CLOPIDOGREL (Generic for PLAVIX)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May be administered without regard to feedings/meals.
Extemporaneous Compounding-Oral
Extemporaneous 5 mg/ml Oral Suspension
-Triturate four 75 mg tablets in a glass mortar into a fine powder.
-Mix 30 ml of Ora-Plus with 30 ml of Ora-Sweet
-Add vehicle in geometric proportions until a smooth suspension is formed; transfer mixture into a 2 ounce amber bottle.
-Rinse the contents of the mortar with enough vehicle to bring final volume to 60 ml.
-Storage: Suspension is stable for 60 days at room temperature or refrigerated.
-Shake well before administration.

Bleeding, including fatal hemorrhage, may occur at any site due to drug-induced platelet dysfunction. Most bleeding events have been minor (e.g., epistaxis, melena, easy skin bruising) in clinical studies of clopidogrel in children; however, serious bleeding complications (e.g., GI bleeding, intracranial bleeding) have been reported. Some of the reported bleeding events have occurred when clopidogrel was coadministered with aspirin and/or warfarin. In a retrospective case cohort study of pediatric inpatients using the Pediatric Health Information System (PHIS) database, 192 bleeding events (14.6%) were identified out of the 1,312 clopidogrel admissions; however, this may have been an overestimate due to coding issues, and true causality could not be determined. In the CLARINET study (n = 906; clopidogrel vs. placebo in infants with congenital heart disease and systemic-to-pulmonary artery shunt; 87.9% receiving concomitant aspirin), bleeding rates were similar between the clopidogrel and placebo groups (18.8% vs. 20.2%). When analyzed according to aspirin use, bleeding rates remained comparable between the 2 groups. Severe bleeding occurred in 4.1% of patients receiving clopidogrel compared with 3.4% of patients receiving placebo; 1 patient in each group experienced a fatal bleeding event. Most of the bleeding events were spontaneous with the most common being GI bleeding and hematochezia occurring in 2.2% and 3.4% of patients, respectively. Other reported adverse bleeding events during clinical trials involving adult patients include intracranial bleeding, epistaxis, hematuria, hematoma, peptic ulcer, rectal hemorrhage, melena, and ocular hemorrhage. In the CAPRIE trial, purpura was reported in 5.3% of adult patients taking clopidogrel vs. 3.7% of adult patients taking aspirin.

Thrombotic thrombocytopenic purpura (TTP) has been reported rarely in adult patients receiving clopidogrel, sometimes after short exposure (< 2 weeks). A case of TTP was also reported in an adolescent patient receiving clopidogrel in a retrospective cohort study; however, definitive causality could not be determined. TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis (plasma exchange). Thrombocytopenia, microangiopathic hemolytic anemia (schistocytes seen on peripheral smear), neurological findings, renal dysfunction, and pyrexia characterize TTP. In world-wide post-marketing experience, TTP has been reported at a rate of about four cases per million patients exposed or about 11 cases per million patient-years. The rate in the general population is approximately four cases per million person-years. Eleven cases of TTP were reported in adults between March 1998 and March 2000; in all but one case, TTP developed within 14 days of beginning clopidogrel therapy. One patient died, eight had complete resolution of TTP after discontinuing clopidogrel and treatment with plasma exchange, and two had relapses up to seven months after the onset of TTP, with recovery after plasma exchange. It should be noted that almost half the patients with clopidogrel-induced TTP had received cholesterol-lowering drugs. In one of the patients, TTP appeared to be induced by atorvastatin, and one patient had a recurrence during treatment with atorvastatin that responded quickly to plasma exchange. In this series of patients, clopidogrel-induced TTP differed from ticlopidine-induced TTP in that it occurred sooner, was prone to recurrence, and required up to 30 plasma exchanges before clinical improvement occurred.

Anemia and leukopenia were reported in 1 patient in a retrospective study of 46 children who received clopidogrel. No underlying causes could be determined and blood counts returned to normal within 2 weeks after clopidogrel discontinuation. Hematological effects that have been reported during post-marketing use of clopidogrel include agranulocytosis, aplastic anemia, pancytopenia, thrombotic thrombocytopenic purpura (see related TTP content), and acquired hemophilia A. Because these reactions are reported voluntarily, it is not possible to reliably estimate their frequency or establish a causal relationship to clopidogrel. Monitor CBC frequently during therapy.

Gastrointestinal adverse events reported in pediatric patients treated with clopidogrel in the CLARINET study (clopidogrel vs. placebo in infants with congenital heart disease and systemic-to-pulmonary-artery shunt) included vomiting (8%), diarrhea (6.3%), and gastroesophageal reflux (3%). Additional gastrointestinal adverse events reported with clopidogrel in adult patients have included abdominal pain, constipation, gastritis, dyspepsia, and nausea. Most of these adverse effects were mild and transient. Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, acute hepatic failure, elevated hepatic enzymes, and hepatitis (non-infectious) have been reported during post-marketing surveillance of clopidogrel. Because these post-marketing reactions are reported voluntarily, it is not possible to reliably estimate their frequency or establish a causal relationship to clopidogrel.

Although not common, allergic reactions, characterized by rash (unspecified), pruritus, and erythema, have been reported in children receiving clopidogrel. In the CLARINET study (n = 906), rash and fever were reported in 1.9% and 5% of patients, respectively; however, the incidence of rash was higher in the placebo group (3.2%). Diaper dermatitis was reported in 2.2% of patients. Alopecia, possibly related to clopidogrel therapy, was reported in 1 patient in a retrospective study of 46 children. In the CAPRIE study (clopidogrel compared to aspirin in adult patients), maculopapular rash and pruritus were reported more commonly in the clopidogrel group compared to the aspirin group. Although uncommon, the frequency of severe rash among patients receiving clopidogrel was twice as high as that reported among aspirin-treated patients. Hypersensitivity reactions, drug-induced hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), anaphylactoid reactions, serum sickness, maculopapular or erythematous rash, exfoliative dermatitis, urticaria, fever, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis (AGEP), angioedema, erythema multiforme, and lichen planus have been reported during post-marketing surveillance of clopidogrel. Because post-marketing reactions are reported voluntarily, it is not possible to reliably estimate their frequency or establish a causal relationship to clopidogrel.

Nervous system adverse reactions reported in pediatric patients treated with clopidogrel in the CLARINET study (n = 906; clopidogrel vs. placebo in infants with congenital heart disease and systemic-to-pulmonary-artery shunt) included seizures (3% vs. 1.6% placebo, p = 0.16) and stroke (1.7% vs. 0% placebo, p = 0.006). In adults, the most frequent neurologic adverse reactions reported in the CAPRIE study (clopidogrel compared to aspirin) were headache, dizziness, and vertigo. Other adverse reactions involving the nervous system that have been reported during postmarketing surveillance include confusion, hallucinations, headache, and taste disorders (ageusia and dysgeusia). Because postmarketing reactions are reported voluntarily, it is not possible to reliably estimate their frequency or establish a causal relationship to clopidogrel.

Adverse events involving the respiratory system that have been reported during post-marketing surveillance of clopidogrel include bronchospasm, interstitial pneumonitis, and eosinophilic pneumonia. Because these reactions are reported voluntarily, it is not possible to reliably estimate their frequency or establish a causal relationship to clopidogrel.

Renal adverse events reported during post-marketing surveillance of clopidogrel include glomerulonephritis and increased creatinine concentrations. Because these reactions are reported voluntarily, it is not possible to reliably estimate their frequency or establish a causal relationship to clopidogrel.

Myalgia, arthralgia, and arthritis have been reported during post-marketing surveillance of clopidogrel. Because these reactions are reported voluntarily, it is not possible to reliably estimate their frequency or establish a causal relationship to clopidogrel.

In the CAPRIE study (clopidogrel compared to aspirin in adults), cardiovascular events reported in patients receiving clopidogrel included hypertension, peripheral edema, and heart rate or rhythm abnormalities. Vasculitis and hypotension have been reported in the post-marketing surveillance of clopidogrel. Because these reactions are reported voluntarily, it is not possible to reliably estimate their frequency or establish a causal relationship to clopidogrel.

Conjunctivitis was reported in 2.6% of pediatric patients treated with clopidogrel in the CLARINET study (n = 906; clopidogrel vs. placebo in infants with congenital heart disease and systemic-to-pulmonary-artery shunt).

Insulin autoimmune syndrome has been reported with postmarketing use of clopidogrel. Insulin autoimmune syndrome may lead to severe hypoglycemia.

Clopidogrel is contraindicated in patients with a known hypersensitivity to clopidogrel or any component of the product. Evaluate patients receiving clopidogrel for a history of thienopyridine hypersensitivity. Hypersensitivity reactions including rash, angioedema, or hematologic reactions have been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines (e.g., ticlopidine, prasugrel).

Clopidogrel increases the risk of bleeding and is contraindicated in patients with active pathological bleeding including GI bleeding and intracranial bleeding. 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 including peptic ulcer disease. When possible, interrupt clopidogrel therapy for 5 days prior to surgery; resume as soon as hemostasis is achieved. Clopidogrel inhibits platelet aggregation for the lifetime of the platelet (7 to 10 days). It may be possible to restore hemostasis by transfusing platelets because the half-life of clopidogrel's active metabolite is short; however, platelets transfused within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective. Use clopidogrel and other drugs that may promote bleeding (e.g., anticoagulants, antiplatelet agents, chronic use of NSAIDs) together with caution.

The manufacturer states no dosage adjustment is necessary in patients with hepatic disease. However, a bleeding diathesis may exist in these patients, especially in those with severe liver disease, which may increase the risk of bleeding associated with clopidogrel. In addition, severe hepatic disease may impair the conversion of clopidogrel, the prodrug, to its active form.

Experience is limited in patients with renal impairment or renal failure. Use clopidogrel cautiously in these patients.

Clopidogrel has a reduced effect on platelet function in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene (i.e., poor metabolizers). Consider another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers. Data in adults have shown that poor metabolizers have a higher risk of mortality, myocardial infarction, and stroke compared to normal metabolizers. The implications of these findings in the pediatric population are unknown. Clopidogrel metabolism and, subsequently, platelet inhibition can also be reduced by drugs that significantly inhibit CYP2C19, such as omeprazole and esomeprazole; concomitant use should be avoided. Dexlansoprazole, lansoprazole, and pantoprazole have less effect on antiplatelet activity. In a subgroup analysis of 49 children from the PICOLO study, a trend toward a lower maximum extent of platelet inhibition (median 6%; interquartile range 0% to 44% vs. 49%; interquartile range 19% to 63%; p = 0.09 ) was noted in patients who were receiving clopidogrel in combination with a proton pump inhibitor (n = 5; n = 4 omeprazole; n = 1 lansoprazole) compared with those patients receiving clopidogrel alone (n = 44). There was also a significant decrease in the number of clopidogrel responders in the combination group (25% vs. 53%; p = 0.04).

In an effort to minimize the risk of cardiovascular events, avoid premature discontinuation or lapses in therapy (i.e., abrupt discontinuation) with clopidogrel. Premature discontinuation may increase the risk for cardiovascular events. If clopidogrel must be temporarily discontinued, restart therapy as soon as possible.

Description: Clopidogrel is an oral irreversible inhibitor of platelet aggregation in the thienopyridine class. It has a structure and mechanism of action similar to that of ticlopidine. Adult data have shown that compared with aspirin, clopidogrel may be associated with a lower risk of gastrointestinal bleeding. Overall tolerability appears similar between clopidogrel and aspirin; however, the CAPRIE study found aspirin to have a slightly higher frequency of gastrointestinal disturbances, such as dyspepsia and abdominal pain, and clopidogrel to have a slightly higher frequency of rash, pruritus, and diarrhea. Studies comparing clopidogrel and aspirin have not been conducted in pediatric patients. Clopidogrel has primarily been used in children for thrombosis prophylaxis after cardiac surgery for congenital heart disease or children with cardiac conditions associated with a high risk for thrombosis (i.e., Kawasaki disease). However, treatment with clopidogrel did not reduce mortality or shunt-related morbidity compared with placebo in young infants with cyanotic congenital heart disease and a systemic-to-pulmonary-artery shunt in the CLARINET study. Clopidogrel is recommended as an alternative for secondary stroke prevention in children who experience recurrent arterial ischemic stroke or transient ischemic attacks while on aspirin or those intolerant of aspirin. Bleeding is the most significant adverse event that may occur with clopidogrel; however, in clinical studies in children, bleeding events have been mostly minor. Clopidogrel is not FDA-approved for use in pediatric patients; however, it is used off-label for thrombosis prophylaxis in pediatric patients as young as neonates.

General Dosing Information:
-Patients identified as CYP2C19 poor metabolizers have a diminished antiplatelet response to clopidogrel. A higher dosage regimen increases antiplatelet response; however, an appropriate dosage regimen for this patient population has not been established in clinical outcome trials.
-CLARINET trial: No significant difference in the rate of the composite primary outcome (death or heart transplantation, shunt thrombosis requiring intervention, or cardiac procedure performed due to a thrombotic event before 120 days of age) or any component of the composite primary outcome was seen in patients treated with clopidogrel (0.2 mg/kg/day) compared with those who received placebo (19.1% vs. 20.5%; absolute risk difference, 1.4%; relative risk reduction with clopidogrel, 11.1%; 95% CI, -19.2 to 33.6; p = 0.43) in a multicenter, double-blind, randomized study of 906 infants (92 days or younger) with cyanotic congenital heart disease and a systemic-to-pulmonary-artery shunt (Clopidogrel to Lower Arterial Thrombotic Risk in Neonates and Infants Trial [CLARINET]). There was no significant difference in bleeding events between groups. Patients in the overall study population who were receiving concomitant aspirin (87.9%) had a significantly lower rate of the primary endpoint compared to those who did not receive aspirin (18.6% vs. 28.2%; absolute risk difference, 9.6%; relative risk reduction, 40.1%; 95% CI, 11.8 to 59.3; p = 0.009) in post hoc analyses.

For arterial thromboembolism prophylaxis* (i.e., thrombosis prophylaxis*, secondary stroke prophylaxis* following arterial ischemic stroke* or transient ischemic attack (TIA)*), including following cardiac surgery* and in other cardiac conditions with a risk for arterial thrombosis (e.g., Kawasaki disease*):
NOTE: In children with recurrent arterial ischemic stroke or TIAs who fail or are intolerant of aspirin, clopidogrel is recommended as an alternative antiplatelet agent.
NOTE: In children with Kawasaki disease who have severe coronary involvement, clopidogrel is recommended to be used with aspirin.
Oral dosage:
Neonates, Infants, and Children <= 2 years: 0.2 mg/kg/day PO provides platelet inhibition levels similar to those achieved by the standard adult dose based on limited data. In the PICOLO study, which included 34 neonates (>= 35 weeks gestational age and >= 2 kg) and 39 infants/children 30 days-24 months, a dose of 0.2 mg/kg/day achieved the target ADP-induced platelet aggregation inhibition (30-50% inhibition of platelet aggregation) for both the maximum extent and the rate of platelet aggregation. Of the patients randomized, 73.3% had undergone placement of a systemic-to-pulmonary artery shunt, 24.4% had an intracardiac or intravascular stent placed, 1.2% had Kawasaki disease, and the remainder had an arterial graft in place. The majority of patients were also taking <= 81 mg/day of aspirin. In another prospective study in 14 children (range, 0.7-84 months; 11 children <= 2 years), 93% of patients (13 out of 14) achieved effective platelet inhibition (30-50% inhibition of platelet aggregation) with a dose of 0.2 mg/kg/day.
Children and Adolescents > 2 years: Dosing not well established. An initial dose of 1 mg/kg/day PO titrated to response has been used most commonly (Max: 75 mg/day) ; in a cohort of 90 pediatric patients (age range: 11 days to 17.9 years, median 6.7 years), the median dose administered was 1.3 mg/kg/day PO. Some studies have reported lower doses of 0.2-0.3 mg/kg/day in children. In a prospective study in 14 children (0.7-84 months; 3 children > 2 years), a dose of 0.2 mg/kg/day resulted in effective platelet inhibition (40-50% inhibition of platelet aggregation) in 2 of the 3 children who were older than 2 years of age. In another study, dosing was initiated with 0.5-1 mg/kg/day with subsequent doses titrated down to 0.2-0.3 mg/kg/day. Higher doses (> 2-6 mg/kg/day) have been reported and were tolerated in a few reported cases in children ; however, the risk of bleeding may be higher with increasing doses.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, doses of 0.2 mg/kg/day PO have been used off-label.
-Infants
Safety and efficacy have not been established; however, doses of 0.2 mg/kg/day PO have been used off-label.
-Children
<= 2 years: Safety and efficacy have not been established; however, doses of 0.2 mg/kg/day PO have been used off-label.
> 2 years: Safety and efficacy have not been established; doses up to 6 mg/kg/day (Max: 75 mg/day) PO have been used off-label.
-Adolescents
Safety and efficacy have not been established; doses up to 6 mg/kg/day (Max: 75 mg/day) PO have been used off-label.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Experience is limited in patients with severe and moderate renal impairment; specific guidelines for dosage adjustments in renal impairment are not available.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Clopidogrel is a thienopyridine compound which acts to antagonize adenosine diphosphate (ADP). Clopidogrel is inactive in vitro and requires hepatic activation to exert its antiplatelet effect. The active metabolite selectively and irreversibly inhibits ADP-induced platelet aggregation. It prevents binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor. Thus, ADP-mediated activation of the glycoprotein GPIIb/IIIa complex is impaired. Because the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, impaired activation of the GPIIb/IIIa complex prevents fibrinogen binding to platelets which ultimately inhibits platelet aggregation. Because the active metabolite of clopidogrel irreversibly modifies the platelet ADP receptor; platelets exposed to the drug are affected for the remainder of their lifespan (7-10 days). In platelet aggregation studies, clopidogrel 75 mg once daily produced inhibition of ADP-induced platelet aggregation equivalent to that of ticlopidine 250 mg twice daily. The active metabolite of clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP; the active metabolite does not inhibit phosphodiesterase.

Pharmacokinetics: Clopidogrel is administered orally; it is inactive in vitro and requires hepatic biotransformation to an active metabolite. Clopidogrel undergoes extensive metabolism by 2 main metabolic pathways. One pathway is mediated by esterases and results in an inactive carboxylic acid derivative, accounting for 85% of circulating metabolites. The other pathway is mediated by multiple cytochrome (CYP) P450 isoenzymes. The cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the intermediate metabolite results in the formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed primarily by CYP2C19; CYP3A, CYP2B6, and CYP1A2 contribute to a lesser extent. The active metabolite rapidly and irreversibly binds to platelet receptors, inhibiting platelet aggregation for the lifespan of the platelet. Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). Approximately 50% of radiolabeled clopidogrel is eliminated in the urine and about 46% via the feces over a period of 5 days. The half-life of clopidogrel is approximately 6 hours in adults; the half-life of the active metabolite is approximately 30 minutes.

Dose dependent inhibition of platelet aggregation can be seen 2 hours after a single oral dose. With repeated doses of 75 mg/day in adults, maximum inhibition of platelet aggregation is achieved within 3 to 7 days. At steady state, platelet aggregation is inhibited by 40% to 60%. Platelet aggregation and bleeding time gradually return to baseline about 5 days after discontinuation of clopidogrel.

Affected cytochrome P450 isoenzymes: CYP2C9, CYP2C19, CYP2C8, CYP3A, CYP2B6, and CYP1A2
Clopidogrel is a substrate and inhibitor of CYP2C19 and a strong inhibitor of CYP2C8. Clopidogrel requires hepatic biotransformation to an active metabolite; this activation is mediated primarily by CYP2C19 and to a lesser extent by CYP3A, CYP2B6, and CYP1A2. At high concentrations in vitro, clopidogrel is a potent inhibitor of CYP2B6 and a mild inhibitor of CYP2C9.


-Route-Specific Pharmacokinetics
Oral Route
Clopidogrel is rapidly absorbed with a bioavailability of at least 50%. Food does not significantly affect absorption. In adults, peak concentrations occur 30 to 60 minutes after administration.


-Special Populations
Hepatic Impairment
Data are unavailable in pediatric patients with hepatic impairment. However, in adults with severe hepatic impairment, platelet inhibition was similar to that observed in healthy subjects.

Renal Impairment
Data are unavailable in pediatric patients with renal impairment. However, in adult patients with moderate (CrCl 30 to 60 mL/minute) or severe renal impairment (CrCl 5 to 15 mL/minute), lower platelet inhibition (25%) was noted after repeated doses of 75 mg/day.