 Xenical (orlistat)
orlistat 120mg capsule
Presentation
XENICAL 12Omg capsules have a turquoise cap and turquoise body with imprint of XENICAL ROCHE 120 on both the cap and body.
Uses
Actions
XENICAL is a potent, specific and long acting inhibitor of gastrointestinal
lipases. It exerts its therapeutic activity in the lumen of the stomach and
small intestine by forming a covalent bond with the active serine site of the
gastric and pancreatic lipases. The inactivated enzyme is thus unable to
hydrolyse dietary fat, in the form of triglycerides, into absorbable free fatty
acids and monoglycerides. As undigested triglycerides are not absorbed, the
resulting caloric deficit has a positive effect on weight control Systemic
absorption is therefore not needed for activity.
Single and repeated dose toxicity studies in rodents and dogs have
demonstrated a similar pattern of dose related effects across species, none of
which is considered relevant to the recommended use in man.
No orlistat associated mutagenicity or genotoxicity has been observed in a
standard battery of five different short-term assays.
Carcinogenicity studies in rats and mice have not shown a carcinogenic
potential for orlistat at doses up to 1000mg/kg/day and 1500mg/kg/day
respectively. These doses are 18Z and 125 times the daily human dose calculated
on a body surface area (mg/m') basis. There was a decreased incidence of mammary
fibroadenoma in female rats in the high dose group. No orlistat associated
adverse effects were observed in Segment I, II and III reproductive toxicity
studies at doses ranging 62-241 times the recommended clinical dose.
Pharmacokinetics
Absorbtion
Studies in normal weight and obese volunteers have shown that the extent of
absorption of orlistat was minimal. Plasma concentrations of intact orlistat
were non-measurable ( < 5 mg/ml) eight hours following oral administration of
orlistat. In general, at therapeutic doses, detection of intact orlistat in
plasma was sporadic and concentrations were extremely low (< 10 mg/ml or 0.02
pM), without evidence of accumulation, and consistent with negligible absorption.
Distribution
The volume of distribution cannot be determined because orlistat is minimally
absorbed and has no defined systemic pharmacokinetics. In vitro orlistat is
>99'/o bound to plasma proteins (lipoproteins and albumin were the major
binding proteins). Orlistat minimally partitions into erythrocytes.
Metabolism
Based on animal data, it is likely that the metabolism of orlistat occurs
mainly within the qastrointestinal wall. Based on a study in obese patients, of
the minute fraction of the dose that was absorbed systematically, two major
metabolites, M1 (4-member lactone ring hydrolysed) and M3 (M1 with N-formyl
leucine moiety cleaved), accounted for approximately 42% of the total plasrna
concentration. M1 arid M3 have an open E-lactone ring and extremely weak lipase
inhibitory activity (1000 and 2500 fold less than orlistat receptively). In view
of this low inhibitory activity and the low plasma levels al therapeutic doses (average
of 26 mg/ml and 108 mg/ml respectively), these metabolites are considered to be
pharmacologically inconsequential.
Elimination
Studies in normal weight and obese subjects have shown that faecal excretion
of the unabsorbed substance was the major route of elimination. Approximately
97% of the administered dose was excreted in faeces and 83% of that as unchanged
orlistat.
The cumulative renal excretion of total orlistat-related materials was < 2%
of the given dose. The time to reach complete excretion (faecal plus urinary)
was 3 to 5 days. The disposition of orlistat appeared to be similar between
normal weight and obese volunteers. Orlistat, M1 and M3 are all subject to
biliary excretion.
Indications
XENICAL is indicated for long-term treatment of significantly obese patients,
including patients with risk factors associated with obesity, in conjunction ion
with a mildly hypocaloric diet. XENICAL is effective in long-term weight control
(weight loss, weight maintenance and prevention of weight regain). Treatment
with XENICAL results in an improvement of risk factors and comorbidities
associated with obesity, including hypercholesterolemia non-insulin-dependent
diabetes mellitus (NIDDM), impaired glucose tolerance, hyperinsulinemia,
hypertension and in a reduction of visceral fat.
Dosage and Adminstration
Adults
The recommended dose of XENICAL is one I 20mg capsule with each main meal (
during or up to one hour after the meal). If a meal is missed or contains no fat,
the dose of XENICAL may be omitted. The therapeutic benefits of XENICAL (including
weight control and improvement of risk factors) are continued with long-term
administration.
The patient should be on a nutritionally balanced, mildly hypocaloric diet that
contains approximately 30% of calories from fat. It is recommended that the diet
should t>e rich in fruit and vegetables The daily intake of fat, carbohydrate
and protein should be distributed over three main meals. Doses above 120mg three
times daily have not been shown to provide additional benefit. No dose
adjustment is necessary for the geriatric patient. Based on faecal fat
measurements, the effect of XENICAL is seen as soon as Z4 to 48 hours after
dosing. Upon discontinuation of therapy, faecaI fat content usually returns to
pre-treatment levels, within 48 to 72 hours.
Hepaticand/or Renal Impariment
Dose adjustment is not required.
Children below the age of 18 years
The safety and efficacy of XENICAL in children have not been established.
Contraindications
XENICAL is contraindicated in patients with chronic malabsorption syndrome
and in patients with known hypersensitivity to orlistat or any of the other
components contained in the capsule.
Warnings And Precautions
No serious adverse reactions or safety hazards related to the use of XENICAL
have been reported to date during large, long-term clinical trials (3300
patients treated with XENICAL for up to 2 years) (see Adverse Effects). Patients
should be advised to adhere to dietary guidelines (see Dosage and
Administration). The possibility of experiencing gastrointestinal events (see
Adverse Effects) may increase when XENICAL is taken with a diet high in fat (e.g.
in a 2000 calorie/day diet, >30% of calories from fat equates to >67g of
fat) The daily intake of fat should be distributed over three main meals. If
XENICAL is taken with any one meal very high in fat, the possibility of
gastrointestinal effects may increase.
Use during pregnancy and lactation
The safety of XENICAL has not been established in pregnant women. In animal
reproductive studies no embryotoxic or teratogenic effects were observed that
were considered to be associated with XFNICAI. However, because animal studies
are not always predictive of human response, XENICAL should not be used during
pregnancy unless the potential benefit outweighs the potential risk. XI-NICAI
should not be taken by nursing women, because it is not known whether XENICAL is
secreted in human milk, unless the potential benefit outweighs the potential
risk.
Effect on ability to drive and use machines
No effects on the patient's ability to drive and use machines have been
reported.
Adverse Effects
The safety of orlistat has not been established beyond two years. Adverse.
reactions to XENICAL are largely gastrointestinal in nature and related to the
pharmacological effect of the substance on preventing the absorption of ingested
fat (see Actions). Commonly observed events are oily spotting, flatus with
discharge, faecal urgency, fatty/oily stool, oily evacuation, increased
defecation and faecal incontinence.
The incidence of these increases the higher the fat content of the diet and thus
faeces. Patients should be counseled as to the possibility of gastrointestinal
effects occurring and how best to handle them such as reinforcing the diet,
particularly the percentage of fat it contains. Consumption of a diet low in fat
will decrease the likelihood of experiencing adverse gastrointestinal events and
this may help patients monitor and regulate their fat intake. In clinical
studies, these pharmacological effects were not considered an impediment to
continuation of therapy. These adverse reactions are generally mild and
transient. Gastrointestinal events occurred early in treatment (within 3 months)
and most patients experienced only one episode. On y 3% of patients experienced
more than two episodes of any one adverse. event.
In a clinical programme with over 4,000 patients treated for up to Z years,
there were a total of 11 reports of breast cancer, all in women 45 years of age
or older. There were 10 reports of breast cancer in the XENICAL treated
subgroups (N=1063) and 1 in the placebo subgroup (N=579!. The total number of
patients reporting breast cancer was small but the, imbalance seen warranted
further evaluation. All study patients 45 years of age or older were followed up
and all available data were thorough y reviewed by independent clinical experts
in the fields of oncology, pathology, radiology and epiderniology. Follow up
revealed two more patients with breast cancer in a XENICAL group and two more in
the placebo group.
For 6 of the XENICAL patients, mammograms were available from before XENICAL
treatment had commenced and in 4 of these 6 it was possible to detect the lesion
when the mammogram was re-examined. Most cancers found were 25mm in diameter
and, as it takes 8 to 12 years for a cancer to grow from a single cell to 10mm,
it is clear that most tumors were pre-existing. A specific marker found in 9
tumors suggests the lesion was at least 5 years old. Of the 1Z patients treated
with XENICAL 1ZOmg, 60mg or 30mg found to have breast cancer, 9 had tumors which
were proved to have been pre-existing. Of the 3 patients treated with placebo
who were found to have breast cancer, one tumor was proven to have been
pre-existing.
In summary, there were 3 cases of breast cancer possibly related to therapy
in patients in the XFNICAL treatment groups (N=1063) and Z cases possibly
related to therapy in patients in the placebo treatment group (N=579).
Epidemiological data suggest that if XENICAL were a promoter of cancer, one
would expect to see other cancers, and if it were an enhance one would expect to
see increased growth around existing tumors. In neither case was this found. A
tabulation of the data is as follows:
Breast Cancer Cases
| Treatment Group |
Sub Group (N) Women >45years |
Actual |
Expected |
Add F/U |
Pre-existing |
Possibly Related |
| Xenical 120mg |
747 |
9 |
3.25 |
2 |
8 |
3 |
| Xenical 30mg/60mg |
316 |
1 |
1.13 |
0 |
1 |
0 |
| Placebo |
579 |
1 |
2.60 |
2 |
1 |
2 |
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