cedazuridine/decitabine (Rx)

Brand and Other Names:Inqovi
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Dosing & Uses

AdultPediatric

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

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Interactions

Interaction Checker

and cedazuridine/decitabine

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            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
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            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
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            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.

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            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)
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            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

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

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            • Compare formulary status to other drugs in the same class.
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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.