July 7, 2020

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212576s000lbl.pdf.

On July 7, 2020, the Food and Drug Administration approved an oral combination of decitabine and cedazuridine (INQOVI, Astex Pharmaceuticals, Inc.) for adult patients with myelodysplastic syndromes (MDS) including the following:

  • previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and
  • intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

Inqovi was investigated in two open-label, randomized, crossover trials. Trial ASTX727-01-B (NCT02103478) included 80 adult patients with MDS (International Prognostic Scoring System [IPSS] Intermediate-1, Intermediate-2, or high-risk) or CMML and trial ASTX727-02 (NCT03306264) included 133 adult patients with MDS or CMML, including all French-American-British classification criteria and IPSS Intermediate-1, Intermediate-2, or high-risk prognostic scores.

In both trials, patients were randomized 1:1 to receive Inqovi (35 mg decitabine and 100 mg cedazuridine) orally in cycle 1 and decitabine 20 mg/m2 intravenously in cycle 2 or the reverse sequence. Both Inqovi and intravenous decitabine were administered once daily on days 1 through 5 of a 28-day cycle. Starting with cycle 3, all patients received Inqovi orally once daily on days 1 through 5 of each 28-day cycle until disease progression or unacceptable toxicity. Both trials provided comparison of exposure and safety in the first two cycles between oral Inqovi and IV decitabine and description of disease response with Inqovi. Comparison of disease response between the Inqovi and IV decitabine was not possible because all patients received Inqovi starting from Cycle 3.

The 01-B trial demonstrated a complete response (CR) rate of 18% (95% CI: 10, 28) and median duration of CR was 8.7 months (range: 1.1, 18.2). Among the 41 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 20 (49%) became independent of RBC and platelet transfusions during any consecutive 56-day post-baseline period. Of the 39 patients who were independent of both RBC and platelet transfusions at baseline, 25 (64%) remained transfusion-independent during any consecutive 56-day post-baseline period.

The 02 trial demonstrated a geometric mean ratio of the 5-day cumulative decitabine AUC following 5 consecutive once daily doses of Inqovi compared to that of intravenous decitabine was 99% (90% CI: 93, 106). Efficacy results demonstrated that 21% of patients achieved CR (95% CI: 15, 29) and median duration of CR was 7.5 months (range: 1.6, 17.5). Among the 57 patients who were dependent on RBC and/or platelet transfusions at baseline, 30 (53%) became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 76 patients who were independent of both RBC and platelet transfusions at baseline, 63% remained transfusion-independent during any 56-day post-baseline period. 

Most common adverse reactions (incidence ≥ 20%) to Inqovi are fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased. The most common grade 3 or 4 laboratory abnormalities (≥ 50%) were leukocytes decreased, platelet count decreased, neutrophil count decreased, and hemoglobin decreased. The overall safety profile of oral Inqovi was similar to IV decitabine. 

The recommended Inqovi dose is 1 tablet (35 mg decitabine and 100 mg cedazuridine) taken orally on an empty stomach once daily on days 1 through 5 of each 28‑day cycle.

View full prescribing information for INQOVI.

This review used the Oncology Center of Excellence Assessment Aid as well as the Office of Pharmaceutical Quality’s Assessment Aid for quality review. These are voluntary submissions from the applicant to facilitate the FDA’s assessment.

The FDA collaborated with international agency counterparts on the review of this application as part of Project Orbis.

This application was granted priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email This email address is being protected from spambots. You need JavaScript enabled to view it..

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Pharmacist’s Application to Practice

Decitabine/cedazuridine (Inqovi) for Adults with Myelodysplastic Syndromes (MDS)

Author: Hope Quattlebaum, PharmD
Hematology/Oncology Clinical Pharmacy Specialist
Central Arkansas Veterans Healthcare System
Little Rock, AR

What is the potential role for decitabine/cedazuridine in the treatment of myelodysplastic syndrome (MDS)?

  • Decitabine/cedazuridine provides an oral treatment option for adult MDS patients with intermediate-1, intermediate-2, or high-risk disease per the International Prognostic Scoring System (IPSS). 1
  • Decitabine/cedazuridine is indicated for both previously-treated and untreated primary and secondary MDS patients with one of the following French-American-British subtypes:
    • refractory anemia
    • refractory anemia with ringed sideroblasts
    • refractory anemia with excess blasts
    • chronic myelomonocytic leukemia (CMML) 1
  • Decitabine is a cytidine analog that when incorporated in DNA inhibits DNA methyltransferase by causing hypomethylation and eventual cell death. Cedazuridine increases bioavailability of decitabine by 20% by blocking metabolic breakdown of decitabine by cytidine deaminase in the liver and gastrointestinal tract.1
  • The National Comprehensive Cancer Network (NCCN) guidelines for treatment of MDS (Version 1.2021) include the option to substitute oral decitabine/cedazuridine as a substitution for intravenous decitabine for all patients for whom decitabine therapy is considered.3
  • FDA approval was based on a phase 2, cross-over study (n=80) that compared systemic decitabine exposure, demethylation activity, and safety of decitabine/cedazuridine and intravenous decitabine 20mg/m2 in patients with intermediate or high risk MDS or CMML.2,3
    • Patients were randomized to either IV or oral decitabine for 1 cycle, then patients crossed over to the alternative formulation for cycle 2. For subsequent cycles, all patients were given oral decitabine/cedazuridine.
    • Decitabine area under the curve (AUC) and demethylation activity were similar between formulations.
    • Efficacy was evaluated by assessing complete and clinical response in the total patient population (n=80). Overall, 60% of patients achieved a clinical response, including 21% who achieved complete response.
    • The incidences of all-grade adverse effects were similar between oral and IV decitabine. Due to cross-over study design, precise incidences of adverse effects for patients receiving only oral or only IV decitabine could not be evaluated.
  • The most common grade 3 and 4 toxicities include the following: neutropenia, thrombocytopenia, febrile neutropenia, and anemia. The most common all-grade toxicities include the following: skin rash, constipation, diarrhea, nausea, stomatitis, dyspnea, and previously mentioned toxicities
  • No head-to-head trials comparing decitabine/cedazuridine to IV azacitidine or other therapy have been published at this time.
  • Astex Pharmaceuticals aims to expand the role of decitabine/cedazuridine into acute myeloid treatment by evaluating its use in combination with venetoclax in ongoing clinical trials (NCT04657081).5

What role can the pharmacist play in the management of patients on decitabine/cedazuridine?

  • Verify medication dose:
    • In contrast to IV decitabine, which is dosed via body surface area (BSA), the recommended dose of oral decitabine/cedazuridine is a flat dose of decitabine 35mg/ cedazuridine 100mg.
    • No dose adjustments are recommended in patients with mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min) or mild hepatic impairment (total bilirubin > 1 to 1.5 × ULN or AST > ULN). Use in patients with severe renal or hepatic impairment has not been studied.1
  • Counsel on appropriate administration: 1
    • Take on empty stomach, at least 2 hours before and 2 hours after food. Take at approximately the same time every day.
    • Take on days 1 through 5 of 28-day cycle.
    • If dose is missed within 12 hours of when dose was due, take dose. If missed dose is greater than 12 hours from scheduled time, do not take until the following day and extend treatment duration to complete 5 days.
    • Do not cut, crush, or chew tablet.
  • Dose reduction due to toxicity:
    • If absolute neutrophil count is less than 1000 cells/mm3 or platelets less than 50,000 cells/mm3, delay next treatment cycle if no active disease.  
    • If hematological recovery takes longer than 2 weeks after achieving remission, delay dosing for an additional 2 weeks, then resume at reduced dose:
      • First dose reduction: Reduce treatment duration to 4 days
      • Second dose reduction: Reduce treatment duration to 3 days
      • Third dose reduction: Administer on days 1, 3, and 5.
    • Renal toxicity, hepatotoxicity, or infection requires delay of next cycle and consideration of dose reduction.
  • Facilitate drug acquisition:
    • Patient assistance is available through Taiho Oncology Patient Support at TiahoPatientSupport.com
      • $0 copay for eligible, privately insured patients
      • Alternate funding support for publicly insured patients, such as Medicare
      • Patient Assistance program for underinsured patients

Clinical Pearls

  • Decitabine/cedazuridine is a hazardous drug and should be handled accordingly. 1
  • Do not substitute for IV decitabine within a treatment cycle.
  • Patients of reproductive potential should use contraception:
    • Females of reproductive potential should use contraception during therapy and for at least 6 months after last dose.
    • Males of reproductive potential should use contraception during therapy and for 3 months after last dose. 1
  • Dose interruptions due to adverse effects occurred in over 40% of patients in clinical trials.1
  • Complete blood counts need to be monitored prior to each cycle and as needed during treatment.  
  • Avoid coadministration with drugs that are metabolized by cytidine deaminase (gemcitabine, cytarabine, etc.).1
  • Decitabine/cedazuridine is available in 35mg/100mg tablets packaged in blister card with 5 tablets (1 cycle).

References

  1. Inqovi (decitabine and cedazuridine) [package insert]. Astex Pharmaceuticals, Inc. Pleasanton, CA. July 2020.
  2. National Comprehensive Cancer Network. Myelodysplastic Syndromes. Version 1.2021. Available at https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf. Accessed Nov 29, 2020.
  3. Garcia-Manero G, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood 2020;136:674–683.
  4. National Comprehensive Cancer Network. Myelodysplastic Syndromes. Version 1.2021. Available at https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf. Accessed Nov 29, 2020.
  5. National Institutes of Health. U.S. National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/. Accessed December 10, 2020.