FEDRATINIB Drug Interactions: What You Need to Know

INTERACTIONS

• Strong CYP3A4 Inhibitors: Reduce INREBIC dose as recommended ( 2.3 , 7.1 ).
• Strong and Moderate CYP3A4 Inducers: Avoid use of INREBIC ( 7.1 ).
• CYP3A4, CYP2C19, or CYP2D6 Substrates: Dose modifications of substrates drugs may be needed ( 7.2 ).
• OCT2 and MATE1/2-K Substrates: Dose modifications of substrate drugs may be needed ( 7.2 ).

7.1 Effect of Other Drugs on INREBIC Strong CYP3A4 Inhibitors Coadministration of INREBIC with a strong CYP3A4 inhibitor increases fedratinib exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Increased exposure may increase the risk of adverse reactions. Consider alternative therapies that do not strongly inhibit CYP3A4 activity. Alternatively, reduce the dose of INREBIC when administering with a strong CYP3A4 inhibitor <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . Strong and Moderate CYP3A4 Inducers Coadministration of INREBIC with a strong or moderate CYP3A4 inducer can decrease fedratinib exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Decreased exposure may reduce the effectiveness of INREBIC. Avoid INREBIC with strong and moderate CYP3A4 inducers. Dual CYP3A4 and CYP2C19 Inhibitors Coadministration of INREBIC with a dual CYP3A4 and CYP2C19 inhibitor increases fedratinib exposure <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Increased exposure may increase the risk of adverse reactions. Due to potential increase of exposure, patients taking concomitant dual CYP3A4 and CYP2C19 inhibitors require more intensive safety monitoring and, if necessary, dose modifications of INREBIC based on adverse reactions <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span> .

7.2 Effect of INREBIC on Other Drugs 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . 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.

None. None.

AND PRECAUTIONS

• Anemia and Thrombocytopenia: Manage by dose reduction, interruption, or transfusion ( 5.2 ).
• Gastrointestinal Toxicity: Manage by dose reduction or interruption if patient develops severe diarrhea, nausea, or vomiting. Prophylaxis with antiemetics and treatment with antidiarrhea medications are recommended ( 5.3 ).
• Hepatic Toxicity: Manage by dose reduction or interruption ( 5.4 ).
• Amylase and Lipase Elevation: Manage by dose reduction or interruption ( 5.5 ).
• Uveitis: Monitor for symptoms and refer for ophthalmological evaluation ( 5.6 ).
• Major Adverse Cardiac Events (MACE): Monitor for development of MACE ( 5.7 ).
• Thrombosis: Evaluate and treat symptoms of thrombosis promptly ( 5.8 ).
• Secondary Malignancies: Monitor for development of secondary malignancies, particularly in patients who are current or past smokers ( 5.9 ).

5.1 Encephalopathy, Including Wernicke&apos;s Serious and fatal encephalopathy, including Wernicke&apos;s encephalopathy, has occurred in INREBIC-treated patients. Serious cases were reported in 1.3% (8/608) of patients treated with INREBIC in clinical trials and 0.16% (1/608) of cases were fatal. Wernicke&apos;s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Signs and symptoms of Wernicke&apos;s encephalopathy may include ataxia, mental status changes, and ophthalmoplegia (e.g., nystagmus, diplopia). Any change in mental status, confusion, or memory impairment should raise concern for potential encephalopathy, including Wernicke&apos;s, and prompt a full evaluation including a neurologic examination, assessment of thiamine levels, and imaging. Assess thiamine levels in all patients prior to starting INREBIC. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.7) and Adverse Reactions (6.1) ]</span> .

5.2 Anemia and Thrombocytopenia Treatment with INREBIC can cause anemia and thrombocytopenia.

Anemia

New or worsening Grade 3 anemia occurred in 34% of INREBIC-treated patients. The median time to onset of the first Grade 3 anemia was approximately 2 months, with 75% of cases occurring within 3 months. Mean hemoglobin levels reached nadir after 12 to 16 weeks with partial recovery and stabilization after 16 weeks. Red blood cell transfusions were received by 51% of INREBIC-treated patients and permanent discontinuation of INREBIC occurred due to anemia in 1% of patients. Consider dose reduction for patients who become red blood cell transfusion dependent [see Dosage and Administration (2.6) ] .

Thrombocytopenia

New or worsening Grade ≥3 thrombocytopenia during the randomized treatment period occurred in 12% of INREBIC-treated patients. The median time to onset of the first Grade 3 thrombocytopenia was approximately 1 month; with 75% of cases occurring within 4 months. Platelet transfusions were received by 3.1% of INREBIC-treated patients. Permanent discontinuation of treatment due to thrombocytopenia and bleeding that required clinical intervention both occurred in 2.1% of INREBIC-treated patients. Obtain a complete blood count (CBC) at baseline, periodically during treatment, and as clinically indicated.

For Grade

3 thrombocytopenia with active bleeding or Grade 4 thrombocytopenia, interrupt INREBIC until resolved to less than or equal to Grade 2 or baseline. Restart dose at 100 mg daily below the last given dose and monitor platelets as clinically indicated [see Dosage and Administration (2.6) ].

5.3 Gastrointestinal Toxicity Gastrointestinal toxicities are the most frequent adverse reactions in INREBIC-treated patients. During the randomized treatment period, diarrhea occurred in 66% of patients, nausea in 62% of patients, and vomiting in 39% of patients.

Grade

3 diarrhea and vomiting occurred in 5% and 3.1% of patients, respectively. The median time to onset of any grade nausea, vomiting, and diarrhea was 1 day, with 75% of cases occurring within 2 weeks of treatment. Consider providing appropriate prophylactic antiemetic therapy (e.g., 5-HT3 receptor antagonists) during INREBIC treatment. Treat diarrhea with antidiarrheal medications promptly at the first onset of symptoms.

For Grade

3 or higher nausea, vomiting, or diarrhea not responsive to supportive measures within 48 hours, interrupt INREBIC until resolved to Grade 1 or less or baseline. Restart dose at 100 mg daily below the last given dose [see Dosage and Administration (2.6 ) ] . Monitor thiamine levels and replete as needed.

5.4 Hepatic Toxicity Elevations of ALT and AST (all grades) during the randomized treatment period occurred in 43% and 40%, respectively, with Grade 3 or 4 in 1% and 0%, respectively, of INREBIC-treated patients. The median time to onset of any grade transaminase elevation was approximately 1 month, with 75% of cases occurring within 3 months. Monitor hepatic function at baseline, periodically during treatment, and as clinically indicated.

For Grade

3 or higher ALT and/or AST elevations (greater than 5 × ULN), interrupt INREBIC dose until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose. If reoccurrence of a Grade 3 or higher elevation of ALT/AST, discontinue treatment with INREBIC [see Dosage and Administration (2.6) ].

5.5 Amylase and Lipase Elevation Grade 3 or higher amylase and/or lipase elevations developed in 2% and 10%, respectively, of INREBIC-treated patients. The median time to onset of any grade amylase or lipase elevation was 15 days, with 75% of cases occurring within 1 month of starting treatment. One patient developed pancreatitis in the fedratinib clinical development program (n=608) and pancreatitis resolved with treatment discontinuation. Monitor amylase and lipase at baseline, periodically during treatment, and as clinically indicated.

For Grade

3 or higher amylase and/or lipase elevations, interrupt INREBIC until resolved to Grade 1 or less or to baseline. Restart dose at 100 mg daily below the last given dose [see Dosage and Administration (2.6) ].

5.6 Uveitis Uveitis has been observed in post-approval clinical studies with an overall incidence of 4% (11/251). Among patients with INREBIC-associated uveitis, more than half cases observed were in Japanese patients (55%; 6/11). INREBIC-associated uveitis is a late-onset adverse reaction, with the first episode occurring at a median of 14 months after starting treatment, with a range of 8 to 22 months. Recurrent uveitis was reported in some patients who continued INREBIC. The uveitis episodes varied in severity, with grade 1/2 in 60% of episodes, and grade 3/4 in 40% of episodes. Topical steroids were sufficient for treatment in 75% of episodes, and systemic steroids were required in 25% of episodes. Among the patients developing uveitis, INREBIC was discontinued due to uveitis in 27% of patients. Advise patients on the risks of developing uveitis before starting INREBIC therapy. Common uveitis symptoms include eye pain, redness, photophobia, floaters, and decreased vision. In case of symptoms, prompt ophthalmologic evaluation is recommended.

5.7 Major Adverse Cardiac Events (MACE)

Another Janus

Kinase (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.

5.8 Thrombosis 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. Promptly evaluate and treat patients with symptoms of thrombosis.

5.9 Secondary Malignancies Another JAK-inhibitor has increased the risk of lymphoma and other malignancies excluding nonmelanoma 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.