Inrebic

1 INDICATIONS AND USAGE INREBIC ® is indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF). INREBIC is a kinase inhibitor indicated for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF) ( 1 ).

2 DOSAGE AND ADMINISTRATION • Recommended Dosage: 400 mg orally once daily with or without food for patients with a baseline platelet count of greater than or equal to 50 × 10 9 /L ( 2.2 ). • For patients who have difficulty swallowing capsules whole or those with a nasogastric tube, the content of the capsule(s) may be dispersed in Ensure ® Plus ( 2.2 ). • Reduce dose for patients taking strong CYP3A inhibitors or with severe renal impairment ( 2.3 , 2.4 , 7.1 , 8.6 ). 2.1 Required Concomitant Medications During treatment with INREBIC, all patients should receive prophylaxis with thiamine 100 mg orally daily [see Dosage and Administration (2.7) and Warnings and Precautions (5.1) ]. 2.2 Recommended Dosage Conduct baseline testing of thiamine (Vitamin B1) levels prior to initiation of INREBIC [see Dosage and Administration (2.7) , Warnings and Precautions (5.1) ] . The recommended dosage of INREBIC is 400 mg taken orally once daily for patients with a baseline platelet count of greater than or equal to 50 × 10 9 /L. Modify the dose for patients using concomitant strong CYP3A4 inhibitors, and in patients with severe renal impairment (creatinine clearance (CL cr ) 15 mL/min to 29 mL/min) [see Dosage and Administration (2.4 , 2.5) ] . Patients that are on treatment with ruxolitinib before the initiation of INREBIC must taper and discontinue according to the ruxolitinib prescribing information. Administration Information: • INREBIC may be taken with or without food. Administration with a high fat meal may reduce the incidence of nausea and vomiting. • If a dose of INREBIC is missed, the next scheduled dose should be taken the following day. • For patients who have difficulty swallowing capsule(s) whole or those with a nasogastric tube: o Open the capsule(s). o In a glass container, mix the content of the capsule(s) with approximately 180 mL of Ensure ® Plus liquid nutritional supplement [see Clinical Pharmacology (12.3) ] at room temperature [between 20°C to 25°C (68°F to 77°F)]. o Promptly administer the mixture orally or through a nasogastric tube (French size 14 or 16) within 2 hours of preparation. o If using a nasogastric tube, flush it with 60 mL of water after administering the mixture [see Clinical Pharmacology (12.3 )]. o Discard the prepared dose if not given within 2 hours. 2.3 Monitoring for Safety Obtain the following blood tests prior to starting treatment with INREBIC, periodically during treatment, and as clinically indicated [see Warnings and Precautions (5.1 , 5.2 , 5.4 , 5.5) ]: • Thiamine (Vitamin B1) level • Complete blood count with platelets • Creatinine and BUN • Hepatic panel • Amylase and lipase 2.4 Dose Modifications with Concomitant Use of Strong CYP3A4 Inhibitors Reduce INREBIC dose when administering with strong CYP3A4 inhibitors to 200 mg once daily. In cases where coadministration with a strong CYP3A4 inhibitor is discontinued, INREBIC dosage should be increased to 300 mg once daily during the first two weeks after discontinuation of the CYP3A4 inhibitor, and then to 400 mg once daily thereafter as tolerated [see Drug Interactions (7.1) ] . 2.5 Dose Modifications for Severe Renal Impairment Reduce INREBIC dose to 200 mg once daily in patients with severe renal impairment (creatinine clearance (CL cr ) 15 mL/min to 29 mL/min as estimated by Cockcroft-Gault (C-G) equation). 2.6 Dose Modifications for Adverse Reactions Modify dose for hematologic and nonhematologic adverse reactions per Table 1 and Table 2. Discontinue INREBIC in patients unable to tolerate a dose of 200 mg daily. See Warnings and Precautions for other mitigating strategies. Table 1: Dose Modifications for Hematologic Adverse Reactions Hematologic Adverse Reactions Dose Reduction Grade 4 Thrombocytopenia or Grade 3 Thrombocytopenia with active bleeding Interrupt dose until resolved to Grade 2 or lower or baseline. Restart dose at 100 mg daily below the last given dose. Grade 4 Neutropenia Interrupt dose until resolved to Grade 2 or lowe…

5 WARNINGS 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 ). • Symptom Exacerbation Following Interruption or Discontinuation of Treatment: Manage with supportive care and consider resuming treatment with INREBIC ( 5.10 ). 5.1 Encephalopathy, Including Wernicke's Serious and fatal encephalopathy, including Wernicke'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's encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Signs and symptoms of Wernicke'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'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 [see Dosage and Administration (2.7) and Adverse Reactions (6.1) ] . 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 Do…

4 CONTRAINDICATIONS None None

7 DRUG 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 [see Clinical Pharmacology (12.3) ] . 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 [see Dosage and Administration (2.4) ] . 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 Coadministration of INREBIC with a dual CYP3A4 and CYP2C19 inhibitor increases fedratinib exposure [see Clinical Pharmacology (12.3) ] . 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 [see Dosage and Administration (2.6) ] . 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 [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.

8.1 Pregnancy Risk Summary There are no available data on INREBIC use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of fedratinib to pregnant rats during organogenesis at doses considerably lower than the recommended human daily dose of 400 mg/day resulted in adverse developmental outcomes (see Data ) . Consider the benefits and risks of INREBIC for the mother and possible risks to the fetus when prescribing INREBIC to a pregnant woman. The background risk of major birth defects and miscarriage for the indicated population is unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. 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 Animal Data In an embryo-fetal development study in pregnant rats, fedratinib administration at a dose of 30 mg/kg/day during organogenesis (gestation days 6 to 17) was associated with adverse developmental outcomes including skeletal variations (such as additional ossification center of neuronal arches). These effects occurred in rats at approximately 0.1 times the clinical exposure based on AUC at the recommended daily dose. At lower doses of 10 mg/kg/day (0.01 times the clinical exposure at the recommended daily dose), fedratinib administered to pregnant rats resulted in maternal toxicity of decreased gestational weight gain. In an embryo-fetal development study in pregnant rabbits, fedratinib administration during organogenesis (gestation Days 6 to 18) did not produce developmental or maternal toxicity at doses up to the highest dose level tested, 30 mg/kg/day (approximately 0.08 times the clinical exposure at the recommended daily dose). In a separate study, administration of 80 mg/kg/day fedratinib to rabbits resulted in maternal mortality. In a pre- and postnatal study in rats, fedratinib was administered to pregnant female rats at doses of 3, 10, or 30 mg/kg/day from Day 6 of gestation through Day 20 of lactation, with weaning on Day 21. A slight decrease in maternal body weight gain during gestation occurred at 30 mg/kg/day. The offspring from the high dose (30 mg/kg) had decreased body weight preweaning in both sexes and postweaning through the maturation phase in males. These effects occurred at exposures approximately 0.1 times the clinical exposure at the recommended daily dose.

6 ADVERSE REACTIONS 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) ] • Uveitis [see Warnings and Precautions (5.6) ] • Major Adverse Cardiac Events [see Warnings and Precautions (5.7) ] • Thrombosis [see Warnings and Precautions (5.8) ] • Secondary Malignancies [see Warnings and Precautions (5.9) ] • Symptom Exacerbation Following Interruption or Discontinuation of Treatment [see Warnings and Precautions (5.10) ] The most common adverse reactions (≥20%) are diarrhea, nausea, anemia, and vomiting ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the WARNINGS AND PRECAUTIONS Section 5.1 Encephalopathy, including Wernicke's, reflect exposure to INREBIC as a single agent in 608 patients who received more than one dose (ranging from 30 mg to 800 mg) in Studies JAKARTA, ARD11936, JAKARTA2, ARD12042, ARD12888, TED12037/TED12015, INT12497, and TES13519, of whom 459 were patients with myelofibrosis, including 97 patients previously treated with ruxolitinib. Among the 608 patients receiving INREBIC, the median drug exposure was 37 weeks and the median number of cycles initiated was 9 cycles. Fifty-nine percent of 608 patients were exposed for 6 months or longer and 39% were exposed for 12 months or longer. Using the dataset described above, the most common adverse reactions in >20% of patients (N=608) were diarrhea, nausea, anemia, vomiting, fatigue, thrombocytopenia, and constipation. JAKARTA Trial The safety of INREBIC was evaluated in the randomized treatment period of the JAKARTA trial [see Clinical Studies (14) ] . Key eligibility criteria included adult patients with intermediate-2 or high-risk primary MF or post-PV MF or post-ET MF with splenomegaly, platelet count ≥50 × 10 9 /L, and no splenectomy. Patients received INREBIC at 400 mg daily (n=96) or placebo (n=95). Among patients receiving INREBIC, 82% were exposed for more than 6 months and 65% for more than one year. Patients had a median duration of exposure to INREBIC 400 mg daily of 15.5 months compared with placebo where patients were treated for 6 months or until disease progression after which patients were allowed to crossover to active treatment. The median age of patients who received INREBIC was 65 years (range: 27 to 86 years), 59% were male, 90% were White, 8% were Asian, 1% were Black, 1% were Other, and 92% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Serious adverse reactions occurred in 21% of INREBIC-treated patients. Serious adverse reactions in ≥2% of patients receiving INREBIC 400 mg daily included cardiac failure (5%) and anemia (2%). Fatal adverse reactions of cardiogenic shock occurred in 1% of patients receiving INREBIC 400 mg daily. Permanent discontinuation due to an adverse reaction occurred in 14% of patients receiving INREBIC. Most frequent reasons for permanent discontinuation in ≥2% of patients receiving INREBIC included cardiac failure (3%), thrombocytopenia, myocardial ischemia, diarrhea, and increased blood creatinine (2% each). Dosage interruptions due to an adverse reaction during the randomized treatment period occurred in 21% of patients who received INREBIC. Adverse reactions requiring dosage interruption in >3% of patients who receiv…