Inrebic Drug Information

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).

Required Concomitant Medications

During treatment with INREBIC, all patients should receive prophylaxis with thiamine 100 mg orally daily.

Recommended Dosage

Conduct baseline testing of thiamine (Vitamin B1) levels prior to initiation of INREBIC. 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). 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 at room temperature. 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. o Discard the prepared dose if not given within 2 hours.

Monitoring for Safety Obtain the following blood tests prior to starting treatment with INREBIC, periodically during treatment, and as clinically indicated: • Thiamine (Vitamin B1) level • Complete blood count with platelets • Creatinine and BUN • Hepatic panel • Amylase and lipase

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.

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).

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 Consider dose reductions for patients who become transfusion-dependent during treatment with INREBIC. Table 2:

Management of Thiamine Levels and Wernicke's Encephalopathy (WE) Assess thiamine levels and nutritional status 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 INREBIC treatment all patients should receive prophylaxis with daily 100 mg oral thiamine and should have thiamine levels assessed as clinically indicated. If Wernicke's encephalopathy is suspected, immediately discontinue treatment with INREBIC and initiate parenteral thiamine treatment. Monitor until symptoms resolve or improve and thiamine levels normalize.

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 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.

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. 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.

Serious adverse reactions occurred in 21% of INREBIC-treated patients. 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 received INREBIC included diarrhea and nausea.

Tables 3 and 4 summarize the common adverse reactions and laboratory abnormalities, respectively, in JAKARTA during randomized treatment. Changes in selected postbaseline laboratory values that were observed are shown in Table 4 for the JAKARTA trial during randomized treatment. Table 4: Selected Laboratory Abnormalities That Have Worsened from Baseline (≥20%) in Patients Receiving INREBIC with a Difference between Arms of >10% When Compared to Placebo in JAKARTA during Randomized Treatment 5 0 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.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of INREBIC. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Eye Disorders: Uveitis Metabolism and nutrition disorders: Hypoglycemia (class effect)

Effect of Other Drugs on INREBIC Strong CYP3A4 Inhibitors Coadministration of INREBIC with a strong CYP3A4 inhibitor increases fedratinib exposure. 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. Strong and Moderate CYP3A4 Inducers Coadministration of INREBIC with a strong or moderate CYP3A4 inducer can decrease fedratinib exposure. 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. 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.

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. 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.

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.

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 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. 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.

Pediatric Use The safety and effectiveness of INREBIC in pediatric patients have not been established.

Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.