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.

INREBIC (NDA-212327)

(FEDRATINIB HYDROCHLORIDE)

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

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07/30/2024 (SUPPL-6)

Approved Drug Label (PDF)

Boxed Warning

Additions and/or revisions underlined:

WARNING: ENCEPHALOPATHY INCLUDING WERNICKE’S

Serious and fatal encephalopathy, including Wernicke’s, has occurred in patients treated with INREBIC. Wernicke’s encephalopathy is a neurologic emergency. Assess thiamine levels in all patients prior to starting INREBIC. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. While on treatment all patients should receive prophylaxis with daily oral thiamine and should have thiamine levels assessed as clinically indicated. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize [see Dosage and Administration (2.6), Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

5 Warnings and Precautions

5.1 Encephalopathy, Including Wernicke’s

Additions and/or revisions underlined:

… Do not start INREBIC in patients with thiamine deficiency. However, if thiamine levels are low, replete thiamine prior to starting treatment. While on treatment all patients should receive prophylaxis with oral thiamine and should have thiamine levels assessed as clinically indicated. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize [see Dosage and Administration (2.7) and Adverse Reactions (6.1)].

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

In FEDR-MF-002, a randomized controlled post-marketing study of INREBIC (n=134) vs. best available therapy (BAT, n=67), the incidence of thiamine levels below the lower limit of normal (< 70 nmol/L) was 21% for INREBIC vs 5% for BAT. Thiamine levels < 30 nmol/L were not observed in the study. The median time to the first low thiamine level after initiation of INREBIC was 30 days. The frequency of low thiamine levels in participants receiving INREBIC was 2% in those receiving thiamine supplementation 100 mg orally per day vs. 39% in those not receiving thiamine supplementation.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Encephalopathy, including Wernicke’s

…

Instruct patients that they should receive prophylaxis with thiamine 100 mg orally daily while taking INREBIC [see Dosage and Administration (2.7)].

…

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about INREBIC? INREBIC may cause serious side effects, including:

Encephalopathy (including Wernicke’s encephalopathy). A serious and sometimes fatal neurological problem called encephalopathy (including Wernicke’s encephalopathy) has happened in some people who take INREBIC.
Wernicke’s encephalopathy is a neurologic emergency that can happen if you do not have enough Vitamin B1 (thiamine) in your body. Your healthcare provider will do a blood test to check your Vitamin B1 level and treat you with Vitamin B1 if your level is too low before starting treatment with INREBIC. Your healthcare provider may also check your Vitamin B1 level during treatment with INREBIC. You should take a Vitamin B1 supplement (100 mg of thiamine) during treatment with INREBIC.
Your healthcare provider may tell you to stop taking INREBIC if you develop side effects during treatment with INREBIC.
…
Before taking INREBIC, tell your healthcare provider about all your medical conditions, including if you:

have low Vitamin B1 (thiamine) levels
have low red blood cell or platelet counts
have or have had liver problems
have or have had kidney problems
are a current or past smoker
have had a blood clot, heart attack, other heart problems, or stroke
have or have had any other cancer
are pregnant or plan to become pregnant. It is not known if INREBIC may harm your unborn baby.
are breastfeeding or plan to breastfeed. It is not known if INREBIC passes into your breast milk. You should not breastfeed during treatment with INREBIC and for at least 1 month after your last dose. Talk to your healthcare provider about the best way to feed your baby during treatment with INREBIC.
…
How should I take INREBIC?

Take INREBIC exactly as your healthcare provider tells you to. Do not change your dose or stop taking INREBIC unless your healthcare provider tells you to.
Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with INREBIC if you develop side effects.
Take INREBIC 1 time each day.
Take INREBIC with or without food. Taking INREBIC with a high fat meal may help to reduce nausea and vomiting symptoms.
Take Vitamin B1 (thiamine 100 mg) by mouth daily to prevent low Vitamin B1 levels during treatment with INREBIC.
If you miss a dose of INREBIC, skip the missed dose and take your usual dose the next day at your regularly scheduled time. Do not take 2 doses to make up for the missed dose.
…

05/15/2023 (SUPPL-5)

12/03/2021 (SUPPL-3)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Effect of Other Drugs on INREBIC

Additions and/or revisions underlined:

Strong CYP3A4 Inhibitors

Coadministration of INREBIC with a strong CYP3A4 inhibitor increases fedratinib exposure [see Clinical Pharmacology (12.3)]. Increased exposure may increase the risk of adverse reactions [see Warnings and Precautions (5), and Adverse Reactions (6.1)]. Consider alternative therapies that do not strongly inhibit CYP3A4 activity. Alternatively, reduce the dose of INREBIC when administering with a strong CYP3A4 inhibitor [see Dosage and Administration (2.3)].

Strong and Moderate CYP3A4 Inducers

Coadministration of INREBIC with a strong or moderate CYP3A4 inducer can decrease fedratinib exposure [see Clinical Pharmacology (12.3)]. Decreased exposure may reduce the effectiveness of INREBIC. Avoid INREBIC with strong and moderate CYP3A4 inducers.

Dual CYP3A4 and CYP2C19 Inhibitors

Avoid INREBIC with dual CYP3A4 and CYP2C19 inhibitor. The effect of concomitant administration of a dual CYP3A4 and CYP2C19 inhibitor with INREBIC has not been studied [see Clinical Pharmacology (12.3)].

7.2 Effect of INREBIC on Other Drugs

Additions and/or revisions underlined:

CYP3A4, CYP2C19, or CYP2D6 Substrate Drugs

Coadministration of INREBIC with drugs that are CYP3A4 substrates, CYP2C19 substrates, or CYP2D6 substrates increases the concentrations of these drugs, which may increase the risk of adverse reactions of these drugs [see Clinical Pharmacology (12.3)]. Monitor for adverse reactions and adjust the dose of drugs that are CYP3A4, CYP2C19, or CYP2D6 substrates as necessary when coadministered with INREBIC.

OCT2 and MATE1/2-K Substrate Drugs

Coadministration of INREBIC with drugs that are renally excreted via organic cation transporter (OCT2) and multidrug and toxin extrusion (MATE)1/2-K can decrease renal clearance of those drugs [see Clinical Pharmacology (12.3)]. Monitor for adverse reactions and consider dose modifications for drugs that are renally excreted via OCT2 or MATE1/2-K (e.g., metformin), as necessary when coadministered with INREBIC.

11/23/2021 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Major Adverse Cardiac Events (MACE)

Newly added section:

Another JAK-inhibitor has increased the risk of MACE, including cardiovascular death, myocardial infarction, and stroke (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which INREBIC is not indicated.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with INREBIC, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors.

Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur.

5.7 Thrombosis

Newly added section:

Another JAK-inhibitor has increased the risk of thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which INREBIC is not indicated. In patients with MF treated with INREBIC in clinical trials, the rates of thromboembolic events were similar in INREBIC and placebo treated patients.

Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately.

5.8 Secondary Malignancies

Newly added section:

Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding non-melanoma skin cancer (NMSC) (compared to those treated with TNF blockers) in patients with rheumatoid arthritis, a condition for which INREBIC is not indicated. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with INREBIC, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy, and patients who are current or past smokers.

6 Adverse Reactions

Additions and revisions underlined:

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

Encephalopathy, including Wernicke’s [see Warnings and Precautions (5.1)]
Anemia and Thrombocytopenia [see Warnings and Precautions (5.2)]
Gastrointestinal Toxicity [see Warnings and Precautions (5.3)]
Hepatic Toxicity [see Warnings and Precautions (5.4)]
Amylase and Lipase Elevation [see Warnings and Precautions (5.5)]
Major Adverse Cardiac Events [see Warnings and Precautions (5.6)]
Thrombosis [see Warnings and Precautions (5.7)]
Secondary Malignancies [see Warnings and Precautions (5.8)]

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

Medication Guide

Additions and revisions underlined:

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

• have low red blood cell or platelet counts

• have or have had liver problems

• have or have had kidney problems

• have had cancer in the past

• are a current or past smoker

• have had a blood clot, heart attack, other heart problems, or stroke

INREBIC can cause serious side effects, including. . .

• Increased risk of major cardiac events such as heart attack, stroke, or death in people who have

cardiovascular risk factors and who are current or past smokers while using another JAK inhibitor to treat rheumatoid arthritis.

Get emergency help right away if you have any symptoms of a heart attack or stroke while taking INREBIC, including:

o discomfort in the center of your chest that lasts for more than a few minutes, or that goes away and comes back

o severe tightness, pain, pressure, or heaviness in your chest, throat, neck, or jaw

o pain or discomfort in your arms, back, neck, jaw, or stomach

o shortness of breath with or without chest discomfort

o breaking out in a cold sweat

o nausea or vomiting

o feeling lightheaded

o weakness in one part or on one side of your body

o slurred speech

• Increased risk of blood clots. Blood clots in the veins of your legs (deep vein thrombosis, DVT) or lungs

(pulmonary embolism, PE) have happened in people taking another JAK inhibitor for rheumatoid arthritis and may be life-threatening.

Tell your healthcare provider right away if you have any signs and symptoms of blood clots during treatment with INREBIC, including:

o swelling, pain, or tenderness in one or both legs

o sudden unexplained chest or upper back pain

o shortness of breath or difficulty breathing

• Possible increased risk of new (secondary) cancers. People who take another JAK inhibitor for rheumatoid arthritis have an increased risk of new (secondary) cancers, including lymphoma and other cancers. People who smoke or who smoked in the past have an added risk of new cancers.

Patient Counseling Information

Newly added information:

Major Adverse Cardiac Events (MACE)

Advise patients that events of major adverse cardiac events (MACE) including myocardial infarction, stroke, and cardiovascular death, have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which INREBIC is not indicated. Advise patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions (5.6)].

Thrombosis

Advise patients that events of DVT and PE have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which INREBIC is not indicated. Advise patients to tell their healthcare provider if they develop any signs or symptoms of a DVT or PE [see Warnings and Precautions (5.7)].

Secondary Malignancies

Advise patients, especially current or past smokers and patients with a known secondary malignancy (other than a successfully treated NMSC), that lymphoma and other malignancies (excluding NMSC) have been reported in clinical studies with another JAK-inhibitor used to treat rheumatoid arthritis, a condition for which INREBIC is not indicated [see Warnings and Precautions (5.8)].