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.

KEPIVANCE (BLA-125103)

(PALIFERMIN)

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

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12/18/2019 (SUPPL-176)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Based on findings in animal studies, Kepivance may cause fetal harm when administered to pregnant women . There are no data available on Kepivance use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, intravenous administration of palifermin to pregnant rabbits and rats during the period of organogenesis resulted in embryo-fetal mortality and alterations to growth [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 defect, 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 2-4% and 15-20%, respectively.

Data

Animal data

In embryo-fetal development studies, palifermin was administered intravenously to pregnant rabbits and rats during the perid of organogenesis. Doses were 5, 60, and 150 µg/kg/day in rabbits (gestation days 6-18) and 100, 300, and 1000 µg/kg/day in rats (gestation days 6 through 17). Increased post-implantation loss and decreased fetal body weights occurred along with maternal toxicity (clinical signs and reductions in body weight gain and food consumption) at doses of 150 µg/kg/day in rabbits and 1000 µg/kg/day in rats. Increased skeletal variations was noted in rats at 1000 µg/kg/day. Doses of 150 µg/kg/day in rabbits and 1000 µg/kg/day in rats are approximately 5-times (rabbits) and 35-times (rats) the exposure (AUC) in patients receiving the recommended dose of 60 µg/kg/day,.

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of Kepivance in human milk, the effect on the breastfed child, or the effect on milk production. Since many drugs are secreted into human milk, and because of the potential for serious adverse reactions in a nursing child, breastfeeding should be discontinued during treatment and for at least 2 weeks after the last dose.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Infertility

Based on findings from animal studies, palifermin may impair fertility in females and males of reproductive potential . The reversibility of the effects on fertility is unknown.

07/01/2016 (SUPPL-172)

Approved Drug Label (PDF)

5 Warnings and Precautions

Potential for Stimulation of Tumor Growth

Kepivance has been shown to enhance the growth of human epithelial tumor cell lines in vitro … (in vitro added to sentence)

6 Adverse Reactions

The following paragraph was moved from the general Adverse Reaction subsection to the Clinical Trial Experience subsection: The most common adverse reactions attributed to Kepivance were skin toxicities (rash, erythema, edema, pruritus), oral toxicities (dysesthesia, tongue discoloration, tongue thickening, alteration of taste), pain, arthralgias, and dysesthesia. The median time to onset of cutaneous toxicity was 6 days following the first of 3 consecutive daily doses of Kepivance, with a median duration of 5 days. In patients receiving Kepivance, dysesthesia (including hyperesthesia, hypoesthesia, and paresthesia) was usually localized to the perioral region, whereas in patients receiving placebo dysesthesias were more likely to occur in extremities.

Infections: In a randomized, double-blind, placebo-controlled post-approval study designed to determine the efficacy of Kepivance with a high-dose melphalan preparative regimen, the incidence of treatment-emergent infections was significantly greater in patients treated with Kepivance compared to placebo. A total of 281 patients were randomized to 3 arms: Kepivance before melphalan on days -6, -5, -4 and after melphalan on days 0, 1, and 2 (pre-post) (n=115); Kepivance before melphalan on days -6, -5, -4 (pre) (n=109); or placebo (n=57). The incidence of reported infections were pre-post - 50%; pre - 47%; and placebo – 25 (This section added)