Dosing & Uses
Dosage Forms & Strengths
cedazuridine/decitabine
tablet
- 100mg/35mg
Myelodysplastic Syndrome
Indicated for treatment of adults with myelodysplastic syndromes (MDSs), 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) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups
Each cycle is 28 days
Days 1-5: 1 tablet (100 mg cedazuridine/35 mg decitabine) PO qDay of each cycle
Continue for a minimum of 4 cycles until disease progression or unacceptable toxicity
A complete or partial response may take longer than 4 cycles
Dosage Modifications
Hematologic adverse reactions
- Obtain complete blood cell (CBC) count prior to initiation and before each cycle
- Delay next cycle if absolute neutrophil count (ANC) <1,000/mcL and platelets <50,000/mcL in the absence of active disease
- Monitor CBC count until ANC ≥1,000/mcL and platelets ≥50,000/mcL
-
Hematologic recovery (ANC ≥1,000/mcL and platelets ≥50,000/mcL)
- ANC and platelets recover within 2 weeks of achieving remission: Resume at the same dose
- ANC and platelet recovery not achieved within 2 weeks of achieving remission: Delay for up to 2 additional weeks; resume at reduced dose (ie, administering on Days 1-4); consider further dose reductions in the order listed below if myelosuppression persists after dose reduction
- Maintain or increase dose in subsequent cycles as clinically indicated
- Manage persistent severe neutropenia and febrile neutropenia with supportive treatment
-
Dose reductions for myelosuppression
- First dose reduction: 1 tablet PO qDay on Days 1-4
- Second dose reduction: 1 tablet PO qDay on Days 1-3
- Third dose reduction: 1 tablet PO qDay on Days 1, 3, and 5
Nonhematologic adverse reactions
-
Delay next cycle and resume at same or reduced dose upon resolution
- Serum creatinine ≥2 mg/dL
- Serum bilirubin ≥2x ULN
- AST or ALT ≥2x ULN
- Active or uncontrolled infection
Renal impairment
- Mild (CrCl 60-89 ml/min): No dosage adjustment necessary
- Moderate (CrCl 30-59 mL/min): Monitor frequently for adverse reactions
- Severe or end-stage renal disease (CrCl<29 mL): Not studied
Hepatic impairment
- Mild (total bilirubin >1 to 1.5x ULN or AST >ULN): No effect on pharmacokinetics of decitabine or cedazuridine
- Moderate-to-severe (total bilirubin >1.5x ULN and any AST): Pharmacokinetics of decitabine or cedazuridine are unknown
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (5)
- azacitidine
cedazuridine will increase the level or effect of azacitidine by decreasing metabolism. Avoid or Use Alternate Drug. Cedazuridine, a CDA inhibitor, is used with decitabine to increase systemic exposure of decitabine. Use with other drugs metabolized by CDA may increase levels and toxicities of those drugs.
- capecitabine
cedazuridine will increase the level or effect of capecitabine by decreasing metabolism. Avoid or Use Alternate Drug. Cedazuridine, a CDA inhibitor, is used with decitabine to increase systemic exposure of decitabine. Use with other drugs metabolized by CDA may increase levels and toxicities of those drugs.
- cytarabine
cedazuridine will increase the level or effect of cytarabine by decreasing metabolism. Avoid or Use Alternate Drug. Cedazuridine, a CDA inhibitor, is used with decitabine to increase systemic exposure of decitabine. Use with other drugs metabolized by CDA may increase levels and toxicities of those drugs.
- gemcitabine
cedazuridine will increase the level or effect of gemcitabine by decreasing metabolism. Avoid or Use Alternate Drug. Cedazuridine, a CDA inhibitor, is used with decitabine to increase systemic exposure of decitabine. Use with other drugs metabolized by CDA may increase levels and toxicities of those drugs.
- palifermin
palifermin increases toxicity of decitabine by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hrbefore, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.
Monitor Closely (10)
- acalabrutinib
acalabrutinib, decitabine. Either increases toxicity of the other by pharmacodynamic synergism. Use Caution/Monitor. Coadministration may increase risk of myelosuppressive effects.
- cholera vaccine
decitabine decreases effects of cholera vaccine by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids (used in greater than physiologic doses), may reduce the immune response to cholera vaccine.
- dengue vaccine
decitabine decreases effects of dengue vaccine by immunosuppressive effects; risk of infection. Use Caution/Monitor. Immunosuppressive therapies (eg, irradiation, antimetabolites, alkylating agents, cytotoxic drugs, corticosteroids [greater than physiologic doses]) may reduce immune response to dengue vaccine.
- dichlorphenamide
dichlorphenamide and decitabine both decrease serum potassium. Use Caution/Monitor.
dichlorphenamide, decitabine. Either increases toxicity of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely. Both drugs can cause metabolic acidosis. - ethotoin
decitabine increases levels of ethotoin by unknown mechanism. Use Caution/Monitor. Based on case reports.
- fingolimod
decitabine increases effects of fingolimod by immunosuppressive effects; risk of infection. Modify Therapy/Monitor Closely. Concomitant therapy is expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects. .
- hydroxyurea
decitabine, hydroxyurea. Other (see comment). Use Caution/Monitor. Comment: Combination may increase risk of myelosuppression.
- ponesimod
ponesimod and decitabine both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.
- siponimod
siponimod and decitabine both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.
- sipuleucel-T
decitabine decreases effects of sipuleucel-T by pharmacodynamic antagonism. Modify Therapy/Monitor Closely.
Minor (4)
- maitake
maitake increases effects of decitabine by pharmacodynamic synergism. Minor/Significance Unknown. Maitake mushroom has anti-tumor effects (animal/in vitro research).
- taurine
decitabine decreases levels of taurine by unspecified interaction mechanism. Minor/Significance Unknown.
- vitamin A
vitamin A, decitabine. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Antioxidants such as vitamin A enhance the efficacy, and reduce toxicity, of antineoplastic drugs.
- vitamin E
vitamin E, decitabine. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Antioxidants such as vitamin E enhance the efficacy, and reduce toxicity, of antineoplastic drugs.
Adverse Effects
>10%
All grades
- Leukocytes decreased (79-87%)
- Platelet count decreased (79-82%)
- Neutrophil count decreased (70-73%)
- Hemoglobin decreased (58-71%)
- Fatigue (29-55%)
- Glucose increased (19-54%)
- Albumin decreased (22-45%)
- Constipation (20-44%)
- Hemorrhage (24-43%)
- Alkaline phosphatase increased (22-42%)
- Myalgia (9-42%)
- Mucositis (18-41%)
- Nausea (25-40%)
- Glucose decreased (14-40%)
- Arthralgia (9-40%)
- Dyspnea (17-38%)
- Diarrhea (16-37%)
- ALT increased (13-37%)
- Dizziness (16-33%)
- Rash (12-33%)
- Febrile neutropenia (10-33%)
- Headache (22-30%)
- Calcium decreased (16-30%)
- Edema (10-30%)
- Sodium decreased (9-30%)
- AST increased (6-30%)
- Creatinine increased (7-29%)
- Cough (7-28%)
- Decreased appetite (10-24%)
- Upper respiratory tract infection (6-23%)
- Pneumonia (7-21%)
- Transaminase increased (12-21%)
- Abdominal pain (9-19%)
- Pyrexia (7-19%)
- Renal impairment (9-18%)
- Vomiting (5-15%)
- Sepsis (6-14%)
- Neuropathy (4-13%)
- Insomnia (6-12%)
- Cellulitis (4-12%)
- Fall (4-12%)
- Hypotension (4-11%)
- Arrhythmia (3-11%)
Grade 3-4
- Leukocytes decreased (65-81%)
- Platelet count decreased (65-76%)
- Neutrophil count decreased (65-71%)
- Hemoglobin decreased (41-55%)
- Febrile neutropenia (10-32%)
- Pneumonia (7-15%)
- Sepsis (6-11%)
1-10%
All grades
- Decreased weight (5-10%)
- Acute febrile neutrophilic dermatosis (Sweet syndrome) (1%)
Grade 3-4
- Glucose increased (7%)
- Dyspnea (3-6%)
- Fatigue (2-5%)
- Cellulitis (1-5%)
- Sodium decreased (2-4%)
- Mucositis (1-4%)
- Myalgia (2-3%)
- Hemorrhage (2-3%)
- Arthralgia (1-3%)
- Transaminases increased (1-3%)
- Calcium decreased (2%)
- Hypotension (2%)
- AST increased (1-2%)
- ALT increased (1-2%)
- Albumin decreased (1-2%)
- Decreased appetite (1-2%)
- Dizziness (1-2%)
- Glucose decreased (1%)
- Arrhythmia (1%)
- Fall (1%)
- Decreased weight (1%)
- Upper respiratory tract infection (1%)
- Abdominal pain (1%)
- Diarrhea (1%)
- Pyrexia (1%)
- Alkaline phosphatase increased (0.5-1%)
- Rash (0.5-1%)
<1%
All grades
- Tumor lysis syndrome (0.5%)
Grade 3-4
- Creatinine increased (0.5%)
- Insomnia (0.5%)
- Nausea (0.5%)
- Edema (0.5%)
Postmarketing Reports
Blood and lymphatic system disorders: Differentiation syndrome
Respiratory, thoracic, and mediastinal disorders: Interstitial lung disease
Cardiomyopathy
Warnings
Contraindications
None
Cautions
May cause fetal harm when administered to pregnant females
Myelosuppression
- Fatal and serious myelosuppression (ie, thrombocytopenia, neutropenia, anemia, febrile neutropenia) can occur
- Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycle and may not necessarily indicate progression of underlying MDS
- Obtain CBC count prior to initiation and monitor before each cycle, and as clinically indicated
- Administer growth factors and anti-infective therapies for treatment or prophylaxis as appropriate
Drug interaction overview
-
Drugs metabolized by cytidine deaminase
- Cedazuridine is an inhibitor of the cytidine deaminase (CDA) enzyme
- Avoid coadministration with drugs metabolized by CDA; may result in increased systemic exposure and toxicity of these drugs
Pregnancy & Lactation
Pregnancy
Based on findings from human data, animal studies, and its mechanism of action, may cause fetal harm when administered to pregnant females
No data available on use in pregnant females
Verify pregnancy status in females of reproductive potential prior to initiation
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)
Animal data
- IV administration of decitabine to pregnant mice and rats during organogenesis at doses ~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 females of the potential risk to a fetus
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 6 months after the last dose
- Males with female partners of reproductive potential: Use effective contraception during treatment and for 3 months after the last dose
Infertility
- Based on findings of decitabine and cedazuridine in animals, male fertility may be impaired
- Reversibility of the effect on fertility is unknown
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
Advise women not to breastfeed during treatment and for at least 2 weeks after the last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Cedazuridine
- CDA is a key enzyme in the catabolism of cytidines (eg, decitabine), since their deamination results in a loss of their pharmacological activity
- Cedazuridine binds to and inhibits CDA, primarily found in the GI tract, and liver that catalyzes the deamination of cytidine and cytidine analogs
- When administered in combination with a cytidine, it specifically prevents its breakdown and increases its bioavailability and efficacy
Decitabine
- Cytidine antimetabolite analogue
- Inhibits DNA methyltransferase, causing hypomethylation of DNA and intra-S-phase arrest of DNA replication
Absorption
Steady-state reached for decitabine and cedazuridine in 2 days
AUC (Day 1)
- Decitabine: 103 ng⋅hr/mL
- Cedazuridine: 2950 ng⋅hr/mL
Cumulative 5-day AUC
- Decitabine: 851 ng·hr/mL
Steady-state AUC
- Decitabine: 178 ng⋅hr/mL
- Cedazuridine: 3291 ng⋅hr/mL
Peak plasma concentration
- Decitabine: 145 ng/mL
- Cedazuridine: 371 ng/mL
Peak plasma time
- Decitabine: 1 hr
- Cedazuridine: 3 hr
Bioavailability
- Decitabine: Cedazuridine increases oral decitabine exposure
- Cedazuridine: 20%
Distribution
Vd (steady-state)
- Decitabine: 417 L
- Cedazuridine: 296 L
Fraction unbound
- Decitabine: 94-96% (17-342 ng/mL)
- Cedazuridine: 62-66% (1000-50,000 ng/mL)
Metabolism
Decitabine: Primarily by CDA and by physicochemical degradation
Cedazuridine: Conversion to epimer by physicochemical degradation
Elimination
Half-life at steady-state
- Decitabine: 1.5 hr
- Cedazuridine: 6.7 hr
Clearance
- Decitabine: 197 L/hr
- Cedazuridine: 30.3 L/hr
Excretion
- Cedazuridine: Urine (46%, 21% unchanged); feces (51%, 27% unchanged)
Administration
Oral Administration
Hazardous drug; follow applicable special handling procedures
Take on an empty stomach; do not consume food 2 hr before and 2 hr after each dose
Administer at the same time each day
Swallow tablets whole; do not cut, crush, or chew tablets
Missed dose
- Within 12 hr of the scheduled time: Take missed dose as soon as possible, then resume the normal daily dosing schedule
- More than 12 hr of the scheduled time: Do not take additional doses to make up dose; take next scheduled dose on the following day
- Extend dosing period by 1 day for every missed dose to complete 5 daily doses for each cycle
- Vomiting after administration: Do not take an additional dose, but continue with the next schedule dose
Storage
Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)
Dispense medication in the original packaging
Follow applicable disposal procedures
Images
Formulary
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