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.

IDHIFA (NDA-209606)

(ENASIDENIB MESYLATE)

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

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12/21/2023 (SUPPL-6)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

…

Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with IDHIFA and for 2 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for 2 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

7 Drug Interactions

7.1 Effect of IDHIFA on Other Drugs

Additions and/or revisions underlined:

Certain CYP1A2 Substrates

Avoid concomitant use with IDHIFA unless otherwise recommended in the Prescribing Information for CYP1A2 substrates where minimal concentration changes may lead to serious adverse reactions. Consider reducing the frequency of caffeine intake from various food and beverages in a 24 hour period while taking IDHIFA because IDHIFA may increase the effect of caffeine in patients who are sensitive to it.

Enasidenib is a CYP1A2 inhibitor. Concomitant use of IDHIFA increases the exposure of CYP1A2 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to the substrates.

Certain CYP2C19 substrates

Avoid concomitant use with IDHIFA unless otherwise recommended in the Prescribing Information for CYP2C19 substrates where minimal concentration changes may lead to serious adverse reactions.

Enasidenib is a CYP2C19 inhibitor. Concomitant use of IDHIFA increases the exposure of CYP2C19 substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates.

Certain CYP3A substrates

Avoid concomitant use with IDHIFA unless otherwise recommended in the Prescribing Information for CYP3A substrates where minimal concentration changes may lead to reduced efficacy.

Do not administer IDHIFA with anti-fungal agents that are substrates of CYP3A due to expected loss of antifungal efficacy.

Co-administration of IDHIFA may decrease the concentrations of hormonal contraceptives. Consider alternative methods of contraception in patients receiving IDHIFA [See use in Specific Population (8.1, 8.3)].

Enasidenib is a CYP3A inducer. Concomitant use of IDHIFA decreases the exposure of CYP3A substrates [see Clinical Pharmacology (12.3)], which may reduce the efficacy of the substrates.

Certain OATP1B1, OATP1B3, and BCRP Substrates

Avoid coadministration of IDHIFA with OATP1B1, OATP1B3, and BCRP substrates, for which minimal concentration changes may lead to serious toxicities. If coadministration cannot be avoided, decrease the OATP1B1, OATP1B3, and BCRP substrates dosage(s) in accordance with the respective Prescribing Information.

Enasidenib is an OATP1B1, OATP1B3, and BCRP transporter inhibitor. Concomitant use of IDHIFA increases the exposure of OATP1B1, OATP1B3, and BCRP substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to these substrates.

Certain P-glycoprotein (P-gp) Substrates

When coadministered with IDHIFA, follow recommended P-gp substrates Prescribing Information and monitor more frequently for adverse reactions related to these substrates.

Enasidenib is a P-gp transporter inhibitor. Concomitant use of IDHIFA increases the exposure of P-gp substrates [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions related to the substrates.

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Additions and/or revisions underlined:

…

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with IDHIFA and for 2 months after the last dose. Coadministration of IDHIFA may decrease the concentrations of combined hormonal contraceptives. Advise patients using hormonal contraceptives to use an effective non-hormonal contraceptive method during treatment with IDHIFA and for 2 months after the last dose [see Drug Interactions (7.1)].

…

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Embryo-Fetal Toxicity

…

Advise females of reproductive potential to use an effective non-hormonal contraceptive method during treatment with IDHIFA and for 2 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for 2 months after the last dose. Coadministration of IDHIFA may decrease the concentrations of combined hormonal contraceptives. [see Drug Interactions (7.1) and Use in Specific Populations (8.3)].

…

Dosing and Storage Instructions

Advise patients not to chew, split, or crush the tablets but swallow whole with a cup of water.
…
MEDICATION GUIDE
Additions and/or revisions underlined:
…
Before taking IDHIFA, tell your healthcare provider about all of your medical conditions, including if you:

Are pregnant or plan to become pregnant. IDHIFA can cause harm to your unborn baby if taken during pregnancy.
…
- IDHIFA may affect how hormonal contraceptives work and may cause them to not work as well. You should use an effective non-hormonal contraceptive method during treatment with IDHIFA and for 2 months after your last dose of IDHIFA if you use hormonal contraceptives.
  …

11/24/2020 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Embryo-Fetal Toxicity

Additions underlined

…

Advise pregnant women of the potential risk to the fetus.

…

7 Drug Interactions

7.1 Effect of IDHIFA on Other Drugs

New subsection added

OATP1B1, OATP1B3, and BCRP Substrates

IDHIFA is an OATP1B1, OATP1B3, and BCRP inhibitor. Coadministration of IDHIFA increases the exposure of OATP1B1, OATP1B3, and BCRP substrates, which may increase the incidence and severity of adverse reactions of these substrates [see Clinical Pharmacology (12.3)]. Decrease the dosage of OATP1B1, OATP1B3, and BCRP substrate(s) as recommended in the respective prescribing information, and as clinically indicated.

Certain P-glycoprotein (P-gp) Substrates

IDHIFA is a P-gp inhibitor. Coadministration of IDHIFA increases the exposure of P-gp substrates, which may increase the incidence and severity of adverse reactions of these substrates [see Clinical Pharmacology (12.3)]. For a P-gp substrate where small concentration changes may lead to serious adverse reactions, decrease the dose or modify the dosing frequency of such a P-gp substrate and monitor for adverse reactions as recommended in the respective prescribing information.

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

MEDICATION GUIDE

Additions underlined

…

Before taking IDHIFA, tell your healthcare provider about all of your medical conditions, including if you:

…

Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with IDHIFA.
…

PATIENT COUNSELING INFORMATION

Additions underlined

…

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.2), Use in Specific Populations (8.1)].

…

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant products, including over-the- counter products and supplements [see Drug Interactions (7.1)].

…

09/27/2019 (SUPPL-2)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Differentiation Syndrome

(additions and/or revisions are underlined)

In the clinical trial, 14% of patients treated with IDHIFA experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for differentiation syndrome, symptoms in patients treated with IDHIFA included acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also been observed.

Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, in as early as 1 day and up to 5 months after IDHIFA initiation.

If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt IDHIFA until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended.

5.2 Embryo-Fetal Toxicity

(additions and/or revisions are underlined)

Based on animal embryo-fetal toxicity studies, IDHIFA can cause embryo-fetal harm when administered to a pregnant woman. In animal embryo-fetal toxicity studies, enasidenib caused embryo- fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area under the concentration-time curve (AUC) at the recommended human dose. Advise females of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 2 months after the last dose of IDHIFA. Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 2 months after the last dose of IDHIFA. Pregnant women, patients becoming pregnant while receiving IDHIFA, or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

8 Use in Specific Populations

8.2 Lactation

(additions and/or revisions are underlined)

Risk Summary

There are no data on the presence of enasidenib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed children, advise women not to breastfeed during treatment with IDHIFA and for at least 2 months after the last dose.

8.3 Females and Males of Reproductive Potential

(additions and/or revisions are underlined)

Pregnancy Testing

Based on animal embryo-fetal toxicity studies, IDHIFA can cause fetal harm when administered to a pregnant woman.

Obtain a pregnancy test on females of reproductive potential prior to starting treatment with IDHIFA.

Contraception

Females

Advise females of reproductive potential to avoid becoming pregnant while receiving IDHIFA. Advise females of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 2 months after the last dose. Coadministration of IDHIFA may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time.

Males

Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 2 months after the last dose of IDHIFA.

Infertility

Based on findings in animals, IDHIFA may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.

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

MEDICATION GUIDE

(additions and/or revisions are underlined)

Before taking IDHIFA, tell your healthcare provider about all of your medical conditions, including if you:

Are pregnant or plan to become pregnant. IDHIFA can cause harm to your unborn baby if taken during pregnancy.
- If you are able to become pregnant, your healthcare provider will do a pregnancy test before you start taking IDHIFA.
- Females who are able to become pregnant and who take IDHIFA should use effective birth control (contraception) during treatment with IDHIFA and for at least 2 months after your last dose of IDHIFA.
- Males who have female partners that are able to become pregnant should use effective birth control during treatment with IDHIFA and for at least 2 months after your last dose of IDHIFA.
- IDHIFA may affect how hormonal contraceptives work and may cause them to not work as well.
- Talk to your healthcare provider about birth control methods that may be right for you while taking IDHIFA.
- IDHIFA may cause fertility problems in females and males, which may affect your ability to have children. Talk to your healthcare provider if you have concerns about fertility.
Are breastfeeding or plan to breastfeed. It is not known if IDHIFA passes into your breast milk. You should not breastfeed during your treatment with IDHIFA and for at least 2 months after your last dose of IDHIFA.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

PATIENT COUNSELING INFORMATION

(additions and/or revisions are underlined)

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

Differentiation Syndrome

Advise patients on the risks of developing differentiation syndrome as early as 1 day and during the first 5 months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, bone pain, rapid weight gain or swelling of their arms or legs, to their healthcare provider for further evaluation.

Tumor Lysis Syndrome

Advise patients on the risks of developing tumor lysis syndrome. Advise patients on the importance of maintaining high fluid intake, and the need for frequent monitoring of blood chemistry values.

Gastrointestinal Adverse Reactions

Advise patients on risk of experiencing gastrointestinal reactions such as diarrhea, nausea, vomiting, decreased appetite, and changes in their sense of taste. Ask patients to report these events to their healthcare provider, and advise patients how to manage them.

Elevated Blood Bilirubin

Inform patients that taking IDHIFA may cause elevated blood bilirubin, which is due to its mechanism of action, and not due to liver damage. Advise patients to report any changes to the color of their skin or the whites of their eyes to their healthcare provider for further evaluation.

Embryo-Fetal Toxicity and Use of Contraceptives

Advise female patients with reproductive potential to use effective contraceptive methods while receiving IDHIFA and to avoid pregnancy while on treatment and for 2 months after completion of treatment. Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during IDHIFA treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with IDHIFA and for at least 2 months after the last dose of IDHIFA. Coadministration of IDHIFA may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time.

Lactation

Advise women not to breastfeed during treatment with IDHIFA and for at least 2 months after the final dose.

Dosing and Storage Instructions

Advise patients not to chew or split the tablets but swallow whole with a cup of water.
Instruct patients that if they miss a dose or vomit after a dose of IDHIFA, to take it as soon as possible on the same day and return to normal schedule the following day. Warn patients not to take 2 doses to make up for the missed dose.

Keep IDHIFA in the original container. Keep the container tightly closed with desiccant canister inside to protect the tablets from moisture.