramine patients and approximately 2 lbs
for the placebo patients

MERIDIA® (sibutramine hydrochloride monohydrate) Capsules induced weight
loss has been accompanied by beneficial changes in serum lipids that are similar to
those seen with nonpharmacologically-mediated weight loss. A combined, weighted
analysis of the changes in serum lipids in 11 placebo-controlled obesity studies
ranging in length from 12 to 52 weeks is shown below for the last observation
carried forward (LOCF) analysis.
Combined Analysis (11 Studies) of Percentage Change in
Serum Lipids (N) – LOCF
Category TG CHOL LDL-C HDL-C
All Placebo 0.53 (475) -1.53 (475) -0.09 (233) -0.56 (248)
< 5% Weight
Loss
4.52 (382) -0.42 (382) -0.70 (205) -0.71 (217)
5% Weight
Loss
-15.30 (92) -6.23 (92) -6.19 (27) 0.94 (30)
All Sibutramine -8.75 (1164) -2.21 (1165) -1.85 (642) 4.13 (664)
< 5% Weight
Loss
-0.54 (547) 0.17 (548) -0.37 (320) 3.19 (331)
5% Weight
Loss
-16.59 (612) -4.87 (612) -4.56 (317) 4.68 (328)
Baseline mean values:
Placebo:TG 187 mg/dL; CHOL 221 mg/dL; LDL-C 140 mg/dL; HDL-C 47 mg/Dl
Sibutramine: TG 172 mg/dL; CHOL 215 mg/dL: LDL-C 140 mg/dL; HDL-C
47 mg/dL
MERIDIA induced weight loss has been accompanied by reductions in serum uric
acid.
Certain centrally-acting weight loss agents that cause release of serotonin from nerve
terminals have been associated with cardiac valve dysfunction. The possible
occurrence of cardiac valve disease was specifically investigated in two studies. In
one study 2-D and color Doppler echocardiography were performed on 210 patients
(mean age, 54 years) receiving MERIDIA 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 another study, 25
patients underwent 2-D and color Doppler echocardiography before treatment with
MERIDIA and again after treatment with MERIDIA 5 to 30 mg daily for three
months; there were no cases of valvular heart disease.

The effect of sibutramine 15 mg once daily on measures of 24-hour blood pressure
was evaluated in a 12-week placebo-controlled study. Twenty-six male and female,
primarily Caucasian individuals with an average BMI of 34 kg/m2 and an average
age of 39 years underwent 24-hour ambulatory blood pressure monitoring (ABPM).
The mean changes from baseline to Week 12 in various measures of ABPM are
shown in the following table.3
Parameter
mm Hg
Systolic Diastolic
Placebo
n=12
Sibutramine Placebo Sibutramine
15 mg
n=14
20 mg
n=16
15 mg
n=12
20 mg
n=16
Daytime 0.2 3.9 4.4 0.5 5.0 5.7
Nighttime -0.3 4.1 6.4 -1.0 4.3 5.4
Early am -0.9 9.4 5.3 -3.0 6.7 5.8
24-hour mean -0.1 4.0 4.7 0.1 5.0 5.6
Normal diurnal variation of blood pressure was maintained5.

INDICATIONS AND USAGE
MERIDIA® (sibutramine hydrochloride monohydrate) Capsules 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 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.

CONTRAINDICATIONS
MERIDIA® (sibutramine hydrochloride monohydrate) Capsules is contraindicated
in patients receiving monoamine oxidase inhibitors (MAOIs) (see “WARNINGS”).
MERIDIA is contraindicated in patients with hypersensitivity to sibutramine or any
of the inactive ingredients of MERIDIA.
MERIDIA is contraindicated in patients who have anorexia nervosa.
MERIDIA is contraindicated in patients taking other centrally acting appetite
suppressant drugs.

WARNINGS
Blood Pressure and Pulse
MERIDIA SUBSTANTIALLY INCREASES BLOOD PRESSURE IN SOME
PATIENTS. REGULAR MONITORING OF BLOOD PRESSURE IS
REQUIRED WHEN PRESCRIBING MERIDIA.6
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 treated 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.
Percent Outliers in Studies 1 and 27
% Outliers*
Dose (mg) SBP DBP Pulse
Placebo 9 7 12
5 6 20 16
10 12 15 28
15 13 17 24
20 14 22 37
* Outlier defined as increase from baseline of 15 mm Hg for three consecutive visits
(SBP), 10 mm Hg for three consecutive visits (DBP), or pulse 10 bpm for three
consecutive visits.

Potential Interaction With Monoamine Oxidase Inhibitors
MERIDIA® (sibutramine hydrochloride monohydrate) Capsules 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® (sibutramine hydrochloride monohydrate) Capsules. 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 <0.1% of MERIDIA treated
patients. MERIDIA should be used cautiously in patients with a history of seizures.
It should be discontinued in any patient who develops seizures.
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 part of the package insert that
is relevant to them. In particular, the importance of keeping appointments for followup
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® (sibutramine hydrochloride
monohydrate) Capsules 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 a MAOI.
At least 2 weeks should elapse between discontinuation of a MAOI and initiation of treatment with MERIDIA. Similarly, at
least 2 weeks should elapse between discontinuation of MERIDIA and initiation of
treatment with a 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 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 MERIDIA inhibits serotonin reuptake, in general, it should not be
administered with other serotonergic agents such as those listed above. However, if
such a combination is clinically indicated, appropriate observation of the patient is
warranted.
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 ephedrine, or pseudoephedrine. Caution should be used
when prescribing MERIDIA to patients who use these medications.
Drugs That Inhibit Cytochrome P450(3A4) Metabolism: In vitro studies indicated
that the cytochrome P450(3A4)-mediated metabolism of sibutramine was inhibited
by ketoconazole and to a lesser extent by erythromycin. Clinical interaction trials
were conducted on these substrates. The potential for such interactions is described
below.
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 Cmax of 58% and 36% for M1
and of 20% and 19% for M2, respectively.
Erythromycin: The steady-state pharmacokinetics of sibutramine and metabolites
M1 and M2 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 M1 and M2 . A small reduction in Cmax
for M1 (11%) and a slight increase in Cmax for M2 (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 (M1 and M2) plasma Cmax (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® (sibutramine
hydrochloride monohydrate) Capsules 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 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 i

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