Fedratinib

Fedratinib (available as Inrebic) is approved for one specific cancer indication in adults:

• Inrebic is used to treat adults with intermediate-2 or high-risk myelofibrosis (MF) — a bone marrow cancer that leads to scarring of the marrow and abnormal blood cell production.
• This includes primary myelofibrosis (which arises on its own) and secondary myelofibrosis that developed after polycythemia vera (post-PV MF) or essential thrombocythemia (post-ET MF).
• Inrebic has been studied in patients who are newly starting treatment as well as those who were previously treated with ruxolitinib.

Fedratinib is a kinase inhibitor — a drug that blocks specific proteins that tell cells to grow and divide. It targets JAK2 (Janus Associated Kinase 2), a protein that is abnormally overactive in myelofibrosis and drives the out-of-control production of blood cells. Fedratinib also blocks a related protein called FLT3. By selectively inhibiting JAK2 more than the closely related family members JAK1, JAK3, and TYK2, it disrupts the faulty signaling cascade — slowing abnormal cell growth, reducing spleen enlargement, and helping restore more normal blood cell levels.

In laboratory and animal models, fedratinib reduced the activity of STAT3 and STAT5 proteins (key messengers downstream of JAK2), inhibited cancer cell growth, and triggered cell death in abnormal cells — including those carrying common myelofibrosis mutations like JAK2 V617F.

Inrebic capsules are taken once daily by mouth. They can be taken with or without food, though taking them with a high-fat meal may help reduce nausea and vomiting. If you have difficulty swallowing capsules whole — or if you have a nasogastric tube — the capsule contents can be opened and mixed into approximately 180 mL of Ensure® Plus nutritional supplement, then administered within 2 hours.

• Take your dose at roughly the same time each day.
• If you miss a dose, skip it and resume the next day — do not take two doses to make up for a missed one.
• All patients must take a daily oral thiamine (vitamin B1) supplement throughout treatment.
• Never stop or interrupt Inrebic without talking to your doctor first — abrupt discontinuation can cause a dangerous flare of myelofibrosis symptoms.

The most common side effects of Inrebic (reported in more than 20% of patients) are:

• Diarrhea
• Nausea
• Vomiting
• Anemia (low red blood cell count)
• Fatigue or weakness
• Thrombocytopenia (low platelet count)
• Constipation

More serious reactions — including severe drops in blood counts, liver enzyme elevations, elevated pancreatic enzymes, eye inflammation (uveitis), heart events, blood clots, and the potentially fatal brain condition Wernicke's encephalopathy — require prompt medical attention and may lead to dose changes or stopping the medication.

• Wernicke's encephalopathy: A potentially fatal brain condition caused by thiamine deficiency has occurred in Inrebic-treated patients. Thiamine levels must be checked before starting, and all patients must take daily thiamine supplements. Warning signs — confusion, coordination loss, abnormal eye movements — require immediate discontinuation and emergency thiamine treatment.
• Anemia and low platelets: Significant drops in red blood cells and platelets are common, often developing within the first few months. Regular blood count monitoring and possible dose adjustments or transfusions may be needed.
• Gastrointestinal toxicity: Diarrhea, nausea, and vomiting are very frequent and typically begin within the first few days. Anti-nausea and anti-diarrheal medications are recommended; severe cases may require a dose interruption.
• Liver and pancreatic enzyme elevations: Liver enzymes (ALT, AST) and pancreatic enzymes (amylase, lipase) can rise, sometimes to serious levels, requiring monitoring and possible dose changes.
• Uveitis (eye inflammation): Has occurred in post-approval use, sometimes appearing more than a year after starting treatment. Symptoms include eye pain, redness, light sensitivity, floaters, and vision changes.
• Heart events, blood clots, and secondary cancers: Based on data from a related class of drugs (JAK inhibitors), there is a potential increased risk of serious cardiovascular events, thrombosis (blood clots), and secondary cancers — particularly in current or past smokers.
• Symptom flare after stopping: Stopping Inrebic suddenly can cause a dangerous worsening of myelofibrosis symptoms. Always taper under a doctor's guidance.

Fedratinib is processed by liver enzymes (CYP3A4, CYP2C19) and can affect how other drugs are metabolized — making interactions an important consideration:

• Strong CYP3A4 inhibitors (e.g., ketoconazole): Significantly raise fedratinib levels, increasing side effect risk — a dose reduction of Inrebic is required.
• Dual CYP3A4 and CYP2C19 inhibitors (e.g., fluconazole): Also raise fedratinib exposure — closer monitoring and possible dose adjustment needed.
• Strong or moderate CYP3A4 inducers (e.g., rifampin, efavirenz): Lower fedratinib levels, potentially making it less effective — avoid this combination.
• CYP3A4, CYP2C19, or CYP2D6 substrate drugs (many common medications including certain sedatives, antidepressants, and heart drugs): Fedratinib can raise their blood levels, increasing their side effects — dosing adjustments may be needed.
• Metformin and other OCT2/MATE substrate drugs: Fedratinib can slow kidney clearance of these drugs, raising their levels in the blood — monitoring and dose adjustments may be needed.

This is not a complete list of interactions. Always talk with your doctor or pharmacist before starting, stopping, or changing any medication.

• Thiamine deficiency: Inrebic must NOT be started if your thiamine (vitamin B1) levels are low — they must be corrected first.
• Severe kidney disease: Patients with severe renal impairment require a lower dose of Inrebic; moderate impairment calls for closer monitoring.
• All other medications: Tell your doctor and pharmacist about every medication, supplement, and herbal product you take, as many can interact with fedratinib.
• Pregnancy: Inrebic can harm a developing baby based on animal studies. Discuss the risks carefully with your doctor if you are pregnant or could become pregnant.
• Breastfeeding: Do not breastfeed while taking Inrebic or for at least one month after the last dose, due to the potential for serious harm to a nursing infant.
• Children: Safety and effectiveness in patients under 18 have not been established.
• Older adults: Patients over 65 have been included in clinical trials without an overall difference in safety or effectiveness, though close monitoring is still important.
• Current or past smokers: There may be additional risk of serious heart events and secondary cancers — discuss benefits and risks with your doctor.

There is limited specific information about what an overdose of fedratinib would look like. If you or someone else takes too much Inrebic, contact the Poison Help Line at 1-800-222-1222 or go to the nearest emergency room. A medical toxicologist can provide additional guidance on managing an overdose.

After a dose of fedratinib, the drug begins blocking JAK2 signaling measurably within about 2 hours — seen as reduced phosphorylation (activation) of a key messenger protein called STAT3 in the blood. This effect largely returns to baseline levels within 24 hours, but with once-daily dosing at steady state, the level of JAK2 inhibition is maintained consistently throughout treatment. At the doses used clinically, no large effects on the QTc interval (a measure of heart rhythm) were detected, suggesting a low risk of medication-induced heart rhythm problems at recommended doses.

Fedratinib is taken by mouth and reaches peak blood levels in about 3 hours. It builds up gradually in the body, reaching steady-state levels within about 15 days of daily dosing, with roughly 3–4 times more drug present at steady state than after a single dose. The drug has a long effective half-life of about 41 hours (meaning it takes days to fully clear), and it is primarily broken down by liver enzymes (CYP3A4 and CYP2C19). Most of the drug leaves the body through the stool (about 77%), with a small amount excreted in urine (about 5%). Food modestly increases absorption but does not require dose timing adjustments.

Store below 30°C (86°F).