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.

ESBRIET (NDA-022535)

(PIRFENIDONE)

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

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02/24/2023 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Severe Cutaneous Adverse Reactions

New subsection added:

Severe cutaneous adverse reactions (SCAR), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported in association with the use of ESBRIET in the postmarketing setting. If signs or symptoms of SCAR occur, interrupt ESBRIET treatment until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, permanently discontinue ESBRIET.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.3)]

6.2 Postmarketing Experience

Addition of the following to the line listing:

Skin and Subcutaneous Tissue Disorders: Severe Cutaneous Adverse Reactions (SCAR)

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Severe Cutaneous Adverse Reactions

Advise patients about signs and symptoms of severe cutaneous adverse reactions (SCAR). Advise patients to contact their healthcare provider immediately if they experience signs and symptoms of SCAR [see Warnings and Precautions (5.3)].

…

PATIENT INFORMATION

Additions and/or revisions underlined:

…

What are the possible side effects of ESBRIET?

ESBRIET may cause serious side effects, including:

…

severe skin reactions. Call your doctor right away if you have a severe skin reaction such as skin blisters, rash, sores in the mouth, hives or any other severe skin symptoms. Your doctor may stop your treatment with ESBRIET.
…

07/31/2019 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

(additions underlined)

5.1 Elevated Liver Enzymes and Drug-Induced Liver Injury

Cases of drug-induced liver injury (DILI) have been observed with ESBRIET. In the postmarketing period, non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported.

…

Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with ESBRIET, monthly for the first 6 months, every 3 months thereafter, and as clinically indicated. Measure liver function tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. Dosage modification or interruption may be necessary for liver enzyme elevations

6 Adverse Reactions

(addition underlined)

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

Liver Enzyme Elevations and Drug-Induced Liver Injury

…

6.2 Postmarketing Experience

(addition underlined)

…

Hepatobiliary Disorders

Drug-induced liver injury

01/11/2017 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Elevated Liver Enzymes

(addition underlined)

Increases in ALT and AST >3 × ULN have been reported in patients treated with ESBRIET. In some cases these have been associated with concomitant elevations in bilirubin. Patients treated with ESBRIET 2403 mg/day in the three Phase 3 trials had a higher incidence of elevations in ALT or AST greater than or equal to3 × ULN than placebo patients (3.7% vs. 0.8%, respectively). Elevations greater than or equal to10 × ULN in ALT or AST occurred in 0.3% of patients in the ESBRIET greater than or equal to10 ×2403 mg/day group and in 0.2% of patients in the placebo group. Increases in ALT and AST greater than or equal to 3 × ULN were reversible with dose modification or treatment discontinuation. No cases of liver transplant or death due to liver failure that were related to ESBRIET have been reported. However, the combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury, that could lead to death or the need for liver transplants in some patients. Conduct liver function tests (ALT, AST, and bilirubin) prior to the initiation of therapy with ESBRIET in all patients, then monthly for the first 6 months and every 3 months thereafter. Dosage modifications or interruption may be necessary for liver enzyme elevations.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, additions underlined)

Risk Summary

The data with ESBRIET use in pregnant women are insufficient to inform on drug associated risks for major birth defects and miscarriage. In animal reproduction studies, pirfenidone was not teratogenic in rats and rabbits at oral doses up to 3 and 2 times, respectively, the maximum recommended daily dose (MRDD) in adults [see Data].

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

Animal reproductive studies were conducted in rats and rabbits. In a combined fertility and embryofetal development study, female rats received pirfenidone at oral doses of 0, 50, 150, and 1000 mg/kg/day from 2 weeks prior to mating, during the mating phase, and throughout the periods of early embryonic development from gestation days (GD) 0 to 5 and organogenesis from GD 6 to 17. In an embryofetal development study, pregnant rabbits received pirfenidone at oral doses of 0, 30, 100, and 300 mg/kg/day throughout the period of organogenesis from GD 6 to 18. In these studies, pirfenidone at doses up to 3 and 2 times, respectively, the maximum recommended daily dose (MRDD) in adults (on mg/m2 basis at maternal oral doses up to 1000 mg/kg/day in rats and 300 mg/kg/day in rabbits, respectively) revealed no evidence of impaired fertility or harm to the fetus due to pirfenidone. In the presence of maternal toxicity, acyclic/irregular cycles (e.g., prolonged estrous cycle) were seen in rats at doses approximately equal to and higher than the MRDD in adults (on a mg/m2 basis at maternal doses of 450 mg/kg/day and higher). In a pre- and post-natal development study, female rats received pirfenidone at oral doses of 0, 100, 300, and 1000 mg/kg/day from GD 7 to lactation day 20. Prolongation of the gestation period, decreased numbers of live newborn, and reduced pup viability and body weights were seen in rats at an oral dosage approximately 3 times the MRDD in adults (on a mg/m2 basis at a maternal oral dose of 1000 mg/kg/day).

8.2 Lactation

(PLLR conversion, additions underlined)

Risk Summary

No information is available on the presence of pirfenidone in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. The lack of clinical data during lactation precludes clear determination of the risk of ESBRIET to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ESBRIET and the potential adverse effects on the breastfed child from ESBRIET or from the underlying maternal condition.

Data

Animal Data: A study with radio-labeled pirfenidone in rats has shown that pirfenidone or its metabolites are excreted in milk. There are no data on the presence of pirfenidone or its metabolites in human milk, the effects of pirfenidone on the breastfed child, or its effects on milk production.