ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1

2 1. NAME OF THE MEDICINAL PRODUCT XENICAL 120 mg hard capsules. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each hard capsule contains 120 mg orlistat. 3. PHARMACEUTICAL FORM Capsule, hard. It is presented as turquoise cap and turquoise body bearing the imprint of ROCHE XENICAL 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. 2

3 4.3 Contra-indications - Chronic malabsorption syndrome. - Cholestasis. - Breast-feeding. - Known hypersensitivity to orlistat or any of the excipients contained in the medicinal product. Orlistat is not recommended for use during pregnancy. 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. 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 fibrates, acarbose, biguanides 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 digoxin, phenytoin, oral contraceptives, nifedipine GITS, nifedipine slow release or alcohol have been observed. + Pravastatin If orlistat is administered to patients taking pravastatin, there is an increased risk of (doserelated) pravastatin adverse events, including rhabdomyolysis, due to an increase in pravastatin plasma concentrations. Dose adjustment of pravastatin may be required. + 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). 3

4 4.6 Use during pregnancy and lactation 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 wellconducted studies were performed in two species. At present, insufficient data are available in pregnant women taking orlistat to enable an evaluation of the potential for orlistat to cause foetal malformations or foetal toxicity. The use of orlistat during pregnancy is therefore not recommended. As it is not known whether orlistat is secreted into human milk, orlistat is contra-indicated during breast-feeding. 4

5 4.7 Effects on ability to drive and use machines No effects on the patient's ability to drive and use machines have been reported. 4.8 Undesirable effects Adverse reactions to orlistat are largely gastrointestinal in nature. During the first year of treatment, commonly observed 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), increased defecation (11% of patients) and 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 : Gastrointestinal System : abdominal pain/discomfort, flatulence, liquid stools, soft stools, rectal pain/discomfort, tooth disorder, gingival disorder. Respiratory System : upper respiratory infection, lower respiratory infection. Resistance Mechanism : influenza. Central Nervous System : headache. Reproductive Disorders : menstrual irregularity. Psychiatric Disorders : anxiety. Body as a Whole : fatigue. Urinary System Disorders : urinary tract infection. 4.9 Overdose Overdose of orlistat has not 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 kg. In type II diabetic patients the percentage of responders ( 10% of bodyweight loss) was 9% with 5

6 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. 6

7 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 Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and reproductive toxicology. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsule filling: Microcrystalline cellulose, sodium starch glycollate, povidone, sodium lauryl sulphate and talc. 7

8 Capsule shell: Gelatine, indigo carmine (E132), titanium dioxide (E171) and edible printing ink. 6.2 Incompatibilities Not applicable. 8

9 6.3 Shelf-life 3 years 6.4 Special precautions for storage For blister strips : Store below 25 C and keep in a dry place. For glass bottles with desiccant : Store below 30 C and keep in a dry place. 6.5 Nature and content of container PVC/PE/PVDC blisters and glass bottles with desiccant containing 21, 42 and 84 hard capsules. 6.6 Instructions for use, handling and disposal (if appropriate) Not applicable. 7. MARKETING AUTHORISATION HOLDER Roche Registration Limited 40 Broadwater Road Welwyn Garden City Hertfordshire AL7 3AY United Kingdom. 8. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT 9

10 ANNEX II THE MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR IMPORT AND BATCH RELEASE AND CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 10

11 A MANUFACTURING AUTHORISATION HOLDER Manufacturer responsible for import and batch release in the European Economic Area Hoffmann-La Roche AG, Emil-Barell-Strasse 1, D Grenzach-Whylen, Germany. Manufacturing Authorisation issued on 16 August 1996 by the Regierungspräsidium Freiburg, Germany. B CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to medical prescription 11

12 ANNEX III LABELLING AND PACKAGE LEAFLET 12

13 A. LABELLING 13

14 TEXT FOR THE OUTER PACKAGE FOR XENICAL 120 MG (BLISTER PACKS, 21 CAPSULES) Xenical 120 mg hard capsules Orlistat 21 capsules Each capsule contains 120 mg orlistat. Also includes microcrystalline cellulose, sodium starch glycollate, sodium lauryl sulphate and the colourants indigo carmine E132 and titanium dioxide E171 and other constituents. For oral use Refer to the package leaflet before use Keep out of the reach of children Store below 25 C and keep in a dry place Expiry date: month/year Roche Registration Limited, 40 Broadwater Road, Welwyn Garden City, Hertfordshire, AL7 3AY, United Kingdom. EU/.../... Batch number: Medicinal product subject to medical prescription 14

15 TEXT FOR THE OUTER PACKAGE FOR XENICAL 120 MG (BLISTER PACKS, 42 CAPSULES) Xenical 120 mg hard capsules Orlistat 42 capsules Each capsule contains 120 mg orlistat. Also includes microcrystalline cellulose, sodium starch glycollate, sodium lauryl sulphate and the colourants indigo carmine E132 and titanium dioxide E171 and other constituents. For oral use Refer to the package leaflet before use Keep out of the reach of children Store below 25 C and keep in a dry place Expiry date: month/year Roche Registration Limited, 40 Broadwater Road, Welwyn Garden City, Hertfordshire, AL7 3AY, United Kingdom. EU/.../... Batch number: Medicinal product subject to medical prescription 15

16 TEXT FOR THE OUTER PACKAGE FOR XENICAL 120 MG (BLISTER PACKS, 84 CAPSULES) Xenical 120 mg hard capsules Orlistat 84 capsules Each capsule contains 120 mg orlistat. Also includes microcrystalline cellulose, sodium starch glycollate, sodium lauryl sulphate and the colourants indigo carmine E132 and titanium dioxide E171 and other constituents. For oral use Refer to the package leaflet before use Keep out of the reach of children Store below 25 C and keep in a dry place Expiry date: month/year Roche Registration Limited, 40 Broadwater Road, Welwyn Garden City, Hertfordshire, AL7 3AY, United Kingdom. EU/.../... Batch number: Medicinal product subject to medical prescription 16

17 TEXT FOR THE OUTER PACKAGE AND BOTTLE LABEL FOR XENICAL 120 MG (BOTTLES, 21 CAPSULES) Xenical 120 mg hard capsules Orlistat 21 capsules Each capsule contains 120 mg orlistat. Also includes microcrystalline cellulose, sodium starch glycollate, sodium lauryl sulphate and the colourants indigo carmine E132 and titanium dioxide E171 and other constituents. For oral use Refer to the package leaflet before use Keep out of the reach of children Store below 30 C and keep in a dry place Expiry date: month/year Roche Registration Limited, 40 Broadwater Road, Welwyn Garden City, Hertfordshire, AL7 3AY, United Kingdom. EU/.../... Batch number: Medicinal product subject to medical prescription 17

18 TEXT FOR THE OUTER PACKAGE AND BOTTLE LABEL FOR XENICAL 120 MG (BOTTLES, 42 CAPSULES) Xenical 120 mg hard capsules Orlistat 42 capsules Each capsule contains 120 mg orlistat. Also includes microcrystalline cellulose, sodium starch glycollate, sodium lauryl sulphate and the colourants indigo carmine E132 and titanium dioxide E171 and other constituents. For oral use Refer to the package leaflet before use Keep out of the reach of children Store below 30 C and keep in a dry place Expiry date: month/year Roche Registration Limited, 40 Broadwater Road, Welwyn Garden City, Hertfordshire, AL7 3AY, United Kingdom. EU/.../... Batch number: Medicinal product subject to medical prescription 18

19 TEXT FOR THE OUTER PACKAGE AND BOTTLE LABEL FOR XENICAL 120 MG (BOTTLES, 84 CAPSULES) Xenical 120 mg hard capsules Orlistat 84 capsules Each capsule contains 120 mg orlistat. Also includes microcrystalline cellulose, sodium starch glycollate, sodium lauryl sulphate and the colourants indigo carmine E132 and titanium dioxide E171 and other constituents. For oral use Refer to the package leaflet before use Keep out of the reach of children Store below 30 C and keep in a dry place Expiry date: month/year Roche Registration Limited, 40 Broadwater Road, Welwyn Garden City, Hertfordshire, AL7 3AY, United Kingdom. EU/.../... Batch number: Medicinal product subject to medical prescription 19

20 TEXT FOR THE BLISTER FOIL FOR XENICAL Xenical 120 mg capsules Orlistat Roche Registration Ltd Batch: Exp.: month/year 20

21 B. PACKAGE LEAFLET 21

22 Patient Leaflet Please read this leaflet carefully because it contains important information for you. If you want to know more about this product, or if you are not sure about a particular item in the leaflet please ask your doctor or pharmacist. Name of the medicinal product XENICAL 120 mg hard capsules (Orlistat) Composition Each XENICAL capsule contains 120 mg of the active substance orlistat. The capsule also contains the additional excipients microcrystalline cellulose, sodium starch glycollate, povidone, sodium lauryl sulphate and talc. The capsule shell consists of gelatine, indigo carmine (E132), titanium dioxide (E171) and edible printing ink. Pharmaceutical form and contents XENICAL is supplied as hard capsules in blister packs and glass bottles, containing 21, 42 and 84 capsules. Type of Medicine Pharmaco-therapeutic group: Anti-obesity agent XENICAL is an anti-obesity agent. It does not suppress your appetite. It is a potent, specific and long-acting inhibitor of gastrointestinal lipases. The inactivated enzyme is thus unavailable to hydrolyse dietary fat, and this allows about 30% of the fat eaten in the meal to pass through the gut undigested. Your body therefore, cannot use this dietary fat as a source of energy and convert it to fat tissue. This will help you reduce your weight. Marketing authorisation holder Roche Registration Limited, 40 Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AY, United Kingdom Manufacturer Hoffmann-La Roche AG, Postfach 1270, Grenzach-Wyhlen, Germany. When should XENICAL be used? XENICAL is indicated in the treatment of obesity in conjunction with a mildly hypocaloric diet Important information before taking XENICAL Treatment with XENICAL 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. When should XENICAL not be used? You should not take XENICAL if you have: chronic malabsorption syndrome (insufficient absorption of nutrients from alimentary tract), cholestasis (liver disorder), a known allergy to orlistat or any of the other components contained in the capsule. 22

23 You should not breast-feed while on XENICAL. XENICAL is not recommended for use during pregnancy. Precautions for use Inform your doctor before starting treatment with XENICAL if you: suffer from chronic malabsorption syndrome; are allergic to other medicines, foods or dyes; are taking other medicines, including those you have obtained without a prescription. Weight loss may also affect the dose of medication taken for other conditions (e.g. high cholesterol or diabetes). Be sure to discuss these and other drugs you may be taking with your doctor. Losing weight may mean you need adjustments to the dose of these medications. To gain the maximum benefit from XENICAL you should follow the nutrition program recommended to you by your doctor. As with any weight-control program, over-consumption of fat and calories may negate any weight loss effect. This medicine can cause harmless changes in your bowel habits, such as fatty or oily stools, due to the elimination of undigested fat in your faeces. The possibility of this happening may increase if XENICAL is taken with a diet high in fat. In addition your daily intake of fat should be distributed evenly over three main meals because if XENICAL is taken with a meal very high in fat, the possibility of gastrointestinal effects may increase. Interactions with other medicinal products and other forms of interaction Before starting treatment, make sure your doctor knows if you are taking other medicines (including those not prescribed by your doctor). This is important as using more than one medicine at the same time can strengthen or weaken the effects of the medicines. XENICAL increases the effect of some lipid lowering drugs and therefore your doctor may change your dose of this medicine. XENICAL may modify the activity of anticoagulant drugs (e.g. warfarin). Your doctor may need to monitor your blood coagulation. XENICAL reduces the absorption of supplements of some fat soluble nutrients, particularly beta-carotene and vitamin E. You should therefore follow your doctor s advice in taking a well balanced diet rich in fruit and vegetables. Your doctor may suggest you take a multivitamin supplement. Use in Children XENICAL is not intended to be used in children. Use during pregnancy and breast-feeding You should not take XENICAL if you are pregnant or intend to become pregnant. You should not breast-feed your infant during treatment with XENICAL as it is not known whether XENICAL passes into human milk. Effects on ability to drive and use machinery XENICAL has no known effect on your ability to drive a car or operate machinery. How to take XENICAL Dosage and frequency of administration Follow the directions for using this medicine provided by your doctor, otherwise you will not fully benefit from XENICAL. 23

24 The recommended dose of XENICAL is one 120 mg capsule taken with each of the three main meals per day. It can be taken immediately before, during a meal or up to one hour after a meal. XENICAL should be taken with a well-balanced, calorie controlled diet that is rich in fruit and vegetables and contains an average of 30% of the calories from fat. Your daily intake of fat, carbohydrate and protein should be distributed over three meals. This means you will usually take one capsule at breakfast time, one capsule at lunch time and one capsule at dinner time. To gain optimal benefit, avoid the intake of food containing fat between meals, such as biscuits, chocolate and savoury snacks. XENICAL only works in the presence of dietary fat. Therefore, if you miss a main meal or if you have a meal containing no fat, XENICAL need not be taken. Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective or well tolerated and may change your treatment unnecessarily. Your doctor will discontinue the treatment with XENICAL after 12 weeks if you have not lost at least 5% of your body weight as measured at the start of treatment with XENICAL. Method and route of administration Your medicine should be swallowed with water. Duration of treatment XENICAL should be prescribed for no longer than 2 years Actions to be taken in case of overdose If you take more capsules than you have been told to take, or if someone else accidentally takes your medicine, contact a doctor, pharmacist or hospital as you may need medical attention. Action to be taken when one or more doses have not been taken If you forget to take your medicine at any time, take it as soon as you remember provided this is within one hour of your last meal, then continue to take it at the usual times. Do not take a double dose. If you have missed several doses, please inform your doctor and follow the advice given to you. Do not change the prescribed dose yourself unless your doctor tells you to. Undesirable effects under normal use Along with its desired effects, a medicine may cause some unwanted effects. Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking XENICAL. The majority of unwanted effects related to the use of XENICAL result from its local action in your digestive system. These commonly include: urgent or increased need to open the bowels, flatulence (wind) with discharge, oily discharge and oily or fatty stools. These symptoms are generally mild, occur at the beginning of treatment, go away after some time and are particularly experienced after meals containing high levels of fat. Normally, these symptoms disappear if you continue treatment and keep to your recommended diet. If you are concerned about these or notice other effects not mentioned in this leaflet you should inform your doctor or pharmacist. How to store XENICAL 24

25 Do not take the capsules after the expiry date shown on the pack. The blister packs of XENICAL should be stored below 25 C and kept in a dry place. The glass bottles of XENICAL should be stored below 30 ºC and kept in a dry place. Keep this medicine out of reach of children. Date on which the package insert was last revised 25

26 Other information For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder. België/Belgien/Belgique N.V. Roche S.A, Rue Dantestraat 75, B-1070 Bruxelles - Brussel Tel: (02) Danmark Roche a/s, Industriholmen 59, DK-2650 Hvidovre Tel: Deutschland Hoffmann-La Roche AG, Emil-Barell-Str. 1, D Grenzach-Wyhlen Tel: (07624) 140 Ελλάδα Roche (Hellas) A.E., 4 Οδός Αλαμάνας και Δελφών, GR Μαρούσι, Αττική Tel: (01) España Productos Roche S.A., C a. Carabanchel a la de Andalucía s/n, Ε Madrid Tel: (91) France Produits Roche, 52 Boulevard du Parc. F Neuilly-Sur-Seine Tel: (01) Ireland Roche Pharmaceuticals, 3 Richview, Clonskeagh, Dublin 14-IRL Tel: (01) Italia Roche S.p.A., Piazza Durante 11, I Milano Tel: (02) 2884 Luxembourg N.V Roche S.A, Rue Dantestraat 75, B-1070 Bruxelles - Brussel Tel: (02) Nederland Roche Nederland B.V., Postbus 42, NL-3640 AA Mijdrecht Tel: (0297) Österreich Hoffmann-La Roche Wien Gesellschaft m.b.h, Jacquingasse 16-18, A-1030 Wien Tel: (01) Portugal Roche Farmacêutica Química Lda, Estrada Nacional 249-1, P-2720 Amadora Tel: (01)

27 Suomi/Finland Roche Oy, PL 12, FIN Espoo/Esbo Puh/Tel: (09) Sverige Roche AB, Box 47327, S Stockholm Tel: (08) United Kingdom Roche Products Ltd, 40 Broadwater Road, Welwyn Garden City, Hertfordshire, AL7 3AY-UK Tel: (01707)