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Xenical small print |
The small print almost nobody bothers to read:
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1. NAME OF THE MEDICINAL PRODUCT
XENICAL 120 mg hard capsules. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each hard capsule contains 120 mg orlistat. For excipients, see 6.1.
3. PHARMACEUTICAL FORM Capsule, hard. It is presented as 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/m², or overweight patients (BMI > 28 kg/m²) with associated risk factors. Treatment with orlistat 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 as measured at the start of drug therapy.
4.2 Posology and method of administration Adults The recommended dose of orlistat is one 120 mg capsule which should be taken 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. There are no safety and efficacy data beyond 2 years, therefore the duration of treatment with orlistat should not be longer than 2 years.
Special populations The effect of orlistat in patients with hepatic and/or renal impairment, children and elderly patients has not been studied. Orlistat is not intended to be used in children.
4.3 Contraindications
4.4 Special warnings and special 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 drug treatment may have to be closely monitored when taking orlistat. Treatment with orlistat may potentially impair the absorption of fat-soluble vitamins (ADEK). The vast majority of patients receiving up to two 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. Patients should be advised to adhere to the dietary recommendations they are given (see section 4.2 Posology and method of administration). The possibility of experiencing gastrointestinal events (see section 4.8 Undesirable effects) 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 effects may increase. A reduction in cyclosporin plasma levels has been observed when orlistat is co-administered. Therefore it is recommended to monitor more frequently than usual the cyclosporin plasma levels when orlistat is coadministered and to continue this monitoring when orlistat is discontinued until cyclosporin levels have stabilised (see section 4.5, Interaction with other medicinal products and other forms of interaction).
4.5 Interaction with other medicinal products and other forms of interaction In the absence of pharmacokinetic interaction studies, the concomittant administration of orlistat with acarbose, or anorectic drugs is not recommended. When warfarin or other anticoagulants are given in combination with orlistat (high dose and long term treatment), international normalised ratio (INR) values should be monitored. No interactions with biguanides, digoxin, fibrates, phenytoin, oral contraceptives, nifedipine GITS, nifedipine slow release or alcohol have been observed. +Vitamins and beta-carotene Decreases in the absorption of vitamin D, E, and beta-carotene should be taken into account (see section 4.4, Special warnings and special precautions for use). +Cyclosporin A reduction in cyclosporin plasma levels has been observed when orlistat is co-administered. Therefore it is recommended to monitor more frequently than usual the cyclosporin plasma levels when orlistat is coadministered and to continue this monitoring when orlistat is discontinued until cyclosporin levels have stabilised (see section 4.4, Special warnings and special precautions for use).
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 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 breastfeeding.
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. During the first year of treatment, very common events were oily spotting from the rectum (27% of patients), flatus with discharge (24% of patients), faecal urgency (22% of patients), fatty/oily stool (20% of patients), oily evacuation (12% of patients) and increased defecation (11% of patients). Common events were faecal incontinence (8% of patients). The incidence of adverse events decreased with prolonged use of orlistat. Other treatment-emergent adverse events that occurred at a frequency of > 2% and with an incidence > 1% above placebo were :
Very rare cases of bullous eruptions have been reported during the post marketing. Very rare cases of increase in liver transaminases and in alkaline phophatase and exceptional cases of hepatitis that may be serious have been reported during the post-marketing.
4.9 Overdose No case of overdose has been reported. Single doses of 800 mg orlistat and multiple doses of up to 400 mg tid 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. 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: Anti obesity agent, ATC code A08A B01. 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. Pooled data from five 2 year studies showed that, after one year of treatment associated with a hypocaloric diet, the percentage of patients taking 120 mg orlistat who lost 10% or more of their body weight was 20% with orlistat 120 mg compared to 8% of patients taking placebo. The mean difference in weight loss with the drug compared to placebo was - 3.2 kg. In type II diabetic patients the percentage of responders (> 10% of bodyweight loss) was 9% with orlistat as compared to 4% with placebo. The mean difference in weight loss with the drug compared to placebo was - 2.1 kg in these patients.
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 6 similar between normal weight and obese volunteers. Orlistat, M1 and M3 are all subject to biliary excretion.
5.3 Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, andtoxicity 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, drugs 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, sodium starch glycollate, povidone, sodium lauryl sulphate and talc. Capsule shell: Gelatine, indigo carmine (E132), titanium dioxide (E171) and edible printing ink.
6.2 Incompatibilities Not applicable.
6.3 Shelf life 3 years
6.4 Special precautions for storage For blister strips : Do not store above 25°C. Store in original package in order to protect from moisture. For glass bottles with desiccant : 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 and glass bottles with desiccant containing 21, 42 and 84 hard capsules.
6.6 Instructions for use and handling No special requirements
7. MARKETING AUTHORISATION HOLDER Roche Registration Limited
8. MARKETING AUTHORISATION NUMBERS EU/1/98/071/001-006
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 29 July 1998
10. DATE OF REVISION OF THE TEXT 31 October 2001 |