Plavix

Plavix

clopidogrel

Manufacturer:

Sanofi-Aventis

Distributor:

DKSH
Full Prescribing Info
Contents
Clopidogrel.
Description
Each film-coated tablet contains clopidogrel hydrogen sulphate 97.875 mg (molar equivalent of clopidogrel base 75 mg) or clopidogrel hydrogen sulphate 391.5 mg (molar equivalent of clopidogrel base 300 mg).
Plavix also contains the following excipients: Hydrogenated castor oil, hydroxypropyl cellulose, mannitol E421, microcrystalline cellulose and polyethylene glycol 6000 as inactive ingredient. The pink film coating contains ferric oxide E172, hypromellose 2910, lactose, titanium dioxide and triacetin. The tablets are polished with carnauba wax.
Clopidogrel hydrogen sulfate is methyl(+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1). It has an empirical formula of C16H16CINO2S·H2SO4 and a molecular weight of 419.9.
Clopidogrel hydrogen sulfate is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex.
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 also dissolves freely in methanol, dissolves slightly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.
Action
Pharmacotherapeutic Group: Platelet aggregation inhibitors excluding heparin. ATC Code: BO1AC/04.
Pharmacology: Pharmacodynamics: Clopidogrel is a prodrug, whose metabolites is an inhibitor of platelet aggregation. It must be metabolised by cytochrome P-450 (CYP450) enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein (GP) IIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.
Repeated doses of 75 mg/day produced substantial inhibition of ADP-induced platelet aggregation from the 1st day; this increased progressively and reached steady state between days 3 and 7. At steady state, the average inhibition level observed with a dose of 75 mg/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 5 double-blind studies involving >88,000 patients: Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study, a comparison of clopidogrel to acetylsalicylic acid (ASA), and the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE), Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY), Clopidogrel and Metoprolol Myocardial Infarction Trial (COMMIT) and Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-A) study, 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 (PAD): The CAPRIE study included 19,185 patients with atherothrombosis as manifested by recent MI (<35 days), recent ischaemic stroke (between 7 days and 6 months) or established PAD. Patients were randomised to clopidogrel 75 mg/day or ASA 325 mg/day, and were followed for 1-3 years. In the MI subgroup, most of the patients received ASA for the 1st few days following the acute MI.
Clopidogrel significantly reduced the incidence of new ischaemic events (combined endpoint of MI, ischaemic stroke and vascular death) when compared to ASA. In the intention to treat analysis, 939 events were observed in the clopidogrel group and 1020 events with ASA [relative risk reduction (RRR) 8.7%, (95% CI: 0.2-16.4); p=0.045], which corresponds, for every 1000 patients treated for 2 years, to 10 (CI: 0-20) 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%).
In a subgroup analysis by qualifying condition (MI, 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 MI) (RRR=23.7%; CI: 8.9-36.2) 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 MI, clopidogrel was numerically inferior, but not statistically different from ASA (RRR=-4%; CI: -22.5 to 11.7). In addition, a subgroup analysis by age suggested that the benefit of clopidogrel in patients >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 (RRR) 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 MI), and presenting within 24 hrs of onset of the most recent episode of chest pain or symptoms consistent with ischaemia. Patients were required to have either electrocardiogram (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=6259) or placebo (N=6303), both given in combination with ASA (75-325 mg once daily) and other standard therapies. Patients were treated for up to 1 year. In CURE, 823 (6.6%) patients received concomitant GPIIb/IIIa receptor antagonist therapy. Heparins were administered in >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, MI or stroke] was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% RRR (95% CI of 10-28%; p=0.00009) for the clopidogrel-treated group [17% RRR when patients were treated conservatively, 29% when they underwent PTCA with or without stent and 10% when they underwent coronary artery bypass graft (CABG)]. New CV events (primary endpoint) were prevented, with RRRs 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, >3 months of treatment, the benefit observed in the clopidogrel + ASA group was not further increased, whereas the risk of haemorrhage persisted (see Precautions).
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% RRR (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 populations with different characteristics (eg, 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. In particular, in a post hoc analysis in 2172 patients (17% of the total CURE population) who underwent stent placement (Stent-CURE), the data showed that clopidogrel compared to placebo, demonstrated a significant RRR of 26.2% favouring clopidogrel for the co-primary endpoint (CV death, MI, stroke) and also a significant RRR of 23.9% for the 2nd co-primary endpoint (CV death, MI, stroke or refractory ischaemia). Moreover, the safety profile of clopidogrel in this subgroup of patients did not raise any particular concern. Thus, the results from this subset are in line with the overall trial results.
The benefits observed with clopidogrel were independent of other acute and long-term CV therapies [eg, heparin/low molecular weight heparin (LMWH), GPIIb/IIIa antagonists, lipid-lowering drugs, β-blockers and ACE inhibitors]. The efficacy of clopidogrel was observed independently of the dose of ASA (75-325 mg once daily).
In patients with acute ST-segment elevation MI, safety and efficacy of clopidrogrel have been evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT.
The CLARITY trial included 3491 patients presenting within 12 hrs 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 (150-325 mg as a loading dose, followed by 75-162 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 infarct-related 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 MI 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% β-blockers, 54.7% ACE inhibitors and 63% statins. Fifteen percent (15%) 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 hrs of the onset of the symptoms of suspected MI with supporting ECG abnormalities (ie, 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 1st 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 hrs.
Atrial Fibrillation: The ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included patients with atrial fibrillation (AF) who had at least 1 risk factor for vascular events. Based on enrollment criteria, physicians enrolled patients in ACTIVE-W if they were candidates for vitamin K antagonist (VKA) therapy (eg, warfarin). The ACTIVE-A study included patients who could not receive VKA therapy because they were unable or unwilling to receive the treatment.
The ACTIVE-W study demonstrated that treatment with vitamin K antagonists was more effective than with clopidogrel and ASA.
The ACTIVE-A study (N=7554) was a multicenter, randomized, double-blind, placebo-controlled study which compared clopidogrel 75 mg/day + ASA (N=3772) to placebo + ASA (N=3782). The recommended dose for ASA was 75-100 mg/day. Patients were treated for up to 5 years.
Patients randomized in the ACTIVE program were those presenting with documented AF ie, either permanent AF or at least 2 episodes of intermittent AF in the past 6 months, and had at least 1 of the following risk factors: Age ≥75 years or 55-74 years and either diabetes mellitus requiring drug therapy, or documented previous MI or documented coronary artery disease; treated for systemic hypertension; prior stoke, transient ischaemic attack (TIA) or non-central nervous system (CNS) systemic embolus; left ventricular dysfunction with left ventricular ejection fraction <45%; or documented peripheral vascular disease. The mean CHADS2 score was 2 (range 0-6).
Seventy-three percent (73%) of patients enrolled into the ACTIVE-A study were unable to take VKA due to physician assessment, inability to comply with international normalised ratio (INR) monitoring, predisposition to falling or head trauma, or specific risk of bleeding; for 26% of the patients, the physician's decision was based on the patient's unwillingness to take VKA.
The patient population included 41.8% women. The mean age was 71 years, 41.6% of patients were ≥75 years. A total of 23% of patients received antiarrhythmics, 52.1% β-blockers, 54.6% ACE inhibitors and 25.4% statins.
The number of patients who reached the primary endpoint (time to first occurrence of stroke, MI, non-CNS systemic embolism or vascular death) was 832 (22.1%) in the group treated with clopidogrel + ASA and 924 (24.4%) in the placebo + ASA group.
The benefit of clopidogrel + ASA was noted early and was maintained throughout the duration of the study up to 5 years; the rate of primary events was consistently lower in the clopidogrel + ASA group compared with the placebo + ASA group.
The reduction in the risk of major vascular events in the group treated with clopidogrel + ASA was primarily due to a large reduction in the incidence of strokes. Strokes occurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) patients receiving placebo + ASA.
The rate of ischaemic stroke was significantly lower in the clopidogrel + ASA group than in the placebo + ASA group (6.2% vs 9.1%; RRR, 32.4%; 95% CI, 20.2-42.7%).
The risk of stroke of any severity was reduced with the use of clopidogrel + ASA. In addition, 46 fewer non-disabling strokes and 69 fewer disabling or fatal strokes were reported with clopidogrel + ASA as compared to placebo + ASA.
There was a trend for reduction in the rates of MI in the group treated with clopidogrel + ASA (RRR, 21.9%; 95% CI, -3% to 40.7%; p=0.08). The rates of non-CNS systemic embolism and death from vascular causes were similar between the 2 groups.
The effectiveness of clopidogrel + ASA was noted early and was maintained throughout the duration of the study up to 5 years; the rate of stroke was consistently lower in the clopidogrel + ASA group compared with the placebo + ASA group.
Clopidogrel + ASA reduced the total number of hospital days for CV causes. The total number of days of CV hospitalizations was 30,276 for clopidogrel + ASA and 34,813 for placebo + ASA.
Paediatric Studies: A randomised, placebo-controlled trial (CLARINET) did not demonstrate a clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt. In this study, 906 paediatric patients (neonates and infants) with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt were randomised to receive clopidogrel 0.2 mg/kg/day (n=467) or placebo (n=439) along with concomitant background therapy up to the time of 2nd stage surgery. The mean time between shunt palliation and first administration of study medicinal product was 20 days. Approximately 88% of patients received concomitant ASA (range of 1-23 mg/kg/day). There was no significant difference between groups in the primary composite endpoint of death, shunt thrombosis or cardiac related intervention prior to 120 days of age following an event considered of thrombotic nature [89 (19.1%) for the clopidogrel group and 90 (20.5%) for the placebo group]. Bleeding was the most frequently reported adverse reaction in both clopidogrel and placebo groups; however, there was no significant difference in the bleeding rate between groups.
Pharmacokinetics: Absorption: After single and repeated oral dose of 75 mg/day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/mL after a single 75-mg oral dose) occurred approximately 45 min after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
The kinetics of the main circulating metabolite were linear (plasma concentrations increased in proportion to dose) in the dose range of 50-150 mg of clopidogrel.
Distribution: Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro over a wide concentration range.
Metabolism: Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to 2 main metabolic pathways: One (1) mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple CYP450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.
The peak plasma concentration (Cmax) of the active metabolite is twice as high following a single clopidogrel 300 mg loading dose as it is after 4 days of 75-mg maintenance dose. Peak plasma concentration occurs approximately 30-60 min after dosing.
Elimination: 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-hr interval after dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life (t½) of approximately 6 hrs. The elimination t½ of the main circulating (inactive) metabolite was 8 hrs after single and repeated administration.
Pharmacogenetics: CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype.
The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and CYP2C19*3 alleles are nonfunctional. The CYP2C19*2 and CYP2C19*3 alleles account for the majority of reduced function alleles in White (85%) and Asian (99%) poor metabolisers. Other alleles associated with absent or reduced metabolism are less frequent, and include, but are not limited to CYP2C19*4, *5, *6, *7, and *8. A patient with poor metaboliser status will possess 2 loss-of-function alleles as defined in previous texts. Published frequencies for poor CYP2C19 metaboliser genotypes are approximately 2% for Whites, 4% for Blacks and 14% for Chinese. Tests are available to determine a patient's CYP2C19 genotype.
A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metaboliser groups (ultrarapid, extensive, intermediate and poor), evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg/day and 600 mg followed by 150 mg/day, each for a total of 5 days (steady state). No substantial differences in active metabolite exposure and mean inhibition of platelet aggregation (IPA) were observed between ultrarapid, extensive and intermediate metabolisers. In poor metabolisers, active metabolite exposure was decreased by 63-71% compared to extensive metabolisers. After the 300 mg/75 mg dose regimen, antiplatelet responses were decreased in the poor metabolisers with mean IPA (5 mM ADP) of 24% (24 hrs) and 37% (day 5) as compared to IPA of 39% (24 hrs) and 58% (day 5) in the extensive metabolisers and 37% (24 hrs) and 60% (day 5) in the intermediate metabolisers. When poor metabolisers received the 600 mg/150 mg regimen, active metabolite exposure was greater than with the 300 mg/75 mg regimen. In addition, IPA was 32% (24 hrs) and 61% (day 5), which were greater than in poor metabolisers receiving the 300 mg/75 mg regimen, and were similar to the other CYP2C19 metaboliser groups receiving the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.
Consistent with the results, in a meta-analysis including 6 studies of 335 clopidogrel-treated subjects at steady state, it was shown that active metabolite exposure was decreased by 28% for intermediate metabolisers, and 72% for poor metabolisers while platelet aggregation inhibition (5 mM ADP) was decreased with differences in IPA of 5.9% and 21.4%, respectively, when compared to extensive metabolisers.
The influence of CYP2C19 genotype on clinical outcomes in patients treated with clopidogrel has not been evaluated in prospective, randomized, controlled trials. There have been a number of retrospective analyses; however, to evaluate this effect in patients treated with clopidogrel for whom there are genotyping results: CURE (n=2721), CHARISMA (n=2428), CLARITY-TIMI 28 (n=227) and TRITON-TIMI 38 (n=1477) as well as a number of published cohort studies.
In TRITON-TIMI 38 and 3 of the cohort studies (Collet, Sibbing, Giusti) the combined group of patients with either intermediate or poor metaboliser status had a higher rate of CV events (death, MI and stroke) or stent thrombosis compared to extensive metabolisers.
In CHARISMA and 1 cohort study (Simon), an increased event rate was observed only in poor metabolisers when compared to extensive metabolisers.
In CURE, CLARITY, ACTIVE-A and 1 of the cohort studies (Trenk), no increased event rate was observed based on metaboliser status.
None of these analyses was adequately sized to detect differences in outcome in poor metabolisers.
Special Populations: The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations.
Gender: 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 (CAPRIE), the incidence of clinical outcome events, other adverse clinical events and abnormal clinical laboratory parameters was similar in men and women.
Elderly: In elderly (≥75 years) volunteers compared to young healthy volunteers, there were no differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.
Paediatric Patients: No information available.
Hepatic Impairment: After repeated doses of clopidogrel 75 mg/day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the 2 groups.
Renal Impairment: After repeated doses of clopidogrel 75 mg/day in patients with severe renal impairment (creatinine clearance from 5-15 mL/min), inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy volunteers, however, the prolongation of bleeding time was similar to healthy volunteers receiving clopidogrel 75 mg/day.
Ethnicity: The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to ethnicity (see Pharmacogenetics as aforementioned). From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.
Toxicology: Preclinical Safety Data: During preclinical 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/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.
Indications/Uses
Prevention of Atherothrombotic Events in Adults: Patients suffering from MI (from a few days until <35 days), ischaemic stroke (from 7 days until <6 months) or PAD.
Patients Suffering from Acute Coronary Syndrome: Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave MI).
ST segment elevation acute MI, in combination with ASA in medically treated patients eligible for thrombolytic therapy.
Patients undergoing a stent placement following percutaneous coronary intervention (PCI), in combination with ASA.
Prevention of Atherothrombotic and Thromboembolic Events in Adults: Atrial Fibrillation (AF): In patients with AF at increased risk of vascular events who can take VKA therapy, VKA has been shown to be associated with a better clinical benefit than ASA alone or the combination of clopidogrel and ASA for the reduction of stroke.
In patients with AF who have at least 1 risk factor for vascular events and who cannot take VKA therapy (eg, specific risk of bleeding, physician assessment that patient is unable to comply with INR monitoring or that VKA use is inappropriate), clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke. Clopidogrel in combination with ASA has been shown to reduce the rate of the combined endpoint of stroke, MI, non-CNS systemic embolism or vascular death, largely through a reduction in stroke (see Pharmacology: Pharmacodynamics under Actions).
Dosage/Direction for Use
Adults & Elderly: 75 mg as a single daily dose. Clopidogrel can be administered with or without food.
Clopidogrel 300 mg is intended for use as a loading dose in patients suffering from acute coronary syndrome.
Non-ST Segment Elevation Acute Coronary Syndrome (Unstable Angina or Non-Q-Wave MI): Initially, a single 300-mg loading dose and then continued at 75 mg once a day (with ASA 75-325 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 of up to 12 months, and the maximum benefit was seen at 3 months (see Pharmacology: Pharmacodynamics under Actions).
ST Segment Elevation Acute Myocardial Infarction: 75 mg as a single daily dose initiated with or without a loading dose in combination with ASA and with or without thrombolytics (see Pharmacology: Pharmacodynamics under Actions). For patients >75 years, 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 4 weeks. The benefit of the combination of clopidogrel with ASA >4 weeks has not been studied in this setting (see Pharmacology: Pharmacodynamics under Actions).
Atrial Fibrillation: 75 mg as a single daily dose. Acetylsalicylic acid (75-100 mg daily) should be initiated and continued in combination with clopidogrel (see Pharmacology: Pharmacodynamics under Actions).
Pharmacogenetics: CYP2C19 poor metaboliser status is associated with diminished antiplatelet response to clopidogrel. A higher dose regimen (600-mg loading dose followed by 150 mg once daily) in poor metabolisers increases antiplatelet response (see Pharmacology: Pharmacokinetics: Pharmacogenetics under Actions). Consider the use of higher clopidogrel doses in patients who are poor CYP2C19 metabolisers. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.
Overdosage
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.
Contraindications
Hypersensitivity to clopidogrel or any of the excipients of Plavix. Severe liver impairment; active pathological bleeding eg, peptic ulcer or intracranial haemorrhage. Breastfeeding (see Use in lactation as follows).
Use in Lactation: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether Plavix is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to a nursing woman.
Special Precautions
Bleeding and Haematological Disorders: 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 Adverse Reactions).
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, NSAIDs or selective serotonin reuptake inhibitors (SSRIs). Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the 1st weeks of treatment and/or after invasive cardiac procedures or surgery. Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution. (See Interactions.)
If a patient is to undergo elective surgery and antiplatelet effect is not necessary, clopidogrel should be discontinued 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). Drugs that might induce gastrointestinal lesions (eg, ASA and NSAIDs) should be used with caution in patients taking clopidogrel.
Patients should be informed that it might take longer than usual to stop bleeding when they are taking clopidogrel (alone or in combination with ASA), and that any unusual bleeding (site or duration) should be reported to the physician. Patients should inform the physician and dentist that they are taking clopidogrel before any surgery is scheduled and before any new drug is taken.
Recent Ischaemic Stroke: In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic events, the combination of ASA and clopidogrel has been shown to increase major bleeding. Therefore, such addition should be undertaken with caution outside of clinical situations where the combination has proven to be beneficial.
In view of the lack of data, clopidogrel cannot be recommended in acute ischaemic stroke (<7 days).
Thrombotic Thrombocytopenic Purpura (TTP): 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 neurological findings, renal dysfunction or fever. Thrombotic thrombocytopenic purpura is a potentially fatal condition requiring prompt treatment including plasmapheresis (plasma exchange).
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 clopidogrel should be discontinued.
Cytochrome P-450 2C19 (CYP2C19): Pharmacogenetics: In patients who are CYP2C19 poor metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Poor metabolisers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses may exhibit higher CV event rates than do patients with normal CYP2C19 function (see Pharmacology: Pharmacokinetics: Pharmacogenetics under Actions). Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. Consider the use of higher clopidogrel doses in patients who are known CYP2C19 poor metabolisers (see Pharmacogenetics under Dosage & Administration).
Cross-Reactivity Among Thienopyridines: Patients should be evaluated for history of hypersensitivity to another thienopyridine (eg, ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see Adverse Reactions). Thienopyridines may cause mild to severe allergic reactions eg, rash, angioedema or haematological reactions eg, thrombocytopaenia and neutropaenia. Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for cross-reactivity is advised.
Renal Impairment: Therapeutic experience with clopidogrel is limited in patients with severe renal impairment. Therefore, clopidogrel should be used with caution in these population.
Hepatic Impairment: Experience is limited in patients with severe hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.
Excipients: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Plavix.
Effects on the Ability to Drive or Operate Machinery: Clopidogrel has no or negligible influence on the ability to drive and use machines.
Use in Pregnancy: As no clinical data on exposed pregnancies are available, Plavix should not be used during pregnancy, unless, in the opinion of the physician, there is a clear need. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see Pharmacology: Toxicology under Actions).
Use in Children: The safety and effectiveness in pediatric populations and adolescents have not been established (see Pharmacology: Pharmacodynamics under Actions).
Use In Pregnancy & Lactation
Use in Pregnancy: As no clinical data on exposed pregnancies are available, Plavix should not be used during pregnancy, unless, in the opinion of the physician, there is a clear need. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see Pharmacology: Toxicology under Actions).
Use in Lactation: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether Plavix is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to a nursing woman.
Adverse Reactions
Clinical Studies Experience: Clopidogrel has been evaluated for safety in >44,000 patients, including >12,000 patients treated for ≥1 year. The clinically relevant adverse effects observed in the CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A studies are discussed as follows. 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 ethnicity.
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% and required hospitalisation in 0.7%. In patients that received ASA, the corresponding rates were 2.7% and 1.1%, respectively.
The overall 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 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: Major bleeds (3.7% clopidogrel + ASA vs 2.7% placebo + ASA), non-life-threatening major bleeds (1.6% clopidogrel + ASA vs 1% 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 (<100 mg: 2.6%; 100-200 mg: 3.5%; >200mg: 4.9%) as was the major bleeding event rate for placebo + ASA (<100 mg: 2%; 100-200 mg: 2.3%; >200 mg: 4%).
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%)].
There was no excess in major bleeds within 7 days after coronary bypass graft surgery in patients who stopped therapy >5 days prior to surgery (4.4% clopidogrel + ASA vs 5.3% placebo + ASA). In patients who remained on therapy within 5 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%) versus the placebo + ASA group (12.9%). The incidence of major bleeding was similar between groups (1.3% vs 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% vs 0.6% in the clopidogrel + ASA and the placebo + ASA groups, respectively) and intracranial hemorrhage (0.5% vs 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 bleedings was low and similar in both groups (0.6% vs 0.5% in the clopidogrel + ASA and the placebo + ASA groups, respectively).
In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7% vs 4.3%). Major bleeding was mostly of extracranial origin in both groups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo + ASA group), mainly in the gastrointestinal tract (3.5% vs 1.8%). There was an excess of intracranial bleeding in the clopidogrel + ASA treatment group compared to the placebo + ASA group (1.4% vs 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding and hemorrhagic stroke (0.8% and 0.6%, respectively) between groups.
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; very rare cases of platelet count ≤30 g/L have been reported.
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, COMMIT and ACTIVE-A studies with an incidence >0.1% as well as all serious and relevant adverse drug reactions are listed as follows.
The following CIOMS frequency rating is used: Very common (≥10%); common (≥1 and <10%); uncommon (≥0.1 and <1%); rare (≥0.01 and <0.1%); very rare (<0.01%); unknown (cannot be estimated from available data).
Central and Peripheral Nervous System Disorders: Uncommon: Headache, dizziness and paraesthesia. Rare: Vertigo.
Gastrointestinal System Disorders: Common: Dyspepsia, abdominal pain, diarrhoea. Uncommon: Nausea, gastritis, flatulence, constipation, vomiting, gastric and duodenal ulcer.
Platelet, Bleeding and Clotting Disorders: Uncommon: Increased bleeding time and decreased platelets.
Skin and Appendages Disorders: Uncommon: Rash and pruritus.
White Cell and RES Disorders: Uncommon: Leucopenia, decreased neutrophils and eosinophilia.
Post-Marketing Experience: Bleeding is the most common reaction reported in the post-marketing experience and was mostly reported during the 1st month of treatment.
Bleeding: Some cases were reported with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage); serious cases of skin bleeding (purpura), musculoskeletal 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 ASA or clopidogrel with ASA and heparin (see Precautions).
Frequencies for the following adverse reactions are not known (cannot be estimated form available data).
Blood and Lymphatic System Disorders: Serious cases of bleeding, mainly skin, musculoskeletal, eye (conjunctival, ocular, retinal) and respiratory tract bleeding, epistaxis, haematuria and haemorrhage of operative wound; cases of bleeding with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage); agranulocytosis, aplastic anaemia/pancytopenia, TTP, acquired haemophilia A.
Immune System Disorders: Anaphylactoid reactions, serum sickness; cross-reactive drug hypersensitivity among thienopyridines (eg, ticlopidine, prasugrel) (see Precautions).
Psychiatric Disorders: Confusion, hallucinations.
Nervous System Disorder: Taste disturbances.
Vascular Disorders: Vasculitis, hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.
Gastrointestinal Disorders: Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis.
Hepatobiliary Disorders: Hepatitis, acute liver failure.
Skin and Subcutaneous Tissue Disorders: Maculopapular, erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic (DRESS), eczema, lichen planus.
Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, arthritis, myalgia.
Renal and Urinary Disorders: Glomerulopathy.
General Disorders and Administration Site Conditions: Fever.
Investigations: Abnormal liver function test, increased blood creatinine.
Drug Interactions
Oral Anticoagulants: Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution.
Glycoprotein IIb/IIIa Inhibitors: As a pharmacodynamic interaction between clopidogrel and glycoprotein IIb/IIIa inhibitors is possible, concomitant use should be undertaken with caution.
Acetylsalicylic Acid: Acetylsalicylic acid 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 ASA 500 mg twice daily for 1 day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. As a pharmacodynamic interaction between clopidogrel and ASA is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see Precautions). However, clopidogrel and ASA have been administered together for up to 1 year (see Pharmacology: Pharmacodynamics under Actions).
Injectable Anticoagulants: 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 IPA induced by clopidogrel. As a pharmacodynamic interaction between clopidogrel and heparin is possible, concomitant use should be undertaken with caution.
Thrombolytics: The safety of the concomitant administration of clopidogrel, thrombolytic agents and heparins was assessed in patients with acute MI. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparins are co-administered with ASA. (See Adverse Reactions.)
Nonsteroidal 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 Precautions).
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: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. Concomitant use of strong or moderate CYP2C19 inhibitors (eg, omeprazole) should be discouraged (see Pharmacology: Pharmacokinetics: Pharmacogenetics under Actions and Precautions). If a proton-pump inhibitor is to be used concomitantly with clopidogrel, consider using one with less CYP2C19 inhibitory activity eg, pantoprazole.
Proton-Pump Inhibitors (PPI): In a crossover clinical study, clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 45% (day 1) and 40% (day 5) when clopidogrel and omeprazole were administered together. Mean IPA with 5 mM ADP was diminished by 39% (24 hrs) and 21% (day 5) when clopidogrel and omeprazole were administered together.
In a 2nd interaction study with omeprazole 80 mg administered 12 hrs apart from the clopidogrel standard regimen, the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19.
In a 3rd interaction study with omeprazole 80 mg administered with a higher dose regimen of clopidogrel (600-mg loading dose followed by 150 mg/day), a degree of interaction was observed similar to that noted in the other omeprazole interaction studies. However, active metabolite formation and platelet aggregation were at the same level as clopidogrel administered alone at the standard dose regimen.
In a crossover clinical study, healthy subjects were administered clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with pantoprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 20% (day 1) and 14% (day 5) when clopidogrel and pantoprazole were administered together. Mean IPA was diminished by 15% (24 hrs) and 11% (day 5) when clopidogrel and pantoprazole were administered together. These results indicate that clopidogrel can be administered with pantoprazole.
The CURRENT trial compared 2 dosing regimens of clopidogrel (600-mg loading dose, then 150 mg/day for 6 days followed by 75 mg/day up to 30 days vs 300-mg loading dose followed by 75 mg/day up to 30 days). A subanalysis (n=18,432) correlated PPI use (mainly omeprazole and pantoprazole) at randomization and hospital discharge and demonstrated no interaction between clopidogrel and PPI use for the primary endpoint (CV death, MI or stroke) or any secondary endpoints, including stent thrombosis.
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, 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.
Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, co-administration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. It is unlikely that clopidogrel may interfere with the metabolism of drugs eg, phenytoin and tolbutamide and the NSAIDs, which are metabolised by cytochrome P-450 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 previously, 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, β-blockers, ACE inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy and GP IIb/IIIa antagonists without evidence of clinically significant adverse interactions.
Incompatibilities: Not applicable.
Storage
75 mg: Store between 15°C and 30°C. 300 mg: Do not store above 30°C.
Shelf-Life: 3 years.
ATC Classification
B01AC04 - clopidogrel ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
Presentation/Packing
FC tab 75 mg (pink, round, biconvex, engraved with "75" on one side and "1171" on the other side) x 14's. 300 mg (pink, round, biconvex, engraved with "300" on one side and "1332" on the other side) x 3 x 14's.
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