Clopiwin Plus 75 mg FC tablets.

CLOPIWIN PLUS is indicated in adults for the reduction of atherothrombotic events in adult patients already taking both clopidogrel and acetylsalicylic acid (ASA). CLOPIWIN PLUS is a fixed-dose combination product for continuation of therapy in:

Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave myocardial infarction [MI]) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG (coronary artery bypass graft), clopidogrel in combination with ASA has been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischaemia.

For patients with ST-segment elevation acute myocardial infarction, clopidogrel in combination with ASA has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction or stroke.

Posology

Acute Coronary Syndrome: CLOPIWIN PLUS should be given as a single daily dose (i.e. one CLOPIWIN PLUS tablet daily). CLOPIWIN PLUS is used following an initial loading dose of clopidogrel in combination with ASA. It may be given with or without food.

• In patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, but the maximum benefit was seen at 3 months.
• In patients with ST segment elevation acute myocardial infarction: 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. For patients older than 75 years of age therapy should be initiated without a loading dose of clopidogrel.

Pharmacogenetics: CYP2C19 poor metaboliser status is associated with diminished antiplatelet response to clopidogrel. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.

Due to the presence of clopidogrel and acetylsalicylic acid in the medicine, CLOPIWIN PLUS is contraindicated in case of:

• Hypersensitivity to the active substances or to any of the excipients of CLOPIWIN PLUS (see section 6.1).
• Active or history of pathological bleeding such as recurrent peptic ulcer/haemorrhage/perforations or intracranial haemorrhage.
• Safety and efficacy in subjects below the age of 18 have not been established. ASA has been implicated in Reyeu2019s syndrome, a rare but serious illness in children and teenagers with chickenpox and influenza. A doctor should be consulted before aspirin is used in such patients.
• Safety and efficacy in pregnancy and lactation have not been established (see section 4.6).
• Severe hepatic impairment.
• Thrombocytopenia and platelet dysfunction.

In addition, due to the presence of ASA, CLOPIWIN PLUS is also contraindicated in:

• Patients with hypersensitivity (allergy) to non-steroidal anti-inflammatory drugs (NSAIDs) and syndrome of asthma, rhinitis, and nasal polyps. Patients with pre-existing mastocytosis, in whom the use of acetylsalicylic acid may induce severe hypersensitivity reactions (including circulatory shock with flushing, hypotension, tachycardia and vomiting).
• Patients with severe renal impairment.
• Patients with heart failure.
• Patients with a history of gastrointestinal bleeding, ulceration or perforation (PUBs) related to previous NSAIDs.
• Pregnancy and lactation (see section 4.6).

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP) HAS BEEN REPORTED TO OCCUR WITH CLOPIWIN PLUS DURING POST-MARKETING EXPERIENCE. MOST CASES WERE REPORTED IN THE FIRST TWO WEEKS OF TREATMENT. PRESCRIBERS SHOULD ALSO WARN PATIENTS ABOUT THE SIGNS AND SYMPTOMS OF THROMBOTIC THROMBOCYTOPENIC PURPURA. IT IS CHARACTERISED BY THROMBOCYTOPENIA AND MICROANGIOPATHIC HAEMOLYTIC ANAEMIA ASSOCIATED WITH EITHER NEUROLOGICAL FINDINGS, RENAL DYSFUNCTION OR FEVER. TTP IS A POTENTIALLY FATAL CONDITION REQUIRING PROMPT TREATMENT, INCLUDING PLASMAPHERESIS (PLASMA EXCHANGE).

Recent transient ischaemic attack or stroke: In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic events, the combination of aspirin and clopidogrel has been shown to increase major bleeding.

Acquired haemophilia: Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and CLOPIWIN PLUS should be discontinued.

Fluid retention and oedema: In view of the inherent potential of NSAIDs, including ASA, to cause fluid retention, heart failure may be precipitated in some compromised patients. Caution is required in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with CLOPIWIN PLUS therapy.

Elderly: The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding, ulceration and perforation (PUBs) which may be fatal.

Due to the presence of ASA caution is required:

• In patients with a history of asthma or allergic disorders since they are at increased risk of hypersensitivity reactions.
• In patients with gout since low doses of ASA increase serum uric acid concentrations.
• There is an association between ASA and Reyeu2019s syndrome when ASA is given to children. Reyeu2019s syndrome is a very rare disease which can be fatal.
• Alcohol may increase the risk of gastrointestinal injury when taken with ASA. Therefore, alcohol should be used with caution in patients taking CLOPIWIN PLUS (see section 4.5). Patients should be counselled about the bleeding risks involved with chronic, heavy alcohol use while taking CLOPIWIN PLUS.
• CLOPIWIN PLUS must be administered under close medical supervision in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to risk of haemolysis (see section 4.8).
• Concomitant treatment with levothyroxine and salicylates, specifically at doses greater than 2,0 g/day, should be avoided (see section 4.5).

There are no studies on the concomitant use of clopidogrel and acetylsalicylic acid with other medicines. The information below was obtained with clopidogrel or ASA alone. Safety of CLOPIWIN PLUS and the concomitant use with the medicines mentioned below have not been established.

Medicines associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of medicines associated with bleeding risk should be undertaken with caution.

Nicorandil: In patients concomitantly receiving nicorandil and NSAIDs including acetylsalicylic acid (ASA) and lysine acetylsalicylic acid (LAS), there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and haemorrhage (see section 4.4).

Injectable anticoagulants: 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. As a pharmacodynamic interaction between CLOPIWIN PLUS and heparin is possible, concomitant use should be undertaken with caution.

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 heparins are co-administered with acetylsalicylic acid. However, the concomitant use of CLOPIWIN PLUS with thrombolytic agents should be undertaken with caution.

Oral anticoagulants: Because of the increased risk of bleeding, the concomitant administration of warfarin with CLOPIWIN PLUS is not recommended (see section 4.4).

Glycoprotein IIb/IIIa inhibitors: CLOPIWIN PLUS should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and who receive concomitant glycoprotein IIb/IIIa inhibitors.

Non-Steroidal Anti-Inflammatory Agents (NSAIDs): In healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. Consequently, the concomitant use of NSAIDs, including Cox-2 inhibitors, is not recommended with CLOPIWIN PLUS (see section 4.4).

Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly (see section 5.1). However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.

Selective Serotonin Reuptake Inhibitors (SSRIs): Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution.

Other concomitant therapy with clopidogrel: Inducers of CYP2C19: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicines that induce the activity of this enzyme would be expected to result in increased medicine levels of the active metabolite of clopidogrel. Rifampicin strongly induces CYP2C19, resulting in both an increased level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be discouraged (see Section 4.4).

Inhibitors of CYP2C19: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicine that inhibit the activity of this enzyme would be expected to result in reduced medicine levels of the active metabolite of clopidogrel and a reduction in clinical efficacy. Concomitant use of strong or moderate CYP2C19 inhibitors (e.g., omeprazole and esomeprazole) should be discouraged (see section 4.4 and section 5.2, Pharmacogenetics). If a proton pump inhibitor is to be used concomitantly with CLOPIWIN PLUS, consider using one with less CYP2C19 inhibitory activity.

Other medicinal products: No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of clopidogrel was not significantly influenced by the co-administration of phenobarbital 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 clopidogrel could inhibit the activity of one of the Cytochrome P450 (CYP) enzymes (CYP2C9). This could potentially lead to increased plasma levels of medicines such as phenytoin, tolbutamide, torsemide, tamoxifen, fluvastatin and NSAIDs which are metabolised by CYP2C9. Data indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.

CYP2C8 substrate medicines: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and medicines primarily cleared by CYP2C8 metabolism (e.g. repaglinide, paclitaxel) should be undertaken with caution.

Pregnancy

CLOPIWIN PLUS should not be used during pregnancy (see section 4.3).

Breastfeeding

Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether clopidogrel is excreted in human breast milk. ASA is known to be excreted in human breast milk. Mothers treated with CLOPIWIN PLUS should not breastfeed their infants (see section 4.3).

CLOPIWIN PLUS has no or negligible influence on the ability to drive and use machines.

Bleeding is the most common reaction reported both in clinical studies where frequencies varied from common to very common, as well as in post-marketing experience. In the CAPRIE study, for patients treated with clopidogrel, the overall incidence of any bleeding was 9,3 %. For clopidogrel, the incidence of severe cases was 1,4 %, and gastrointestinal bleeding occurred at a rate of 2,0 %, and required hospitalisation in 0,7 %. In the CURE study, the incidence of major and minor bleeding in the clopidogrel + ASA group was 3,7 % and 5,1 %, respectively. The principal sites for major bleeding included gastrointestinal and at arterial puncture sites. In an acute coronary syndrome study where clopidogrel was administered concomitantly with ASA, the major bleeding event rate for clopidogrel + ASA was dose-dependent on ASA ( 200 mg: 4,9 %) There was no excess in major bleeds with clopidogrel + ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (4,4 % clopidogrel + ASA). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9,6 % for clopidogrel + ASA.

Adverse reactions have been ranked under heading of system-organ class and frequency using the following convention: Very common ( u2265 1/10); common ( u2265 1/100, < 1/10); uncommon ( u2265 1/1 000, < 1/100); rare ( u2265 1/10 000, < 1/1 000); very rare (< 1/10 000).

Blood and lymphatic system disorders: Uncommon: thrombocytopenia (sometimes severe), increased bleeding time, leucopenia, eosinophilia, neutropenia (sometimes severe), platelets decreased. Very rare: aplastic anaemia. These events related to myelotoxicity should be considered when a patient receiving CLOPIWIN PLUS demonstrates fever or other sign of infection.

Nervous system disorders: Uncommon: intracranial bleeding, headache, dizziness, paraesthesia.

Eye disorders: Uncommon: eye bleeding (mainly conjunctival).

Ear and labyrinth disorders: Rare: vertigo.

Vascular disorders: Common: haematoma.

Respiratory, thoracic and mediastinal disorders: Common: epistaxis.

Gastrointestinal system disorders: Common: dyspepsia, abdominal pain, diarrhoea. Uncommon: nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer, duodenal ulcer.

Skin and subcutaneous tissue disorders: Common: bruising. Uncommon: rash, pruritus, purpura.

Renal and urinary disorders: Uncommon: haematuria.

General disorders and administrative site conditions: Common: bleeding at the puncture site.

Post marketing experience: Bleeding is the most common reaction reported in the post-marketing experience with clopidogrel or ASA.

There is no information concerning overdosage with the fixed-dose combination, CLOPIWIN PLUS.

Signs and symptoms:

Clopidogrel: Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications.

Acetylsalicylic acid (ASA): Overdosage is manifested by the following symptoms: Moderate overdose: ringing in the ears, sensation of reduced hearing, headaches, vertigo and gastrointestinal symptoms (nausea, vomiting and gastric pain). Severe overdose: fever, hyperventilation, ketosis, respiratory alkalosis, metabolic acidosis, coma, cardiovascular collapse, respiratory failure, severe hypoglycaemia. Non-cardiogenic pulmonary oedema can occur with acute and chronic acetylsalicylic acid overdose (see section 4.8).

Management:

Clopidogrel: 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. Further treatment is symptomatic and supportive.

Acetylsalicylic acid (ASA): If a toxic dose has been ingested then admission to hospital is necessary. With moderate intoxication an attempt can be made to induce vomiting; if this fails, gastric lavage is indicated. Activated charcoal (adsorbent) and sodium sulphate (laxative) are then administered. Alkalising of the urine (250 mmol sodium bicarbonate for 3 hours) while monitoring the urine pH is indicated. Haemodialysis is the preferred treatment for severe intoxication. Treat other signs of intoxication symptomatically.