OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Fedratinib – Inrebic®

DRUG CLASS

Antineoplastic Agents, Tyrosine Kinase Inhibitor

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Fedratinib	936091-26-8	C27-H36-N6-O3-S

ANNOTATED BIBLIOGRAPHY

References updated: 20 August 2022

Abbreviations: FLT-3, FMS-like tyrosine kinase; HBV, hepatitis B virus; JAK, Janus associated kinase; STAT, signal transducer and activator of transcription.

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase receptor inhibitors).
• DeLeve LD. Kinase inhibitors. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents, does not discuss fedratinib).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2019/212327Orig1s000MultidisciplineR.pdf.

  (FDA website with product labels and initial multidiscipline review of the safety and efficacy of fedratinib; states that patients with myelofibrosis frequently have elevations in bilirubin and serum enzymes, but patients treated with fedratinib have a higher rate of ALT elevations [58%] compared to placebo [17%], but these elevations are generally mild and above 5 times ULN in 9% vs 1% with placebo; despite this, significant liver injury attributable to fedratinib is uncommon).
• Zhang M, Xu CR, Shamiyeh E, Liu F, Yin JY, von Moltke LL, Smith WB. A randomized, placebo-controlled study of the pharmacokinetics, pharmacodynamics, and tolerability of the oral JAK2 inhibitor fedratinib (SAR302503) in healthy volunteers. J Clin Pharmacol. 2014;54:415–21. [PubMed: 24165976]

  (A pharmacologic study in 57 healthy controls given one of 7 doses of fedratinib, found significant inhibition of STAT-signaling with doses of 300 mg or higher).
• Pardanani A, Harrison C, Cortes JE, Cervantes F, Mesa RA, Milligan D, Masszi T, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643–51. [PubMed: 26181658]

  (Among 289 adults with myelofibrosis treated with fedratinib [400 or 500 mg] or placebo daily for 24 weeks, spleen responses occurred in 36% and 40% on fedratinib vs 1% on placebo and symptom responses in 36% and 34% vs 7%, while adverse events occurred in almost all patients, including ALT elevations in 46% and 53% vs 17%, but values above 5 times ULN arose in only 3% and 3% vs none; severe adverse events included 4 cases of suspected Wernicke’s encephalopathy in fedratinib treated subjects).
• Pardanani A, Tefferi A, Jamieson C, Gabrail NY, Lebedinsky C, Gao G, Liu F, et al. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J. 2015;5:e335. [PMC free article: PMC4558588] [PubMed: 26252788]

  (Among 31 patients with myelofibrosis treated with fedratinib [400, 500 or 600 mg once daily] for 24 weeks, reduction in spleen size averaged 30%, 33% and 43%, and all patients had at least one adverse event, ALT elevations being frequent [30%, 50%, and 91% ), two patients developing ALT levels above 5 times and one above 20 times ULN accompanied by jaundice, symptoms and signs of hepatic failure which resolved after fedratinib was discontinued).
• Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Tiu RV, Zachee P, Jourdan E, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4:e317–e324. [PMC free article: PMC8207822] [PubMed: 28602585]

  (Among 83 patients with myelofibrosis resistant or intolerant to ruxolitinib who were treated with fedratinib for 24 weeks, 55% had a clinical response [at least a 35% reduction in spleen size] while side effects included diarrhea [58%], nausea [56%] constipation [21%], pruritus [16%], fatigue [15%], headache [13%], ALT elevations [6%], cardiac failure [3%], and tumor lysis syndrome [2%]).
• Fedratinib becomes new option in myelofibrosis. Cancer Discov. 2019;9:1332. [PubMed: 31471287]

  (News report on the approval of fedratinib for therapy of myelofibrosis after a hold had been placed on it for several years because of cases of Wernicke’s encephalopathy, although only one was proven).
• Blair HA. Fedratinib: first approval. Drugs. 2019;79:1719–1725. [PubMed: 31571162]

  (Review of the history of development, mechanism of action, pharmacology, clinically efficacy and safety of fedratinib shortly after its approval in the US for immediate- and high-risk myelofibrosis mentions that common adverse reactions are diarrhea, nausea and anemia, less common but potentially serious reactions include Wernicke’s encephalopathy, myelosuppression, gastrointestinal toxicity, amylase and lipase elevations and serum aminotransferase elevations, which occur in 43% of treated subjects versus 14% in placebo controls, but are above 5 times ULN in only 9% vs 1%).
• Talpaz M, Kiladjian JJ. Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis. Leukemia. 2021;35:1–17. [PMC free article: PMC7787977] [PubMed: 32647323]

  (Review of the clinical features and pathogenesis of myelofibrosis and the mechanism of action, pharmacology, clinical efficacy and safety of fedratinib).
• Coltro G, Vannucchi AM. The safety of JAK kinase inhibitors for the treatment of myelofibrosis. Expert Opin Drug Saf. 2021;20:139–154. [PubMed: 33327810]

  (Review of the mechanism of action and safety of JAK inhibitors used in the treatment of myelofibrosis including fedratinib and ruxolitinib as well as several experimental agents; mentions that fedratinib has been associated with ALT elevations during therapy).
• Pardanani A, Tefferi A, Masszi T, Mishchenko E, Drummond M, Jourdan E, Vannucchi A, et al. Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Br J Haematol. 2021;195:244–8. [PMC free article: PMC9292894] [PubMed: 34331348]

  (Updated analysis of the randomized controlled trial of fedratinib in patients with myelofibrosis that had been placed on hold in 2013 because of serious adverse events [Wernicke’s encephalopathy], based up 96 enrolled subjects treated with 400 mg of fedratinib vs 96 treated with placebo for 24 weeks, in whom spleen responses occurred in 47% vs 1% and improved symptom burden in 40% vs 9%, common adverse events being diarrhea [66%], nausea [62%], anemia [40%], vomiting [39%], fatigue [19%], muscle spasms [12%], creatinine elevations [59% vs 19%], lipase elevations [35% vs 7%] and ALT elevations [43% vs 14%] being 5 times ULN or more [1% vs none] with no patient developing clinically apparent liver injury).
• Harrison CN, Schaap N, Vannucchi AM, Kiladjian JJ, Passamonti F, Zweegman S, Talpaz M, et al. Safety and efficacy of fedratinib, a selective oral inhibitor of Janus kinase-2 (JAK2), in patients with myelofibrosis and low pretreatment platelet counts. Br J Haematol. 2022;198:317–327. [PMC free article: PMC9541243] [PubMed: 35476316]

  (Reanalysis of trials of fedratinib in patients with myelofibrosis comparing those with low vs higher platelet counts [50,000 to 100,000 vs >100,000 per µL] found that response rates were similar and adverse event rates were similar except for thrombocytopenia; no mention of ALT elevations or hepatotoxicity).