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Name of medicine
Orlistat 120mg capsule
Presentation
XENICAL 120mg 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 182 and 125 times the daily human dose calculated
on a body surface area (mg/m 2) 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 l, ll and Ill reproductive toxicity studies at
doses ranging 62-241 times the recommended clinical dose.
Absorption
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 ng/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 ng/ml or 0.02
mM), 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% 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 gastrointestinal wall. Based
on a study in obese patients, of the minute fraction of the
dose that was absorbed systemically, two major metabolises,
M1 (4-member lactone ring hydrolysed) and M3 (M1 with N-formyl
leucine moiety cleaved), accounted for approximately 42% of
the total plasma concentration.
M1and M3 have an open
b-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
at therapeutic doses (average of 26 ng/mL and 108 ng/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.
XENICAL is indicated for long-term treatment
of significantly obese patients, including patients with risk
factors associated with obesity, in conjunction 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.
Adults
The recommended dose of XENICAL is one 120mg 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 be rich in fruit and vegetables. The
daily intake of fat, carbohydrate and protein should be distributed
over three main meals. Doses above 120 mg 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 24 to 48 hours after dosing. Upon discontinuation
of therapy, faecal fat content usually returns to pre-treatment
levels, within 48 to 72 hours.
Hepatic and/or Renal
Impairment
Dose adjustment is not required.
Children below the
age of 18 years
The safety and efficacy of XENICAL in children have not been
established.
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.
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 XENICAL. 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. XENICAL 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.
Effects on ability
to drive and use machines
No effects on the patient's ability to drive and use machines
have been reported.
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 counselled 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. Only 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 2 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 thoroughly reviewed by independent clinical experts in
the fields of oncology, pathology, radiology and epidemiology.
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 tumours were pre-existing. A specific marker found
in 9 tumours suggests the lesion was at least 5 years old.
Of the 12 patients treated with XENICAL 120mg, 60mg or 30mg
found to have breast cancer, 9 had tumours which were proved
to have been pre-existing. Of the 3 patients treated with
placebo who were found to have breast cancer, one tumour was
proven to have been pre-existing.
In summary, there were
3 cases of breast cancer possibly related to therapy in patients
in the XENICAL treatment groups (N=1063) and 2 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 enhancer one would expect to see increased
growth around existing tumours. In neither case was this found.
Re-examination of the
pre-clinical data (doses 100 to 1,000 fold the human dose)
revealed a lower incidence of mammary tumours in female rats
on XENICAL than on placebo.
The expert review of
the additional data concluded that there was no evidence that
XENICAL or its metabolites, directly or indirectly, initiates,
promotes or enhances the growth of breast tumours.
There are no interactions with commonly prescribed
medications such as digoxin, phenytoin, warfarin, oral contraceptives,
nifedipine, nifedipine retard, glyburide, furosemide, captopril,
atenolol or alcohol.
However, orlistat enhanced
the bioavailability (plasma concentrations increased by approximately
30%) and lipid lowering effect of pravastatin.
In clinical studies,
a wide variety of concomitant medications were used without
evidence of clinically significant adverse interactions.
In pharmacokinetic interaction
studies, orlistat inhibited absorption of oral supplements
of some fat-soluble nutrients such as b-carotene (about one
third) and vitamin E acetate (about one-half) but not vitamin
A acetate or the nutritionally-derived levels of vitamin K.
During clinical studies
there were decreases in levels of some fat soluble vitamins
and analogues. The vast majority of patients in up to two
years of treatment had vitamin levels that stayed well within
normal range, and there was no evidence of clinical sequelae.
Weight loss induced by
XENICAL is accompanied by improved metabolic control in diabetics
which might allow or require reduction in the dose of oral
hyperglycaemic medication (e.g. sulfonylureas).
Overdose of XENICAL has not been established.
Single doses of 800mg XENICAL and multiple doses of up to 400mg
three times daily for 15 days have been studied in normal weight
and obese subjects without significant adverse findings. In
addition, doses of 240mg three times daily have been administered
to obese patients for 6 months. Doses above the recommended
dose of 120mg three times daily have not been found to appreciably
improve efficacy and may increase gastrointestinal events.
Should a significant
overdose of XENICAL occur, it is recommended that the patient
be observed for 24 hours. Based on human and animal studies,
any systemic effects attributable to the lipase inhibiting
properties of orlistat should be rapidly reversible.
Incompatibilities
Not applicable.
Shelf-life
Three years.
Special precautions
for storage
Store below 25°C and protect from moisture.
PVC/PE/PVDC blisters.
Prescription Medicine.
Pack Size
XENICAL 120mg 84's.
Capsule filling
Microcrystalline cellulose, sodium starch glycollate, povidone,
sodium lauryl sulphate and talc.
Capsule shell
Gelatine, indigo carmine (E132) and titanium dioxide (E171).
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