XENICAL 120mg capsules medication leaflet

Xenical 120 mg hard capsules

Each hard capsule contains 120 mg orlistat.

For a full list of excipients, see 6.1.

Hard capsule.

The capsule has a turquoise cap and turquoise body bearing the imprint of “XENICAL 120”.

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.

Treatment with orlistat should be discontinued after 12 weeks if patients have been unable to lose atleast 5 % of the body weight as measured at the start of therapy.

The recommended dose of orlistat is one 120 mg capsule taken with water immediately before, duringor up to one hour after each main meal. If a meal is missed or contains no fat, the dose of orlistatshould be omitted.

The patient should be on a nutritionally balanced, mildly hypocaloric diet that contains approximately30 % of calories from fat. It is recommended that the diet should be rich in fruit and vegetables. Thedaily intake of fat, carbohydrate and protein should be distributed over three main meals.

Doses of orlistat above 120 mg three times daily have not been shown to provide additional benefit.

The effect of orlistat results in an increase in faecal fat as early as 24 to 48 hours after dosing. Upondiscontinuation of therapy, faecal fat content usually returns to pre-treatment levels, within 48 to 72hours.

The effect of orlistat in patients with hepatic and/or renal impairment, children and elderly patients hasnot been studied.

There is no relevant indication for use of Xenical in children.

- Hypersensitivity to the active substance or to any of the excipients.

- Chronic malabsorption syndrome.

- Cholestasis.

- Breast-feeding.

In clinical trials, the decrease in bodyweight with orlistat treatment was less in type II diabetic patientsthan in non-diabetic patients. Antidiabetic medicinal product treatment may have to be closelymonitored when taking orlistat.

Co-administration of orlistat with ciclosporin is not recommended (see section 4.5).

Patients should be advised to adhere to the dietary recommendations they are given (see section 4.2).

The possibility of experiencing gastrointestinal adverse reactions (see section 4.8) may increase whenorlistat is taken with a diet high in fat (e.g. in a 2000 kcal/day diet, > 30 % of calories from fat equatesto > 67 g of fat). The daily intake of fat should be distributed over three main meals. If orlistat is takenwith a meal very high in fat, the possibility of gastrointestinal adverse reactions may increase.

Cases of rectal bleeding have been reported with Xenical. Prescribers should investigate further incase of severe and/or persistent symptoms.

The use of an additional contraceptive method is recommended to prevent possible failure of oralcontraception that could occur in case of severe diarrhoea (see section 4.5).

Coagulation parameters should be monitored in patients treated with concomitant oral anticoagulants(see section 4.5 and 4.8).

The use of orlistat may be associated with hyperoxaluria and oxalate nephropathy leading sometimesto renal failure. This risk is increased in patients with underlying chronic kidney disease and/orvolume depletion (see section 4.8).

Rare occurrence of hypothyroidism and/or reduced control of hypothyroidism may occur. Themechanism, although not proven, may involve a decreased absorption of iodine salts and/orlevothyroxine (see section 4.5).

Antiepileptics patient: Orlistat may unbalance anticonvulsant treatment by decreasing the absorptionof antiepileptic drugs, leading to convulsions (see section 4.5).

Antiretrovirals for HIV: Orlistat may potentially reduce the absorption of antiretroviral medicines for

HIV and could negatively affect the efficacy of antiretroviral medications for HIV (see section 4.5).

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially‘sodium-free’.

A decrease in ciclosporin plasma levels has been observed in a drug-drug-interaction study and alsoreported in several cases, when orlistat was administered concomitantly. This can lead to a decrease ofimmunosuppressive efficacy. Therefore the combination is not recommended (see section 4.4).

However, if such concomitant use is unavoidable, more frequent monitoring of ciclosporin bloodlevels should be performed both after addition of orlistat and upon discontinuation of orlistat inciclosporin treated patients. Ciclosporin blood levels should be monitored until stabilised.

Acarbose

In the absence of pharmacokinetic interaction studies, the concomitant administration of orlistat withacarbose should be avoided.

Oral anticoagulants

When warfarin or other anticoagulants are given in combination with orlistat, international normalisedratio (INR) values should be monitored (see section 4.4).

Fat soluble vitamins

Treatment with orlistat may potentially impair the absorption of fat-soluble vitamins (A, D, E and K).

The vast majority of patients receiving up to four full years of treatment with orlistat in clinical studieshad vitamin A, D, E and K and beta-carotene levels that stayed within normal range. In order to ensureadequate nutrition, patients on a weight control diet should be advised to have a diet rich in fruit andvegetables and use of a multivitamin supplement could be considered. If a multivitamin supplement isrecommended, it should be taken at least two hours after the administration of orlistat or at bedtime.

Amiodarone

A slight decrease in plasma levels of amiodarone, when given as a single dose, has been observed in alimited number of healthy volunteers who received orlistat concomitantly. In patients receivingamiodarone treatment, the clinical relevance of this effect remains unknown but may becomeclinically relevant in some cases. In patients receiving concomitant amiodarone treatment,reinforcement of clinical and ECG monitoring is warranted.

Convulsions have been reported in patients treated concomitantly with orlistat and antiepileptic drugse.g. valproate, lamotrigine, for which a causal relationship to an interaction cannot be excluded.

Therefore, these patients should be monitored for possible changes in the frequency and/or severity ofconvulsions.

Rare occurrence of hypothyroidism and/or reduced control of hypothyroidism may occur. Themechanism, although not proven, may involve a decreased absorption of iodine salts and/orlevothyroxine (see section 4.4).

There are some case reports of reduced efficacy of antiretroviral HIV medicines, antidepressantsantipsychotics (including lithium) and benzodiazepines coincidental to the initiation of orlistattreatment in previously well-controlled patients. Therefore orlistat treatment should only be initiatedafter careful consideration of the possible impact in these patients.

Lack of interactions

No interactions with amitriptyline, atorvastatin, biguanides, digoxin, fibrates, fluoxetine, losartan,phenytoin, phentermine, pravastatin, nifedipine Gastrointestinal Therapeutic System (GITS),nifedipine slow release, sibutramine or alcohol have been observed. The absence of these interactionshas been demonstrated in specific drug-drug-interaction studies.

The absence of an interaction between oral contraceptives and orlistat has been demonstrated inspecific drug-drug interaction studies. However, orlistat may indirectly reduce the availability of oralcontraceptives and lead to unexpected pregnancies in some individual cases. An additionalcontraceptive method is recommended in case of severe diarrhoea (see section 4.4).

For orlistat no clinical data on exposed pregnancies are available.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,embryonal/foetal development, parturition or postnatal development (see section 5.3).

Caution should be exercised when prescribing to pregnant women.

As it is not known whether orlistat is secreted into human milk, orlistat is contra-indicated duringbreast-feeding.

Xenical has no influence on the ability to drive and use machines.

Adverse reactions to orlistat are largely gastrointestinal in nature. The incidence of adverse eventsdecreased with prolonged use of orlistat.

Adverse events are listed below by system organ class and frequency. Frequencies are defined as:very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000to <1/1,000) and very rare (<1/10,000) including isolated reports.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The following table of undesirable effects (first year of treatment) is based on adverse events thatoccurred at a frequency of > 2 % and with an incidence ≥ 1 % above placebo in clinical trials of 1 and2 years duration:

System organ class Adverse reaction/event

Very common: Headache

Very common: Upper respiratory infection

Common: Lower respiratory infection

Very common: Abdominal pain/discomfort

Oily spotting from the rectum

Flatus with discharge

Faecal urgency

Fatty/oily stool

Flatulence

Liquid stools

Oily evacuation

Increased defecation

Common: Rectal pain/discomfort

Soft stools

Faecal incontinence

Abdominal distension*

Tooth disorder

Gingival disorder

Common: Urinary tract infection

Very common: Hypoglycemia*

Very common: Influenza

General disorders and administration siteconditions

Common: Fatigue

Common: Menstrual irregularity

Common: Anxiety

* only unique treatment adverse events that occurred at a frequency of > 2 % and with an incidence≥ 1 % above placebo in obese type 2 diabetic patients.

In a 4 year clinical trial, the general pattern of adverse event distribution was similar to that reportedfor the 1 and 2 year studies with the total incidence of gastrointestinal related adverse events occurringin year 1 decreasing year on year over the four year period.

The following table of undesirable effects is based on post-marketing spontaneous reports, andtherefore the frequency remains unknown:

System organ class Adverse reaction

Increase in liver transaminases and in alkalinephosphatase.

Decreased prothrombin, increased INR andunbalanced anticoagulant treatment resulting invariations of haemostatic parameters have beenreported in patients treated with anticoagulants inassociation with orlistat (see section 4.4 and 4.5)

Gastrointestinal disorders Rectal bleeding

Diverticulitis

Bullous eruptions

Hypersensitivity (e.g. pruritus, rash, urticaria,angioedema, bronchospasm and anaphylaxis)

Hepatitis that may be serious. Some fatal cases orcases requiring liver transplantation have beenreported.

Renal and urinary disorders Oxalate nephropathy that may lead to renal failure

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V*.

Single doses of 800 mg orlistat and multiple doses of up to 400 mg three times daily for 15 days havebeen studied in normal weight and obese subjects without significant adverse findings. In addition,doses of 240 mg tid have been administered to obese patients for 6 months. The majority of orlistatoverdose cases received during post-marketing reported either no adverse events or adverse events thatare similar to those reported with recommended dose.

Should a significant overdose of orlistat occur, it is recommended that the patient be observed for 24hours. Based on human and animal studies, any systemic effects attributable to the lipase-inhibitingproperties of orlistat should be rapidly reversible.

Pharmaco-therapeutic group: Peripherally acting antiobesity agent, ATC code A08AB01.

Orlistat is a potent, specific and long-acting inhibitor of gastrointestinal lipases. It exerts its therapeuticactivity in the lumen of the stomach and small intestine by forming a covalent bond with the activeserine site of the gastric and pancreatic lipases. The inactivated enzyme is thus unavailable tohydrolyse dietary fat, in the form of triglycerides, into absorbable free fatty acids and monoglycerides.

In the 2-year studies and the 4-year study, a hypocaloric diet was used in association with treatment inboth the orlistat and the placebo treated groups.

Pooled data from five 2 year studies with orlistat and a hypocaloric diet showed that 37 % of orlistatpatients and 19 % of placebo patients demonstrated a loss of at least 5 % of their baseline body weightafter 12 weeks of treatment. Of these, 49 % of orlistat treated patients and 40 % of placebo treatedpatients went on to lose ≥ 10 % of their baseline body weight at one year. Conversely, of patientsfailing to demonstrate a loss of 5 % of their baseline body weight after 12 weeks of treatment, only5 % of orlistat treated patients and 2 % of placebo treated patients went on to lose ≥ 10 % of theirbaseline body weight at one year. Overall, after one year of treatment, the percentage of patientstaking 120 mg orlistat who lost 10 % or more of their body weight was 20 % with orlistat 120 mgcompared to 8 % of patients taking placebo. The mean difference in weight loss with the drugcompared to placebo was 3.2 kg.

Data from the 4-year XENDOS clinical trial showed that 60 % of orlistat patients and 35 % of placebopatients demonstrated a loss of at least 5 % of their baseline body weight after 12 weeks of treatment.

Of these, 62 % of orlistat treated patients and 52 % of placebo treated patients went on to lose ≥ 10 %of their baseline body weight at one year. Conversely, of patients failing to demonstrate a loss of 5 %of their baseline body weight after 12 weeks of treatment, only 5 % of orlistat treated patients and 4 %of placebo treated patients went on to lose ≥ 10 % of their baseline body weight at one year. After1 year of treatment, 41 % of the orlistat treated patients versus 21 % of placebo treated patients lost≥ 10 % of body weight with a mean difference of 4.4 kg between the two groups. After 4 years oftreatment 21 % of the orlistat treated patients compared to 10 % of the placebo treated patients had lost≥ 10 % of body weight, with a mean difference of 2.7 kg.

More patients on orlistat or placebo lost baseline body weight of at least 5 % at 12 weeks or 10 % atone year in the XENDOS study than in the five 2-year studies. The reason for this difference is that thefive 2-year studies included a 4-week diet and placebo lead-in period during which patients lost onaverage 2.6 kg prior to commencing treatment.

Data from the 4-year clinical trial also suggested that weight loss achieved with orlistat delayed thedevelopment of type 2 diabetes during the study (cumulative diabetes cases incidences: 3.4 % in theorlistat group compared to 5.4 % in the placebo-treated group). The great majority of diabetes casescame from the subgroup of patients with impaired glucose tolerance at baseline, which represented21 % of the randomised patients. It is not known whether these findings translate into long-termclinical benefits.

In obese type 2 diabetic patients insufficiently controlled by antidiabetic agents, data from four one-year clinical trials showed that the 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 fromplacebo in weight loss was 1.83 kg to 3.06 kg and the mean difference from placebo in HbA1creduction was 0.18 % to 0.55 %. It has not been demonstrated that the effect on HbA1c is independentfrom weight reduction.

In a multi-centre (US, Canada), parallel-group, double-blind, placebo-controlled study, 539 obeseadolescent patients were randomised to receive either 120 mg orlistat (n=357) or placebo (n=182)three times daily as an adjunct to a hypocaloric diet and exercise for 52 weeks. Both populationsreceived multivitamin supplements. The primary endpoint was the change in body mass index (BMI)from baseline to the end of the study.

The results were significantly superior in the orlistat group (difference in BMI of 0.86 kg/m2 in favourof orlistat). 9.5 % of the orlistat treated patients versus 3.3 % of the placebo treated patients lost≥ 10 % of body weight after 1 year with a mean difference of 2.6 kg between the two groups. Thedifference was driven by the outcome in the group of patients with ≥ 5 % weight loss after 12 weeks oftreatment with orlistat representing 19 % of the initial population. The side effects were generallysimilar to those observed in adults. However, there was an unexplained increase in the incidence ofbone fractures (6 % versus 2.8 % in the orlistat and placebo groups, respectively).

Studies in normal weight and obese volunteers have shown that the extent of absorption of orlistat wasminimal. Plasma concentrations of intact orlistat were non-measurable (< 5 ng/ml) eight hoursfollowing oral administration of orlistat.

In general, at therapeutic doses, detection of intact orlistat in plasma was sporadic and concentrationswere extremely low (< 10 ng/ml or 0.02 µmol), with no evidence of accumulation, which is consistentwith minimal absorption.

The volume of distribution cannot be determined because the drug is minimally absorbed and has nodefined systemic pharmacokinetics. In vitro orlistat is > 99 % bound to plasma proteins (lipoproteinsand albumin were the major binding proteins). Orlistat minimally partitions into erythrocytes.

Based on animal data, it is likely that the metabolism of orlistat occurs mainly within thegastrointestinal wall. Based on a study in obese patients, of the minimal fraction of the dose that wasabsorbed systemically, two major metabolites, M1 (4-member lactone ring hydrolysed) and M3 (M1with N-formyl leucine moiety cleaved), accounted for approximately 42 % of the total plasmaconcentration.

M1 and M3 have an open beta-lactone ring and extremely weak lipase inhibitory activity (1000 and2500 fold less than orlistat respectively). In view of this low inhibitory activity and the low plasmalevels at therapeutic doses (average of 26 ng/ml and 108 ng/ml respectively), these metabolites areconsidered to be pharmacologically inconsequential.

Studies in normal weight and obese subjects have shown that faecal excretion of the unabsorbed drugwas the major route of elimination. Approximately 97 % of the administered dose was excreted infaeces and 83 % of that as unchanged orlistat.

The cumulative renal excretion of total orlistat-related materials was < 2 % of the given dose. The timeto reach complete excretion (faecal plus urinary) was 3 to 5 days. The disposition of orlistat appearedto be similar between normal weight and obese volunteers. Orlistat, M1 and M3 are all subject tobiliary excretion.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity toreproduction.

In animal reproductive studies, no teratogenic effect was observed. In the absence of a teratogeniceffect in animals, no malformative effect is expected in man. To date, active substances responsible formalformations in man have been found teratogenic in animals when well-conducted studies wereperformed in two species.

Capsule filling:microcrystalline cellulose (E460)sodium starch glycolate (type A)povidone (E1201)sodium laurilsulfatetalc

Capsule shell:gelatineindigo carmine (E132)titanium dioxide (E171)edible printing ink (black iron oxide, ammonia solution concentrated, potassium hydroxide, shellac,propylene glycol)

Not applicable.

2 years.

Blisters: Do not store above 25 °C. Store in original package and keep the blister in the outer carton inorder to protect from light and moisture.

Bottles: Do not store above 30 °C. Keep the container tightly closed in order to protect from moisture.

PVC/ PVDC blisters containing 21, 42 and 84 hard capsules.

Glass bottles with desiccant containing 21, 42 and 84 hard capsules.

Not all pack sizes may be marketed.

No special requirements.

CHEPLAPHARM Arzneimittel GmbH

Ziegelhof 2417489 Greifswald

Germany

EU/1/98/071/001-006

Date of first authorisation: 29 July 1998

Date of latest renewal: 17 June 2008

Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu