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FDA News: Issue 18, July 2020

Author: [AUTHOR] Published on 7/20/2020 11:06:00 AM


FDA Approves INQOVI (Decitabine and Cedazuridine) for Adult Patients with Previously Treated and Untreated Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

On July 7, 2020, the US Food and Drug Administration (FDA) approved INQOVI (decitabine and cedazuridine) for treatment of adult patients with myelodysplastic syndromes (MDS), including 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.

The approved recommended dosage of INQOVI is 1 tablet (35 mg decitabine and 100 mg cedazuridine) taken orally once daily on Days 1 through 5 of each 28-day cycle for a minimum of 4 cycles until disease progression or unacceptable toxicity. A complete or partial response may take longer than 4 cycles. INQOVI should be taken on an empty stomach. INQOVI must not be substituted for an intravenous decitabine product within a cycle.

Additional information regarding dosage and administration, including dosage modifications for adverse reactions, as well as warnings and precautions about myelosuppression and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)
  • MOA: INQOVI was a combination of decitabine, a nucleoside metabolic inhibitor, and cedazuridine, a cytidine deaminase (CDA) inhibitor. CDA catalyzed degradation of cytidine, including cytidine analog decitabine. Therefore, coadministration of cedazuridine increases systemic exposure of decitabine.
  • General PK: The geometric mean ratio (GMR) of the 5-day cumulative decitabine AUC, the primary outcome measure, was 99% (90% confidence intervals (CI): 93, 106) following 5 consecutive once daily doses of INQOVI compared to that of intravenous (IV) decitabine. Decitabine and cedazuridine Cmax and AUC over the dosing interval increase in an approximately dose-proportional manner following administration of oral decitabine at 20 mg to 40 mg once daily (0.6 to 1.1 times the recommended dose) in combination with 100 mg oral cedazuridine, and for cedazuridine following administration of oral cedazuridine at 40 to 100 mg once daily (0.4 to 1.0 times the recommended dose) in combination with 20 mg oral decitabine. At steady state, decitabine and cedazuridine Cmax [coefficient of variation (%CV)] were 145 ng/mL (55%) and 371 ng/mL (52%), respectively, and AUC were 178 ng·hr/mL (53%) and 3291 ng·hr/mL (45%), respectively, following the approved recommended dosage of INQOVI for 5 consecutive days. Steady state was achieved at Day 2 for decitabine and cedazuridine following daily dosing of INQOVI. The accumulation ratio of decitabine was 1.7 (42%), and cedazuridine was 1.1 (63%).
  • Absorption: Cedazuridine bioavailability was 20% (23%). Oral decitabine exposure was increased with cedazuridine. The median Tmax (range) was 1 hour (0.3 to 3.0) for decitabine and 3 hours (1.5 to 6.1) for cedazuridine following administration of INQOVI.
  • Distribution: Decitabine and cedazuridine V/F (%CV) at steady state were 417 L (54%) and 296 L (51%), respectively. The fraction unbound for decitabine was 96% (4%) to 94% (2%) between 17 ng/mL to 342 ng/mL, and for cedazuridine was 66% (6%) to 62% (2%) between 1000 ng/mL and 50000 ng/mL.
  • Elimination: At steady state, the mean terminal half-life was 1.5 hours (27%) for decitabine and 6.7 hours (19%) for cedazuridine; and the CL/F was 197 L/hour (53%) for decitabine and 30.3 L/hour (46%) for cedazuridine.
  • Metabolism: Decitabine was primarily metabolized by CDA and by physicochemical degradation, while cedazuridine was converted to epimer by physicochemical degradation.
  • Excretion: 46% of cedazuridine was excreted in urine (21% unchanged) and 51% in feces (27% unchanged).
  • PD :Decitabine induced hypomethylation both in vitro and in vivo. In patients administered the recommended dosage of decitabine and cedazuridine, the maximum change from baseline in the long interspersed nucleotide elements-1 (LINE-1) demethylation was observed at Day 8, with less than complete recovery of LINE-1 methylation to baseline at the end of the treatment cycle. Based on the exposure-response analyses, a relationship between an increase in 5-day cumulative daily decitabine exposure and a greater likelihood of some adverse reactions (e.g., any grade neutropenias, thrombocytopenia) was observed in clinical studies.
Drug Interactions
Avoid coadministration of INQOVI with drugs that are metabolized by CDA, as INQOVI may result in increased systemic exposure of these drugs and potentially increase their toxicity.

Use in Specific Populations
No clinically meaningful effect of age (32 to 90 years), sex, body surface area (1.3 to 2.9 m2), body weight (41 to 158 kg), mild to moderate renal impairment (CLcr 30 to 89 mL/min based on Cockcroft Gault), and mild hepatic impairment (total bilirubin > 1 to 1.5 × ULN or AST > ULN) on pharmacokinetics of decitabine or cedazuridine with INQOVI. The effects of moderate (total bilirubin > 1.5 to 3 × ULN and any AST) and severe hepatic impairment (total bilirubin > 3 × ULN and any AST) or severe renal impairment (CLcr 15 to <30 mL/min) and ESRD (CLcr <15 mL/min) on INQOVI pharmacokinetic were unknown.

Efficacy and Safety
The primary outcome measure was comparison of the 5-day cumulative decitabine AUC between INQOVI and IV decitabine in an open-label, randomized, 2-cycle, 2-sequence crossover study in 133 patients (refer to General PK in earlier section). In addition, efficacy of INQOVI, established based on complete response (CR) and the rate of conversion from transfusion dependence to transfusion independence, was demonstrated as supportive data from two trials. Refer to the full prescribing information linked below for additional information regarding efficacy in these trials.

Most common adverse reactions (incidence ≥ 20%) were fatigue, constipation, hemorrhage, myalgia, mucositis, arthralgia, nausea, dyspnea, diarrhea, rash, dizziness, febrile neutropenia, edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and increased transaminase. The most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were decreased leukocytes, decreased platelet count, decreased neutrophil count, and decreased hemoglobin.

Full prescribing information is available at https://go.usa.gov/xfCWQ.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

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 by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at http://go.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.

We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to ocp@fda.hhs.gov.

This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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