Fedratinib - Uses & Side Effects

On August 16, 2019, the Food and Drug Administration approved fedratinib (INREBIC, Impact Biomedicines, Inc.) for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).

The drug is the first new therapy approved for myleofibrosis in nearly a decade.

Myleofibrosis causes blood-forming bone marrow to be replaced with fibrous scar tissue. This deprives patients of energy and makes them vulnerable to infection. Blood-forming cells move to the spleen, liver and other parts of the body, causing additinoal complications.

Fedratinib has an unusually complicated history. It sprang out of research at San Diego’s TargeGen, was tested by Sanofi, then shelved because a few patients developed a dangerous brain inflammation, with one death.
But after Sanofi withdrew the drug from clinical testing in 2013, some patients who had thrived on it died. Others survived on alternatives. Since then, Jamieson and John Hood, who led early research on the drug, had searched for ways to bring it back.

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 x 109/L.

Reduce dose for patients taking strong CYP3A inhibitors or with severe renal impairment.

Side Effects:

The most common adverse reactions (≥20%) are diarrhea, nausea, anemia, and vomiting.

Warnings and Precautions

Encephalopathy, Including Wernicke’s

Serious and fatal encephalopathy, including Wernicke’s encephalopathy, has occurred in INREBIC-treated patients.

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, periodically during treatment, and as clinically indicated. Do not start INREBIC in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue INREBIC and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

Anemia and Thrombocytopenia

Treatment with INREBIC can cause anemia and thrombocytopenia.

Gastrointestinal Toxicity

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.

Hepatic Toxicity

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.

Amylase and Lipase Elevation

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.

* The Content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition.