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 |
| Molecular Weight | 377.42 |
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 | Avoid use due to potential teratogenicity; animal studies show embryo-fetal toxicity. |
| 2nd trimester | Avoid use; no adequate human data, but potential for fetal harm based on animal studies. |
| 3rd trimester | Avoid use; risk of fetal myelosuppression and other adverse effects. |
Clinical note
Comprehensive clinical and safety monograph for INREBIC (INREBIC).
| Placental transfer | Predicted to cross placenta based on molecular weight and animal studies; specific data on human placental transfer not available. |
| Breastfeeding | No data on presence in human milk; due to potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for at least 2 weeks after last dose. |
| Lactation Rating |
■ 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 |
Hypersensitivity to fedratinib or any excipientsConcurrent use with strong CYP3A4 inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin, St. John's wort) - due to significant drug interactionSevere hepatic impairment (Child-Pugh class C)
| 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 |
| Food/Dietary | Avoid grapefruit and grapefruit juice. Administer with food to improve tolerability. |
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| L5 |
| 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. |
| 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. |
| Clinical Pearls | INREBIC (fedratinib) is a JAK2-selective inhibitor indicated for myelofibrosis. Monitor for Wernicke’s encephalopathy; obtain thiamine levels before and during treatment. Avoid use in patients with thiamine deficiency. Dose reduce for strong CYP3A4 inhibitors. Baseline and periodic complete blood counts and liver function tests required. |
| Patient Advice | Take with food to reduce nausea. · Do not take with grapefruit or grapefruit juice. · Report signs of Wernicke's encephalopathy: confusion, loss of coordination, vision changes. · Use effective contraception during treatment and for 1 month after last dose. · Avoid live vaccines during treatment. |