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.

VESANOID (NDA-020438)

(TRETINOIN)

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

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10/04/2024 (SUPPL-9)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Effects of Other Drugs on VESANOID

Additions and revisions underlined:

Strong or moderate CYP3A Inhibitors

Avoid concomitant use of VESANOID with strong CYP3A inhibitors if possible and monitor more frequently if concomitant use is unavoidable. Monitor patients taking moderate CYP3A inhibitors concomitantly with VESANOID more frequently for adverse reactions.

Tretinoin is a CYP3A substrate. Concomitant use with a strong CYP3A4 inhibitor increases tretinoin plasma concentrations, which may increase the risk of adverse reactions [see Clinical Pharmacology (12.3)].

Strong CYP3A Inducers

Concomitant use of VESANOID with strong CYP3A4 inducers may decrease tretinoin plasma concentrations, which may reduce its efficacy. Avoid concomitant use with strong CYP3A inducers if possible.

02/21/2023 (SUPPL-7)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: EMBRYO-FETAL TOXICITY and DIFFERENTIATION SYNDROME

VESANOID can cause embryo-fetal loss and malformations when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Females of reproductive potential must have a negative pregnancy test before initiating VESANOID. Advise females of reproductive potential to use two effective methods of contraception during treatment with VESANOID and for 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with VESANOID and for 1 week after the last dose [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.3)].
Differentiation Syndrome, which can be life-threatening or fatal, occurred in about 26% of patients with APL who received VESANOID. At first signs or symptoms of this syndrome, immediately initiate high-dose corticosteroid therapy and hemodynamic monitoring until resolution of signs and symptoms. Consider withholding VESANOID for moderate and severe Differentiation Syndrome until resolution [see Warnings and Precautions (5.2)].

4 Contraindications

Additions and/or revisions underlined

VESANOID is contraindicated in patients with a known hypersensitivity to VESANOID, any of its components, or other retinoids. Reactions have included rash, pruritus, face edema, and dyspnea. [see Adverse Reactions (6.1)].

5 Warnings and Precautions

The following subsections created to comply with Physician Labeling Rule (PLR); please refer to label for complete information.

5.1 Embryo-Fetal Toxicity

5.2 Differentiation Syndrome

5.3 Patients Without t(15;17) Translocation or PML/RAR? Fusion

5.4 Leukocytosis

5.5 Intracranial Hypertension

5.6 Lipid Abnormalities

5.7 Hepatotoxicity

5.8 Thromboembolic Events

6 Adverse Reactions

Bulleted line listing created:

The following clinically significant adverse reactions are described elsewhere in the labeling:

Differentiation Syndrome [see Warnings and Precautions (5.2)]
Leukocytosis [see Warnings and Precautions (5.4)]
Intracranial hypertension [see Warnings and Precautions (5.5)]
Lipid abnormalities [see Warnings and Precautions (5.6)]
Hepatotoxicity [see Warnings and Precautions (5.7)]
Thromboembolic events [see Warnings and Precautions (5.8)]
6.1 Clinical Trials Experience
Newly added subsection; please refer to label for complete information.
6.2 Postmarketing Experience
Newly added subsection; please refer to label for complete information.

7 Drug Interactions

he following subsections created to comply with Physician Labeling Rule (PLR); please refer to label for complete information.

7.1 Effects of Other Drugs on VESANOID

7.2 Concomitant Use of Products Known to Cause Intracranial Hypertension

7.3 Vitamin A

7.4 Anti-fibrinolytic Agents

8 Use in Specific Populations

8.4 Pediatric Use

Subsection revised, additions and/or revisions underlined:

Safety and effectiveness of VESANOID has been established in pediatric patients 1 year of age and older and the information on this use is discussed throughout the labeling. The maximum tolerated dose is lower in pediatric patients compared to adults. Some pediatric patients experience severe headache and intracranial hypertension, which required management with an analgesic and a lumbar puncture. Dose reduction may be considered for pediatric patients experiencing serious and/or intolerable adverse reactions.

Safety and effectiveness in pediatric patients less than 1 year of age have not been established.

8.5 Geriatric Use

Additions and/or revisions underlined:

Across clinical studies of VESANOID, 21% were 60 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.

8.1 Pregnancy

PLLR conversion

Risk Summary

Based on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], VESANOID can cause embryo-fetal loss and malformations when administered to a pregnant woman. VESANOID is a retinoid and there is an increased risk of major congenital malformations, spontaneous abortions and premature births following exposure to retinoids during pregnancy in humans. Tretinoin was teratogenic and embryotoxic in mice, rats, hamsters, rabbits and pigtail monkeys at doses less than the human dose on a mg/m2 basis (see Data). Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population(s) 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% to 4% and 15% to 20%, respectively.

Data

Human Data

VESANOID is a retinoid and increased spontaneous abortions and major fetal abnormalities related to the use of retinoids have been documented in humans. Reported malformations include abnormalities of the central nervous system, musculoskeletal system, external ear, eye, thymus and great vessels; and facial dysmorphia, cleft palate, and parathyroid hormone deficiency. Some of these abnormalities were fatal.

IQ scores less than 85, with or without obvious CNS abnormalities, have been reported in pediatrics exposed to retinoids in utero.

Animal Data

Tretinoin causes fetal resorptions and a decrease in live fetuses in all animals studied. Gross external, soft tissue and skeletal alterations occurred at doses higher than 0.7 mg/kg/day in mice, 2 mg/kg/day in rats, 7 mg/kg/day in hamsters, and at a dose of 10 mg/kg/day, the only dose tested, in pigtail monkeys (about 1/20, 1/4, and 1/2 and 4 times the human dose, respectively, on a mg/m2 basis).

8.2 Lactation

PLLR conversion

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

8.3 Use in Females and Males of Reproductive Potential

PLLR conversion

VESANOID can cause embryo-fetal loss and malformations when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating VESANOID. Females of reproductive potential must have a negative pregnancy test within 1 week prior to initiating VESANOID with a sensitivity of at least 50 mIU/mL.

Contraception

Females

Advise females of reproductive potential to abstain continuously from sexual intercourse or to use two effective methods of contraception. Counsel patients to use two effective methods of contraception during treatment with VESANOID and for 1 month after the last dose. Two methods of effective contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Refer females of reproductive potential to a qualified provider of contraceptive methods, if needed.

Males

Advise males with female partners of reproductive potential to use effective contraception during and after treatment with VESANOID and for 1 week after the last dose.

Infertility

Males

Based on testicular toxicities observed in dogs, VESANOID may impair male fertility [see Nonclinical Toxicology (13.1)]. The reversibility of effect on fertility is unknown.

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

PATIENT COUNSELING INFORMATION

New section created; please refer to label for complete information.

Other

PLR conversion, please refer to label.