PLAVIX

Clopidogrel hydrogen sulfate

Description

Clopidogrel hydrogen sulfate is designated chemically as methyl (+)-(S)-(-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate sulfate (1:1).

The empirical formula of clopidogrel hydrogen sulfate is C₁₆H₁₆ClNO₂S. H₂SO₄ and its molecular weight is 419.9.

CAS Number: 120202-66-6 (Clopidogrel hydrogen sulfate),

113 665-84-2 (Clopidogrel base).

Clopidogrel hydrogen sulfate is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It is freely soluble in methanol, sparingly soluble in methylene chloride and is practically insoluble in ethyl ether. It has a specific optical rotation of about + 56°.

Each tablet contains mannitol, macrogol 6000, microcrystalline cellulose, castor oil-hydrogenated, hydroxypropylcellulose. The coating contains lactose, hypromellose, titanium dioxide, glycerol triacetate, iron oxide red and carnauba wax.

Pharmacology

Pharmacodynamics

Clopidogrel is a specific and potent inhibitor of platelet aggregation. Platelets have an established role in the pathophysiology of atherosclerotic disease and thrombotic events. Long term use of anti-platelet drugs has shown consistent benefit in the prevention of ischaemic stroke, myocardial infarction and vascular death in patients at increased risk of such outcomes, including those with established atherosclerosis or a history of atherothrombosis.

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. However, an active metabolite responsible for the activity of the drug has not been isolated. 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 (approximately 7 days).

Statistically significant and dose-dependent inhibition of platelet aggregation was noted 2 hours after single oral doses of clopidogrel. 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 7 days after treatment was discontinued.

Pharmacokinetics

After repeated oral doses of 75 mg per day, a single oral dose of 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.

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.

Plasma concentrations of the main circulating metabolite were significantly higher in elderly subjects (( 75 years) as compared to young healthy volunteers. However, these higher plasma levels were not associated with differences in platelet aggregation and bleeding time.

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 healthy subjects, after repeated doses of 75 mg/day. 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.

Special Populations

Geriatric Patients

Plasma concentrations of the main circulating metabolite are significantly higher in the elderly (≥ 75 years) compared to young healthy volunteers but these higher plasma levels were not associated with differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.

Renally Impaired Patients

After repeated doses of 75 mg clopidogrel per day, plasma levels of the main circulating metabolite were lower in patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) compared to subjects with moderate renal impairment (creatinine clearance 30 to 60 mL/min) or healthy subjects. Although inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy volunteers, the prolongation of bleeding time was similar in healthy volunteers receiving 75 mg of clopidogrel per day. No dosage adjustment is needed in renally impaired patients. However, experience with clopidogrel is limited in patients with severe renal impairment. Therefore clopidogrel should be used with caution in this population.

Gender

No significant difference was observed in the plasma levels of the main circulating metabolite between males and females. In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in prolongation of bleeding time. In the large, controlled clinical study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events; CAPRIE), the incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.

Race

Pharmacokinetic differences due to race have not been studied.

Clinical Trials

The safety and efficacy of clopidogrel in preventing vascular ischaemic events has been evaluated in two double-blind studies: the CAPRIE study, a comparison of clopidogrel to aspirin and the CURE study, a comparison of clopidogrel in combination with aspirin, to placebo with aspirin).

The CAPRIE study included 19,185 patients with established atherosclerosis or history of atherothrombosis as manifested by myocardial infarction, ischaemic stroke or peripheral arterial disease. Patients were randomised to clopidogrel 75 mg/day or aspirin 325 mg/day, and were followed for 1 to 3 years.

The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.

Outcome Events of the Primary Analysis

As shown in the table, clopidogrel was associated with a lower incidence of outcome events of every kind. The overall risk reduction (9.78% vs. 10.64%) was 8.7%, P=0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was again lower in the clopidogrel group.

The curves showing the overall event rate are shown in the figure. The event curves separated early and continued to diverge over the 3-year follow-up period.

The CURE study included 12,562 patients with acute coronary syndrome (unstable angina or non-ST-elevation 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=6244) or placebo (n = 6287), both given in combination with aspirin (75-325 mg once daily) and other standard therapies (oral anti-coagulants and long term NSAIDs were not permitted). Patients were treated for up to one year.

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=0.00009) for the clopidogrel-treated group. The benefits of clopidogrel were seen within a few hours and maintained throughout the course of the study (up to 12 months). The primary outcome was reduced to a similar extent within the first 30 days (relative risk reduction of 22%), from 30 days to one year (relative risk reduction of 19%), and for the entire one year study (relative risk reduction of 20%).

The number of patients experiencing the co-primary endpoint (CV death, MI, stroke or refractory ischemia) 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, a benefit which was consistent for each component, indicating that clopidogrel reduced a range of atherothrombotic events.

In the course of the study, patients who underwent cardiac revascularisation (surgical or percutaneous coronary intervention with or without coronary stent implantation), received similar benefit from clopidogrel + aspirin (including standard therapies) as those who did not have a cardiac revascularisation.

The results obtained in populations with different characteristics (e.g. unstable angina or non-ST-elevation 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 aspirin (75-325 mg once daily).

Indications

Prevention of vascular ischaemia associated with atherothrombotic events (MI, stroke and vascular death) in patients with a history of symptomatic atherosclerotic disease.

In acute coronary syndrome (unstable angina or non-ST elevation MI) in combination with aspirin, Plavix is indicated for early and long-term reduction of atherothrombotic events (myocardial infarction, stroke, vascular death and refractory ischaemia) whether or not patients undergo cardiac revascularisation (surgical or PCI, with or without stent).

Contraindications

Hypersensitivity to clopidogrel or any of the excipients.

Severe liver impairment.

Active pathological bleeding such as peptic ulcer and intracranial haemorrhage.

Breast-feeding (see PRECAUTIONS-Pregnancy and Lactation).

Precautions

As with the other anti-platelet agents, clopidogrel prolongs bleeding time and should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions, as follows:

• If a patient is to undergo elective surgery and an anti-platelet effect is not desired, clopidogrel should be discontinued at least 5 days prior to surgery.
• If the patient is at high risk of ophthalmic bleeding due to intraocular lesions clopidogrel should be used with extra caution.
• Although clopidogrel has shown a lower incidence of gastrointestinal bleeding compared to aspirin in a large controlled clinical trial (CAPRIE), the drug should be used with caution in patients who have lesions with a propensity to bleed. Drugs that might induce such lesions (such as aspirin and Non-Steroidal Anti-Inflammatory Drugs) should be used with caution in patients taking clopidogrel. (See PRECAUTIONS-Interactions With Other Drugs).

Patients should be told that it may take longer than usual for bleeding to stop when they take clopidogrel (alone or in combination with aspirin), 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.

Experience with clopidogrel is limited in patients with severe renal impairment. Therefore clopidogrel should be used with caution in this population.

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

In the CAPRIE study, it was not mandatory to discontinue study medication in the case of an acute outcome event (acute myocardial infarction, ischaemic stroke or lower extremity amputation) and the patients had a favourable outcome as compared to the aspirin group.

In view of the lack of data, clopidogrel cannot be recommended in acute ischaemic stroke (less than 7 days).

Coronary Artery Bypass Surgery

When coronary artery bypass surgery is to be performed, clopidogrel should be suspended at least 5 days before surgery to reduce the risk of bleeding (see ADVERSE REACTIONS)

Haematological

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 condition requiring prompt treatment.

Thrombocytopenia, neutropenia, aplastic anaemia and pancytopenia have also been reported very rarely in patients taking clopidogrel (see ADVERSE REACTIONS).

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. As with other anti-platelet 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 aspirin, non-steroidal anti-inflammatory drugs, heparin, glycoprotein IIb/IIIa inhibitors or thrombolytics. 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.

Carcinogenicity, mutagenicity and impairment of fertility

There was no evidence of carcinogenic effects when clopidogrel was given in the diet for 78 weeks to mice and 104 weeks to rats at doses up to 77 mg/kg per day (representing an exposure » 18 times the anticipated patient exposure, based on plasma AUC for the main circulating metabolite in elderly subjects).

Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by the oral route in mice).

Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day and was not teratogenic in rats (up to 500 mg/kg per day) and rabbits (up to 300 mg/kg per day).

Use in Pregnancy

Clopidogrel and/or its metabolites are known to cross the placenta in pregnant rats and rabbits. However, teratology studies in rats and rabbits at doses up to 500 mg and 300 mg/kg/day PO, respectively, revealed no evidence of embryotoxicity or teratogenicity. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should not be used in women during pregnancy.

Use in Lactation

Studies in rats have shown that clopidogrel and/or its metabolites are excreted in breast milk (See CONTRAINDICATIONS).

Interactions with other drugs

Aspirin

A pharmacodynamic interaction between clopidogrel and aspirin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. (See PRECAUTIONS). However, clopidogrel and aspirin have been administered together for up to one year.

Heparin

A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.

Thrombolytics

The safety of the concomitant administration of clopidogrel, rt-PA and heparin was assessed in patients with recent myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when rt-PA and heparin are co-administered with aspirin. The safety of the administration of clopidogrel with other thrombolytic agents has not been established and should be undertaken with caution. In the CURE study, amongst patients who received clopidogrel plus aspirin and went on to have thrombolytic therapy, 8.5% had a life-threatening or major bleed. In comparison, life-threatening/major bleeds occurred in 11.9% of patients taking placebo plus aspirin who went on to receive a thrombolytic agent. However, experience is very limited and caution should be exercised in this situation.

Warfarin

Due to the increased risk of bleeding. concomitant administration of these two agents should be undertaken with caution.

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. Consequently, there is a potential increased risk of gastro-intestinal bleeding and NSAIDs and clopidogrel should be co-administered with caution (See PRECAUTIONS).

Drugs metabolised by Cytochrome P450 2C9

At high concentrations in vitro, clopidogrel inhibits cytochrome P450 (2C9). Accordingly, Plavix may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is co-administered with Plavix.

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.

In addition to the above specific interaction studies, patients entered into clinical trials with clopidogrel (including CAPRIE and CURE) received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, anti-diabetic agents (including insulin), anti-epileptic agents, GPIIb/IIIa antagonists and hormone replacement therapy without evidence of clinically significant adverse interactions.

Effects on ability to drive and use machines

No impairment of driving or psychometric performance was observed following clopidogrel administration.

Adverse Reactions

Clopidogrel has been evaluated for safety in more than 17,500 patients, including over 9,000 patients treated for 1 year or more.

Clopidogrel was well tolerated compared to aspirin in a large controlled clinical trial (CAPRIE). The overall tolerability of clopidogrel in this study was similar to aspirin, regardless of age, gender and race. The clinically relevant adverse events observed in CAPRIE and CURE are discussed below.

Haemorrhagic

In CAPRIE, the overall incidence of any bleeding in patients treated with either clopidogrel or aspirin was similar (9.3%). The incidence of severe bleeds was 1.4% in the clopidogrel group and 1.6% in the aspirin group.

Gastrointestinal haemorrhage was significantly less frequent with clopidogrel (1.99%) compared to aspirin (2.66%). The incidence of intracranial haemorrhage was 0.35% for clopidogrel compared to 0.49% for aspirin.

In CURE, the administration of clopidogrel + aspirin as compared to placebo + aspirin, was not associated with an increase in life-threatening or fatal bleeds (event rates 2.2% vs. 1.8% and 0.2% vs. 0.2%, respectively). The incidence of intra-cranial bleeding was 0.1% in both groups.

There was a significant difference between the two treatment groups for other types of bleeding: non life- threatening major bleeds (1.6% clopidogrel + aspirin vs. 1.0% placebo + aspirin), primarily gastrointestinal and at puncture sites, and minor bleeds (5.1% clopidogrel + aspirin vs. 2.4% placebo + aspirin). The major bleeding event rate for clopidogrel + aspirin was dose-dependent on aspirin (<100mg: 2.6%; 100-200mg: 3.5%; >200mg: 4.9%) as was the major bleeding event rate for placebo + aspirin (<100mg: 2.0%; 100-200mg: 2.3%; >200mg: 4.0%).

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 + aspirin vs. 5.3% placebo + aspirin). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel + aspirin, and 6.3% for placebo + aspirin.

Haematological

In CAPRIE. patients were intensively monitored for thrombocytopenia and neutropenia.

Clopidogrel was not associated with an increase in the incidence of thrombocytopenia compared to aspirin. Very rare cases of platelet count ≤ 30 × 10⁹/L have been reported.

Severe neutropenia (<0.45 × 10⁹/L) was observed in four patients (0.04%) that received clopidogrel and in two patients that received aspirin. Two of the 9599 patients who received clopidogrel and none of the patients who received aspirin had a neutrophil count of zero. One of the clopidogrel treated patients was receiving cytostatic chemotherapy, and another recovered and returned to the trial after only temporarily interrupting treatment with clopidogrel.

In CURE, the numbers of patients with thrombocytopenia (19 clopidogrel + aspirin vs. 24 placebo + aspirin) or neutropenia (3 vs. 3) were similar in both groups.

Although the risk of myelotoxicity with clopidogrel appears to be quite low, this possibility should be considered when a patient receiving clopidogrel demonstrates fever or other signs of infection.

Gastrointestinal

In CAPRIE, overall the incidence of gastrointestinal events (e.g. abdominal pain, dyspepsia, gastritis and constipation) in patients receiving clopidogrel was significantly lower than in those receiving aspirin. The incidence of peptic, gastric, or duodenal ulcers was 0.68% for clopidogrel and 1.15% for aspirin. Cases of diarrhoea were reported at a higher frequency in the clopidogrel group (4.46%) compared to the aspirin group (3.36%).

In CURE, there was no significant difference in the incidence of non-haemorrhagic gastrointestinal effects in the clopidogrel or placebo groups.

Rash

In CAPRIE. there were significantly more patients with rash in the clopidogrel group (4.2%) compared to the aspirin group (3.5%).

In CURE, rash occurred in more patients in the clopidogrel group.

Treatment Discontinuation

In the clopidogrel and aspirin treatment groups of the CAPRIE study, discontinuation due to adverse events occurred in approximately 13% of patients after 2 years of treatment. Adverse events occurring in ≥ 2.5% of patients on clopidogrel in the CAPRIE controlled clinical trial are shown in the table below regardless of relationship to clopidogrel. The median duration of therapy was 20 months, with a maximum of 3 years.

In CURE, the overall incidence of discontinuation due to adverse events was greater in the clopidogrel group than in the placebo group (366 [5.8%] and 247 [3.9%] patients, respectively), with the main differences being in events in the platelet, bleeding and clotting disorders (1.1% versus 0.7%) and skin disorders (0.7% versus 0.3%). The increase in the rate of study drug discontinuation due to non-hemorrhagic adverse events was primarily due to the increase in rash seen in the clopidogrel group. There was no apparent difference between the 2 treatment groups in the rates of discontinuations due to other adverse events.

Adverse events occurring in ≥ 2.5% of patients receiving Clopidogrel

* indicates statistical significance (p≤0.05)

Incidence of discontinuation, regardless of relationship to therapy is shown in parentheses.

Body as a whole - general

• Rarely: Hypersensitivity reactions. These mainly include skin reactions (maculopapular or erythematous rash, urticaria) and/or pruritus. Very rare cases of bronchospasm, angioedema , anaphylactoid reactions and bullous eruption (erythema multiforme) have been observed.
• Very rarely: Fever

Musculoskeletal

• Very rarely: Arthralgia, arthritis

Collagen Disorder

• Very rarely: vasculitis

Haematological:

• Uncommon: Fatal haemorrhage, including 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 aspirin or clopidogrel with aspirin and heparin (see Interactions with Other Drugs).
• Rare cases of thrombotic thrombocytopenic purpura (TTP) have been reported. TTP was not observed in clinical studies involving more than 11,300 patients receiving clopidogrel (including over 9000 patients treated for one year or more).
• Very Rare: Agranulocytosis, aplastic anaemia, neutropenia, pancytopenia

Neurological

• Very rarely: confusion, hallucinations, syncope, taste disorders

Liver and biliary

• Very rarely: abnormal liver function tests, hepatitis

Gastrointestinal

• Very rarely: colitis (including ulcerative or lymphocytic colitis)

Respiratory

• Very rarely: bronchospasm

Urinary system:

• Very rarely: glomerulopathy, abnormal creatinine levels

Note very common ≥ 1/10 (≥ 10%)
common ≥1/100 and < 1/10 ( ≥ 1% and < 10%)
uncommon ≥ 1/1000 and < 1/100 ( ≥ 0.1% and < 1.0%)
rare ≥ 1/10,000 and < 1/1000 (≥ 0.01% and < 0.1%)
very rare < 1/10,000 (< 0.01%)

Dosage and Administration

Clopidogrel should be taken once a day with or without food.

Adults

Generally, Clopidogrel should be given as a single daily dose of 75 mg.

In patients with acute coronary syndrome (unstable angina or non-ST elevation myocardial infarction), clopidogrel treatment should be initiated with a single 300 mg loading dose and then continued long-term at 75 mg once a day (with aspirin 75 mg-325 mg daily).

No dosage adjustment is necessary for either elderly patients or patients with renal impairment. (See Pharmacokinetics).

Children and Adolescents

Safety and efficacy in subjects below the age of 18 have not been established.

Poisoning and Overdosage

In animals, clopidogrel at single oral doses ≥ 1500 mg/kg caused necrotic-haemorrhagic gastritis, oesophagitis and enteritis in mice, rats and baboons. Necrotic tubulopathy and tubulo-interstitial nephritis were also noted in mice.

One case of deliberate overdosage with clopidogrel has been reported. A 34 year old woman took a single 1,050 mg dose of clopidogrel (equivalent to 14 standard 75 mg tablets). There were no associated adverse events. No special therapy was instituted and she recovered without sequelae.

No adverse events were reported after single oral administration of 600 mg (equivalent to 8 standard 75 mg tablets) of clopidogrel to healthy subjects. The bleeding time was prolonged by a factor of 1.7 which is similar to that typically observed with the therapeutic dose of 75 mg per day.

Presentation

75 mg film coated tablets - pink, round, biconvex and engraved with '75" on one side and "1171" on the reverse. 28 tablets packed in blister strips in cardboard cartons.

Store below 25°C (77°F).

   Inhouse Drugstore Europe