Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1407
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Xenical (Capsule)
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dailymed-instance:dosage |
The recommended dose of XENICAL is one 120-mg capsule
three times a day with each main meal containing fat (during or up
to 1 hour after the meal). The patient should
be on a nutritionally balanced, reduced-calorie diet that contains
approximately 30% of calories from fat. The daily intake of fat, carbohydrate,
and protein should be distributed over three main meals. If a meal
is occasionally missed or contains no fat, the dose of XENICAL can
be omitted. Because XENICAL has been shown to
reduce the absorption of some fat-soluble vitamins and beta-carotene,
patients should be counseled to take a multivitamin containing fat-soluble
vitamins to ensure adequate nutrition . The supplement should be taken
at least 2 hours before or after the administration of XENICAL, such
as at bedtime. For patients receiving both orlistat
and levothyroxine therapy, administer levothyroxine and orlistat at
least 4 hours apart. Doses above 120 mg three
times a day have not been shown to provide additional benefit. Based on fecal fat measurements, the effect of XENICAL
is seen as soon as 24 to 48 hours after dosing. Upon discontinuation
of therapy, fecal fat content usually returns to pretreatment levels
within 48 to 72 hours. The safety and effectiveness
of XENICAL beyond 4 years have not been determined at this time.
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dailymed-instance:descripti... |
XENICAL (orlistat) is a lipase inhibitor for obesity
management that acts by inhibiting the absorption of dietary fats. Orlistat is (S)-2-formylamino-4-methyl-pentanoic acid
(S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl]-dodecyl ester.
Its empirical formula is CHNO, and its molecular weight is 495.7. It is a single diastereomeric
molecule that contains four chiral centers, with a negative optical
rotation in ethanol at 529 nm. The structure is: Orlistat is a white to off-white crystalline powder. Orlistat
is practically insoluble in water, freely soluble in chloroform, and
very soluble in methanol and ethanol. Orlistat has no pKwithin the physiological
pH range. XENICAL is available for oral administration
in dark-blue, hard-gelatin capsules, with light-blue imprinting. Each
capsule contains 120 mg of the active ingredient, orlistat. The capsules
also contain the inactive ingredients microcrystalline cellulose,
sodium starch glycolate, sodium lauryl sulfate, povidone, and talc.
Each capsule shell contains gelatin, titanium dioxide, and FD&C
Blue No.1, with printing of pharmaceutical glaze NF, titanium dioxide,
and FD&C Blue No.1 aluminum lake.
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dailymed-instance:clinicalP... |
Mechanism of Action: Orlistat is a reversible inhibitor of lipases. It
exerts its therapeutic activity in the lumen of the stomach and small
intestine by forming a covalent bond with the active serine residue
site of gastric and pancreatic lipases. The inactivated enzymes are
thus unavailable to hydrolyze dietary fat in the form of triglycerides
into absorbable free fatty acids and monoglycerides. As undigested
triglycerides are not absorbed, the resulting caloric deficit may
have a positive effect on weight control. Systemic absorption of the
drug is therefore not needed for activity. At the recommended therapeutic
dose of 120 mg three times a day, orlistat inhibits dietary fat absorption
by approximately 30%.<br/>Pharmacokinetics:<br/>Absorption: Systemic exposure to orlistat is minimal. Following
oral dosing with 360 mgC-orlistat, plasma radioactivity
peaked at approximately 8 hours; plasma concentrations of intact orlistat
were near the limits of detection (<5 ng/mL). In therapeutic studies
involving monitoring of plasma samples, detection of intact orlistat
in plasma was sporadic and concentrations were low (<10 ng/mL or
0.02��M), without evidence of accumulation, and consistent with
minimal absorption. The average absolute bioavailability
of intact orlistat was assessed in studies with male rats at oral
doses of 150 and 1000 mg/kg/day and in male dogs at oral doses of
100 and 1000 mg/kg/day and found to be 0.12%, 0.59% in rats and 0.7%,
1.9% in dogs, respectively.<br/>Distribution: In vitro orlistat was>99% bound to plasma proteins
(lipoproteins and albumin were major binding proteins). Orlistat minimally
partitioned into erythrocytes.<br/>Metabolism: Based on animal data, it is likely that the metabolism
of orlistat occurs mainly within the gastrointestinal wall. Based
on an oralC-orlistat mass balance study in obese patients,
two metabolites, M1 (4-member lactone ring hydrolyzed) and M3 (M1
with N-formyl leucine moiety cleaved), accounted for approximately
42% of total radioactivity in plasma. M1 and M3 have an open��-lactone
ring and extremely weak lipase inhibitory activity (1000- and 2500-fold
less than orlistat, respectively). In view of this low inhibitory
activity and the low plasma levels at the therapeutic dose (average
of 26 ng/mL and 108 ng/mL for M1 and M3, respectively, 2 to 4 hours
after a dose), these metabolites are considered pharmacologically
inconsequential. The primary metabolite M1 had a short half-life (approximately
3 hours) whereas the secondary metabolite M3 disappeared at a slower
rate (half-life approximately 13.5 hours). In obese patients, steady-state
plasma levels of M1, but not M3, increased in proportion to orlistat
doses.<br/>Elimination: Following a single oral dose of 360 mgC-orlistat in both normal weight and obese subjects, fecal excretion
of the unabsorbed drug was found to be the major route of elimination.
Orlistat and its M1 and M3 metabolites were also subject to biliary
excretion. Approximately 97% of the administered radioactivity was
excreted in feces; 83% of that was found to be unchanged orlistat.
The cumulative renal excretion of total radioactivity was<2% of
the given dose of 360 mgC-orlistat. The time to reach
complete excretion (fecal plus urinary) was 3 to 5 days. The disposition
of orlistat appeared to be similar between normal weight and obese
subjects. Based on limited data, the half-life of the absorbed orlistat
is in the range of 1 to 2 hours.<br/>Special Populations: Because the drug is minimally absorbed, studies in
special populations (geriatric, different races, patients with renal
and hepatic insufficiency) were not conducted.<br/>Pediatrics: Plasma concentrations of orlistat and its metabolites
M1 and M3 were similar to those found in adults at the same dose level.
Daily fecal fat excretions were 27% and 7% of dietary intake in orlistat
and placebo treatment groups, respectively.<br/>Drug-Drug Interactions: Drug-drug interaction studies indicate that XENICAL
had no effect on pharmacokinetics and/or pharmacodynamics of alcohol,
digoxin, glyburide, nifedipine (extended-release tablets), oral contraceptives,
phenytoin, pravastatin, or warfarin. Alcohol did not affect the pharmacodynamics
of orlistat.<br/>Other Short-term Studies:<br/>Adults: In several studies of up to 6-weeks duration, the
effects of therapeutic doses of XENICAL on gastrointestinal and systemic
physiological processes were assessed in normal weight and obese subjects.
Postprandial cholecystokinin plasma concentrations were lowered after
multiple doses of XENICAL in two studies but not significantly different
from placebo in two other experiments. There were no clinically significant
changes observed in gallbladder motility, bile composition or lithogenicity,
or colonic cell proliferation rate, and no clinically significant
reduction of gastric emptying time or gastric acidity. In addition,
no effects on plasma triglyceride levels or systemic lipases were
observed with the administration of XENICAL in these studies. In a
3-week study of 28 healthy male volunteers, XENICAL (120 mg three
times a day) did not significantly affect the balance of calcium,
magnesium, phosphorus, zinc, copper,and iron.<br/>Pediatrics: In a 3-week study of 32 obese adolescents aged 12
to 16 years, XENICAL (120 mg three times a day) did not significantly
affect the balance of calcium, magnesium, phosphorus, zinc, or copper.
The iron balance was decreased by 64.7��mole/24 hours and 40.4��mole/24 hours in orlistat and placebo treatment groups, respectively.<br/>Dose-response Relationship: A simple maximum effect (E) model was
used to define the dose-response curve of the relationship between
XENICAL daily dose and fecal fat excretion as representative of gastrointestinal
lipase inhibition. The dose-response curve demonstrated a steep portion
for doses up to approximately 400 mg daily, followed by a plateau
for higher doses. At doses greater than 120 mg three times a day,
the percentage increase in effect was minimal.
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dailymed-instance:contraind... |
XENICAL is contraindicated in patients with chronic
malabsorption syndrome or cholestasis, and in patients with known
hypersensitivity to XENICAL or to any component of this product.
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dailymed-instance:supply |
XENICAL is a dark-blue, hard-gelatin capsule containing
pellets of powder. XENICAL 120 mg Capsules:
Dark-blue, two-piece, No. 1 opaque hard-gelatin capsule imprinted
with Roche and XENICAL 120 in light-blue ink���bottle of 90
(NDC 0004-0256-52).<br/>Storage Conditions: Store at 25��C (77��F); excursions permitted
to 15��to 30��C (59��to 86��F) [see USP Controlled
Room Temperature]. Keep bottle tightly closed. XENICAL should not be used after the given expiration date. 27899513 PI Revised: July 2008
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dailymed-instance:genericDr... | |
dailymed-instance:activeMoi... | |
dailymed-instance:inactiveI... |
dailymed-ingredient:FD&C_Blue_No._1,
dailymed-ingredient:FD&C_Blue_No._1_aluminum_lake,
dailymed-ingredient:gelatin,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:pharmaceutical_glaze,
dailymed-ingredient:povidone,
dailymed-ingredient:sodium_lauryl_sulfate,
dailymed-ingredient:sodium_starch_glycolate,
dailymed-ingredient:talc,
dailymed-ingredient:titanium_dioxide
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dailymed-instance:possibleD... | |
dailymed-instance:overdosag... |
Single doses of 800 mg XENICAL and multiple doses
of up to 400 mg three times a day for 15 days have been studied in
normal weight and obese subjects without significant adverse findings. Should a significant overdose of XENICAL occur, it is
recommended that the patient be observed for 24 hours. Based on human
and animal studies, systemic effects attributable to the lipase-inhibiting
properties of orlistat should be rapidly reversible.
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dailymed-instance:genericMe... |
orlistat
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dailymed-instance:fullName |
Xenical (Capsule)
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dailymed-instance:adverseRe... |
Commonly Observed (based on
first year and second year data - XENICAL 120 mg three times a day
versus placebo):: Gastrointestinal (GI) symptoms were the most commonly
observed treatment-emergent adverse events associated with the use
of XENICAL in the seven double-blind, placebo-controlled clinical
trials and are primarily a manifestation of the mechanism of action.
(Commonly observed is defined as an incidence of���5% and an
incidence in the XENICAL 120 mg group that is at least twice that
of placebo.) These and other commonly observed adverse reactions
were generally mild and transient, and they decreased during the second
year of treatment. In general, the first occurrence of these events
was within 3 months of starting therapy. Overall, approximately 50%
of all episodes of GI adverse events associated with orlistat treatment
lasted for less than 1 week, and a majority lasted for no more than
4 weeks. However, GI adverse events may occur in some individuals
over a period of 6 months or longer.<br/>Discontinuation of Treatment: In controlled clinical trials, 8.8% of patients treated
with XENICAL discontinued treatment due to adverse events, compared
with 5.0% of placebo-treated patients. For XENICAL, the most common
adverse events resulting in discontinuation of treatment were gastrointestinal.<br/>Incidence in Controlled Clinical
Trials: The following table lists other treatment-emergent
adverse events from seven multicenter, double-blind, placebo-controlled
clinical trials that occurred at a frequency of���2% among
patients treated with XENICAL 120 mg three times a day and with an
incidence that was greater than placebo during year 1 and year 2,
regardless of relationship to study medication. In the 4-year XENDOS study, the general pattern
of adverse events was similar to that reported for the 1- and 2-year
studies with the total incidence of gastrointestinal-related adverse
events occurring in year 1 decreasing each year over the 4-year period.<br/>Other
Clinical Studies or Postmarketing Surveillance: Rare cases of hypersensitivity have been reported
with the use of XENICAL. Signs and symptoms have included pruritus,
rash, urticaria, angioedema, bronchospasm and anaphylaxis. Very rare
cases of bullous eruption, increase in transaminases and in alkaline
phosphatase, and exceptional cases of hepatitis that may be serious
have been reported. No causal relationship or physiopathological mechanism
between hepatitis and orlistat therapy has been established. Reports
of decreased prothrombin, increased INR and unbalanced anticoagulanttreatment resulting in change of hemostatic parameters have been reported
in patients treated concomitantly with orlistat and anticoagulants.
Hypothyroidism has been reported in patients treated concomitantly
with orlistat and levothyroxine. Pancreatitis has been reported with
the use of XENICAL in postmarketing surveillance. No causal relationship
or physiopathological mechanism between pancreatitis and obesity therapy
has been definitively established. In clinical
trials in obese diabetic patients, hypoglycemia and abdominal distension
were also observed. Preliminary data from a
XENICAL and cyclosporine drug interaction study indicate a reduction
in cyclosporine plasma levels when XENICAL was coadministered with
cyclosporine .<br/>Pediatric Patients: In clinical trials with XENICAL in adolescent patients
ages 12 to 16 years, the profile of adverse reactions was generally
similar to that observed in adults.
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dailymed-instance:indicatio... |
XENICAL is indicated for obesity management including
weight loss and weight maintenance when used in conjunction with a
reduced-calorie diet. XENICAL is also indicated to reduce the risk
for weight regain after prior weight loss. XENICAL is indicated for
obese patients with an initial body mass index (BMI)���30 kg/mor���27 kg/min the presence of other
risk factors (eg, hypertension, diabetes, dyslipidemia). Table 8 illustrates body
mass index (BMI) according to a variety of weights and heights. The
BMI is calculated by dividing weight in kilograms by height in meters
squared. For example, a person who weighs 180 lbs and is 5'5" would
have a BMI of 30.
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dailymed-instance:name |
Xenical
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