Dosage & Administration
Inrebic Prescribing Information
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
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 lower or baseline. Restart dose at 100 mg daily below the last given dose. |
Consider dose reductions for patients who become transfusion-dependent during treatment with INREBIC.
Nonhematologic Adverse Reactions | Dose Reduction |
Grade 3 or higher Nausea, Vomiting, or Diarrhea not responding to supportive measures within 48 hours | Interrupt dose until resolved to Grade 1 or lower or baseline. Restart dose at 100 mg daily below the last given dose. |
Grade 3 or higher ALT, AST, or Bilirubin | Interrupt dose until resolved to Grade 1 or lower or baseline. Restart dose at 100 mg daily below the last given dose. |
Grade 3 or higher Other Nonhematologic Toxicities | Interrupt dose until resolved to Grade 1 or lower or baseline. Restart dose at 100 mg daily below the last given dose. |
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
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.
The safety of INREBIC was evaluated in the randomized treatment period of the JAKARTA trial
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 received INREBIC included diarrhea and nausea.
Dosage reductions due to an adverse reaction during the randomized treatment period occurred in 19% of patients who received INREBIC. Adverse reactions requiring dosage reduction in >2% of patients who received INREBIC included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).
The most common adverse reactions (reported in ≥20%) were diarrhea, nausea, anemia, and vomiting.
Tables 3 and 4 summarize the common adverse reactions and laboratory abnormalities, respectively, in JAKARTA during randomized treatment.
| aCTCAE version 4.03. bOnly 1 Grade 4 event (anemia). cIncludes cystitis. | ||||
Adverse Reaction a | INREBIC 400 mg (n=96) | Placebo (n=95) | ||
All Grades % | Grade ≥3 b% | All Grades % | Grade ≥3 % | |
Diarrhea | 66 | 5 | 16 | 0 |
Nausea | 62 | 0 | 15 | 0 |
Anemia | 40 | 30 | 14 | 7 |
Vomiting | 39 | 3.1 | 5 | 0 |
Fatigue or asthenia | 19 | 5 | 16 | 1.1 |
Muscle spasms | 12 | 0 | 1.1 | 0 |
Blood creatinine increased | 10 | 1 | 1.1 | 0 |
Pain in extremity | 10 | 0 | 4.2 | 0 |
Alanine aminotransferase Increased | 9 | 0 | 1.1 | 0 |
Headache | 9 | 0 | 1.1 | 0 |
Weight increased | 9 | 0 | 4.2 | 0 |
Dizziness | 8 | 0 | 3.2 | 0 |
Bone pain | 8 | 0 | 2.1 | 0 |
Urinary tract infectionc | 6 | 0 | 1.1 | 0 |
Dysuria | 6 | 0 | 0 | 0 |
Aspartate aminotransferase increased | 5 | 0 | 1.1 | 0 |
Clinically significant adverse reactions reported in 5% or less of patients: hypertension of all grades was reported in 4.2% of patients and Grade 3 or higher in 3% of INREBIC-treated patients.
Changes in selected postbaseline laboratory values that were observed are shown in Table 4 for the JAKARTA trial during randomized treatment.
INREBIC 400 mg (n=96) | Placebo (n=95) | |||
Laboratory Parameter | All Grades % | Grade ≥3 % | All Grades % | Grade ≥3 % |
Hematology | ||||
Anemia | 74 | 34 | 32 | 10 |
Thrombocytopenia | 47 | 12 | 26 | 10 |
Neutropenia | 23 | 5 | 13 | 3.3 |
Biochemistry | ||||
Creatinine increased | 59 | 3.1 | 19 | 1.1 |
ALT increased | 43 | 1 | 14 | 0 |
AST increased | 40 | 0 | 16 | 1.1 |
Lipase increased | 35 | 10 | 7 | 2.2 |
Hyponatremia | 26 | 5 | 11 | 4.3 |
Amylase increased | 24 | 2.1 | 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.
Boxed Warning | 07/2024 |
Dosage and Administration ( 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)]. | 07/2024 |
Warnings and Precautions ( 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) ] . | 07/2024 |
Warnings and Precautions ( 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. | 05/2025 |
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).
• 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 Recommended DosageConduct baseline testing of thiamine (Vitamin B1) levels prior to initiation of INREBIC
[seeDosage 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 (CLcr) 15 mL/min to 29 mL/min)
[seeDosage 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.
• 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 Recommended DosageConduct baseline testing of thiamine (Vitamin B1) levels prior to initiation of INREBIC
[seeDosage 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 (CLcr) 15 mL/min to 29 mL/min)
[seeDosage 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.
• Reduce dose for patients taking strong CYP3A inhibitors or with severe renal impairment (,2.3 Monitoring for SafetyObtain 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 InhibitorsReduce 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)].,7.1 Effect of Other Drugs on INREBICStrong CYP3A4 InhibitorsCoadministration 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[seeDosage and Administration (2.4)].Strong and Moderate CYP3A4 InducersCoadministration 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 InhibitorsCoadministration 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[seeDosage and Administration (2.6)].).8.6 Renal ImpairmentReduce INREBIC dose when administered to patients with severe renal impairment (CLcr15 mL/min to 29 mL/min by Cockcroft-Gault)
[seeDosage 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 (CLcr30 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[seeDosage and Administration (2.6)].
Capsules: 100 mg, reddish brown, opaque size 0, printed with "FEDR 100 mg" in white ink.
• Lactation: Advise not to breastfeed ().8.2 LactationRisk SummaryThere are no data on the presence of fedratinib or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with INREBIC, and for at least 1 month after the last dose.