Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

PLAVIX (NDA-020839)

(CLOPIDOGREL BISULFATE)

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

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09/16/2022 (SUPPL-78)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 General Risk of Bleeding

Additions and/or revisions underlined:

…

Risk factors for bleeding include concomitant use of other drugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, and chronic use of NSAIDs) [see Drug Interactions (7.4, 7.5, 7.6, 7.7)].

7 Drug Interactions

7.7 Other Antiplatelet Agents

Newly added subsection:

Coadministration of antiplatelet agents increase the risk of bleeding due to an additive effect. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with other antiplatelet agents [see Warnings and Precautions (5.2)].

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

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Taking Plavix 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 Plavix to treat your condition.
nonsteroidal 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.
rifampin (used to treat severe infections)
other antiplatelet agents

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

…

General information about Plavix

Medicines are sometimes used for purposes other than those listed in a Medication Guide. Do not take Plavix for a condition for which it was not prescribed. Do not give Plavix 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 Plavix. If you would like more information, talk to your doctor. Ask your doctor or pharmacist for information about Plavix that was written for healthcare professionals.

For more information, go to www.sanofi-aventis.us or call 1-800-633-1610.

03/01/2021 (SUPPL-74)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 General Risk of Bleeding

Additions and/or revisions underlined:

P2Y12 inhibitors (Thienopyridines), including Plavix, increase the risk of bleeding.

P2Y12 inhibitors (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.

Use of drugs that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. As a precaution, avoid concomitant use of strong CYP2C19 inducers [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

7 Drug Interactions

Newly added subsection:

7.1 CYP3C19 Inducers

Since clopidogrel is metabolized to its active metabolite partly by CYP2C19, use of drugs that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel.

Rifampin strongly induces CYP2C19 resulting to both an increase level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, avoid concomitant use of strong CYP2C19 inducers [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

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

MEDICATION GUIDE

What should I tell my doctor before taking Plavix?

Especially tell your doctor if you take:

Newly added information:

rifampin (used to treat severe infections)

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