CoPlavix

CoPlavix

Manufacturer:

Sanofi-Aventis

Distributor:

DKSH
Full Prescribing Info
Contents
Clopidogrel hydrogen sulphate, acetylsalicylic acid.
Description
Each film-coated tablet contains clopidogrel (as hydrogen sulphate) 75 mg and acetylsalicylic acid (ASA) 75 mg.
It also contains the following excipients: Mannitol (E421), macrogol 6000, microcrystalline cellulose, low substituted hydroxypropylcellulose, maize starch, hydrogenated castor oil 3.3 mg, stearic acid, colloidal anhydrous silica, lactose monohydrate 7 mg, hypromellose (E464), titanium dioxide (E171), triacetin (E1518), yellow iron oxide (E172) and carnauba wax.
Action
Pharmacotherapeutic Group: Platelet aggregation inhibitors excluding heparin. ATC Code: B01AC30.
Pharmacology: Pharmacodynamics: Clopidogrel is a prodrug, whose metabolites is an inhibitor of platelet aggregation. Clopidogrel 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 GIIb/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 medicinal products, not all patients will have adequate platelet inhibition.
Repeated doses of clopidogrel 75 mg/day produced substantial inhibition of ADP-induced platelet aggregation from the 1st 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/day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued.
Acetylsalicylic acid inhibits platelet aggregation by irreversible inhibition of prostaglandin cyclooxygenase and thus inhibits the generation of thromboxane A2, an inducer of platelet aggregation and vasoconstriction. This effect lasts for the life of the platelet.
Experimental data suggest that ibuprofen may inhibit the effect of low-dose aspirin on platelet aggregation when they are dosed concomitantly. In 1 study, when a single dose of ibuprofen 400 mg was taken within 8 hrs before or within 30 min after immediate-release aspirin dosing (81 mg), a decreased effect of acetylsalicylic acid (ASA) on the formation of thromboxane or platelet aggregation occurred. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.
Clinical Efficacy/Clinical Studies: The safety and efficacy of clopidogrel plus ASA have been evaluated in 5 double-blind studies involving over 88,000 patients: The CAPRIE, CURE, CLARITY, COMMIT and atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE-A) studies, comparing clopidogrel plus ASA to ASA alone, both treatments given in combination with 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 1-3 years. In the MI 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 endpoint 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 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 myocardial infarction) (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 myocardial infarction, 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 over 75 years was less than that observed in patients ≤75 years.
Since the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is not clear whether the differences in relative risk reduction across qualifying conditions are real, or a result of chance.
Acute Coronary Syndrome: The CURE study included 12,562 patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction) and presenting within 24 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) plus ASA (75-325 mg once daily) or ASA alone (N=6303), (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 plus ASA and ASA alone 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 plus ASA group and 719 (11.4%) in the ASA group, a 20% RRR (95% CI of 10-28%; p=0.00009) for the clopidogrel plus ASA group [17% RRR when patients were treated conservatively, 29% when they underwent percutaneous transluminal coronary angioplasty (PTCA) with or without stent and 10% when they underwent coronary artery bypass graft (CABG)]. New cardiovascular events (primary endpoint) were prevented, with RRR of 22% (CI: 8.6, 33.4), 32% (CI: 12.8, 46.4), 4% (CI: -26.9, 26.7), 6% (CI: -33.5, 34.3) and 14% (CI: -31.6, 44.2), during the 0-1, 1-3, 3-6, 6-9 and 9-12 month study intervals, respectively. Thus, beyond 3 months of treatment, the benefit observed in the clopidogrel plus 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 for 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 plus ASA group and 1187 (18.8%) in the ASA group, a 14% RRR (95% CI of 6-21%, p=0.0005) for the clopidogrel plus ASA group. This benefit was mostly driven by the statistically significant reduction in the incidence of MI [287 (4.6%) in the clopidogrel plus ASA group and 363 (5.8%) in the ASA group]. There was no observed effect on the rate of re-hospitalisation for unstable angina.
The results obtained in 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.
In patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been evaluated in 2 randomised, placebo-controlled, double-blind studies, CLARITY and COMMIT.
The CLARITY trial included 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) plus ASA or ASA alone (n=1739), (150-325 mg as 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% angiotensin-converting enzyme (ACE) inhibitors and 63% statins.
Fifteen percent (15%) of patients in the clopidogrel plus ASA group and 21.7% in the group treated with ASA alone reached the primary endpoint, representing an absolute reduction of 6.7% and a 3.6% 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 pre-specified 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) plus ASA (162 mg/day) or ASA alone (162 mg/day) (n=22,891) for 28 days or until hospital discharge. The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The population included 27.8% women, 58.4% patients ≥60 years (26% ≥70 years) and 54.5% patients who received fibrinolytics.
Clopidogrel plus ASA 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 one 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 atrial fibrillation (AF) ie, either permanent AF or at least 2 episodes of intermittent AF in the past 6 months, and had at least one of the following risk factors: ≥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 stroke, transient ischaemic attack (TIA), or non-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 anti-arrhythmics, 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 cardiovascular causes. The total number of days of cardiovascular hospitalizations was 30,276 for clopidogrel + ASA and 34,813 for placebo + ASA.
Paediatric Population: The European Medicines Agency has waived the obligation to submit the results of studies with CoPlavix in all subsets of the paediatric population in the treatment of coronary atherosclerosis (see Dosage & Administration).
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 1st 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] (see Dosage & Administration). 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: Clopidogrel: Absorption: After single and repeated oral doses 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 (inactive) 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.
Metabolism: Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to 2 main metabolic pathways: One 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.
Acetylsalicylic Acid (ASA): Absorption: Following absorption, the ASA in CoPlavix is hydrolyzed to salicylic acid with peak plasma levels of salicylic acid occurring within 1 hr of dosing, such that plasma levels of ASA are essentially undetectable 1.5-3 hrs after dosing.
Distribution: Acetylsalicylic acid is poorly bound to plasma proteins and its apparent volume of distribution is low (10 L). Its metabolite, salicylic acid, is highly bound to plasma proteins, but its binding is concentration dependent (nonlinear). At low concentrations (<100 mcg/mL), approximately 90% of salicylic acid is bound to albumin. Salicylic acid is widely distributed to all tissues and fluids in the body, including the central nervous system, breast milk and foetal tissues.
Metabolism and Elimination: The ASA in CoPlavix is rapidly hydrolyzed in plasma to salicylic acid, with a t½ of 0.3-0.4 hrs for ASA doses from 75-100 mg. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. Salicylic acid in CoPlavix has a plasma t½ of approximately 2 hrs. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (1020 g), the plasma t½ may be increased to over 20 hrs. At high ASA doses, the elimination of salicylic acid follows zero-order kinetics (ie, the rate of elimination is constant in relation to plasma concentration), with an apparent t½ of ≥6 hrs. Renal excretion of unchanged active substance depends upon urinary pH. As urinary pH rises >6.5, the renal clearance of free salicylate increases from <5% to >80%. Following therapeutic doses, approximately 10% is found excreted in the urine as salicylic acid, 75% as salicyluric acid, 10% phenolic- and 5% acyl-glucuronides of salicylic acid.
Based on the pharmacokinetic and metabolic characteristics of both compounds, clinically significant pharmacokinetic interactions are unlikely.
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 previously. 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 4 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 mentioned previously, 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 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 (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.
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.
Renal Impairment: After repeated doses of clopidogrel 75 mg/day in subjects with severe renal disease (creatinine clearance from 5-15 mL/min), inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen in healthy subjects receiving clopidogrel 75 mg/day. In addition, clinical tolerance was good in all patients.
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.
Race: The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity (see Pharmacogenetics in the previous texts). 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: Clopidogrel: During nonclinical 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 radiolabeled 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.
Acetylsalicylic Acid: Single-dose studies have shown that the oral toxicity of ASA is low. Repeat-dose toxicity studies have shown that levels up to 200 mg/kg/day are well tolerated in rats; dogs appear to be more sensitive, probably due to the high sensitivity of canines to the ulcerogenic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). No genotoxicity or clastogenicity issues of concern have been found with ASA. Although no formal carcinogenicity studies have been performed with ASA, it has been shown that it is not a tumour promoter.
Reproduction toxicity data show that ASA is teratogenic in several laboratory animals.
In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and post-implantation loss and embryofoetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.
Indications/Uses
Prevention of atherothrombotic events in adult patients already taking both clopidogrel and ASA. CoPlavix is a fixed-dose combination medicinal product for continuation of therapy in: Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave MI); ST segment elevation acute MI in medically treated patients eligible for thrombolytic therapy; patients suffering from acute coronary syndrome and undergoing a stent placement following percutaneous coronary intervention.
CoPlavix (clopidogrel plus ASA fixed combination) is indicated in adults for the prevention of atherothrombotic and thromboembolic events in: Atrial Fibrillation: In patients with AF at increased risk of vascular events who can take vitamin K antagonist (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 atrial fibrillation 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 international normalised ratio (INR) monitoring or that VKA use is inappropriate], CoPlavix (clopidogrel plus ASA) is indicated 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 and Clinical Efficacy/Clinical Studies under Actions).
Dosage/Direction for Use
Adults and Elderly: CoPlavix should be given as a single daily dose.
CoPlavix is used following an initial loading dose of clopidogrel 300 mg in combination with aspirin in patients with acute coronary syndrome: Patients with Non-ST Segment Elevation Acute Coronary Syndrome (Unstable Angina or Non-Q-Wave Myocardial Infarction): Treatment should be initiated with a single loading dose of clopidogrel 300 mg plus the appropriate dose of aspirin. Four (4) tablets of CoPlavix (clopidogrel 75 mg/aspirin 75 mg) can alternatively be given if the aspirin dosing is deemed appropriate. Long term daily treatment should be continued with one CoPlavix tablet (75 mg/75 mg or 75 mg/100 mg) once daily taken with adequate water. The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months and the maximum benefit was seen at 3 months (see Pharmacology: Pharmacodynamics under Actions). If the use of CoPlavix is discontinued, patients may benefit with continuation of one antiplatelet medicinal product.
Patients with ST Segment Elevation Acute Myocardial Infarction: Treatment should be initiated with or without a loading dose of clopidogrel 300 mg in combination with aspirin and with or without thrombolytics. 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).
Daily treatment should continue with one CoPlavix tablet (75 mg/75 mg or 75 mg/100 mg) once daily taken with adequate water.
Atrial Fibrillation: Clopidogrel + ASA should be given as a single daily 75 mg/75 mg or 75 mg/100 mg dose. (See Pharmacology: Pharmacodynamics and Clinical Efficacy/Clinical Studies under Actions.)
No dosage adjustment is necessary for maintenance therapy in elderly patients.
Missed Dose: Within <12 hrs after regular scheduled time, patients should take the dose immediately and then take the next dose at the regular scheduled time.
For >12 hrs: Patients should take the next dose at the regular scheduled time and should not double the dose.
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 and 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.
Administration: CoPlavix is for oral use. It may be given with or without food.
Overdosage
Clopidogrel: 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.
Acetylsalicylic Acid: The following symptoms are associated with moderate intoxication: Dizziness, headache, tinnitus, confusion and gastrointestinal symptoms (nausea, vomiting and gastric pain).
With severe intoxication, serious disturbances of the acid-base equilibrium occur. Initial hyperventilation leads to respiratory alkalosis. Subsequently, a respiratory acidosis occurs as a result of a suppressive effect on the respiratory centre. A metabolic acidosis also arises due to the presence of salicylates. Given that children, infants and toddlers are often only seen at a late stage of intoxication, they will usually have already reached the acidosis stage.
The following symptoms can also arise: Hyperthermia and perspiration, leading to dehydration, restlessness, convulsions, hallucinations and hypoglycaemia. Depression of the nervous system can lead to coma, cardiovascular (CV) collapse and respiratory arrest. The lethal dose of ASA is 25-30 g. Plasma salicylate concentrations >300 mg/L (1.67 mmol/L) suggest intoxication.
Overdosage with salicylates, particularly in young children, can result in severe hypoglycemia and potentially fatal poisoning.
Noncardiogenic pulmonary edema can occur with acute and chronic acetylsalicylic acid overdose (see Adverse Reactions).
If a toxic dose has been ingested then admission to hospital is necessary. With moderate intoxication, an attempt can be made to induce vomiting; if this fails, gastric lavage is indicated. Activated charcoal (adsorbent) and sodium sulphate (laxative) are then administered. Alkalising of the urine (sodium bicarbonate 250 mmol for 3 hrs) while monitoring the urine pH is indicated. Haemodialysis is the preferred treatment for severe intoxication. Treat other signs of intoxication symptomatically.
Contraindications
Hypersensitivity to clopidogrel, ASA and NSAIDs or to any of the excipients of CoPlavix. Severe hepatic impairment; active pathological bleeding eg, peptic ulcer or intracranial haemorrhage.
In addition, due to the presence of ASA, CoPlavix is also contraindicated in patients with syndrome of asthma, rhinitis and nasal polyps and preexisting mastocytosis, in whom the use of ASA may induce severe hypersensitivity reactions (including circulatory shock with flushing, hypotension, tachycardia and vomiting); severe renal impairment [creatinine clearance (CrCl) <30 mL/min); 3rd trimester of pregnancy (see Use in pregnancy under Precautions).
Special Precautions
Bleeding and Haematological Disorders: Due to the risk of bleeding and haematological adverse reactions, 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 a dual antiplatelet agent, CoPlavix 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 other NSAIDs including COX-2 inhibitors, heparin, glycoprotein IIb/IIIa inhibitors, selective serotonin reuptake inhibitors (SSRIs) or thrombolytics. 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. The concomitant administration of CoPlavix with oral anticoagulants is not recommended since it may increase the intensity of bleeding (see Interactions).
Patients should inform physicians and dentists that they are taking CoPlavix before any surgery is scheduled and before any new medicinal product is taken. Where elective surgery is being considered, the need for dual antiplatelet therapy should be reviewed and consideration given to the use of a single antiplatelet agent. If a patient is to undergo elective surgery and an antiplatelet effect is not desired, CoPlavix should be discontinued 5-7 days prior to surgery.
CoPlavix 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 also be told that it might take longer than usual to stop bleeding when they take CoPlavix and that they should report any unusual bleeding (site or duration) to their physician.
Thrombotic Thrombocytopenic Purpura (TTP): Thrombotic thrombocytopenic purpura 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. 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.
Recent Transient Ischaemic Attack or Stroke: In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic events, the combination of 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.
Cytochrome P4502C19 (CYP2C19): Pharmacogenetics: In patients who are CYP2C19 poor metabolizers, 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 Pharmacology: Pharmacokinetics: Pharmacogenetics under Actions and 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.
Caution Required Due to Acetylsalicylic Acid: Patients with a history of asthma or allergic disorders since they are at increased risk of hypersensitivity reactions; patients with gout since low doses of ASA increase urate concentrations; children <18 years since there is a possible association between ASA and Reye's syndrome. Reye's syndrome is a very rare disease which can be fatal.
Due to the presence of aspirin, patients should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking CoPlavix. CoPlavix must be administered under close medical supervision in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency due to risk of hemolysis (see Adverse Reactions).
Gastrointestinal: CoPlavix should be used with caution in patients with a history of peptic ulcer or gastroduodenal haemorrhage or minor upper gastrointestinal symptoms as this may be due to gastric ulceration which may lead to gastric bleeding. Gastrointestinal undesirable effects including stomach pain, heartburn, nausea, vomiting and gastrointestinal bleeding may occur. Minor upper gastrointestinal symptoms eg, dyspepsia, are common and can occur anytime during therapy. Physicians should remain alert for signs of gastrointestinal ulceration and bleeding, even in the absence of previous gastrointestinal symptoms. Patients should be told about the signs and symptoms of gastrointestinal undesirable effects and what steps to take if they occur (see Adverse Reactions).
Excipients: CoPlavix contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take CoPlavix.
CoPlavix also contains hydrogenated castor oil which may cause stomach upset and diarrhoea.
Effects on the Ability to Drive or Operate Machinery: CoPlavix has no or negligible influence on the ability to drive and use machines.
Renal Impairment: CoPlavix must not be used in patients with severe renal impairment (see Contraindications). Therapeutic experience is limited in patients with mild to moderate renal impairment. Therefore, CoPlavix should be used with caution in these population.
Hepatic Impairment: CoPlavix must not be used in patients with severe hepatic impairment (see Contraindications). Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Therefore, CoPlavix should be used with caution in these population.
Impairment of Fertility: There are no fertility data with CoPlavix. Clopidogrel was not shown to alter fertility in animal studies.
For Acetylsalicylic Acid Doses ≥500 mg/day: There is some evidence that drugs which inhibit cyclooxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.
Use in Pregnancy: No clinical data on exposure to CoPlavix during pregnancy are available. CoPlavix should not be used during the first 2 trimesters of pregnancy unless the clinical condition of the woman requires treatment with clopidogrel/ASA.
Due to the presence of ASA, CoPlavix is contraindicated during the 3rd trimester of pregnancy.
Clopidogrel: There are no adequate data from the use of clopidogrel in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology under Actions).
Acetylsalicylic Acid: Low doses (up to 100 mg/day): Clinical studies indicate that doses up to 100 mg/day for restricted obstetrical use, which require specialised monitoring, appear safe.
Doses of 100-500 mg/day: There is insufficient clinical experience regarding the use of doses >100 mg/day up to 500 mg/day. Therefore, the recommendations as follows for doses of ≥500 mg/day apply also for this dose range.
Doses of ≥500 mg/day: Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for CV malformation was increased from <1% up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in reproductive toxicity (see Pharmacology: Toxicology under Actions). Until the 24th amenorrhea week (5th month of pregnancy), ASA should not be given unless clearly necessary. If ASA is used by a woman attempting to conceive or until the 24th amenorrhea week (5th month of pregnancy), the dose should be kept as low and duration of treatment as short as possible.
From the beginning of the 6th month of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension), renal dysfunction which may progress to renal failure with oligohydroamniosis. May also expose the mother and the neonate at the end of pregnancy to possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; inhibition of uterine contractions resulting in delayed or prolonged labour.
Use in Lactation: It is unknown whether clopidogrel is excreted in human milk. Acetylsalicylic acid is known to be excreted in limited amounts in human milk. Breastfeeding should be discontinued during treatment with CoPlavix.
Use in Children: The safety and efficacy of CoPlavix in children and adolescents <18 years have not been established. CoPlavix is not recommended in this population.
Use In Pregnancy & Lactation
Use in Pregnancy: No clinical data on exposure to CoPlavix during pregnancy are available. CoPlavix should not be used during the first 2 trimesters of pregnancy unless the clinical condition of the woman requires treatment with clopidogrel/ASA.
Due to the presence of ASA, CoPlavix is contraindicated during the 3rd trimester of pregnancy.
Clopidogrel: There are no adequate data from the use of clopidogrel in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see Pharmacology: Toxicology under Actions).
Acetylsalicylic Acid: Low doses (up to 100 mg/day): Clinical studies indicate that doses up to 100 mg/day for restricted obstetrical use, which require specialised monitoring, appear safe.
Doses of 100-500 mg/day: There is insufficient clinical experience regarding the use of doses >100 mg/day up to 500 mg/day. Therefore, the recommendations as follows for doses of ≥500 mg/day apply also for this dose range.
Doses of ≥500 mg/day: Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for CV malformation was increased from <1% up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy. In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in reproductive toxicity (see Pharmacology: Toxicology under Actions). Until the 24th amenorrhea week (5th month of pregnancy), ASA should not be given unless clearly necessary. If ASA is used by a woman attempting to conceive or until the 24th amenorrhea week (5th month of pregnancy), the dose should be kept as low and duration of treatment as short as possible.
From the beginning of the 6th month of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension), renal dysfunction which may progress to renal failure with oligohydroamniosis. May also expose the mother and the neonate at the end of pregnancy to possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses; inhibition of uterine contractions resulting in delayed or prolonged labour.
Use in Lactation: It is unknown whether clopidogrel is excreted in human milk. Acetylsalicylic acid is known to be excreted in limited amounts in human milk. Breastfeeding should be discontinued during treatment with CoPlavix.
Adverse Reactions
Clopidogrel has been evaluated for safety in >44,000 patients who have participated in clinical studies, including over 30,000 patients treated with clopidogrel plus ASA and over 12,000 patients treated for ≥1 year. The clinically relevant adverse reactions observed in 4 major studies, the CAPRIE study (a study comparing clopidogrel alone to ASA) and the CURE, CLARITY and COMMIT studies (studies comparing clopidogrel plus ASA to ASA alone) are discussed as follows. Overall, clopidogrel 75 mg/day was similar 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.
Haemorrhagic Disorders: Bleeding is the most common reaction reported both in clinical studies as well as in the post-marketing experience where it was mostly reported during the 1st 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% and 1.6% in the clopidogrel and ASA groups, respectively.
In patients receiving clopidogrel, gastrointestinal bleeding occurred at a rate of 2% and required hospitalisation in 0.7%. In patients receiving ASA, the corresponding rates were 2.7% and 1.1%, respectively.
The overall incidence of other bleeding disorders was higher in the clopidogrel group (7.3%) compared to ASA (6.5%). However, the incidence of severe events was similar in both treatment groups (0.6% vs 0.4%). The most frequent events reported 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% for clopidogrel compared to 0.5% for ASA.
In CURE, there was an increase in major and minor bleeding between the clopidogrel + ASA group compared with the placebo + ASA group (event rates 3.7% vs 2.7%, for major, respectively, and 5.1% vs 2.4% for minor). The principal sites for major bleeding included gastrointestinal and at arterial puncture sites. The increase in life-threatening bleeding in the clopidogrel + ASA group compared to the placebo + ASA group was not statistically significant (2.2% vs 1.8%). There was no difference between the 2 groups in the rate of fatal bleeding (0.2% in both groups). The rate of non-life-threatening major bleeding was significantly higher in the clopidogrel + ASA group compared with the placebo + ASA group (1.6% vs 1%), and 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%; >200 mg: 4.9%) as was the major bleeding event rate for placebo + ASA (<100 mg: 2%; 100-200 mg: 2.3%; >200 mg: 4%).
There was no excess in major bleeds with clopidogrel plus ASA 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 plus ASA, and 6.3% for placebo plus ASA.
In CLARITY, there was an overall increase in bleeding in the clopidogrel plus ASA group versus the group taking ASA alone. The incidence of major bleeding was similar between groups (1.3% vs 1.1% in the clopidogrel + ASA and in 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 in the placebo + ASA groups, respectively) and intracranial hemorrhage (0.5% vs 0.7%, respectively) was low and similar in both groups.
The overall rate of noncerebral major bleeding or cerebral bleeding in COMMIT was low and similar in both groups.
In COMMIT, the overall rate of noncerebral major bleeding or cerebral bleeding was low and similar in both groups.
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 neutropaenia (<0.45 g/L) was observed in 4 patients (0.04%) on clopidogrel and 2 patients (0.02%) on ASA.
Two (2) of the 9,599 patients who received clopidogrel and none of the 9,586 patients who received ASA had neutrophils counts of zero. 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 sign of infection.
One case of aplastic anaemia occurred on clopidogrel treatment.
The incidence of severe thrombocytopaenia (<80 g/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 and CURE, CLARITY and COMMIT studies with an incidence <0.1% as well as all serious and relevant adverse drug reaction with an incidence <0.1% are presented as follows.
Adverse reactions that occurred with clopidogrel alone, with ASA alone or with clopidogrel in combination with ASA either during clinical studies or that were spontaneously reported are presented as follows. Their frequency is defined using the following conventions: Common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each system organ class, adverse reactions are presented in order of decreasing seriousness.
Central and Peripheral Nervous System Disorders: Uncommon: Headache, dizziness, paraesthesia. Rare: Vertigo.
Gastrointestinal System Disorders: Common: Dyspepsia, abdominal pain, diarrhoea, gastrointestinal haemorrhage. Uncommon: Nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer, duodenal ulcer. Rare: Retroperitoneal haemorrhage. Very Rare, Not Known: Gastrointestinal and retroperitoneal haemorrhage with fatal outcome.
Platelet, Bleeding and Clotting Disorders: Uncommon: Increased bleeding time, decreased neutrophil count and platelets.
Skin and Appendages Disorders: Common: Bruising. Uncommon: Rash, skin bleeding (purpura), pruritus.
White Cell and RES Disorders: Uncommon: Leucopenia, decreased neutrophils, thrombocytopenia, eosinophilia. Rare: Neutropenia, including severe neutropenia. Very Rare, Not Known: Severe thrombocytopenia, granulocytopenia, anaemia.
Post-Marketing Experience: Clopidogrel: Frequencies for the following adverse reactions are not known (cannot be estimated from available data).
Blood and the 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, thrombotic thrombocytopenic purpura (TTP) (see Precautions), 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 Disorders: Taste disturbances.
Vascular Disorders: Vasculitis, hypotension, serious haemorrhage, haemorrhage of operative wound, haematoma.
Respiratory, Thoracic and Mediastinal Disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding (haemoptysis, pulmonary haemorrhage), epistaxis, 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 symptoms (DRESS), eczema, lichen planus.
Musculoskeletal, Connective Tissue and Bone Disorders: Arthralgia, arthritis, myalgia, musculoskeletal bleeding (haemarthrosis).
Renal and Urinary Disorders: Glomerulopathy, increased blood creatinine, haematuria.
General Disorders and Administration Site Conditions: Fever, bleeding at the puncture site.
Investigations: Abnormal liver function test, increased blood creatinine.
Acetylsalicylic Acid: Blood and the Lymphatic System Disorders: Thrombocytopaenia, haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, pancytopenia, bicytopenia, aplastic anemia, bone marrow failure, agranulocytosis, neutropenia, leukopenia (see Precautions).
Immune System Disorders: Anaphylactic shock, aggravation of allergic symptoms of food allergy.
Nervous System Disorders: Intracranial haemorrhage may be fatal, especially in the elderly.
Metabolism and Nutrition Disorders: Hypoglycaemia, gout (see Precautions).
Ear and Labyrinth Disorders: Hearing loss or tinnitus, vertigo.
Respiratory, Thoracic and Mediastinal Disorders: Noncardiogenic pulmonary edema with chronic use and in the context of a hypersensitivity reaction due to acetylsalicylic acid.
Gastrointestinal Disorders: Oesophagitis, oesophageal ulceration, perforation. Erosive gastritis, erosive duodenitis, gastroduodenal ulcer/perforations, upper gastrointestinal symptom eg, gastralgia. (See Precautions.)
Small (jejunum and ileum) and large (colon and rectum) intestinal ulcers, colistis and intestinal perforation. These reactions may or may not be associated with haemorrhage, and may occur at any dose of acetylsalicylic acid and in patients with or without warning symptoms or a previous history of serious gastrointestinal events.
Hepatobiliary Disorders: Elevation of hepatic enzymes liver injury, mainly hepatocellular, chronic hepatitis.
Renal and Urinary Disorders: Acute renal impairment (especially in patients with existing renal impairment, heart decompensation, nephritic syndrome or concomitant treatment with diuretics), renal failure.
Skin and Subcutaneous Tissue Disorders: Fixed eruption.
Drug Interactions
Oral Anticoagulants: The concomitant administration of CoPlavix with oral anticoagulants is not recommended since it may increase the intensity of bleeding (see Precautions).
Glycoprotein IIb/IIIa Inhibitors: As a pharmacodynamic interaction between clopidogrel and glycoprotein IIb/IIIa inhibitors is possible, CoPlavix should be used with caution.
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 inhibition of platelet aggregation 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, fibrin or non-fibrin-specific 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 heparin are co-administered with ASA (see Adverse Reactions). The safety of the concomitant administration of CoPlavix with other thrombolytic agents has not been formally established and should be undertaken with caution (see Precautions).
Nonsteroidal Anti-Inflammatory Drugs: In a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. Consequently, the concomitant use of NSAIDs including COX-2 inhibitors is not recommended (see Precautions).
Experimental data suggest that ibuprofen may inhibit the effect of low-dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use (see Pharmacology: Pharmacodynamics under Actions).
Selective Serotonin Reuptake Inhibitors (SSRIs): Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution.
Other Concomitant Therapy with Clopidogrel: 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 inhibition of platelet aggregation (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 inhibition of platelet aggregation 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 CYP450 2C9. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.
Other Concomitant Therapy with Acetylsalicylic Acid: Interactions with the following medicinal products have been reported with ASA: Uricosurics (Benzbromarone, Probenecid, Sulfinpyrazone): Caution is required because ASA may inhibit the effect of uricosuric agents through competitive elimination of uric acid.
Methotrexate: Due to the presence of ASA, methotrexate used at doses >20 mg/week should be used with caution with CoPlavix as it can inhibit renal clearance of methotrexate, which may lead to bone marrow toxicity.
Metamizole: Metamizole may reduce the effect of ASA on platelet aggregation when taken concomitantly. Therefore, this combination should be used with caution in patients taking low-dose ASA for cardioprotection.
Other Interactions with Acetylsalicylic Acid: Interactions with the following medicinal products with higher (anti-inflammatory) doses of ASA have also been reported: Angiotensin converting enzyme inhibitors, acetazolamide, anticonvulsants (phenytoin and valproic acid), β-blockers, diuretics and oral hypoglycaemic agents.
Other Interactions with Clopidogrel and Acetylsalicylic Acid: In addition to the previously mentioned specific interaction studies, >30,000 patients entered into clinical trials with clopidogrel plus ASA at maintenance doses ≤325 mg and received a variety of concomitant medicinal products including diuretics, β-blockers, ACE inhibitors, calcium antagonists, cholesterol-lowering agents, coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions.
Apart from the specific medicinal product interaction information described previously, interaction studies with CoPlavix and some medicinal products commonly administered in patients with atherothrombotic disease have not been performed.
Incompatibilities: Not applicable.
Storage
Store below 25°C.
Shelf-Life: 2 years.
ATC Classification
B01AC30 - combinations ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
Presentation/Packing
FC tab (yellow, oval, slightly biconvex, engraved with "C75" on one side and "A75" on the other side) x 30's.
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