Clopidogrel Mylan 75 mg film-coated tablets

Each film-coated tablet contains 75 mg of clopidogrel (as hydrochloride).

Excipient:

Each film-coated tablet contains 13 mg hydrogenated castor oil.

For a full list of excipients, see section 6.1.

Film-coated tablet.

Pink, round and slightly convex film-coated tablets.

Clopidogrel is indicated in adults 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.

For further information please refer to section 5.1.

• Adults and elderly

Clopidogrel should be given as a single daily dose of 75 mg with or without food.

• Paediatric patients

The safety and efficacy of clopidogrel in children and adolescents have not yet been established.

• Renal impairment

Therapeutic experience is limited in patients with renal impairment (see section 4.4).

• Hepatic impairment

Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses (see section 4.4).

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

• Severe liver impairment.

• Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

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, heparin, glycoprotein IIb/IIIa inhibitors or non-steroidal anti-inflammatory drugs including Cox2 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 oral anticoagulants 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 temporarily not desirable, clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal product is taken. 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.

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 haemolytic anaemia 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 during the first 7 days after acute ischaemic stroke.

Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used with caution in these patients (see section 4.2).

Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population (see section 4.2).

This product contains hydrogenated castor oil which may cause stomach upset and diarrhoea.

Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants 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 medicinal products 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 coadministration 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 medicinal products 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 medicinal product interaction information described above, interaction studies with clopidogrel and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medicinal products including diuretics, beta blockers, ACEI, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.

As no clinical data on exposure to clopidogrel during pregnancy 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).

It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be continued during treatment with Clopidogrel Mylan.

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

Clopidogrel has been eva luated for safety in more than 42,000 patients, who have participated in clinical studies, including over 9,000 patients treated for 1 year or more. The clinically relevant adverse reactions observed in the CAPRIE, CURE, CLARITY and COMMIT studies are discussed below. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender and race. In addition to clinical studies experience, adverse reactions have been spontaneously reported.

Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing experience where it was mostly reported during the first month of treatment.

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 CURE, the major bleeding event rate for clopidogrel+ASA was dose-dependent on ASA (<100 mg: 2.6%; 100200 mg: 3.5%; >200 mg: 4.9%) as was the major bleeding event rate for placebo+ASA (<100 mg: 2.0%; 100200 mg: 2.3%; >200 mg: 4.0%). The risk of bleeding (life-threatening, major, minor, other) decreased during the course of the trial: 01 months (clopidogrel: 9.6%; placebo: 6.6%), 13 months (clopidogrel: 4.5%; placebo: 2.3%), 36 months (clopidogrel: 3.8%; placebo: 1.6%), 69 months (clopidogrel: 3.2%; placebo: 1.5%), 912 months (clopidogrel: 1.9%; placebo: 1.0%). 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 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.

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).

Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the table below. Their frequency is defined using the following conventions: common (1/100 to <1/10); uncommon (1/1,000 to < 1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000).

Within each system organ class, adverse drug reactions are presented in order of decreasing seriousness.

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.

Pharmacotherapeutic group: platelet aggregation inhibitors excl. heparin, ATC code: B01AC-04.

Clopidogrel selectively inhibits the binding of adenosine 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 eva luated 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 medicinal products 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 [p=0.258]). 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: -22.5 to 11.7 [p=0.639]). 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 eva luate 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.

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 (0.00025 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. 3 mg/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-oxo-clopidogrel 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 120hour interval after dosing. The elimination halflife 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 (ChildPugh class A or B). Daily dosing for 10 days with clopidogrel 75 mg/day was safe and well tolerated. Clopidogrel C_max 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.