INREBIC
Clinical safety rating: caution
Comprehensive clinical and safety monograph for INREBIC (INREBIC).
Fedratinib is a selective Janus kinase 2 (JAK2) inhibitor. It inhibits JAK2 and its mutant forms, including JAK2V617F, leading to reduced phosphorylation of signal transducer and activator of transcription (STAT) proteins and decreased proliferation of abnormal hematopoietic cells.
| Metabolism | Primarily metabolized by CYP2C19 and CYP3A4, with minor contributions from CYP2D6 and flavin-containing monooxygenase (FMO) enzymes. |
| Excretion | Fecal (77.6% as metabolites, 2.2% as unchanged drug); renal (8.5% as metabolites, <1% as unchanged drug) |
| Half-life | Terminal elimination half-life approximately 14 hours; supports twice-daily dosing for steady-state attainment within 3 days |
| Protein binding | 95.1% protein bound (primarily to albumin) |
| Volume of Distribution | 3.5 L/kg (large Vd indicating extensive tissue distribution) |
| Bioavailability | Oral: 20–30% (absolute bioavailability); absorption is rapid with Tmax 2–4 hours |
| Onset of Action | Oral: Clinical response (e.g., reduction in spleen volume or symptom improvement) observed within 4–8 weeks; plasma concentrations reach Cmax at 2–4 hours post-dose |
| Duration of Action | Sustained JAK2 inhibition for 12 hours; consistent twice-daily dosing maintains therapeutic effect |
100 mg orally twice daily continuously until disease progression or unacceptable toxicity.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (GFR ≥30 mL/min). Safety and efficacy not established in severe renal impairment (GFR <30 mL/min) or dialysis; use not recommended. |
| Liver impairment | Child-Pugh A: No dose adjustment. Child-Pugh B: Reduce dose to 75 mg twice daily. Child-Pugh C: Avoid use. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no approved dosing. |
| Geriatric use | No specific dose adjustment recommended based on age alone; monitor for adverse events due to potential age-related renal or hepatic function decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for INREBIC (INREBIC).
| Breastfeeding | No data on the presence of INREBIC in human milk, effects on breastfed infants, or milk production. Because of the potential for serious adverse reactions, breastfeeding is not recommended during treatment and for at least 1 month after the last dose. M/P ratio not available. |
| Teratogenic Risk | First trimester: Based on animal studies and mechanism of action (JAK2 inhibitor), INREBIC (fedratinib) may cause fetal harm. There are no adequate human data. Animal studies show embryofetal toxicity including decreased fetal weights, skeletal variations, and malformations at exposures below human exposure at the recommended dose. Second and third trimesters: Potential for fetal harm remains; avoid use unless benefit outweighs risk. Women of childbearing potential must use effective contraception during treatment and for at least 1 month after the last dose. |
■ FDA Black Box Warning
WARNING: ENCEPHALOPATHY, INCLUDING WERNICKE'S ENCEPHALOPATHY. Serious and fatal cases of encephalopathy, including Wernicke's encephalopathy, have occurred. Use of INREBIC is contraindicated in patients with thiamine deficiency. Perform thiamine levels before starting and monitor during treatment. Interrupt or discontinue INREBIC if encephalopathy is suspected and promptly treat with thiamine replacement.
| Serious Effects |
["Thiamine deficiency","Concomitant use with strong or moderate CYP2C19 inhibitors or inducers","Concomitant use with strong CYP3A4 inhibitors or inducers"]
| Precautions | ["Encephalopathy, including Wernicke's encephalopathy","Gastrointestinal toxicity (severe diarrhea, nausea, vomiting)","Thrombocytopenia and anemia","Hepatotoxicity","Pancreatitis","Major adverse cardiac events (MACE)","Thrombosis","Embryo-fetal toxicity"] |
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| Fetal Monitoring | Monitor complete blood counts (CBC) with differential, electrolytes, renal function, liver function, and amylase/lipase at baseline and periodically during treatment. Assess for signs of Wernicke encephalopathy (neurological symptoms, thiamine levels). Discontinue if Wernicke encephalopathy suspected. In pregnant patients, additional fetal monitoring (ultrasound, growth assessment) is recommended. |
| Fertility Effects | In animal studies, INREBIC caused reduced fertility in male and female rats at exposures below human therapeutic exposure. In humans, potential adverse effects on spermatogenesis and ovarian function are unknown. May impair fertility in both males and females. Contraception recommendations apply. |