OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Cedazuridine and Decitabine – Inqovi®

DRUG CLASS

Antineoplastic Agents

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
Cedazuridine	1141397-80-9	C9-H14-F2-N2-O5
Decitabine	2353-33-5	C8-H12-N4-O4

ANNOTATED BIBLIOGRAPHY

References updated: 27 July 2023

Abbreviations used: iv, intravenous; MDS, myelodysplastic syndrome.

• 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 cedazuridine).
• DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 549-68.

  (Review of hepatotoxicity of cancer chemotherapeutic agents published in 2013 does not discuss cedazuridine).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Inhibitors of histone deacetylase. 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, p. 1203-36.

  (Textbook of pharmacology and therapeutics).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2020/212576Orig1s000TOC.cfm

  (FDA website with product label and the multidiscipline review of data on efficacy and safety of the combination of cedazuridine and decitabine mentions that in the total experience in 208 treated subjects, 37% had had at least one elevation in ALT or AST, which were above 5 times ULN in 2%, and 3 participants ALT or AST elevations above 3 times ULN accompanied by jaundice, but in all 3 cases the abnormalities were attributed to either sepsis or myocarditis rather than drug induced liver injury).
• Savona MR, Odenike O, Amrein PC, Steensma DP, DeZern AE, Michaelis LC, Faderl S, et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: a multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019;6:e194-e203. [PubMed: 30926081]

  (Among 44 patients with various MDS treated with intravenous (iv) decitabine or various combinations of oral decitabine and cedazuridine, oral doses of 30 or 40 mg of decitabine and 100 mg of cedazuridine yielded 5-day area under the curve concentrations most similar to iv decitabine, with similar adverse event rates and ALT elevations in 20% of subjects, all values being less than 3 times ULN).
• Dhillon S. Decitabine/Cedazuridine: first approval. Drugs. 2020;80:1373-1378. [PMC free article: PMC7708383] [PubMed: 32860582]

  (Review of the mechanism of action, history of development, pharmacokinetics, clinical efficacy, and safety of the combination of oral decitabine and cedazuridine shortly after its approval for use in MDS in the US, discusses adverse events of myelosuppression and gastrointestinal upset but does not mention ALT elevations or hepatotoxicity).
• Garcia-Manero G, Griffiths EA, Steensma DP, Roboz GJ, Wells R, McCloskey J, Odenike O, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020;136:674-683. [PMC free article: PMC7414597] [PubMed: 32285126]

  (Among 80 patients with MDS or chronic myelomonocytic leukemia treated with oral cedazuridine/decitabine or iv decitabine alone for 5 days in cycle one with cross over to the other regimen in cycle 2, area-under-the-curve plasma concentrations were similar in both groups as were demethylation rates and the clinical response rate with continued cycles of combination therapy was 60%, common adverse events were neutropenia and thrombocytopenia; no mention of ALT elevations or hepatotoxicity).
• Sekeres MA, Taylor J. Diagnosis and treatment of myelodysplastic syndromes: a review. JAMA. 2022;328:872-880. [PubMed: 36066514]

  (Concise review of clinical features, natural history, diagnosis, and management of MDS; adverse events are listed in tables but without mention or discussion of ALT elevations or hepatotoxicity).
• Kim N, Norsworthy KJ, Subramaniam S, Chen H, Manning ML, Kitabi E, Earp J, et al. FDA approval summary: decitabine and cedazuridine tablets for myelodysplastic syndromes. Clin Cancer Res. 2022;28:3411-3416. [PMC free article: PMC9378483] [PubMed: 35435961]

  (Summary of the basis for the FDA approval of an oral fixed dose combination of decitabine and cedazuridine with efficiency and safety results from a phase 3 open label trial in 133 patients, which demonstrated complete remissions in 18-21% of subjects and with an adverse event profile similar to that of iv decitabine; ALT elevations arose in 37% of patients but were above 5 times ULN in only 2%; no mention of serious hepatic adverse events).
• Garcia-Manero G. Myelodysplastic syndromes: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98:1307-1325. [PubMed: 37288607]

  (Review of the classification of MDS and risk categorization with an update on management including discussion of hypomethylation agents and luspatercept; no mention of ALT elevations or hepatotoxicity).
• Randall MP, DeZern AE. The management of low-risk myelodysplastic syndromes-current standards and recent advances. Cancer J. 2023;29:152-159. [PubMed: 37195771]

  (Review of treatment of low-risk MDS including erythropoietin, iron chelation, lenalidomide, luspatercept and low dose hypomethylating agents; no discussion of hepatotoxicity).