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  • CLASSES

    Small Molecule Antineoplastic DNA Methyltransferase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Pyrimidine antimetabolite
    Used in adult patients with myelodysplastic syndrome
    Myelosuppression has been reported; monitor complete blood counts during therapy

    COMMON BRAND NAMES

    Dacogen

    HOW SUPPLIED

    Dacogen/Decitabine Intravenous Inj Pwd F/Sol: 50mg

    DOSAGE & INDICATIONS

    For the treatment myelodysplastic syndrome (MDS).
    NOTE: Decitabine is designated an orphan drug by the FDA for the treatment of MDS.
    For the treatment of previously treated or untreated and de novo or secondary MDS including all French-American-British subtypes and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
    Intravenous dosage
    Adults

    3-day regimen, 15 mg/m2 IV over 3 hours every 8 hours for 3 days; repeated every 6 weeks; or 5-day regimen, 20 mg/m2 IV over 1 hour daily on days 1, 2, 3, 4, and 5 repeated every 4 weeks. Continue therapy for at least 4 cycles; a complete or partial response may take longer than 4 cycles. Do not start a new cycle until the absolute neutrophil count is 1,000 cells/microL or greater and the platelet count is 50,000 cells/microL or greater. Therapy delay or a dose reduction may be necessary in patients who experience toxicity. Consider prophylactic antiemetics prior to each dose of decitabine. The overall response (ORR) rate was significantly improved (17% vs. 0%; p less than 0.001) in patients who received a 3-day regimen of decitabine (n = 89) compared with best supportive care (n = 81) in a randomized trial. However, the median time to AML transformation or death was not significantly delayed in the decitabine arm (12.1 months vs. 7.8 months). The ORR was 32% and the overall hematologic improvement rate was 51%in patients who received a 5-day regimen of decitabine in a single-arm trial (n = 99). Among patients experiencing a hematologic improvement, 82% achieved their best response within the first 2 cycles.

    For the treatment of chronic myelogenous leukemia (CML)†.
    Intravenous infusion
    Adults

    In 1 clinical trial in 35 patients with CML (all phases) resistant or intolerant to imatinib, decitabine 10 to 15 mg/m2 IV over 1 hour 5 days a week for 2 weeks every 6 weeks was given. Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in 7 patients (20%), for an overall response rate of 54%. Of the patients responding, 83% were in chronic phase, 41% in accelerated phase, and 34% in blast phase. Some patients were treated with hydroxyurea during the first 1 to 2 cycles. The overall cytogenic response was 46% (major cytogenic response in 6 patients and minor response in 10 patients). Median duration of response was 3.5 months, range 2 to 13+ months. There did not appear to cross-sensitivity to imatinib. In another clinical trial of 28 patients with either accelerated phase (AP) or myeloid blastic phase (BP) CML, decitabine 15 mg/m2 IV over 1 hour 5 days a week for 2 weeks every 6 weeks was administered in combination with imatinib 600 mg PO once daily. Complete hematological responses were observed in 32% of patients (7 patients in AP, 2 patients in BP), while a cytogenetic response was observed in 33% and 20% of patients in AP and BP, respectively. Of note, out of 7 patients with BCR-ABL kinase mutation, only 1 patient exhibited a hematologic response (14%) compared to 10 out of 19 patients (53%) with no BCR-ABL kinase mutation detected. Other doses of decitabine have been studied for the treatment of CML and have shown activity. In a study of 130 patients with CML (all phases), decitabine 50 mg/m2 IV over 6 hours every 12 hours for 5 days every 4 to 8 weeks produced objective responses in 63%, 55%, and 28% of patients in chronic phase, accelerated phase, and blastic phase CML, respectively. Higher doses of decitabine (75 mg/m2 and 100 mg/m2) were also administered in this study, but did not show an increase in response rates. Myelosuppression was significant with each of the 3 decitabine dosage regimens considered in this study.

    For the treatment of acute myelogenous leukemia (AML)†.
    NOTE: Decitabine has been designated an orphan drug by the FDA for the treatment of AML.
    For the treatment of newly-diagnosed AML in adults who are age 75 years or older or who have comorbidities that make them ineligible for intensive induction chemotherapy, in combination with venetoclax†.
    NOTE: Venetoclax is FDA approved in combination with decitabine for this indication.
    Intravenous dosage
    Adults

    20 mg/m2 IV daily on days 1, 2, 3, 4, and 5 repeated every 28 days starting on day 1 of cycle 1 in combination with oral venetoclax. The venetoclax dose is increased during a ramp-up phase as follows: 100 mg on day 1; 200 mg on day 2; 400 mg on day 3; and 400 mg once daily on day 4 and beyond. Continue treatment until disease progression. Treatment with venetoclax plus decitabine was evaluated in patients with newly diagnosed AML who were 75 years of age or older or had comorbidities in a nonrandomized trial (n = 13; median age, 75 years; range, 68 to 86 years). The complete remission (CR) and CR with partial hematological recovery (CRh) rates were 54% and 7.7%, respectively; the median time to first CR or CRh was 1.9 months (range, 0.8 to 4.2 months). At a median follow-up was 11 months (range, 0.7 to 38.8 months), the median duration of CR was 12.7 months in patients who received venetoclax plus decitabine. Comorbidities included severe cardiac disease (7.7%) or a creatinine clearance of less than 45 mL/min (7.7%).[60706]

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Myelodysplastic syndrome3-day regimen: 15 mg/m2 IV every 8 hours for 3 days repeated every 6 weeks.5-day regimen: 20 mg/m2 IV daily on days 1, 2, 3, 4, and 5 repeated every 4 weeks.

    Geriatric

    Myelodysplastic syndrome3-day regimen: 15 mg/m2 IV every 8 hours for 3 days repeated every 6 weeks.5-day regimen: 20 mg/m2 IV daily on days 1, 2, 3, 4, and 5 repeated every 4 weeks.

    Adolescents

    Safety and efficacy not established.

    Children

    Safety and efficacy not established.

    Infants

    Safety and efficacy not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in patients with baseline hepatic impairment are not available; it appears that no initial dosage adjustments are needed.
    Treatment-related hepatic impairment (ALT level or total bilirubin level 2-times the upper limit of normal or greater): hold decitabine therapy until the toxicity resolves.

    Renal Impairment

    Specific guidelines for dosage adjustments in patients with baseline renal impairment are not available; it appears that no initial dosage adjustments are needed.
    Treatment-related renal impairment (serum creatinine level of 2 mg/dL or higher): hold decitabine therapy until the toxicity resolves.

    ADMINISTRATION

    Caution: Observe and exercise usual precautions for handling, preparing, and administering cytotoxic drugs.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Decitabine is available as a single-use 50-mg lyophilized powder vial from multiple manufacturers.
    Recommended vial diluent, dilution solutions, and storage following reconstitution and dilution differ among products; refer to the manufacturer package insert for specific instructions.
    Reconstitution:
    Add 10 mL of diluent to the 50-mg lyophilized powder vial for a final concentration of 5 mg/mL.
    Dilution:
    Immediately after reconstitution, withdraw the appropriate dose from the vial and further dilute to a final admixture concentration between 0.1 to 1 mg/mL.
    Storage following dilution: The diluted admixture may be used within 15 minutes or stored refrigerated (2 to 8 degrees C; 36 to 46 degrees F) for a maximum of 4 hours or 7 hours until administration (depending on the product used).
    Intravenous (IV) Infusion:
    Administer the diluted admixture IV over 1 or 3 hours; infusion time depends on the treatment regimen.[60995]

    STORAGE

    Dacogen:
    - Discard unused portion. Do not store for later use.
    - Store reconstituted product in accordance with package insert instructions
    - Store unreconstituted product at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Anemia, bone marrow suppression, infection, neutropenia, thrombocytopenia

    Severe bone marrow suppression/myelosuppression (e.g., anemia, thrombocytopenia, and neutropenia) has been reported with decitabine therapy; some cases were fatal. Myelosuppression and worsening neutropenia occur frequently in the first or second treatment cycle and may not indicate progression or underlying MDS. Obtain complete blood counts at baseline, prior to each cycle of therapy, and as clinically indicated to monitor for response and toxicity. Therapy delay or a dose reduction may be necessary in patients who experience delayed hematologic recovery. Severe infection (e.g., pneumonia) has also been reported with decitabine therapy. In patients who have an active or uncontrolled infection, hold decitabine therapy until the infection resolves. Start growth factor and/or anti-infective therapy as clinically indicated.

    Hepatic disease

    The use of decitabine in patients with hepatic disease has not been studied. Obtain liver function tests at baseline and as clinically indicated during therapy. Hold decitabine therapy until hepatotoxicity resolves in patients who develop hepatic impairment (i.e., ALT level or total bilirubin level 2-times the upper limit of normal or greater).

    Renal disease

    The use of decitabine in patients with renal disease has not been studied. Obtain renal function tests at baseline (e.g., serum creatinine (SCr) level) and as clinically indicated during therapy. Hold decitabine therapy until nephrotoxicity resolves in patients who develop renal impairment (i.e., SCr level of 2 mg/dL or higher).

    Pregnancy

    Decitabine may cause fetal harm when administered to a pregnant woman, based on human and animal data and its mechanism of action. Advise females of reproductive potential to avoid becoming pregnant while taking decitabine. Discuss the potential hazard to the fetus if decitabine is used during pregnancy or if a patient becomes pregnant while taking this drug. Limited published data of decitabine use in the first trimester during pregnancy describe adverse developmental fetal outcomes including major birth defects (i.e., structural abnormalities). In a single case report, structural abnormalities (i.e., holoprosencephaly, absence of nasal bone, mid-facial deformity, cleft lip and palate, polydactyly and rocker-bottom feet) were reported in a fetus (gestational age, 18 weeks) following use of 6 cycles of decitabine therapy in a 39-year old woman with a hematologic malignancy. Additionally, decitabine caused adverse developmental outcomes including malformations and embryo-fetal lethality in mice and rats in animal studies.

    Contraception requirements, infertility, male-mediated teratogenicity, pregnancy testing, reproductive risk

    Discuss contraception requirements with both male and female patients due to the potential for reproductive risk with decitabine. Females of reproductive potential should undergo pregnancy testing prior to initiation of decitabine. These patients should be advised to use effective contraception while taking decitabine and for 6 months after the last dose. Because of the potential risk of male-mediated teratogenicity, men with female partners of reproductive potential should be advised to use effective contraception while on treatment and for 3 months after their last dose. Infertility may occur in male patients based on data from animal studies.

    Breast-feeding

    It is not known if decitabine or its active metabolites are secreted in human milk or if it has effects on the breast-fed infant or milk production. Because there is a potential for adverse reactions in nursing infants from decitabine, women should discontinue breast-feeding during decitabine therapy and for at least 2 weeks after the last dose.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 0-87.0
    thrombocytopenia / Delayed / 0-85.0
    hyperkalemia / Delayed / 0-13.0
    pulmonary edema / Early / 0-6.0
    pancytopenia / Delayed / 0-5.0
    heart failure / Delayed / 0-5.0
    pleural effusion / Delayed / 0-5.0
    myocardial infarction / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    cardiomyopathy / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    differentiation syndrome / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 30.0-35.0
    hyperglycemia / Delayed / 6.0-33.0
    dyspnea / Early / 0-29.0
    hypomagnesemia / Delayed / 5.0-24.0
    hypoalbuminemia / Delayed / 7.0-24.0
    hypokalemia / Delayed / 12.0-22.0
    hyponatremia / Delayed / 0-19.0
    edema / Delayed / 5.0-18.0
    erythema / Early / 5.0-14.0
    hyperbilirubinemia / Delayed / 6.0-14.0
    lymphadenopathy / Delayed / 0-12.0
    stomatitis / Delayed / 11.0-12.0
    confusion / Early / 8.0-12.0
    hypotension / Rapid / 6.0-11.0
    elevated hepatic enzymes / Delayed / 10.0-11.0
    candidiasis / Delayed / 6.0-10.0
    ascites / Delayed / 0-10.0
    hypoxia / Early / 0-10.0
    depression / Delayed / 0-9.0
    hemorrhoids / Delayed / 8.0-8.0
    dehydration / Delayed / 6.0-8.0
    sinus tachycardia / Rapid / 0-8.0
    oral ulceration / Delayed / 5.0-7.0
    dysphagia / Delayed / 5.0-6.0
    hypochloremia / Delayed / 0-6.0
    bone pain / Delayed / 0-6.0
    chest pain (unspecified) / Early / 6.0-6.0
    hypertension / Early / 0-6.0
    dysuria / Early / 0-6.0
    blurred vision / Early / 0-6.0
    metabolic acidosis / Delayed / 0-5.0
    metabolic alkalosis / Delayed / 0-5.0
    hematoma / Early / 5.0-5.0
    splenomegaly / Delayed / Incidence not known
    supraventricular tachycardia (SVT) / Early / Incidence not known
    peripheral edema / Delayed / Incidence not known
    interstitial lung disease / Delayed / Incidence not known
    hemoptysis / Delayed / Incidence not known

    Mild

    fever / Early / 6.0-53.0
    fatigue / Early / 0-46.0
    nausea / Early / 40.0-42.0
    cough / Delayed / 27.0-40.0
    petechiae / Delayed / 12.0-39.0
    diarrhea / Early / 28.0-34.0
    headache / Early / 23.0-28.0
    insomnia / Early / 14.0-28.0
    vomiting / Early / 16.0-25.0
    anorexia / Delayed / 16.0-23.0
    infection / Delayed / 0-22.0
    ecchymosis / Delayed / 9.0-22.0
    chills / Rapid / 16.0-22.0
    dizziness / Early / 18.0-21.0
    arthralgia / Delayed / 17.0-20.0
    rash / Early / 11.0-19.0
    back pain / Delayed / 17.0-18.0
    pharyngitis / Delayed / 0-16.0
    asthenia / Delayed / 0-15.0
    abdominal pain / Early / 5.0-14.0
    epistaxis / Delayed / 0-13.0
    dyspepsia / Early / 10.0-12.0
    lethargy / Early / 0-12.0
    hypoesthesia / Delayed / 0-11.0
    pruritus / Rapid / 9.0-11.0
    anxiety / Delayed / 9.0-11.0
    weight loss / Delayed / 0-9.0
    myalgia / Early / 5.0-9.0
    alopecia / Delayed / 8.0-8.0
    xerosis / Delayed / 0-8.0
    injection site reaction / Rapid / 5.0-8.0
    sinusitis / Delayed / 5.0-6.0
    musculoskeletal pain / Early / 5.0-6.0
    urticaria / Rapid / 0-6.0
    otalgia / Early / 0-6.0
    gastroesophageal reflux / Delayed / 5.0-5.0
    weakness / Early / 0-5.0
    increased urinary frequency / Early / 0-5.0
    night sweats / Early / 0-5.0
    nasal congestion / Early / 0-5.0
    malaise / Early / 0-5.0

    DRUG INTERACTIONS

    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and decitabine together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.

    PREGNANCY AND LACTATION

    Pregnancy

    Decitabine may cause fetal harm when administered to a pregnant woman, based on human and animal data and its mechanism of action. Advise females of reproductive potential to avoid becoming pregnant while taking decitabine. Discuss the potential hazard to the fetus if decitabine is used during pregnancy or if a patient becomes pregnant while taking this drug. Limited published data of decitabine use in the first trimester during pregnancy describe adverse developmental fetal outcomes including major birth defects (i.e., structural abnormalities). In a single case report, structural abnormalities (i.e., holoprosencephaly, absence of nasal bone, mid-facial deformity, cleft lip and palate, polydactyly and rocker-bottom feet) were reported in a fetus (gestational age, 18 weeks) following use of 6 cycles of decitabine therapy in a 39-year old woman with a hematologic malignancy. Additionally, decitabine caused adverse developmental outcomes including malformations and embryo-fetal lethality in mice and rats in animal studies.

    It is not known if decitabine or its active metabolites are secreted in human milk or if it has effects on the breast-fed infant or milk production. Because there is a potential for adverse reactions in nursing infants from decitabine, women should discontinue breast-feeding during decitabine therapy and for at least 2 weeks after the last dose.

    MECHANISM OF ACTION

    Decitabine is an antimetabolite that can replace cytosine in DNA but, unlike cytosine, it cannot be methylated. The exact mechanism of decitabine activity has not been determined and may involve multiple pathways. Decitabine is thought to primarily act by correcting DNA methylation, a major mechanism for gene expression. In some cancer cells, hypermethylation blocks the activity of tumor suppressor genes, which regulate cell division and differentiation to prevent malignant transformation. When suppressor gene activity is blocked, cell division becomes unregulated, leading to the formation of neoplastic cells. Decitabine regulates DNA methylation (specifically targets methyltransferase), effectively demethylating and reactivating different tumor suppressor genes. Because hypermethylation occurs early in the malignant transformation of cells, decitabine may have activity in chemoprevention. Other possible mechanisms for decitabine activity include cytotoxicity due to incorporation into DNA similar to other antimetabolites, methylation-independent induction of gene expression, and degradation of DNA methyltransferase 1.

    PHARMACOKINETICS

    Decitabine is administered by intravenous (IV) infusion. Plasma protein binding of decitabine is less than 1%. In a pharmacokinetic evaluation, the mean clearance values were 125 L/hour/m2 (coefficient of variance (CV), 53%) and 210 L/hour/m2 (CV, 47%) in 11 patients who received 15 mg/m2 IV over 3 hours every 8 hours for 3 days (option 1) and 14 patients who received 20 mg/m2 IV over 1 hour daily for 5 days (option 2), respectively. The half-life values were 0.62 hour (CV, 49%) and 0.54 hour (CV, 43%) with option 1 and option 2, respectively. Decitabine appears to be eliminated via deamination by cytidine deaminase, which is found intracellularly in the liver, granulocytes, intestinal epithelium, and whole blood. Decitabine is unlikely to inhibit or induce cytochrome P450 enzymes.

    Intravenous Route

    Pharmacokinetic (PK) parameters were evaluated in 11 patients who received 15 mg/m2 IV over 3 hours every 8 hours for 3 days (option 1) and 14 patients who received 20 mg/m2 IV over 1 hour daily for 5 days (option 2). The Cmax values were 73.8 ng/mL (CV, 66%) and 147 ng/mL (CV, 49%) with option 1 and 2, respectively. Plasma concentration-time profiles following the decitabine infusion showed a biexponential decline. Systemic accumulation of decitabine or significant changes in PK parameters did not occur with repeat doses. The cumulative decitabine AUC value per cycle was 2.3-fold lower with option 2 (570 ng/mL X hour) compared with option 1 (1,332 ng/mL X hour).