Clopidogrel Bisulfate

Plavix (clopidogrel bisulfate) is a thienopyridine class inhibitor of P2Y12ADP 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, hydroxypropylcellulose, 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.

Dosage Forms And Sterngths

• 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

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
NDC 63653-1332-3     Unit-dose packages of 100

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

Distributed by:Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership Bridgewater, NJ 08807. Revised: Sep 2016

Included as part of the "PRECAUTIONS" Section

Clopidogrel keeps your blood from coagulating (clotting) to prevent unwanted blood clots that can occur with certain heart or blood vessel conditions. Because of this drug action, clopidogrel can make it easier for you to bleed, even from a minor injury.

Call your doctor or seek emergency medical attention if you have bleeding that will not stop. You may also have bleeding on the inside of your body, such as in your stomach or intestines. Call your doctor at once if you have black or bloody stools, or if you cough up blood or vomit that looks like coffee grounds. These could be signs of bleeding in your digestive tract.

Avoid drinking alcohol. It may increase your risk of bleeding in your stomach or intestines.

Tell your doctor about all other medicines you use to prevent blood clots.

If you need surgery or dental work, tell the surgeon or dentist ahead of time that you take clopidogrel.

Platelet-aggregation inhibitor; thienopyridine P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist.1

Reduction of Cardiovascular and Cerebrovascular Events

Reduction of the risk of cardiovascular or cerebrovascular events (new MI, new ischemic stroke, and vascular death) in patients with a history of recent MI, recent ischemic stroke, or established peripheral arterial disease.1 2 6 8 23 1009 1010 1011

The American College of Chest Physicians (ACCP) recommends long-term antiplatelet therapy with either aspirin or clopidogrel in patients with established CAD.1010 Because of cost considerations, clopidogrel generally recommended as an alternative to aspirin in those with aspirin intolerance or contraindications (e.g., allergy).5 6 20 23 992

ACCP, the American Stroke Association (ASA), and AHA consider clopidogrel an acceptable antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke or TIAs; other options include aspirin monotherapy, cilostazol, or the combination of aspirin and extended-release dipyridamole.990 1009

Oral anticoagulation (e.g., warfarin, dabigatran) rather than antiplatelet therapy is recommended in patients with a history of ischemic stroke or TIA and concurrent atrial fibrillation; however, in patients who cannot take or choose not to take oral anticoagulants (e.g., those with difficulty maintaining stable INRs, compliance issues, dietary restrictions, cost limitations), dual antiplatelet therapy with clopidogrel and aspirin is recommended.1009

Recommended by ACCP and other experts as an acceptable antiplatelet therapy for secondary prevention of cardiovascular events in patients with symptomatic peripheral arterial disease,992 1011 1017 including those with intermittent claudication and those undergoing revascularization procedures (peripheral artery percutaneous transluminal angioplasty or peripheral artery bypass graft surgery, carotid endarterectomy).1011

Recommended by ACCP as an option for long-term antiplatelet therapy in patients with symptomatic carotid stenosis†, including in patients who are intolerant of aspirin and those who have undergone recent carotid endarterectomy.1011 1017

ACS: Unstable Angina/Non-ST-Segment Elevation MI (NSTEMI)

Used in combination with aspirin for reduction of the risk of cardiovascular or cerebrovascular events in patients with non-ST-segment elevation ACS (NSTE ACS), including unstable angina and NSTEMI.1 5 18 35 992 993 994 1010 Used in patients who are managed medically or with coronary intervention (e.g., PCI with or without coronary artery stenting, CABG).1 5 18 35 992 993 994 1010

Dual-drug antiplatelet therapy with a P2Y12-receptor antagonist and aspirin is considered part of the current standard of care in patients with ACS.991 992 993 994 1010 The American College of Cardiology Foundation (ACCF), AHA, and other experts recommend antiplatelet therapy with a P2Y12-receptor antagonist (clopidogrel, prasugrel, or ticagrelor) in conjunction with aspirin for treatment and secondary prevention in patients with ACS, including those undergoing PCI.991 992 993 994 1010

Ticagrelor or clopidogrel generally is recommended in patients treated medically without stent placement; ticagrelor, clopidogrel, or prasugrel is recommended in patients undergoing PCI with stent placement (bare-metal or drug-eluting).992 993 994 1010

Experts generally recommend continuing treatment with a P2Y12-receptor antagonist for up to 12 months in patients managed medically without stenting and ≥12 months in those with coronary artery stents (bare-metal or drug-eluting); continue aspirin therapy indefinitely.992 993 994 1010 (See Risks of Premature Discontinuance of Therapy under Cautions.)

ACCP suggests use of ticagrelor over clopidogrel in patients with ACS, regardless of whether PCI is performed; other expert guidelines make no specific recommendations regarding P2Y12-receptor antagonist of choice.992 993 994 1010 When selecting an appropriate antiplatelet regimen, consider individual patient (e.g., ischemic and bleeding risk) and drug-related (e.g., adverse effects, drug interaction potential) factors.140 141

Efficacy of pretreatment with clopidogrel prior to diagnostic cardiac catheterization is controversial; balance potential benefit of pretreatment against increased risk of bleeding should emergency CABG be needed.35 994

Temporarily discontinue therapy ≥5 days prior to CABG.1 35 40 1004

ACS: ST-Segment Elevation MI (STEMI)

Used in combination with aspirin for reduction of the rate of ischemic cardiovascular and cerebrovascular events in patients with STEMI.1 31 36 134

Experts recommend treatment for 14–28 days in addition to aspirin, with or without reperfusion therapy (i.e., thrombolytic therapy, primary PCI†), in patients with suspected STEMI.68

In patients in whom CABG is planned, withhold clopidogrel for ≥5 days prior to surgery.1004

In patients with STEMI in whom PCI is planned†, experts recommend a loading dose of a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) before or at the time of PCI in conjunction with aspirin therapy.994

Continue therapy for ≥12 months after stent implantation (bare-metal or drug-eluting), unless risk of bleeding outweighs anticipated net benefit; continue aspirin therapy indefinitely.992 993 994 (See Risks of Premature Discontinuance of Therapy under Cautions.)

The addition of warfarin to antiplatelet therapy is recommended in STEMI patients who have indications for anticoagulation (e.g., atrial fibrillation, left ventricular dysfunction, cerebral emboli, extensive wall-motion abnormality, mechanical heart valves).993 1007 1010

Triple antithrombotic therapy† with clopidogrel, low-dose aspirin, and warfarin (target INR 2–3) is suggested by ACCP in patients with anterior MI and left ventricular thrombus (or at high risk for such thrombi) undergoing stent implantation; recommended duration of triple antithrombotic therapy is dependent on whether patient has a bare-metal or drug-eluting stent.1010

Suggested by the American Diabetes Association (ADA) as alternative to aspirin for primary prevention of MI† in aspirin-allergic patients with type 1 or type 2 diabetes mellitus who are at high risk for cardiovascular events (i.e., family history of CHD, smoking, hypertension, obesity, albuminuria, elevated blood cholesterol or triglyceride concentrations).95

Stent Thrombosis

Has been used in combination with aspirin (dual-drug therapy) to prevent stent thrombosis following implantation of coronary artery stents†.43 44 45 46 50 51 52 54 134 992 993 994 1010

Current expert guidelines recommend such dual-drug therapy for ≥12 months in patients with any type of coronary artery stent (bare-metal or drug-eluting).993 994 1010

Some evidence suggests benefits of an even longer duration of dual-drug antiplatelet therapy (e.g., at least 30 months), but such prolonged therapy has been associated with an increased risk of bleeding.1019

Chronic Stable Angina

May be used as an alternative to aspirin in patients with symptomatic chronic stable angina who cannot tolerate aspirin†.96

Embolism Associated with Atrial Fibrillation and/or Valvular Heart Disease

Has been used in combination with aspirin as an alternative to warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation†.995 997 1007

In patients with atrial fibrillation at increased risk of stroke who cannot or choose not to take oral anticoagulants for reasons other than concerns about major bleeding (e.g., those with difficulty maintaining stable INRs, compliance issues, dietary restrictions, cost limitations), combination therapy with clopidogrel and aspirin rather than aspirin alone is recommended.998 1007

In patients with atrial fibrillation and mitral stenosis† who cannot or choose not to take warfarin therapy for reasons other than concerns about major bleeding, ACCP recommends combination therapy with clopidogrel and aspirin rather than aspirin alone.1007

Antithrombotic therapy of atrial flutter generally managed in same manner as atrial fibrillation.999 1007

Storage

Oral

25°C (may be exposed to 15–30 °C).1

• Importance of counseling patients about potential risks versus benefits of clopidogrel.1

• Importance of informing patients that they may bleed more easily and that a longer than normal time will be required to stop bleeding when taking clopidogrel.1

• Before implantation of drug-eluting stent (DES), determine likelihood of patient compliance with ≥12 months of aspirin–clopidogrel combination therapy.45

• Importance of informing patients prior to hospital discharge about risks associated with premature discontinuance of such combination therapy.45 Importance of informing patient not to discontinue therapy without consulting their prescribing clinician, even if instructed to do so by another health-care professional (e.g., dentist).1 45

• Importance of patient informing clinician about any unanticipated, prolonged, or excessive bleeding, or blood in urine or stool.1 6

• Importance of patient informing clinician about clopidogrel therapy before any surgery is scheduled.1 6 Prior to scheduling an invasive procedure, patients should inform their clinicians (including dentists) that they are currently taking clopidogrel; clinicians performing the invasive procedure should consult with the prescribing clinician before discontinuing clopidogrel therapy.1

• Importance of patient informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, particularly omeprazole (including Prilosec OTC) or esomeprazole and drugs that affect bleeding (e.g., warfarin, NSAIAs).1 76 100 101 102 114 352

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)