SCIENTIFIC DISCUSSION
This module reflects the initial scientific discussion for the approval of Xenical. This scientificdiscussion has been updated until 1 November 2003. For information on changes after this dateplease refer to module 8B.
1.

Introduction

Obesity is a disease characterised by an excess body fat. It is often measured by calculation of the
body mass index (BMI), i.e. the body weight in kg divided by body surface area in m2. Individuals
may be regarded as obese with a BMI >25-27 kg/m² (depending on age). A number of concomitantpathological processes and diseases are associated with obesity including coronary heart disease,
hypertension, stroke, non-insulin dependent diabetes mellitus and certain forms of cancer. Besides
changes in diet, behaviour and physical activities, obesity may be treated by surgery or
pharmacological therapy. All currently available medicinal products for obesity treatment are appetite
suppressants (amphetamine-like products) that act via the central nervous system (CNS). However,they may not be prescribed during longer periods than 3 months, due to the potential risk of abuse.
Thus, there is a need for medicinal products that can be used in chronic treatment together with dietaryand behavioural modifications.
Orlistat belongs to a new class of pharmacological agents. It inhibits the action of gastrointestinal
lipases and thereby impairs the metabolism of lipids in the intestinal lumen leading to a prevention oflipid absorption.
Xenical is indicated in conjunction with a mildly hypocaloric diet for the treatment of obese patientswith a body mass index (BMI) greater or equal to 30 kg/m², or overweight patients (BMI > 28 kg/m²)
with associated risk factors. The treatment should only be started if diet alone has previously produced
a weight loss of at least 2.5 kg over a period of 4 consecutive weeks. Treatment with orlistat should be
discontinued after 12 weeks if patients have been unable to lose at least 5% of the body weight asmeasured at the start of drug therapy. The recommended dose of orlistat is one 120 mg capsule threetimes daily, which should be taken immediately before, during or up to one hour after each main meal.
2.

Chemical, pharmaceutical and biological aspects

Orlistat, a hydrogenated derivative of lipstatin and an inhibitor of gastrointestinal lipases produced bychemical synthesis, is presented as Xenical 120 mg capsules in different pack sizes.
Composition
Xenical is presented as a conventional hard gelatin capsule (size 1) containing pellets with an active
substance concentration of 50%. The excipients cellulose microcrystalline (as diluent andextrusion/spheronisation aid), sodium starch glycollate (as desintegrant), sodium lauryl sulphate (aswetting agent), povidone K30 (as binder and stabiliser), and talc is added (for lubrication) to thepellets before encapsulation.
Different clinical trial formulae and dosage strengths were used during Phase I-III studies.
Bioequivalence was demonstrated between the formulations and strengths used in the Phase I-III
studies and those proposed for marketing.
The different steps in the development of the marketing formulation are well described: satisfactory
details have been provided to justify and to optimise the retained form (hard gelatin capsules which
fulfil the various demands, i.e. drug load, technology and compliance), the formulation (the selectedconcentration of each excipients are correctly fixed). Process development has also been welldescribed and studied.
Method of preparation
The manufacturing process involves granulation, extrusion and spheronisation, drying, lubrication andencapsulation.
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All operating procedures comply with GMP. The choice of in-process controls and frequency of
testing ensure that the process is controlled, particularly with regard to the critical parameters. It isconsidered that the manufacturing process has been fully validated on both pilot and full scale batches,
and is reproducible.
Control of starting materials
Orlistat is a white to off-white crystalline powder. It is a lipophilic substance with very low solubility
in water within the physiological pH range. Two polymorphic forms have been found, A and B, but
only B is produced by the current synthetic route as defined in Part II of the dossier. Sixteen
stereoisomers are possible in theory, because of the four chiral centres.
In the early phase of the development, the synthetic route evolved from an “alpha-pyrone” synthesis toa “delta-lactone” synthesis. Pre-clinical studies were performed with orlistat obtained by these
prototype routes. Finally orlistat, as intended for marketing, is synthesised in a 5-step process using acontrolled stereoselective route (i.e. “the dihydropyrone” synthesis) ensuring consistent production of
only one of the possible stereoisomers in the desired physical form, B. The preclinical toxicity
programme showed there were no significant differences between the two polymorphs. Fourintermediates are isolated and controlled in this process.
Starting material specifications, in-process control of the key intermediates and release specifications
ensures the quality and the stereospecificity of synthesis. The chromatograms referring to the three
synthetic routes showed that the level of impurities in the chromatogram of “the dihydropyrone”
synthesis appears lower as compared to the other routes of synthesis. All raw materials and synthesis
intermediates are controlled according to suitable specifications and using specific and validated
methods, which are chirally selective where necessary.
Active substance
Orlistat is tested and released according to an in-house monograph. The active substance specification
includes tests for characterisation, identity, purity, assay, residual solvents, water, sulphated ash, heavy
metals and others. All potential organic impurities are detected using the combined chromatographic
systems, HPLC/GC/TLC. The validation of the analytical methods used is acceptable in relation to
ICH recommendations. The proposed specification limits are based on data arising from 50 pilot-scale
and 50 clinical batches made by the dihydropyrone synthesis, and on safety studies. Results of thesebatches confirm their consistent quality.
Other ingredients
All excipients comply with Ph. Eur. requirements. The capsule shells contain commonly used
excipients. The excipients and colouring agents in the capsule shell comply with the EEC
requirements.
The proposed standard containers are PVC/PE/PVDC/Alu blister packs, and amber glass bottles fittedwith a plastic screw closure and containing a desiccant unit. Essential verifications have been
performed for all materials and test results are satisfactory.
Control tests on the finished product
The specification includes standard tests for appearance, identification of the active substance (IR andHPLC), assay, determination of degradation impurities (HPLC-system I), dissolution test, and a
periodic microbial test performed according to the Ph. Eur. requirements. The dissolution specification
limit is 75% (Q) after 45 minutes. The limits for the total of all degradation products are set up to ≤0.5% at release and 2.0% at shelf life. The proposed specification for the control of the finishedproduct is suitable for assessing batch-to-batch consistency. Certificates of analysis for 3 pilot-scaleand 1 full-scale production batches demonstrate consistent quality of the finished product whenmanufactured according to the process defined in the dossier.
Stability of the product
The stability of the active substance, orlistat, obtained from different sources has been investigatedunder stressed conditions as well as under accelerated and long-term conditions. The stability results
show that a three year re-test period is acceptable when samples are stored below 30°C in perforated
low density polyethylene (LDPE) bags in closed metal drums gassed with nitrogen.
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However, long-term stability studies up to 3 years duration, without gassing, are on going. Until the
results are available, orlistat is stored in LDPE bags inside closed steel drums gassed with nitrogen.
Stability of the finished product has been studied on 4 batches stored in both blister packs and amberglass bottles for up to 18 months at 25°C/60%RH and up to 12 months at 30°C/75%RH; both pilot andproduction scale batches were included. In addition, supportive stability data with clinical batches, up
to 3 years in both packaging and up to 3 years in blisters, were provided. Appearance, impurities,
assay and dissolution test were monitored using stability-indicating methods. For the whole shelf-life
period, the assay limits of orlistat are maintained at 95-105% of the theoretical value, and the total
impurity limit should be set at 2.0% at shelf life.
The results showed no change in the capsules’ appearance and in dissolution rate after 45 minutes.
However, available stability data showed that the degradation products increased when the storage iscarried out at 30°C/75%RH, as expected. Degradation was less in glass bottles than in blisters, and ahigher storage temperature is therefore possible.
These results support the shelf-life and storage conditions for Xenical capsules as defined in the SPC,
i.e. three years when keep in a dry place and stored below 25°C in blister packs, and below 30°C in
glass bottles with desiccant.
3.

Toxico-pharmacological aspects

All pivotal preclinical studies were conducted in compliance with GLP and when applicable, in
accordance with internationally accepted guidelines.
Orlistat can exist in two crystalline forms, polymorphs A and B, which have similar physico-chemical
properties. Polymorph B is the more thermodynamically stable of the two polymorphs. It is the only
form used in the clinical development and is the form intended for marketing. Both forms were used in
the preclinical toxicity programme, and there were no significant differences between the twopolymorphs.
Pharmacodynamics
The pharmacodynamic action of orlistat has been studied in vitro and in vivo. Studies using different
in vitro enzyme preparations of mammalian source showed that orlistat was a specific, long lasting
inhibitor of a wide range of tri- and di-acylglycerol lipases. However, it had weak or no inhibitory
effects on other hydrolytic enzymes (e.g. acetylcholine esterase, liver carboxylesterase, α-amylase,trypsin, chymotrypsin, phospholipase A2) and it had only marginal effects on subsequent steps of fat
absorption. In the presence of emulsified triglycerides as substrate, inhibition was mainly determinedby the concentration of the drug in the lipid phase. After orlistat withdrawal, the lipase activity was
rapidly restored due to a continuous secretion of enzymes.
Using in vivo animal models, a dose dependent and rapidly reversible inhibition of triglyceride
absorption was demonstrated, with IC50 ranging from 1.4 (dog) to 67 (mouse) mg/kg body weight or
0.8 (dog) to 2.9 (mouse) mg/g dietary fat. The highest inhibitory effect was seen when the drug wasdissolved in dietary fat. The magnitude of inhibition did not change during long-term administration.
Effects on plasma and hepatic lipids varied between species, and a biphasic dose response wasobserved, with hypolipidaemia at low doses (effects on intestinal absorption) and hyperlipidemia at
higher doses (systemic effects).
Studies in animal models of obesity showed dose dependent reductions of body weight and body fat(e.g. genetically obese mice: 17% (weight), 21% (body fat) after 114 mg/kg/d for 43 days, geneticallyobese rats 15% (weight), 24% (body fat) after 42 mg/kg/d for 77 days). However, the predictability ofthese data for clinical efficacy and safety was regarded to be limited, since animals compensatedpartially for the loss of dietary fat by increased food intake.
Orlistat administration resulted in a non-physiologic phase of unabsorbed lipids in the intestine.
Consequently, absorption of apolar lipids was reduced (e.g. lipid soluble vitamins, carotenoids andcholesterol) while polar lipids (fatty acids, bile acids, phospholipids and retinol) were not affected.

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In vitro studies with the two main human metabolites (M1, M3) indicated that they had very weaklipase inhibitory effects.
The general pharmacology program did not indicate adverse effects on the central nervous,
cardiovascular, gastrointestinal- or immune systems or on systemic lipase metabolism after doses thatwere considered to be therapeutically relevant.
Pharmacokinetics
The pharmacokinetics of orlistat was studied in mouse, rat, rabbit and dog, the main species used in
the preclinical program. In all species, absorption after oral administration of C14-labelled orlistat waslow (1-22% depending on formulation and feeding state). Binding to albumin and lipoproteins washigh (>99%) in all species including humans. Distribution studies in rats given oral doses ofradiolabelled orlistat, showed the highest tissue levels of drug-related radioactivity in the liver andkidney after a single dose. After 30 days repeated oral administration, a 3-5 fold tissue accumulation
was observed in liver, kidney and fat. In pregnant rats, no placental transfer of drug-related
radioactivity to foetal tissues was observed. Excretion into milk has not been studied. The low
absorption of orlistat together with the occurrence of first pass metabolism resulted in a very low oral
bioavailability (<1%), and thus only minor amounts of unchanged orlistat reaching the systemic
circulation.
The fraction of orlistat that is absorbed undergoes extensive metabolism, with similar metabolic
patterns in the animal species studied and in humans. The major part of an oral C14-orlistat dose was
excreted in faeces (85-99% in rats and dogs). The remaining part of the dose was excreted inapproximately equal amounts via urine and bile. The excretion balance was similar after 2 years
administration of unlabelled orlistat to rats.
Overall, the pharmacokinetic profile of orlistat was similar in the animal species used for safetyassessment and in humans. Toxicokinetic data from animals given high doses in the toxicity studies
showed that the systemic exposure to orlistat and the two main human metabolites (M1 and M3) werehigher than that of humans given therapeutic doses.
Toxicology
Single dose toxicity of orlistat after oral administration was studied in mice, rats, young rats and dogs.
The acute toxicity was considered to be low, with no signs of toxicity after doses of 1000 mg/kg (dog,given pyramiding doses from 50-1000 mg/kg), 2000 mg/kg (2 week old rat) and 5000 mg/kg (rat,mouse).
Repeated dose toxicity of orlistat after oral administration was studied in mice (3 months duration),rats and dogs (up to 12 months duration). In all species, signs of toxicity were related to exaggerated
pharmacodynamic responses to orlistat i.e. inhibition of gastrointestinal lipases and at high doses,
inhibition of systemic lipases. Both rodents and dogs showed increased food intake without
concomitant increase in body weight gain. In rats given doses > 500 mg/kg/d, disturbances in the lipid
metabolism were evident, e.g. hypertriglyceridemia, hyperbilirubinemia and hypocholesterolemia andhistopathology showed lipidic infiltration in liver, heart, bone marrow and adrenal glands. A reduced
absorption of liposoluble vitamins (A, D3, E) was also evident in all species. The 24 months
carcinogenicity study in rats showed a similar pattern of toxicity together with an increased turnoverof red blood cells possibly due to lipemia-induced hemolysis. In rats and dogs, the non-toxic doselevels after 12 months administration, were 125 and 300 mg/kg/d, respectively. In rats, 25 mg/kg/d for
12 months did not affect lipid metabolism.
Reproductive toxicity of orlistat was studied in standard segment II, III studies and I with doses up to
400 mg/kg/d (I, III) and 800 mg/kg/d (II). Fertility studies in rats did not indicate impairment of maleor female reproductive functions. After administration of orlistat to rats and rabbits during theorganogenetic period, no teratogenicity or embryotoxicity were observed. Peri-post natal exposure ofdams and follow-up of offspring did not reveal any concern.
In a standard battery of in vitro and in vivo genotoxicity tests, orlistat lacked genotoxic potential.
Carcinogenicity was studied in mice and rats following 2 years of administration. In these studies,
there was no indication of drug-related neoplastic potential. Using a Proliferating Cell Nuclear
Antigen test, a dose and time dependent proliferation of rectal cells (rats at 500 mg/kg/d) and of
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colonic cells (male mice at 25 mg/kg/d, female mice 750 mg/kg/d) was revealed. Additional studies inrats fed a high fat and low calcium diet, revealed colonic mucosal proliferation without neoplasticchanges after up to 1-month administration. However, there were no orlistat-related changes in thecolonic mucosa after 3, 6 or 9 months administration.
A number of special toxicity studies did not reveal cause for concern with respect to local tolerance orantigenicity.
Summary and conclusion on preclinical pharmacology and toxicology
The pharmacological activity of orlistat results in partial inhibition of triglyceride absorption by
reducing hydrolysis and production of absorbable unesterified fatty acids and monoglycerides. Due tostructural similarities with triglycerides, orlistat interacts with the lipases in a substrate like manner.
Studies in animal models of obesity showed dose dependent reductions of body weight and body fat
although the predictability of these data for clinical efficacy and safety was considered to be limited.
The pharmacokinetic properties of orlistat were similar in the animal species used for safetyassessment and in humans. Overall, the toxicology program revealed effects mainly related to thepharmacodynamic action of orlistat, i.e. inhibition of lipases leading to fatty faeces, reduction of bodyweight gain, changes in triglycerides, bilirubin and cholesterol, and reduction of absorption ofliposoluble vitamins. No abnormalities were seen in reproductive toxicity or genotoxicity studies.
Carcinogenicity studies revealed proliferation of rectal or colonic mucosa, without any indication of
drug-related neoplastic potential.
4.

Clinical aspects

The marketing application is supported by adequately designed clinical studies, conducted andanalysed according to current GCP recommendations.
The core dossier consists of seven long-term (1 to 2 years) clinical trials**. They were double blind,comparative (vs. placebo and different dosages), randomised, multicentre trials aimed at evaluating theefficacy of orlistat combined with a hypocaloric diet in weight reduction and prevention of weightregain. The effects on obesity risk factors (lipids, blood pressure, fasting glucose, and insulin), vitaminlevels and faecal fat excretion were explored as secondary efficacy criteria.
The main characteristics of these studies are presented below:
Numberof studies
51

Phase

Treatments and dose schedule

Sample size

DesignIorlistat: from 50 to 360 mg

1004 subjects

19

I

orlistat: from 10 to 400 mg t.i.d.

308 subjects

10

II

7

III

1421 patients
10, 60, 120 mg (3 mos)30, 60, 120, 240 mg (6 mos)80, 160 mg (2 mos)
10, 30, 60, 120 mg (2 mos)PL run-in (1 to 6 mos), then PL or 4188 patients
30*, 60 or 120 mg t.i.d.

singledose,
open,pharmacokinetics
repeated dose, versus PL,
5- to 42 days duration
dose-ranging

DB, R, PG, PL, 1-yr or 2yr duration

DB= double blind; R= randomised; PG= parallel group; PL= placebo; t.i.d.= tris in die* only one study** BM14119B, NM 14302, NM14161, BM14149, NM14185, BM14119C and NM14336 (indiabetic patients)

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Clinical pharmacology
Pharmacodynamics
Orlistat belongs to a new class of pharmacological agents. Its mechanism of action is through the
inhibition of action of gastrointestinal lipase, impairing the metabolism of lipids in the intestinal lumen
and preventing absorption. Nineteen phase I trials have been carried out in order to elucidate themechanism of action in humans.
The degree of inhibition of dietary fat absorption was measured using faecal fat excretion in a
retrospective population-based meta-analysis. The activity is dose-dependent, with about 30% of
inhibition at the 120 mg dosage which plateaus at about 35% inhibition after doses greater than 400
mg t.i.d..
In clinical trials, fat excretion was approximately 2.6 g/24 h at day 1 compared to 23 g/24 h after 1year treatment with orlistat 120 mg t.i.d.. The mean change in 72-hour fat excretion fromrandomisation to the end of week 52 was 15.4 ± 12.1 g and 20.9 ± 15.1 g, after orlistat 60 mg and 120
mg t.i.d., respectively.
The effect of the drug on the colon, due to the excess of fat in faeces, was investigated in 12 obese
patients during 6 weeks of treatment with 120 mg t.i.d. and no increase in cell proliferation wasobserved.
Hepatobiliary physiology was extensively studied in phase I trials since the drug has been detected in
the bile even in small amounts. It was not affected by orlistat.
As in animal experiments the systemic absorption of orlistat is 10% or more when the drug is takenwith food, food interaction was investigated in faze I clinical trials in healthy volunteers. No increasein orlistat absorption was shown when the drug was taken with food. In addition, it was shown thatorlistat has no effect on systemic lipase activities.
An effect on intracellular lipases, which would in turn affect autacoids production and could hinder
the digestion, was also ruled out because orlistat is minimally absorbed from the gastrointestinal tractand its metabolites have poor lipase inhibitory activity.
Pharmacokinetics
Pharmacokinetics was investigated in 31 clinical studies and in other additional Phase I, II and III
studies, in which orlistat concentrations were measured.
The drug is absorbed to a minimal extent, with a Cmax in blood < 5 ng/ml. The drug is extensively
bound to plasma proteins, > 99%. Absolute bioavailability was not calculated because of the lack of an
acceptable intravenous formulation for human use. The drug is poorly excreted in urine (1.1 –4.1% of
the dose) and extensively in faeces (> 96% of the dose total and 83% of the dose unchanged). Biliary
concentrations of orlistat up to 43 ng/ml i.e. much higher than plasma concentrations show that thisdrug is partially excreted in the bile and may be subject to enterohepatic cycling. Two major
metabolites have been identified in plasma, M1 and M3, which are 1000- and 2500-fold less potent
than orlistat, respectively. The elimination half-life for orlistat, although not accurately measured
because of the low plasma concentrations, was estimated to be <2 h; more than 95% of theadministered dose was eliminated within 2-3 days.
The effect of orlistat in special populations (paediatric, elderly, hepatic and renal insufficiency) was
not investigated because of the low systemic exposure of orlistat. No data on secretion in human milk
were provided and, therefore, this lipophilic drug should be contraindicated in nursing mothers.
Interaction studies
Many drug interaction studies were undertaken to investigate the possible effect of orlistat treatment
on the pharmacokinetics of drugs with a narrow range therapeutic window and likely to beadministered concomitantly to orlistat.
Orlistat was shown not to alter the pharmacokinetics of digoxin, fibrates, phenytoin, warfarin,
nifedipine, alcohol and vitamin A. No interaction was noted with oral contraceptives.

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Pilot studies were performed to investigate the interaction of orlistat with furosemide, captopril,
atenolol and glyburide and no pharmacokinetic alteration was seen. It has to be underlined that orlistat
was not given at the proposed therapeutic dose and therefore no conclusions could be drawn.
Co-administration of orlistat with pravastatin increases after 10 days of administration by 26% theCmax and by 33% the AUC of pravastatin, which may result in an enhancement of dose related adverse
drug reactions. In absence of pharmacokinetic interaction studies, the concomitant administration oforlistat with fibrate, acarbose, biguanide and anorectic drugs is not recommended.
The impairment of the absorption of fat-soluble vitamins was investigated. It showed a nonstatistically significant decrease in fat-soluble vitamins; therefore the risk of deficiency in vitamin A
during long-term treatment with orlistat was not considered to be relevant. On the contrary, vitamins
D, E and β-carotene showed a statistically significant decrease after long-term treatment with the drugin combination with a diet. A slight decrease in vitamin K absorption might affect the prothrombin
time and might be detrimental to some patients. This is mentioned in the special warnings andprecautions for use section of the SPC.
An interaction study was performed with cyclosporin, which showed reductions in cyclosporin plasma
levels when combined with orlistat. Monitoring of cyclosporin plasma levels until stabilisation istherefore recommended in the section 4.4 of the SPC as well as in the package leaflet.
In January 2000, the section 4.4 of the SPC was updated regarding the interaction with cyclosporin
giving a recommendation to monitor cyclosporin plasma levels more frequently than usual whenorlistat is co-administered and to continue this monitoring when orlistat is discontinued
In November 2002, information was added to the section 4.5 of the SPC regarding interactions withother products. No interaction with amitriptyline, atorvastatin, biguanides, digoxin, fibrates,
fluoxetine, losartan, phenytoin, oral contraceptives, phentermine, pravastatin, and nifedipine GITS,
nifedipine slow release, sibutramine or alcohol have been observed. However, when given as a single
dose, a small decrease in plasma levels of amiodarone has been observed in a limited number ofhealthy volunteers who received orlistat concomitantly. The clinical relevance of this effect in patients
receiving amiodarone treatment remains unknown but may be of minor relevance, in patients
receiving concomitant amiodarone treatment, reinforcement of clinical and ECG monitoring iswarranted.
Clinical efficacy
Dose-response studies and main clinical studies
The efficacy of orlistat was investigated in 4 dose-ranging studies (phase II clinical trials) of 2- to 6months duration, comparing different doses, from 10 to 240 mg t.i.d., and in 7 long-term (1- to 2-years
duration) phase III clinical trials. The latter were double blind, randomised, multicentre, comparing
doses of 30, 60 and 120 mg t.i.d. versus placebo, aimed at evaluating the efficacy of orlistat combinedwith hypocaloric or eucaloric diet. All the studies were preceded by a 1-month run-in placebo period(except study NM 14336 with a 5 week run-in period and study NM 14302: 6-month run-in placebo)and were performed according to the same protocol:•

Inclusion criteria - BMI value between 28 and 43 kg/m2.

•

Efficacy criteria - The primary efficacy criterion was change in body weight (weight reduction
after a 1-year treatment and prevention of weight regain during the 2nd year of treatment). The
secondary efficacy criteria were related to obesity risk factors: lipids (total, LDL, HDL and
VLDL cholesterol; triglycerides); lipoprotein a, apoproteins A-1 and B; blood pressure, insulin
and glucose; anthropometric measurements, such as waist circumference, and quality of life.

•

Safety criteria - Undesirable effects related to its pharmacological effect: decreased systemic
absorption of lipophilic substances, e.g. fat-soluble vitamins; impairment of calcium and bonemetabolism; enhanced faecal fat excretion with increased amounts of fat in the colon.
Laboratory assessments of routine test of organs’ function.

•

Diet - A mild hypocaloric diet (<1500 kcal/day), containing approximately 30% of calories
from fat, was prescribed during the run-in period and the first year of treatment (except for
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study NM14302 where an eucaloric diet was given during the 1-year treatment period), then an
eucaloric diet was prescribed during the second year.
1.

Results - Primary efficacy criteria

After randomisation, the placebo-treated patients lost 2.6 kg, compared to 6.1 kg for the orlistattreated patients (refer to the table below on Primary efficacy criteria in pooled studies over 1 year).
The difference, calculated as least square mean difference (LSM, adjusted means on factors includedin the model: centre; stratum for weight loss after the run-in period or percentage of weight loss;
interaction centre×stratum, centre×treatment and treatment×stratum) was –3.2 kg, and it was
statistically significant (p< 0.001).
Primary efficacy criteria in pooled studies over 1 year:
Orlistat 60 mg
Orlistat 120 mg
Placebo (n=1119)(n=452)(n=1561)
Initial body weight at
97.3
97.0
97.1
randomisation (kg)
Mean weight loss
-6.1
-2.6
LSM of difference
-2.6
-3.2
(kg)
p value<0.001<0.001
The clinical relevance of such a modest effect was questioned. After a formal request from the CPMP
and according to the “Note for guidance on clinical investigation of drugs used in weight control”, thecompany was requested to provide the percentage of the responders, i.e. ≥ 10% loss in body weight.
After 1 year of drug treatment (excluding the 4-weeks run-in period), 8.3% of the patients in theplacebo and 20.2% in the orlistat 120 mg group had a body weight loss ≥10%, which was statisticallysignificant.
The frequency of distribution of weight loss (≥ 5% and ≥ 10%), after 1-year orlistat therapy incomparison with placebo, is reported below (meta-analysis of 5 studies of the core dossier, excluding
the study in diabetic patients). The calculations were performed comparing the data after 1-year
treatment versus the baseline after the run-in period.
% of weight loss

All studies (except study in diabetics)• ≥ 5%• ≥ 10%Study in diabetics• ≥ 5%• ≥ 10%

Placebo (N= 1119)

Orlistat 120 mg (N= 1561)

p-value

23.4%
8.3%

45.3%
20.2%

< 0.001< 0.001

13.2%
4.4%

30.2%
9.3%

< 0.001=0.09

No clinically relevant difference was seen between the 60 and the 120-mg dosages (16.6% versus
20.2% weight loss ≥ 10%), although the absolute difference in weight loss of 0.6 kg was close tostatistical significance (p< 0.10).
In type II diabetic patients, the percentage of responders (≥ 10% of bodyweight loss in addition to thediet run-in period) was 9% with orlistat as compared to 4% with placebo. The mean difference inweight loss with the drug compared to placebo was – 2.1 kg in these patients.
The meta-analysis of mean change (LSM) in body weight (kg) from the second-year baseline to week
104 (weight regain during the second-year therapy without diet; studies NM14161, BM14149,
NM14185, BM14119C) showed that the patients in the placebo group gained +2.5 (± 4.3) kg, those inorlistat 60 mg t.i.d. +3.2 (± 4.3) kg and those in orlistat 120 mg gained +2.9 (± 4.5) kg. No difference
between groups was observed. After a 6-month period of diet alone where a 10 kg-loss was observed,
patients regained 3.0 kg with orlistat 120 mg and 5.1 kg with placebo respectively in the following
year without diet (study NM14302).
In order to select those patients likely to respond, as well as not to unduly expose patients to the drug,
the CPMP requested a two-step selection of patients. The patients who, despite an appropriate
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hypocaloric diet, were unable to lose more than 2.5 kg during 4 consecutive weeks should not betreated (negative predictive value=0.90, sensitivity=0.52 and specificity=0.61). After 12 weeks oftreatment, if the patient did not lose at least 5% of his/her body weight as measured at the start of drug
therapy, then the drug should be discontinued. These criteria (of losing at least 5% of body weightafter 12 weeks of therapy) have a positive predictive value=0.48, sensitivity=0.83 andspecificity=0.77.
2.

Results - Secondary efficacy criteria

The effect of 1-year treatment with orlistat on obesity-associated risk factors was analysed combining
all the core dossier studies (meta-analysis); the sub-group of responders (body weight loss ≥ 10%) was
also analysed. The data are summarised below:
Placebo *Initialvalue

Orlistat **diff. ′

p-value

Mean change

Initialvalue

Mean change

5.2
≥ 4.8

+ 0.2 (± 0.6)
+ 0.1 (± 0.7)

5.1
5.0

- 0.1 (± 0.7)
- 0.3 (± 0.7)

- 0.3
- 0.3

< 0.001< 0.001

3.4≥ 3.1+ 0.1 (± 0.5)
- 0.04 (± 0.6)

3.3
3.3

- 0.2 (± 0.6)
- 0.3 (± 0.6)

- 0.3
- 0.3

< 0.001< 0.0011.2≥ 1.1+ 0.1 (± 0.2)
+ 0.3 (± 0.2)

1.2
1.1

+ 0.1 (± 0.2)
+ 0.2 (± 0.2)

- 0.03- 0.1< 0.001< 0.001

1.6≥ 1.3- 0.03 (± 0.7)
- 0.2 (± 0.5)

1.5
1.5

- 0.05 (± 0.8)
- 0.3 (± 1.1)

-0.02
+ 0.08

0.37
0.08

123.7
≥ 120.0+ 0.6 (± 13.7)- 3.0 (± 14.0)

122.6
122.5

- 1.0 (± 13.6)- 3.8 (± 12.5)

- 1.0
+ 1.0

0.021
0.44

79.2
≥ 77.1+ 0.5 (± 9.4)
- 1.6 (± 9.5)

78.7
78.7

- 1.2 (± 9.2)
- 4.2 (± 9.1)

- 1.5
- 1.5

0.001
0.13

5.7
≥ 5.4

0.0 (± 0.6)
- 0.1 (± 0.5)

5.6
5.6

- 0.04 (± 0.6)
- 0.2 (± 0.5)

- 0.07- 0.03

0.001
0.48

95.5
≥ 83.1+ 24.0 (± 129.4)- 14.6 (± 53.1)

92.2
82.0

- 18.6 (± 66.5)- 18.6 (± 66.5)

- 9.6
- 3.7

0.002
0.37

Total cholesterol (mmol/l)-

globalbody weight loss
10%
LDL (mmol/l)- global- body weight loss
10%
HDL (mmol/l)- global- body weight loss
10%
Triglycerides (mmol/l)- global- body weight loss
10%
Systolic (mm Hg)- global- body weight loss
10%
Diastolic (mm Hg)- global- body weight loss
10%
glucose (mmol/l)- global- body weight loss
10%
insulin (mmol/l)- global- body weight loss
10%*

placebo N.~900 (global ); N.~90 (body weight loss ≥ 10%)**orlistat 120 mg t.i.d. N.~1300 (global); N= 300 (body weight loss ≥ 10%)
figures have been rounded up′
Mean change in obesity-related risk factors was also analysed in a subgroup of patients with abnormal
initial values (all the patients and a subgroup of responders). The results are presented below:
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diff. ′p-value- 0.3 (± 0.6)
- 0.6 (± 0.6)

- 0.3
- 0.3

< 0.001= 0.0050.8
0.8+ 0.1 (± 0.1)
+ 0.2 (± 0.1)

0.0
- 0.01= 0.87= 0.79- 0.7 (± 1.6)
- 1.7 (± 0.4)

3.6
4.5

- 0.6 (± 2.0)
- 2.5 (± 4.4)

+ 0.2
- 0.3

= 0.16= 0.2894.0
92.1- 5.4 (± 9.1)
- 11.0 (± 9.1)

93.7
94.0

- 7.9 (± 8.2)
- 11.0 (± 7.6)

- 1.9
+ 2.3

= 0.06= 0.43

global146.2
body weight loss ≥ 141.5
10%- 6.4 (± 118.5)- 25.8 (± 90.2)

144.4
132.3

- 23.8 (± 142.9)- 42.9 (± 106.4)- 19.7- 7.3= 0.02= 0.42

Placebo *Orlistat **Initialvalue

Mean change

Initialvalue

Mean change

4.1
4.0

+ 0.02 (± 0.6)
- 0.2 (± 0.8)

4.1
4.0

0.8
0.8

+ 0.2 (± 0.1)
+ 0.2 (± 0.1)

3.5
3.4

LDL (≥ 3.362 mmol/l)-

globalbody weight loss ≥10%
HDL (<0.905 mmol/l)- global- body weight loss ≥10%
Triglycerides(≥ 2.54 mmol/l)- global- body weight loss ≥10%
Diastolic (≥ 90 mm Hg)- global- body weight loss ≥10%
insulin (≥ 90 mmol/l)*

Total number of patient with abnormal values in the placebo group: LDL (N= 506),
HDL (N= 213), triglycerides (N= 105), diastolic blood pressure (N= 197) and insulin (N= 392)** Total number of patient with abnormal values in the orlistat group: LDL (N= 648), HDL (N=294), triglycerides (N= 138), diastolic blood pressure (N= 222) and insulin (N= 560)
* Number of patient responders (body weight loss ≥ 10%) with abnormal values in the placebogroup: LDL (N= 32), HDL (N= 20), triglycerides (N= 4), diastolic blood pressure (N= 13) andinsulin (N= 30)**

Number of patient responders (body weight loss ≥ 10%) with abnormal values in the orlistat group: LDL(N= 138), HDL (N= 76), triglycerides (N= 15), diastolic blood pressure (N= 38) and insulin (N= 99)′

figures have been rounded up.

Clinical studies in special populations
No specific effect of orlistat on obesity-related risk factors was shown other than that due to bodyweight loss. In the study in diabetic patients (subgroup of responders), the obesity-related risk factors
were not modified by treatment: glucose decreased by 1.3 (± 1.2) mmol/l and 0.8 (± 1.3) mmol/l after
1 year treatment with placebo and orlistat 120 t.i.d., respectively. Insulin decreased by 72.9 (±82.4)
pmol/l after 1 year treatment with placebo and by 56.9 (± 57.7) pmol/l after 1 year treatment withorlistat 120 t.i.d.. No statistically significant difference between groups was detected.
Supportive studies
The clinical benefit, in terms of cardiovascular parameters, was not clearly demonstrated in the
responders, although a slight improvement was observed in systolic and diastolic blood pressure: -3.8
and – 4.2 mm Hg, respectively.
The quality of life, although subjective and difficult to interpret, seemed to improve after 1 year 120
mg t.i.d orlistat treatment. Overweight distress, depression, satisfaction with treatment and self-regard
improved in comparison with placebo (at least p < 0.04).

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Clinical safety
Patient exposure
The safety assessment was based on over 4800 patients receiving at least one dose of orlistat.
Approximately 2150 patients received orlistat for at least one year and 880 for two years. The total
percentage of premature withdrawals over the first year, whatever the reason, was 35.3% in theplacebo group, 25.3% in the orlistat 30-mg t.i.d., 26.0% in the orlistat 60-mg t.i.d. and 29.1% in theorlistat 120 mg t.i.d.. The highest number of patients who dropped out as treatment failure and werelost to follow-up was recorded in the placebo group, while the orlistat group(s) had the highest
incidence of patients withdrawn for adverse drug events:
Reason forwithdrawal
Adverse events
Treatment failure
Lost to follow-up
Other
Total

Placebo(N= 1466)
4.9%
2.6%
9.8%
18.0%
35.3%

Orlistat 30 mg Orlistat 60 mg Orlistat 120 mg
t.i.d. (N= 186)
t.i.d. (N= 623)
t.i.d. (N= 1913)
9.7%
6.9%
8.8%
1.1%
1.6%
1.0%
5.4%
6.1%
7.7%
9.2%
11.4%
11.6%
25.3%
26.0%
29.1%

Adverse events and serious adverse events/deaths
In the phase III studies, approximately 6% of the patients (total number = 2722) reported serious
adverse events (AE) over one year in both orlistat (all tested dose schedules) and placebo groups. The
body systems showing the most serious AEs were: reproductive female disorders, body as a whole,gastrointestinal system disorders and musculo-skeletal system disorders. Hypersensitivity reactions
have been reported post marketing.
According to the mechanism of action of the drug, the major safety concern is the gastrointestinal
tolerability of the drug, notably oily spotting from the rectum, flatus with discharge, faecal urgency,
fatty/oil stool, oil stool, oily evacuation, increased defecation and faecal incontinence. Although they
were rarely serious and a cause for premature discontinuation from the study, they were 10- to 20-foldmore frequent with orlistat than with placebo. The respective percentages of oily spotting from therectum were: 18.8% with orlistat 60 mg t.i.d., 26.6% with orlistat 120 mg t.i.d. and 1.3% with placebo;
the respective percentages of flatus with discharge were: 18.85% with orlistat 60 mg t.i.d., 23.9% withorlistat 120 mg t.i.d. and 1.4% with placebo. Faecal urgency was 3 times higher in the orlistat groups:
20.2% with orlistat 60 mg t.i.d., 22.1% with orlistat 120 mg t.i.d. and 6.7% with placebo. These
adverse drug reactions (ADR) were dose-dependent, higher and more severe in comparison withplacebo.
During the second year of treatment, however, the frequency of oily spotting from the rectum, flatus
with discharge and faecal urgency decreased from about 20.0% of the patients to about 4%. About
15% of the patients experienced gastrointestinal ADRs which lasted for more than 4 weeks; the datacollected and analysed according to the protocol do not provide sufficient information to judge
whether the ADRs were truly continuous or if they were individual episodes occurring on a weekly
basis.
Overall, the gastrointestinal ADRs remain the most common ADRs. As far as the other adverse events
recorded during the clinical trials are concerned, no difference in the safety profile between orlistat
and placebo was detected and no AE seemed to be dose-related. The biological tolerability of the drug,
tested by the routine laboratory examinations was good and no difference versus placebo was
observed with all the dose schedules tested.
Ten cases of breast cancer in the orlistat groups (60 and 120 mg t.i.d. doses) versus one in the placebo
were reported. During the evaluation phase, a follow-up survey found two new cases in the 120 mggroup and one in the placebo group. The data provided by the company were also analysed by a panelof experts appointed by the company. The observed cases were not evenly distributed across studies
and the histological types were different. No predictive elements have been found in the preclinicalstudies. In addition, the occurrence was too early in some cases (36 to 38 days from the beginning oftreatment) and the timing necessary to development of the tumor was not consistent with drug
exposure. Furthermore, direct toxicity is unlikely since the drug is negligibly absorbed. A detection
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bias was ruled out: women with breast cancer were not found having lost more weight than those
without tumors. However to rule out any promoting effect of the drug on the tumoral growth,
additional data will be produced from an ongoing 2-year study in Sweden, which is expected to
produce data on 3350 patients (estimate end in the year 2000). The protocol foresees a mammography
at entry, at one year, and at the end of the study.
The possibility of colonic cancer was raised in the view of increased lipid content in the colonic fecal
content and current epidemiological data linking human colon cancer and increased fat intake. The
review of recent available epidemiological evidence showed that the relationship between fat intake
and colon cancer is doubtful. Increased energy intake was incriminated as the main risk factor whereas
fat intake could be a confounding factor, taking into account the fact that the drug is neither genotoxic,
nor carcinogenic and that clinical data in the exposed population did not indicate a risk of coloncancer.
Laboratory findings
The following table presents the mean changes in the absorption of fat-soluble vitamins in the trials
with the non-US patients after 2-year treatment with orlistat 120 mg t.i.d.:
Vitamins (reference
interval)
vitamin A (1.58-3.97µmol/l)β-carotene (0.09-1.06µmol/l)vitamin D (18-121
nmol/l)vitamin E (18.1-50.6µmol/l)Placebo
Initial
value
2.4

diff.

p-value- 0.01 (± 0.5)

Orlistat 120mg
InitialMean change
value
2.5
- 0.1 (± 0.5)

- 0.07= 0.100.4+ 0.04 (± 0.3)

0.4

- 0. 1 (± 0.4)

- 0.1

< 0.001

60.1+ 4.4 (± 20.7)

60.3- 4.5 (± 21.9)- 8.2< 0.001

27.6+ 3.1 (± 4.5)

28.4

- 0.7 (± 7.0)

- 3.0

< 0.001

Mean change

The decreases observed were clinically relevant for β-carotene, vitamin E, and vitamin D. The decline
in 25-OH-D resulted in no detectable changes in calcium or bone metabolism. In a subgroup ofpatients plasma calcium and parathyroid hormone levels showed no change (total and ionised calcium)or a slight decrease (parathyroid hormone), from 33.2 to 31.5 ng/l, in comparison with placebo, from
32.5 to 31.9, remaining, however, in the reference interval (13.3-60.2 ng/l). Another evidence of theabsence of metabolic and clinical consequences on calcium and bone metabolism was offered by thedata on bone mineral content and density performed in 40 patients (14 with placebo and 16 withorlistat 120 mg t.i.d.), which did show any difference between day 1 and day 52 neither intra- nor
between group. Due to these changes in vitamin D, E, and β-carotene levels, the SPC mentions thatmultivitamin supplementation may be considered.
Safety in special populations
Analysis of estrogen levels resulting from 80 postmenopausal women indicated no significant
difference in estrogen changes from baseline for orlistat group or placebo.
Efficacy and safety discussion
After 1-year treatment with orlistat (120 mg t.i.d.) in association with a mild hypocaloric diet, amodest effect of orlistat on body weight was observed. The mean effect at one year was –3.2 kg
weight loss as compared to placebo. Patients who lose more than 10% of their body weight wereconsidered responders. Responder rates were 8% in the placebo group as compared to 20% in orlistat
120 mg group. During the second year, orlistat associated with a eucaloric diet did not prevent weightregain. The drug was less effective in type II diabetes. No specific effect of orlistat on obesity related
risk factors was shown.
The gastrointestinal ADRs remain the most common ADRs. Due to the changes in vitamin D, E, andβ-carotene levels, the SPC mentions that multivitamin supplementation may be considered. Breast
cancer occurrence was likely to be a chance finding. To rule out any promoting effect of orlistat on the

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tumour growth, additional data are requested to the company from the ongoing 2-year study in
Sweden.
Moreover, in order to select those patients likely to respond, as well as not to unduly expose patientsto the medicinal product, the CPMP requested a two-step selection of patients. The patients who,
despite an appropriate hypocaloric diet, were unable to lose more than 2.5 kg over a period of 4
consecutive weeks should not be treated. After 12 weeks of treatment, if the patient does not lose atleast 5% of his/her body weight as measured at the start of drug therapy, then the treatment withorlistat should be discontinued. As there are no safety and efficacy data beyond 2 years, the maximal
duration of treatment should not be longer than 2 years.
The majority of CPMP agreed that the mean effect of orlistat is modest. Some CPMP members held adivergent view. They considered the therapeutic effect of Xenical too small to be clinically relevant,whereas the adverse events are incompletely understood, especially concerning breast cancer.
However, the majority of the CPMP considered that, although modest, this effect is clinically relevant,and it was also recognised that currently there is no safe medicinal product for long-term treatment ofobesity available.
In July 1999, the section 4.8 of the SPC was updated to with information that rare cases ofhypersensitivity have been reported and that main clinical symptoms are pruritus, rash, urticaria,
angioedema and anaphylaxis.
In January 2001, the section 4.8 of the SPC was updated to include information on that in very rarecases an increase in liver transaminases and in alkaline phophatase have been reported during the post
marketing phase.
In June 2001, the section 4.8 of the SPC was updated with information that very rare cases of bullous
eruptions having been reported during post marketing phase.
In March 2002, the section 5.1 of the SPC was updated to include information on obese type 2 diabetic
patients insufficiently controlled by antidiabetics. Data from four one-year clinical trials showed thatthe percentage of responders (≥10% of body weight loss) was 11.3% with orlistat as compared to
4.5% with placebo. In orlistat-treated patients, the mean difference from placebo in weight loss was
1.83 kg to 3.06 kg and the mean difference from placebo in HbA1c reduction was 0.18 % to 0.55%. It
has not been demonstrated that the effect on HbA1c is independent from weight reduction.
5. Overall conclusions and benefit/risk assessment
Benefit/risk assessment
The quality of orlistat 120 mg capsules, as demonstrated in the chemical and pharmaceutical
documentation is considered acceptable.
The pharmacological activity of orlistat has been shown in animals and man to inhibit, proportionallywith the dose, the action of gastrointestinal lipase, impairing the metabolism of lipids in the intestinal
lumen and preventing absorption.
The clinical data provided showed, in obese patients with an initial body weight of about 100 kg, a
modest effect of orlistat on body weight after 1-year treatment in association with a mild hypocaloric
diet, and no specific effects on obesity-associated risk factors. At one year, the mean effect was –3.2
kg weight loss as compared to placebo. The percentage of patients losing at least 10% of their initial
body weight after the start of medicinal treatment was 20.2% and 8.3% in the orlistat 120 mg andplacebo-treated groups, respectively. During the second year orlistat associated with a eucaloric diet
did not prevent weight regain. The overall safety issues have been adequately addressed andappropriate warnings and precautions have been included in the SPC. With regards to the occurrenceof breast cancer, it was likely to be a chance finding.
In order to select those patients likely to respond, as well as not to unduly expose patients to orlistat,
the patients who, despite an appropriate hypocaloric diet, were unable to lose more than 2.5 kg over a
period of 4 consecutive weeks should not be treated. After 12 weeks of treatment, if the patient does
not lose at least 5% of his/her body weight as measured at the start of drug therapy, and then the
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treatment with orlistat should be discontinued. The maximal duration of treatment should not belonger than 2 years. Moreover, to rule out any promoting effect of the medicinal product on thetumour growth, additional data from the ongoing 2-years study in Sweden are requested from thecompany.
CPMP recommendation
Therefore, the CPMP considered the benefit to risk assessment positive and the granting of aMarketing Authorisation was recommended for this medicinal product. At the time of the 5-year
renewal, the CPMP considered that the benefit/risk profile of Xenical continued to be favourable andrecommended the renewal of the Community Marketing Authorisation on 26 June 2003.

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