These Highlights Do Not Include All The Information Needed To Use Inrebic Safely And Effectively. See Full Prescribing Information For Inrebic.

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) ].

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.

Store below 30°C (86°F).

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

INREBIC (fedratinib) is a kinase inhibitor with the chemical name N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate. Its empirical formula is C₂₇H₃₆N₆O₃S∙2HCl∙H₂O and a molecular weight of 615.62. Fedratinib exhibits pH-dependent aqueous solubility; it is freely soluble in the acidic condition (>100 mg/mL at pH 1) and practically insoluble in the neutral condition (4 mcg/mL at pH 7.4). The chemical structure is:

INREBIC (fedratinib) is available as 100-mg (equivalent to 117.3 mg of fedratinib dihydrochloride monohydrate) hard gelatin capsules for oral administration. Each capsule contains inactive ingredients of silicified microcrystalline cellulose and sodium stearyl fumarate. The capsule shell contains gelatin, red iron oxide, titanium dioxide and white ink.

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.

INREBIC (fedratinib) 100 mg capsules: Reddish brown, opaque, size 0 capsule, printed with "FEDR 100 mg" in white ink.

• •
  Bottles of 120 capsules (NDC 59572-720-12)

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

Of the total number of patients with myelofibrosis who received an INREBIC dose of 400 mg in the clinical studies, 47.3% were greater than 65 years of age and 12.3% were greater than 75 years of age. No overall differences in safety or effectiveness of INREBIC were observed between these patients and younger patients.

None.

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) ]

• •
  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).

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) ].

Reduce INREBIC dose when administered to patients with severe renal impairment (CL_cr 15 mL/min to 29 mL/min by Cockcroft-Gault) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. No modification of the starting dose is recommended for patients with mild to moderate renal impairment (CL_cr 30 mL/min to 89 mL/min by Cockcroft-Gault). Due to potential increase of exposure, patients with preexisting moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions [see Dosage and Administration (2.6) ].

Fedratinib inhibited cytokine-induced STAT3 phosphorylation in whole blood from patients with myelofibrosis. The inhibition of STAT3 phosphorylation was maximal approximately 2 hours after the first dose, with values returning to near baseline at 24 hours. After daily administration of fedratinib, levels of inhibition at steady state PK were similar to the maximal inhibition reached after the first dose of 300 (0.75 times the recommended dose), 400 or 500 mg (1.25 times the recommended dose) of fedratinib.

INREBIC at 300 mg to 500 mg once daily (0.75 to 1.25 times the recommended dose) results in a dose proportional increase in geometric mean fedratinib peak concentrations (C_max) and the area under the plasma concentration time curve over the dosing interval (AUC_tau). The mean steady state levels are achieved within 15 days of daily dosing. The mean accumulation ratio ranged between 3- to 4-fold.

At the dose of 400 mg once daily, the geometric mean (coefficient of variation, %CV) fedratinib C_max is 1804 ng/mL (49%) and AUC_tau is 26870 ng.hr/mL (43%) in patients with myelofibrosis.

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 × 10⁹/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.

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).

Fedratinib is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a JAK2-selective inhibitor with higher inhibitory activity for JAK2 over family members JAK1, JAK3 and TYK2. Abnormal activation of JAK2 is associated with myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera. In cell models expressing mutationally active JAK2^V617F or FLT3^ITD, fedratinib reduced phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited cell proliferation, and induced apoptotic cell death. In mouse models of JAK2^V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT3/5, and improved survival, white blood cell counts, hematocrit, splenomegaly, and fibrosis.

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

• •
  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).

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.

• •
  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 × 10⁹/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).

Capsules: 100 mg, reddish brown, opaque size 0, printed with "FEDR 100 mg" in white ink.

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

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.

• •
  Lactation: Advise not to breastfeed (8.2).

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.

Treatment with INREBIC can cause anemia and thrombocytopenia.

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) ].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Discuss the following with patients prior to and during treatment with INREBIC.

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)].

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.

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) ].

The JAK/STAT pathway has been implicated in bone formation and metabolism, and its inhibition may cause bone abnormalities, e.g., in developing bone. There is currently no evidence of bone abnormalities in patients who received INREBIC.

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.

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

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)].

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).

NDC 59572-720-12

INREBIC^®

(fedratinib) capsules

100 mg

Dispense the accompanying Medication Guide to each patient.

Rx only

120 Capsules

Fedratinib was not carcinogenic in the 6-month Tg.rasH2 transgenic mouse model.

Fedratinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration assay (Chinese hamster ovary cells) or in vivo in a micronucleus test in rats.

In a fertility study in rats, fedratinib was administered for at least 70 days (males) and 14 days (females) prior to cohabitation and up to the implantation day (gestation day 7). Fedratinib had no effect on the estrous cycle parameters, mating performance, fertility, pregnancy rate or reproductive parameters in male or female rats at doses up to 30 mg/kg. The exposure (AUC) at the dose of 30 mg/kg/day is approximately 0.10 to 0.13 times the clinical exposure at the recommended daily dose.

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 [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

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)].

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) ].

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.

Store below 30°C (86°F).

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

INREBIC (fedratinib) is a kinase inhibitor with the chemical name N-tert-butyl-3-[(5-methyl-2-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}pyrimidin-4-yl)amino]benzenesulfonamide dihydrochloride monohydrate. Its empirical formula is C₂₇H₃₆N₆O₃S∙2HCl∙H₂O and a molecular weight of 615.62. Fedratinib exhibits pH-dependent aqueous solubility; it is freely soluble in the acidic condition (>100 mg/mL at pH 1) and practically insoluble in the neutral condition (4 mcg/mL at pH 7.4). The chemical structure is:

INREBIC (fedratinib) is available as 100-mg (equivalent to 117.3 mg of fedratinib dihydrochloride monohydrate) hard gelatin capsules for oral administration. Each capsule contains inactive ingredients of silicified microcrystalline cellulose and sodium stearyl fumarate. The capsule shell contains gelatin, red iron oxide, titanium dioxide and white ink.

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.

INREBIC (fedratinib) 100 mg capsules: Reddish brown, opaque, size 0 capsule, printed with "FEDR 100 mg" in white ink.

• •
  Bottles of 120 capsules (NDC 59572-720-12)

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

Of the total number of patients with myelofibrosis who received an INREBIC dose of 400 mg in the clinical studies, 47.3% were greater than 65 years of age and 12.3% were greater than 75 years of age. No overall differences in safety or effectiveness of INREBIC were observed between these patients and younger patients.

None.

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) ]

• •
  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).

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) ].

Reduce INREBIC dose when administered to patients with severe renal impairment (CL_cr 15 mL/min to 29 mL/min by Cockcroft-Gault) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. No modification of the starting dose is recommended for patients with mild to moderate renal impairment (CL_cr 30 mL/min to 89 mL/min by Cockcroft-Gault). Due to potential increase of exposure, patients with preexisting moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions [see Dosage and Administration (2.6) ].

Fedratinib inhibited cytokine-induced STAT3 phosphorylation in whole blood from patients with myelofibrosis. The inhibition of STAT3 phosphorylation was maximal approximately 2 hours after the first dose, with values returning to near baseline at 24 hours. After daily administration of fedratinib, levels of inhibition at steady state PK were similar to the maximal inhibition reached after the first dose of 300 (0.75 times the recommended dose), 400 or 500 mg (1.25 times the recommended dose) of fedratinib.

INREBIC at 300 mg to 500 mg once daily (0.75 to 1.25 times the recommended dose) results in a dose proportional increase in geometric mean fedratinib peak concentrations (C_max) and the area under the plasma concentration time curve over the dosing interval (AUC_tau). The mean steady state levels are achieved within 15 days of daily dosing. The mean accumulation ratio ranged between 3- to 4-fold.

At the dose of 400 mg once daily, the geometric mean (coefficient of variation, %CV) fedratinib C_max is 1804 ng/mL (49%) and AUC_tau is 26870 ng.hr/mL (43%) in patients with myelofibrosis.

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 × 10⁹/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.

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).

Fedratinib is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a JAK2-selective inhibitor with higher inhibitory activity for JAK2 over family members JAK1, JAK3 and TYK2. Abnormal activation of JAK2 is associated with myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera. In cell models expressing mutationally active JAK2^V617F or FLT3^ITD, fedratinib reduced phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited cell proliferation, and induced apoptotic cell death. In mouse models of JAK2^V617F-driven myeloproliferative disease, fedratinib blocked phosphorylation of STAT3/5, and improved survival, white blood cell counts, hematocrit, splenomegaly, and fibrosis.

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

• •
  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).

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.

• •
  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 × 10⁹/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).

Capsules: 100 mg, reddish brown, opaque size 0, printed with "FEDR 100 mg" in white ink.

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

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.

• •
  Lactation: Advise not to breastfeed (8.2).

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.

Treatment with INREBIC can cause anemia and thrombocytopenia.

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) ].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Discuss the following with patients prior to and during treatment with INREBIC.

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)].

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.

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) ].

The JAK/STAT pathway has been implicated in bone formation and metabolism, and its inhibition may cause bone abnormalities, e.g., in developing bone. There is currently no evidence of bone abnormalities in patients who received INREBIC.

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.

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

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)].

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).

NDC 59572-720-12

INREBIC^®

(fedratinib) capsules

100 mg

Dispense the accompanying Medication Guide to each patient.

Rx only

120 Capsules

Fedratinib was not carcinogenic in the 6-month Tg.rasH2 transgenic mouse model.

Fedratinib was not mutagenic in a bacterial mutagenicity assay (Ames test) or clastogenic in in vitro chromosomal aberration assay (Chinese hamster ovary cells) or in vivo in a micronucleus test in rats.

In a fertility study in rats, fedratinib was administered for at least 70 days (males) and 14 days (females) prior to cohabitation and up to the implantation day (gestation day 7). Fedratinib had no effect on the estrous cycle parameters, mating performance, fertility, pregnancy rate or reproductive parameters in male or female rats at doses up to 30 mg/kg. The exposure (AUC) at the dose of 30 mg/kg/day is approximately 0.10 to 0.13 times the clinical exposure at the recommended daily dose.

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 [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

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)].