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.

TYKERB (NDA-022059)

(LAPATINIB DITOSYLATE)

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

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03/27/2022 (SUPPL-31)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions underlined

…

Skin and Subcutaneous Tissue Disorders: Nail disorders, including paronychia. Severe cutaneous adverse reactions, including Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), skin fissures.

…

12/06/2018 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Embryo-Fetal Toxicity

(additions underlined)

Based on its mechanism of action and findings in animal studies, TYKERB can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, administration of lapatinib to pregnant rats during the period of organogenesis and through lactation led to death of offspring within the first 4 days after birth at maternal exposures that were greater than or equal to 3.3 times the human clinical exposure based on AUC following 1250 mg dose of lapatinib plus capecitabine. When administered to pregnant animals during the period of organogenesis, lapatinib caused fetal anomalies (rats) or abortions (rabbits) at maternally toxic doses (with maternal exposures approximately 6.4 and 0.2 times, respectively, the human clinical exposure based on AUC following 1250 mg dose of lapatinib plus capecitabine).

Advise pregnant women and females of reproductive potential of the potential risk to the fetus . Verify the pregnancy status of females of reproductive potential prior to initiation of TYKERB. Advise females of reproductive potential to use effective contraception during treatment with TYKERB and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TYKERB and for 1 week after the last dose

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Hormone Receptor-Positive, HER2+ Metastatic Breast Cancer: In another randomized, Phase 3 clinical trial of postmenopausal patients (N = 355) with hormone receptor positive (HR+), HER2-positive metastatic breast cancer (MBC) which had progressed after prior trastuzumab-containing chemotherapy and endocrine therapies patients received TYKERB with trastuzumab and an aromatase inhibitor (AI) (letrozole, exemestane, or anastrozole), TYKERB with an AI, or trastuzumab with an AI. In this trial, the safety profile of the treatment groups was consistent with the known safety of these agents. The most frequent study treatment-related AEs (>10%) in each of the TYKERB-containing treatment arms were diarrhea, rash, paronychia, nausea, stomatitis, dermatitis acneiform, and decreased appetite, which were infrequent to absent in the trastuzumab treatment arm. The frequency of cardiac AEs (mostly decrease in ejection fraction) was 7% in the TYKERB+trastuzumab+AI group, 2% in the TYKERB+AI group and 3% in the trastuzumab+AI group. Adverse reactions which occurred in at least 10% of patients in the treatment arms are shown in Table 5.

(please refer to label to view table 5)

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8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Based on findings in animal studies and its mechanism of action, TYKERB can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data to inform of the drug associated risks. In an animal reproduction study, administration of lapatinib to pregnant rats during organogenesis and through lactation led to death of offspring within the first 4 days after birth at maternal exposures that were ? 3.3 times the human clinical exposure based on AUC following 1250 mg dose of lapatinib plus capecitabine. When administered to pregnant animals during the period of organogenesis, lapatinib caused fetal anomalies (rats) or abortions (rabbits) at maternally toxic doses [see Data].

Advise pregnant women and females of reproductive potential of the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

Data

Animal Data

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of lapatinib at 30, 60, and 120 mg/kg/day during the period of organogenesis. Minor anomalies (left-sided umbilical artery, cervical rib, and precocious ossification) occurred in rats at the maternally toxic dose of 120 mg/kg/day (approximately 6.4 times the human clinical exposure based on AUC following 1,250 mg dose of lapatinib plus capecitabine). In rabbits, lapatinib was associated with maternal toxicity at 60 and 120 mg/kg/day (approximately 0.07 and 0.2 times the human clinical exposure, respectively, based on AUC following 1,250 mg dose of lapatinib plus capecitabine) and abortions at 120 mg/kg/day. Maternal toxicity was associated with decreased fetal body weights and minor skeletal variations.

In a pre- and post-natal development study, rats were given oral doses of 20, 60, and 120 mg/kg/day during gestation through lactation up to weaning. In rats, doses of 60 and 120 mg/kg/day (approximately 3.3 and 6.4 times the human clinical exposure, respectively, based on AUC following 1,250 mg dose of lapatinib plus capecitabine) led to decrease in F1 postnatal survival (91% and 34% of the pups died by the fourth day after birth, at 60 and 120 mg/kg/day, respectively).

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of lapatinib in human milk, or its effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions in a breastfed child from TYKERB, advise lactating women not to breastfeed during treatment with TYKERB and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to the initiation of TYKERB. Contraception

Females

Based on findings in animal studies, TYKERB can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with TYKERB and for 1 week after the last dose.

Males

Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with TYKERB and for 1 week after the last dose.

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

PATIENT INFORMATION

(additions underlined)

…

What should I tell my doctor before taking TYKERB?

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are pregnant or plan to become pregnant. TYKERB can harm your unborn baby. You should not become pregnant while taking TYKERB. You should use effective contraception while receiving TYKERB and for at least 5 days after the last dose of TYKERB. Tell your doctor right away if you become pregnant during treatment with TYKERB.
are breastfeeding or plan to breastfeed. It is not known if TYKERB passes into your breast milk. You should not breastfeed while receiving TYKERB and for 5 days after the last dose of TYKERB. You and your doctor should decide if you will take TYKERB or breastfeed. You should not do both.

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Other

(PLLR conversion)

12/06/2018 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 QT Prolongation

(additions underlined)

QT prolongation has been associated with TYKERB. Monitor patients who have or may develop prolongation of QTc during treatment with TYKERB. These conditions include patients with hypokalemia or hypomagnesemia, with congenital long QT syndrome, patients taking antiarrhythmic medicines or other medicinal products with known risk for QT prolongation/ Torsades de Pointes (TdP), and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to TYKERB administration.

04/06/2017 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

The following adverse reactions have been identified during post-approval use of TYKERB. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Hypersensitivity reactions including anaphylaxis.

Skin and Subcutaneous Tissue Disorders: Nail disorders including paronychia. Severe cutaneous adverse Skin reactions including Stevens Johnson Syndrome (SJS) and toxic epidural necrolysis (TEN).

Cardiac Disorders: Ventricular arrhythmias/Torsades de Points (TdP). Electrocardiogram QT prolongation.

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

Patient Information

(additions underlined)

What are the possible side effects of TYKERB?

…

severe skin reactions. TYKERB may cause severe skin reactions. Tell your doctor right away if you develop a skin rash, red skin, blistering of the lips, eyes,or mouth, peeling of the skin, fever, or any combination of these. As severe skin reactions can be life-threatening, your doctor may tell you to stop taking TYKERB.
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