Note: Do not substitute decitabine and cedazuridine oral tablets for IV decitabine within a treatment cycle.
Myelodysplastic syndromes: Oral: Decitabine 35 mg/cedazuridine 100 mg once daily on days 1 to 5 of each 28-day treatment cycle for a minimum of 4 cycles, until disease progression or unacceptable toxicity. May take longer than 4 cycles for a complete or partial response.
Missed dose: If a dose is missed within 12 hours of the time it is usually administered, administer the missed dose as soon as possible and then resume the normal daily dosing schedule. Extend the dosing period by 1 day for every missed dose to complete 5 daily doses for each cycle. If a dose is vomited, do not administer an additional dose (continue with the next scheduled dose).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: Renal function may be estimated using the Cockcroft-Gault equation.
CrCl ≥60 mL/minute: No dosage adjustment necessary.
CrCl ≥30 to 59 mL/minute: No dosage adjustment necessary; monitor for increased incidence of adverse reactions.
CrCl 15 to 29 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
CrCl <15 mL/minute (end-stage renal disease): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Renal toxicity during treatment: Serum creatinine ≥2 mg/dL: Delay the next cycle and resume at the same or at a reduced dose (eg, administer fewer days per cycle) upon resolution.
Mild impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN): There are no dosage adjustments provided in the manufacturer’s labeling; however, mild impairment had no effect on decitabine or cedazuridine pharmacokinetics.
Moderate (total bilirubin >1.5 to 3 times ULN and any AST) to severe (total bilirubin >3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Hepatotoxicity during treatment:
Serum bilirubin ≥2 times ULN: Delay the next cycle and resume at the same or at a reduced dose (eg, administer fewer days per cycle) upon resolution.
AST or ALT ≥2 times ULN: Delay the next cycle and resume at the same or at a reduced dose (eg, administer fewer days per cycle) upon resolution.
Refer to adult dosing.
Hematologic toxicity:
ANC <1,000/mm3 or platelets <50,000/mm3 (in the absence of active disease): Delay next treatment cycle and monitor CBC until ANC ≥1,000/mm3 and platelets ≥50,000/mm3.
If hematologic recovery (ANC ≥1,000/mm3 and platelets ≥50,000/mm3) occurs within 2 weeks of achieving remission, continue decitabine and cedazuridine at the same dose.
If hematologic recovery (ANC ≥1,000/mm3 and platelets ≥50,000/mm3) does not occur within 2 weeks of achieving remission, delay decitabine and cedazuridine for up to 2 additional weeks AND resume at a reduced dose (administer decitabine and cedazuridine on days 1 through 4). If myelosuppression persists after a dose reduction, consider further dose reductions (see Table). Maintain or increase dose in subsequent cycles as clinically indicated.
|
Usual (initial) dose |
Decitabine 35 mg/cedazuridine 100 mg once daily on days 1 through 5 of a 28-day treatment cycle |
|
Dose Reduction Level |
Decitabine and Cedazuridine Dose Reduction Schedule |
|
First |
Decitabine 35 mg/cedazuridine 100 mg once daily on days 1 through 4 |
|
Second |
Decitabine 35 mg/cedazuridine 100 mg once daily on days 1 through 3 |
|
Third |
Decitabine 35 mg/cedazuridine 100 mg once daily on days 1, 3, and 5 |
Nonhematologic toxicity: Active or uncontrolled infection: Delay the next cycle and resume at the same or at a reduced dose (eg, administer fewer days per cycle) upon resolution.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Inqovi: 35-100 MG
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Inqovi: 35-100 MG
Oral: Administer at approximately the same time of day. Swallow tablet whole; do not cut, crush, or chew. Administer on an empty stomach; do not consume food 2 hours before and 2 hours after dose.
Decitabine is a hazardous agent (NIOSH 2016 [group 1]); decitabine/cedazuridine is a cytotoxic drug (per product labeling).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Myelodysplastic syndromes: Treatment of 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, in adults.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults. Also see decitabine.
>10%:
Dermatologic: Skin rash (12%)
Endocrine & metabolic: Decreased serum albumin (22%), decreased serum calcium (16%), decreased serum glucose (14%), increased serum glucose (19%)
Gastrointestinal: Constipation (20%), diarrhea (16%), nausea (25%), stomatitis (18%; grades 3/4: 1%)
Hematologic & oncologic: Anemia (71%; grades 3/4: 55%), febrile neutropenia (10% to 33%; grades 3/4: 10% to 32%), hemorrhage (24%; grades 3/4: 2%), leukopenia (79%; grades 3/4: 65%), neutropenia (73%; grades 3/4: 71%), thrombocytopenia (82%; grades 3/4: 76%)
Hepatic: Increased serum alanine aminotransferase (13%), increased serum alkaline phosphatase (22%), increased serum transaminase (12%)
Infection: Sepsis (6% to 14%)
Nervous system: Dizziness (16%), fatigue (29%), headache (22%)
Respiratory: Dyspnea (17%), pneumonia (7% to 21%)
1% to 10%:
Cardiovascular: Cardiac arrhythmia (3%), edema (10%), hypotension (4%)
Dermatologic: Cellulitis (4%), Sweet’s syndrome (1%)
Endocrine & metabolic: Decreased serum sodium (9%), weight loss (5%)
Gastrointestinal: Abdominal pain (9%), decreased appetite (10%), vomiting (5%)
Hepatic: Increased serum aspartate aminotransferase (6%)
Nervous system: Falling (4%), insomnia (6%), neuropathy (4%)
Neuromuscular & skeletal: Arthralgia (9%), myalgia (9%)
Renal: Increased serum creatinine (7%), renal insufficiency (9%)
Respiratory: Cough (7%), upper respiratory tract infection (6%)
Miscellaneous: Fever (7%)
<1%: Hematologic & oncologic: Tumor lysis syndrome
Postmarketing:
Cardiovascular: Cardiomyopathy
Hematologic & oncologic: Differentiation syndrome
Respiratory: Interstitial pulmonary disease
There are no contraindications listed in the US manufacturer's labeling.
Canadian labeling: Hypersensitivity to decitabine, cedazuridine, or any component of the formulation.
Concerns related to adverse effects:
• Bone marrow suppression: Fatal and serious myelosuppression can occur with decitabine and cedazuridine. New or worsening thrombocytopenia (including grades 3 or 4) occurred commonly. Neutropenia and anemia (including grades 3 or 4) were also common. Neutropenic fever occurred in one-third of patients; grades 3 or 4 neutropenic fever events were reported. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying myelodysplastic syndromes. Obtain CBC counts prior to treatment initiation, prior to each cycle, and as clinically indicated to monitor response and toxicity. Hematologic toxicity (thrombocytopenia, neutropenia, anemia, and febrile neutropenia) is the most frequent cause of decitabine and cedazuridine treatment interruption and/or dose reduction. Administer growth factor support and anti-infective prophylaxis and treatment as clinically appropriate. Delay the next treatment cycle and resume at the same or reduced dose as recommended; may require permanent discontinuation.
• Infection: Serious and sometimes fatal complications due to infection have occurred with decitabine and cedazuridine. Pneumonia and sepsis have been observed, including grade 3 or 4 events; rare fatalities due to pneumonia, sepsis, and septic shock were also reported. Administer anti-infective prophylaxis and treatment as clinically appropriate.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Cedazuridine: May increase the serum concentration of Cytidine Deaminase Substrates. Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Cytidine Deaminase Substrates: Cedazuridine may increase the serum concentration of Cytidine Deaminase Substrates. Risk X: Avoid combination
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Risk D: Consider therapy modification
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Risk D: Consider therapy modification
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Evaluate pregnancy status prior to use in females of reproductive potential.
Females of reproductive potential should use effective contraception during therapy and for 6 months after the last dose of decitabine/cedazuridine. Males with female partners of reproductive potential should use effective contraception during therapy and for 3 months after the last decitabine/cedazuridine dose.
Based on the mechanism of action, data from animal reproduction studies, as well as limited human data, in utero exposure to decitabine/cedazuridine may cause fetal harm.
It is not known if decitabine or cedazuridine are present in breast milk.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for at least 2 weeks after the last decitabine/cedazuridine dose.
Monitor CBC (at baseline, prior to each cycle, and as clinically indicated); monitor serum creatinine, CrCl, AST, ALT, total bilirubin. Evaluate pregnancy status prior to use (in females of reproductive potential). Monitor for signs/symptoms of infection. Monitor adherence.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Decitabine is a hypomethylating agent. After phosphorylation, decitabine is incorporated into DNA and inhibits DNA methyltransferase causing hypomethylation and subsequent cell death (within the S-phase of the cell cycle). Hypomethylation in cancer cells may restore normal function to genes that are necessary for control of cellular differentiation and proliferation.
Cedazuridine is a cytidine deaminase (CDA) inhibitor. CDA is an enzyme that catalyzes the degradation of cytidine, including the cytidine analog decitabine; high CDA levels in the GI tract and liver degrade decitabine and limit its oral bioavailability. The combination of cedazuridine with decitabine increases systemic decitabine exposure.
Distribution: V/Fss (apparent): Decitabine: 417 L; Cedazuridine: 296 L.
Metabolism: Decitabine: Primarily via cytidine deaminase, also via physiochemical degradation; Cedazuridine: Conversion to epimer via physiochemically degradation.
Bioavailability: Decitabine: Cedazuridine increases oral decitabine exposure; Cedazuridine: 20%.
Half-life elimination: Decitabine: 1.5 hours; Cedazuridine: 6.7 hours.
Time to peak: Decitabine: 1 hour (range: 0.3 to 3 hours); Cedazuridine: 3 hours (range: 1.5 to 6.1 hours).
Excretion: Cedazuridine: Feces (51%; 27% as unchanged drug); Urine (46%; 21% as unchanged drug).
Clearance (apparent): Decitabine: 197 L/hour; Cedazuridine: 30.3 L/hour.
Tablets (Inqovi Oral)
35-100 mg (per each): $1,834.78
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