Fedratinib Disease Interactions

The pharmacokinetics of fedratinib have not been evaluated in patients with severe hepatic impairment (total bilirubin > 3 times ULN and any AST), and its use should be avoided on these patients.

Serious and fatal encephalopathy, including Wernicke's disease, has occurred in patients treated with fedratinib. Wernicke's encephalopathy is a neurologic emergency. Assess thiamine levels in all patients prior to starting treatment, periodically during treatment, and as clinically indicated. Do not start fedratinib in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue fedratinib and initiate parenteral thiamine. Patients who develop any change in their mental status during treatment, including confusion or memory impairment, should be evaluated for potential encephalopathy (e.g., neurologic examination, thiamine level assessment, imaging). Monitor until symptoms resolve or improve and thiamine levels normalize.

Gastrointestinal (GI) toxicities are the most frequent adverse reactions reported with fedratinib; diarrhea, nausea, and vomiting occurred in more than half of patients. The median time to onset was 1 day, with 75% of cases occurring within 2 weeks of initiating therapy. Consuming a high-fat meal with fedratinib may reduce GI adverse events. Prophylactic antiemetic therapy (e.g., 5-HT3 receptor antagonists) should be considered. Treat diarrhea with antidiarrheals at the first onset of symptoms. For Grade 3 or higher nausea, vomiting, or diarrhea not responsive to supportive measures within 48 hours: Interrupt this drug until resolved to Grade 1 or less or baseline; restart dose at 100 mg/day below the last given dose.

In a major safety study of a Janus kinase (JAK) inhibitor, tofacitinib, in rheumatoid arthritis patients 50 years and older with at least 1 cardiovascular risk factor, higher rates of all-cause mortality (including sudden cardiovascular death) and major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) were observed with the JAK inhibitor when compared with tumor necrosis factor (TNF) blockers; patients who are current or past smokers are at additional increased risk. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including baricitinib, upadacitinib, ruxolitinib, fedratinib, ritlecitinib, and pacritinib. Before starting or continuing therapy, the benefits and risks for the individual patient should be considered, especially in patients with other cardiovascular risk factors and patients who are current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and what to do if they occur. Tofacitinib, baricitinib, and upadacitinib are indicated for patients with inadequate response or intolerance to 1 or more TNF blockers, but should be discontinued in patients who have experienced a myocardial infarction or stroke. The dosage recommended for tofacitinib should not be exceeded; for the treatment of ulcerative colitis, tofacitinib should be used at the lowest effective dose and for the shortest duration needed to achieve and/or maintain therapeutic response.

Malignancies (including lymphomas and solid tumors) have been reported in patients treated with tofacitinib and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions; lymphomas and other malignancies have been seen in patients treated with baricitinib or upadacitinib. Patients who are current or past smokers are at additional increased risk of malignancies. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including ruxolitinib, pacritinib, and fedratinib. Before starting or continuing therapy, the benefits and risks for the individual patient should be considered, especially in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer), patients who develop a malignancy during therapy, and patients who are current or past smokers. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Thrombosis (including deep venous thrombosis, pulmonary embolism, and arterial thrombosis) has occurred in patients treated for inflammatory conditions with Janus kinase (JAK) inhibitors, including baricitinib, tofacitinib, and upadacitinib; many of these adverse events were serious and some resulted in death. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including ruxolitinib, fedratinib, and pacritinib. Baricitinib, pacritinib, tofacitinib, and upadacitinib should be avoided in patients who may be at increased risk of thrombosis; for the treatment of ulcerative colitis, tofacitinib should be used at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response. If symptoms of thrombosis occur, baricitinib, pacritinib, tofacitinib, and upadacitinib should be discontinued and patients should be evaluated promptly and treated appropriately.

Due to potential increase of exposure, patients with preexisting-existing moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions when treated with fedratinib. Reduce fedratinib dose when administered to patients with severe renal impairment (CrCl 15 mL/min to 29 mL/min by Cockcroft-Gault). No modification of the starting dose is recommended for patients with mild to moderate renal impairment (CrCl 30 mL/min to 89 mL/min by Cockcroft-Gault).

Adverse hematologic effects including neutropenia, thrombocytopenia, and anemia have been associated with the use of fedratinib. It is recommended to modify the starting dose in patients with a baseline platelet count (PLT) less than 50 x 10(9)/L. Therapy should be interrupted until grade 4 thrombocytopenia, grade 3 thrombocytopenia with active bleeding, OR grade 4 neutropenia has normalized to grade 2 or lower (or baseline), then restart treatment at 100 mg/day below the last given dose. Fedratinib dose reductions should be considered in patients who become dependent on red blood cell transfusions. CBC counts should be monitored at baseline and every 3 months thereafter; treatment should be modified based on PLT levels and active bleeding. Caution is recommended in patients who may be at increased risk.

Pancreatitis occurred in patients receiving fedratinib. It is recommended to monitor lipase and amylase prior to the start of therapy with fedratinib and periodically thereafter as clinically indicated. Therapy should be interrupted until grade 3 or higher elevations in amylase and/or lipase levels resolve to grade 1 or less (or baseline), then restart treatment at 100 mg/day below the last given dose. Care is recommended when using this agent in patients at risk.