Drug Safety-related Labeling Changes (SrLC)

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INREBIC (NDA-212327)

(FEDRATINIB HYDROCHLORIDE)

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

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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)].

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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