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Xenical 120mg hard capsules

1. Name Of The Medicinal Product

Xenical 120 mg hard capsules

2. Qualitative And Quantitative Composition

Each hard capsule contains 120 mg orlistat.

For a full list of excipients, see 6.1.

3. Pharmaceutical Form

Hard capsule.

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

4. Clinical Particulars

4.1 Therapeutic Indications

Xenical is indicated in conjunction with a mildly hypocaloric diet for the treatment of obese patients with a body mass index (BMI) greater or equal to 30 kg/m?, or overweight patients (BMI > 28 kg/m?) with associated risk factors.

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

4.2 Posology And Method Of Administration

Adults

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

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 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. Upon discontinuation of therapy, faecal fat content usually returns to pre-treatment levels, within 48 to 72 hours.

Special populations

The effect of orlistat in patients with hepatic and/or renal impairment, children and elderly patients has not been studied.

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

4.3 Contraindications

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

- Chronic malabsorption syndrome.

- Cholestasis.

- Breast-feeding.

4.4 Special Warnings And Precautions For Use

In clinical trials, the decrease in bodyweight with orlistat treatment was less in type II diabetic patients than in non-diabetic patients. Antidiabetic medicinal product treatment may have to be closely monitored 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 when orlistat is taken with a diet high in fat (e.g. in a 2000 kcal/day diet,> 30 % of calories from fat equates to> 67 g of fat). The daily intake of fat should be distributed over three main meals. If orlistat is taken with 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 in case of severe and/or persistent symptoms.

The use of an additional contraceptive method is recommended to prevent possible failure of oral contraception 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 in patients with underlying chronic kidney disease and/or volume depletion (see section 4.8).

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

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

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Ciclosporin

A decrease in ciclosporin plasma levels has been observed in a drug-drug-interaction study and also reported in several cases, when orlistat was administered concomitantly. This can lead to a decrease of immunosuppressive efficacy. Therefore the combination is not recommended (see section 4.4). However, if such concomitant use is unavoidable, more frequent monitoring of ciclosporin blood levels should be performed both after addition of orlistat and upon discontinuation of orlistat in ciclosporin treated patients. Ciclosporin blood levels should be monitored until stabilised.

Acarbose

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

Oral anticoagulants

When warfarin or other anticoagulants are given in combination with orlistat, international normalised ratio (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 studies had vitamin A, D, E and K and beta-carotene levels that stayed within normal range. In order to ensure adequate nutrition, patients on a weight control diet should be advised to have a diet rich in fruit and vegetables and use of a multivitamin supplement could be considered. If a multivitamin supplement is recommended, 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 a limited number of healthy volunteers who received orlistat concomitantly. In patients receiving amiodarone treatment, the clinical relevance of this effect remains unknown but may become clinically 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 drugs e.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 of convulsions.

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

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 interactions has been demonstrated in specific drug-drug-interaction studies.

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

4.6 Pregnancy And Lactation

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 during breast-feeding.

4.7 Effects On Ability To Drive And Use Machines

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

4.8 Undesirable Effects

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

Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (

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 that occurred at a frequency of> 2 % and with an incidence

System organ class

Adverse reaction/event

Nervous system disorders

 

Very common:

Headache

Respiratory, thoracic and mediastinal disorders

 

Very common:

Upper respiratory infection

Common:

Lower respiratory infection

Gastrointestinal disorders

 

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

Renal and urinary disorders

 

Common:

Urinary tract infection

Metabolism and nutrition disorders

 

Very common:

Hypoglycaemia*

Infections and infestations

 

Very common:

Influenza

General disorders and administration site conditions

 

Common:

Fatigue

Reproductive system and breast disorders

 

Common:

Menstrual irregularity

Psychiatric disorders

 

Common:

Anxiety

* only unique treatment adverse events that occurred at a frequency of> 2 % and with an incidence

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

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

System organ class

Adverse reaction

Investigations

 

Increase in liver transaminases and in alkaline phosphatase.

Decreased prothrombin, increased INR and unbalanced anticoagulant treatment resulting in variations of haemostatic parameters have been reported in patients treated with anticoagulants in association with orlistat (see section 4.4 and 4.5)

Gastrointestinal disorders

 

Rectal bleeding

Diverticulitis

Pancreatitis

Skin and subcutaneous tissue disorders

Bullous eruptions

Immune system disorders

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

Hepatobiliary disorders

Cholelithiasis

Hepatitis that may be serious

Renal and urinary disorders

Oxalate nephropathy

4.9 Overdose

Single doses of 800 mg orlistat and multiple doses of up to 400 mg three times daily for 15 days have been 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 orlistat overdose cases received during post-marketing reported either no adverse events or adverse events that are similar to those reported with recommended dose.

Should a significant overdose of orlistat 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.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

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 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 unavailable to hydrolyse 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 in both the orlistat and the placebo treated groups.

Pooled data from five 2 year studies with orlistat and a hypocaloric diet showed that 37 % of orlistat patients and 19 % of placebo patients demonstrated a loss of at least 5 % of their baseline body weight after 12 weeks of treatment. Of these, 49 % of orlistat treated patients and 40 % of placebo treated patients went on to lose

Data from the 4-year XENDOS clinical trial showed that 60 % of orlistat patients and 35 % of placebo patients 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

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

Data from the 4-year clinical trial also suggested that weight loss achieved with orlistat delayed the development of type 2 diabetes during the study (cumulative diabetes cases incidences: 3.4 % in the orlistat group compared to 5.4 % in the placebo-treated group). The great majority of diabetes cases came from the subgroup of patients with impaired glucose tolerance at baseline, which represented 21 % of the randomised patients. It is not known whether these findings translate into long-term clinical 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 (

In a multi-centre (US, Canada), parallel-group, double-blind, placebo-controlled study, 539 obese adolescent 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 populations received 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 favour of orlistat). 9.5 % of the orlistat treated patients versus 3.3 % of the placebo treated patients lost

5.2 Pharmacokinetic Properties

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 µmol), with no evidence of accumulation, which is consistent with minimal absorption.

Distribution

The volume of distribution cannot be determined because the drug 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 minimal fraction of the dose that was absorbed systemically, 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 plasma concentration.

M1 and M3 have an open beta-lactone ring and extremely weak lipase inhibitory activity (1000 and 2500 fold less than orlistat respectively). In view of this low inhibitory activity and the low plasma levels at 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 drug 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.

5.3 Preclinical Safety Data

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

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

6. Pharmaceutical Particulars

6.1 List Of Excipients

Capsule filling:

microcrystalline cellulose (E460)

sodium starch glycollate

povidone (E1201)

sodium lauryl sulphate

talc

Capsule shell:

gelatine

indigo carmine (E132)

titanium dioxide (E171)

edible printing ink (black iron oxide, ammonium hydroxide, potassium hydroxide, shellac)

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Blisters: Do not store above 25 °C. Store in original package in order to protect from moisture.

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

6.5 Nature And Contents Of Container

PVC/PE/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.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Roche Registration Limited

6 Falcon Way

Shire Park

Welwyn Garden City

AL7 1TW

United Kingdom

8. Marketing Authorisation Number(S)

EU/1/98/071/001-006

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 29 July 1998

Date of latest renewal: 29 July 2008

10. Date Of Revision Of The Text

25 March 2009

LEGAL STATUS

POM





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