Clopidogrel Bisulfate

Torrent Pharmaceuticals Limited
Torrent Pharma, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use clopidogrel tablets safely and effectively. See full prescribing information for clopidogrel tablets. Clopidogrel Tablets, USP for oral use Initial U.S. Approval: 1997 BOXED WARNING WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS See full prescribing information for complete boxed warning. Effectiveness of clopidogrel bisulfate depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1) Poor metabolizers treated with clopidogrel bisulfate at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. (12.5) Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. (12.5) Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. (2.3, 5.1) RECENT MAJOR CHANGESWarnings and Precautions (5.6)                                                12/2013INDICATIONS AND USAGEClopidogrel tablets, USP are  P2Y12 platelet inhibitor indicated for: ●  Acute coronary syndrome - For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], clopidogrel tablets, USP have been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia. (1.1) - For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets, USP have been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary PCI is unknown. (1.1) ●  Recent MI, recent stroke, or established peripheral arterial disease. Clopidogrel tablets, USP have been shown to reduce the combined endpoint of new ischemic stroke, new MI, and other vascular death. (1.2) DOSAGE AND ADMINISTRATION●    Acute coronary syndrome (2.1)- UA/NSTEMI: 300 mg loading dose followed by 75 mg once daily, in combination with aspirin (75-325 mg once daily) - STEMI: 75 mg once daily, in combination with aspirin (75-325 mg once daily), with or without a loading dose and with or without thrombolytics   ●  Recent MI, recent stroke, or established peripheral arterial disease:  75 mg once daily (2.2) DOSAGE FORMS AND STRENGTHSTablets: 75 mg (3) CONTRAINDICATIONS Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage (4.1) Hypersensitivity to clopidogrel or any component of the product (4.2) WARNINGS AND PRECAUTIONS CYP2C19 function: Avoid concomitant use of omeprazole or esomeprazole. (5.1) Bleeding: Clopidogrel bisulfate increases risk of bleeding.  Discontinue 5 days prior to elective surgery. (5.2) Premature discontinuation increases risk of cardiovascular events. (5.3) Recent transient ischemic attack or stroke: Combination use of clopidogrel bisulfate and aspirin is not more effective than clopidogrel bisulfate alone, but increase major bleeding. (5.4) Thrombotic thrombocytopenic purpura (TTP) has been reported (5.5) Cross-reactivity among thienopyridines has been reported. (5.6) Side EffectsBleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-269-544-2299 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS   Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. (7.2,7.3,7.4) USE IN SPECIFIC POPULATIONSNursing mothers: Discontinue drug or nursing. (8.3)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1. CLOPIDOGREL BISULFATE INDICATIONS AND USAGE
  • 1.1 Acute Coronary Syndrome (ACS)
  • 1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
• 2. CLOPIDOGREL BISULFATE DOSAGE AND ADMINISTRATION
  • 2.1 Acute Coronary Syndrome
  • 2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease
  • 2.3 CYP2C19 Poor Metabolizers
  • 2.4 Use with Proton Pump Inhibitors (PPI)
• 3. DOSAGE FORMS AND STRENGTHS
• 4. CLOPIDOGREL BISULFATE CONTRAINDICATIONS
  • 4.1 Active Bleeding
  • 4.2 Hypersensitivity
• 5. WARNINGS AND PRECAUTIONS
  • 5.1 Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function
  • 5.2 General Risk of Bleeding
  • 5.3 Discontinuation of Clopidogrel Bisulfate
  • 5.4 Patients with Recent Transient Ischemic Attack (TIA) or Stroke
  • 5.5 Thrombotic Thrombocytopenic Purpura (TTP)
  • 5.6 Cross-Reactivity among Thienopyridines
• 6. CLOPIDOGREL BISULFATE ADVERSE REACTIONS
  • 6.1 Clinical Studies Experience
  • 6.2 Postmarketing Experience
• 7. DRUG INTERACTIONS
  • 7.1 CYP2C19 Inhibitors
  • 7.2 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
  • 7.3 Warfarin (CYP2C9 Substrates)
  • 7.4 SSRIs and SNRIs
• 8. USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
• 10. OVERDOSAGE
• 11. CLOPIDOGREL BISULFATE DESCRIPTION
• 12. CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.5 Pharmacogenomics
• 13. NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14. CLINICAL STUDIES
  • 14.1 Acute Coronary Syndrome
  • 14.2 Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease
  • 14.3 Lack of Established Benefit of Clopidogrel Bisulfate plus Aspirin in Patients with Multiple Risk Factors or Established Vascular Disease
• 16. HOW SUPPLIED/STORAGE AND HANDLING
• 17. PATIENT COUNSELING INFORMATION
  • 17.1 Benefits and Risks
  • 17.2 Bleeding
  • 17.3 Other Signs and Symptoms Requiring Medical Attention
  • 17.4 Invasive Procedures
  • 17.5 Concomitant Medications
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS

The effectiveness of clopidogrel bisulfate is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1)]. Clopidogrel bisulfate at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel bisulfate at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy [see Clinical Pharmacology (12.5)].  Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers [see Dosage and Administration (2.3)].

1. INDICATIONS AND USAGE

1.1 Acute Coronary Syndrome (ACS)

• For 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, clopidogrel tablets, USP have been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.
• For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets, USP have been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary percutaneous coronary intervention is unknown.

1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel tablets, USP have been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

2. DOSAGE AND ADMINISTRATION

2.1 Acute Coronary Syndrome

Clopidogrel bisulfate tablets can be administered with or without food [see Clinical Pharmacology (12.3)].

• For patients with non-ST-elevation ACS (UA/NSTEMI), initiate clopidogrel bisulfate tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin (75-325 mg once daily) and continue in combination with clopidogrel bisulfate [see Clinical Studies (14.1)].
• For patients with STEMI, the recommended dose of clopidogrel bisulfate tablets is 75 mg once daily orally, administered in combination with aspirin (75-325 mg once daily), with or without thrombolytics. Clopidogrel bisulfate tablets may be initiated with or without a loading dose [see Clinical Studies (14.1)].

2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

The recommended daily dose of clopidogrel bisulfate tablets are 75 mg once daily orally, with or without food [see Clinical Pharmacology (12.3)].

2.3 CYP2C19 Poor Metabolizers

CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response [see Clinical Pharmacology (12.5)], an appropriate dose regimen for this patient population has not been established.

2.4 Use with Proton Pump Inhibitors (PPI)

Avoid using omeprazole or esomeprazole with clopidogrel bisulfate tablets. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of clopidogrel bisulfate tablets. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite [see Warnings and Precautions (5.1), Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

3. DOSAGE FORMS AND STRENGTHS

• 75 mg tablets: Light pink colored, round, beveled edge, biconvex film coated tablets printed "41" with black ink on one side and plain on the other side.

4. CONTRAINDICATIONS

4.1 Active Bleeding

Clopidogrel bisulfate tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

4.2 Hypersensitivity

Clopidogrel bisulfate tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions (6.2)].

5. WARNINGS AND PRECAUTIONS

5.1 Diminished Antiplatelet Activity Due to 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 [see Boxed Warning] and by concomitant medications that interfere with CYP2C19.

Proton Pump Inhibitors

Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel bisulfate [see Drug Interactions (7.1) and Dosage and Administration (2.4)].

5.2 General Risk of Bleeding

Thienopyridines, including clopidogrel bisulfate, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel bisulfate five days prior to surgery. In patients who stopped therapy more than five days prior to CABG the rates of major bleeding were similar (event rate 4.4% clopidogrel bisulfate + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel bisulfate + aspirin, and 6.3% for placebo + aspirin.

Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. 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.

5.3 Discontinuation of Clopidogrel Bisulfate

Avoid lapses in therapy, and if clopidogrel bisulfate must be temporarily discontinued, restart as soon as possible. Premature discontinuation of clopidogrel bisulfate may increase the risk of cardiovascular events.

5.4 Patients with Recent Transient Ischemic Attack (TIA) or Stroke

In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and clopidogrel bisulfate has not been shown to be more effective than clopidogrel bisulfate alone, but the combination has been shown to increase major bleeding.

5.5 Thrombotic Thrombocytopenic Purpura (TTP)

TTP, sometimes fatal, has been reported following use of clopidogrel bisulfate, 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 [see Adverse Reactions (6.2)].

5.6 Cross-Reactivity among Thienopyridines

Hypersensitivity including rash, angioedema or hematologic reaction have been reported in patients receiving clopidogrel bisulfate, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines [see Contraindications (4.2) and Adverse Reactions (6.2)].

6. ADVERSE REACTIONS

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

• Bleeding [see Warnings and Precautions (5.2)]
• Thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.5)]

6.1 Clinical Studies 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.

Clopidogrel bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The clinically important adverse reactions observed in trials comparing clopidogrel bisulfate plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below.

Bleeding

CURE

In CURE, clopidogrel bisulfate 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.  

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of clopidogrel bisulfate. 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.

•   Blood and lymphatic system disorders : Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A
•   Eye disorders : Eye (conjunctival, ocular, retinal) bleeding
•   Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea  
•   General disorders and administration site condition : Fever, hemorrhage of operative wound
•   Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test
•   Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness
•   Musculoskeletal , connective tissue and bone disorders: Musculoskeletal bleeding, myalgia, arthralgia, arthritis
•   Nervous system disorders : Taste disorders, fatal intracranial bleeding, headache
•   Psychiatric disorders: Confusion, hallucinations
•   Respiratory , thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding, 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, angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, skin bleeding, lichen planus, generalized pruritus
•   Vascular disorders: Vasculitis, hypotension

7. DRUG INTERACTIONS

7.1 CYP2C19 Inhibitors

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Warnings and Precautions (5.1) and Dosage and Administration (2.4)].

Proton Pump Inhibitors (PPI)

Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce the antiplatelet activity of clopidogrel bisulfate when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel bisulfate. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel bisulfate than did omeprazole or esomeprazole [see Dosage and Administration (2.4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

7.2 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Coadministration of clopidogrel bisulfate and NSAIDs increases the risk of gastrointestinal bleeding.

7.3 Warfarin (CYP2C9 Substrates)

Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, coadministration of clopidogrel bisulfate with warfarin increases the risk of bleeding because of independent effects on hemostasis.

However, at high concentrations in vitro, clopidogrel inhibits CYP2C9.

7.4 SSRIs and SNRIs

Since selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.

8. USE IN SPECIFIC POPULATIONS

8.1 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, clopidogrel bisulfate should be used during pregnancy only if clearly needed.

8.3 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.

8.4 Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

Additional information describing a clinical study in which efficacy was not demonstrated in neonates and infants is approved in the package insert for Bristol-Myers Squibb’s clopidogrel tablets. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

8.5 Geriatric Use

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

The observed risk of bleeding events with clopidogrel bisulfate plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively [see Adverse Reactions (6.1)]. No dosage adjustment is necessary in elderly patients.

8.6 Renal Impairment

Experience is limited in patients with severe and moderate renal impairment [see Clinical Pharmacology (12.2)].

8.7 Hepatic Impairment

No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.2)].

10. OVERDOSAGE

Platelet inhibition by clopidogrel bisulfate 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.

11. DESCRIPTION

Clopidogrel bisulfate is a thienopyridine class inhibitor of P2Y₁₂ ADP platelet receptors. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C₁₆H₁₆ClNO₂S•H₂SO₄ and its molecular weight is 419.9.

     The structural formula is as follows:

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

Clopidogrel tablets, USP for oral administration are provided as light pink colored, round, beveled edge, biconvex, film-coated tablets containing 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of clopidogrel base.

Each tablet contains colloidal silicon dioxide, hydrogenated castor oil, lactose monohydrate, low substituted hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose and polyethylene glycol 6000 as inactive ingredients. The light pink film coating contains ferric oxide red, hypromellose 2910, and titanium dioxide.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y₁₂ class of ADP receptors on platelets.

12.2 Pharmacodynamics

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 clopidogrel bisulfate. Repeated doses of 75 mg clopidogrel bisulfate 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 clopidogrel bisulfate 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 clopidogrel bisulfate 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 clopidogrel bisulfate 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.

12.3 Pharmacokinetics

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 

Clopidogrel bisulfate can be administered with or without food. In a study in healthy male subjects when clopidogrel bisulfate 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 AUC_0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a clopidogrel bisulfate 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-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

The C_max 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. C_max 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: increasing the dose by a factor of four results in 2.0- and 2.7-fold increases in C_max 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.

Drug Interactions 

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

Proton Pump Inhibitors (PPI) 

The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel tablets 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1.

            Figure 1: Exposure to Clopidogrel Active Metabolite Following Multiple Doses of clopidogrel tablets 75 mg Alone or with Proton Pump Inhibitors (PPIs)

Change relative to clopidogrel tablets administered alone

Pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole.

12.5 Pharmacogenomics

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. Genetic variants of other CYP450 enzymes may also affect the formation of clopidogrel’s active metabolite.

The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and *3 alleles are nonfunctional. CYP2C19*2 and *3 account for the majority of reduced function alleles in white (85%) and Asian (99%) poor metabolizers. 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 metabolizer status will possess two loss-of-function alleles as defined above. Published frequencies for poor CYP2C19 metabolizer genotypes are approximately 2% for whites, 4% for blacks and 14% for Chinese. Tests are available to determine a patient’s CYP2C19 genotype.  

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups. When poor metabolizers received the 600 mg/150 mg regimen, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen (see Table 3). An appropriate dose regimen for this patient population has not been established in clinical outcome trials.

Some published studies suggest that intermediate metabolizers have decreased active metabolite exposure and diminished antiplatelet effects.

The relationship between CYP2C19 genotype and clopidogrel bisulfate treatment outcome was evaluated in retrospective analyses of clopidogrel bisulfate-treated subjects in CHARISMA (n=2428) and TRITON-TIMI 38 (n=1477), and in several published cohort studies. In TRITON-TIMI 38 and the majority of the cohort studies, the combined group of patients with either intermediate or poor metabolizer status had a higher rate of cardiovascular events (death, myocardial infarction, and stroke) or stent thrombosis compared to extensive metabolizers. In CHARISMA and one cohort study, the increased event rate was observed only in poor metabolizers.

13. NONCLINICAL TOXICOLOGY

13.1 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).

14. CLINICAL STUDIES

14.1 Acute Coronary Syndrome

CURE

The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥65 years of age.

Patients were randomized to receive clopidogrel bisulfate (300-mg loading dose followed by    75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75-325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.

The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the clopidogrel bisulfate-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p < 0.001) for the clopidogrel bisulfate-treated group (see Table 4).

14.2 Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease

CAPRIE

The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing clopidogrel bisulfate (75 mg daily) to aspirin (325 mg daily).  The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).

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

As shown in table 6, clopidogrel bisulfate was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p=0.045.  Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the clopidogrel bisulfate group.

The curves showing the overall event rate are shown in Figure 8. The event curves separated early and continued to diverge over the 3-year follow-up period.

Figure 8: Fatal or Non-Fatal Vascular Events in the CAPRIE Study

The statistical significance favoring clopidogrel bisulfate over aspirin was marginal (p=0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel bisulfate is substantial.

The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of clopidogrel bisulfate relative to aspirin was heterogeneous across these randomized subgroups (p=0.043). It is not clear whether this difference is real or a chance occurrence.  Although the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel bisulfate over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel bisulfate was not numerically superior to aspirin.

14.3 Lack of Established Benefit of Clopidogrel Bisulfate plus Aspirin in Patients with Multiple Risk Factors or Established Vascular Disease

CHARISMA

The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel bisulfate (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75-162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the clopidogrel bisulfate group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p=0.22). Bleeding of all severities was more common in the subjects randomized to clopidogrel bisulfate.

16. HOW SUPPLIED/STORAGE AND HANDLING

Clopidogrel tablets, USP 75-mg are available as light pink colored, round, beveled edge, biconvex film coated tablets printed "41" with black ink on one side and plain on the other side. Tablets are provide as follow:

                       Bottles of 30                                      NDC 13668-141-30

                       Bottles of 90                                      NDC 13668-141-90

                       Bottles of 100                                    NDC 13668-141-01

                       Bottles of 500                                    NDC 13668-141-05

                       Bottles of 1000                                  NDC 13668-141-10

                       Bottles of 3100                                  NDC 13668-141-44

                       100 (10 X 10) Unit Dose Tablets      NDC 13668-141-74

Store at 20°- 25° C (68°- 77° F); excursions permitted to 15°- 30° C (59°- 86° F) [See USP Controlled Room Temperature].

17. PATIENT COUNSELING INFORMATION

[See Medication Guide]

17.1 Benefits and Risks

• Summarize the effectiveness features and potential side effects of clopidogrel tablets.
• Tell patients to take clopidogrel tablets exactly as prescribed.
• Remind patients not to discontinue clopidogrel tablets without first discussing it with the physician who prescribed clopidogrel tablets.

17.2 Bleeding

Inform patients that they:

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

17.3 Other Signs and Symptoms Requiring Medical Attention

• Inform patients that TTP is a rare but serious condition that has been reported with clopidogrel tablets and other drugs in this class of drugs.
• Instruct patients to get prompt medical attention if they experience any of the following symptoms that cannot otherwise be explained: fever, weakness, extreme skin paleness, purple skin patches, yellowing of the skin or eyes, or neurological changes.

17.4 Invasive Procedures

Instruct patients to:  

• inform physicians and dentists that they are taking clopidogrel tablets before any invasive procedure is scheduled.
• tell the doctor performing the invasive procedure to talk to the prescribing health care professional before stopping clopidogrel tablets.

17.5 Concomitant Medications

Ask patients to list all prescription medications, over-the-counter medications, or dietary supplements they are taking or plan to take [see Warnings and Precautions (5) and Drug Interactions (7)].

Manufactured by:

      TORRENT PHARMACEUTICALS LTD., Indrad-382 721, Dist. Mehsana, INDIA.

For:

     TORRENT PHARMA INC., 150 Allen Road, Suite 102, Basking Ridge, NJ 07920

8044790                                                                                    Revised January 2014

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Clopidogrel Tablets, USP 75 mg