PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Pyrimidine Analogs

    DEA CLASS

    Rx

    DESCRIPTION

    Cytosine analog and the deoxy derivative of 5-azacytidine; acts by inhibiting methylation of DNA, is a more potent inhibitor of methylation that 5-azacytidine in vitro; approved for the treatment of myelodysplastic syndrome (MDS).

    COMMON BRAND NAMES

    Dacogen

    HOW SUPPLIED

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

    DOSAGE & INDICATIONS

    For the treatment myelodysplastic syndrome (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
    Intravenous infusion
    Adults

    15 mg/m2 IV over 3 hours every 8 hours (45 mg/m2/day) for 3 days (1 cycle - 135 mg/m2/cycle); repeat every 6 weeks. It is recommended that patients be treated for a minimum of 4 cycles; however a complete response may take longer than 4 cycles. Treatment may be continued as long as the patient experiences benefit. If hematologic recovery (ANC 1000/mm3 or higher and platelets 50,000/mm3or higher) from a cycle of decitabine requires longer than 6 weeks, the dose of decitabine should be adjusted. In a phase III trial, 170 patients were randomized to decitabine therapy or best supportive care. Decitabine therapy was associated with increased overall response rate (17% vs. none) and tended towards a longer median time to AML transformation and survival (12.1 months vs. 7.8 months) as compared to supportive care. In addition, decitabine therapy was associated with increases in quality of life parameters including decreased transfusion requirements. An alternate dosage schedule of decitabine 20 mg/m2/day IV over 1 hour on days 1 through 5 repeated every 4 weeks may also be given. If myelosuppression is present, subsequent treatment cycles should be delayed until ANC 1000/mm3 or higher and platelets 50,000/mm3 or higher. It is recommended that patients be treated for a minimum of 4 cycles; however a complete response may take longer than 4 cycles. Treatment may be continued as long as the patient experiences benefit. In a clinical trial of 99 patients, the overall response rate was 32% and the overall hematologic improvement rate was 51%. 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    The suggested maximum tolerated dose (MTD) for decitabine is dependent on performance status, other chemotherapy agents or radiation given in combination, and disease state. Therefore, dosing may vary from protocol to protocol. If questions arise, clinicians should consult the appropriate references to verify the dose.

    Adults

    In MDS, the manufacturer recommends maximum biologic dose of 135 mg/m2/cycle IV. The MTD of decitabine is not established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    During clinical trials, decitabine was not administered to patients with transaminase > 2-times upper limit of normal or serum bilirubin > 1.5 mg/dL.

    Renal Impairment

    During clinical trials, decitabine was not administered to patients with a serum creatinine > 2 mg/dL.

    ADMINISTRATION

    Observe and exercise usual precautions for handling, preparing, and administering solutions of 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 (Otsuka America Pharmaceutical, Inc., Dr.Reddy's Laboratories Limited, Sandoz Inc., Sun Pharma Global FZE, Accord Healthcare Inc.).
    Recommended vial diluent, dilution solutions, and storage following reconstitution differ among products.
     
    Reconstitution:
    Add 10 mL of diluent to the 50-mg lyophilized powder vial for a final concentration of 5 mg/mL; the pH of the reconstituted vial is 6.7 to 7.3.
    Use sterile water for injection (Otsuka America Pharmaceutical, Inc., Dr.Reddy's Laboratories Limited, Sandoz Inc., Accord Healthcare Inc. ) or supplied diluent (Sun Pharma Global FZE ) for vial reconstitution.
    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.
    0.9% sodium chloride injection and 5% dextrose injection are recommended dilution solutions for all products; Lactated Ringer’s injection is also a recommended dilution solution for decitabine products from Sandoz Inc. and Sun Pharma Global FZE.
    Storage following dilution: The diluted admixture may be used within 15 minutes. Otherwise, decitabine admixtures prepared using refrigerated (2 to 8 degrees C; 36 to 46 degrees F) infusion fluids and stored under refrigeration are stable as follows: up to a maximum of 4 hours until administration (Otsuka America Pharmaceutical, Inc., Dr.Reddy's Laboratories Limited, Accord Healthcare Inc. ) or up to a maximum of 7 hours until administration (Sandoz Inc., Sun Pharma Global FZE ).
    Intravenous Infusion:
    The diluted admixture is administered intravenously over 1 or 3 hours; infusion time depends on the treatment regimen.

    STORAGE

    Dacogen:
    - Discard unused portion. Do not store for later use.
    - Store unreconstituted product at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Anemia, bone marrow suppression, fungal infection, herpes infection, infection, neutropenia, thrombocytopenia, varicella, viral infection

    Decitabine is associated with bone marrow suppression, including anemia, thrombocytopenia, and neutropenia. Decitabine should be used only by clinicians experienced in the use of cancer chemotherapy. Complete blood counts, including differential and platelet counts, should be performed as needed, but, at a minimum, prior to each dosing cycle. After administration of the recommended dosage in the first cycle, decitabine dosage for subsequent cycles should be reduced or delayed based on hematologic recovery. Patients with an active infection, including fungal infection, should be treated prior to initiating decitabine therapy. Patients with a history of varicella zoster, other herpes infection (e.g., herpes simplex), or other viral infection are at risk for reactivation of the infection when treated with chemotherapy. Clinicians should consider the need for growth factors and/or antimicrobial agents for prevention or treatment of infections in patients with myelodysplastic syndrome receiving decitabine.

    Hepatic disease, renal impairment

    There are no data regarding the use of decitabine in patients with renal impairment or hepatic disease; decitabine should be used in caution in these patients. In clinical trials, decitabine was not administered to patients with serum creatinine > 2 mg/dl, transaminase > 2-times upper limit of normal, or serum bilirubin > 1.5 mg/dl. Liver function tests and serum creatinine levels should be obtained prior to beginning decitabine therapy.

    Contraception requirements, male-mediated teratogenicity, 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 be advised to use effective contraception while taking decitabine and for at least 1 month after the last dose. Women who become pregnant or suspect a pregnancy should contact their healthcare provider. 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 at least 2 months after their last dose.

    Pregnancy

    Decitabine, classified as pregnancy category D, may cause fetal harm when administered to a pregnant woman, based on animal data and it’s 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. Decitabine was teratogenic, fetotoxic, and embryotoxic in mice and rats. Reduced fetal survival and decreased fetal weight occurred in mice exposed to a single, intraperitoneal (IP) decitabine injection (at doses about 2% and/or 7% of the recommended daily clinical dose) on gestational day 8, 9, 10, or 11. Fetal defects including supernumerary ribs, fused vertebrae and ribs, cleft palate, vertebral defects, hind limb defects, and digital defects of fore- and hind-limbs were also observed. Additionally, a single, intraperitoneal decitabine injection (at doses about 8% and/or 13% of the recommended daily clinical dose) on gestational day 9, 10, 11, or 12 resulted in reduced fetal survival, decreased fetal weight, and fetal defects (vertebral and rib anomalies, exophthalmia, exencephaly, cleft palate, fore digit defects, and reduced size and ossification of long bones of the fore-limb and hind-limb) in rats.

    Breast-feeding

    It is not known whether decitabine is secreted in human milk in a woman who is breast-feeding. Because of the potential of serious adverse reactions in nursing infants, women should be advised to discontinue breast-feeding or discontinue decitabine.

    ADVERSE REACTIONS

    Severe

    neutropenia / Delayed / 38.0-87.0
    thrombocytopenia / Delayed / 24.0-85.0
    anemia / Delayed / 0-22.0
    leukopenia / Delayed / 0-22.0
    hyperkalemia / Delayed / 13.0-13.0
    pulmonary edema / Early / 6.0-6.0
    pancytopenia / Delayed / 5.0-5.0
    heart failure / Delayed / 5.0-5.0
    pleural effusion / Delayed / 5.0-5.0
    cardiomyopathy / Delayed / Incidence not known
    atrial fibrillation / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    cardiac arrest / Early / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    intracranial 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

    Moderate

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

    Mild

    fever / Early / 6.0-53.0
    fatigue / Early / 46.0-46.0
    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 (unspecified) / Early / 11.0-19.0
    back pain / Delayed / 17.0-18.0
    pharyngitis / Delayed / 16.0-16.0
    asthenia / Delayed / 15.0-15.0
    abdominal pain / Early / 5.0-14.0
    epistaxis / Delayed / 13.0-13.0
    dyspepsia / Early / 10.0-12.0
    lethargy / Early / 12.0-12.0
    hypoesthesia / Delayed / 11.0-11.0
    pruritus / Rapid / 9.0-11.0
    anxiety / Delayed / 9.0-11.0
    weight loss / Delayed / 9.0-9.0
    myalgia / Early / 5.0-9.0
    injection site reaction / Rapid / 5.0-8.0
    alopecia / Delayed / 8.0-8.0
    xerosis / Delayed / 8.0-8.0
    sinusitis / Delayed / 5.0-6.0
    musculoskeletal pain / Early / 5.0-6.0
    urticaria / Rapid / 6.0-6.0
    otalgia / Early / 6.0-6.0
    gastroesophageal reflux / Delayed / 5.0-5.0
    weakness / Early / 5.0-5.0
    increased urinary frequency / Early / 5.0-5.0
    night sweats / Early / 5.0-5.0
    nasal congestion / Early / 5.0-5.0
    malaise / Early / 5.0-5.0

    DRUG INTERACTIONS

    Anticoagulants: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Antithrombin III: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Apixaban: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Argatroban: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Azathioprine: (Minor) Additive immunosuppressant affects may be seen when azathioprine is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Basiliximab: (Minor) Additive immunosuppressant affects may be seen when basiliximab is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Betrixaban: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Bivalirudin: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely.
    Celecoxib: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cyclosporine: (Minor) Additive immunosuppressant affects may be seen when cyclosporine is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Dabigatran: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Dalteparin: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Danaparoid: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Desirudin: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    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.
    Diclofenac: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
    Diphenhydramine; Ibuprofen: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Edoxaban: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Efalizumab: (Minor) Concurrent use of efalizumab with other agents which cause bone marrow or immune suppression such as antineoplastic agents may result in additive effects. Dosage reductions may be required.
    Enoxaparin: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Esomeprazole; Naproxen: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Etodolac: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Famotidine; Ibuprofen: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Flurbiprofen: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fondaparinux: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Heparin: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Hydrocodone; Ibuprofen: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Indomethacin: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketoprofen: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lansoprazole; Naproxen: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lepirudin: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Meclofenamate Sodium: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nabumetone: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Sumatriptan: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nonsteroidal antiinflammatory drugs: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Oxaprozin: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Pentosan: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Piroxicam: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Rivaroxaban: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Rofecoxib: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sulindac: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tinzaparin: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Tolmetin: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    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.
    Valdecoxib: (Major) Due to the thrombocytopenic effects of decitabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors (including aspirin), strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Warfarin: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.

    PREGNANCY AND LACTATION

    Pregnancy

    Decitabine, classified as pregnancy category D, may cause fetal harm when administered to a pregnant woman, based on animal data and it’s 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. Decitabine was teratogenic, fetotoxic, and embryotoxic in mice and rats. Reduced fetal survival and decreased fetal weight occurred in mice exposed to a single, intraperitoneal (IP) decitabine injection (at doses about 2% and/or 7% of the recommended daily clinical dose) on gestational day 8, 9, 10, or 11. Fetal defects including supernumerary ribs, fused vertebrae and ribs, cleft palate, vertebral defects, hind limb defects, and digital defects of fore- and hind-limbs were also observed. Additionally, a single, intraperitoneal decitabine injection (at doses about 8% and/or 13% of the recommended daily clinical dose) on gestational day 9, 10, 11, or 12 resulted in reduced fetal survival, decreased fetal weight, and fetal defects (vertebral and rib anomalies, exophthalmia, exencephaly, cleft palate, fore digit defects, and reduced size and ossification of long bones of the fore-limb and hind-limb) in rats.

    It is not known whether decitabine is secreted in human milk in a woman who is breast-feeding. Because of the potential of serious adverse reactions in nursing infants, women should be advised to discontinue breast-feeding or discontinue decitabine.

    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 infusion. When administered at 20—30 mg/m2/day to solid tumor patients, the pharmacokinetics of decitabine were characterized by a biphasic disposition. The terminal half-life was 0.51 +/- 0.31 hour. Plasma protein binding is negligible (< 1%). The metabolism and route of elimination is not known in humans. One probable route of elimination is 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. In a pharmacokinetic analysis, twenty-five patients received decitabine 15 mg/m2 IV over 3 hours every 8 hours for 3 days (option 1) or 20 mg/m2 IV over 1 hour once daily for 5 days (option 2). The clearance of decitabine was higher after treatment option 2.

    Intravenous Route

    In a pharmacokinetic analysis, twenty-five patients received decitabine 15 mg/m2 IV over 3 hours every 8 hours for 3 days (option 1) or 20 mg/m2 IV over 1 hour once daily for 5 days (option 2). No systemic accumulation of decitabine or changes in pharmacokinetic parameters occurred with repeat dosing in either group. In a population pharmacokinetic analysis comparing the same treatment arms (n = 35), the cumulative AUC per cycle was 2.3-fold lower in the treatment option 2 group.