Drug Safety-related Labeling Changes (SrLC)

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PLAVIX (NDA-020839)

(CLOPIDOGREL BISULFATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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05/17/2019 (SUPPL-72)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of ‘insulin autoimmune syndrome, which can lead to severe hypoglycemia’ to Immune systems disorders.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What are the possible side effects of Plavix? Plavix can cause serious side effects including:

Addition of the following:

  • Persistent low blood sugar symptoms

10/11/2018 (SUPPL-69)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Available data from cases reported in published literature and postmarketing surveillance with clopidogrel use in pregnant women have not identified any drug-associated risks for major birth defects or miscarriage [see Data].There are risks to the pregnant woman and fetus associated with myocardial infarction and stroke [see Clinical Considerations]. No evidence of fetotoxicity was observed when clopidogrel was administered to pregnant rats and rabbits during organogenesis at doses corresponding to 65 and 78 times the recommended daily human dose [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Myocardial infarction and stroke are medical emergencies. Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of clopidogrel on the fetus.

Labor or delivery

Clopidogrel use during labor or delivery will increase the risk of maternal bleeding and hemorrhage. Avoid neuraxial blockade during clopidogrel use because of the risk of spinal hematoma. When possible, discontinue clopidogrel 5 to 7 days prior to labor, delivery, or neuraxial blockade.

Data Human data

The available data from published case reports over two decades of postmarketing use have not identified an association with clopidogrel use in pregnancy and major birth defects, miscarriage, or adverse fetal outcomes.

Animal data

Embryo-fetal developmental toxicology studies were performed in pregnant rats and rabbits with doses up to 500 and 300 mg/kg/day, respectively, administered during organogenesis. These doses, corresponding to 65 and 78 times the recommended daily human dose, respectively, on a mg/m2 basis, revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel.

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of clopidogrel in human milk or the effects on milk production. No adverse effects on breastfed infants have been observed with maternal clopidogrel use during lactation in a small number of postmarketing cases. Studies in rats have shown that clopidogrel and/or its metabolites are present in the milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for PLAVIX and any potential adverse effects on the breastfed infant from PLAVIX or from underlying maternal condition.

05/25/2018 (SUPPL-70)

Approved Drug Label (PDF)

7 Drug Interactions

7.2 Opioids

(Newly Added Subsection)

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. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

10/31/2017 (SUPPL-68)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Nervous system disorders: Taste disorders, headache, ageusia

07/10/2017 (SUPPL-67)

Approved Drug Label (PDF)

7 Drug Interactions

7.5 Repaglinide (CYP2C8 Substrates)

(Additions and/or revisions are underlined)

Plavix increased repaglinide exposures by 3.9- to 5.1-fold. Avoid concomitant use of repaglinide with Plavix. If concomitant use cannot be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg.

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

09/16/2016 (SUPPL-62)

Approved Drug Label (PDF)

7 Drug Interactions

CYP2C19 Inhibitors (revised)

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.

Proton Pump Inhibitors (PPI) ( Revised and changed to): Omeprazole or esomeprazole:

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

omeprazole was shown to reduce significantly the antiplatelet activity of Plavix when

given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with Plavix. Dexlansoprazole, lansoprazole

and pantoprazole had less effect on the antiplatelet activity of Plavix than did omeprazole

or esomeprazole

Repaglinide (CYP2C8 Substrates) (added)

The acyl-?-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Plavix

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

thereby needing dose-adjustment and/or appropriate monitoring.

Concomitant administration of Plavix with repaglinide significantly increases systemic

exposures to repaglinide [see Clinical Pharmacology (12.3)]. When concomitant use is

required in a patient maintained on clopidogrel, initiate repaglinide at 0.5 mg with each

meal and titrate based on blood glucose levels. Do not exceed a total daily dose of 4 mg.

If concomitant use of clopidogrel is required in a patient stabilized on higher doses of

repaglinide, down titrate the dose of repaglinide based on blood glucose levels to not

exceed a total daily dose of 4 mg.

8 Use in Specific Populations

PLLR conversion, please refer to label.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

(The following section revised)

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

non-prescription medicines, vitamins and herbal supplements.

Plavix may affect the way other medicines work, and other medicines may affect

how Plavix works. See “What is the most important information I should

know about Plavix?”

Plavix may increase blood levels of other medicines such as repaglinide (Prandin®). (sentence added)


PATIENT COUNSELING INFORMATION (revised)

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

Discontinuation

Advise patients not to discontinue Plavix without first discussing it with the health care provider

who prescribed it.

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.


Thrombotic Thrombocytopenic Purpura

Instruct patients to get prompt medical attention if they experience symptoms of TTP that cannot

otherwise be explained.

Invasive Procedures

Advise patients to inform physicians and dentists that they are taking Plavix before any surgery

or dental procedure.

Proton Pump Inhibitors

Advise patients not to take omeprazole or esomeprazole while taking Plavix. Dexlansoprazole,

lansoprazole and pantoprazole had less pronounced effects on the antiplatelet activity of Plavix

than did omeprazole or esomeprazole.

09/16/2016 (SUPPL-64)

Approved Drug Label (PDF)

Boxed Warning

(revised)

WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO

LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE

The effectiveness of Plavix results from its antiplatelet activity, which is dependent on its

conversion to an active metabolite by the cytochrome P450 (CYP) system, principally

CYP2C19. Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of

another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.

5 Warnings and Precautions

 Diminished Antiplatelet Activity in Patients with Impaired CYP2C19 Function (revised)

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.

 

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

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

because both significantly reduce the antiplatelet activity of Plavix.

General Risk of Bleeding (revised)

Thienopyridines, including Plavix, increase the risk of bleeding.

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

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

by administering exogenous platelets; however, platelet transfusions within 4 hours of the

loading dose or 2 hours of the maintenance dose may be less effective.

Discontinuation of Plavix (revised)

Discontinuation of Plavix increases the risk of cardiovascular events. If Plavix must be

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

restart it as soon as possible. When possible, interrupt therapy with Plavix for five days prior to

such surgery. Resume Plavix as soon as hemostasis is achieved.

6 Adverse Reactions

Postmarketing Experience (revised)

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

Plavix.

• 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, hemorrhage of operative

wound

• Hepato biliary disorders: Acute liver failure, hepatitis (non infectious), abnormal

liver function test

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

sickness

• Musculoskeletal, connective tissue and bone disorders: Myalgia, arthralgia, arthritis

• Nervous system disorders: Taste disorders, fatal intracranial bleeding, headache

• 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

 

 

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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