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.

ZELBORAF (NDA-202429)

(VEMURAFENIB)

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

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05/18/2020 (SUPPL-19)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib

(Additions and/or revisions underlined)

Strong CYP3A4 Inhibitors

Coadministration of a strong CYP3A4 inhibitor increased vemurafenib plasma concentrations and may lead to increased toxicity. Avoid coadministration of ZELBORAF with strong CYP3A4 inhibitors. If coadministration of a strong CYP3A4 inhibitor is unavoidable, consider dose reduction of ZELBORAF, if clinically indicated.

Strong CYP3A4 Inducers

Coadministration of ZELBORAF with rifampin, a strong CYP3A4 inducer, decreased vemurafenib plasma concentrations and may result in decreased efficacy. Avoid coadministration of ZELBORAF with strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin), and replace these drugs with alternative drugs when possible. If coadministration of a strong CYP3A4 inducer is unavoidable, increase the dose of ZELBORAF by 240 mg (one tablet) as tolerated.

11/06/2017 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 New Primary Malignancies

(additions underlined)

Cutaneous Malignancies

Cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving ZELBORAF compared to those in the control arm in Trial 1. The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the ZELBORAF arm was 24% compared to

< 1% in the dacarbazine arm.The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving ZELBORAF experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using ZELBORAF included age (greater than or equal to 65 years), prior skin cancer, and chronic sun exposure.

In Trial 4, in patients with ECD, the incidence of cuSCC and/or keratoacanthomas was 40.9% (9/22). The median time to first appearance of cuSCC amongst patients with at least one occurrence was 12.1 weeks.

In Trial 1, in patients with unresectable or metastatic melanoma, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving ZELBORAF compared to none of the patients receiving dacarbazine.

Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of ZELBORAF.

…

Cases of myeloid neoplasms amongst patients with ECD have been observed, including in patients who have received ZELBORAF. Monitoring complete blood count in ECD patients with co-existing myeloid malignancies is recommended.

5.11 Renal Failure

(additions underlined)

Renal failure, including acute interstitial nephritis and acute tubular necrosis, can occur with ZELBORAF. In Trial 1, in patients with metastatic melanoma, 26% of ZELBORAF-treated patients and 5% of dacarbazine-treated patients experienced Grade 1-2 creatinine elevations [greater than 1 and up to 3 times upper limit of normal (ULN)]; 1.2% of ZELBORAF-treated patients and 1.1% of dacarbazine-treated patients experienced Grade 3-4 creatinine elevations (greater than 3 times ULN).

In Trial 4, in patients with ECD, 86% (19/22) of patients experienced Grade 1/2 creatinine elevations and 9.1% (2/22) of patients experienced Grade 3 creatinine elevations.

Measure serum creatinine before initiation of ZELBORAF and periodically during treatment.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions and revisions, please refer to label)

8 Use in Specific Populations

8.4 Pediatric Use

(subsection revised, additions underlined)

The safety and effectiveness of ZELBORAF in pediatric patients have not been established. Vemurafenib was studied in 6 adolescent patients 15 to 17 years of age with unresectable or metastatic melanoma with BRAF V600 mutation. A maximum tolerated dose was not reached with doses up to vemurafenib 960 mg twice daily. No new safety signals were observed. Vemurafenib steady-state exposure in these 6 adolescent patients was generally similar to that in adults.

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

PATIENT COUNSELING INFORMATION

(addition underlined)

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

Healthcare providers should advise patients of the potential benefits and risks of ZELBORAF and instruct their patients to read the Medication Guide before starting ZELBORAF therapy. Inform patients of the following:

Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients with melanoma for whom treatment with ZELBORAF is indicated.

…

09/13/2017 (SUPPL-14)

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information:

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

MEDICATION GUIDE

General information about ZELBORAF

Additions and/or revisions underlined below:

… If you would like more information, talk with your healthcare provider. You can ask your healthcare provider …

09/13/2017 (SUPPL-15)

5 Warnings and Precautions

5.12 Dupuytren’s Contracture and Plantar Fascial Fibromatosis

Newly added subsection:

Dupuytren’s contracture and plantar fascial fibromatosis have been reported with ZELBORAF. The majority of cases were mild to moderate, but severe, disabling cases of Dupuytren’s contracture have also been reported.

6 Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the label:

Addition of the following:

Dupuytren’s Contracture and Plantar Fascial Fibromatosis

6.1 Clinical Trials Experience

Clinically relevant adverse reactions reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include:

Additions and/or revisions underlined:

Musculoskeletal and connective tissue disorders: arthritis, Dupuytren’s contracture

6.2 Postmarketing Experience

Addition of the following:

Musculoskeletal and connective tissue disorders: Dupuytren’s contracture and plantar fascial fibromatosis

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about ZELBORAF?

ZELBORAF can cause serious side effects, including:

Risk of new cancers. ZELBORAF may cause certain types of skin cancer called cutaneous squamous cell carcinoma (cuSCC) and keratoacanthoma. New melanoma lesions have occurred in people who take ZELBORAF. ZELBORAF may also cause another type of cancer called non-cutaneous squamous cell carcinoma (non-cuSCC).

PATIENT COUNSELING INFORMATION

Lactation

Addition of the following:

Advise patients to contact their health care provider for symptoms of Dupuytren’s contracture or plantar fascial fibromatosis

04/17/2017 (SUPPL-12)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib

(Additions and/or revisions are underlined)

Strong CYP3A4 Inhibitors

Vemurafenib is a substrate of CYP3A4; therefore, coadministration of strong CYP3A4 inhibitors may increase vemurafenib plasma concentrations and may lead to increased toxicity…

Strong CYP3A4 Inducers

08/31/2016 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

Embryo-Fetal Toxicity

Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant 115 woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to 116 use effective contraception during treatment with ZELBORAF and for 2 weeks after the final dose.

8 Use in Specific Populations

Females and Males of Reproductive Potential (PLLR Conversion)

Contraception

Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ZELBORAF and for 2 weeks after the final dose.

Lactation (PLLR Conversion)

There is no information available regarding the presence of vemurafenib in human milk, effects on the breastfed infant, or effects on milk production. Because of the potential for serious adverse reactions in a breastfed infant, including malignancy, severe dermatologic reactions, QT prolongation, hepatotoxicity, photosensitivity, and ophthalmologic toxicity, advise women not to breastfeed during treatment with ZELBORAF and for 2 weeks after the final dose.

Pregnancy (PLLR Conversion)

Risk Summary

Based on its mechanism of action, ZELBORAF can cause fetal harm when administered to a pregnant woman. There are no available data on the use of ZELBORAF in pregnant women to determine the drug-associated risk; however, placental transfer of vemurafenib to a fetus has been reported. Exposure to vemurafenib could not be achieved in animals at levels sufficient to fully address its potential toxicity in pregnant women. Advise pregnant women of the potential harm to a fetus. The estimated background risks of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Data

Animal Data

Vemurafenib showed no evidence of developmental toxicity in rat fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the clinical exposure at 960 mg twice daily based on AUC) or rabbit fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the clinical exposure at 960 mg twice daily based on (AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus.

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

MG - What should I tell my healthcare provider before taking ZELBORAF?

Before you take ZELBORAF, tell your healthcare provider if you:

are pregnant or plan to become pregnant. ZELBORAF can harm your unborn baby (revised below)
- Females who are able to become pregnant should use effective birth control during ZELBORAF treatment and for 2 weeks after the final dose.
are breastfeeding or plan to breastfeed (revised below)
- Do not breastfeed during treatment with ZELBORAF and for 2 weeks after the final dose. Talk to your healthcare provider about the best way to feed your baby during this time.

PCI

Embryo-fetal Toxicity (reformatted and revised)

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZELBORAF and for 2 weeks after the final dose.
Advise female patients to contact their health-care provider immediately with a known or suspected Pregnancy.

Lactation

Advise a woman not to breastfeed during treatment with ZELBORAF and for 2 weeks after the final dose.

05/09/2016 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

Radiation Sensitization and Radiation Recall

subsequent to vemurafenib treatment.. Fatal cases have been reported in patients with visceral organ involvement.

Renal Failure

Renal failure, including acute interstitial nephritis and acute tubular necrosis, can occur with ZELBORAF. Twenty-six percent of ZELBORAF-treated patients and 5% of dacarbazine-treated patients experienced Grade 1-2 creatinine elevations [greater than 1 and up to 3 times upper limit of normal (ULN)]; 1.2% of ZELBORAF-treated patients and 1.1% of dacarbazine-treated patients experienced Grade 3-4 creatinine elevations (greater than 3 times ULN).
Measure serum creatinine before initiation of ZELBORAF and periodically during treatment.

6 Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the label:

Renal Failure

Postmarketing Experience

Renal and urinary disorders: Acute interstitial nephritis, acute tubular necrosis

7 Drug Interactions

Effect of Vemurafenib on CYP1A2 Substrates

Coadministration of ZELBORAF with tizanidine, a sensitive CYP1A2 substrate, increased tizanidine systemic exposure by 4.7-fold. Avoid concomitant use of ZELBORAF with drugs having a narrow therapeutic window that are predominantly metabolized by CYP1A2. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.

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

MG - What are the possible side effects of ZELBORAF?

ZELBORAF may cause serious side effects, including:

Kidney injury. Your healthcare provider should do blood tests to check your kidney function before you start taking ZELBORAF and during treatment.

Renal failure can occur in patients treated with ZELBORAF. Advise patients of the importance of monitoring serum creatinine prior to and during ZELBORAF treatment.