OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Ponatinib – Inclusig®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

View in own window

DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Ponatinib	943319-70-8	C29-H27-F3-N6-O

ANNOTATED BIBLIOGRAPHY

References updated: 10-May-2020

Abbreviations: CML, chronic myelogenous leukemia; REMS, risk evaluation and mitigation strategy.

• 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 kinase inhibitors and ponatinib).
• DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 541-67.

  (Review of hepatotoxicity of cancer chemotherapeutic agents; imatinib, gefitinib, erlotinib and crizotinib are discussed, but not ponatinib).
• 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).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, one case was attributed to imatinib, but none to other kinase inhibitors).
• Reuben A, Koch DG, Lee WM., Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology. 2010;52:2065–76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, none of which were attributed to kinase inhibitors).
• Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O'Hare T, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075–88. [PMC free article: PMC3777383] [PubMed: 23190221]

  (Among 81 patients with previously treated, resistant hematologic malignancies [60 with CML] hematologic responses occurred independent of BCR-ABL mutations, and adverse events included pancreatitis [14%] and ALT elevations [10%] which were mostly mild, only one being ≥5 times ULN).
• Goldman JM. Ponatinib for chronic myeloid leukemia. N Engl J Med. 2012;367:2148–9. [PubMed: 23190226]

  (Editorial in response to Cortes [2012] discussing ponatinib as a third generation tyrosine kinase inhibitor with activity against mutated forms of BCR-ABL).
• Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf. 2013;36:491–503. [PubMed: 23620168]

  (Review of the hepatotoxicity of 18 tyrosine kinase inhibitors approved for use in cancer in the US as of 2013; ponatinib is listed as having the potential to cause clinically apparent liver injury and hepatic failure, for which reason it has a "boxed warning" and routine liver test screening is recommended).
• Shah NP, Talpaz M, Deininger MW, Mauro MJ, Flinn IW, Bixby D, Lustgarten S, et al. Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study. Br J Haematol. 2013;162:548–52. [PMC free article: PMC3866040] [PubMed: 23691988]

  (Among 12 patients with AML and FLT3 mutations, responses to ponatinib therapy occurred in 3; no mention of hepatotoxicity).
• Ponatinib (Inclusig) for CML and Ph+ ALL. Med Lett Drugs Ther. 2013;55(1424):71–2. [PubMed: 25970013]

  (Concise summary of mechanism of action, efficacy, safety and costs of ponatinib of Philadelphia chromosome positive CML or ALL shortly after its approval, mentions the potential of serious hepatic toxicity).
• Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, et al. PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369:1783–96. [PMC free article: PMC3886799] [PubMed: 24180494]

  (Among 449 patients with CML or ALL with BCR-ABL and resistance or intolerance to other tyrosine kinase receptor inhibitors who were treated with ponatinib for an average of 12.8 months, common side effects were rash, dry skin and abdominal pain with ALT elevations in 3-12%, and values above 5 times ULN in 2-3%).
• Prasad V, Mailankody S. The accelerated approval of oncologic drugs: lessons from ponatinib. JAMA. 2014;311:353–4. [PubMed: 24449310]

  (Editorial on the accelerated approval of ponatinib and subsequent withdrawal when rates of vascular thrombosis at 2.7 years were found to be 48%).
• Mayer K, Gielen GH, Willinek W, Müller MC, Wolf D. Fatal progressive cerebral ischemia in CML under third-line treatment with ponatinib. Leukemia. 2014;28:976–7. [PubMed: 24170029]

  (55 year old man with CML developed visual loss 3 weeks after starting ponatinib, with subsequent deterioration and death, autopsy showing brain edema and bilateral cerebral infarcts).
• Narasimhan NI, Dorer DJ, Davis J, Turner CD, Marbury TC, Sonnichsen D. Evaluation of pharmacokinetics and safety of ponatinib in subjects with chronic hepatic impairment and matched healthy subjects. Cancer Chemother Pharmacol. 2014;74:341–8. [PubMed: 24934866]

  (In a study of 16 patients with cirrhosis given a single dose of ponatinib, pharmacokinetic parameters were similar despite varying degrees of liver disease severity [Child class A, B and C], and laboratory tests remained stable, except for a rise in amylase and lipase in one patient who developed pancreatitis 2 days after the single dose).
• Jain P, Kantarjian H, Jabbour E, Gonzalez GN, Borthakur G, Pemmaraju N, Daver N, et al. Ponatinib as first-line treatment for patients with chronic myeloid leukaemia in chronic phase: a phase 2 study. Lancet Haematol. 2015;2:e376–83. [PMC free article: PMC4587395] [PubMed: 26436130]

  (Among 51 patients with CML in the chronic phase treated with ponatinib for a median of 20.9 months, all except one had a complete hematologic response and adverse events were common including skin rash [69%], lipase elevations [63%], cardiovascular effects [49%, mostly hypertension], and ALT elevations in 27% [8% above 5 times ULN], such that 88% required drug reductions).
• Mingard C, Paech F, Bouitbir J, Krähenbühl S. Mechanisms of toxicity associated with six tyrosine kinase inhibitors in human hepatocyte cell lines. J Appl Toxicol. 2018;38:418–31. [PubMed: 29072336]

  (In hepatocyte cell culture experiments, ponatinib impaired oxidative metabolism and induced apoptosis, and in higher doses affect mitochondria function and glycolysis).
• Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, Nicolini FE, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132:393–404. [PMC free article: PMC6071555] [PubMed: 29567798]

  (Among 267 patients with chronic phase CML treated with ponatinib [Cortes 2013], 5 year follow up demonstrated that 60% achieved a major cytogenetic response and 5 year survival was 73%, while adverse events were common including rash [47%], abdominal pain [46%], thrombocytopenia [46%], headache [43%] and constipation [41%], no mention of hepatotoxicity).
• Breccia M, Efficace F, Iurlo A, Luciano L, Abruzzese E, Gozzini A, Pregno P, et al. Intolerance to tyrosine kinase inhibitors in chronic myeloid leukemia: the possible role of ponatinib. Expert Opin Drug Saf. 2018;17:623–8. [PubMed: 29845876]

  (Review of the mechanism of action, clinical efficacy and safety of ponatinib and its role in treatment of patients with CML who are intolerant to other tyrosine kinase inhibitors, mentions that increased liver enzymes arose in 19-53% of patients in four prospective trials and were above 5 times ULN in 2-8%).
• Heiblig M, Rea D, Chrétien ML, Charbonnier A, Rousselot P, Coiteux V, Escoffre-Barbe M, et al. Ponatinib evaluation and safety in real-life chronic myelogenous leukemia patients failing more than two tyrosine kinase inhibitors: the PEARL observational study. Exp Hematol. 2018;67:41–8. [PubMed: 30195076]

  (Analysis of a national health database identified 48 patients with CML treated with ponatinib, in whom the 5 year overall survival was 81% and cardiovascular adverse events arose in 47% including hypertension [19%], atrial fibrillation [6%], myocardial infarction [8%], stroke [3%], arterial and deep vein thrombosis [5% each]; no mention of clinically apparent liver injury ).
• García-Gutiérrez V, Hernández-Boluda JC. Tyrosine kinase inhibitors available for chronic myeloid leukemia: efficacy and safety. Front Oncol. 2019;9:603. [PMC free article: PMC6617580] [PubMed: 31334123]

  (Review of current therapy of CML using first [imatinib], second [nilotinib, dasatinib, bosutinib], and third generation [ponatinib] tyrosine kinase inhibitors, ponatinib being used only after failure of 1 or 2 other agents, its major shortcoming being high rate of adverse effects including major cardiovascular complications particularly with high doses of ponatinib; no discussion of hepatotoxicity).
• Kim J, Nair A, Keegan P, Beaver JA, Kluetz PG, Pazdur R, Chuk M, Blumenthal GM. Evaluation of serious postmarket safety signals within 2 years of FDA approval for new cancer drugs. Oncologist. 2020;25:348–54. [PMC free article: PMC7160417] [PubMed: 32297444]

  (Between 2010 and 2016, 53 new molecular entities for treatment of cancer were approved by the FDA, 9 of which subsequently had substantial safety related changes in labeling or indications, including 1 of 32 with regular approval and 7 of 23 with accelerated approval; ponatinib has the most changes [warning, boxed warning, withdrawal and REMS).