CLOPIDOGREL- clopidogrel bisulfate tablet, film coated
For Healthcare Providers >

1. Clopidogrel Bisulfate Tablets Are A Prescription Medicine Used To Treat People Who Have Any Of The Following:
2. Before You Take Clopidogrel Tablets, Tell Your Doctor If You:
3. How Should I Take Clopidogrel Tablets?
4. Active Ingredient:
5. Inactive Ingredients:
6. Distributed By:
7. What Is The Most Important Information I Should Know About Clopidogrel Tablets?
8. May Not Work As Well In People Who:
9. Taking Clopidogrel Tablets With Certain Other Medicines May Increase Your Risk Of Bleeding.especially Tell Your Doctor If You Take:
10. What Are The Possible Side Effects Of Clopidogrel Tablets?
11. Can Cause Serious Side Effects Including:
12. How Should I Store Clopidogrel Tablets?
13. Active Ingredient:
14. Inactive Ingredients:
15. Marketed/packaged By:
16. Patient Information
17. Advise Patients That They:
18. 1. Clopidogrel Tablets May Not Work As Well In People Who:
19. Call Your Doctor Right Away If You Have Any Of These Signs Or Symptoms Of Bleeding:
20. Clopidogrel Tablets Are A Prescription Medicine Used To Treat People Who Have Any Of The Following:
21. Do Not Take Clopidogrel Tablets If You:
22. Clopidogrel Tablets Can Cause Serious Side Effects Including:
23. What Are The Ingredients In Clopidogrel Tablets, Usp?
24. Manufactured For:

Clopidogrel Bisulfate 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 is 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.

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. "

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

are breastfeeding or plan to breastfeed. It is not known if clopidogrel passes into your breast milk. A decision should be made with your healthcare provider to avoid or discontinue breastfeeding when continuing clopidogrel is needed.

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. "

Clopidogrel may increase blood levels of other medicines such as repaglinide (Prandin).

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 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.

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

If you take too much clopidogrel, 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.

Active Ingredient: ⮝

clopidogrel bisulfate

Inactive Ingredients: ⮝

Tablet: anhydrous lactose, colloidal silicon dioxide, crospovidone, methylcellulose and zinc stearate

Film coating: ferric oxide red, hydroxypropyl cellulose, hypromellose, polyethylene glycol and titanium dioxide.

All registered trademarks in this document are the property of their respective owners.

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

APOTEX INC.

CLOPIDOGREL TABLETS, USP 75 mg and 300 mg

Manufactured by	Manufactured for
Apotex Inc.	Apotex Corp.
Toronto, Ontario	Weston, Florida
Canada M9L 1T9	33326

Distributed By: ⮝

MAJOR PHARMACEUTICALS

17177 N Laurel Park Dr., Suite 233

Livonia, MI 48152

Revised: June 2019

Rev. 26

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

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.

What Are The Possible Side Effects Of Clopidogrel Tablets? ⮝

Clopidogrel tablets

Can Cause Serious Side Effects Including: ⮝

• 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 including skin reactions 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 20 to 25 C (68 to 77 F); excursions permitted to 15 to 30 C (59 to 86 F).

Keep clopidogrel tabletsand 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 tablets 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, call 1-866-850-2876.

Active Ingredient: ⮝

clopidogrel bisulfate

Inactive Ingredients: ⮝

Tablet: anhydrous lactose, colloidal silicon dioxide, crospovidone, methylcellulose and zinc stearate

Film coating: hydroxypropyl cellulose, hypromellose, polyethylene glycol, red ferric oxide and titanium dioxide.

All registered trademarks in this document are the property of their respective owners.

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

APOTEX INC.

CLOPIDOGREL TABLETS, USP 75 mg and 300 mg

Manufactured by	Manufactured for
Apotex Inc.	Apotex Corp.
Toronto, Ontario	Weston, Florida
Canada M9L 1T9	33326

Revised: November 2017

Rev. 23

Coumadinis a registered trademark of Bristol-Myers Squibb Pharma Company.
Prilosecis a registered trademark of AstraZeneca.
Prandinis a registered trademark of Novo Nordisk Inc.
Jantovenis a registered trademark of USL Pharma.

Marketed/packaged By: ⮝

GSMS, Inc.

Camarillo, CA 93012

Patient 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[seeWarnings 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[seeWarnings 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[seeWarnings 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[seeWarnings 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[seeDrug Interactions (7.1)].

Dispense with Medication Guide available at:www.aurobindousa.com/product-medication-guides

1. Clopidogrel Tablets May Not Work As Well In People Who: ⮝

• have certain genetic factors that affect how the body breaks down clopidogrel.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.

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 tablets help 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.

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.

Clopidogrel Tablets Can Cause Serious Side Effects Including: ⮝

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

  Keep clopidogrel tablets 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 tablets 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, contact AvKARE, Inc. at 1-855-361-3993.

What Are The Ingredients In Clopidogrel Tablets, Usp? ⮝

Active ingredient: clopidogrel bisulfate, USP

Inactive ingredients:

Tablet: microcrystalline cellulose, mannitol, croscarmellose sodium, hydroxy propyl cellulose, hydroxy propyl methyl cellulose and hydrogenated castor oil.

Film coating: Hypromellose, titanium dioxide, polyethylene glycol and red iron oxide.

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

The brands listed are trademarks of their respective owners and are not trademarks of AvKARE, Inc. The makers of these brands are not affiliated with and do not endorse AvKARE Inc., or its products.

Manufactured For: ⮝

AvKARE, Inc.

Pulaski, TN 38478

Mfg. Rev. 11/18

AV 10/19 (P)

AvPAK

1. No Title 1572551540
2. Highlights Of Prescribing Information
3. See Full Prescribing Information For Complete Boxed Warning.
4. Indications And Usage
5. Dosage And Administration
6. Dosage Forms And Strengths
7. Contraindications
8. Warnings And Precautions
9. Adverse Reactions
10. Drug Interactions
11. Warning: Diminished Antiplatelet Effect In Patients With Two Loss-of-function Alleles Of The Cyp2c19 Gene
12. 1 Indications And Usage
13. 2 Dosage And Administration
14. 3 Dosage Forms And Strengths
15. 4 Contraindications
16. 5 Warnings And Precautions
17. 6 Adverse Reactions
18. 7 Drug Interactions
19. 8 Use In Specific Populations
20. 10 Overdosage
21. 11 Description
22. 12 Clinical Pharmacology
23. 13 Nonclinical Toxicology
24. 14 Clinical Studies
25. 16 How Supplied/storage And Handling
26. Package/label Display Panel
27. Principal Display Panel
28. Principal Display Panel
29. Use In Specific Populations
30. Warning: Diminished Effectiveness In Poor Metabolizers
31. Clopidogrel Tablets, Usp 75mg
32. Recent Major Changes
33. 14 Clinical Studies
34. 16 How Supplied/storage And Handling
35. Package Label-principal Display Panel - 75 Mg (30 Tablet Blister Card)
36. Warning: Diminished Effectiveness In Poor Metabolizerssee Full Prescribing Information For Complete Boxed Warning.
37. Package Label-principal Display Panel - 75 Mg (30 Tablets Bottle)
38. Warning: Diminished Antiplatelet Effect In Patients With Two Loss-of-function Alleles Of The Cyp2c19 Genesee Full Prescribing Information For Complete Boxed Warning.
39. Storage
40. Clopidogrel Bisulfate
41. No Title 1572454824
42. Clopidogrel Tablets, Usp 75 Mg
43. Package Label-principal Display Panel - 75 Mg (90 Tablet Bottle)
44. Package Label-principal Display Panel - 75 Mg Blister Carton (10 X 10 Unit-dose)
45. See Full Prescribing Information For Complete Boxed Warning.
46. 3 Dosage Forms And Strengths
47. 12 Clinical Pharmacology
48. Principal Display Panel - 300 Mg Tablet Bottle Label
49. Packaging Information
50. Package/label Display Panel Carton 75 Mg
51. Package/label Display Panel Blister 75 Mg
52. Package/label Display Panel Carton 300 Mg
53. Package/label Display Panel Blister 300 Mg
54. 340b Clopidogrel 75mg Tablet
55. Clopidogrel 75mg Tablet

No Title 1572551540 ⮝

CLOPIDOGREL TABLETS, USP
75 mg

Manufactured by Apotex, Inc.
Toronto, Ontario
Canada M9L 1T9

Distributed by Cambridge Therapeutic Technologies, LLC
Teaneck, NJ 07666

Packaged by Legacy Pharmaceutical Packaging, LLC
Earth City, MO 63045

Revised: December 2016
20551

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 tablets, for oral use
Initial U.S. Approval: 1997

See Full Prescribing Information For Complete Boxed Warning.  ⮝

• Effectiveness of clopidogrel bisulfate depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1)
• Poor metabolizers treated with clopidogrel bisulfate at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. (12.5)
• Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. (12.5)
• Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. (2.3, 5.1)

Indications And Usage ⮝

Clopidogrel tablets are 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]), clopidogrel tablets have been shown to reduce the rate of myocardial infarction (MI) and stroke. (1.1)

- For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets have been shown to reduce the rate of MI and stroke. (1.1)

• Recent MI, recent stroke, or established peripheral arterial disease. Clopidogrel tablets have been shown to reduce the rate of 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)

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)

Adverse Reactions ⮝

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

To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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)

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.

1 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 tablets are 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 tablets 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.

2 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)].

3 Dosage Forms And Strengths ⮝

75 mg tablets: Pink colored, round, biconvex, beveled edge, film-coated tablets debossed with E on one side and 34 on the other side.

4 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)].

5 Warnings And Precautions ⮝

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 bisulfate 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 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 Clopidogrel Bisulfate

Discontinuation of clopidogrel bisulfate 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)].

6 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 Trials 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 bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for one year or more. The clinically important adverse reactions observed in trials comparing clopidogrel bisulfate plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone 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)
* Life-threatening and other major bleeding. Led to interruption of study medication.
Major bleeding*	3.7	2.7
Life-threatening bleeding	2.2	1.8
Fatal	0.2	0.2
5 g/dL hemoglobin drop	0.9	0.9
Requiring surgical intervention	0.7	0.7
Hemorrhagic strokes	0.1	0.1
Requiring inotropes	0.5	0.5
Requiring transfusion ( 4 units)	1.2	1
Other major bleeding	1.6	1
Significantly disabling	0.4	0.3
Intraocular bleeding with significant loss of vision	0.05	0.03
Requiring 2 to 3 units of blood	1.3	0.9
Minor bleeding	5.1	2.4

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 bleeds were cerebral bleeds or noncerebral bleeds thought to have caused death or that required transfusion.
Major* noncerebral or cerebral bleeding	0.6	0.5	0.59
Major noncerebral	0.4	0.3	0.48
Fatal	0.2	0.2	0.9
Hemorrhagic stroke	0.2	0.2	0.91
Fatal	0.2	0.2	0.81
Other noncerebral bleeding (nonmajor)	3.6	3.1	0.005
Any noncerebral bleeding	3.9	3.4	0.004

CAPRIE (Clopidogrel Bisulfate vs. Aspirin)

In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2% in those taking clopidogrel bisulfate versus 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 bisulfate group were epistaxis and hematoma.

Other Adverse Events

In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo.

In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. 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 postapproval use of clopidogrel bisulfate. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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: 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 (noninfectious), abnormal liver function test
• Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness
• Musculoskeletal, connective tissue and bone disorders: Myalgia, arthralgia, arthritis
• Nervous system disorders: Taste disorders, headache, ageusia
• Psychiatric disorders: Confusion, hallucinations
• Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, 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

7 Drug Interactions ⮝

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 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 P2Y12 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- -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.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Teratogenic Effects

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/m2 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 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 P2Y12 ADP platelet receptors. Chemically it is methyl (+)-(S)- -(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate sulfate (1:1). The molecular formula of clopidogrel bisulfate is C16H16ClNO2S H2SO4 and its molecular weight is 419.9.

The structural formula is as follows:

Clopidogrel bisulfate USP 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 colored, round, biconvex, beveled edge, debossed, film-coated tablets containing 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of clopidogrel base.

Each film-coated tablet contains crospovidone, hydrogenated castor oil, hydroxypropyl cellulose low substituted, hypromellose 15cP, iron oxide red, lactose monohydrate, mannitol, microcrystalline cellulose, polyethylene glycol 6000, titanium dioxide, and triacetin as inactive ingredients.

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 P2Y12 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 P2Y12 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 bisulfate 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 bisulfate per 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 AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a clopidogrel bisulfate 300 mg loading dose was administered with a high-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 Cmax 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. Cmax 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: 4-fold the dose results in 2-fold and 2.7-fold the Cmax and AUC, respectively.

Elimination

Following an oral dose of 14C-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.

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 Cmax 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 bisulfate increased the systemic exposure to repaglinide (AUC0- ) 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

* Intermediate metabolizers have one but not two nonfunctional alleles. Ultrarapid metabolizers have at least one gain-of-function allele. Inhibition of platelet aggregation with 5 mcM ADP; larger value indicates greater platelet inhibition. Vasodilator-stimulated phosphoprotein platelet reactivity index; smaller value indicates greater platelet inhibition. Values are mean (SD).
	Dose	Poor (n=10)	Intermediate* (n=10)	Normal (n=10)	Ultrarapid (n=10)
Cmax (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/m2 basis).

14 Clinical Studies ⮝

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. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients 65 years of age.

Patients were randomized to receive clopidogrel (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 number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the clopidogrel-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 (+ aspirin)* (n=6259)	Placebo (+ aspirin)* (n=6303)	Relative Risk Reduction (%) (95% CI)
* 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.
Primary outcome (Cardiovascular death, MI, stroke)	582 (9.3%)	719 (11.4%)	20% (10.3, 27.9) p < 0.001
All Individual Outcome Events:
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 clopidogrel 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).

In CURE, the use of clopidogrel was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with clopidogrel 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 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.

The use of clopidogrel in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2,253 patients [36.0%] in the clopidogrel group, 2,324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).

COMMIT

In patients with STEMI, the safety and efficacy of clopidogrel 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 (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 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 Analysis

Event	Clopidogrel (+ 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 (0.70, 1.13)	0.029 0.011 0.33

* The difference between the composite endpoint and the sum of death+non-fatal MI+non-fatal stroke indicates that 9 patients (2 clopidogrel and 7 placebo) suffered both a non-fatal stroke and a non-fatal MI.

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

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 (see Figure 7). Such subgroup analyses should be interpreted cautiously.

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 (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 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

	Clopidogrel	Aspirin
Patients	n=9599	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, clopidogrel 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 group.

The curves showing the overall event rate are shown in Figure 8. The event curves separated early and continued to diverge over the 3-year follow-up period.

The statistical significance favoring clopidogrel 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 is substantial.

The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of clopidogrel relative to aspirin was heterogeneous across these randomized subgroups (p=0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was not numerically superior to aspirin.

14.3 Lack of Established Benefit of Clopidogrel 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 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.

16 How Supplied/storage And Handling ⮝

Clopidogrel tablets, USP 75 mg are pink, round, biconvex, film coated tablets, engraved "APO" on one side and "CL" over "75" on the other side. They are supplied as follows:

Blistercards of 30 NDC 0615-8014-39

Blistercards of 15 NDC 0615-8014-05

Unit-Dose Boxes of 30 NDC 0615-8014-30

Clopidogrel tablets USP, 300 mg are pink, oblong, biconvex, film-coated tablets, engraved "APO" on one side and "CL 300" on the other side.

Store at 25 C(77 F); excursions permitted from 15 to 30 C (59 to 86 F) [See USP Controlled Room Temperature]. Protect from moisture.

Package/label Display Panel  ⮝

Clopidogrel Tablets, USP

300 mg

30 Tablets

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0904-6467(NDC:60505-3532) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 300 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) METHYLCELLULOSE (15 MPA.S) (UNII: NPU9M2E6L8) ZINC STEARATE (UNII: H92E6QA4FV) FERRIC OXIDE RED (UNII: 1K09F3G675) HYDROXYPROPYL CELLULOSE (70000 WAMW) (UNII: 66O7AQV0RT) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color PINK Score no score Shape CAPSULE (oblong) Size 9mm Flavor Imprint Code APO;CL300 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0904-6467-07 30 in 1 CARTON 04/06/2015 1 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076274 04/06/2015

Labeler - Major Pharmaceuticals (191427277)

Revised: 10/2019 Document Id: 4ce54a41-ffb4-456b-a66c-2cf86b07a8a1 34391-3 Set id: 4cd07a3c-9673-4aa0-b76a-d79df2399ee1 Version: 4 Effective Time: 20191021 Major Pharmaceuticals

Principal Display Panel  ⮝

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

APOTEX CORP. NDC 60505-0253-1

Clopidogrel Tablets, USP

75 mg

Rx

30 count

Principal Display Panel ⮝

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

GSMS, Inc. NDC 51407-032-30

Clopidogrel Tablets, USP

75 mg

Rx

30 count

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:51407-032(NDC:60505-0253) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 75 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSPOVIDONE (UNII: 68401960MK) METHYLCELLULOSE (15 CPS) (UNII: NPU9M2E6L8) ZINC STEARATE (UNII: H92E6QA4FV) FERRIC OXIDE RED (UNII: 1K09F3G675) HYPROMELLOSES (UNII: 3NXW29V3WO) POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color pink Score no score Shape ROUND Size 9mm Flavor Imprint Code APO;CL;75 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:51407-032-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 01/01/2018 2 NDC:51407-032-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 01/01/2018 3 NDC:51407-032-10 1000 in 1 BOTTLE; Type 0: Not a Combination Product 01/01/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076274 01/01/2018

Labeler - Golden State Medical Supply Inc. (603184490)

Registrant - Golden State Medical Supply Inc. (603184490)

Establishment
Name	Address	ID/FEI	Business Operations
Golden State Medical Supply Inc.		603184490	relabel(51407-032) , repack(51407-032)

Revised: 10/2018 Document Id: 78893108-970f-d632-e053-2991aa0a5e13 34391-3 Set id: 84bb2c2c-4c41-4aa4-a52b-3d6eed794ada Version: 2 Effective Time: 20181018 Golden State Medical Supply Inc.

Use In Specific Populations ⮝

Nursing mothers: Discontinue drug or nursing. (8.3)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 6/2018

Warning: Diminished Effectiveness In Poor Metabolizers ⮝

The effectiveness of clopidogrel bisulfate is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1)]. Clopidogrel bisulfate at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel bisulfate at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy [see Clinical Pharmacology (12.5)]. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers [see Dosage and Administration (2.3)].

Clopidogrel Tablets, Usp 75mg ⮝

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0615-8014(NDC:60505-0253) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 75 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSPOVIDONE (UNII: 68401960MK) METHYLCELLULOSE (15 CPS) (UNII: NPU9M2E6L8) ZINC STEARATE (UNII: H92E6QA4FV) FERRIC OXIDE RED (UNII: 1K09F3G675) HYDROXYPROPYL CELLULOSE (TYPE H) (UNII: RFW2ET671P) HYPROMELLOSES (UNII: 3NXW29V3WO) POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color PINK Score no score Shape ROUND Size 9mm Flavor Imprint Code APO;CL;75 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0615-8014-30 6 in 1 BOX, UNIT-DOSE 05/17/2012 1 5 in 1 BLISTER PACK; Type 0: Not a Combination Product 2 NDC:0615-8014-05 15 in 1 BLISTER PACK; Type 0: Not a Combination Product 05/17/2012 3 NDC:0615-8014-39 30 in 1 BLISTER PACK; Type 0: Not a Combination Product 05/17/2012

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076274 05/17/2012

Labeler - NCS HealthCare of KY, Inc dba Vangard Labs (050052943)

Establishment
Name	Address	ID/FEI	Business Operations
NCS HealthCare of KY, Inc dba Vangard Labs		050052943	RELABEL(0615-8014) , REPACK(0615-8014)

Revised: 5/2016 Document Id: 05145126-ca1e-409b-b854-7c40b8802f52 34391-3 Set id: d14849e1-58f8-44de-9a9d-a1bb23d1f294 Version: 3 Effective Time: 20160524 NCS HealthCare of KY, Inc dba Vangard Labs

Recent Major Changes ⮝

Warnings and Precautions (5.6) 09/2013

14 Clinical Studies ⮝

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 bisulfate-treated group (see Table 4).

Table 4: Outcome Events in the CURE Primary Analysis

* Other standard therapies were used as appropriate. 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.
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%)	20% (10.3, 27.9) p < 0.001
All Individual Outcome Events:
CV death	318 (5.1%)	345 (5.5%)	7% (-7.7, 20.6)
MI	324 (5.2%)	419 (6.6%)	23% (11, 33.4)
Stroke	75 (1.2%)	87 (1.4%)	14% (-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

The effect of clopidogrel 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, 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 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 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, 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 COMMIT

* 9 patients (2 clopidogrel and 7 placebo) suffered both a nonfatal stroke and a nonfatal MI. Nonfatal MI and nonfatal stroke exclude patients who died (of any cause).
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 Nonfatal MI Nonfatal 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*

*All 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 clopidogrel bisulfate 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 Clopidogrel Bisulfate to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study

* CI is 95% for Overall row only

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 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	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%)
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 Nonfatal 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 bisulfate (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 ⮝

Product: 50090-2082

NDC: 50090-2082-0 30 TABLET, FILM COATED in a BOTTLE

NDC: 50090-2082-1 90 TABLET, FILM COATED in a BOTTLE

Package Label-principal Display Panel - 75 Mg (30 Tablet Blister Card) ⮝

Clopidogrel Tablets, USP
75 mg
Rx only

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:58118-0357(NDC:65862-357) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 75 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) HYDROGENATED CASTOR OIL (UNII: ZF94AP8MEY) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 2165RE0K14) HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W) FERRIC OXIDE RED (UNII: 1K09F3G675) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MANNITOL (UNII: 3OWL53L36A) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIACETIN (UNII: XHX3C3X673)

Product Characteristics Color pink Score no score Shape ROUND (Biconvex) Size 9mm Flavor Imprint Code E;34 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:58118-0357-3 30 in 1 BOTTLE; Type 0: Not a Combination Product 05/17/2012 12/09/2016 2 NDC:58118-0357-6 60 in 1 BOTTLE; Type 0: Not a Combination Product 05/17/2012 12/09/2016 3 NDC:58118-0357-9 90 in 1 BOTTLE; Type 0: Not a Combination Product 05/17/2012 12/09/2016 4 NDC:58118-0357-8 30 in 1 BLISTER PACK; Type 0: Not a Combination Product 05/17/2012

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090540 05/17/2012

Labeler - Clinical Solutions Wholesale (078710347)

Registrant - Clinical Solutions Wholesale (078710347)

Establishment
Name	Address	ID/FEI	Business Operations
Clinical Solutions Wholesale		078710347	repack(58118-0357) , relabel(58118-0357)

Revised: 7/2019 Document Id: 8d6be5e2-f107-0be6-e053-2a95a90ab8b9 34391-3 Set id: 7c96b52e-99c9-4b70-b467-3d00bbc58acf Version: 7 Effective Time: 20190711 Clinical Solutions Wholesale

Warning: Diminished Effectiveness In Poor Metabolizerssee Full Prescribing Information For Complete Boxed Warning.  ⮝

• Effectiveness of clopidogrel bisulfate depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1)
• Poor metabolizers treated with clopidogrel bisulfate at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. (12.5)
• Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. (12.5)
• Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. (2.3, 5.1)

Package Label-principal Display Panel - 75 Mg (30 Tablets Bottle) ⮝

30 Tablets NDC 57237-189-30
Clopidogrel Tablets, USP
75 mg
PHARMACIST: Dispense the Medication Guide
provided separately to each patient.
Rx only Citron Pharma

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:57237-189 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 75 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (UNII: 68401960MK) HYDROGENATED CASTOR OIL (UNII: ZF94AP8MEY) HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED (UNII: 2165RE0K14) HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W) FERRIC OXIDE RED (UNII: 1K09F3G675) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MANNITOL (UNII: 3OWL53L36A) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIACETIN (UNII: XHX3C3X673)

Product Characteristics Color PINK Score no score Shape ROUND (Biconvex) Size 9mm Flavor Imprint Code E;34 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:57237-189-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 2 NDC:57237-189-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 3 NDC:57237-189-05 500 in 1 BOTTLE; Type 0: Not a Combination Product 4 NDC:57237-189-99 1000 in 1 BOTTLE; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090540 05/17/2012

Labeler - Citron Pharma LLC (078731527)

Revised: 2/2016 Document Id: 954a65d1-79ed-4705-be2d-4d7e6f13f538 34391-3 Set id: 954a65d1-79ed-4705-be2d-4d7e6f13f538 Version: 1 Effective Time: 20160206 Citron Pharma LLC

Warning: Diminished Antiplatelet Effect In Patients With Two Loss-of-function Alleles Of The Cyp2c19 Genesee Full Prescribing Information For Complete Boxed Warning.  ⮝

• Effectiveness of clopidogrel bisulfate 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)

Storage ⮝

Store at 20 to 25 C (68 to 77 F); excursions permitted to 15 to 30 C (59 to 86 F) [see USP Controlled Room Temperature]. Protect from moisture. Preserve in well-closed containers.

Clopidogrel Bisulfate ⮝

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-2082(NDC:65862-357) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 75 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) HYDROGENATED CASTOR OIL (UNII: ZF94AP8MEY) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 2165RE0K14) HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W) FERRIC OXIDE RED (UNII: 1K09F3G675) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MANNITOL (UNII: 3OWL53L36A) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIACETIN (UNII: XHX3C3X673)

Product Characteristics Color PINK Score no score Shape ROUND (Biconvex) Size 9mm Flavor Imprint Code E;34 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-2082-0 30 in 1 BOTTLE; Type 0: Not a Combination Product 10/08/2015 2 NDC:50090-2082-1 90 in 1 BOTTLE; Type 0: Not a Combination Product 10/08/2015

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090540 05/17/2012

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-2082) , REPACK(50090-2082)

Revised: 6/2018 Document Id: 613b47db-2a95-4ba8-9a0f-d886f9335aba 34391-3 Set id: e19174f4-ec3c-4cd6-ad7d-d1e882f9d7b4 Version: 6 Effective Time: 20180627 A-S Medication Solutions

No Title 1572454824 ⮝

CLOPIDOGREL TABLETS, USP
75 mg

Manufactured by Apotex, Inc.
Toronto, Ontario
Canada M9L 1T9

Distributed by Cambridge Therapeutic Technologies, LLC
Teaneck, NJ 07666

Packaged by Legacy Pharmaceutical Packaging, LLC
Earth City, MO 63045

Revised: December 2016
20551

Clopidogrel Tablets, Usp 75 Mg ⮝

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:70882-116(NDC:60505-0253) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 75 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSPOVIDONE (UNII: 2S7830E561) METHYLCELLULOSE (15 CPS) (UNII: NPU9M2E6L8) ZINC STEARATE (UNII: H92E6QA4FV) FERRIC OXIDE RED (UNII: 1K09F3G675) HYDROXYPROPYL CELLULOSE (TYPE H) (UNII: RFW2ET671P) HYPROMELLOSES (UNII: 3NXW29V3WO) POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color PINK Score no score Shape ROUND Size 9mm Flavor Imprint Code APO;CL;75 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:70882-116-30 30 in 1 BLISTER PACK; Type 0: Not a Combination Product 05/17/2012

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076274 05/17/2012

Labeler - Cambridge Therapeutics Technologies, LLC (080072003)

Revised: 3/2017 Document Id: 782ff485-7564-4446-8a45-4b121c59287c 34391-3 Set id: 944cfe97-75f3-4194-8a9b-b2a004bf4708 Version: 1 Effective Time: 20170309 Cambridge Therapeutics Technologies, LLC

Package Label-principal Display Panel - 75 Mg (90 Tablet Bottle) ⮝

NDC 33261-0987-90
Clopidogrel Tablets, USP
75 mg
PHARMACIST: Dispense the Medication Guide
provided separately to each patient.
Rx only 90 Tablets

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:33261-987(NDC:65862-357) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 75 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (UNII: 68401960MK) HYDROGENATED CASTOR OIL (UNII: ZF94AP8MEY) HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED (UNII: 2165RE0K14) HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W) FERRIC OXIDE RED (UNII: 1K09F3G675) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MANNITOL (UNII: 3OWL53L36A) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIACETIN (UNII: XHX3C3X673)

Product Characteristics Color PINK Score no score Shape ROUND (Biconvex) Size 9mm Flavor Imprint Code E;34 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:33261-987-90 90 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090540 05/17/2012

Labeler - Aidarex Pharmaceuticals LLC (801503249)

Revised: 12/2013 Document Id: 0ea55b0e-a44e-4b1f-be1b-314d92b7ccc2 34391-3 Set id: 354db20d-93d8-4ee0-acd5-981ebeeb8c04 Version: 1 Effective Time: 20131218 Aidarex Pharmaceuticals LLC

Package Label-principal Display Panel - 75 Mg Blister Carton (10 X 10 Unit-dose) ⮝

NDC 65862-357-10
Rx only
Clopidogrel Tablets, USP
75 mg
PHARMACIST: Dispense the Medication Guide provided
separately to each patient.
AUROBINDO 100 (10 x 10) Unit-dose Tablets

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:65862-357 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 75 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (120 .MU.M) (UNII: 68401960MK) HYDROGENATED CASTOR OIL (UNII: ZF94AP8MEY) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 2165RE0K14) HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W) FERRIC OXIDE RED (UNII: 1K09F3G675) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MANNITOL (UNII: 3OWL53L36A) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIACETIN (UNII: XHX3C3X673)

Product Characteristics Color PINK Score no score Shape ROUND (Biconvex) Size 9mm Flavor Imprint Code E;34 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:65862-357-30 30 in 1 BOTTLE; Type 0: Not a Combination Product 05/17/2012 2 NDC:65862-357-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 05/17/2012 3 NDC:65862-357-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 05/17/2012 4 NDC:65862-357-05 500 in 1 BOTTLE; Type 0: Not a Combination Product 05/17/2012 5 NDC:65862-357-99 1000 in 1 BOTTLE; Type 0: Not a Combination Product 05/17/2012 6 NDC:65862-357-10 10 in 1 CARTON 05/17/2012 6 10 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090540 05/17/2012

Labeler - Aurobindo Pharma Limited (650082092)

Establishment
Name	Address	ID/FEI	Business Operations
Aurobindo Pharma Limited		918917642	ANALYSIS(65862-357) , MANUFACTURE(65862-357)

Revised: 9/2019 Document Id: 42a01b65-562c-4994-8f1b-a847087291e0 34391-3 Set id: 0078fb3d-3595-4ae1-a059-1d5e81c879cf Version: 12 Effective Time: 20190910 Aurobindo Pharma Limited

See Full Prescribing Information For Complete Boxed Warning. ⮝

• Effectiveness of clopidogrel 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 P2Y 12 inhibitor in patients identified as CYP2C19 poor metabolizers. ( 5.1)

3 Dosage Forms And Strengths  ⮝

• Clopidogrel Tablets, USP 75 mg tablets: Pink colored, Round shaped, biconvex, film coated tablets de-bossed on one side with SG and 124 on other side.
• Clopidogrel Tablets, USP 300 mg tablets: Pink colored, Modified oval shaped, film coated tablets de-bossed on one side with SG and 121 on other side.

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 12 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 12 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. Repeated doses of 75 mg clopidogrel 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 per 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 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 can be administered with or without food. In a study in healthy male subjects when clopidogrel 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 0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite C max. Similar results were observed when a clopidogrel 300 mg loading dose was administered with a high-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 contribution 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 max 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 max 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: 4-fold the dose results in 2.0-fold and 2.7-fold the C max and AUC, respectively.

Elimination

Following an oral dose of 14C-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

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 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 75 mg Alone or with Proton Pump Inhibitors (PPIs)
Co-administered PPI	Effect on active metabolite AUC Mean and 90% confidence interval
Change relative to clopidogrel administered alone

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 max 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 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 increased the systemic exposure to repaglinide (AUC 0- ) 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 [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

	Dose	Poor (n=10)	Intermediate * (n=10)	Normal (n=10)	Ultrarapid (n=10)
* Intermediate metabolizers have one but not two nonfunctional alleles. Ultrarapid metabolizers have at least one gain-of-function allele. Inhibition of platelet aggregation with 5 mcM ADP; larger value indicates greater platelet inhibition. Vasodilator-stimulated phosphoprotein platelet reactivity index; smaller value indicates greater platelet inhibition. Values are mean (SD).
C max (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)

Principal Display Panel - 300 Mg Tablet Bottle Label ⮝

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50268-184(NDC:69367-194) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 300 mg

Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) HYDROGENATED CASTOR OIL (UNII: ZF94AP8MEY) HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P) MANNITOL (UNII: 3OWL53L36A) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) FERRIC OXIDE RED (UNII: 1K09F3G675)

Product Characteristics Color pink Score no score Shape OVAL Size 19mm Flavor Imprint Code SG;121 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50268-184-12 20 in 1 BOX 10/11/2019 1 NDC:50268-184-11 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA204165 10/11/2019

Labeler - AvPAK (832926666)

Revised: 10/2019 Document Id: 94a5dc19-7a59-7464-e053-2995a90a905e 34391-3 Set id: 94a5cdc4-e063-1d46-e053-2995a90a7e15 Version: 1 Effective Time: 20191011 AvPAK

Packaging Information ⮝

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Apotex Corp. as follows:
(75 mg / 100 UD) NDC 68084-536-01 packaged from NDC 60505-0253
(300 mg / 30 UD) NDC 68084-752-25 packaged from NDC 60505-3532

Distributed by:
American Health Packaging
Columbus, OH 43217

8275225/0418

Package/label Display Panel Carton 75 Mg ⮝

NDC 68084- 536-01

Clopidogrel
Tablets, USP

75 mg

100 Tablets (10 10) Rx Only

PHARMACIST: Dispense with the accompanying Medication
Guide to each patient.

Each Film-Coated Tablet Contains:
97.875 mg of clopidogrel bisulfate equivalent to 75 mg of
clopidogrel base.

Usual Dosage: See package insert for full prescribing
information.

Store at 20 to 25 C (68 to 77 F); excursions permitted
between 15 to 30 C (59 to 86 F) [see USP Controlled
Room Temperature]. Protect from moisture.

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or
broken.

The drug product contained in this package is from
NDC # 60505-0253, Apotex Corp.

Packaged and Distributed by:
American Health Packaging
Columbus, Ohio 43217

053601
0253601/1118

Package/label Display Panel Blister 75 Mg ⮝

Clopidogrel
Tablet, USP

75 mg

Package/label Display Panel Carton 300 Mg ⮝

NDC 68084- 752-25

Clopidogrel
Tablets, USP

300 mg

30 Tablets (5 6) Rx Only

PHARMACIST: Dispense with the accompanying Medication
Guide to each patient.

Each tablet contains 392 mg of clopidogrel
bisulfate equivalent to 300 mg of clopidogrel base.

Usual Dosage: See package insert for full
prescribing information.

Store at 20 to 25 C (68 to 77 F); excursions
permitted to 15 to 30 C (59 to 86 F) [see
USP Controlled Room Temperature]. Protect from
moisture.

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is
torn or broken.

The drug product contained in this package is
from NDC # 60505-3532, Apotex Corp.

Packaged and Distributed by:
American Health Packaging
Columbus, Ohio 43217

075225
0275225/0319

Package/label Display Panel Blister 300 Mg ⮝

Clopidogrel
Tablet, USP

300 mg

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68084-536(NDC:60505-0253) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 75 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) METHYLCELLULOSE (15 MPA.S) (UNII: NPU9M2E6L8) ZINC STEARATE (UNII: H92E6QA4FV) HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B) FERRIC OXIDE RED (UNII: 1K09F3G675) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color pink Score no score Shape ROUND Size 9mm Flavor Imprint Code APO;CL;75 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68084-536-01 100 in 1 BOX, UNIT-DOSE 04/18/2014 1 NDC:68084-536-11 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076274 04/18/2014

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68084-752(NDC:60505-3532) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 300 mg

Inactive Ingredients Ingredient Name Strength ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) METHYLCELLULOSE (15 MPA.S) (UNII: NPU9M2E6L8) ZINC STEARATE (UNII: H92E6QA4FV) HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P) HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO) POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B) FERRIC OXIDE RED (UNII: 1K09F3G675) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color pink Score no score Shape CAPSULE (oblong) Size 9mm Flavor Imprint Code APO;CL300 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68084-752-25 30 in 1 BOX, UNIT-DOSE 03/28/2014 1 NDC:68084-752-95 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076274 03/28/2014

Labeler - American Health Packaging (929561009)

Establishment
Name	Address	ID/FEI	Business Operations
American Health Packaging		929561009	repack(68084-536, 68084-752)

Revised: 3/2019 Document Id: 84eb7545-2166-0960-e053-2991aa0a902a 34391-3 Set id: 65ea4dc6-acb2-4609-9a4c-4866ef0ccb11 Version: 5 Effective Time: 20190325 American Health Packaging

340b Clopidogrel 75mg Tablet ⮝

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:63629-6857(NDC:65862-357) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 75 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) HYDROGENATED CASTOR OIL (UNII: ZF94AP8MEY) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 2165RE0K14) HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W) FERRIC OXIDE RED (UNII: 1K09F3G675) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MANNITOL (UNII: 3OWL53L36A) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIACETIN (UNII: XHX3C3X673)

Product Characteristics Color PINK Score no score Shape ROUND (Biconvex) Size 9mm Flavor Imprint Code E;34 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:63629-6857-1 30 in 1 BOTTLE; Type 0: Not a Combination Product 11/25/2015

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090540 05/17/2012

Labeler - Bryant Ranch Prepack (171714327)

Establishment
Name	Address	ID/FEI	Business Operations
Bryant Ranch Prepack		171714327	REPACK(63629-6857) , RELABEL(63629-6857)

Revised: 5/2017 Document Id: cf66090e-527f-4f42-9892-7f39ddadd7bf 34391-3 Set id: f334484b-a385-4aeb-8560-def0644fce2f Version: 1 Effective Time: 20170522 Bryant Ranch Prepack

Clopidogrel 75mg Tablet ⮝

CLOPIDOGREL clopidogrel bisulfate tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71335-0080(NDC:65862-357) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CLOPIDOGREL BISULFATE (UNII: 08I79HTP27) (CLOPIDOGREL - UNII:A74586SNO7) CLOPIDOGREL 75 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) HYDROGENATED CASTOR OIL (UNII: ZF94AP8MEY) LOW-SUBSTITUTED HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 2165RE0K14) HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W) FERRIC OXIDE RED (UNII: 1K09F3G675) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MANNITOL (UNII: 3OWL53L36A) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) POLYETHYLENE GLYCOL 6000 (UNII: 30IQX730WE) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIACETIN (UNII: XHX3C3X673)

Product Characteristics Color PINK Score no score Shape ROUND (Biconvex) Size 9mm Flavor Imprint Code E;34 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:71335-0080-4 20 in 1 BOTTLE; Type 0: Not a Combination Product 05/31/2012 2 NDC:71335-0080-1 90 in 1 BOTTLE; Type 0: Not a Combination Product 05/31/2012 3 NDC:71335-0080-2 30 in 1 BOTTLE; Type 0: Not a Combination Product 05/31/2012 4 NDC:71335-0080-3 60 in 1 BOTTLE; Type 0: Not a Combination Product 05/31/2012

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA090540 05/17/2012

Labeler - Bryant Ranch Prepack (171714327)

Establishment
Name	Address	ID/FEI	Business Operations
Bryant Ranch Prepack		171714327	REPACK(71335-0080) , RELABEL(71335-0080)

Revised: 12/2017 Document Id: 86aaa353-bebf-4d31-b01e-cefbc0eeb1dc 34391-3 Set id: e8f98886-4771-4be3-8b57-edfbbc1b4661 Version: 1 Effective Time: 20171228 Bryant Ranch Prepack