Fedratinib

Last updated on: 08.07.2021

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Definition
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Fedratinib is a highly selective inhibitor of Janus kinase (JAK) 2 and FMS-like tyrosine kinase 3 (FLT3). The drug is indicated for the treatment of disease-related splenomegaly (enlargement of the spleen) and symptoms of primary and secondary myelofibrosis.

Fedratinib is the first once-daily oral medicine to demonstrate a clinically meaningful response in terms of spleen volume reduction and improvement in disease-related symptom burden in patients with myelofibrosis who have not responded to treatment with ruxolitinib or who have not yet received a JAK inhibitor.

Spectrum of action
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Fedratinib is a kinase inhibitor with activity against wild-type and mutation-activated Janus-associated kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). The drug is a JAK2-selective inhibitor that exhibits higher potency for JAK2 than against the other members of the JAK family (JAK1, JAK3, and TYK2). Abnormal activation of JAK2 is associated with myeloproliferative neoplasms, including myelofibrosis and polycythaemia-vera.

In cell models expressing mutation-activated JAK2 or FLT3, fedratinib decreased phosphorylation of STAT3/5 proteins (signal transducers and activators of transcription; STAT), inhibited cell proliferation, and induced apoptosis.

Indication
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The drug is approved for the treatment of disease-related splenomegaly (enlargement of the spleen) or symptoms in adult patients not pretreated with a Janus-associated kinase (JAK) inhibitor or treated with ruxolitinib with:

  • Primary myelofibrosis
  • Post-polycythaemia vera myelofibrosis
  • Post-essential thrombocythemia myelofibrosis

Pregnancy/nursing period
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Pregnancy: Fedratinib is contraindicated during pregnancy. Based on the mechanism of action of fedratinib, the drug may cause harm to the fetus. JAK inhibitors are known to have caused embryo-fetal mortality and teratogenicity in animal experiments.

Women of childbearing potential must use a reliable method of contraception during treatment and for at least one month after the last dose.

Breastfeeding: It is not known whether fedratinib or its metabolites pass into breast milk. A risk to the breastfed child cannot be excluded, therefore women should not breastfeed during treatment and for at least one month after the last dose of fedratinib.

Dosage and method of use
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The recommended dose of fedratinib is 400 mg once daily.

Undesirable effects
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Very common side effects of fedratinib (which may affect more than 1 in 10 people treated) are:

Anaemia, thrombocytopenia and neutropenia: anaemia, thrombocytopenia and neutropenia may occur during therapy (usually within the first three months of treatment).

Gastrointestinal events: nausea, vomiting, and diarrhea are among the most common side effects of fedratinib. Most side effects are grade 1 or 2 and usually occur within the first 2 weeks of treatment.

Other side effects include:

  • Encephalopathy, including Wernicke's encephalopathy: Cases of serious and fatal encephalopathy, including Wernicke's encephalopathy (neurological emergency due to a deficiency of thiamine - vitamin B1- have been reported with the use of fedratinib).
  • Hepatic toxicity: Increases in liver enzymes such as pancreatic enzymes (amylase/lipase) are possible. One case of liver failure has been reported during therapy.

  • Elevated creatinine: Elevations in creatinine levels have been reported during treatment with fedratinib. In cases of severe renal impairment (CLcr 15 ml/min to 29 ml/min by C-G), dose adjustments are recommended

Interactions
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Fedratinib is metabolized in vitro by several CYP enzymes, predominantly by CYP3A4 and to a lesser extent by CYP2C19, and by flavin-containing monooxygenases (FMO), therefore the following interactions should be noted:

Co-administration of fedratinib with strong CYP3A4 inhibitors increases fedratinib exposure. If strong CYP3A4 inhibitors cannot be substituted, the dose of Inrebic should be reduced when administered with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir).

Agents that simultaneously inhibit CYP3A4 and CYP2C19 (e.g., fluconazole, fluvoxamine), or the combination of CYP3A4 and CYP2C19 inhibitors, may increase fedratinib exposure and should be avoided in patients receiving Inrebic.

Agents that strongly or moderately induce CYP3A4 (e.g., phenytoin, rifampicin, efavirenz) may decrease fedratinib exposure and should be avoided.

If fedratinib is to be co-administered with a substrate of CYP3A4 (e.g., midazolam, simvastatin), CYP2C19 (e.g., omeprazole, S-mephenytoin), or CYP2D6 (e.g., metoprolol, dextromethorphan), dose adjustments of co-administered drugs should be made as needed with close monitoring of safety and efficacy.

Contraindication
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Fedratinib must not be used in cases of hypersensitivity to the active substance or to any other constituent of the medicinal product, or during pregnancy.

Preparations
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InrebicĀ®

Note(s)
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Fedratinib is taken orally. The capsules must not be opened, broken or chewed. Patients who are treated with ruxolitinib prior to starting fedratinib treatment must gradually discontinue ruxolitinib according to the Ruxolitinib SmPC. Before starting and at regular intervals during treatment with fedratinib, the following values should be obtained:

  • Thiamine (vitamin B1)
  • a complete blood count
  • Liver values
  • amylase/lipase
  • blood urea nitrogen
  • Creatinine

If thiamine deficiency is present, treatment should not be started until thiamine levels have been replenished.

If the baseline platelet count is below 50 x 109/l and the absolute neutrophil count (ANC) is below 1.0 x 109/l, it is not recommended to start treatment with fedratinib.

Prophylactic antiemetic use according to local standards of care is recommended for the first eight weeks of treatment and thereafter continue as clinically indicated. When fedratinib is administered with a high-fat meal, the frequency of nausea and vomiting may be reduced.

Incoming links (1)

Januskinase-Inhibitors;

Last updated on: 08.07.2021