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Decitabine and Cedazuridine

Class: Antineoplastic Agents
Chemical Name: 4-amino-1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,3,5-triazin-2-one
Molecular Formula: C8H12N4O4C9H14F2N2O5
CAS Number: 22432-95-7
Brands: Inqovi

Medically reviewed by Drugs.com on Jul 27, 2020. Written by ASHP.

Introduction

The fixed combination of decitabine and cedazuridine is an antineoplastic agent.

Uses for Decitabine and Cedazuridine

Decitabine and cedazuridine has the following uses:

Decitabine and cedazuridine is a fixed-dose combination of decitabine, a nucleoside metabolic inhibitor, and cedazuridine, a cytidine deaminase inhibitor, indicated 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.

Decitabine and Cedazuridine Dosage and Administration

General

Decitabine and cedazuridine is available in the following dosage form(s) and strength(s):

Tablets: 35 mg decitabine and 100 mg cedazuridine.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration
  • The recommended dosage of decitabine and cedazuridine is 1 tablet (35 mg decitabine and 100 mg cedazuridine) taken orally once daily on days 1 through 5 of each 28-day cycle.

  • Take decitabine and cedazuridine on an empty stomach.

Cautions for Decitabine and Cedazuridine

Contraindications

None.

Warnings/Precautions

Myelosuppression

Fatal and serious myelosuppression can occur with decitabine and cedazuridine. Based on laboratory values, new or worsening thrombocytopenia occurred in 82% of patients, with grade 3 or 4 occurring in 76%. Neutropenia occurred in 73% of patients, with grade 3 or 4 occurring in 71%. Anemia occurred in 71% of patients, with grade 3 or 4 occurring in 55%. Febrile neutropenia occurred in 33% of patients, with grade 3 or 4 occurring in 32%. Myelosuppression (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is the most frequent cause of decitabine and cedazuridine dose reduction or interruption, occurring in 36% of patients. Permanent discontinuation due to myelosuppression (febrile neutropenia) occurred in 1% of patients. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.

Fatal and serious infectious complications can occur with decitabine and cedazuridine. Pneumonia occurred in 21% of patients, with grade 3 or 4 occurring in 15%. Sepsis occurred in 14% of patients, with grade 3 or 4 occurring in 11%. Fatal pneumonia occurred in 1% of patients, fatal sepsis in 1%, and fatal septic shock in 1%.

Obtain complete blood cell counts prior to initiation of decitabine and cedazuridine, prior to each cycle, and as clinically indicated to monitor response and toxicity. Administer growth factors and anti-infective therapies for treatment or prophylaxis as appropriate. Delay the next cycle and resume at the same or reduced dose as recommended.

Embryofetal Toxicity

Based on findings from human data, animal studies, and its mechanism of action, decitabine and cedazuridine can cause fetal harm when administered to a pregnant woman. In nonclinical studies with decitabine in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic at doses less than the recommended human dose.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with decitabine and cedazuridine and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with decitabine and cedazuridine and for 3 months after the last dose.

Specific Populations

Pregnancy

Risk Summary: Based on findings from human data, animal studies, and its mechanism of action, decitabine and cedazuridine can cause fetal harm when administered to a pregnant woman. A single published case report of intravenous decitabine use throughout the first trimester during pregnancy describes adverse developmental outcomes, including major birth defects (structural abnormalities). In animal reproduction studies, intravenous administration of decitabine to pregnant mice and rats during organogenesis at doses approximately 7% of the recommended human dose on a body surface area (mg/m2) basis caused adverse developmental outcomes, including increased embryofetal mortality, alterations to growth, and structural abnormalities. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Human Data: There are no available data on decitabine and cedazuridine use in pregnant women.

A single published case report of intravenous decitabine pregnancy exposure in a 39-year-old woman with a hematologic malignancy described multiple structural abnormalities after 6 cycles of therapy in the 18th week of gestation. These abnormalities included holoprosencephaly, absence of nasal bone, mid-facial deformity, cleft lip and palate, polydactyly, and rocker-bottom feet. The pregnancy was terminated.

Animal Data: No reproductive or developmental toxicity studies have been conducted with decitabine and cedazuridine or cedazuridine.

In utero exposure to decitabine causes temporally related defects in the rat and/or mouse, which include growth suppression, exencephaly, defective skull bones, rib/sternabrae defects, phocomelia, digit defects, micrognathia, gastroschisis, and micromelia. Decitabine inhibits proliferation and increases apoptosis of neural progenitor cells of the fetal central nervous system (CNS) and induces palatal clefting in the developing murine fetus. Studies in mice have also shown that decitabine administration during osteoblastogenesis (day 10 of gestation) induces bone loss in offspring.

In mice exposed to single intraperitoneal decitabine injections (0, 0.9 and 3.0 mg/m2, approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation days 8, 9, 10 or 11, no maternal toxicity was observed, but reduced fetal survival was observed after treatment at 3 mg/m2 and decreased fetal weight was observed at both dose levels. The 3 mg/m2 dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hindlimb defects, and digital defects of forelimbs and hindlimbs.

In rats given a single intraperitoneal injection of 2.4, 3.6 or 6 mg/m2 decitabine (approximately 5, 8, or 13% the daily recommended clinical dose, respectively) on gestation days 9–12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m2 was seen when decitabine was given on gestation day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6 mg/m2. Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m2. Reduced size and ossification of long bones of the forelimb and hindlimb were noted at 6 mg/m2.

The effect of decitabine on postnatal development and reproductive capacity was evaluated in mice administered a single 3-mg/m2 intraperitoneal injection (approximately 7% the recommended daily clinical dose) on day 10 of gestation. Body weights of males and females exposed in utero to decitabine were significantly reduced relative to controls at all postnatal time points. No consistent effect on fertility was seen when female mice exposed in utero were mated to untreated males. Untreated females mated to males exposed in utero showed decreased fertility at 3 and 5 months of age (36% and 0% pregnancy rate, respectively). Follow up studies indicated that treatment of pregnant mice with decitabine on gestation day 10 was associated with a reduced pregnancy rate resulting from effects on sperm production in the F1 generation.

Lactation

There are no data on the presence of cedazuridine, decitabine, or their metabolites in human milk or on their effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with decitabine and cedazuridine and for at least 2 weeks after the last dose.

Females and Males of Reproductive Potential

Decitabine and cedazuridine can cause fetal harm when administered to a pregnant woman.

Verify the pregnancy status in females of reproductive potential prior to initiating decitabine and cedazuridine.

Advise females of reproductive potential to use effective contraception during treatment with decitabine and cedazuridine and for 6 months after the last dose.

Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with decitabine and cedazuridine and for 3 months after the last dose.

Based on findings of decitabine and cedazuridine in animals, decitabine and cedazuridine may impair male fertility. The reversibility of the effect on fertility is unknown.

Pediatric Use

The safety and effectiveness of decitabine and cedazuridine have not been established in pediatric patients.

Geriatric Use

Of the 208 patients in clinical studies who received decitabine and cedazuridine, 75% were age 65 years and older, while 36% were age 75 years and older. No overall differences in safety or effectiveness were observed between patients age 65 years and older, 75 years and older, and younger patients.

Renal Impairment

No dosage modification of decitabine and cedazuridine is recommended for patients with mild or moderate renal impairment (creatinine clearance [Clcr] of 30 to 89 mL/min based on Cockcroft-Gault). Due to the potential for increased adverse reactions, monitor patients with moderate renal impairment (Clcr 30 to 59 mL/min) frequently for adverse reactions. Decitabine and cedazuridine has not been studied in patients with severe renal impairment (Clcr 15 to 29 mL/min) or end-stage renal disease (ESRD: Clcr <15 mL/min) .

Common Adverse Effects

Most common adverse reactions (incidence ≥20%) 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.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Drugs Metabolized by Cytidine Deaminase: Avoid coadministration with decitabine and cedazuridine.

Actions

Mechanism of Action

Decitabine is a nucleoside metabolic inhibitor that is believed to exert its effects after phosphorylation and direct incorporation into DNA and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation and/or apoptosis. Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis. Decitabine-induced hypomethylation in cancer cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation. In rapidly dividing cells, the cytotoxicity of decitabine may also be attributed to the formation of covalent adducts between DNA methyltransferase and decitabine incorporated into DNA. Non-proliferating cells are relatively insensitive to decitabine.

Cytidine deaminase (CDA) is an enzyme that catalyzes the degradation of cytidine, including the cytidine analog decitabine. High levels of CDA in the gastrointestinal tract and liver degrade decitabine and limit its oral bioavailability. Cedazuridine is a CDA inhibitor. Administration of cedazuridine with decitabine increases systemic exposure of decitabine.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Myelosuppression

Advise patients of the risk of myelosuppression and to report any symptoms of fever, infection, anemia, or bleeding to their healthcare provider as soon as possible. Advise patients of the need for laboratory monitoring.

Embryofetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment with decitabine and cedazuridine and for 6 months after the last dose.

Advise males with female partners of reproductive potential to use effective contraception during treatment with decitabine and cedazuridine and for 3 months after the last dose.

Lactation

Advise women not to breastfeed during treatment with decitabine and cedazuridine and for 2 weeks after the last dose.

Administration

Advise patients to take decitabine and cedazuridine at approximately the same time each day on an empty stomach. Instruct patients to avoid eating for at least 2 hours before and 2 hours after taking decitabine and cedazuridine. Advise patients on what to do when a dose is missed or vomited.

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Decitabine and Cedazuridine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, Film-coated

35 mg decitabine, 100 mg cedazuridine

Inqovi

Taiho Pharmaceutical Co. Ltd.

AHFS Drug Information. © Copyright 2021, Selected Revisions July 27, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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