Plavix 300 MG (clopidogrel bisulfate 391.5 MG) Oral Tablet
Generic Name: CLOPIDOGREL BISULFATE
Brand Name: Plavix
- Substance Name(s):
- CLOPIDOGREL BISULFATE
DRUG INTERACTIONS
7 Opioids: Decreased exposure to clopidogrel.
Consider use of parenteral antiplatelet agent.
(7.2) Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding.
(7.3, 7.4, 7.5) Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations.
(7.6) 7.1 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 [see Warnings and Precautions (5.1)].
Omeprazole or Esomeprazole Avoid concomitant use of Plavix with omeprazole or esomeprazole.
In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of Plavix when given concomitantly or 12 hours apart.
A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with Plavix.
Dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity of Plavix than did omeprazole or esomeprazole [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
7.2 Opioids As with other oral P2Y12 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 [see Clinical Pharmacology (12.3)].
Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists.
7.3 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Coadministration of Plavix and NSAIDs increases the risk of gastrointestinal bleeding.
7.4 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 Plavix with warfarin increases the risk of bleeding because of independent effects on hemostasis.
However, at high concentrations in vitro, clopidogrel inhibits CYP2C9.
7.5 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.
7.6 Repaglinide (CYP2C8 Substrates) The acyl-β-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8.
Plavix can increase the systemic exposure to drugs that are primarily cleared by CYP2C8, thereby needing dose adjustment and appropriate monitoring.
Plavix increased repaglinide exposures by 3.9-fold to 5.1-fold [see Clinical Pharmacology (12.3)].
Avoid concomitant use of repaglinide with Plavix.
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.
OVERDOSAGE
10 Platelet inhibition by Plavix 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.
DESCRIPTION
11 Plavix (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 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°.
Plavix for oral administration is provided as either pink, round, biconvex, debossed, film-coated tablets containing 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of clopidogrel base or pink, oblong, debossed, film-coated tablets containing 391.5 mg of clopidogrel bisulfate which is the molar equivalent of 300 mg of clopidogrel base.
Each tablet contains hydrogenated castor oil, hydroxypropyl cellulose, mannitol, microcrystalline cellulose, and polyethylene glycol 6000 as inactive ingredients.
The pink film coating contains ferric oxide, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.
The tablets are polished with Carnauba wax.
Chemical Structure
CLINICAL STUDIES
14 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.
Patients were randomized to receive Plavix (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 patient population was largely White (82%) and included 38% women, and 52% age ≥65 years of age.
Only about 20% of patients underwent revascularization during the initial hospitalization and few underwent emergent or urgent revascularization.
The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the Plavix-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 Plavix-treated group (see Table 4).
Table 4: Outcome Events in the CURE Primary Analysis Outcome Plavix (+ aspirin)Other standard therapies were used as appropriate.
Placebo (+ aspirin) Relative Risk Reduction (%) (95% CI) (n=6259) (n=6303) Primary outcome (Cardiovascular death, MI, stroke) 582 (9.3%) 719 (11.4%) 20% (10.3, 27.9) p <0.001 All Individual Outcome Events:The individual components do not represent a breakdown of the primary and coprimary outcomes, but rather the total number of subjects experiencing an event during the course of the study.
CV death 318 (5.1%) 345 (5.5%) 7% (-7.7, 20.6) MI 324 (5.2%) 419 (6.6%) 23% (11.0, 33.4) Stroke 75 (1.2%) 87 (1.4%) 14% (-17.7, 36.6) Most of the benefit of Plavix occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months) (see Figure 2).
Figure 2: Cardiovascular Death, Myocardial Infarction, and Stroke in the CURE Study The effect of Plavix did not differ significantly in various subgroups, as shown in Figure 3.
The benefits associated with Plavix were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE inhibitors.
The efficacy of Plavix was observed independently of the dose of aspirin (75–325 mg once daily).
The use of oral anticoagulants, nonstudy antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.
Figure 3: Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study The use of Plavix in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the Plavix group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the Plavix group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%).
The use of Plavix in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting) (2253 patients [36.0%] in the Plavix group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).
COMMIT In patients with STEMI, the safety and efficacy of Plavix were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT.
COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block).
Patients were randomized to receive Plavix (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.
The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.
The patient population was 28% women and 58% age ≥60 years (26% age ≥70 years).
Fifty-five percent (55%) of patients received thrombolytics and only 3% underwent PCI.
As shown in Table 5 and Figure 4 and Figure 5 below, Plavix significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002).
Table 5: Outcome Events in COMMIT Event Plavix (+ aspirin) (N=22961) Placebo (+ aspirin) (N=22891) Odds ratio (95% CI) p-value Composite endpoint: Death, MI, or Stroke9 patients (2 clopidogrel and 7 placebo) suffered both a nonfatal stroke and a nonfatal MI.
2121 (9.2%) 2310 (10.1%) 0.91 (0.86, 0.97) 0.002 Death 1726 (7.5%) 1845 (8.1%) 0.93 (0.87, 0.99) 0.029 Nonfatal MINonfatal MI and nonfatal stroke exclude patients who died (of any cause).
270 (1.2%) 330 (1.4%) 0.81 (0.69, 0.95) 0.011 Nonfatal Stroke 127 (0.6%) 142 (0.6%) 0.89 (0.70, 1.13) 0.33 Figure 4: Cumulative Event Rates for Death in the COMMIT StudyAll treated patients received aspirin.
Figure 5: Cumulative Event Rates for the Combined Endpoint Re-Infarction, Stroke or Death in the COMMIT Study All treated patients received aspirin.
The effect of Plavix did not differ significantly in various prespecified subgroups as shown in Figure 6.
The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history.
Such subgroup analyses should be interpreted cautiously.
Figure 6: Effects of Adding Plavix to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study * CI is 95% for Overall row only.
Figure Figure Figure Figure Figure 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 Plavix (75 mg daily) to aspirin (325 mg daily).
To be eligible to enroll, patients had to have: 1) recent history of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; and/or 3) established peripheral arterial disease (PAD).
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.
Table 6: Outcome Events in the CAPRIE Primary Analysis Patients Plavix n=9599 Aspirin n=9586 Ischemic stroke (fatal or not) 438 (4.6%) 461 (4.8%) MI (fatal or not) 275 (2.9%) 333 (3.5%) Other vascular death 226 (2.4%) 226 (2.4%) Total 939 (9.8%) 1020 (10.6%) As shown in Table 6, Plavix 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 Plavix group.
The curves showing the overall event rate are shown in Figure 7.
The event curves separated early and continued to diverge over the 3-year follow-up period.
Figure 7: Fatal or Nonfatal Vascular Events in the CAPRIE Study The statistical significance favoring Plavix 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 Plavix is substantial.
The CAPRIE trial enrolled a population that had recent MI, recent stroke, or PAD.
The efficacy of Plavix relative to aspirin was heterogeneous across these subgroups (p=0.043) (see Figure 8).
Nonetheless, this difference may be a chance occurrence because the CAPRIE trial was not designed to evaluate the relative benefit of Plavix over aspirin in the individual patient subgroups.
The benefit was most apparent in patients who were enrolled because of peripheral arterial disease and less apparent in stroke patients.
In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, Plavix was not numerically superior to aspirin.
Figure 8: Hazard Ratio and 95% CI by Baseline Subgroups in the CAPRIE Study Figure Figure 14.3 No Demonstrated Benefit of Plavix 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 Plavix (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 Plavix 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 Plavix.
HOW SUPPLIED
16 /STORAGE AND HANDLING Plavix (clopidogrel bisulfate) 75 mg tablets are available as pink, round, biconvex, film-coated tablets debossed with “75” on one side and “1171” on the other.
Tablets are provided as follows: NDC 63653-1171-6 Bottles of 30 NDC 63653-1171-1 Bottles of 90 NDC 63653-1171-5 Bottles of 500 NDC 63653-1171-3 Blisters of 100 Plavix (clopidogrel bisulfate) 300 mg tablets are available as pink, oblong, film-coated tablets debossed with “300” on one side and “1332” on the other.
Tablets are provided as follows: NDC 63653-1332-2 Unit-dose packages of 30 Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F) [see USP Controlled Room Temperature].
GERIATRIC USE
8.5 Geriatric Use Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with Plavix were 65 years of age and older, and 15% were 75 years and older.
In COMMIT, approximately 58% of the patients treated with Plavix were 60 years and older, 26% of whom were 70 years and older.
The observed risk of bleeding events with Plavix 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.
DOSAGE FORMS AND STRENGTHS
3 75 mg tablets: Pink, round, biconvex, film-coated tablets debossed with “75” on one side and “1171” on the other 300 mg tablets: Pink, oblong, film-coated tablets debossed with “300” on one side and “1332” on the other Tablets: 75 mg, 300 mg (3)
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
1 Plavix is a 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]), Plavix has been shown to reduce the rate of myocardial infarction (MI) and stroke.
(1.1) –For patients with ST-elevation myocardial infarction (STEMI), Plavix has been shown to reduce the rate of MI and stroke.
(1.1) Recent MI, recent stroke, or established peripheral arterial disease.
Plavix has been shown to reduce the rate of MI and stroke.
(1.2) 1.1 Acute Coronary Syndrome (ACS) Plavix is indicated to reduce the rate of myocardial infarction (MI) and stroke in patients with non–ST-segment elevation ACS (unstable angina [UA]/non–ST-elevation myocardial infarction [NSTEMI]), including patients who are to be managed medically and those who are to be managed with coronary revascularization.
Plavix should be administered in conjunction with aspirin.
Plavix is indicated to reduce the rate of myocardial infarction and stroke in patients with acute ST-elevation myocardial infarction (STEMI) who are to be managed medically.
Plavix should be administered in conjunction with aspirin.
1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke Plavix is indicated to reduce the rate of MI and stroke.
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in pediatric populations have not been established.
A randomized, placebo-controlled trial (CLARINET) did not demonstrate a clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt.
Possible factors contributing to this outcome were the dose of clopidogrel, the concomitant administration of aspirin, and the late initiation of therapy following shunt palliation.
It cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population.
PREGNANCY
8.1 Pregnancy Risk Summary Available data from cases reported in published literature and postmarketing surveillance with clopidogrel use in pregnant women have not identified any drug-associated risks for major birth defects or miscarriage [see Data].There are risks to the pregnant woman and fetus associated with myocardial infarction and stroke [see Clinical Considerations].
No evidence of fetotoxicity was observed when clopidogrel was administered to pregnant rats and rabbits during organogenesis at doses corresponding to 65 and 78 times the recommended daily human dose [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown.
All pregnancies have a background risk of birth defects, loss, or other adverse outcomes.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Myocardial infarction and stroke are medical emergencies.
Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of clopidogrel on the fetus.
Labor or delivery Clopidogrel use during labor or delivery will increase the risk of maternal bleeding and hemorrhage.
Avoid neuraxial blockade during clopidogrel use because of the risk of spinal hematoma.
When possible, discontinue clopidogrel 5 to 7 days prior to labor, delivery, or neuraxial blockade.
Data Human data The available data from published case reports over two decades of postmarketing use have not identified an association with clopidogrel use in pregnancy and major birth defects, miscarriage, or adverse fetal outcomes.
Animal data Embryo-fetal developmental toxicology studies were performed in pregnant rats and rabbits with doses up to 500 and 300 mg/kg/day, respectively, administered during organogenesis.
These doses, corresponding to 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.
BOXED WARNING
WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE See full prescribing information for complete boxed warning.
Effectiveness of Plavix depends on conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
(5.1, 12.3) Tests are available to identify patients who are CYP2C19 poor metabolizers.
(12.5) Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
(5.1) The effectiveness of Plavix results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1), Clinical Pharmacology (12.3)].
Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed “CYP2C19 poor metabolizers”).
Tests are available to identify patients who are CYP2C19 poor metabolizers [see Clinical Pharmacology (12.5)].
Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS CYP2C19 inhibitors: Avoid concomitant use of omeprazole or esomeprazole.
(5.1) Bleeding: Plavix 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 Plavix with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of Plavix [see Drug Interactions (7.1)].
5.2 General Risk of Bleeding Thienopyridines, including Plavix, increase the risk of bleeding.
Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7–10 days).
Because the half-life of clopidogrel’s active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.
5.3 Discontinuation of Plavix Discontinuation of Plavix increases the risk of cardiovascular events.
If Plavix 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 Plavix for five days prior to such surgery.
Resume Plavix as soon as hemostasis is achieved.
5.4 Thrombotic Thrombocytopenic Purpura (TTP) TTP, sometimes fatal, has been reported following use of Plavix, 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)].
5.5 Cross-Reactivity among Thienopyridines Hypersensitivity including rash, angioedema or hematologic reaction has been reported in patients receiving Plavix, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines [see Contraindications (4.2) and Adverse Reactions (6.2)].
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise patients to read FDA approved patient labeling (Medication Guide).
Discontinuation Advise patients not to discontinue Plavix without first discussing it with the healthcare provider who prescribed it [see Warnings and Precautions (5.3)].
Bleeding Advise patients that they: will bruise and bleed more easily will take longer than usual to stop bleeding must report any unanticipated, prolonged, or excessive bleeding, or blood in their stool or urine [see Warnings and Precautions (5.2)] Thrombotic Thrombocytopenic Purpura Instruct patients to get prompt medical attention if they experience symptoms of TTP that cannot otherwise be explained [see Warnings and Precautions (5.4)].
Invasive Procedures Advise patients to inform physicians and dentists that they are taking Plavix before any surgery or dental procedure [see Warnings and Precautions (5.2, 5.3)].
Proton Pump Inhibitors Advise patients not to take omeprazole or esomeprazole while taking Plavix.
Dexlansoprazole, lansoprazole, and pantoprazole had less pronounced effects on the antiplatelet activity of Plavix than did omeprazole or esomeprazole [see Drug Interactions (7.1)].
DOSAGE AND ADMINISTRATION
2 Acute coronary syndrome (2.1) –Initiate Plavix with a single 300 mg oral loading dose and then continue at 75 mg once daily.
–Initiating Plavix without a loading dose will delay establishment of an antiplatelet effect by several days.
Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily orally without a loading dose.
(2.2) 2.1 Acute Coronary Syndrome In patients who need an antiplatelet effect within hours, initiate Plavix with a single 300 mg oral loading dose and then continue at 75 mg once daily.
Initiating Plavix without a loading dose will delay establishment of an antiplatelet effect by several days [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)].
2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease 75 mg once daily orally without a loading dose [see Clinical Pharmacology (12.3) and Clinical Studies (14.2)].