CLOPIDOGREL BISULFATE: 46,012 Adverse Event Reports & Safety Profile

Clopidogrel tablets, USP is a thienopyridine class inhibitor of P2Y 12 ADP platelet receptors. Chemically it is methyl (+)-( S )-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4 H )-acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C 16 H 16 ClNO 2 S•H 2 SO 4 and its molecular weight is 419.9 g/mol. The structural formula is as follows: Clopidogrel bisulfate 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 75 mg for oral administration are provided as pink, round, biconvex, film coated tablets, engraved “APO” on one side, “CL” over “75” on the other side. The tablets contain 97.875 mg of clopidogrel bisulfate, which is the molar equivalent of 75 mg of clopidogrel base. Clopidogrel tablets, USP 300 mg for oral administration are provided as pink, oblong, biconvex, film coated tablets engraved "APO" on one side and "CL 300" on the other side. The tablets contain 392.0 mg of clopidogrel bisulfate, which is the molar equivalent of 300 mg of clopidogrel base. Each tablet contains anhydrous lactose, colloidal silicon dioxide, crospovidone, methylcellulose and zinc stearate as inactive ingredients. The pink film coating contains ferric oxide red, hydroxypropyl cellulose, hypromellose, polyethylene glycol and titanium dioxide. clopiodgrel-01.jpg

AND USAGE Clopidogrel tablets USP are a P2Y 12 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 )

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. The optimal duration of clopidogrel tablet USP therapy in ACS 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.

AND ADMINISTRATION

• Acute coronary syndrome ( 2.1 )
• UA/NSTEMI: 300 mg loading dose followed by 75 mg once daily, in combination with aspirin (75 to 325 mg once daily)
• STEMI: 75 mg once daily, in combination with aspirin (75 to 325 mg once daily), with or without a loading dose
• Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily ( 2.2 )

2.1 Acute Coronary Syndrome Clopidogrel tablets can be administered with or without food [ see Clinical Pharmacology ( 12.3 ) ].

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

4 CONTRAINDICATIONS

• Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage ( 4.1 )
• Hypersensitivity to clopidogrel or any component of the product ( 4.2 )

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

4.2 Hypersensitivity Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .

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 ) ] Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 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 plus aspirin to placebo plus aspirin and trials comparing clopidogrel alone to aspirin alone are discussed below. Bleeding CURE In CURE, clopidogrel 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)

Event

Clopidogrel (+ aspirin) Other standard therapies were used as appropriate. (n = 6259) Placebo (+ aspirin) (n = 6303) Major bleeding Life-threatening and other major bleeding.

3.7 Major bleeding event rate for clopidogrel + aspirin was dose-dependent on aspirin: &lt; 100 mg = 2.6%; 100 to 200 mg = 3.5%; &gt; 200 mg = 4.9% Major bleeding event rates for clopidogrel + aspirin by age were: &lt; 65 years = 2.5%, ≥ 65 to &lt; 75 years = 4.1%, ≥ 75 years = 5.9%

2.7 Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: &lt; 100 mg = 2.0%; 100 to 200 mg = 2.3%; &gt; 200 mg = 4.0% Major bleeding event rates for placebo + aspirin by age were: &lt; 65 years = 2.1%, ≥ 65 to &lt; 75 years = 3.1%, ≥ 75 years = 3.6% Life-threatening bleeding 2.2

1.8 Fatal 0.2 0.2 5 g/dL hemoglobin drop 0.9

0.9 Requiring surgical intervention 0.7

0.7 Hemorrhagic strokes 0.1

0.1 Requiring inotropes 0.5

0.5 Requiring transfusion (≥ 4 units) 1.2

1.0 Other major bleeding 1.6

1.0 Significantly disabling 0.4

0.3 Intraocular bleeding with significant loss of vision 0.05

0.03 Requiring 2 to 3 units of blood 1.3

0.9 Minor bleeding Led to interruption of study medication. 5.1

2.4 Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.

Commit

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

Table

2: Incidence of Bleeding Events in COMMIT (% Patients) Type of bleeding Clopidogrel (+ aspirin) (n = 22961) Placebo (+ aspirin) (n = 22891) p-value Major Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion. noncerebral or cerebral bleeding The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for clopidogrel + aspirin by age were: < 60 years = 0.3%, ≥ 60 to < 70 years = 0.7%, ≥ 70 years = 0.8%. Event rates for placebo + aspirin by age were: < 60 years = 0.4%, ≥ 60 to < 70 years = 0.6%, ≥ 70 years = 0.7%. 0.6 0.5

0.59 Major noncerebral 0.4 0.3

0.48 Fatal 0.2 0.2

0.90 Hemorrhagic stroke 0.2 0.2

0.91 Fatal 0.2 0.2

0.81 Other noncerebral bleeding (non-major) 3.6 3.1

0.005 Any noncerebral bleeding 3.9 3.4

0.004 CAPRIE (Clopidogrel vs. Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel vs. 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 clopidogrel compared to 0.5% for aspirin. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis and hematoma.

Other Adverse

Events In CURE and CHARISMA, which compared clopidogrel plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel and placebo. In CAPRIE, which compared clopidogrel to aspirin, pruritus was more frequently reported in those taking clopidogrel. No other difference in the rate of adverse events (other than bleeding) was reported.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clopidogrel. 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, acute generalized exanthematous pustulosis (AGEP), 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

AND PRECAUTIONS

• CYP2C19 inhibitors: Avoid concomitant use of omeprazole or esomeprazole. (5.1)
• Bleeding: Clopidogrel tablets increases risk of bleeding. (5.2)
• Discontinuation: Premature discontinuation increases risk of cardiovascular events.

Discontinue

5 days prior to elective surgery that has a major risk of bleeding. (5.3)

• Thrombotic thrombocytopenic purpura (TTP) has been reported. ( 5.4 )
• Cross-reactivity among thienopyridines has been reported. ( 5.5 )

5.1 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 [ see Boxed Warning ]. The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid concomitant use of clopidogrel with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel <span class="opacity-50 text-xs">[see Drug Interactions ( 7.2 )]</span> .

5.2 General Risk of Bleeding P2Y12 inhibitors (thienopyridines), including clopidogrel tablets, increase the risk of bleeding. P2Y12 inhibitors (thienopyridines), inhibit platelet aggregation for the lifetime of the platelet (7 to 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. Use of drugs that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. As a precaution, avoid concomitant use of strong CYP2C19 inducers <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )]</span> . Risk factors for bleeding include concomitant use of other drugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, and chronic use of NSAIDs) <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 , 7.5 , 7.6 , 7.7 )]</span> .

5.3 Discontinuation of Clopidogrel Tablets Discontinuation of clopidogrel tablets increases the risk of cardiovascular events. If clopidogrel 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 clopidogrel for five days prior to such surgery. Resume clopidogrel as soon as hemostasis is achieved.

5.4 Thrombotic Thrombocytopenic Purpura (TTP) TTP, sometimes fatal, has been reported following use of clopidogrel tablets, sometimes after a short exposure (&lt;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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>.

5.5 Cross-Reactivity among Thienopyridines Hypersensitivity including rash, angioedema or hematologic reaction has been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines <span class="opacity-50 text-xs">[see Contraindications ( 4.2 ) and Adverse Reactions ( 6.2 )]</span> .

5.5 Cross-Reactivity among Thienopyridines Hypersensitivity including rash, angioedema or hematologic reaction has been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines <span class="opacity-50 text-xs">[see Contraindications ( 4.2 ) and Adverse Reactions ( 6.2 )]</span> .

INTERACTIONS CYP2C19 inducers: Increases levels of clopidogrel active metabolite and increases platelet inhibition. (7.1) Opioids: Decreased exposure to clopidogrel. Consider use of parenteral antiplatelet agent. ( 7. 3) Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. ( 7. 4, 7. 5, 7. 6)

Other Antiplatelet

Agents: Increases the risk of bleeding due to an additive effect. (7.7) Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations. ( 7. 8)

See

17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 09/2023

7.1 CYP2C19 Inducers Since clopidogrel is metabolized to its active metabolite partly by CYP2C19, use of drugs that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel. Rifampin strongly induces CYP2C19 resulting to both an increase level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, avoid concomitant use of strong CYP2C19 inducers <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]</span>.

7.2 CYP2C19 Inhibitors Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . Omeprazole or Esomeprazole Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of clopidogrel bisulfate when given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel bisulfate. Dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity of clopidogrel bisulfate than did omeprazole or esomeprazole <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]</span>.

7.3 Opioids As with other oral P2Y 12 inhibitors, coadministration of opioid agonists delay and reduce the absorption of clopidogrel, presumably because of slowed gastric emptying, resulting in reduced exposure to its metabolites <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists.

7.4 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Coadministration of clopidogrel bisulfate and NSAIDs increases the risk of gastrointestinal bleeding.

7.5 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 vitr o, clopidogrel inhibits CYP2C9.

7.6 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.

7.7 Other Antiplatelet Agents Coadministration of antiplatelet agents increase the risk of bleeding due to an additive effect. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with other antiplatelet agents <span class="opacity-50 text-xs">[see WARNINGS AND PRECAUTIONS (5.2)]</span>.

7.8 Repaglinide (CYP2C8 Substrates) The acyl-β-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Clopidogrel bisulfate can increase the systemic exposure to drugs that are primarily cleared by CYP2C8, thereby needing dose adjustment and appropriate monitoring. Clopidogrel bisulfate increased repaglinide exposures by 3.9-fold to 5.1-fold <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Avoid concomitant use of repaglinide with clopidogrel bisulfate. If concomitant use cannot be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg. Increased frequency of glucose monitoring may be required during concomitant use.