Active Ingredient: Fedratinib
Fedratinib is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis who are Janus Associated Kinase (JAK) inhibitor naïve or have been treated with ruxolitinib.
For this indication, competent medicine agencies globally authorize below treatments:
For: Adults (18-64) Elders (65+)
Oral, 400 milligrams fedratinib, once daily.
Patients who are on treatment with ruxolitinib, prior to starting treatment with fedratinib, must taper and discontinue ruxolitinib according to the ruxolitinib prescribing information.
Baseline testing of thiamine (vitamin B1) levels, complete blood count, hepatic panel, amylase/lipase, blood urea nitrogen (BUN) and creatinine should be obtained prior to starting treatment with fedratinib, periodically during treatment and as clinically indicated. Fedratinib treatment should not be started in patients with thiamine deficiency, until thiamine levels have been corrected. Initiating treatment with fedratinib is not recommended in patients with a baseline platelet count below 50 × 109/L and ANC <1.0 × 109/L.
It is recommended that prophylactic anti-emetics be used according to local practice for the first 8 weeks of treatment and continued thereafter as clinically indicated. Administration of fedratinib with a high fat meal may reduce the incidence of nausea and vomiting.
The recommended dose of fedratinib is 400 mg once daily.
Treatment may be continued for as long as patients derive clinical benefit. Dose modifications should be considered for haematologic and non-haematologic toxicities (Table 1). Fedratinib should be discontinued in patients who are unable to tolerate a dose of 200 mg daily.
If a dose is missed, the next scheduled dose should be taken the following day. Extra capsules should not be taken to make up for the missed dose.
Dose modifications for haematologic toxicities, non-haematologic toxicities and management of Wernicke’s encephalopathy (WE) are shown in Table 1.
Before treatment initiation and during treatment, thiamine levels should be replenished if they are low. During treatment, thiamine levels should be assessed periodically (e.g. monthly for the first 3 months and every 3 months thereafter) and as clinically indicated.
If the adverse reaction due to fedratinib that resulted in a dose reduction is controlled with effective management and the toxicity is resolved for at least 28 days, the dose level may be re-escalated to one dose level higher per month up to the original dose level. Dose re-escalation is not recommended if the dose reduction was due to a Grade 4 non-haematologic toxicity, ≥ Grade 3 alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin elevation, or reoccurrence of a Grade 4 haematologic toxicity.
Table 1. Dose reductions for haematologic, non-haematologic treatment emergent toxicities and management of Wernicke’s encephalopathy:
|Haematologic toxicity||Dose reduction|
|Grade 3 thrombocytopenia with active bleeding (platelet count <50 × 109/L) or Grade 4 thrombocytopenia (platelet count <25 × 109/L)||Interrupt fedratinib dose until resolved to ≤ Grade 2 (platelet count <75 × 109/L) or baseline. Restart dose at 100 mg daily below the last given dose.|
|Grade 4 neutropenia (absolute neutrophil count [ANC] <0.5 × 109/L)||Interrupt fedratinib dose until resolved to ≤ Grade 2 (ANC <1.5 × 109/L) or baseline. Restart dose at 100 mg daily below the last given dose. Granulocyte growth factors may be used at the physician’s discretion.|
|Grade 3 and higher anaemia, transfusion indicated (haemoglobin level <8.0 g/dL)||Interrupt fedratinib dose until resolved to ≤ Grade 2 (haemoglobin level <10.0 g/dL) or baseline. Restart dose at 100 mg daily below the last given dose.|
|Recurrence of a Grade 4 haematologic toxicity||Fedratinib discontinuation as per physician’s discretion.|
|Non-haematologic toxicity||Dose reduction|
|≥ Grade 3 nausea, vomiting or diarrhoea not responding to supportive measures within 48 hours||Interrupt fedratinib dose until resolved to ≤ Grade 1 or baseline. Restart dose at 100 mg daily below the last given dose.|
|≥ Grade 3 ALT/ AST (>5.0 to 20.0 x upper limit of normal [ULN]) or bilirubin (> 3.0 to 10.0 ULN)||Interrupt fedratinib dose until resolved to ≤ Grade 1 (AST/ALT (> ULN – 3.0 x ULN) or bilirubin (> ULN – 1.5 x ULN)) or baseline. Restart dose at 100 mg daily below the last given dose. Monitor ALT, AST and bilirubin (total and direct) every 2 weeks for at least 3 months following the dose reduction. If re-occurrence of a Grade 3 or higher elevation, discontinue treatment with fedratinib.|
|≥ Grade 3 amylase / lipase (>2.0 to 5.0 x ULN)||Interrupt fedratinib dose until resolved to Grade 1 (> ULN – 1.5 x ULN) or baseline. Restart dose at 100 mg daily below the last given dose. Monitor amylase/lipase every 2 weeks for at least 3 months following the dose reduction. If re-occurrence of a Grade 3 or higher elevation, discontinue treatment with fedratinib.|
|≥ Grade 3 other non-haematologic toxicities||Interrupt fedratinib dose until resolved to ≤ Grade 1 or baseline. Restart dose at 100 mg daily below the last given dose.|
|Management of thiamine levels and Wernicke’s encephalopathy||Dose reduction|
|For thiamine levels < normal range (74 to 222 nmol/L)* but ≥30 nmol/L without signs or symptoms of WE||Interrupt fedratinib treatment. Dose with daily 100 mg oral thiamine until thiamine levels are restored to normal range*. Consider re-starting fedratinib treatment when thiamine levels are within normal range*.|
|For thiamine levels <30 nmol/L without signs or symptoms of WE||Interrupt fedratinib treatment. Initiate treatment with parenteral thiamine at therapeutic dosages until thiamine levels are restored to normal range*. Consider re-starting fedratinib treatment when thiamine levels are within normal range*.|
|For signs or symptoms of WE regardless of thiamine levels||Discontinue fedratinib treatment and immediately administer parenteral thiamine at therapeutic dosages.|
* the normal thiamine range may differ depending on the methods used by the laboratory
The fedratinib capsules should not be opened, broken or chewed. They should be swallowed whole, preferably with water, and may be taken with or without food. Administration with a high fat meal may reduce the incidence of nausea and vomiting, therefore it is recommended to be taken with food.
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