CLOPIDOGREL BISULFATE tablet, film coated

United States - English - NLM (National Library of Medicine)

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Active ingredient:
CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7)
Available from:
ACI Healthcare USA, Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
- Clopidogrel tablets are 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. Clopidogrel tablets should be administered in conjunction with aspirin. - Clopidogrel tabletsare 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. Clopidogrel should be administered in conjunction with aspirin. In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke Clopidogrel tablets are indicated to reduce the rate of MI and stroke. Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. Clopidogrel tablets are contraindi
Product summary:
Clopidogrel Tablets USP, 75 mg are supplied as a pink, film coated, round, biconvex tablet debossed with product identification "54 834" on one side and plain on the other. Storage Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). [See USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
71093-142-04, 71093-142-05

ACI Healthcare USA, Inc.

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Medication Guide

Clopidogrel (kloh pid’ oh grel) Tablets, USP

Read this Medication Guide before you start taking clopidogrel tablets and each time you get a refill. There

may be new information. This Medication Guide does not take the place of talking with your doctor about

your medical condition or your treatment.

What is the most important information I should know about clopidogrel tablets?

1. Clopidogrel tablets may not work as well in people who:

have certain genetic factors that affect how the body breaks down Clopidogrel tablets. Your doctor

may do genetic tests to make sure clopidogrel tablets are right for you.

take certain medicines, especially omeprazole (Prilosec®) or esomeprazole (Nexium®). Your doctor

may change the medicine you take for stomach acid problems while you take Clopidogrel tablets.

2. Clopidogrel tablets can cause bleeding which can be serious and can sometimes lead to death. Clopidogrel

is a blood thinner medicine that lowers the chance of blood clots forming in your body. While you take

clopidogrel tablets

you may bruise and bleed more easily

you are more likely to have nose bleeds

it will take longer for any bleeding to stop

Call your doctor right away if you have any of these signs or symptoms of bleeding:

unexpected bleeding or bleeding that lasts a long time

blood in your urine (pink, red or brown urine)

red or black stools (looks like tar)

bruises that happen without a known cause or get larger

cough up blood or blood clots

vomit blood or your vomit looks like coffee grounds

Do not stop taking clopidogrel tablets without talking to the doctor who prescribes it for you. People who

stop taking clopidogrel tablets too soon have a higher risk of having a heart attack or dying. If you must stop

clopidogrel tablets because of bleeding, your risk of a heart attack may be higher.

What are clopidogrel tablets?

Clopidogrel tablets are a prescription medicine used to treat people who have any of the following:

chest pain due to heart problems

poor circulation in their legs (peripheral arterial disease)

a heart attack

a stroke

Clopidogrel tablets are used alone or with aspirin to lower your chance of having another serious problem

with your heart or blood vessels such as heart attack, stroke, or blood clot that can lead to death.

Platelets are blood cells that help your blood clot normally. Clopidogrel helps to prevent platelets from

sticking together and forming a clot that can block an artery.

It is not known if clopidogrel tablets are safe and effective in children.

Who should not take clopidogrel?

Do not take clopidogrel tablets if you:

currently have a condition that causes bleeding, such as a stomach ulcer

are allergic to clopidogrel or other ingredients in Clopidogrel Tablets. See the end of this leaflet for a

complete list of ingredients in Clopidogrel Tablets.

What should I tell my doctor before taking clopidogrel?

Before you take clopidogrel tablets, tell your doctor if you:

have a history of bowel (gastrointestinal) or stomach ulcers

have a history of bleeding problems

plan to have surgery or a dental procedure. See “How should I take clopidogrel tablets?"

are pregnant or plan to become pregnant. It is not known if clopidogrel tablets will harm your unborn

baby

are breastfeeding or plan to breastfeed. It is not known if clopidogrel bisulfate passes into your breast

milk. You and your doctor should decide if you will take clopidogrel tablets or breastfeed. You

should not do both without talking to your doctor.

have had an allergy or reaction to any medicine used to treat your disease.

Tell all of your doctors and your dentist that you are taking clopidogrel tablets. They should talk to the doctor

who prescribed clopidogrel tablets for you before you have any surgery or invasive procedure.

Tell your doctor about all the medicines you take, including prescription, non-prescription medicines,

vitamins and herbal supplements.

Clopidogrel tablets may affect the way other medicines work, and other medicines may affect how

clopidogrel tablets work. See “What is the most important information I should know about clopidogrel?”

Taking clopidogrel tablets with certain other medicines may increase your risk of bleeding. Especially tell

your doctor if you take:

aspirin, especially if you have had a stroke. Always talk to your doctor about whether you should take

aspirin along with clopidogrel tablets to treat your condition.

Non-steroidal anti-inflammatory drugs (NSAIDs). Ask your doctor or pharmacist for a list of NSAID

medicines if you are not sure.

warfarin (Coumadin®, Jantoven®)

selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors

(SNRIs). Ask your doctor or pharmacist for a list of SSRI or SNRI medicines if you are not sure.

Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new

medicine.

How should I take clopidogrel tablets?

Take clopidogrel tablets exactly as your doctor tells you.

Do not change your dose or stop taking clopidogrel tablets without talking to your doctor first.

Stopping clopidogrel tablets may increase your risk of heart attack or stroke.

Take clopidogrel tablets with aspirin as instructed by your doctor.

You can take clopidogrel tablets with or without food.

If you miss a dose, take clopidogrel tablets as soon as you remember. If it is almost time for your next

dose, skip the missed dose. Take the next dose at your regular time. Do not take 2 doses of

clopidogrel at the same time unless your doctor tells you to.

If you take too much clopidogrel tablets, call your doctor or go to the nearest emergency room right

away.

Talk with your doctor about stopping your clopidogrel tablets before you have surgery. Your doctor

may tell you to stop taking clopidogrel tablets at least 5 days before you have surgery to avoid

excessive bleeding during surgery.

What are the possible side effects of clopidogrel tablets?

Clopidogrel can cause serious side effects including:

See “What is the most important information I should know about clopidogrel tablets?"

A blood clotting problem called Thrombotic Thrombocytopenic Purpura (TTP). TTP can happen with

clopidogrel tablets, sometimes after a short time (less than 2 weeks). TTP is a blood clotting problem

where blood clots form in blood vessels; and can happen anywhere in the body. TTP needs to be

treated in a hospital right away, because it may cause death. Get medical help right away if you have

any of these symptoms and they can not be explained by another medical condition:

purplish spots (called purpura) on the skin or in the mouth (mucous membranes) due to

bleeding under the skin

your skin or the whites of your eyes are yellow (jaundice)

you feel tired or weak

your skin looks very pale

fever

fast heart rate or feeling short of breath

headache

speech changes

confusion

coma

stroke

seizure

low amount of urine, or urine that is pink or has blood in it

stomach area (abdominal) pain

nausea, vomiting, or diarrhea

vision changes

Tell your doctor if you have any side effect that bothers you or that does not go away. Tell your doctor if you

develop an allergic reaction while taking clopidogrel tablets

These are not all the possible side effects of clopidogrel tablets. For more information, ask your doctor or

pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-

1088.

How should I store clopidogrel tablets?

Store clopidogrel tablets at 59°F to 86°F (15°C to 30°C).

Keep clopidogrel and all medicines out of the reach of children.

General information about clopidogrel tablets

Medicines are sometimes used for purposes other than those listed in a Medication Guide. Do not take

clopidogrel for a condition for which it was not prescribed. Do not give clopidogrel tablets to other people,

even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about clopidogrel tablets. If you would

like more information, talk to your doctor. Ask your doctor or pharmacist for information about clopidogrel

tablets that was written for healthcare professionals.

For more information, go to www.acihealthcareusa.com or call 1-888-802-1213

What are the ingredients in clopidogrel tablets?

Active ingredient: clopidogrel bisulfate

Inactive ingredients: crospovidone, lactose anhydrous, magnesium stearate, microcrystalline cellulose,

Opadry II (pink), and povidone. Opadry II (pink) contains FD&C Blue #2, FD&C Red #40, FD&C Yellow

#6, hypromellose, polyethylene glycol, polydextrose, titanium dioxide, and triacetin.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Elysium Pharmaceuticals Limited

Plot No. 1175

P.O. Dabhasa, Vadodara, Gujarat 391440, India (IND)

Distributed by:

ACI Healthcare USA, Inc.

10100 W. Sample Road,

Suite 406 Coral Springs, FL 33065

Rev.: 07/2018

Coumadin® is a registered trademark of Bristol-Myers Squibb Pharma Company.

Prilosec® and Nexium® are registered trademarks of AstraZeneca.

Jantoven® is a registered trademark of USL Pharma.

Revised: 12/2019

Document Id: 57acd51c-5b74-407b-8087-6ad20bf223a4

34391-3

Set id: 52902cfe-2863-490a-b700-3f47dfe3cf50

Version: 3

Effective Time: 20191212

ACI Healthcare USA, Inc.

CLOPIDOGREL BISULFATE- clopidogrel bisulfate tablet, film coated

ACI Healthcare USA, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use CLOPIDOGREL tablets, safely and

effectively. See full prescribing information for CLOPIDOGREL tablets.

CLOPIDOGREL(clopidogrel bisulfate) tablets, for oral use

Initial U.S. Approval: 1997

See full prescribing information for complete boxed warning.

Effectiveness of Clopidogrel Tablets, USP 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)

INDICATIONS AND USAGE

Clopidogrel tablets are a P2Y platelet inhibitor indicated for:

Acute coronary syndrome

For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction

(NSTEMI)] Clopidogrel tablets, have been shown to decrease the rate of myocardial infarction (MI), stroke. (1.1)

For patients with ST-elevation myocardial infarction (STEMI), Clopidogrel tablets have been shown to decrease the

rate of myocardial infarction (MI) and stroke. (1.1)

Recent MI, recent stroke, or established peripheral arterial disease.

Clopidogrel tablets have been shown to reduce the rate of

myocardial infarction (MI) and stroke. (1.2)

DOSAGE AND ADMINISTRATION

Acute coronary syndrome (2.1)

– Initiate Clopidogrel tablets with a single 300-mg oral loading dose and then continue at 75 mg once daily.

– Initiating Clopidogrel tablets 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)

DOSAGE FORMS AND STRENGTHS

Tablets: 75 mg (3)

CONTRAINDICATIONS

Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage (4.1)

Hypersensitivity to clopidogrel or any component of the product (4.2)

ADVERSE REACTIONS

Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact ACI Healthcare USA, Inc. at 1- 888-802-1213.or

www.acihealthcareusa.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

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)

USE IN SPECIFIC POPULATIONS

Nursing mothers: Discontinue drug or nursing. (8.3)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 9/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-

OF-FUNCTION ALLELES OF THE CYP2C19 GENE

INDICATIONS AND USAGE

1.1 Acute Coronary Syndrome (ACS)

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

DOSAGE AND ADMINISTRATION

2.1 Acute Coronary Syndrome

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

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

4.1 Active Bleeding

4.2 Hypersensitivity

WARNINGS AND PRECAUTIONS

5.1 Diminished Antiplatelet Activity in patients with Impaired CYP2C19 Function

5.2 General Risk of Bleeding

5.3 Discontinuation of Clopidogrel bisulfate

5.4 Thrombotic Thrombocytopenic Purpura (TTP)

5.5 Cross-Reactivity Among Thienopyridines

ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

DRUG INTERACTIONS

7.1 CYP2C19 Inhibitors

7.2 Opioids

7.3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

7.4 Warfarin (CYP2C9 Substrates)

7.5 SSRIs and SNRIs

7.6 Repaglinide (CYP2C8 Substrates)

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.5 Pharmacogenomics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Acute Coronary Syndrome

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

14.3 No Demonstrated Benefit of Clopidogrel bisulfate, plus Aspirin in Patients with Multiple Risk

Factors or Established Vascular Disease

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO

LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE

The effectiveness of clopidogrel bisulfate 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)].

Clopidogrel bisulfate 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 .

INDICATIONS AND USAGE

1.1 Acute Coronary Syndrome (ACS)

Clopidogrel tablets are 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. Clopidogrel tablets should be administered in conjunction

with aspirin.

Clopidogrel tabletsare 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.

Clopidogrel 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 Clopidogrel tablets are indicated to reduce the rate of MI and stroke.

DOSAGE AND ADMINISTRATION

2.1 Acute Coronary Syndrome

In patients who need an antiplatelet effect within hours, initiate clopidogrel tablets with a single 300-mg

oral loading dose and then continue at 75 mg once daily. Initiating clopidogrel tablets 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)].

DOSAGE FORMS AND STRENGTHS

Sections or subsections omitted from the full prescribing information are not listed.

75 mg tablets: Pink, film coated, round, biconvex tablets debossed with “54 834” on one side and plain

on the other.

CONTRAINDICATIONS

4.1 Active Bleeding

Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic

ulcer or intracranial hemorrhage.

4.2 Hypersensitivity

Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to

clopidogrel or any component of the product [see Adverse Reactions (6.2)] .

WARNINGS AND PRECAUTIONS

CYP2C19 inhibitors: Avoid concomitant use of omeprazole or esomeprazole. (5.1)

Bleeding: Clopidogrel bisulfate increases risk of bleeding. (5.2)

Discontinuation: Premature discontinuation increases risk of cardiovascular events. Discontinue 5

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

Thrombotic thrombocytopenic purpura (TTP) has been reported. (5.4)

Cross-reactivity among thienopyridines has been reported. (5.5)

5.1 Diminished Antiplatelet Activity in patients with Impaired CYP2C19 Function

Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an

active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic

variations in CYP2C19 [see Boxed Warning].

The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as

omeprazole or esomeprazole. Avoid concomitant use of Clopidogrel with omeprazole or esomeprazole

because both significantly reduce the antiplatelet activity of Clopidogrel bisulfate [see Drug

Interactions (7.1) ]

5.2 General Risk of Bleeding

Thienopyridines, including Clopidogrel bisulfate, increase the risk of bleeding.

Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days). Because the

half-life of clopidodrel’s active metabolite is short, it may be possible to restore hemostasis by

administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or

2 hours of the maintenance dose may be less effective.

5.3 Discontinuation of Clopidogrel bisulfate

Discontinuation of clopidogrel increases the risk of cardiovascular events. If clopidogrel bisulfate

must be temporarily discontinued (e.g., to treat bleeding or for surgery with a major risk of bleeding),

restart it as soon as possible. When possible, interrupt therapy with clopidogrel bisulfate for five days

prior to such surgery. Resume clopidogrel bisulfate as soon as hemostasis is achieved.

5.4 Thrombotic Thrombocytopenic Purpura (TTP)

TTP, sometimes fatal, has been reported following use of clopidogrel bisulfate, sometimes after a

short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including

plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic

hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings,

renal dysfunction, and fever [see Adverse Reactions (6.2)].

5.5 Cross-Reactivity Among Thienopyridines

Hypersensitivity including rash, angioedema or hematologic reaction has been reported in patients

receiving clopidogrel bisulfate, including patients with a history of hypersensitivity or hematologic

reaction to other thienopyridines [see Contraindications (4.2) and Adverse Reactions (6.2)].

ADVERSE REACTIONS

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

Bleeding [see Warnings and Precautions (5.2)]

Thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.4)].

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions and durations of follow up,

adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in

the clinical trials of another drug and may not reflect the rates observed in practice.

Clopidogrel bisulfatehas been evaluated for safety in more than 54,000 patients, including over 21,000

patients treated for 1 year or more. The clinically important adverse reactions observed in trials

comparing clopidogrel bisulfate plus aspirin to placebo plus aspirin and trials comparing clopidogrel

bisulfatealone to aspirin alone are discussed below.

Bleeding CURE

In CURE, clopidogrel bisulfate use with aspirin was associated with an increase in major bleeding

(primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1). The

incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups.

Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis,

hematuria, and bruise.

The overall incidence of bleeding is described in Table 1.

Table 1: CURE Incidence of Bleeding Complications (% patients)

Event

Clopidogrel bisulfate

(+ aspirin)

(n=6259)

Placebo

(+ aspirin)

(n=6303)

Major Bleeding

Life-threatening bleeding

Fatal

5 g/dL hemoglobin drop

Requiring surgical

intervention

Hemmorrhagic strokes

Requiring inotropes

Requiring transfusion (4

units)

Other major bleeding

Significantly disabling

Intraocular bleeding with

significant loss of vision

0.05

0.03

*

Requiring 2 to 3 units of

blood

Minor Bleeding

COMMIT

In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo

groups, both of which also received aspirin (see Table 2).

Table 2: Incidence of Bleeding Events in COMMIT (% patients)

Type of bleeding

Clopidogrel bisulfate

(+ aspirin)

(n=22961)

Placebo

(+ aspirin)

(n=22891)

p-value

Major

noncerebral or

cerebral bleeding

0.59

Major noncerebral

0.48

Fatal

Hemorrhagic stroke

0.91

Fatal

0.81

Other noncerebral

bleeding (non-major)

0.005

Any noncerebral

bleeding

0.004

CAPRIE (Clopidogrel bisulfate vs. Aspirin)

In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel bisulfate

vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%,

respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel bisulfate compared

to 0.5% for aspirin.

Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis and

hematoma.

Other Adverse Events

In CURE and CHARISMA, which compared clopidogrel bisulfateplus aspirin to aspirin alone, there

was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfateand

placebo.

In CAPRIE, which compared clopidogrel bisulfateto aspirin, pruritus was more frequently reported in

those taking clopidogrel. No other difference in the rate of adverse events (other than bleeding) was

reported.

6.2 Postmarketing Experience

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

bisulfate. Because these reactions are reported voluntarily from a population of an unknown size, it is

Life-threatening and other major bleeding.

Led to interruption of study medication.

Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death

or that required transfusion.

not always possible to reliably estimate their frequency or establish a causal relationship to drug

exposure.

Hemorrhages, including those with fatal outcome, have been reported in patients treated with

clopidogrel bisulfate.

Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic

thrombocytopenic purpura (TTP), acquired hemophilia A

Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome,

colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer,

diarrhea

General disorders and administration site condition: Fever.

Hepatobiliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test

Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness

Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, myalgia, arthralgia,

arthritis

Nervous system disorders: Taste disorders, headache, ageusia.

Psychiatric disorders: Confusion, hallucinations

Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory

tract bleeding, eosinophilic pneumonia

Renal and urinary disorders: Increased creatinine levels

Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria,

bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute

generalized exanthematous pustulosis (AGEP), angioedema, drug-induced hypersensitivity

syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme,

lichen planus, generalized pruritus

Vascular disorders: Vasculitis, hypotension

DRUG INTERACTIONS

7.1 CYP2C19 Inhibitors

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain

drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active

metabolite of clopidogrel and a reduction in platelet inhibition [see Warnings and Precautions (5.1)]

Omeprazole or Esomeprazole

Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole. In clinical studies,

omeprazole was shown to reduce significantly the antiplatelet activity of clopidogrel bisulfate when

given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with

esomeprazole when given concomitantly with clopidogrel bisulfate. Dexlansoprazole, lansoprazole and

pantoprazole had less effect on the antiplatelet activity of clopidogrel bisulfate than did omeprazole or

esomeprazole [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]

7.2 Opioids

As with other oral P2Y inhibitors, co-administration 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 co-administration of morphine or other

opioid agonists.

7.3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Coadministration of clopidogrel bisulfate 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 clopidogrel bisulfate with warfarin increases the risk of bleeding because of independent effects on

hemostasis.

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

7.5 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. Clopidogrel

bisulfate can increase the systemic exposure to drugs that are primarily cleared by CYP2C8, thereby

needing dose adjustment and appropriate monitoring.

Clopidogrel bisulfate increased repaglinide exposures by 3.9-fold to 5.1-fold [see Clinical

Pharmacology (12.3)]. Avoid concomitant use of repaglinide with clopidogrel bisulfate. If concomitant

use cannot be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed a total daily

dose of 4 mg. Increased frequency of glucose monitoring may be required during concomitant use.

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively

(65 and 78 times the recommended daily human dose, respectively, on a mg/m basis), revealed no

evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and

well-controlled studies in pregnant women. Because animal reproduction studies are not always

predictive of a human response, clopidogrel bisulfate should be used during pregnancy only if clearly

needed.

8.3 Nursing Mothers

Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not

known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and

because of the potential for serious adverse reactions in nursing infants from clopidogrel, a decision

should be made whether to discontinue nursing or to discontinue the drug, taking into account the

importance of the drug to the mother.

8.4 Pediatric Use

Safety and effectiveness in the pediatric 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.

8.5 Geriatric Use

Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately

50% of patients treated with clopidogrel bisulfate were 65 years of age and older, and 15% were 75

years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel bisulfate

were 60 years and older, 26% of whom were 70 years and older.

The observed risk of bleeding events with clopidogrel bisulfate plus aspirin versus placebo plus

aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials,

respectively [see Adverse Reactions (6.1)]. No dosage adjustment is necessary in elderly patients.

8.6 Renal Impairment

Experience is limited in patients with severe and moderate renal impairment [see Clinical Pharmacology

(12.2)].

8.7 Hepatic Impairment

No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology

(12.2)].

10 OVERDOSAGE

Platelet inhibition by clopidogrel bisulfate is irreversible and will last for the life of the platelet.

Overdose following clopidogrel administration may result in bleeding complications. A single oral

dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons.

Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal

hemorrhage in animals.

Based on biological plausibility, platelet transfusion may restore clotting ability.

11 DESCRIPTION

Clopidogrel bisulfate is a thienopyridine class inhibitor of P2Y 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

molecular formula of clopidogrel bisulfate is C

H ClNO SH SO 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°.

Clopidogrel tablets USP for oral administration are provided as pink, film coated, round, biconvex

tablets containing 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of

clopidogrel base.

Each tablet contains the following inactive ingredients: crospovidone, lactose anhydrous, magnesium

stearate, microcrystalline cellulose, Opadry II (pink), and povidone. Opadry II (pink) contains FD&C

Blue #2, FD&C Red #40, FD&C Yellow #6, hypromellose, polyethylene glycol, polydextrose, titanium

dioxide, and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its

active metabolite to the P2Y class of ADP receptors on platelets.

12.2 Pharmacodynamics

Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits

platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine

diphosphate (ADP) to its platelet P2Y receptor and the subsequent ADP-mediated activation of the

glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible.

Consequently, platelets exposed to clopidogrel's active metabolite are affected for the remainder of

their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also

inhibited by blocking the amplification of platelet activation by released ADP.

Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of

clopidogrel bisulfate. Repeated doses of 75 mg clopidogrel bisulfate per day inhibit ADP-induced

platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At

steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was

between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after

treatment is discontinued, generally in about 5 days.

Geriatric Patients

Elderly (≥75 years) and young healthy subjects had similar effects on platelet aggregation.

Renally Impaired Patients

After repeated doses of 75 mg clopidogrel bisulfateper day, patients with severe renal impairment

(creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30

to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.

Hepatically-Impaired Patients

After repeated doses of 75 mg clopidogrel bisulfate per day for 10 days in patients with severe hepatic

impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy

subjects.

Gender

In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was

observed in women.

12.3 Pharmacokinetics

Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive

metabolites.

Absorption

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is

at least 50%, based on urinary excretion of clopidogrel metabolites.

Effect of Food

Clopidogrel bisulfate can be administered with or without food. In a study in healthy male subjects when

clopidogrel bisulfate 75 mg per day was given with a standard breakfast, mean inhibition of ADP-

induced platelet aggregation was reduced by less than 9%. The active metabolite AUC

unchanged in the presence of food, while there was a 57% decrease in active metabolite C

. Similar

results were observed when a clopidogrel bisulfate 300 mg loading dose was administered with a high-

0–24

fat breakfast.

Metabolism

Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and

leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and

one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-

oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate

metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active

metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes,

including CYP1A2, CYP2B6 and CYP3A. The active thiol metabolite binds rapidly and irreversibly to

platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

The C

of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose

as it is after four days of 75 mg maintenance dose. C

occurs approximately 30 to 60 minutes after

dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from

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

and AUC, respectively.

Elimination

Following an oral dose of

C-labeled clopidogrel in humans, approximately 50% of total radioactivity

was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral

dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active

metabolite is about 30 minutes.

Drug Interactions

Effect of other drugs on clopidogrel bisulfate

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain

inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of

clopidogrel and a reduction in platelet inhibition.

Proton Pump Inhibitors (PPI)

The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active

metabolite following multiple doses of clopidogrel bisulfate 75 mg evaluated in dedicated drug

interaction studies is presented in Figure 1.

Figure 1: Exposure to Clopidogrel Active Metabolite Following Multiple Doses of Clopidogrel

bisulfate 75 mg Alone or with Proton Pump Inhibitors (PPIs)

Pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction

was highest with omeprazole and least with dexlansoprazole.

Opioids

Co-administration of 5 mg intravenous morphine with 600 mg loading dose of clopidogrel in healthy

adults decreased the AUC and C

of clopidogrel’s thiol metabolites by 34%. Mean platelet

aggregation was higher up to 2 to 4 hours with morphine co-administration.

Effect of Clopidogrel bisulfate on other drugs

In vitro studies have shown that the glucuronide metabolite of clopidogrel is a strong inhibitor of

CYP2C8. Concomitant administration of repaglinide with clopidogrel bisulfateincreased the systemic

exposure to repaglinide (AUC

) by 5.1-fold following the loading dose (300 mg) and by 3.9-fold on

day 3 of the maintenance dose (75 mg) of clopidogrel bisulfate [see Drug Interactions (7.6)].

12.5 Pharmacogenomics

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel

intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as

measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype.

Patients who are homozygous for nonfunctional alleles of the CYP2C19 gene are termed CYP2C19

poor metabolizers. Approximately 2% of White and 4% of Black patients are poor metabolizers; the

prevalence of poor metabolism is higher in Asian patients (e.g., 14% of Chinese). Tests are available to

identify patients who are CYP2C19 poor metabolizers.

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated

pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg

followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and

diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to

the other groups.

Table 3: Active Metabolite Pharmacokinetics and Antiplatelet Responses by CYP2C19

Metabolizer Status

Poor

Intermediate

Normal

Ultrarapid

0-∞

*

Dos e

(n=10)

(n=10)

(n=10)

(n=10)

(ng/mL)

300 mg

(24 h)

11 (4)

23 (11)

32 (21)

24 (10)

600 mg

(24 h)

17 (6)

39 (23)

44 (27)

36 (13)

75 mg

(Day 5)

4 (1)

12 (5)

13 (7)

12 (6)

150 mg

(Day 5)

7 (2)

18 (7)

19 (5)

16 (9)

IPA (%)

300 mg

(24 h)

24 (26)

37 (21)

39 (28)

40 (21)

600 mg

(24 h)

32 (25)

56 (22)

49 (23)

51 (28)

75 mg

(Day 5)

37 (23)

60 (18)

58 (19)

56 (13)

150 mg

(Day 5)

61 (14)

74 (14)

73 (9)

68 (18)

VASP-PRI

300 mg

(24 h)

91 (12)

78 (12)

68 (16)

73 (12)

600 mg

(24 h)

85 (14)

56 (26)

48 (20)

51 (20)

75 mg

(Day 5)

83 (13)

50 (16)

39 (14)

40 (9)

150 mg

(Day 5)

61 (18)

29 (11)

24 (10)

20 (10)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and

104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures >25 times that in

humans at the recommended daily dose of 75 mg.

Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes,

gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human

lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).

Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400

mg/kg per day (52 times the recommended human dose on a mg/m basis).

14 CLINICAL STUDIES

Intermediate metabolizers have one but not two nonfunctional alleles.

Ultrarapid metabolizers have at least one gain-of-function allele

Inhibition of platelet aggregation with 5mcM ADP; larger value indicates greater platelet inhibition

Vasodilator-stimulated phosphoprotein platelet reactivity index; smaller value indicates greater platelet inhibit

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 clopidogrel bisulfate (300 mg loading dose followed by 75 mg

once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75 to 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 clopidogrel bisulfate -treated group and 719 (11.4%) in the placebo-treated group, a 20% relative

risk reduction (95% CI of 10% to 28%; p<0.001) for the clopidogrel-treated group (see Table 4).

Table 4: Outcome Events in the CURE Primary Analysis

Outcome

Clopidogrel

bisulfate

(+ aspirin)

(n=6259)

Placebo

(+ aspirin)

(n=6303)

Relative Risk

Reduction (%)

(95% CI)

Primary Outcome

(Cardiovascular death,

MI, Stroke)

582 (9.3%)

719 (11.4%)

(10.3, 27.9)

p<0.001

All Individual Outcome Events:

CV death

318 (5.1%)

345 (5.5%)

(-7.7, 20.6)

324 (5.2%)

419 (6.6%)

(11.0, 33.4)

Stroke

75 (1.2%)

87 (1.4%)

(-17.7, 36.6)

Most of the benefit of clopidogrel bisulfate 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

Other standard therapies were used as appropriate.

The individual components do not represent a breakdown of the primary and co-primary

outcomes, but rather the total number of subjects experiencing an event during the course

of the study.

*

The effect of clopidogrel bisulfate did not differ significantly in various subgroups, as shown in

Figure 3. The benefits associated with clopidogrel bisulfate 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

clopidogrel bisulfate was observed independently of the dose of aspirin (75 to 325 mg once daily). The

use of oral anticoagulants, non-study 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 clopidogrel bisulfate in CURE was associated with a decrease in the use of thrombolytic

therapy (71 patients [1.1%] in the clopidogrel bisulfate group, 126 patients [2%] in the placebo group;

relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel

bisulfate group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of

clopidogrel bisulfate in CURE did not affect the number of patients treated with CABG or PCI (with or

without stenting), (2253 patients [36%] in the clopidogrel bisulfate group, 2324 patients [36.9%] in the

placebo group; relative risk reduction of 4%).

COMMIT

In patients with STEMI, the safety and efficacy of clopidogrel bisulfate 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 clopidogrel bisulfate (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 included 28% women, 58% age 60 years (26% age 70 years), 55% patients who

received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI.

As shown in Table 5 and Figure 4 and Figure 5 below, clopidogrel bisulfate 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 the COMMIT

Event

Clopidogrel

bisulfate

(+ aspirin)

(N=22961)

Placebo

(+ aspirin)

(N=22891)

Odds

ratio

(95% CI)

p-value

Composite

endpoint: Death,

MI, or Stroke

2121 (9.2%)

2310 (10.1%)

0.91

(0.86,

0.97)

0.002

Death

Non-fatal MI

Non-fatal Stroke

1726 (7.5%)

270 (1.2%)

127 (0.6%)

1845 (8.1%)

330 (1.4%)

142 (0.6%)

0.93

(0.87,

0.99)

0.81

(0.69,

0.95)

0.89 (0.7,

1.13)

0.029

0.011

0.33

Figure 4: Cumulative Event Rates for Death in the COMMIT Study

9 patients (2 clopidogrel and 7 placebo) suffered both a non-fatal stroke and a non-fatal

Non-fatal MI and non-fatal stroke exclude patients who died (of any cause).

*

Figure 5: Cumulative Event Rates for the Combined Endpoint Re-Infarction, Stroke or Death in

the COMMIT Study

The effect of clopidogrel did not differ significantly in various pre-specified 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 Clopidogrel to Aspirin on Combined Primary Endpoint Across

Baseline and Concomitant Medication Subgroups for the COMMIT Study

2

3

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

CAPRIE

The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-

group study comparing clopidogrel bisulfate (75 mg daily) to aspirin (325 mg daily). To be eligible to

enroll, patients had to have: 1) recent histories of myocardial infarction (within 35 days); 2) recent

histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3)

established peripheral arterial disease. Patients received randomized treatment for an average of 1.6

years (maximum of 3 years).

The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new

myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular

causes were all classified as vascular.

Table 6: Outcome Events in the CAPRIE Primary Analysis

Patients

Clopidogrel bisulfate 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%)

All treated patients received aspirin.

All treated patients received aspirin.

CI is 95% for Overall row only

Total

939 (9.8%)

1020 (10.6%)

As shown in Table 6, clopidogrel bisulfate was associated with a lower incidence of outcome events,

primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p=0.045. Similar results

were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality

and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial

infarction, the incidence of subsequent events was lower in the clopidogrel bisulfate group.

The curves showing the overall event rate are shown in Figure 7. The event curves separated early and

continued to diverge over the 3-year follow-up period.

Figure 7: Fatal or Non-Fatal Vascular Events in the CAPRIE Study

The statistical significance favoring clopidogrel bisulfate over aspirin was marginal (p=0.045).

However, because aspirin is itself effective in reducing cardiovascular events in patients with recent

myocardial infarction or stroke, the effect of clopidogrel bisulfate is substantial.

The CAPRIE trial enrolled a population that had recent MI, recent stroke, or PAD. The efficacy of

clopidogrel bisulfate 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 clopidogrel bisulfate 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, clopidogrel bisulfate was not numerically superior to aspirin.

Figure 8: Hazard Ratio and 95% CI by Baseline Subgroups in the CAPRIE Study

14.3 No Demonstrated Benefit of Clopidogrel bisulfate, plus Aspirin in Patients with Multiple

Risk Factors or Established Vascular Disease

CHARISMA

The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing

clopidogrel (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 to 162 mg daily.

The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the

occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%)

patients in the clopidogrel bisulfate group versus 573 (7.4%) patients in the placebo group experienced

a primary outcome event (p=0.22). Bleeding of all severities was more common in the subjects

randomized to clopidogrel bisulfate.

16 HOW SUPPLIED/STORAGE AND HANDLING

Clopidogrel Tablets USP, 75 mg are supplied as a pink, film coated, round, biconvex tablet debossed

with product identification "54 834" on one side and plain on the other.

71093-142-04

75 mg, pink, round tablet, bottle of 90

71093-142-05

75 mg, pink, round tablet, bottle of 500

Storage

Store at 25ºC (77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF). [See USP Controlled Room

Temperature].

17 PATIENT COUNSELING INFORMATION

Advise patients to read FDA approved patient labeling (Medication Guide).

Discontinuation

Advise patients not to discontinue clopidogrel bisulfate, 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 clopidogrel bisulfate 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 clopidogrel bisulfate.

Dexlansoprazole, lansoprazole and pantoprazole had less pronounced effects on the antiplatelet activity

of clopidogrel bisulfate than did omeprazole or esomeprazole [see Drug Interactions (7.1)].

Medication Guide

Clopidogrel (kloh pid’ oh grel) Tablets, USP

Read this Medication Guide before you start taking clopidogrel tablets and each time you get a refill.

There may be new information. This Medication Guide does not take the place of talking with your

doctor about your medical condition or your treatment.

What is the most important information I should know about clopidogrel tablets?

1. Clopidogrel tablets may not work as well in people who:

have certain genetic factors that affect how the body breaks down Clopidogrel tablets. Your

doctor may do genetic tests to make sure clopidogrel tablets are right for you.

take certain medicines, especially omeprazole (Prilosec

) or esomeprazole (Nexium ). Your

doctor may change the medicine you take for stomach acid problems while you take Clopidogrel

tablets.

2. Clopidogrel tablets can cause bleeding which can be serious and can sometimes lead to death.

Clopidogrel is a blood thinner medicine that lowers the chance of blood clots forming in your body.

While you take clopidogrel tablets

you may bruise and bleed more easily

you are more likely to have nose bleeds

®

®

it will take longer for any bleeding to stop

Call your doctor right away if you have any of these signs or symptoms of bleeding:

unexpected bleeding or bleeding that lasts a long time

blood in your urine (pink, red or brown urine)

red or black stools (looks like tar)

bruises that happen without a known cause or get larger

cough up blood or blood clots

vomit blood or your vomit looks like coffee grounds

Do not stop taking clopidogrel tablets without talking to the doctor who prescribes it for you. People

who stop taking clopidogrel tablets too soon have a higher risk of having a heart attack or dying. If you

must stop clopidogrel tablets because of bleeding, your risk of a heart attack may be higher.

What are clopidogrel tablets?

Clopidogrel tablets are a prescription medicine used to treat people who have any of the following:

chest pain due to heart problems

poor circulation in their legs (peripheral arterial disease)

a heart attack

a stroke

Clopidogrel tablets are used alone or with aspirin to lower your chance of having another serious

problem with your heart or blood vessels such as heart attack, stroke, or blood clot that can lead to

death.

Platelets are blood cells that help your blood clot normally. Clopidogrel helps to prevent platelets from

sticking together and forming a clot that can block an artery.

It is not known if clopidogrel tablets are safe and effective in children.

Who should not take clopidogrel?

Do not take clopidogrel tablets if you:

currently have a condition that causes bleeding, such as a stomach ulcer

are allergic to clopidogrel or other ingredients in Clopidogrel Tablets. See the end of this leaflet

for a complete list of ingredients in Clopidogrel Tablets.

What should I tell my doctor before taking clopidogrel?

Before you take clopidogrel tablets, tell your doctor if you:

have a history of bowel (gastrointestinal) or stomach ulcers

have a history of bleeding problems

plan to have surgery or a dental procedure. See “How should I take clopidogrel tablets?"

are pregnant or plan to become pregnant. It is not known if clopidogrel tablets will harm your unborn

baby

are breastfeeding or plan to breastfeed. It is not known if clopidogrel bisulfate passes into your

breast milk. You and your doctor should decide if you will take clopidogrel tablets or breastfeed.

You should not do both without talking to your doctor.

have had an allergy or reaction to any medicine used to treat your disease.

Tell all of your doctors and your dentist that you are taking clopidogrel tablets. They should talk to the

doctor who prescribed clopidogrel tablets for you before you have any surgery or invasive procedure.

Tell your doctor about all the medicines you take, including prescription, non-prescription

medicines, vitamins and herbal supplements.

Clopidogrel tablets may affect the way other medicines work, and other medicines may affect how

clopidogrel tablets work. See “What is the most important information I should know about

clopidogrel?

Taking clopidogrel tablets with certain other medicines may increase your risk of bleeding. Especially

tell your doctor if you take:

aspirin, especially if you have had a stroke. Always talk to your doctor about whether you should

take aspirin along with clopidogrel tablets to treat your condition.

Non-steroidal anti-inflammatory drugs (NSAIDs). Ask your doctor or pharmacist for a list of

NSAID medicines if you are not sure.

warfarin (Coumadin , Jantoven )

selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors

(SNRIs). Ask your doctor or pharmacist for a list of SSRI or SNRI medicines if you are not sure.

Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a

new medicine.

How should I take clopidogrel tablets?

Take clopidogrel tablets exactly as your doctor tells you.

Do not change your dose or stop taking clopidogrel tablets without talking to your doctor first.

Stopping clopidogrel tablets may increase your risk of heart attack or stroke.

Take clopidogrel tablets with aspirin as instructed by your doctor.

You can take clopidogrel tablets with or without food.

If you miss a dose, take clopidogrel tablets as soon as you remember. If it is almost time for your

next dose, skip the missed dose. Take the next dose at your regular time. Do not take 2 doses of

clopidogrel at the same time unless your doctor tells you to.

If you take too much clopidogrel tablets, call your doctor or go to the nearest emergency room right

away.

Talk with your doctor about stopping your clopidogrel tablets before you have surgery. Your

doctor may tell you to stop taking clopidogrel tablets at least 5 days before you have surgery to

avoid excessive bleeding during surgery.

What are the possible side effects of clopidogrel tablets?

Clopidogrel can cause serious side effects including:

See “What is the most important information I should know about clopidogrel tablets?"

A blood clotting problem called Thrombotic Thrombocytopenic Purpura (TTP). TTP can

happen with clopidogrel tablets, sometimes after a short time (less than 2 weeks). TTP is a blood

clotting problem where blood clots form in blood vessels; and can happen anywhere in the body.

TTP needs to be treated in a hospital right away, because it may cause death. Get medical help right

away if you have any of these symptoms and they can not be explained by another medical condition:

purplish spots (called purpura) on the skin or in the mouth (mucous membranes) due to bleeding

under the skin

your skin or the whites of your eyes are yellow (jaundice)

you feel tired or weak

your skin looks very pale

fever

fast heart rate or feeling short of breath

headache

speech changes

confusion

coma

stroke

seizure

low amount of urine, or urine that is pink or has blood in it

stomach area (abdominal) pain

nausea, vomiting, or diarrhea

vision changes

Tell your doctor if you have any side effect that bothers you or that does not go away. Tell your doctor

if you develop an allergic reaction while taking clopidogrel tablets

These are not all the possible side effects of clopidogrel tablets. For more information, ask your

doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-

FDA-1088.

How should I store clopidogrel tablets?

Store clopidogrel tablets at 59°F to 86°F (15°C to 30°C).

Keep clopidogrel and all medicines out of the reach of children.

General information about clopidogrel tablets

Medicines are sometimes used for purposes other than those listed in a Medication Guide. Do not take

clopidogrel for a condition for which it was not prescribed. Do not give clopidogrel tablets to other

people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about clopidogrel tablets. If you

would like more information, talk to your doctor. Ask your doctor or pharmacist for information about

clopidogrel tablets that was written for healthcare professionals.

For more information, go to www.acihealthcareusa.com or call 1-888-802-1213

What are the ingredients in clopidogrel tablets?

Active ingredient: clopidogrel bisulfate

Inactive ingredients: crospovidone, lactose anhydrous, magnesium stearate, microcrystalline

cellulose, Opadry II (pink), and povidone. Opadry II (pink) contains FD&C Blue #2, FD&C Red #40,

FD&C Yellow #6, hypromellose, polyethylene glycol, polydextrose, titanium dioxide, and triacetin.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

Elysium Pharmaceuticals Limited

Plot No. 1175

P.O. Dabhasa, Vadodara, Gujarat 391440, India (IND)

Distributed by:

ACI Healthcare USA, Inc.

10100 W. Sample Road,

Suite 406 Coral Springs, FL 33065

Rev.: 07/2018

Coumadin is a registered trademark of Bristol-Myers Squibb Pharma Company.

Prilosec

and Nexium are registered trademarks of AstraZeneca.

Jantoven is a registered trademark of USL Pharma.

CLOPIDOGREL BISULFATE

clopidogrel bisulfate tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:710 9 3-142

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

CLO PIDO GREL BISULFATE (UNII: 0 8 I79 HTP27) (CLOPIDOGREL - UNII:A7458 6 SNO7)

CLOPIDOGREL

75 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CRO SPO VIDO NE (UNII: 2S78 30 E56 1)

ACI Healthcare USA, Inc.

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

PO VIDO NE (UNII: FZ9 8 9 GH9 4E)

FD&C BLUE NO . 2 (UNII: L0 6 K8 R7DQK)

FD&C RED NO . 4 0 (UNII: WZB9 127XOA)

FD&C YELLO W NO . 6 (UNII: H77VEI9 3A8 )

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

PO LYETHYLENE GLYCO L (UNII: 3WJQ0 SDW1A)

PO LYDEXTRO SE (UNII: VH2XOU12IE)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIACETIN (UNII: XHX3C3X6 73)

Product Characteristics

Color

pink

S core

no sco re

S hap e

ROUND (bico nvex)

S iz e

9 mm

Flavor

Imprint Code

54;8 34

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:710 9 3-142-0 4

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /27/20 18

2

NDC:710 9 3-142-0 5

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 6 /27/20 18

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 0 0 4

0 5/17/20 17

Labeler -

ACI Healthcare USA, Inc. (080430318)

Registrant -

T he ACME Laboratories Ltd. (731655606)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Elysium Pharmaceuticals Limited

9 156 6 448 6

ma nufa c ture (710 9 3-142)

Revised: 12/2019

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