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1 75 PLAVIX Film-coated Tablets 75mg 讀 說 說 讀 若 不 狀 了 clopidogrel 75 clopidogrel 露 E421 macrogal 6000 糖 hypromellose E464E1518 E172 E171 蠟 1. 什 數 `75 數 ` clopidogrel 降 狀 狀 狀 塞 例 了 降 狀 ` 不 ` 塞 2. 列 clopidogrel 狀 例 列 易 行 來 類 參 欄 不 18 年 療 立 不 車 力 不 車 力 療 Warfarin 降 不 類 療 / 降 不 說來 24 量不 1000 不 什 論 3. 不

2 量 75 律 療 量 療 療 來 量 立 量 量 12 來 立 量 量 12 量 不 量 漏 量 不 4. 見 例 流 尿 數 例 便 不良 暈 降 異 異 列 立 見 狀 度 見 異 療 不 類 什 說 5. 不見 識 參 Clopidogrel 量 Clopidogrel hydrogen sulphate mg( Clopidogrel base 75mg) 75mg 數 75 數 1171 降 塞 狀 狀 ( 塞 ) aspirin 降 ST ( 不 Q 塞 ) 狀 塞 量 老年 Clopidogrel 量 75mg ST ( 不 Q 塞 ) Clopidogrel 量 (loading dose) 300mg 75mg ASA 75mg-325mg 量 ASA ASA 量不 100mg 療 立 臨 數 12 ( 參 欄 ) 年 18 年 療 立 不良 ( 參 欄 ) 不良 療 數 臨 狀 立

3 行 ( 參 不良 欄 ) Clopidogrel 例 理狀 ASA 類 (NSAID) glycoprotein IIb/IIIa 匿 療 warfarin 不 Clopidogrel ( 參 欄 ) 若 療 不 行 7 Clopidogrel Clopidogrel 流 () Clopidogrel( 論 ASA ) 更 若 不 狀 立 行 Clopidogrel Clopidogrel 數 (TTP) 例 ( ) 狀 不良 TTP 立 療 療 療 (plasmapheresis) 臨 料 ST 塞 塞 數 不 Clopidogrel 臨 料 Clopidogrel 不 ( 7 ) Clopidogrel 不良 Clopidogrel 度 不良 Warfarin 不 clopidogrel warifarin 參 欄 Glycoprotein IIb/IIIa Clopidogrel glycoprotein Iib/IIIa 理狀 參 欄 Acetylsalicylic acid(asa) ASA 不 Clopidogrel Clopidogrel ASA collagen-induced ASA 500mg 兩 不 Clopidogrel Clopidogrel ASA ( 參 欄 ) Clopidogrel ASA 臨 年 ( 參 欄 ) (Heparin) Clopidogrel 不 不 量 不 clopidogrel Clopidogrel ( 參 欄 ) (Thrombolytics) Clopidogrel rt-pa 塞 率 ASA rt-pa Clopidogrel 立 ( 參 欄 ) 類 (NSAIDs) naproxen Clopidogrel 匿 NSAIDs Clopidogrel NSAIDs Clopidogrel 不 NSAIDs Clopidogrel ( 參 欄 ) 療 了 Clopidogrel 行了數 臨 Clopidogrel atenolol nifedipine atenolol nifedipine 臨 Clopidogrel 不 phenobarbital cimetidine oestrogen digoxin theophylline 不 Clopidogrel 不 Clopidogrel 度 Clopidogrel carboxylic acid Cytochrome P 450 2C9 Clopidogrel Cytochrome P 450 2C9 phenytoin tolbutamide NSAIDs 度 CAPRIE phenytoin tolbutamide Clopidogrel 了 Clopidogrel 狀 行 參 臨 利尿 beta ACE 離 降 狀 糖尿 ( ) 療 GPIIb/IIIa Clopidogrel 列 臨 不良 / 料不 不 Clopidogrel Clopidogrel 類 不 ( 參 欄 )

4 車 力 Clopidogrel 車 力 不良 臨 17,500 Clopidogrel 來 療 年 9,000 CAPRIE ASA 325mg/day Clopidogrel 75mg/day Clopidogrel ASA 類 不 年 CAPRIE CURE 臨 不良 論 CAPRIE Clopidogrel ASA 率 9.3% 例 率 Clopidogrel 1.4% ASA 1.6% Clopidogrel 率 2.0% 0.7% ASA 率 2.7% 1.1% 率 Clopidogrel ASA (7.3% vs. 6.5%) 兩 率類 (0.6% vs. 0.4%) / / (epistaxis) 尿 ( ) 率 Clopidogrel 0.4% ASA 0.5% CURE Clopidogrel+ASA placebo+asa ( 率 2.2% vs. 1.8% 0.2% vs. 0.2%) Clopidogrel+ASA placebo+asa 率 (1.6% Clopidogrel+ASA vs. 1.0% placebo+asa) 率 (5.1% Clopidogrel+ASA vs.2.4% placebo+asa) 兩 率 0.1% 率 Clopidogrel+ASA ASA 量 (<100mg: 2.6%; mg: 3.5%; >200mg: 4.9%) placebo+asa (<100mg: 2.0%; mg: 2.3%; >200mg:4.0%). 臨 行 降 ( ): 0-1 months [Clopidogrel: 599/6259(9.6%); placebo: 413/6303(6.6%)], 1-3 months [Clopidogrel: 276/6123(4.5%); placebo: 144/6168(2.3%)], 3-6 months [Clopidogrel: 228/6037(3.8%); placebo: 99/6048(1.6%)], 6-9 months [Clopidogrel: 162/5005(3.2%); placebo: 74/4972(1.5%)], 9-12 months [Clopidogrel: 73/3841(1.9%); placebo: 40/3844(1.0%)]. 狀 行 5 7 度 (4.4% Clopidogrel+ASA vs. 5.3% placebo+asa) 狀 行 5 療 Clopidogrel+ASA 率 9.6% placebo+asa 率 6.3% 異 CAPRIE (<0.45 x 10 9 /l) 4 Clopidogrel(0.04%) 2 ASA(0.02%) 9599 Clopidogrel 2 數 零 9586 ASA 數 零 Clopidogrel 療 不良 (aplastic anaemia) 例 (<80 x 10 9 /l) 率 Clopidogrel ASA 0.2% 0.1% CURE 數 (19 Clopidogrel+ASA vs. 24 placebo+asa) 數 (3 vs. 3) 兩 療 類 CAPRIE CURE 臨 不良 不良 率 >0.1% 列 率 見 (>1/100, <1/10) 不 見 (>1/1,000 <1/100) 見 (>1/10,000 <1/1,000) 異 - 不 見 暈 異 (paraesthesia) - 見 - 見 不良 - 不 見 便 異 - 不 見 (appendage) 異 - 不 見 狀 異 - 不 見 臨 列 不良 不良 例 例 ( ) 例 ( ) ( )( )( ) 尿 Clopidogrel ASA Clopidogrel ASA 例 ( 參 欄 ) 了臨 列 MedDRA 類 率 見

5 <1/10,000 淋 不良 - 見 (TTP) Clopidogrel 參 欄 ( 數 < 30 x 10 9 /l) 粒 不良 / 不良 - 見 (anaphylactoid reactions) 不良 - 見 亂 不良 - 見 異 不良 - 見 (mediastinal) 不良 - 見 不良 - 見 ( 淋 ) 不良 - 見 - 見 ( ) 不良 - 見 泌尿 - 見 不良 - 見 異 - 見 異 度 量 量 例 34 女 1050mg Clopidogrel ( 14 75mg ) 不良 療 女 行 復 600mg Clopidogrel ( 8 75mg ) 來 mg Clopidogrel 類 Clopidogrel 若 立 Clopidogrel 理 理 療 類 Heparin ATC Code:B01AC/04 Clopidogrel ADP ADP 便 ADP GPIIb/IIIa Clopidogrel 了 ADP ADP Clopidogrel Clopidogrel ADP 不 Clopidogrel 復 率 率 量 75mg Clopidogrel ADP 3 7 狀 狀 75mg 量 度 40% 60% 復 5 兩 臨 Clopidogrel 療 CAPRIE Clopidogrel ASA CURE Clopidogrel+ASA +ASA CAPRIE 19,185 狀 狀 塞 塞 (<35 ) ( 7 6 )(PAD) 兩 75mg Clopidogrel 325mg ASA 1~3 年 塞 塞 數 ASA ASA Clopidogrel 降 率 ( 塞 ) 參 (intention to treat analysis) Clopidogrel 939 ASA 1020 ( 降 8.7% [95%CI:0.2 to 16.4] p=0.045) 1000 療兩年 10 [CI:0 to 20] 率 Clopidogrel 療 (5.8%) ASA 療 (6.0%) 異 CAPRIE ( 塞 ) Clopidogrel ( 塞 ) 療 ( P=0.003 降 23.7% CI:8.9 to 36.2) 療 ( ASA 療 異 降 7.3% CI:-5.7 to 18.7) 塞 Clopidogrel 療 數 ASA 療 ( 降 -4.0% CI:-22.5 to 11.7) 年 Clopidogrel 療 CAPRIE 不 來 力不 來 療

6 CURE 12,562 ST ( 不 Q 塞 ) 狀 24 troponin I troponin T 兩 Clopidogrel 療 ( 量 300mg 75mg 6259 ) 療 ( 6303 ) 兩 ASA( 75~325mg) 療 療 年 CURE 823(6.6%) GPIIb/IIIa 療 90% 療 率 Clopidogrel 療 療 塞 (primary endpoint) Clopidogrel 療 582(9.3%) 療 719(11.4%) Clopidogrel 療 降 20%(95% CI of 10%~28%; p= )( 療 降 17% 療 [ 不論 ] 降 29% 狀 療 降 10%) 療 降 率 22%(CI:8.6, 33.4) 32%(CI:12.8, 46.4) 4%(CI:-26.9, 26.7) 6%(CI:-33.5, 34.3) 14%(CI:-31.6, 44.2) 療 3 Clopidogrel+ASA 療 不 ( 參 欄 ) CURE Clopidogrel 降 ( 降 43.3% CI:24.3%, 57.5%) GPIIb/IIIa ( 降 18.2% CI:6.5%, 28.3%) 療 塞 復 (co-primary endpoint) Clopidogrel 療 1035(16.5%) 療 1187(18.8%) Clopidogrel 療 降 14%(95% CI of 6%~21%; p=0.0005) 塞 率 降 [Clopidogrel 療 287(4.6%) 療 363(5.8%) ] 不 率 不 ( 不 Q 塞 度 糖尿 行 年 ) Clopidogrel 療 療 ( / 量 GPIIb/IIIa 降 beta ACE ) Clopidogrel 療 ASA 量 ( 75mg-325mg) 量 Clopidogrel 75mg Clopidogrel 2 (parent compound) 度 量 ( mg/l) 尿 50% Clopidogrel Clopidogrel 行 carboxylic acid 不 85% 度 ( 75mg Clopidogrel 度 3mg/l) Clopidogrel prodrug thiol Clopidogrel 2-oxo-clopidogrel Clopidogrel Cytochrome P450 isoenzymes 2B6 3A4 數 Cytochrome P450 isoenzymes 1A1 1A2 2C19 thiol 離 來 不 來 Clopidogrel 量 mg ( 度 量 例 ) Clopidogrel 率 98% 94% 度 類 14 C Clopidogrel % 尿 46% 便 量 量 (the main circulating metabolite) 8 Clopidogrel 75mg 不良 (creatinine 廓 率 5 15mL/min) 度 度 不良 (creatinine 廓 率 30 60mL/min) 25% Clopidogrel 75mg 類 臨 良 (Child-Pugh class A or B) 量 量 Clopidogrel Clopidogrel 75mg 連 10 來說 良 Clopidogrel 度 數 兩 度 ADP 異不 臨 料 類 量 (75mg/day) 25 類 療 量 Clopidogrel 類 量 ( 類 量 250 ) Clopidogrel

7 ( 爛 ) 77mg/kg/day Clopidogrel 類 量 (75mg/day) 25 老 Clopidogrel (genotoxicity) Clopidogrel 力 (teratogenic) Clopidogrel Clopidogrel Clopidogrel 泌 () () 不 Mannitol (E421) Macrogol 6000 Microcrystalline cellulose Hydrogenated castor oil Low substituted hydroxypropylcellulose Hypromellose (E464) Lactose Triacetin (E1518) Titanium dioxide (E171) Red iron oxide (E172) Carnauba wax 年 Sanofi Winthrop Industrie (p) 1 rue de la Vierge Ambares,France (o) Sanofi Synthelabo France 174, Avenue de France, Paris, France License Holder: Sanofi Pharma Bristol-Myers Squibb SNC 174, Avenue de France, Paris, rance 諾 拉 北 路 樓 6 SmPC: October 8, 2003

8 PLAVIX 75 mg film-coated tablets (CLOPIDOGREL) Read all of this leaflet carefully before you start taking this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or your pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Plavix is and what it is used for 2. Before you take Plavix 3. How to take Plavix 4. Possible side effects 5. How to store Plavix 6. Further information 1. WHAT PLAVIX IS AND WHAT IT IS USED FOR Clopidogrel, the active ingredient in Plavix tablets, belongs to a group of medicines called antiplatelet medicinal products. Platelets are very small structures, smaller than red or white blood cells, which clump together during blood clotting. By preventing this clumping, antiplatelet medicinal products reduce the chances of blood clots forming (a process called thrombosis). Plavix is taken to prevent blood clots (thrombi) forming in hardened blood vessels (arteries), a process known as atherothrombosis, which can lead to atherothrombotic events (such as stroke, heart attack, or death). You have been prescribed Plavix to help prevent blood clots and reduce the risk of these severe events because : - You have a condition of hardening of arteries (also known as atherosclerosis), and - You have previously experienced a heart attack, stroke or have a condition known as peripheral arterial disease, or - You have experienced a severe type of chest pain known as unstable angina or myocardial infarction (heart attack). In this case you should also be given acetylsalicylic acid (a substance present in many medicines used to relieve pain and lower fever as well as to prevent blood clotting) by your doctor. 2. BEFORE YOU TAKE PLAVIX Do not take Plavix: If you are allergic (hypersensitive) to clopidogrel or any of the other ingredients of Plavix; If you have a medical condition that is currently causing bleeding such as a stomach ulcer; If you suffer from severe liver disease; If you are breast-feeding. If you think you may have any of these problems, or if you are in any doubt at all, consult your doctor before taking Plavix. Take special care with Plavix: If any of the situations mentioned below apply to you, you should tell your doctor before taking Plavix: if you have a risk of haemorrhage such as - a medical condition that puts you at risk of internal bleeding (such as a stomach ulcer) - a blood disorder that makes you prone to internal bleeding (bleeding inside any tissues, organs or joints of your body). - a recent serious injury - a recent surgery (including dental) - a planned surgery (including dental) in the next seven days if you are taking another type of medication (see Taking other medicines ). if you have kidney or liver disease If you have been told by your doctor that you have an intolerance to some sugars, contact you doctor before taking this medicine. Plavix is not intended for use in children or adolescents less than 18 years of age. Taking other medicines: Some other medicines may influence the use of Plavix or vice versa. Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. The use of warfarin (a drug used to reduce blood clotting) with Plavix is not recommended. You should specifically tell your doctor if you take a non-steroidal anti-inflammatory medicinal product, usually used to treat painful and/or inflammatory conditions of muscle or joints, or if you take heparin, another drug used to reduce blood clotting. If you have experienced severe chest pain (unstable angina or heart attack), you may be prescribed Plavix in combination with acetylsalicylic acid, a substance present in many medicines used to relieve pain and lower fever. An occasional use of acetylsalicylic acid (no more than 1000 mg in any 24 hour period) should generally not cause a problem, but prolonged use in other circumstances should be discussed with your doctor. Taking clopidogrel with food and drink Food/meals have no influence. Plavix may be taken with or without food. Pregnancy and breast-feeding If you are pregnant or suspect that you are pregnant, you should tell your doctor or your pharmacist before taking Plavix. If you become pregnant while taking Plavix, consult your doctor immediately. If you are a mother breast-feeding a baby, you should not take Plavix. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines: Plavix is unlikely to affect your ability to drive or to use machines. Important information about some of the ingredients of Plavix: Plavix contains mannitol, lactose and colouring agents (E171, E172). 3. HOW TO TAKE PLAVIX Always take Plavix exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. The usual dose is one 75 mg tablet of Plavix per day to be taken orally with or without food. You should take your medicine regularly and at the same time each day. In addition, if you have experienced severe chest pain, your doctor may give you 300 mg of Plavix (4 tablets of 75 mg) at the start of treatment. If a surgery is planned (including dental), you should tell your doctor that you take Plavix. You should take Plavix for as long as your doctor continues to prescribe it. If you take more Plavix than you should: Contact your doctor or the nearest emergency department because of the increased risk of bleeding. If you forget to take Plavix: If you forget to take a dose of Plavix, but remember within 12 hours of your usual time, take your tablet straightaway and then take your next tablet at the usual time. If you forget for more than 12 hours, simply take the next single dose at the usual time. Do not take a double dose to make up for the forgotten individual doses. For the 28 and 84 tablets packsizes, you can check the day on which you last took a tablet of Plavix by referring to the calendar printed on the blister. If you stop taking Plavix: Do not stop the treatment. Contact your doctor or pharmacist before stopping. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Plavix can cause side effects, although not everybody gets them. The most common side effect reported with Plavix is bleeding such as bruising, haematoma, nose bleed, blood in the urine, bleeding in the stomach or bowels. In a small number of cases, bleeding in the eye, inside the head, the lung or the joints has also been reported. The other side effects reported with Plavix are: Diarrhoea, abdominal pain, constipation, nausea, vomiting, indigestion or heartburn, inflammation of the mouth (stomatitis); Vertigo, headache, decrease in blood pressure, confusion, hallucinations; Skin disorders such as rashes and itching, swelling in the mouth, blisters of the skin, generalised allergic reactions; Joint pain, muscular pain, fever, taste disorders. Breathing difficulties, sometimes associated with cough. Contact immediately your doctor if you experience: - fever, signs of infection or extreme tiredness due to rare decrease of some blood cells. - signs of liver problems such as yellowing of the skin and/or the eyes (jaundice), whether or not associated with bleeding and/or confusion. If you experience prolonged bleeding when taking Plavix If you cut or injure yourself, it may take slightly longer than usual for bleeding to stop. This is linked to the way your medicine works. For minor cuts and injuries e.g., cutting yourself, shaving, this is of no concern. However, if you are in any doubt at all, you should contact your doctor straightaway. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE PLAVIX Keep out of the reach and sight of children. Do not use Plavix after the expiry date which is stated on the carton and on the blister; This medicinal product does not require any special storage conditions. Store in the original package. Do not use Plavix if you notice any visible sign of deterioration. Medicines should not be disposed of via wastewater at household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6 FURTHER INFORMATION What Plavix contains The active substance is clopidogrel. Each tablet contains 75 mg of clopidogrel. The other ingredients are mannitol (E421), hydrogenated castor oil, microcrystalline cellulose, macrogol 6000 and low-substituted hydroxypropylcellulose in the tablet core, and lactose (milk sugar), hypromellose (E464), triacetin (E1518), iron oxide (E172), titanium dioxide (E171), and carnauba wax in the tablet coating. What Plavix looks like and contents of the pack Plavix tablets are round, biconvex, pink, film-coated tablets engraved on one side with the number 75 and on the other side with the number They are supplied in cardboard cartons containing 28, 50, 84 and 100 tablets in PVC/PVDC/Aluminium blisters or in all aluminium blisters. Not all pack sizes may be marketed. Marketing Authorisation Holder and Manufacturer: Marketing Authorisation Holder: Sanofi Pharma Bristol-Myers Squibb SNC 174 Avenue de France - F Paris France Manufacturers: Sanofi Winthrop Industrie 1, rue de la Vierge, Ambarès & Lagrave, F Carbon Blanc cedex, France 1. NAME OF THE MEDICINAL PRODUCT Plavix 75 mg film-coated tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Clopidogrel hydrogen sulphate mg (molar equivalent of 75 mg of clopidogrel base) Excipients: mannitol (E421), lactose, Titanium dioxide (E171), red iron oxide (E172) For a full list of excipients, see section PHARMACEUTICAL FORM Film-coated tablet. Plavix 75 mg film-coated tablets are pink, round, biconvex, film-coated, engraved with «75» on one side and «1171» on the other side. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Clopidogrel is indicated for the prevention of atherothrombotic events in: Patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. Patients suffering from acute coronary syndrome: - Non-ST segment elevation acute coronary syndrome (unstable angina or non-q-wave myocardial infarction), in combination with acetylsalicylic acid (ASA). - ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy. For further information please refer to section Posology and method of administration Adults and elderly Clopidogrel should be given as a single daily dose of 75 mg with or without food. In patients suffering from acute coronary syndrome: - Non-ST segment elevation acute coronary syndrome (unstable angina or non-q-wave myocardial infarction), clopidogrel treatment should be initiated with a single 300 mg loading dose and then continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding risk it is recommended that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months (see section 5.1). - ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a loading dose in combination with ASA and with or without thrombolytics. For patients greater than 75 years of age clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after symptoms start and continued for at least four weeks The benefit of the combination of clopidogrel with ASA beyond four weeks has not been studied in this setting (see section 5.1). Children and adolescents There is no experience in children. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients of the medicinal product. Severe liver impairment. Active pathological bleeding such as peptic ulcer or intracranial haemorrhage. Breast-feeding (see section 4.6). 4.4 Special warnings and precautions for use Due to the risk of bleeding and haematological undesirable effects, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment (see section 4.8). As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, non-steroidal anti-inflammatory drugs including Cox-2 inhibitors, heparin or glycoprotein IIb/IIIa inhibitors. Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. The concomitant administration of clopidogrel with warfarin is not recommended since it may increase the intensity of bleedings (see section 4.5). If a patient is to undergo elective surgery and antiplatelet effect is not necessary, clopidogrel should be discontinued 1 Packaging Asia/Pacific & Intercontinental Code: Update: V4-19/03/2007 Current item code: - Product/Item type: Notice Plavix 75 NF Country: Thaiwan Languages: EN / TW Market Barcode: - Artwork by: S. GOUTHEROT Plant: AMBARES Format: TC x 210 mm Plant barcode: 6876 (Laetus) Colour(s): 1 - Pantone Reflex Blue U Font(s): OceanSansAV Size: 5 points (mini) Technical Plans: Not TC.1 NOT RL-TC-37g NOT. SPOT. COD. ech1 GENERAL TECHNICAL

9 7 days prior to surgery. Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular). Patients should be told that it might take longer than usual to stop bleeding when they take clopidogrel (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new drug is taken. Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic hemolytic anemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis. In view of the lack of data, clopidogrel cannot be recommended in acute ischaemic stroke (less than 7 days). Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used with caution in these patients. Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction Warfarin: the concomitant administration of clopidogrel with warfarin is not recommended since it may increase the intensity of bleedings (see section 4.4). Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions that receive concomitant glycoprotein IIb/IIIa inhibitors. (see section 4.4) Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4). However, clopidogrel and ASA have been administered together for up to one year (see section 5.1). Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see section 4.4). Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with ASA (see section 4.8). Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): in a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administered with caution (see section 4.4). Other concomitant therapy: a number of other clinical studies have been conducted with clopidogrel and other concomitant medications to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co-administration of phenobarbital, cimetidine, or oestrogen. The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption. Data from studies with human liver microsomes indicated that the carboxylic acid metabolite of clopidogrel could inhibit the activity of Cytochrome P450 2C9. This could potentially lead to increased plasma levels of drugs such as phenytoin and tolbutamide and the NSAIDs, which are metabolised by Cytochrome P450 2C9. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel. Apart from the specific drug interaction information described above, interaction studies with clopidogrel and some drugs commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medications including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions. 4.6 Pregnancy and lactation Pregnancy As no clinical data on exposed pregnancies are available, it is preferable not to use clopidogrel during pregnancy as a precautionary measure. 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). Lactation Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this medicinal product is excreted in human milk. 4.7 Effects on ability to drive and use machines Clopidogrel has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects Clinical studies experience: Clopidogrel has been evaluated for safety in more than 42,000 patients, including over 9,000 patients treated for 1 year or more. The clinically relevant adverse effects observed in the CAPRIE, CURE, CLARITY and COMMIT studies are discussed below. Clopidogrel 75 mg/day was well tolerated compared to ASA 325 mg/day in CAPRIE. The overall tolerability of clopidogrel in this study was similar to ASA, regardless of age, gender and race. Haemorrhagic disorders: In CAPRIE, in patients treated with either clopidogrel or ASA, the overall incidence of any bleeding was 9.3%. The incidence of severe cases was 1.4% for clopidogrel and 1.6% for ASA. In patients that received clopidogrel, gastrointestinal bleeding occurred at a rate of 2.0%, and required hospitalisation in 0.7%. In patients that received ASA, the corresponding rates were 2.7% and 1.1%, respectively. The incidence of other bleedings was higher in patients that received clopidogrel compared to ASA (7.3% vs. 6.5%). However, the incidence of severe events was similar in both treatment groups (0.6% vs. 0.4%). The most frequently reported events in both treatment groups were: purpura/bruising/haematoma, and epistaxis. Other less frequently reported events were haematoma, haematuria, and eye bleeding (mainly conjunctival). The incidence of intracranial bleeding was 0.4% in patients that received clopidogrel and 0.5% for patients that received ASA. In CURE, the administration of clopidogrel+asa as compared to placebo+asa was not associated with a statistically significant increase in life-threatening bleeds (event rates 2.2% vs. 1.8%) or fatal bleeds (0.2% vs. 0.2%), but the risk of major, minor and other bleedings was significantly higher with clopidogrel+asa: non-life-threatening major bleeds (1.6% clopidogrel+asa vs. 1.0% placebo+asa), primarily gastrointestinal and at puncture sites, and minor bleeds (5.1% clopidogrel+asa vs. 2.4% placebo+asa). The incidence of intracranial bleeding was 0.1% in both groups. The major bleeding event rate for clopidogrel+asa was dose-dependent on ASA (<100mg: 2.6%; mg: 3.5%; >200mg: 4.9%) as was the major bleeding event rate for placebo+asa (<100mg: 2.0%; mg: 2.3%; >200mg: 4.0%). The risk of bleeding (life-threatening, major, minor, other) decreased during the course of the trial: 0-1 months [clopidogrel: 599/6259 (9.6%); placebo: 413/6303 (6.6%)], 1-3 months [clopidogrel: 276/6123 (4.5%); placebo: 144/6168 (2.3%)], 3-6 months [clopidogrel: 228/6037 (3.8%); placebo: 99/6048 (1.6%)], 6-9 months [clopidogrel: 162/5005 (3.2%); placebo: 74/4972 (1.5%)], 9-12 months [clopidogrel: 73/3841 (1.9%); placebo: 40/3844 (1.0%)]. There was no excess in major bleeds within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (4.4% clopidogrel+asa vs. 5.3% placebo+asa). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel+asa, and 6.3% for placebo+asa. In CLARITY, there was an overall increase in bleeding in the clopidogrel + ASA group (17.4%) vs. the placebo + ASA group (12.9%). The incidence of major bleeding was similar between groups (1.3% versus 1.1% for the clopidogrel + ASA and the placebo + ASA groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy. The incidence of fatal bleeding (0.8% versus 0.6% in the clopidogrel + ASA and the placebo + ASA groups, respectively) and intracranial hemorrhage (0.5% versus 0.7% in the clopidogrel + ASA and the placebo + ASA groups, respectively) was low and similar in both groups. In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar in both groups (0.6% versus 0.5% in the clopidogrel + ASA and the placebo + ASA groups, respectively). Haematological disorders: In CAPRIE, severe neutropenia (<0.45 x 109/l) was observed in 4 patients (0.04%) that received clopidogrel and 2 patients (0.02%) that received ASA. Two of the 9599 patients who received clopidogrel and none of the 9586 patients who received ASA had neutrophil counts of zero. One case of aplastic anaemia occurred on clopidogrel treatment. The incidence of severe thrombocytopenia (<80 x 109/l) was 0.2% on clopidogrel and 0.1% on ASA. In CURE and CLARITY, the number of patients with thrombocytopenia or neutropenia was similar in both groups. Other clinically relevant adverse drug reactions pooled from CAPRIE, CURE, CLARITY and COMMIT studies with an incidence > 0.1% as well as all serious and relevant ADR are listed below according to the World Health Organisation classification. Their frequency is defined using the following conventions: common (> 1/100, <1/10); uncommon (> 1/1,000, < 1/100); rare (>1/10,000, <1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Central and peripheral nervous system disorders: - Uncommon: Headache, Dizziness and Paraesthesia - Rare: Vertigo Gastrointestinal system disorders - Common: Diarrhoea, Abdominal pain, Dyspepsia - Uncommon: Gastric ulcer and Duodenal ulcer, Gastritis, Vomiting, Nausea, Constipation, Flatulence. Platelet, bleeding and clotting disorders - Uncommon: Bleeding time increased and Platelets decreased Skin and appendages disorders: - Uncommon: Rash and Pruritus 2 White cell and RES disorders - Uncommon: Leucopenia, Neutrophils decreased and Eosinophilia Post-marketing experience: Bleeding is the most common reaction reported in the post-marketing experience and was mostly reported during the first month of treatment. Bleeding: some cases were reported with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage); serious cases of skin bleeding (purpura), musculo-skeletal bleeding (haemarthrosis, haematoma), eye bleeding (conjunctival, ocular, retinal), epistaxis, respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), haematuria and haemorrhage of operative wound have been reported; cases of serious haemorrhage have been reported in patients taking clopidogrel concomitantly with acetylsalicylic acid or clopidogrel with acetylsalicylic acid and heparin (see section 4.4). In addition to clinical studies experience, the following adverse reactions have been spontaneously reported. Within each system organ class (MedDRA classification), they are ranked under heading of frequency. "Very rare" corresponds to <1/10,000. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Blood and lymphatic system disorders: - Very rare: Thrombotic Thrombocytopenic Purpura (TTP) (1/200,000 exposed patients) (see section 4.4), severe Thrombocytopenia (platelet count 30 x109/l), Agranulocytosis, Granulocytopenia, Aplastic Anaemia/Pancytopenia, Anaemia. Immune system disorders: - Very rare: Anaphylactoid reactions, Serum sickness Psychiatric disorders: - Very rare: Confusion, Hallucinations Nervous system disorders: - Very rare: Taste disturbances Vascular disorders: - Very rare: Vasculitis, Hypotension Respiratory, thoracic and mediastinal disorders: - Very rare: Bronchospasm, Interstitial pneumonitis Gastrointestinal disorders: - Very rare: Pancreatitis, Colitis (including ulcerative or lymphocytic colitis), Stomatitis Hepato-biliary disorders - Very rare: Acute liver failure, Hepatitis Skin and subcutaneous tissue disorders: - Very rare: Angioedema, Bullous dermatitis (erythema multiforme, Stevens Johnson Syndrome, toxic epidermal necrolysis), Rash erythematous, Urticaria, Eczema and Lichen planus Musculoskeletal, connective tissue and bone disorders: - Very rare: Arthralgia, Arthritis, Myalgia. Renal and urinary disorders: - Very rare: Glomerulonephritis. General disorders and administration site conditions - Very rare: Fever. Investigations: - Very rare: Abnormal liver function test, Blood creatinine increase 4.9 Overdose Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Appropriate therapy should be considered if bleedings are observed. No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: platelet aggregation inhibitors excl. Heparin, ATC Code: BO1AC/04. Clopidogrel selectively inhibits the binding of adenosine

10 diphosphate (ADP) to its platelet receptor, and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation by released ADP. Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued. The safety and efficacy of clopidogrel have been evaluated in 4 double-blind studies involving over 80,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY and COMMIT studies comparing clopidogrel to placebo, both drugs given in combination with ASA and other standard therapy. Recent myocardial infarction (MI), recent stroke or established peripheral arterial disease The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent myocardial infarction (<35 days), recent ischaemic stroke (between 7 days and 6 months) or established peripheral arterial disease (PAD). Patients were randomised to clopidogrel 75 mg/day or ASA 325 mg/day, and were followed for 1 to 3 years. In the myocardial infarction subgroup, most of the patients received ASA for the first few days following the acute myocardial infarction. Clopidogrel significantly reduced the incidence of new ischaemic events (combined end point of myocardial infarction, ischaemic stroke and vascular death) when compared to ASA. In the intention to treat analysis, 939 events were observed in the clopidogrel group and 1,020 events with ASA (relative risk reduction (RRR) 8.7%, [95% CI: 0.2 to 16.4]; p = 0.045), which corresponds, for every 1000 patients treated for 2 years, to 10 [CI: 0 to 20] additional patients being prevented from experiencing a new ischaemic event. Analysis of total mortality as a secondary endpoint did not show any significant difference between clopidogrel (5.8%) and ASA (6.0%). In a subgroup analysis by qualifying condition (myocardial infarction, ischaemic stroke, and PAD) the benefit appeared to be strongest (achieving statistical significance at p = 0.003) in patients enrolled due to PAD (especially those who also had a history of myocardial infarction) (RRR = 23.7%; CI: 8.9 to 36.2) and weaker (not significantly different from ASA) in stroke patients (RRR = 7.3%; CI: -5.7 to 18.7). In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was numerically inferior, but not statistically different from ASA (RRR = -4.0%; CI: to 11.7). In addition, a subgroup analysis by age suggested that the benefit of clopidogrel in patients over 75 years was less than that observed in patients 75 years. Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear whether the differences in relative risk reduction across qualifying conditions are real, or a result of chance. Acute coronary syndrome The CURE study included 12,562 patients with non-st segment elevation acute coronary syndrome (unstable angina or non-q-wave myocardial infarction), and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to have either ECG changes compatible with new ischaemia or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomised to clopidogrel (300 mg loading dose followed by 75 mg/day, N=6,259) or placebo (N=6,303), both given in combination with ASA ( mg once daily) and other standard therapies. Patients were treated for up to one year. In CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins were administered in more than 90% of the patients and the relative rate of bleeding between clopidogrel and placebo was not significantly affected by the concomitant heparin therapy. The number of patients experiencing the primary endpoint [cardiovascular (CV) death, myocardial infarction (MI), or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p= ) for the clopidogrel-treated group (17% relative risk reduction when patients were treated conservatively, 29% when they underwent PTCA with or without stent and 10% when they underwent CABG). New cardiovascular events (primary endpoint) were prevented, with relative risk reductions of 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1, 1-3, 3-6, 6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the benefit observed in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage persisted (see section 4.4). The use of clopidogrel in CURE was associated with a decrease in the need of thrombolytic therapy (RRR = 43.3%; CI: 24.3%, 57.5%) and GPIIb/IIIa inhibitors (RRR = 18.2%; CI: 6.5%, 28.3%). The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory ischaemia) was 1035 (16.5%) in the clopidogrel-treated group and 1187 (18.8%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the clopidogrel-treated group. This benefit was mostly driven by the statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel treated group and 363 (5.8%) in the placebo treated group]. There was no observed effect on the rate of rehospitalisation for unstable angina. The results obtained in populations with different characteristics (e.g. unstable angina or non-q-wave MI, low to high risk levels, diabetes, need for revascularisation, age, gender, etc.) were consistent with the results of the primary analysis. The benefits observed with clopidogrel were independent of other acute and long-term cardiovascular therapies (such as heparin/lmwh, GPIIb/IIIa antagonists, lipid lowering drugs, beta blockers, and ACE-inhibitors). The efficacy of clopidogrel was observed independently of the dose of ASA ( mg once daily). In patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT. The CLARITY trial included 3,491 patients presenting within 12 hours of the onset of a ST elevation MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, followed by 75 mg/day, n=1752) or placebo (n=1739), both in combination with ASA (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin. The patients were followed for 30 days. The primary endpoint was the occurrence of the composite of an occluded infarctrelated artery on the predischarge angiogram, or death or recurrent MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent myocardial infarction by Day 8 or by hospital discharge. The patient population included 19.7% women and 29.2% patients? 65 years. A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.7%, non- fibrin specific: 31.1%), 89.5% heparin, 78.7% beta blockers, 54.7% ACE inhibitors and 63% statins. Fifteen percent (15.0%) of patients in the clopidogrel group and 21.7% in the placebo group reached the primary endpoint, representing an absolute reduction of 6.7% and a 36 % odds reduction in favor of clopidogrel (95% CI: 24, 47%; p < 0.001), mainly related to a reduction in occluded infarct-related arteries. This benefit was consistent across all prespecified subgroups including patients age and gender, infarct location, and type of fibrinolytic or heparin used. The 2x2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) or placebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge. The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The population included 27.8% women, 58.4% patients 60 years (26% 70 years) and 54.5% patients who received fibrinolytics. Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002), representing an absolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender and with or without fibrinolytics, and was observed as early as 24 hours. 5.2 Pharmacokinetic properties After repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. However, plasma concentrations of the parent compound are very low and below the quantification limit ( mg/l) beyond 2 hours. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites. Clopidogrel is extensively metabolised by the liver and the main metabolite, which is inactive, is the carboxylic acid derivative, which represents about 85% of the circulating compound in plasma. Peak plasma levels of this metabolite (approx. 3mg/l after repeated 75 mg oral doses) occurred approximately 1 hour after dosing. Clopidogrel is a prodrug. The active metabolite, a thiol derivative, is formed by oxidation of clopidogrel to 2-oxoclopidogrel and subsequent hydrolysis. The oxidative step is regulated primarily by Cytochrome P450 isoenzymes 2B6 and 3A4 and to a lesser extent by 1A1, 1A2 and 2C19. The active thiol metabolite, which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation. This metabolite has not been detected in plasma. The kinetics of the main circulating metabolite were linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150 mg of clopidogrel. Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94% respectively). The binding is non-saturable in vitro over a wide concentration range. Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hour interval after dosing. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration. After repeated doses of 75 mg clopidogrel per day, plasma levels of the main circulating metabolite were lower in subjects with severe renal disease (creatinine clearance from 5 to 15 ml/min) compared to subjects with moderate renal disease (creatinine clearance from 30 to 60 ml/min) and to levels observed in other studies with healthy subjects. Although inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, the prolongation of bleeding was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients. The pharmacokinetics and pharmacodynamics of clopidogrel were assessed in a single and multiple dose study in both healthy subjects and those with cirrhosis (Child-Pugh class A or B). Daily dosing for 10 days with clopidogrel 75 mg/day was safe and well tolerated. Clopidogrel Cmax for both single dose and steady state for cirrhotics was many fold higher than in normal subjects. However, plasma levels of the main circulating metabolite together with the effect of clopidogrel on ADP-induced platelet aggregation and bleeding time were comparable between these groups. 5.3 Preclinical safety data During non clinical studies in rat and baboon, the most frequently observed effects were liver changes. These occurred at doses representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day and were a consequence of an effect on hepatic metabolising enzymes. No effect on hepatic metabolising enzymes was observed in humans receiving clopidogrel at the therapeutic dose. At very high doses, a poor gastric tolerability (gastritis, gastric erosions and/or vomiting) of clopidogrel was also reported in rat and baboon. There was no evidence of carcinogenic effect when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats when given at doses up to 77 mg/kg per day (representing at least 25 times the exposure seen in humans receiving the clinical dose of 75 mg/day). Clopidogrel has been tested in a range of in vitro and in vivo genotoxicity studies, and showed no genotoxic activity. Clopidogrel was found to have no effect on the fertility of male and female rats and was not teratogenic in either rats or rabbits. When given to lactating rats, clopidogrel caused a slight delay in the development of the offspring. Specific pharmacokinetic studies performed with radiolabelled clopidogrel have shown that the parent compound or its metabolites are excreted in the milk. Consequently, a direct effect (slight toxicity), or an indirect effect (low palatability) cannot be excluded. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Core: Mannitol (E421) Macrogol 6000 Microcrystalline cellulose Hydrogenated castor oil Low substituted hydroxypropylcellulose Coating: Hypromellose (E464), Lactose, Triacetin (E1518), Titanium dioxide (E171), Red iron oxide (E172), Carnauba wax 6.2 Incompatibilities Not applicable 6.3 Shelf-life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. Store in the original package. 6.5 Nature and content of container 28, 50, 84 and 100 film-coated tablets packed in PVC/PVDC/Aluminium blisters or in all aluminium blisters in cardboard cartons. Not all pack sizes may be marketed. 6.6 Special precautions for disposal No special requirements 7.MARKETING AUTHORISATION HOLDER Sanofi Pharma Bristol-Myers Squibb SNC 174 Avenue de France - F Paris France 8.MARKETING AUTHORISATION NUMBERS EU/1/98/069/001a - Cartons of 28 film-coated tablets in PVC/PVDC/Alu blisters EU/1/98/069/001b - Cartons of 28 film-coated tablets in all aluminium blisters EU/1/98/069/002a - Cartons of 50 film-coated tablets in PVC/PVDC/Alu blisters EU/1/98/069/002b - Cartons of 50 film-coated tablets in all aluminium blisters EU/1/98/069/003a - Cartons of 84 film-coated tablets in PVC/PVDC/Alu blisters EU/1/98/069/003b - Cartons of 84 film-coated tablets in all aluminium blisters EU/1/98/069/004a - Cartons of 100 film-coated tablets in PVC/PVDC/Alu blisters EU/1/98/069/004b - Cartons of 100 film-coated tablets in all aluminium blisters 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 15 July 1998 Date of last renewal: 15 July DATE OF REVISION OF THE TEXT 3