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CLOPIDOGREL AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Clopidogrel and prasugrel, thienopyridine adenosine diphosphate (ADP) receptor antagonists, are antiplatelet agents.

Specific Substances

    A) CLOPIDOGREL
    1) Clopidogrel bisulfate
    2) Clopidogrel hydrogen sulphate
    3) Methyl (S)-2-chlorophenyl (4,5,6,7-tetrahydrothieno(3,2-c)pyridin-5-yl) acetate bisulfate
    4) PCR-4099
    5) SR-25990C
    6) CAS 113665-84-2 (clopidogrel)
    7) CAS 94188-84-8 (clopidogrel)
    8) CAS 120202-66-6 (clopidogrel bisulfate)
    PRASUGREL
    1) LY-640315
    2) Prasugrel, chlorhydrate de
    3) 5-[(1RS)-2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothienol[3,2-c]pyridin-2-yl acetate hydrochloride
    4) CAS 389574-19-0

    1.2.1) MOLECULAR FORMULA
    1) CLOPIDOGREL BISULFATE: C16H16ClNO2S.H2SO4
    2) PRASUGREL HYDROCHLORIDE: C20H20FNO3S.HCl

Available Forms Sources

    A) FORMS
    1) CLOPIDOGREL is available for oral administration as 75 mg and 300 mg tablets (Prod Info PLAVIX(R) oral tablets, 2015).
    2) CLOPIDOGREL/ASPIRIN is a fixed dose combination product available as film coated tablets containing 75 mg clopidogrel (as hydrogen sulphate)/75 mg acetylsalicylic acid or 75 mg clopidogrel (as hydrogen sulphate)/100 mg acetylsalicylic acid (Prod Info DuoCover oral film-coated tablets, 2012; Prod Info DuoPlavin oral film-coated tablets, 2012).
    3) PRASUGREL is available for oral administration as 5 mg and 10 mg tablets (Prod Info EFFIENT(R) oral tablets, 2016).
    B) USES
    1) CLOPIDOGREL is indicated for the reduction of thrombotic events in patients with a history of recent myocardial infarction, recent stroke, established peripheral arterial disease or acute coronary syndrome (unstable angina/non-Q-wave myocardial infarction) (Prod Info PLAVIX(R) oral tablets, 2015).
    2) CLOPIDOGREL/ASPIRIN is a fixed dose combination product used for the prevention of atherothrombotic events in patients with non-ST segment elevation acute coronary syndrome, including patients managed with percutaneous coronary intervention, and in patients with ST segment elevation acute myocardial infarction. This fixed dose combination product is for continuation of therapy in patients already receiving clopidogrel and aspirin as individual agents (Prod Info DuoCover oral film-coated tablets, 2012).
    3) PRASUGREL is indicated for the reduction of thrombotic cardiovascular (CV) events, including stent thrombosis, in patients with acute coronary syndrome (ACS) (such as unstable angina, non-ST-elevation myocardial infarction (MI), or ST-elevation MI) who are to be managed with percutaneous coronary intervention (PCI) (Prod Info EFFIENT(R) oral tablets, 2016).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Clopidogrel and prasugrel are thienopyridines used as platelet inhibitors following intravascular stenting procedures. They are also used for cardiovascular and cerebrovascular thrombosis prophylaxis in patients with allergies to aspirin.
    B) PHARMACOLOGY: The thienopyridines are irreversible P2Y12 receptor inhibitors; they prevent adenosine diphosphate (ADP) to binding to the platelet cell surface and inhibit platelet aggregation. Clopidogrel and prasugrel are pro-drugs requiring hepatic metabolism for activation.
    C) TOXICOLOGY: Toxicity is largely an extension of the therapeutic effects leading to bleeding complications.
    D) EPIDEMIOLOGY: Bleeding associated with clopidogrel is common. Major bleeding complications are uncommon. Intentional overdose is rare.
    E) WITH THERAPEUTIC USE
    1) Minor bleeding is observed in approximately 3% to 5% of patients taking clopidogrel therapeutically. Major bleeding occurs in approximately 1% to 3% of patients taking clopidogrel therapeutically. Cytopenias and hepatitis have been reported as adverse effects from clopidogrel administration in therapeutic doses. Several rash morphologies have been associated with clopidogrel administration, though these reactions are rare. Hemolytic uremic syndrome is rarely associated with clopidogrel therapy.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Very little overdose data are available. In general, no clinical bleeding is expected in the absence of pre-existing bleeding pathology or trauma. Nausea and vomiting are likely to be present after significant acute overdose. Ecchymosis, gum bleeding, and inhibited wound clotting is possible in overdose.
    2) SEVERE TOXICITY: Patients with associated trauma or gastrointestinal bleeding may have prolonged bleeding and large volume blood loss.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) CLOPIDOGREL: Fever has been reported with clopidogrel therapy.
    0.2.20) REPRODUCTIVE
    A) Clopidogrel and prasugrel are classified as FDA pregnancy category B.
    B) In 2 case reports, healthy infants were born to women who were taking clopidogrel throughout their pregnancies. In one of these cases, the baby was delivered cesarean due to repetitive late decelerations in the fetal heart rate. Although the mother was administered prophylactic platelets and local anesthesia, she experienced postoperative bleeding resulting in a blood transfusion which stabilized her hemoglobin levels. There were no further sequelae with infant and mother discharged on postpartum day 4 and the mother reinitiated on clopidogrel.

Laboratory Monitoring

    A) No laboratory studies are needed in asymptomatic patients.
    B) Serial CBCs are recommended in bleeding patients. No single laboratory test is able to adequately measure platelet function.
    C) In patients with significant bleeding, thromboelastography in combination with platelet count and PT/INR studies may give a general estimation of a patient's hemostasis potential, though no one test is well correlated with the in-vivo coagulation propensity.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) No intervention should be instituted for patients with mild to moderate bleeding complications since blood product transfusion may be associated with more risk than benefit in these patients. If discontinuation is necessary due to adverse effects from the drug, alternative anti-platelet therapy should be instituted.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Management of patients with major bleeding complications is difficult. Platelet transfusion has not been shown to improve outcomes and is associated with higher risks of infections, cerebrovascular accidents, and death. It may be impractical to provide enough platelets to overcome the active drug. A more practical approach would be to identify the source of bleeding and provide local hemostasis whenever possible. When local hemostatic control is not practical, red blood cell and platelet transfusions must be considered. Desmopressin has been shown to increase platelet aggregation in patients taking clopidogrel, and administration has a theoretical advantage of bypassing the ADP inhibition leading to subsequent platelet activation. However, no randomized clinical trials exist to support desmopressin use at this time. Epsilon aminocaproic acid (EAPC), aprotinin, and tranexamic acid (TA) have all been used with variable success for prophylaxis of post-surgical bleeding or reversal of platelet inhibition in the setting of cardiac bypass grafting. At this time, aprotinin and TA are clinically available in the United States only under compassionate use applications through the FDA (1-888-842-2937). There is little evidence to support their use in bleeding patients due to clopidogrel toxicity at this time.
    C) DECONTAMINATION
    1) PREHOSPITAL: No pre-hospital decontamination is recommended.
    2) HOSPITAL: Administration of activated charcoal is recommended if a patient presents early after an intentional overdose. No decontamination is warranted for patients with inadvertent ingestion of extra doses. Gastric lavage has no role in the management of clopidogrel overdose or toxicity.
    D) AIRWAY MANAGEMENT
    1) No airway compromise is anticipated from clopidogrel toxicity, though co-ingestions should be considered, and care should be taken not to cause airway trauma during attempts at airway management.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) The serum half-life of clopidogrel is relatively short and the duration of action is prolonged, therefore removal by extracorporeal methods is not likely to significantly change a patient's course and may, in fact, put them at higher risk of bleeding complications from catheter replacement.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Inadvertent ingestion of extra clopidogrel doses may be managed at home with referral for signs of bleeding.
    2) OBSERVATION CRITERIA: Observation for 4 hours should be sufficient in most cases given the expected pharmacokinetic peak at 30 to 60 minutes in therapeutic doses. At the end of the observation period, the physician should assess for signs of bleeding such as tachycardia, shortness of breath, hematochezia, or headache.
    3) ADMISSION CRITERIA: Patients with evidence of active bleeding should be admitted for serial hematocrits.
    4) CONSULT CRITERIA: Hematology should be consulted for patients with major bleeding associated with clopidogrel toxicity. Cardiology should be consulted in patients with coronary stents placed within 1 year in whom reversal of clopidogrel is considered. A toxicologist should be consulted in all overdose cases with significant toxicity.
    H) PITFALLS
    1) Attempting to reverse a patient who does not have major bleeding may result in unintended thrombotic complications, including stent thrombosis. Failure to realize that neurologic symptoms may represent intracranial hemorrhage.
    I) PHARMACOKINETICS
    1) Peak plasma concentrations are dependent upon the individual's metabolic capacity of CYP2C19. In general, the time to peak serum concentrations is 30 to 60 minutes, and the elimination half life is approximately 6 hours.
    J) TOXICOKINETICS
    1) A bleeding risk is expected for several days after an acute overdose. No data has demonstrated drug elimination half-life in overdose settings, though the clinical effect of platelet inhibition is the most pertinent clinical factor. The clinical inhibition of platelet function lasts the life of the platelet. The degree of platelet inhibition cannot be readily monitored by drug concentrations or coagulation studies.
    K) DIFFERENTIAL DIAGNOSIS
    1) Clopidogrel overdose may mimic aspirin overdose with normal coagulation and platelet blood tests with a mild propensity for bleeding. However, aspirin patients are expected to be more systemically ill with progression to multi-organ toxicity in large overdoses. Ingestions of other anticoagulants must be considered in the bleeding overdose patient. Both warfarin and long-acting vitamin K antagonists will differentiate themselves from clopidogrel overdose by virtue of abnormal PT and INR testing. In low-molecular weight heparin (LMWH) overdose, anti-Xa levels can be obtained in many institutions and will be markedly abnormal in the bleeding patient. Subcutaneous ecchymosis is often evident at the site of injection in LMWH overdose patients.

Range Of Toxicity

    A) TOXICITY: No toxic dose has been established. CLOPIDOGREL: Ingestions of 1650 mg and 1050 mg by adults resulted in no toxicity, and a 6300 mg ingestion caused minimal toxicity. In the absence of additional anticoagulants or traumatic injury, no clinical bleeding is expected in the vast majority of cases.
    B) THERAPEUTIC DOSE: CLOPIDOGREL: For patients with a recent myocardial infarction, recent stroke, or established peripheral arterial disease, the recommended dose is 75 mg/day. For patients with acute coronary syndrome (unstable angina, non-Q-wave myocardial infarction), clopidogrel should be started with an oral loading dose of 300 to 600 mg, followed by 75 mg once daily with aspirin (75 mg to 325 mg) once daily. PRASUGREL: The recommended dose is a single 60 mg loading dose followed by 10 mg daily with aspirin (75 mg to 325 mg); consider prasugrel 5 mg daily in patients weighing less than 60 kg.

Clinical Effects

Summary Of Exposure

    A) USES: Clopidogrel and prasugrel are thienopyridines used as platelet inhibitors following intravascular stenting procedures. They are also used for cardiovascular and cerebrovascular thrombosis prophylaxis in patients with allergies to aspirin.
    B) PHARMACOLOGY: The thienopyridines are irreversible P2Y12 receptor inhibitors; they prevent adenosine diphosphate (ADP) to binding to the platelet cell surface and inhibit platelet aggregation. Clopidogrel and prasugrel are pro-drugs requiring hepatic metabolism for activation.
    C) TOXICOLOGY: Toxicity is largely an extension of the therapeutic effects leading to bleeding complications.
    D) EPIDEMIOLOGY: Bleeding associated with clopidogrel is common. Major bleeding complications are uncommon. Intentional overdose is rare.
    E) WITH THERAPEUTIC USE
    1) Minor bleeding is observed in approximately 3% to 5% of patients taking clopidogrel therapeutically. Major bleeding occurs in approximately 1% to 3% of patients taking clopidogrel therapeutically. Cytopenias and hepatitis have been reported as adverse effects from clopidogrel administration in therapeutic doses. Several rash morphologies have been associated with clopidogrel administration, though these reactions are rare. Hemolytic uremic syndrome is rarely associated with clopidogrel therapy.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Very little overdose data are available. In general, no clinical bleeding is expected in the absence of pre-existing bleeding pathology or trauma. Nausea and vomiting are likely to be present after significant acute overdose. Ecchymosis, gum bleeding, and inhibited wound clotting is possible in overdose.
    2) SEVERE TOXICITY: Patients with associated trauma or gastrointestinal bleeding may have prolonged bleeding and large volume blood loss.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) CLOPIDOGREL: Fever has been reported with clopidogrel therapy.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) CLOPIDOGREL: A 59-year-old woman, who underwent percutaneous coronary intervention, presented to the emergency department with a 2-day history of fever and chills. She had been prescribed clopidogrel 3 days prior to presentation. Laboratory data revealed an elevated WBC count and elevated hepatic enzyme levels. The patient's temperature was 101 degrees F. The patient's temperature decreased and her laboratory values normalized after cessation of clopidogrel therapy. The patient's fever returned after restarting clopidogrel therapy, and again normalized following discontinuation of therapy (Ng et al, 2006).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: In clinical trials, edema and hypertension have been reported with clopidogrel use in 4.1% and 4.3% of patients (n=9599), respectively (Prod Info PLAVIX(R) oral tablets, 2006).
    b) PRASUGREL VS CLOPIDOGREL: In patients with acute coronary syndrome who underwent percutaneous coronary intervention, hypertension occurred in 7.5% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 7.1% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) PRASUGREL VS CLOPIDOGREL: In patients with acute coronary syndrome who underwent percutaneous coronary intervention, hypotension occurred in 3.9% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 3.8% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).
    C) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: In clinical trials, chest pain has been reported with clopidogrel use in 8.3% of patients (n=9599) (Prod Info PLAVIX(R) oral tablets, 2006).
    D) HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: In two clinical trials, CAPRIE (n=9599) and CURE (n=6259), cardiac failure and atrial fibrillation have occurred in 1% to 2.5% of patients (Prod Info PLAVIX(R) oral tablets, 2006).
    E) ATRIAL FIBRILLATION
    1) WITH THERAPEUTIC USE
    a) PRASUGREL VS CLOPIDOGREL: In patients with acute coronary syndrome who underwent percutaneous coronary intervention, atrial fibrillation occurred in 2.9% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 3.1% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).
    F) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) PRASUGREL VS CLOPIDOGREL: In patients with acute coronary syndrome who underwent percutaneous coronary intervention, bradycardia occurred in 2.9% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 2.4% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY SYMPTOM
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: Upper respiratory tract infections, dyspnea, rhinitis, bronchitis, and coughing have been reported with clopidogrel use in 8.7%, 4.5%, 4.2%, 3.7%, and 3.1% of patients (n=9599), respectively (Prod Info PLAVIX(R) oral tablets, 2006).
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) PRASUGREL VS CLOPIDOGREL: In patients with acute coronary syndrome who underwent percutaneous coronary intervention, dyspnea occurred in 4.9% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 4.5% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).
    C) COUGH
    1) WITH THERAPEUTIC USE
    a) PRASUGREL VS CLOPIDOGREL: In patients with acute coronary syndrome who underwent percutaneous coronary intervention, cough occurred in 3.9% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 4.1% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PRASUGREL: Irregular respiration was reported in rats following acute exposure to prasugrel (Prod Info EFFIENT oral tablets, 2011).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) INTRACRANIAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: Intracranial hemorrhage occurred in 0.4% of patients (n=9599) in the CAPRIE study (Prod Info PLAVIX(R) oral tablets, 2006).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: In clinical trials, headache, dizziness, and depression have been reported with clopidogrel use in 7.6%, 6.2%, and 3.6% of patients (n=9599), respectively. Neuralgia and paresthesia were reported in 1% to 2.5% of patients (Prod Info PLAVIX(R) oral tablets, 2006).
    C) FATIGUE
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: In clinical trials, fatigue has been reported with clopidogrel use in 3.3% of patients (n=9599) (Prod Info PLAVIX(R) oral tablets, 2006).
    b) PRASUGREL VS CLOPIDOGREL: In patients with acute coronary syndrome who underwent percutaneous coronary intervention, fatigue occurred in 3.7% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 4.8% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) PRASUGREL VS CLOPIDOGREL
    1) In patients with acute coronary syndrome who underwent percutaneous coronary intervention, dizziness occurred in 4.1% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 4.6% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).
    2) In an open-label, randomized, dose-escalation pharmacodynamic study of prasugrel, subjects were given 1 of 4 prasugrel regimens (loading dose (LD)/maintenance dose (MD) in mg: 20/5, 30/7.5, 40/10, or 60/15; n=8 in each group) or clopidogrel 300 mg LD/75 mg MD (n=11). The number of adverse events reported as dizziness for all prasugrel doses (20/5, 30/7.5, 40/10, 60/15) and for the clopidogrel dose (300/75) was 3, 0, 1, 4, and 1, respectively (Jakubowski et al, 2007).
    2) WITH POISONING/EXPOSURE
    a) CLOPIDOGREL: According to a retrospective review of clopidogrel exposures (mean dose 249 mg; range 25 to 7500 mg; most frequently reported dose, 150 mg) reported to the Texas Poison Center Network from 2000 to 2004, dizziness was the most commonly reported neurological effect, occurring in 2.4% of patients (n=169) (Forrester, 2007).
    E) HEADACHE
    1) WITH THERAPEUTIC USE
    a) PRASUGREL VS CLOPIDOGREL
    1) In patients with acute coronary syndrome who underwent percutaneous coronary intervention, headache occurred in 5.5% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 5.3% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).
    2) In an open-label, randomized, dose-escalation pharmacodynamic study of prasugrel, subjects were given 1 of 4 prasugrel regimens (loading dose (LD)/maintenance dose (MD) in mg: 20/5, 30/7.5, 40/10, or 60/15; n=8 in each group) or clopidogrel 300 mg LD/75 mg MD (n=11). The number of adverse events reported as headache for all prasugrel doses (20/5, 30/7.5, 40/10, 60/15) and for the clopidogrel dose (300/75) was 2, 0, 1, 2, and 1, respectively (Jakubowski et al, 2007).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PRASUGREL: Staggering gait and decreased locomotor activity were reported in rats following acute exposure to prasugrel (Prod Info EFFIENT oral tablets, 2011).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOMITING
    1) WITH POISONING/EXPOSURE
    a) CLOPIDOGREL: According to a retrospective review of clopidogrel exposures (mean dose 249 mg; range 25 to 7500 mg; most frequently reported dose, 150 mg) reported to the Texas Poison Center Network from 2000 to 2004, vomiting was the most commonly reported gastrointestinal effect, occurring in 2.4% of patients (n=169) (Forrester, 2007).
    B) NAUSEA
    1) WITH THERAPEUTIC USE
    a) PRASUGREL VS CLOPIDOGREL: In patients with acute coronary syndrome who underwent percutaneous coronary intervention, nausea occurred in 4.6% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 4.3% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).
    C) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: In clinical trials, abdominal pain, dyspepsia, diarrhea, nausea have been reported with clopidogrel use in 5.6%, 5.2%, 4.5%, 3.4% of patients (n=9599), respectively (Prod Info PLAVIX(R) oral tablets, 2006).
    D) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: A 76-year-old woman and a 64-year-old man experienced ageusia (loss of taste) attributed to clopidogrel therapy. The onset of this disorder was 6 to 8 weeks after beginning therapy and was not accompanied by olfactory disturbance. Three to six weeks after clopidogrel discontinuation, the sense of taste returned to normal. In one patient, rechallenge produced a second episode of ageusia that had not abated 6 weeks after clopidogrel withdrawal. The mechanism of this reaction is unknown (Golka et al, 2000).
    E) GASTROINTESTINAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: In two clinical trials, CAPRIE (n=9599) and CURE (n=6259), gastrointestinal hemorrhage occurred in 1% to 2.5% of patients. Perforated gastric ulcer, hemorrhagic gastritis, and hemorrhagic upper GI ulcer have been reported rarely (less than 1%) (Prod Info PLAVIX(R) oral tablets, 2006).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL
    1) In clinical trials, bilirubinemia, fatty liver, and hepatitis have been reported rarely (less than 1%). Hepatic enzyme elevations have been reported following clopidogrel therapy. In two clinical trials, CAPRIE (n=9599) and CURE (n=6259), hepatic enzyme elevations occurred in 1% to 2.5% of patients (Prod Info PLAVIX(R) oral tablets, 2006; Caplain et al, 1996; Anon, 1996).
    2) CASE REPORT: An 81-year-old woman was prescribed clopidogrel 75 mg without a loading dose after implantation of a stent. Within 3 weeks of starting therapy, she developed severe symptoms associated with significant mixed hepatocellular and cholestatic liver injury with an eightfold elevation of liver enzymes. Her long-term medical regimen included fluvastatin. Both fluvastatin and clopidogrel were discontinued. Her liver enzymes returned to normal in 2 months. She was again prescribed fluvastatin without recurrence of abnormal liver enzymes or symptoms(Willens, 2000).
    3) CASE REPORT: A 59-year-old woman, who underwent percutaneous coronary intervention, presented to the emergency department with a 2-day history of fever and chills. She had been prescribed clopidogrel 3 days prior to presentation. Laboratory data revealed an elevated WBC count and elevated hepatic enzyme levels. The patient's temperature was 101 degrees F. The patient's temperature decreased and her laboratory values normalized after cessation of clopidogrel therapy. The patient's fever returned after restarting clopidogrel therapy, and again normalized following discontinuation of therapy (Ng et al, 2006). Another patient, a 56-year-old man, who also underwent percutaneous coronary intervention, experienced hepatotoxicity after taking clopidogrel 75 mg once daily for 2 months. His liver enzymes normalized after the discontinuation of clopidogrel. He developed elevated liver enzymes again after restarting clopidogrel therapy, which normalized following discontinuation of therapy (Wiper et al, 2008).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) PRASUGREL: Vomiting, increased serum alkaline phosphatase and hepatocellular atrophy were reported in dogs following acute exposure to prasugrel (Prod Info EFFIENT oral tablets, 2011).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) NEPHROTIC SYNDROME
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: Clopidogrel therapy was considered the causative factor in a case of stage II membranous nephropathy and nephrotic syndrome without glomerular or tubulointerstitial scarring in a 46-year-old man. Signs and symptoms including lower extremity edema and proteinuria presented approximately 2 months after starting clopidogrel post-coronary stenting (Tholl et al, 1999).
    B) HEMOLYTIC UREMIC SYNDROME
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) has uncommonly been associated with therapeutic use of clopidogrel. It is suggested that this is an immune-mediated reaction. High mortality and morbidity is associated with drug-induced TTP-HUS. (Medina et al, 2001; Moy et al, 2000; Chinnakotla et al, 2000; Oomen et al, 2000).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) HEMATOLOGY FINDING
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL
    1) Purpura and epistaxis have been reported with clopidogrel use in 5.3% and 2.9% of patients (n=9599), respectively. In two clinical trials, CAPRIE (n=9599) and CURE (n=6259), hematoma and decreased platelet counts occurred in 1% to 2.5% of patients(Prod Info PLAVIX(R) oral tablets, 2006).
    2) Rarely, (less than 1%) agranulocytosis, granulocytopenia, leukemia, leukopenia, thrombocytopenia, aplastic anemia and neutropenia have been reported(Prod Info PLAVIX(R) oral tablets, 2006; McCarthy & Kockler, 2003; Anon, 1996; Bendixen & Adams, 1996; Schror, 1995; Verstraete, 1995).
    b) PRASUGREL VS CLOPIDOGREL
    1) In patients with acute coronary syndrome who underwent percutaneous coronary intervention, leukopenia (less than 4 x 10(9) WBC/L) occurred in 2.8% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 3.5% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).
    B) THROMBOTIC THROMBOCYTOPENIC PURPURA
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL
    1) Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) has uncommonly been associated with therapeutic use of clopidogrel. It is suggested that this is an immune-mediated reaction. High mortality and morbidity is associated with drug-induced TTP-HUS. Plasma exchange therapy appears to be appropriate in this setting due to high morbidity, although its role is uncertain (Medina et al, 2001).
    2) A total of 20 cases of thrombotic thrombocytopenic purpura have been reported. Two cases were fatal, 2 required more than 20 total plasma exchanges, and 3 involved relapses (Bennett et al, 2000).
    3) CASE REPORT: Hemolytic uremic syndrome, associated with clopidogrel therapy, has been reported in an adult male and was characterized by thrombocytopenia, microangiopathic hemolytic anemia, and progressive renal failure. Onset of symptoms began 10 days after initiation of clopidogrel and aspirin therapy. The patient recovered following 28 plasmapheresis treatments, prednisone and antibiotic therapy (Moy et al, 2000).
    4) CASE REPORT: A 35-year-old male kidney/pancreas transplant recipient developed thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) after starting clopidogrel for symptomatic coronary artery disease. He was successfully treated with plasmapheresis, methylprednisolone, discontinuation of clopidogrel, and temporary withdrawal of cyclosporine (Chinnakotla et al, 2000).
    5) CASE REPORT: Another case was characterized by rapidly decreasing hemoglobin and platelet counts after clopidogrel initiation post-coronary stenting. Renal function parameters worsened and respiratory failure ensued. The patient showed improvement within a few days of clopidogrel discontinuation (Oomen et al, 2000).
    b) PRASUGREL
    1) Thrombotic thrombocytopenic purpura, characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurological findings, renal dysfunction, and fever has been reported with other thienopyridines after exposure of less than 2 weeks (Prod Info EFFIENT oral tablets, 2011).
    C) APLASTIC ANEMIA
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: Fatal aplastic anemia was reported in an 88-year-old man 4 months following initiation of therapeutic clopidogrel (75 mg/day). Baseline hematological values were normal at the beginning of therapy. Bone marrow biopsy 4 months after initiation of therapy revealed marked hypocellularity without fibrosis. Clopidogrel was discontinued and the patient received 14 red blood cell units. The patient died 5 months later due to pulmonary infection (Trivier et al, 2001).
    D) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL/CASE REPORT: Fatal bone marrow failure associated with clopidogrel was reported in a 34-year-old woman. She was started on long-term anticoagulant therapy because of a severe secondary antiphospholipid syndrome associated with Sneddon's syndrome. Due to gastrointestinal side effects from acetylsalicylic acid, she was started on clopidogrel 75 mg/day.
    1) Four weeks after beginning therapy, platelets, hemoglobin, and leukocytes started to decrease. Clopidogrel was stopped at 12 weeks due to declining platelets and leukocytes. She became transfusion dependent. Bone marrow failure did not recover and she died 17 weeks after beginning clopidogrel therapy of severe septicemia and multi-organ dysfunction (Chemnitz et al, 2003).
    E) BLEEDING
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL
    1) MAJOR BLEEDING/INCIDENCE: The incidence of major bleeding events ranged from 0.8% to 3.7% in patients taking clopidogrel therapeutically during clinical trials.
    a) In the CURE clinical trial (n=6259), major bleeding occurred in 3.7% of patients taking clopidogrel and aspirin, compared with 2.7% of patients taking placebo and aspirin (P=0.001). Major bleeding events for both groups were dose-dependent on aspirin: clopidogrel less than 100 mg 2.6%, 100 to 200 mg 3.5%, greater than 200 mg 4.9%; placebo less than 100 mg 2.0%, 100 to 200 mg 2.3%, greater than 200 mg 4.0% (Prod Info PLAVIX(R) oral tablets, 2011a).
    b) Major bleeding occurred in 1.6% of patients on clopidogrel therapy with aspirin (n=6259), compared with 1% of patients on aspirin therapy alone (n=6303) in a randomized, double-blind, placebo-controlled trial. Bleeding was significantly disabling in 0.4% of patients on clopidogrel therapy with aspirin, compared with 0.3% of patients on aspirin therapy; 2 to 3 units of blood were required to treat 1.3% of patients on clopidogrel therapy with aspirin, compared with 0.9% of patients on aspirin therapy. Bleeding incidence included intraocular bleeding with significant loss of vision in 0.05% of patients on clopidogrel therapy with aspirin, compared with 0.03% of patients on aspirin therapy (Prod Info PLAVIX(R) oral tablets, 2011a).
    2) MINOR BLEEDING/INCIDENCE: The incidence of minor bleeding events ranged from 3.6% to 5.1% in patients taking clopidogrel therapeutically during clinical trials.
    a) Minor bleeding occurred in 5.1% of patients on clopidogrel therapy with aspirin (n=6259), compared with 2.4% of patients on aspirin therapy alone (n=6303) in a randomized, double-blind, placebo-controlled trial (Prod Info PLAVIX(R) oral tablets, 2011a).
    b) Non-major, noncerebral bleeding occurred in 3.6% of patients on clopidogrel therapy with aspirin (n=22,961) compared with 3.1% of patients on aspirin alone (n=22,891), while any noncerebral bleeding occurred in 3.9% of patients on clopidogrel therapy with aspirin compared with 3.4% of patients on aspirin therapy, according to a randomized, double-blind, placebo-controlled trial (Prod Info PLAVIX(R) oral tablets, 2011a).
    b) PRASUGREL
    1) In patients with acute coronary syndrome who underwent percutaneous coronary intervention, minor bleeding not related to CABG occurred in 2.4% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 1.9% of patients who received clopidogrel (n=6716) (p=0.022). Among patients who weighed less than 60 kg, major or minor bleeding occurred in 10.1% of patients who received prasugrel (n=308) compared with 6.5% of patients who received clopidogrel (n=356). For patients who were 75 years of age or older, major or minor bleeding occurred in 9% of patients with prasugrel (n=891) compared with 6.9% of patients with clopidogrel (n=894) (Prod Info EFFIENT oral tablets, 2011).
    2) In patients with acute coronary syndrome who underwent percutaneous coronary intervention, minor bleeding related to CABG occurred in 2.8% of patients who received prasugrel (n=213) in the TRITON-TIMI 38 trial compared with 0.9% of patients who received clopidogrel (n=224). The higher risk for bleeding with prasugrel persisted for up to 7 days from the last dose (Prod Info EFFIENT oral tablets, 2011).
    3) In a 3-way crossover study comparing prasugrel 60 mg loading dose (LD) and daily 10 mg maintenance doses (MD) to clopidogrel 600 mg/75 mg and 300 mg/75 mg LD/MD in 41 healthy, aspirin-free subjects, minor bleeding at venipuncture sites was similar across the 3 treatment groups: 8 of 36 subjects (22%) for prasugrel, 7 of 35 subjects (20%) for clopidogrel 600 mg/75 mg, and 6 of 36 subjects (17%) for clopidogrel 300 mg/75 mg (Payne et al, 2007).
    4) In an open-label, randomized, dose-escalation pharmacodynamic study of prasugrel, subjects were given 1 of 4 prasugrel regimens (loading dose (LD)/maintenance dose (MD) in mg: 20/5, 30/7.5, 40/10, or 60/15; n=8 in each group) or clopidogrel 300 mg LD/75 mg MD (n=11). The majority (161 of 229) of adverse events were mild bleeding events (hematoma), judged to be related to study procedures and resolved spontaneously at the conclusion of the study. The incidence of minor hematomas was greater in the upper 2 prasugrel doses and the number of hematoma events reported for all prasugrel doses (20/5, 30/7.5, 40/10, 60/15) and for the clopidogrel dose (300/75) was 20, 28, 45, 40, and 28, respectively (Jakubowski et al, 2007).
    F) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: A 68-year-old man with a normal baseline platelet count underwent emergent percutaneous transluminal coronary angioplasty with stent placement and was discharged 72 hours later on aspirin and clopidogrel. Approximately 9 days after the procedure he presented with scattered petechiae and profound thrombocytopenia (platelets 3 x 10(9)/L) with no evidence of a microangiopathic hemolytic process. Clopidogrel was discontinued, he was treated with IV IgG and his platelet count returned to normal over 9 days (Elmi et al, 2000).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: In clinical trials, rash and pruritus have been reported with clopidogrel use in 4.2% and 3.3% of patients (n=9599), respectively. Bullous eruption, erythematous or maculopapular rash, and urticaria have been reported rarely (less than 1%) (Prod Info PLAVIX(R) oral tablets, 2006).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL FINDING
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL
    1) In clinical trials, arthralgia and back pain have been reported with clopidogrel use in 6.3% and 5.8% of patients (n=9599), respectively(Prod Info PLAVIX(R) oral tablets, 2006).
    2) CASE REPORTS: Clopidogrel appeared to induce arthritis and tendonitis in 2 patients. A 76-year-old woman developed diffuse pruritus with pain and inflammation in the metacarpophalangeal joints 2 weeks after initiation of clopidogrel; she also exhibited elevated erythrocyte sedimentation rate (ESR) and C reactive protein. Signs and symptoms resolved within 1 week of clopidogrel discontinuation. A 63-year-old man presented with severe quadriceps tendonitis and increased ESR 3 weeks after clopidogrel initiation; recovery followed clopidogrel withdrawal(Garg et al, 2000).
    b) PRASUGREL VS CLOPIDOGREL
    1) In patients with acute coronary syndrome who underwent percutaneous coronary intervention, back pain occurred in 5% of patients who received prasugrel (n=6741) in the TRITON-TIMI 38 trial compared with 4.5% of patients who received clopidogrel (n=6716) (Prod Info EFFIENT oral tablets, 2011).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) CELL-MEDIATED IMMUNE REACTION
    1) WITH THERAPEUTIC USE
    a) CLOPIDOGREL: A case of severe hypersensitivity associated with clopidogrel is reported. On the fifth day of therapy (clopidogrel, 75 mg/day), a male patient developed fever, rash, pruritus and abdominal pain. Three days later he developed shock, bilateral lung rales, Murphy's sign and thrombocytopenia. The drug was stopped and the patient recovered. On re-challenge one month later, the same symptoms returned. Drug hypersensitivity was suspected (Sarrot-Reynauld et al, 2001).
    B) SYSTEMIC INFECTION
    1) WITH THERAPEUTIC USE
    a) PRASUGREL: A 65-year-old man, with a greater than 4-year history of clopidogrel therapy following cardiac stent implantation, presented to the hospital with a persistent cough, sinus infection, and possible pneumonia. Diagnostic cardiac catheterization revealed moderate blockage (60% to 70%) of the mild left anterior descending. Following plans to perform a nuclear stress test, the patient was discharged. At discharge, his prescription for clopidogrel (75 mg/day) was changed to prasugrel 10 mg/day in addition to low-dose aspirin daily. Three days later, a large bruise was noted on his lower right abdomen, with a CT scan indicating nothing unusual. Six days after prasugrel therapy was initiated, the patient developed dizziness, confusion, headaches, weakness, difficulty breathing that necessitated mechanical ventilation, a generalized petechial rash, and a fever of 104 degrees F. Laboratory analysis revealed an elevated white cell count (43,000 K/mcL). A lumber puncture was negative for meningitis. Over the next several days, the patient's condition deteriorated with progressive altered mental status, vision loss and signs of multiorgan failure, with death occurring 16 days after initiating prasugrel therapy due to sepsis complicated with systemic inflammatory response syndrome (SIRS) (Serebruany et al, 2014)
    1) A possible mechanism may be that long-term inhibition of platelets by P2Y12 inhibitors, in addition to aspirin use, may result in an indirect modulation of the immune response causing the loss of stability of platelet thrombi and weakening the platelet-neutrophil-endothelial crosstalk link necessary to fight infections and/or stopping the spread of inflammation (Serebruany et al, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Clopidogrel and prasugrel are classified as FDA pregnancy category B.
    B) In 2 case reports, healthy infants were born to women who were taking clopidogrel throughout their pregnancies. In one of these cases, the baby was delivered cesarean due to repetitive late decelerations in the fetal heart rate. Although the mother was administered prophylactic platelets and local anesthesia, she experienced postoperative bleeding resulting in a blood transfusion which stabilized her hemoglobin levels. There were no further sequelae with infant and mother discharged on postpartum day 4 and the mother reinitiated on clopidogrel.
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) CLOPIDOGREL
    a) Clopidogrel is classified as FDA pregnancy category B (Prod Info PLAVIX(R) oral tablets, 2011).
    2) PRASUGREL
    a) Prasugrel is classified as FDA pregnancy category B (Prod Info EFFIENT(TM) oral tablets, 2009).
    B) LACK OF EFFECT
    1) CLOPIDOGREL
    a) CASE REPORT: A 27-year-old woman who received clopidogrel during pregnancy experienced bleeding complications after delivering a healthy full-term baby by cesarean section. The woman had suffered an acute myocardial infarction which was treated with a drug-eluting coronary stent. Two months before becoming pregnant, she was initiated on clopidogrel (dose not specified) and aspirin. Clopidogrel was continued throughout the pregnancy and aspirin was discontinued. She had taken her clopidogrel dose earlier in the day that she went into labor. She was admitted to the obstetrics unit and clopidogrel was withheld with plans for a vaginal delivery and no platelet treatment. However, fetal monitoring showed repetitive late decelerations and an emergency cesarean delivery was initiated. Prophylactic platelets and general anesthesia were administered and there were no complications during surgery. A Jackson-Pratt drain was placed in case of postoperative bleeding. She was clinically stable with a normal platelet count. On postpartum day 2, however, her hemoglobin level dropped to 5.6 g/dL from a pre-delivery level of 9.2 g/dL. Subsequently, she received a blood transfusion (2 units) for postoperative bleeding. Over the next 2 days, blood counts stabilized resulting in removal of the drain. On postpartum day 4, she and her infant were discharged from the hospital at which time the mother was reinitiated on clopidogrel therapy (Myers et al, 2011).
    b) CASE REPORT: A 24-year-old woman with essential thrombocythemia who received clopidogrel during pregnancy delivered a healthy baby with no complications. The woman, who had suffered an acute anterior wall myocardial infarction and aorta coronary bypass grafting, was taking clopidogrel (75 mg twice daily) when she became pregnant. Clopidogrel was continued throughout the pregnancy. She also received folic acid until week 37 and subQ dalteparin (5000 international units) intermittently during her pregnancy based on thrombocyte counts. Ten days prior to delivery, clopidogrel was discontinued and dalteparin 2500 international units twice daily was administered. On the day of delivery, 3 doses of heparin 5000 international units were given. At 41 weeks of pregnancy, delivery was induced with oxytocin and a healthy baby girl was delivered with no abnormal or excessive bleeding during delivery. The placenta was morphologically normal without any fibrin deposition or infarcts. Five days after delivery, mother and infant were discharged. Upon discharge, the mother's platelet count was 490 giga-particle (gpt)/L and she was receiving dalteparin 2500 international units/day (until day 21 postpartum) and oral clopidogrel which was initiated on day 3 postpartum (Klinzing et al, 2001).
    2) PRASUGREL
    a) A case report describes a successful delivery in a 32-year-old woman following treatment with prasugrel. The patient presented with chest pain, increased cardiac enzymes, and abnormal ischemic ST and T waves. The patient, who had no prior significant medical history, was diagnosed with non-ST elevation myocardial infarction. Treatment with aspirin 325 mg, enoxaparin 1 mg/kg, sublingual nitroglycerin, and morphine 2 mg was initiated and a left heart catheterization was performed. Following the procedure, the patient was started on prasugrel 60 mg loading dose followed by a 10 mg/day maintenance dose. The patient was discharged 3 days later and remained symptom free after one month. A pregnancy test was performed so that patient could enroll in an investigator initiated project, however, the test came back positive. The patient may have been pregnant at the time of her cardiac event. The patient was advised of the possibility of teratogenic effects but refused to terminate the pregnancy. Treatment with metoprolol, lisinopril, and atorvastatin were discontinued but the patient remained on prasugrel and aspirin. The pregnancy was managed according to high-risk pregnancy management recommendations. The patient had no evidence of vaginal bleeding, uterine cramping, or contractions during her pregnancy and was induced at 38 weeks 5 days gestation. The infant was delivered via caesarean section without complications. The patient was restarted on prasugrel 10 mg/day and aspirin 81 mg/day within hours of the delivery. The patient and infant were discharged 3 days after delivery. A follow up appointment revealed no congenital or neonatal disorders or other adverse effects (Tello-Montoliu et al, 2012).
    C) ANIMAL STUDIES
    1) CLOPIDOGREL
    a) RATS, RABBITS: There was no evidence of fetotoxicity when rats and rabbits were exposed to clopidogrel doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m(2) basis) (Prod Info PLAVIX(R) oral tablets, 2011).
    2) PRASUGREL
    a) RATS, RABBITS: Reproductive and developmental studies of prasugrel in rats and rabbits with doses up to 30 times the recommended human exposure found no evidence of fetal harm. In embryo fetal developmental studies, pregnant rats and rabbits received oral doses equal to more than 40 times the human exposure. Only a slight decrease in pup body weight was reported; no structural malformations were noted in either species. Prenatal and postnatal rat studies found no effect on the behavioral or reproductive development of the offspring with prasugrel at doses greater than 150 times the human exposure (Prod Info EFFIENT(TM) oral tablets, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to clopidogrel or prasugrel during lactation in humans (Prod Info PLAVIX(R) oral tablets, 2011; Prod Info EFFIENT(TM) oral tablets, 2009).
    B) BREAST MILK
    1) CLOPIDOGREL
    a) It is unknown whether clopidogrel is excreted in human milk. Because human data are lacking regarding the use of clopidogrel in nursing women, it is recommended that a decision be made to discontinue either the drug or nursing after considering the importance of the drug to the mother (Prod Info PLAVIX(R) oral tablets, 2011).
    2) PRASUGREL
    a) No human data are available. Due to the lack of human safety information, it is recommended that prasugrel should be used while nursing only if the benefit to the mother outweighs the potential risk to the nursing infant (Prod Info EFFIENT(TM) oral tablets, 2009).
    C) ANIMAL STUDIES
    1) CLOPIDOGREL
    a) Rat studies have shown that clopidogrel and/or its metabolites are excreted in breast milk (Prod Info PLAVIX(R) oral tablets, 2011).
    2) PRASUGREL
    a) Rat studies have shown that prasugrel metabolites are excreted in breast milk (Prod Info EFFIENT(TM) oral tablets, 2009).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects on human fertility from exposure to clopidogrel or prasugrel (Prod Info PLAVIX(R) oral tablets, 2011; Prod Info EFFIENT(TM) oral tablets, 2009).
    B) ANIMAL STUDIES
    1) CLOPIDOGREL
    a) RATS: There was no effect on fertility in male or female rats administered oral doses of up to 400 mg/kg/day (52 times the recommended human dose on a mg/m(2) basis) (Prod Info PLAVIX(R) oral tablets, 2011).
    b) RABBITS: There was no evidence of fertility impairment when rabbits were exposed to clopidogrel doses up to 300 mg/kg/day (78 times the recommended daily human dose on a mg/m(2) basis) (Prod Info PLAVIX(R) oral tablets, 2011)
    2) PRASUGREL
    a) RATS: Prasugrel had no effect on fertility in male or female rats at oral doses 80 times the recommended daily human dose of 10 mg (Prod Info EFFIENT(TM) oral tablets, 2009).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS113665-84-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    B) IARC Carcinogenicity Ratings for CAS389574-19-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) Clopidogrel was administered to mice for 78 weeks and rats for 104 weeks at doses up to 77 mg/kg/day (plasma exposures >25 times that in humans at the recommended daily dose). No evidence of tumorigenicity was observed (Prod Info Plavix(R), 2002).

Genotoxicity

    A) CLOPIDOGREL
    1) Clopidogrel was not genotoxic in 4 in vitro tests and 1 in vivo test.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No laboratory studies are needed in asymptomatic patients.
    B) Serial CBCs are recommended in bleeding patients. No single laboratory test is able to adequately measure platelet function.
    C) In patients with significant bleeding, thromboelastography in combination with platelet count and PT/INR studies may give a general estimation of a patient's hemostasis potential, though no one test is well correlated with the in-vivo coagulation propensity.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with evidence of active bleeding should be admitted for serial hematocrits.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Inadvertent ingestion of extra clopidogrel doses may be managed at home with referral for signs of bleeding.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Hematology should be consulted for patients with major bleeding associated with clopidogrel toxicity. Cardiology should be consulted in patients with coronary stents placed within 1 year in whom reversal of clopidogrel is considered. A toxicologist should be consulted in all overdose cases with significant toxicity.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Observation for 4 hours should be sufficient in most cases given the expected pharmacokinetic peak at 30 to 60 minutes in therapeutic doses. At the end of the observation period, the physician should assess for signs of bleeding such as tachycardia, shortness of breath, hematochezia, or headache.

Monitoring

    A) No laboratory studies are needed in asymptomatic patients.
    B) Serial CBCs are recommended in bleeding patients. No single laboratory test is able to adequately measure platelet function.
    C) In patients with significant bleeding, thromboelastography in combination with platelet count and PT/INR studies may give a general estimation of a patient's hemostasis potential, though no one test is well correlated with the in-vivo coagulation propensity.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Activated charcoal can be considered in alert patients with recent substantial overdose.
    6.5.2) PREVENTION OF ABSORPTION
    A) Administration of activated charcoal is recommended if a patient presents early after an intentional overdose. No decontamination is warranted for patients with inadvertent ingestion of extra doses.
    B) CHARCOAL ADMINISTRATION
    1) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    C) CHARCOAL DOSE
    1) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    a) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    2) ADVERSE EFFECTS/CONTRAINDICATIONS
    a) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    b) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) No laboratory studies are needed in asymptomatic patients.
    2) Serial CBCs are recommended in bleeding patients. No single laboratory test is able to adequately measure platelet function.
    3) In patients with significant bleeding, thromboelastography in combination with platelet count and PT/INR studies may give a general estimation of a patient's hemostasis potential, though no one test is well correlated with the in-vivo coagulation propensity.
    B) BLEEDING
    1) Management of patients with major bleeding complications is difficult. Identify the source of bleeding and provide local hemostasis whenever possible. When local hemostatic control is not practical, red blood cell and platelet transfusions must be considered.
    C) PLASMAPHERESIS
    1) Clopidogrel is an analogue of ticlopidine. Several retrospective case series suggest that the mortality from ticlopidine induced thrombotic thrombocytopenic purpura may be reduced by plasma exchange or plasmapheresis (Chen et al, 1999; Steinhubl et al, 1999; Chen & Sutton, 1999a).
    2) A total of 20 cases of thrombotic thrombocytopenic purpura have been reported following clopidogrel therapy; 2 were fatal, 2 required more than 20 total plasma exchanges, and 3 involved relapses (Bennett et al, 2000).
    3) CASE REPORT: A 35-year-old male kidney/pancreas recipient developed thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS) after starting clopidogrel for symptomatic coronary artery disease. He was successfully treated with plasmapheresis, methylprednisolone, discontinuation of clopidogrel, and temporary withdrawal of cyclosporine(Chinnakotla et al, 2000).

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) The serum half-life of clopidogrel is relatively short and the duration of action is prolonged, therefore removal by extracorporeal methods is not likely to significantly change a patient's course and may, in fact, put them at higher risk of bleeding complications from catheter replacement.

Abstracts

Case Reports

    A) ADULT
    1) CLOPIDOGREL: A 34-year-old woman developed NO adverse effects following a deliberate ingestion of 1050 mg of clopidogrel (14 standard 75-mg tablets). No symptomatic therapy was required; no sequelae developed (Prod Info Plavix(R), 2002).

Range Of Toxicity

Summary

    A) TOXICITY: No toxic dose has been established. CLOPIDOGREL: Ingestions of 1650 mg and 1050 mg by adults resulted in no toxicity, and a 6300 mg ingestion caused minimal toxicity. In the absence of additional anticoagulants or traumatic injury, no clinical bleeding is expected in the vast majority of cases.
    B) THERAPEUTIC DOSE: CLOPIDOGREL: For patients with a recent myocardial infarction, recent stroke, or established peripheral arterial disease, the recommended dose is 75 mg/day. For patients with acute coronary syndrome (unstable angina, non-Q-wave myocardial infarction), clopidogrel should be started with an oral loading dose of 300 to 600 mg, followed by 75 mg once daily with aspirin (75 mg to 325 mg) once daily. PRASUGREL: The recommended dose is a single 60 mg loading dose followed by 10 mg daily with aspirin (75 mg to 325 mg); consider prasugrel 5 mg daily in patients weighing less than 60 kg.

Therapeutic Dose

    7.2.1) ADULT
    A) CLOPIDOGREL
    1) MI/STROKE/PAD: 75 mg orally once daily for patients with a recent myocardial infarction, recent stroke, or established peripheral arterial disease, taken with or without food (Prod Info PLAVIX(R) oral tablets, 2015).
    2) ACUTE CORONARY SYNDROME
    a) ACUTE NON-ST SEGMENT ELEVATION MI: Initial loading dose, 300 mg to 600 mg orally with aspirin 75 to 325 mg as soon as possible; maintenance, 75 mg orally plus aspirin 75 to 325 mg once daily (Prod Info PLAVIX(R) oral tablets, 2015; Wright et al, 2011)
    b) ACUTE ST SEGMENT ELEVATION MI: 75 mg orally once daily with aspirin 75 to 325 mg once daily, with or without thrombolytics (Prod Info PLAVIX(R) oral tablets, 2015).
    B) CLOPIDOGREL/ASPIRIN
    1) 1 tablet (either 75 mg/75 mg or 75 mg/100 mg) orally once daily (Prod Info DuoCover oral film-coated tablets, 2012; Prod Info DuoPlavin oral film-coated tablets, 2012).
    C) PRASUGREL
    1) A single 60 mg oral loading dose followed by 10 mg orally once daily with aspirin 75 mg to 325 mg daily; consider prasugrel 5 mg orally once daily in patients weighing less than 60 kg (Prod Info EFFIENT(R) oral tablets, 2016).
    7.2.2) PEDIATRIC
    A) CLOPIDOGREL: Safety and efficacy in the pediatric population have not been established (Prod Info PLAVIX(R) oral tablets, 2015).
    B) CLOPIDOGREL/ASPIRIN: Safety and efficacy have not been established in pediatric patients (Prod Info DuoCover oral film-coated tablets, 2012).
    C) PRASUGREL: The safety and effectiveness of prasugrel have not been established in pediatric patients (Prod Info EFFIENT(R) oral tablets, 2016).

Maximum Tolerated Exposure

    A) CLOPIDOGREL
    1) A 56-year-old woman intentionally ingested 84 x 75-mg (a total of 6300 mg) clopidogrel tablets and presented to the emergency department at least 12 hours after exposure with minor adverse effects. Initial symptoms included nausea and diarrhea, with normal vital signs and a compensated metabolic acidosis. An elevated reticulocyte count (741 billions/L) was observed, but no episodes of bleeding were reported. The patient was discharged after 2 days with no sequelae (Pedersen et al, 2006).
    2) No associated adverse effects were reported in a 34-year-old woman following a single intentional ingestion of 1050 mg of clopidogrel (14 standard 75 mg tablets). The patient was observed and recovered without sequelae (Prod Info Plavix(R), 2002).
    3) When 600 mg was administered as a single oral dose to healthy volunteers, no adverse events were reported. Bleeding time was prolonged by a factor of 1.7, similar to a therapeutic dose (Prod Info Plavix(R), 2002).
    4) A 49-year-old man intentionally ingested 1650 mg of clopidogrel along with other medicines (1400 mg phenytoin and 120 mg simvastatin) in a suicide attempt. Other than platelet aggregation abnormalities measured via an optical platelet aggregator, he remained asymptomatic (Kocabay et al, 2006).

Workplace Standards

    A) ACGIH TLV Values for CAS113665-84-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) ACGIH TLV Values for CAS389574-19-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    C) NIOSH REL and IDLH Values for CAS113665-84-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    D) NIOSH REL and IDLH Values for CAS389574-19-0 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    E) Carcinogenicity Ratings for CAS113665-84-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    F) Carcinogenicity Ratings for CAS389574-19-0 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    G) OSHA PEL Values for CAS113665-84-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

    H) OSHA PEL Values for CAS389574-19-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) CLOPIDOGREL selectively inhibits the binding of adenosine diphosphate (ADP) to the platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thus inhibiting platelet aggregation . Effect on platelet function is irreversible for the life of the platelet (Prod Info PLAVIX(R) oral tablets, 2011a).
    B) PRASUGREL is a thienopyridine which inhibits platelet activation and aggregation via irreversible inhibition of the platelet P2Y12 adenosine diphosphate (ADP) receptor (Prod Info EFFIENT oral tablets, 2011; Jakubowski et al, 2007).
    1) Prasugrel is a prodrug that needs to be metabolically converted to a pharmacologically active compound. The active metabolite of a thienopyridine contains a thiol group that binds to a free cysteine (s) on the P2Y12 receptor and irreversibly blocks ADP binding and receptor activation. After exposure to the prasugrel active metabolite, platelets are affected for their entire lifespan of approximately 7 to 10 days (Farid et al, 2007a).
    2) Prasugrel is converted to its active metabolite by rapid hydrolysis in the intestine by esterases followed by a single CYP-dependent step, unlike clopidogrel which is metabolized by 2 consecutive CYP-dependent steps (Prod Info EFFIENT oral tablets, 2011; Payne et al, 2007).
    3) Clinical trials with prasugrel have shown that prasugrel achieves faster and greater inhibition of platelet aggregation compared to clopidogrel (Wallentin et al, 2008; Payne et al, 2007; Jakubowski et al, 2007).

Physicochemical

Physical Characteristics

    A) CLOPIDOGREL BISULFATE: A white to off-white powder; freely soluble in water at pH of 1; practically insoluble in water at neutral pH; dissolves freely in methanol; dissolves sparingly in methylene chloride; and practically insoluble in ethyl ether (Prod Info PLAVIX(R) oral tablets, 2013)
    B) PRASUGREL HYDROCHLORIDE: A white to practically white solid; dissolves freely in methanol; slightly soluble in 1-propanol, 2-propanol, and acetone; practically insoluble in diethyl ether and ethyl acetate (Prod Info EFFIENT(R) oral tablets, 2013)

Molecular Weight

    A) CLOPIDOGREL BISULFATE: 419.9 (Prod Info PLAVIX(R) oral tablets, 2013)
    B) PRASUGREL HYDROCHLORIDE: 409.9 (Prod Info EFFIENT(R) oral tablets, 2013)

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