Decitabine and cedazuridine (decitabine/cedazuridine) is a fixed-combination antineoplastic agent containing decitabine (a nucleoside metabolic inhibitor) and the cytidine deaminase inhibitor cedazuridine; cedazuridine enhances the oral bioavailability of decitabine by inhibiting its metabolism by cytidine deaminase.1, 3, 4, 7
The fixed combination of decitabine and cedazuridine (decitabine/cedazuridine) is used for the treatment of myelodysplastic syndrome (MDS)1, 3, 4, 5, 6 and is designated an orphan drug by the FDA for use in this condition.2 The drug is indicated for use in adult patients with previously treated or untreated, de novo or secondary MDS with the following French-American-British (FAB) 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 (IPSS) groups.1
The current indication for the fixed combination of decitabine and cedazuridine is based on the results of two randomized, open-label, 2-cycle, 2-sequence crossover studies demonstrating equivalent exposure over 5 days and no erosion of efficacy compared to the 5-day regimen of IV decitabine, which already had been approved for use in this indication.1, 3, 4, 5, 6 The studies (one phase 2 and one phase 3) included adults with MDS (IPSS intermediate-1, intermediate-2, or high-risk) or CMML who had received no more than one prior cycle of azacitidine or decitabine.1, 3, 6 Patients with all FAB subtypes, including patients with a low-risk IPSS score, were eligible for the phase 3 trial.1, 3, 7 In both studies, patients were randomized 1:1 to receive decitabine/cedazuridine (35 mg decitabine and 100 mg cedazuridine) orally in cycle 1 and decitabine 20 mg/m2 IV in cycle 2 or the reverse sequence; both treatments were administered once daily on days 1 through 5 of the 28-day cycle.1, 5, 6 Starting with cycle 3, all patients received decitabine/cedazuridine orally once daily on days 1 through 5 of each 28-day cycle until disease progression or unacceptable toxicity.1, 5, 6
In the phase 3 study (ASTX727-02 [ASCERTAIN, NCT03306264] in 133 patients), the geometric mean ratio (GMR) for the 5-day cumulative decitabine exposure between decitabine/cedazuridine and IV decitabine (the primary outcome measure) was 99%.1, 3, 4, 5 In this study, the complete response rate (after a median follow-up of 12.6 months and median treatment duration of 8.2 months) was 21%, with a median duration of response of 7.5 months (range: 1.6-17.5 months); 20% of all patients went on to receive stem cell transplantation following decitabine/cedazuridine treatment.1, 3, 4
In the phase 2 study (ASTX727-01-B [NCT02103478] in 80 patients), the GMR for the 5-day cumulative decitabine exposure between decitabine/cedazuridine and IV decitabine (the primary outcome measure) was 93.5% for the dose-confirmation stage (during which the two components were administered as separate capsules) and 97.6% for the fixed-dose combination stage.3, 4, 6 In the ASTX727-01-B study, the complete response rate (after a median follow-up of 24 months and median treatment duration of 6.6 months) was 18%, with a median duration of response of 8.7 months (range: 1.1-18.2 months); 15% of all patients went on to receive stem cell transplantation following decitabine/cedazuridine treatment.1, 3, 4
Responses were classified using the MDS International Working Group (IWG) 2006 criteria.3, 6, 9 A complete response to therapy (lasting at least 4 weeks) generally was defined as no more than 5% myeloblasts and normal maturation of all cell lines in bone marrow and improvements in peripheral blood cell counts (i.e., hemoglobin concentration of at least 11 g/dL, absolute neutrophil count [ANC] of at least 1000/mm3, platelet count of at least 100,000/mm3) in the absence of peripheral blast cells; persistent dysplasia was allowed.3, 9 In both studies, complete responses were considered sufficiently durable to demonstrate clinical benefit in this patient population.1, 3 Although durability of complete responses was slightly lower than with IV decitabine, duration of treatment was shorter and many of the responses were ongoing at the time of data cutoff.3 Among 41 patients who were transfusion-dependent (RBC and/or platelet) at baseline in the ASTX727-01-B study, 20 (49%) of these patients became transfusion-independent during any consecutive 56-day period during the study.1 Among 39 patients who were transfusion-independent of both RBC and platelet transfusions at baseline in the ASTX727-01-B study, 25 (64%) of these patients remained transfusion-independent during any consecutive 56-day period during the study.1 Among 57 patients who were transfusion-dependent (RBC and/or platelet) at baseline in the ASCERTAIN study, 30 (53%) of these patients became transfusion-independent during any 56-day period during the study.1 Among 76 patients who were transfusion-independent of both RBC and platelet transfusions at baseline in the ASCERTAIN study, 48 (63%) of these patients remained transfusion-independent during any 56-day period during the study.1
The hypomethylating agents azacitidine and decitabine are the current standard of therapy for the management of MDS in patients who are not eligible for allogeneic hematopoietic stem cell transplantation (HSCT).4, 7, 8 Decitabine/cedazuridine is an orally administered hypomethylating agent that may reduce the burden of monthly, multiple-day, IV infusions or subcutaneous injections of parenterally administered hypomethylating agents in long-term responders.4, 7, 8 Some clinicians offer decitabine/cedazuridine in place of parenteral hypomethylating agents because of the convenience of oral administration.8
Dispensing and Administration Precautions
The fixed combination of decitabine and cedazuridine (decitabine/cedazuridine) is administered orally at the same time each day on an empty stomach, with no food consumed 2 hours before or 2 hours after administration.1 The tablets should be swallowed whole and should not be cut, crushed, or chewed.1
If a dose is missed and is remembered within 12 hours of the time it is usually taken, the patient should take the missed dose as soon as possible and should then resume the normal daily dosing schedule.1 The dosing period should be extended by 1 day for every missed dose to complete 5 daily doses for each cycle.1
If vomiting occurs after administration of the fixed-combination tablets, an extra dose should not be taken; the next dose should be taken as scheduled.1
Decitabine/cedazuridine is commercially available as a fixed-combination tablet containing 35 mg of decitabine and 100 mg of cedazuridine.1
For the treatment of myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS, the recommended dosage of decitabine and cedazuridine is 1 tablet (35 mg decitabine and 100 mg cedazuridine) once daily on days 1 through 5 of each 28-day cycle.1 Therapy should be continued for a minimum of 4 cycles until disease progression or unacceptable toxicity occurs; a complete or partial response may require more than 4 cycles.1
Dosage Modification for Toxicity
If hematologic recovery (i.e., absolute neutrophil count [ANC] of at least 1000/mm3 and platelet count of at least 50,000/mm3 in the absence of active disease) from the previous treatment cycle has not occurred, the next treatment cycle should be delayed until hematologic recovery has occurred.1
If hematologic recovery occurs within 2 weeks of achieving remission, decitabine/cedazuridine should be continued at the same dosage.1
If hematologic recovery does not occur within 2 weeks of achieving remission, the next treatment cycle should be delayed for up to 2 more weeks, and then decitabine/cedazuridine in the next cycle should be administered at a reduced dosage of 1 tablet (35 mg decitabine and 100 mg cedazuridine) once daily on days 1 through 4 of each 28-day cycle.1
If myelosuppression persists after dosage reduction, further dosage reduction should be considered.1 If a second dosage reduction is required, the recommended dosage is 1 tablet (35 mg decitabine and 100 mg cedazuridine) once daily on days 1 through 3 of each 28-day cycle.1 If a third dosage reduction is required, the recommended dosage is 1 tablet (35 mg decitabine and 100 mg cedazuridine) once daily on days 1, 3, and 5 of each 28-day cycle.1
Dosage in each treatment cycle should be maintained at a reduced level or increased as clinically indicated.1 Persistent severe neutropenia and febrile neutropenia should be managed with supportive treatment.1
If serum creatinine concentration increases to ≥2 mg/dL; serum ALT, AST, or total bilirubin concentration increases to ≥2 times the upper limit of normal; or active or uncontrolled infection occurs, decitabine/cedazuridine therapy should not be restarted until the toxicity has resolved.1 When the toxicity has resolved, decitabine/cedazuridine therapy should be resumed at the same or a reduced dosage as clinically appropriate.1
The manufacturer makes no specific dosage recommendations for patients with hepatic impairment.1
No dosage modification of decitabine/cedazuridine is recommended for patients with mild or moderate renal impairment (estimated creatinine clearance 30-89 mL/minute).1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1 Pregnancy should be avoided during therapy.1 Pregnancy status should be verified prior to initiation of therapy in women of reproductive potential; such patients should also be advised to use effective contraception during and for 6 months after discontinuance of decitabine/cedazuridine therapy.1 If used during pregnancy or if pregnancy occurs during therapy, patients should be apprised of the potential fetal hazard.1
Male patients receiving decitabine/cedazuridine who have female partners of reproductive potential should be advised to use effective contraception during and for 3 months after discontinuance of decitabine/cedazuridine therapy.1
Myelosuppression (commonly manifested as anemia, severe neutropenia, and severe thrombocytopenia) has been reported in patients receiving decitabine and cedazuridine and is the most frequent cause of decitabine/cedazuridine dosage reduction or interruption.1 In the phase 3 study of decitabine/cedazuridine in patients with myelodysplastic syndrome (MDS), new or worsening thrombocytopenia occurred in 82% of patients and was grade 3 or 4 in 76% of patients.1, 1 Neutropenia, febrile neutropenia, and anemia occurred in 73, 33, and 71% of patients, respectively, and were grade 3 or 4 in 71, 32, and 55% of patients, respectively.1 Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.1
Fatal and serious infectious complications can occur with decitabine/cedazuridine.1 Pneumonia or sepsis occurred in 21 or 14% of patients, respectively and was grade 3 or 4 in 15 or 11% of patients, respectively.1 Fatal pneumonia, sepsis, and septic shock each occurred in 1% of patients.1
Complete blood cell counts (CBCs) should be performed prior to initiation of decitabine/cedazuridine, prior to each cycle, and as clinically indicated to monitor response and toxicity.1 Growth factors and anti-infective therapies for treatment or prophylaxis should be administered as appropriate.1 The next cycle of therapy should be delayed when necessary and resumed at the same or reduced dosage as recommended.1
There are no adequate data on the developmental risks associated with the use of decitabine and cedazuridine in pregnant women.1 Based on human data, animal studies, and its mechanism of action, decitabine/cedazuridine can cause fetal harm when administered to a pregnant woman.1 A single published case report of IV decitabine use throughout the first trimester during pregnancy describes adverse developmental outcomes, including major birth defects (structural abnormalities).1 In animal reproduction studies, IV administration of decitabine to pregnant mice and rats during organogenesis at doses approximately 7% of the recommended human dose, based on body surface area caused adverse developmental outcomes, including increased embryofetal mortality, alterations to growth, and structural abnormalities.1 Pregnant women should be advised of the potential risk to a fetus.1
It is not known whether decitabine, cedazuridine, or their metabolites are distributed into milk, affect milk production, or affect the breast-fed infant.1 Because of the potential for serious adverse reactions in the breast-fed infant, women should not breast-feed during decitabine/cedazuridine therapy and for at least 2 weeks after the last dose.1
Females and Males of Reproductive Potential
Females of reproductive potential should be advised to use effective contraception during treatment with decitabine/cedazuridine and for 6 months after the last dose.1 Male patients receiving decitabine/cedazuridine who have female partners of reproductive potential should be advised to use effective contraception during and for 3 months after discontinuance of decitabine/cedazuridine therapy.1
Based on nonclinical data, decitabine/cedazuridine may impair male fertility; the reversibility of this effect is unknown.1
Safety and efficacy of decitabine/cedazuridine have not been established in pediatric patients.1
Of 208 patients who received decitabine/cedazuridine in clinical studies, 75% were ≥65 years of age, while 36% were ≥75 years of age.1 No overall differences in safety or efficacy were observed between geriatric and younger patients.1
Systemic exposure to decitabine/cedazuridine does not appear to be altered in patients with mild hepatic impairment.1 The fixed combination of decitabine and cedazuridine has not been studied in patients with moderate or severe hepatic impairment.1
No dosage modification of decitabine/cedazuridine is recommended for patients with mild or moderate renal impairment (creatinine clearance 30-89 mL/minute).1 Due to the potential for increased adverse reactions, patients with moderate renal impairment (creatinine clearance 30-59 mL/minute) should be monitored frequently for adverse reactions.1 Decitabine/cedazuridine has not been studied in patients with severe renal impairment (creatinine clearance 15-29 mL/minute) or end-stage renal disease (creatinine clearance less than 15 mL/minute).1
Adverse reactions occurring in at least 20% of patients receiving decitabine/cedazuridine include fatigue,1, 6 constipation,1, 6 hemorrhage,1 myalgia,1 mucositis,1 arthralgia,1 nausea,1, 6 dyspnea,1, 6 diarrhea,1, 6 rash,1 dizziness,1, 6 febrile neutropenia,1, 6 edema,1 headache,1 cough,1 decreased appetite,1 upper respiratory tract infection,1 pneumonia,1 increased transaminase concentrations,1 leukopenia,1, 6 thrombocytopenia,1, 6 neutropenia,1, 6 and anemia.1, 6
Decitabine is not a substrate of cytochrome P-450 (CYP) enzymes and is considered unlikely to inhibit or induce CYP enzymes.3
Decitabine has no clinically meaningful effect on the pharmacokinetics of cedazuridine.1 Cedazuridine is an inhibitor of cytidine deaminase and increases the systemic exposure of decitabine following oral administration.1
Cedazuridine is not a substrate of CYP enzymes.1 Cedazuridine does not induce CYP1A, CYP2B6, CYP2C9, or CYP3A, and does not inhibit CYP1A, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.1
Cedazuridine is not a substrate of P-glycoprotein (P-gp), multidrug and toxin extrusion transporters (MATE) 1 or MATE2K, organic anion transporters (OAT) 1 or OAT3, organic anion transport proteins (OATP) 1B1, OATP1B3, or OATP2B1, or organic cation transporters (OCT) 1 or OCT2, and does not inhibit P-gp, breast cancer resistance protein (BCRP), MATE1, MATE2K, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2.1
Drugs Metabolized by Cytidine Deaminase
Coadministration of decitabine and cedazuridine with drugs that are metabolized by cytidine deaminase (which is inhibited by cedazuridine) may result in increased systemic exposure of the substrate drug, potentially leading to increased toxicity.1 Coadministration of decitabine/cedazuridine with drugs that are metabolized by cytidine deaminase (e.g., gemcitabine) should be avoided.1, 3
Coadministration of decitabine and cedazuridine with proton pump inhibitors has no clinically important effect on exposure to decitabine or cedazuridine.1
Decitabine is a nucleoside metabolic inhibitor.1 Decitabine is believed to exert its effects after phosphorylation and direct incorporation into DNA (during the S phase of the cell cycle) and inhibition of DNA methyltransferase, causing hypomethylation of DNA and cellular differentiation and/or apoptosis.1, 4, 7 Decitabine inhibits DNA methylation in vitro, which is achieved at concentrations that do not cause major suppression of DNA synthesis.1, 7 Decitabine-induced hypomethylation in cancer cells may restore normal function to genes that are critical for the control of cellular differentiation and proliferation.1 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.1 Nonproliferating cells are relatively insensitive to decitabine.1 In patients administered the recommended dosage of decitabine/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.1 In clinical trials in patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML), there was no significant difference in LINE-1 DNA demethylation between oral decitabine/cedazuridine and IV decitabine.4, 5, 6
Cytidine deaminase is an enzyme that catalyzes the degradation of cytidine, including the cytidine analog decitabine.1 High levels of cytidine deaminase in the GI tract and liver degrade decitabine and limit its oral bioavailability.1 By inhibiting cytidine deaminase, cedazuridine increases the systemic exposure of decitabine.1, 4
Following administration of oral decitabine at 20-40 mg once daily (0.6-1.1 times the recommended dose) in combination with 100 mg of oral cedazuridine, an approximately dose-proportional increase in peak concentrations and area under the plasma-concentration time curve (AUC) over the dosing interval was observed for decitabine.1 Similarly, following administration of oral cedazuridine at 40-100 mg once daily (0.4-1 times the recommended dose) in combination with 20 mg oral decitabine, an approximately dose-proportional increase in peak concentrations and AUC over the dosing interval was observed for cedazuridine.1 The geometric mean ratio (GMR) of decitabine AUC following the first dose of oral decitabine/cedazuridine compared to that of IV decitabine on day 1 was 60% in patients with MDS or CMML.1 The GMR of decitabine AUC following 5 consecutive once-daily doses of decitabine/cedazuridine compared to that of IV decitabine on day 5 was 106% and the GMR of the 5-day cumulative decitabine AUC following 5 consecutive once-daily doses of decitabine/cedazuridine compared to that of IV decitabine was 99%.1, 5
Following oral administration of decitabine/cedazuridine at the recommended dose in patients with MDS or CMML, the mean oral bioavailability of cedazuridine is approximately 20%.1 The median time to peak plasma concentrations is approximately 1 or 3 hours for decitabine or cedazuridine, respectively.1 Administration of decitabine/cedazuridine with food (high-fat, high-calorie meal) has little effect on cedazuridine exposure; however, decitabine exposure parameters are approximately 40% (AUC) to 53.5% (peak concentration) lower compared to those following administration under fasted conditions,3 and the fixed-combination tablets should not be taken within 2 hours of eating.1 In vitro, decitabine is 94-96% unbound to plasma proteins at a concentration of 17-342 ng/mL, and cedazuridine is 62-66% unbound to plasma proteins at a concentration of 1000-50,000 ng/mL.1 Decitabine is metabolized primarily by cytidine deaminase and by physicochemical degradation, and cedazuridine is metabolized primarily via conversion to epimer by physicochemical degradation.1 The mean terminal elimination half-life at steady state is 1.5 or 6.7 hours for decitabine or cedazuridine, respectively.1 In healthy subjects, 46% of a cedazuridine dose is excreted in urine (21% as unchanged drug) and 51% in feces (27% as unchanged drug).1
Age (32-90 years), sex, and mild hepatic impairment do not substantially affect the pharmacokinetics of decitabine or cedazuridine when administered as the fixed combination.1 Decitabine exposure (AUC) increases with decreasing body surface area or body weight, and cedazuridine exposure increases with decreasing creatinine clearance; however, body surface area (1.3-2.9 m2), body weight (41-158 kg), and mild to moderate renal impairment (creatinine clearance 30-89 mL/minute) do not have a clinically important effect on the pharmacokinetics of decitabine and cedazuridine after administration of the fixed combination.1
Additional Information
Overview® (see Users Guide). For additional information on this drug 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 cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 35 mg decitabine, 100 mg cedazuridine | Inqovi® | Taiho Oncology |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions July 22, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Taiho Oncology, Inc. Inqovi® (decitabine and cedazuridine) oral prescribing information. Princeton, NJ; 2020 Jul. [Web]
2. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD; From FDA website. [Web]
3. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 212576Orig1s000: Multi-discipline Review. From FDA website. [Web]
4. Dhillon S. Decitabine/Cedazuridine: First Approval. Drugs . 2020; 80:1373-1378. [PubMed 32860582]
5. Garcia-Manero G, McCloskey J, Griffiths EA et al. Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross over Phase 3 Study (ASCERTAIN study) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine. Blood . 2019; 134 (Suppl 1): 846. [Web]
6. Garcia-Manero G, Griffiths EA, Steensma DP et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood . 2020; 136:674-683. [PubMed 32285126]
7. Patel AA, Cahill K, Saygin C et al. Cedazuridine/decitabine: from preclinical to clinical development in myeloid malignancies. Blood Adv . 2021; 5:2264-2271. [PubMed 33904891]
8. Tremblay D, Rippel N, Feld J et al. Contemporary Risk Stratification and Treatment of Chronic Myelomonocytic Leukemia. Oncologist . 2021; 26:406-421. [PubMed 33792103]
9. Cheson BD, Greenberg PL, Bennett JM et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood . 2006; 108:419-25. [PubMed 16609072]