Dilutix

Acute Coronary Syndrome (ACS)

• Dilutix is indicated to reduce the rate of myocardial infarction (MI) and stroke in patients with non–ST-segment elevation ACS (unstable angina [UA]/non–ST-elevation myocardial infarction [NSTEMI]), including patients who are to be managed medically and those who are to be managed with coronary revascularization. Dilutix should be administered in conjunction with aspirin.
• Dilutix is indicated to reduce the rate of myocardial infarction and stroke in patients with acute ST-elevation myocardial infarction (STEMI) who are to be managed medically. Dilutix should be administered in conjunction with aspirin.

Recent MI, Recent Stroke, Or Established Peripheral Arterial Disease

In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke Dilutix is indicated to reduce the rate of MI and stroke.

Acute Coronary Syndrome

In patients who need an antiplatelet effect within hours, initiate Dilutix with a single 300-mg oral loading dose and then continue at 75 mg once daily. Initiating Dilutix without a loading dose will delay establishment of an antiplatelet effect by several days.

Recent MI, Recent Stroke, Or Established Peripheral Arterial Disease

75 mg once daily orally without a loading dose.

Active Bleeding

Dilutix is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

Hypersensitivity

Dilutix is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Diminished Antiplatelet Activity In Patients With Impaired CYP2C19 Function

Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19.

The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid concomitant use of Dilutix with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of Dilutix.

General Risk Of Bleeding

Thienopyridines, including Dilutix, increase the risk of bleeding.

Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days). Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.

Discontinuation Of Dilutix

Discontinuation of Dilutix increases the risk of cardiovascular events. If Dilutix must be temporarily discontinued (e.g., to treat bleeding or for surgery with a major risk of bleeding), restart it as soon as possible. When possible, interrupt therapy with Dilutix for five days prior to such surgery. Resume Dilutix as soon as hemostasis is achieved.

Thrombotic Thrombocytopenic Purpura (TTP)

TTP, sometimes fatal, has been reported following use of Dilutix, sometimes after a short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.

Cross-Reactivity Among Thienopyridines

Hypersensitivity including rash, angioedema or hematologic reaction has been reported in patients receiving Dilutix, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines.

Patient Counseling Information

Advise patients to read FDA approved patient labeling (Medication Guide).

Discontinuation

Advise patients not to discontinue Dilutix without first discussing it with the healthcare provider who prescribed it.

Bleeding

Advise patients that they:

• will bruise and bleed more easily
• will take longer than usual to stop bleeding
• must report any unanticipated, prolonged, or excessive bleeding, or blood in their stool or urine

Thrombotic Thrombocytopenic Purpura

Instruct patients to get prompt medical attention if they experience symptoms of TTP that cannot otherwise be explained.

Invasive Procedures

Advise patients to inform physicians and dentists that they are taking Dilutix before any surgery or dental procedure.

Proton Pump Inhibitors

Advise patients not to take omeprazole or esomeprazole while taking Dilutix. Dexlansoprazole, lansoprazole and pantoprazole had less pronounced effects on the antiplatelet activity of Dilutix than did omeprazole or esomeprazole.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures >25 times that in humans at the recommended daily dose of 75 mg.

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

Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category B

Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m² basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, Dilutix should be used during pregnancy only if clearly needed.

Nursing Mothers

Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric populations have not been established.

A randomized, 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. Possible factors contributing to this outcome were the dose of clopidogrel, the concomitant administration of aspirin and the late initiation of therapy following shunt palliation. It cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population.

Geriatric Use

Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with Dilutix were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with Dilutix were 60 years and older, 26% of whom were 70 years and older.

The observed risk of bleeding events with Dilutix plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively. No dosage adjustment is necessary in elderly patients.

Renal Impairment

Experience is limited in patients with severe and moderate renal impairment.

Hepatic Impairment

No dosage adjustment is necessary in patients with hepatic impairment.

The following serious adverse reactions are discussed below and elsewhere in the labeling:

• Bleeding
• Thrombotic thrombocytopenic purpura

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions and durations of follow-up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Dilutix has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for one year or more. The clinically important adverse reactions observed in trials comparing Dilutix plus aspirin to placebo plus aspirin and trials comparing Dilutix alone to aspirin alone are discussed below.

Bleeding

CURE

In CURE, Dilutix use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1). The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise.

The overall incidence of bleeding is described in Table 1.

Table 1: CURE Incidence of Bleeding Complications (% patients)

COMMIT

In COMMIT, similar rates of major bleeding were observed in the Dilutix and placebo groups, both of which also received aspirin (see Table 2).

Table 2: Incidence of Bleeding Events in COMMIT (% patients)

CAPRIE (Dilutix vs Aspirin)

In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking Dilutix versus 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for Dilutix compared to 0.5% for aspirin.

Other bleeding events that were reported more frequently in the Dilutix group were epistaxis and hematoma.

Other Adverse Events

In CURE and CHARISMA, which compared Dilutix plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between Dilutix and placebo.

In CAPRIE, which compared Dilutix to aspirin, pruritus was more frequently reported in those taking Dilutix. No other difference in the rate of adverse events (other than bleeding) was reported.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Dilutix. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hemorrhages, including those with fatal outcome, have been reported in patients treated with Dilutix.

• Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A
• Gastrointestinal disorders: Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea
• General disorders and administration site condition: Fever
• Hepatobiliary disorders: Acute liver failure, hepatitis (noninfectious), abnormal liver function test
• Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness
• Musculoskeletal, connective tissue and bone disorders: Myalgia, arthralgia, arthritis
• Nervous system disorders: Taste disorders, headache, ageusia
• Psychiatric disorders: Confusion, hallucinations
• Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, eosinophilic pneumonia
• Renal and urinary disorders: Increased creatinine levels
• Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis (AGEP), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, lichen planus, generalized pruritus
• Vascular disorders: Vasculitis, hypotension

Platelet inhibition by Dilutix is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals.

Based on biological plausibility, platelet transfusion may restore clotting ability.

Clopidogrel must be metabolized by 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 GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.

Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of Dilutix. Repeated doses of 75 mg Dilutix per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg Dilutix per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

Geriatric Patients

Elderly (≥ 75 years) and young healthy subjects had similar effects on platelet aggregation.

Renally Impaired Patients

After repeated doses of 75 mg Dilutix per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.

Hepatically Impaired Patients

After repeated doses of 75 mg Dilutix per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.

Gender

In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.

Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.

Absorption

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Effect Of Food

Dilutix can be administered with or without food. In a study in healthy male subjects when Dilutix 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a Dilutix 300 mg loading dose was administered with a high-fat breakfast.

Metabolism

Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxoclopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: 4-fold the dose results in 2.0-fold and 2.7-fold the Cmax and AUC, respectively.

Elimination

Following an oral dose of ¹⁴C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.