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DECITABINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Decitabine, an antimetabolite antineoplastic agent, causes hypomethylation of DNA and cellular differentiation or apoptosis.

Specific Substances

    1) 5-Aza-2'-deoxycytidine
    2) DAC
    3) NSC-127716
    4) CAS 2353-33-5
    1.2.1) MOLECULAR FORMULA
    1) C8-H12-N4-O4 (Prod Info DACOGEN(R) injection, 2010)

Available Forms Sources

    A) FORMS
    1) Decitabine is available in a single-dose vial as a sterile lyophilized powder and containing 50 mg decitabine per vial (Prod Info decitabine intravenous injection lyophilized powder for solution, 2014).
    B) USES
    1) Decitabine is indicated to treat patients with myelodysplastic syndromes (MDS) including previously treated and untreated MDS of all French-American-British subtypes (eg, refractory anemia, refractory anemia with excess blasts or with excess blasts in transformation, and chronic myelomonocytic leukemia) as well as intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups (Prod Info decitabine intravenous injection lyophilized powder for solution, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Decitabine is indicated to treat patients with myelodysplastic syndromes (MDS) including previously treated and untreated MDS of all French-American-British subtypes (eg, refractory anemia, refractory anemia with excess blasts or with excess blasts in transformation, and chronic myelomonocytic leukemia) as well as intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
    B) PHARMACOLOGY: Following phosphorylation, direct incorporation into DNA, and inhibition of DNA methyltransferase, decitabine causes hypomethylation of DNA and cellular differentiation or apoptosis.
    C) EPIDEMIOLOGY: Overdoses are rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly occurring events following use include effects related to myelosuppression (ie, neutropenia, thrombocytopenia, anemia), fatigue, pyrexia, gastrointestinal symptoms (ie, nausea, vomiting, constipation or diarrhea), skin rash, cough, petechiae, and hyperglycemia. Laboratory alterations that are relatively common with use can include hypomagnesemia, hypokalemia, and hyponatremia.
    2) SERIOUS EVENTS reported with less frequency include myocardial infarction, congestive heart failure, and intracranial hemorrhage, but relationship to therapy is not established.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Overdose data are limited. It is anticipated that clinical effects will likely be an extension of adverse events (ie, myelosuppression, fatigue, nausea, vomiting, diarrhea).
    2) SEVERE TOXICITY: Clinical effects reported at higher doses have included increased myelosuppression with prolonged neutropenia and thrombocytopenia.
    0.2.20) REPRODUCTIVE
    A) Decitabine is classified as FDA pregnancy category D. Although there have been no well-controlled studies conducted in pregnant women, administration of decitabine in mice and rats have resulted in a variety of teratogenic effects including fused vertebrae and ribs, cleft palate, and vertebral, hindlimb, and digital defects.

Laboratory Monitoring

    A) Monitor serial CBC with differential and platelet count.
    B) Monitor vital signs.
    C) Monitor serum electrolytes including magnesium.
    D) Monitor for fever or other clinical evidence of infection.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. For severe neutropenia/neutropenic sepsis, administer colony stimulating factor (eg, filgrastim, sargramostim). Transfusions as needed for severe thrombocytopenia, bleeding. Myelosuppression may be prolonged, protective isolation may help avoid infections complications.
    C) DECONTAMINATION
    1) Decontamination is not necessary; decitabine is administered parenterally.
    D) ANTIDOTE
    1) None
    E) MYELOSUPPRESSION
    1) Administer colony stimulating factor for severe neutropenia/neutropenic sepsis. Filgrastim 5 mcg/kg/day subQ or IV over 15 to 30 minutes or sargramostim 250 mcg/m(2)/day infused over 4 hours. Recombinant erythropoietin may be useful for severe anemia. Transfusions as needed for severe anemia or thrombocytopenia, bleeding. Myelosuppression may be prolonged, protective isolation may help avoid infections complications.
    F) INTRATHECAL INJECTION
    1) No clinical reports of intrathecal injection of decitabine are available. This information was derived from experience with other antineoplastics. Keep the patient upright if possible. Immediately drain at least 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. Follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative-free normal saline or lactated ringers). Consult a neurosurgeon for placement of a ventricular catheter and begin ventriculolumbar perfusion (infuse warmed preservative-free NS or LR through ventricular catheter, drain fluid from lumbar catheter; typical volumes are 80 to 150 mL/hr for 18 to 24 hours). Dexamethasone 4 mg IV every 6 hours to prevent arachnoiditis.
    G) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: Mild to moderately symptomatic patients should be sent to a healthcare facility for evaluation and treatment as necessary.
    2) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    3) CONSULT CRITERIA: Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    H) PITFALLS
    1) Symptoms of overdose may be similar to reported adverse effects of the medication following therapeutic administration.
    I) PHARMACOKINETICS
    1) Plasma protein binding is less than 1%. One metabolism pathway appears to be deamination by cytidine deaminase, primarily found in the liver but also in granulocytes, intestinal epithelium, and whole blood. Half-life ranges from 0.54 to 0.62 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) May include other agents that cause myelosuppression.

Range Of Toxicity

    A) TOXICITY: Overdose data are limited. A specific toxic dose has not been established. Clinical effects reported at higher doses have included increased myelosuppression with prolonged neutropenia and thrombocytopenia.
    B) ADULT THERAPEUTIC DOSING: Two treatment options. OPTION 1: 15 mg/m(2) by continuous IV infusion over 3 hours, repeated every 8 hours for 3 days. This cycle should be repeated every 6 weeks for a minimum of 4 cycles. OPTION 2: 20 mg/m(2) by continuous IV infusion over 1 hour, repeated daily for 5 days. This cycle should be repeated every 4 weeks for a minimum of 4 cycles.

Clinical Effects

Summary Of Exposure

    A) USES: Decitabine is indicated to treat patients with myelodysplastic syndromes (MDS) including previously treated and untreated MDS of all French-American-British subtypes (eg, refractory anemia, refractory anemia with excess blasts or with excess blasts in transformation, and chronic myelomonocytic leukemia) as well as intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.
    B) PHARMACOLOGY: Following phosphorylation, direct incorporation into DNA, and inhibition of DNA methyltransferase, decitabine causes hypomethylation of DNA and cellular differentiation or apoptosis.
    C) EPIDEMIOLOGY: Overdoses are rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly occurring events following use include effects related to myelosuppression (ie, neutropenia, thrombocytopenia, anemia), fatigue, pyrexia, gastrointestinal symptoms (ie, nausea, vomiting, constipation or diarrhea), skin rash, cough, petechiae, and hyperglycemia. Laboratory alterations that are relatively common with use can include hypomagnesemia, hypokalemia, and hyponatremia.
    2) SERIOUS EVENTS reported with less frequency include myocardial infarction, congestive heart failure, and intracranial hemorrhage, but relationship to therapy is not established.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Overdose data are limited. It is anticipated that clinical effects will likely be an extension of adverse events (ie, myelosuppression, fatigue, nausea, vomiting, diarrhea).
    2) SEVERE TOXICITY: Clinical effects reported at higher doses have included increased myelosuppression with prolonged neutropenia and thrombocytopenia.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Pyrexia occurred in 53% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 28% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    2) Pyrexia was reported in 36% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    3) In a phase II trial of 66 patients with myelodysplastic syndrome receiving decitabine (45 mg/m(2)/day for 3 days every 6 weeks), myelotoxicity led to fever (27%), infection (20%), and sepsis (11%). Infection associated with granulocytopenia caused death in 3 patients (Wijermans et al, 2000).
    4) In 31 patients with chronic myeloid leukemia in blastic phase (CML-BP), complications of myelosuppression included fever (85%) and infections (45%). The first 4 patients received an induction dose of 1000 mg/m(2)/course. Prolonged myelosuppression necessitated a reduction of the induction dose to 750 mg/m(2)/course for the next 12 patients, and finally to 500 mg/m(2)/course for the last 15 patients. The schedule for subsequent courses was based on platelet and white blood cell count; the dose ranged from 125 to 187 mg/m(2)/course to allow for administration every 4 to 5 weeks (Sacchi et al, 1999).
    5) In chronic myelogenous leukemia patients receiving 75 to 100 mg/m(2) as 6-hour infusions twice daily for 5 days, febrile episodes were seen in 68% of patients, with 46% developing documented infection (Kantarjian et al, 1997a).
    6) Reports of fever coexisting in patients with psychotic-like symptoms have been published (Wijermans et al, 1997).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) Blurred vision occurred in 6% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 0% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Epistaxis was reported in 13% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Pharyngitis occurred in 16% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 7% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial. Pharyngitis resulted in dose reductions of decitabine in 1% or more of patients (Prod Info DACOGEN(R) injection, 2010).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CHEST DISCOMFORT
    1) WITH THERAPEUTIC USE
    a) Chest discomfort occurred in 7% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 4% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    B) HYPERTENSIVE DISORDER
    1) WITH THERAPEUTIC USE
    a) Hypertension was reported in 6% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    C) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia was reported in 8% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    b) Tachycardia resulted in dose reductions of decitabine in 1% or more patients (n=83) with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    D) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension occurred in 6% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 5% of patients who received best supportive care (n=81) alone in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Hypotension was reported in 11% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    E) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema occurred in 25% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 16% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Peripheral edema was reported in 27% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    F) MYOCARDIAL INFARCTION
    1) WITH THERAPEUTIC USE
    a) Myocardial infarction has been reported in clinical trials of patients with myelodysplastic syndrome treated with decitabine (Prod Info DACOGEN(R) injection, 2010).
    b) Myocardial infarction and acute heart failure, each fatal, have been seen rarely during therapy (acute leukemia and myelodysplastic syndrome) (Petti et al, 1993; Wijermans et al, 1997); however, the underlying condition of these patients was a more likely cause.
    G) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) Congestive heart failure was reported in 5% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY CRACKLES
    1) WITH THERAPEUTIC USE
    a) Lung crackles occurred in 14% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 1% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Rales occurred in 8% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 2% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    B) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) Acute lung injury (pulmonary edema) occurred in 6% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 0% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial. Acute lung injury resulted in dose delays of decitabine in 1% or more of patients (Prod Info DACOGEN(R) injection, 2010).
    C) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough occurred in 40% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 31% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Cough was reported in 27% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia was reported in 15% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    B) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue was reported in 46% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    C) INSOMNIA
    1) WITH THERAPEUTIC USE
    a) Insomnia occurred in 28% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 14% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Insomnia was reported in 14% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    D) INTRACRANIAL HEMORRHAGE
    1) WITH THERAPEUTIC USE
    a) With 72-hour continuous infusions of low-dose decitabine in elderly patients with poor-prognosis myelodysplastic syndrome (n=29), severe pancytopenia was universal; cerebral hemorrhage related to thrombocytopenia was fatal in one patient (Wijermans et al, 1997).
    b) In adult and pediatric acute leukemia patients receiving 36- to 60-hour infusions (37 to 81 mg/kg) (n=27), significant thrombocytopenia and granulocytopenia occurred in all patients. Death related to cerebral hemorrhage was observed in one patient (Momparler et al, 1985a).
    c) Intracranial hemorrhage resulted in discontinuation of decitabine in 1% or more patients (n=83) with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    E) LETHARGY
    1) WITH THERAPEUTIC USE
    a) Lethargy occurred in 12% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 4% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    F) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache occurred in 28% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 14% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Headache was reported in 23% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    G) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness occurred in 18% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 12% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Dizziness was reported in 21% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    H) HYPESTHESIA
    1) WITH THERAPEUTIC USE
    a) Hypoesthesia occurred in 11% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 1% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea occurred in 42% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 16% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Nausea was reported in 40% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    c) Vomiting occurred in 25% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 9% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    d) Vomiting was reported in 16% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation occurred in 35% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 14% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Constipation was reported in 30% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    C) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea occurred in 34% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 16% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Diarrhea was reported in 28% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    D) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) Abdominal pain occurred in 14% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 6% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Abdominal pain was reported in 14% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    E) STOMATITIS
    1) WITH THERAPEUTIC USE
    a) Stomatitis occurred in 12% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 6% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Stomatitis was reported in 11% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    c) In chronic myelogenous leukemia patients receiving 75 to 100 mg/m(2) as 6-hour infusions twice daily for 5 days, the incidence of mucositis was 7% (Kantarjian et al, 1997a). All symptoms were either mild or moderate.
    F) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia occurred in 16% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 10% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Anorexia was reported in 23% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) MYELOSUPPRESSION
    1) WITH THERAPEUTIC USE
    a) In a phase 3, randomized, controlled, clinical trial, fatalities associated with myelosuppression (anemia, neutropenia, thrombocytopenia) or underlying disease state were reported in 6 patients following treatment with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83), and were considered to be at least possibly related to drug therapy. Bone marrow suppression was the most frequent cause of decitabine dose reduction, delay, and discontinuation in this trial. Similarly, in a single-arm study, fatalities associated with myelosuppression were reported in 7 patients following treatment with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99), and were considered to be at least possibly related to drug therapy. Hematologic toxicities and infections were the most frequent causes of decitabine dose delays and discontinuation in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    b) In 31 patients with chronic myeloid leukemia in blastic phase (CML-BP), complications of myelosuppression included fever (85%) and infections (45%). The first 4 patients received an induction dose of 1000 mg/m(2)/course. Prolonged myelosuppression necessitated a reduction of the induction dose to 750 mg/m(2)/course for the next 12 patients, and finally to 500 mg/m(2)/course for the last 15 patients. The schedule for subsequent courses was based on platelet and white blood cell count; the dose ranged from 125 to 187 mg/m(2)/course to allow for administration every 4 to 5 weeks (Sacchi et al, 1999).
    c) In chronic myelogenous leukemia patients receiving 75 to 100 mg/m(2) as 6-hour infusions twice daily for 5 days, delayed and prolonged myelosuppression was observed; the median time to granulocyte recovery was approximately 46 days. Febrile episodes were seen in 68% of patients, with 46% developing documented infection (Kantarjian et al, 1997a).
    d) With 72-hour continuous infusions of low-dose decitabine in elderly patients with poor-prognosis myelodysplastic syndrome (n=29), severe pancytopenia was universal, leading to infection in more than half and death related to infection in 4 (14%). Granulocyte nadirs occurred (median) on day 19. The median time to an absolute neutrophil count (ANC) of greater than 1 x 10(9)/L was 36 days (Wijermans et al, 1997).
    B) NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Neutropenia occurred in 90% (grades 3 or 4, 87%) of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 72% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial. Six patients who received decitabine had fatal events due to myelosuppression (neutropenia, anemia, and thrombocytopenia) and their underlying disease that were considered possibly related to decitabine (Prod Info DACOGEN(R) injection, 2010).
    b) Neutropenia was reported in 38% (grades 3 or 4, 37%) of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    c) In a phase II trial of 66 patients with myelodysplastic syndrome receiving decitabine (45 mg/m(2)/day for 3 days every 6 weeks), myelotoxicity included neutropenia (12%), anemia (11%), thrombocytopenia (5%), and pancytopenia (2%). Myelotoxicity led to fever (27%), infection (20%), and sepsis (11%). Infection associated with granulocytopenia caused death in 3 patients (Wijermans et al, 2000).
    d) Myelosuppression, mainly thrombocytopenia and leukopenia, is the predominant adverse effect, and is dose-limiting; febrile episodes and infections have been common (Wijermans et al, 2000; Sacchi et al, 1999; Momparler et al, 1985a; Pinto & Zagonel, 1993; Kantarjian et al, 1997b; Wijermans et al, 1997; Abele et al, 1987).
    e) The nadir in leukocyte counts was observed on day 21 in solid tumor patients treated with 75 mg/m(2) (1-hour infusion) three times on day 1 (at 7-hour intervals) and repeated every 5 weeks. Grade 3/4 leukopenia in about 25% of patients. Time to recovery was day 33 for leukocytes (Abele et al, 1987).
    f) In adult and pediatric acute leukemia patients receiving 36- to 60-hour infusions (37 to 81 mg/kg) (n=27), significant granulocytopenia occurred in all patients; recovery of granulocyte counts (in patients demonstrating a response to therapy) was observed on day 45 (Momparler et al, 1985a).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) Thrombocytopenia occurred in 89% (grades 3 or 4, 85%) of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 79% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial. Six patients who received decitabine had fatal events due to myelosuppression (neutropenia, anemia, thrombocytopenia) and their underlying disease that were considered possibly related to decitabine (Prod Info DACOGEN(R) injection, 2010).
    b) Thrombocytopenia was reported in 27% (grades 3 or 4, 24%) of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    c) In a phase II trial of 66 patients with myelodysplastic syndrome receiving decitabine (45 mg/m(2)/day for 3 days every 6 weeks), myelotoxicity included neutropenia (12%), anemia (11%), thrombocytopenia (5%), and pancytopenia (2%). Myelosuppression, mainly thrombocytopenia and leukopenia, is the predominant adverse effect, and is dose-limiting(Wijermans et al, 2000).
    d) With 72-hour continuous infusions of low-dose decitabine in elderly patients with poor-prognosis myelodysplastic syndrome (n=29), severe pancytopenia was universal. Cerebral hemorrhage related to thrombocytopenia was fatal in an additional patient. The median platelet count nadir occurred day 15. The median time to platelet recovery was 26 days (Wijermans et al, 1997).
    e) The platelet count nadir was observed on day 14 in solid tumor patients treated with 75 mg/m(2) (1-hour infusion) three times on day 1 (at 7-hour intervals) and repeated every 5 weeks. Grade 3/4 thrombocytopenia occurred in about 3% of patients. Time to recovery was day 20 for platelets (Abele et al, 1987).
    f) In adult and pediatric acute leukemia patients receiving 36- to 60-hour infusions (37 to 81 mg/kg) (n=27), significant thrombocytopenia occurred in all patients; recovery of platelet counts (in patients demonstrating a response to therapy) was observed on day 33. Death related to cerebral hemorrhage was observed in one patient (Momparler et al, 1985a).
    D) ANEMIA
    1) WITH THERAPEUTIC USE
    a) Anemia occurred in 82% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 74% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial. Six patients who received decitabine had fatal events due to myelosuppression (neutropenia, anemia, thrombocytopenia) and their underlying disease that were considered possibly related to decitabine (Prod Info DACOGEN(R) injection, 2010).
    b) Anemia was reported in 31% (grades 3 or 4, 22%) of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    c) In a phase II trial of 66 patients with myelodysplastic syndrome receiving decitabine (45 mg/m(2)/day for 3 days every 6 weeks), myelotoxicity included neutropenia (12%), anemia (11%), thrombocytopenia (5%), and pancytopenia (2%). With 72-hour continuous infusions of low-dose decitabine in elderly patients with poor-prognosis myelodysplastic syndrome (n=29), severe pancytopenia was universal (Wijermans et al, 2000; Wijermans et al, 1997).
    E) FEBRILE NEUTROPENIA
    1) WITH THERAPEUTIC USE
    a) Febrile neutropenia occurred in 29% (grades 3 or 4, 23%) of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 6% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Febrile neutropenia was reported in 20% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    c) In a phase II trial of 66 patients with myelodysplastic syndrome receiving decitabine (45 mg/m(2)/day for 3 days every 6 weeks), myelotoxicity included neutropenia (12%), anemia (11%), thrombocytopenia (5%), and pancytopenia (2%). Myelotoxicity led to fever (27%), infection (20%), and sepsis (11%). Infection associated with granulocytopenia caused death in 3 patients (Wijermans et al, 2000).
    d) In 31 patients with chronic myeloid leukemia in blastic phase (CML-BP), complications of myelosuppression included fever (85%) and infections (45%) (Sacchi et al, 1999).
    e) In chronic myelogenous leukemia patients receiving 75 to 100 mg/m(2) as 6-hour infusions twice daily for 5 days, delayed and prolonged myelosuppression was observed. Febrile episodes were seen in 68% of patients, with 46% developing documented infection (Kantarjian et al, 1997a).
    F) THROMBOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) Thrombocythemia occurred in 5% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 1% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Thrombocythemia was reported in 5% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rash occurred in 19% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 9% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Rash was reported in 11% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    B) ERYTHEMA
    1) WITH THERAPEUTIC USE
    a) Erythema occurred in 14% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 6% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Erythema was reported in 5% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    C) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus occurred in 11% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 2% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Pruritus was reported in 9% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    D) PETECHIAE
    1) WITH THERAPEUTIC USE
    a) Petechiae occurred in 39% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 16% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Petechiae was reported in 12% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    E) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) Alopecia occurred in 8% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 1% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Hair loss has been relatively infrequent (Abele et al, 1987; Wijermans et al, 1997).
    F) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Injection site erythema, pain, and swelling occurred in 5% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 0% to 1% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    G) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Urticaria occurred in 6% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 1% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    H) FACIAL SWELLING
    1) WITH THERAPEUTIC USE
    a) Facial swelling occurred in 6% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 0% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    I) CELLULITIS
    1) WITH THERAPEUTIC USE
    a) Cellulitis occurred in 12% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 7% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Cellulitis was reported in 9% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    J) ECCHYMOSIS
    1) WITH THERAPEUTIC USE
    a) Ecchymosis occurred in 22% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 15% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Ecchymosis was reported in 9% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCULOSKELETAL PAIN
    1) WITH THERAPEUTIC USE
    a) Musculoskeletal discomfort occurred in 6% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 0% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Musculoskeletal pain was reported in 5% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    B) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia occurred in 5% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 1% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Myalgia was reported in 9% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).
    C) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia occurred in 20% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 10% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Arthralgia was reported in 17% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia occurred in 33% of patients with myelodysplastic syndrome treated with decitabine 15 mg/m(2) intravenously every 8 hours for 3 days every 6 weeks plus best supportive care (n=83) compared with 20% of patients who received best supportive care alone (n=81) in a phase 3, randomized, controlled, clinical trial (Prod Info DACOGEN(R) injection, 2010).
    b) Hyperglycemia was reported in 6% of patients treated with decitabine 20 mg/m(2) intravenously infused over 1 hour daily for 5 consecutive days of a 4-week cycle (n=99) in a single-arm study (Prod Info DACOGEN(R) injection, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Decitabine is classified as FDA pregnancy category D. Although there have been no well-controlled studies conducted in pregnant women, administration of decitabine in mice and rats have resulted in a variety of teratogenic effects including fused vertebrae and ribs, cleft palate, and vertebral, hindlimb, and digital defects.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) MICE: Teratogenic effects including fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects, and fore- and hind-limb digital defects have occurred in mice following maternal administration of 3 mg/m(2) decitabine as a single intraperitoneal (IP) injection during gestation days 8, 9, 10, or 11. Supernumerary ribs were also reported in fetal mice following maternal administration of 0.9 and 3 mg/m(2) as single IP injections during gestation days 8, 9, 10, or 11 (Prod Info DACOGEN(R) injection, 2010).
    2) RATS: Maternal administration of 2.4, 3.6, or 6 mg/m(2) decitabine as a single intraperitoneal (IP) injection on gestation days 9 through 12 resulted in increased incidences of vertebral and rib anomalies. Fetal foredigit defects were observed following administration of doses greater than 3.6 mg/m(2), and exophthalmia, exencephaly, cleft palate, and ossification of the long bones of the fore-limb and hind-limb were reported following the 6 mg/m(2) dose (Prod Info DACOGEN(R) injection, 2010).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Decitabine is classified by the manufacturer as FDA pregnancy category D (Prod Info DACOGEN(R) injection, 2010).
    B) ANIMAL STUDIES
    1) MICE: Although there was no maternal toxicity following intraperitoneal (IP) administration of decitabine during gestation days 8, 9, 10, or 11, decreased fetal weight occurred at single IP doses of 0.9 and 3 mg/m(2), and reduced fetal survival was reported at the 3 mg/m(2) dose (Prod Info DACOGEN(R) injection, 2010).
    2) RATS: No live fetuses were observed following decitabine administration of 2.4, 3.6, or 6 mg/m(2) given as a single intraperitoneal (IP) injection on gestation day 9. Decreased fetal survival and reduced fetal weight were reported following administration of doses greater than 3.6 mg/m(2) given as a single IP injection on gestation day 10 (Prod Info DACOGEN(R) injection, 2010).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether decitabine is excreted in human milk (Prod Info DACOGEN(R) injection, 2010).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) MICE: Decreased fertility occurred at 3 and 5 months of age (36% and 0% pregnancy rate, respectively) when untreated females were mated to males exposed in utero to decitabine following maternal administration of a single 3 mg/m(2) intraperitoneal (IP) injection on gestation day 10 (Prod Info DACOGEN(R) injection, 2010).
    2) MICE: A reduction in testes weights and significant decreases in sperm count occurred following IP injections, to male mice, at doses of 0.3 mg/m(2) or higher three times per week for 7 weeks. In female mice, who were mated to males given decitabine at doses of 0.3 mg/m(2) or higher, there was a reduction in pregnancy rate and a significant increase in pre-implantation loss (Prod Info DACOGEN(R) injection, 2010).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) Carcinogenicity studies of decitabine have not been conducted (Prod Info DACOGEN(R) injection, 2010).

Genotoxicity

    A) Decitabine increased the frequency of mutations in L5178 mouse lymphoma cells. Mutations were also produced in an Escherichia colic lac-l transgene in the colonic DNA of decitabine-treated mice (Prod Info DACOGEN(R) injection, 2010).
    B) Chromosomal rearrangements occurred following decitabine administration to the larvae of fruit flies (Prod Info DACOGEN(R) injection, 2010).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serial CBC with differential and platelet count.
    B) Monitor vital signs.
    C) Monitor serum electrolytes including magnesium.
    D) Monitor for fever or other clinical evidence of infection.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who remain symptomatic despite adequate treatment should be admitted.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Mild to moderately symptomatic patients should be sent to a healthcare facility for evaluation and treatment as necessary.

Monitoring

    A) Monitor serial CBC with differential and platelet count.
    B) Monitor vital signs.
    C) Monitor serum electrolytes including magnesium.
    D) Monitor for fever or other clinical evidence of infection.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not necessary; decitabine is administered parenterally.

Range Of Toxicity

Summary

    A) TOXICITY: Overdose data are limited. A specific toxic dose has not been established. Clinical effects reported at higher doses have included increased myelosuppression with prolonged neutropenia and thrombocytopenia.
    B) ADULT THERAPEUTIC DOSING: Two treatment options. OPTION 1: 15 mg/m(2) by continuous IV infusion over 3 hours, repeated every 8 hours for 3 days. This cycle should be repeated every 6 weeks for a minimum of 4 cycles. OPTION 2: 20 mg/m(2) by continuous IV infusion over 1 hour, repeated daily for 5 days. This cycle should be repeated every 4 weeks for a minimum of 4 cycles.

Therapeutic Dose

    7.2.1) ADULT
    A) SUMMARY: There are two treatment options available for patients with myelodysplastic syndromes:
    1) OPTION 1: Continuous IV infusion at a dose of 15 mg/m(2) over a 3-hour period and repeated every 8 hours for 3 days. This cycle should be repeated every 6 weeks for a minimum of 4 cycles (Prod Info decitabine intravenous injection lyophilized powder for solution, 2014).
    2) OPTION 2: Continuous IV infusion at a dose of 20 mg/m(2) over a 1-hour period and repeated daily for 5 days. This cycle should be repeated every 4 weeks for a minimum of 4 cycles (Prod Info decitabine intravenous injection lyophilized powder for solution, 2014).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info decitabine intravenous injection lyophilized powder for solution, 2014).

Maximum Tolerated Exposure

    A) Clinical effects reported at higher doses have included increased myelosuppression with prolonged neutropenia and thrombocytopenia (Prod Info DACOGEN(R) injection, 2010).
    B) In 31 patients with chronic myeloid leukemia in blastic phase (CML-BP), complications of myelosuppression included fever (85%) and infections (45%). The first 4 patients received an induction dose of 1000 mg/m(2)/course. Prolonged myelosuppression necessitated a reduction of the induction dose to 750 mg/m(2)/course for the next 12 patients, and finally to 500 mg/m(2)/course for the last 15 patients. The schedule for subsequent courses was based on platelet and white blood cell count; the dose ranged from 125 to 187 mg/m(2)/course to allow for administration every 4 to 5 weeks (Sacchi et al, 1999).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) After phosphorylation, direct incorporation into DNA, and inhibition of DNA methyltransferase, decitabine causes hypomethylation of DNA and cellular differentiation or apoptosis. The formation of covalent adducts between decitabine and DNA methyltransferase may also contribute to cytotoxicity in rapidly dividing cells. Decitabine has little to no effect on non-proliferating cells. In vitro, decitabine inhibits DNA methylation at concentrations that do not significantly suppress DNA synthesis. Decitabine-induced hypomethylation in neoplastic cells may reestablish normal function of genes crucial for cellular differentiation and proliferation (Prod Info decitabine intravenous injection lyophilized powder for solution, 2014).

Physicochemical

Physical Characteristics

    A) Decitabine is a fine, white to almost white powder that is slightly soluble in ethanol/water (50/50), and methanol/water (50/50) (Prod Info DACOGEN(R) injection, 2010).

Molecular Weight

    A) 228.21 (Prod Info DACOGEN(R) injection, 2010)

References

General Bibliography

    1) Abele R, Clavel M, Dodion P, et al: The EORTC early clinical trials cooperative group experience with 5-aza-2'-deoxycytidine (NSC 127716) in patients with colo-rectal, head and neck, renal carcinomas and malignant melanomas. Eur J Cancer Clin Oncol 1987; 23(12):1921-1924.
    2) Addiego JE, Ridgway D, & Bleyer WA: The acute management of intrathecal methotrexate overdose: pharmacologic rationale and guidelines. J Pediatr 1981; 98(5):825-828.
    3) Beauchesne MF & Shalansky SJ: Nonchemotherapy drug-induced agranulocytosis: a review of 118 patients treated with colony-stimulating factors. Pharmacotherapy 1999; 19(3):299-305.
    4) Blaney SM, Poplack DG, Godwin K, et al: Effect of body position on ventricular CSF methotrexate concentration following intralumbar administration. J Clin Oncol 1995; 13(1):177-179.
    5) Gosselin S & Isbister GK: Re: Treatment of accidental intrathecal methotrexate overdose. J Natl Cancer Inst 2005; 97(8):609-610.
    6) Hartman LC, Tschetter LK, Habermann TM, et al: Granulocyte colony-stimulating factor in severe chemotherapy-induced afebrile neutropenia.. N Engl J Med 1997; 336:1776-1780.
    7) Kantarjian HM, Keating M, Beran M, et al: Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. Leukemia 1997a; 11:1617-1620.
    8) Kantarjian HM, O'Brien SM, Estey E, et al: Decitabine studies in chronic and acute myelogenous leukemia. Leukemia 1997b; 11(suppl 1):S35-S36.
    9) Meggs WJ & Hoffman RS: Fatality resulting from intraventricular vincristine administration. J Toxicol Clin Toxicol 1998; 36(3):243-246.
    10) Momparler RL, Bouffard DY, Momparler LF, et al: Pilot phase I-II study on 5-aza-2'-deoxycytidine (decitabine) in patients with metastatic lung cancer. Anti-Cancer Drugs 1997; 8:358-368.
    11) Momparler RL, Rivard GE, & Gyger M: Clinical trial on 5-aza-2'-deoxycytidine in patients with acute leukemia. Pharmac Ther 1985; 30:277-286.
    12) Momparler RL, Rivard GE, & Gyger M: Clinical trial on 5-aza-2'-deoxycytidine in patients with acute leukemia. Pharmac Ther 1985a; 30:277-286.
    13) O'Marcaigh AS, Johnson CM, & Smithson WA: Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and trathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996; 71:161-165.
    14) Petti AC, Mandelli F, Zagonel V, et al: Pilot study of 5-aza-2'-deoxycytidine (decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results. Leukemia 1993; 7(suppl 1):36-41.
    15) Pinto A & Zagonel V: 5-Aza-2'-deoxycytidine (decitabine) and 5-azacytidine in the treatment of acute myeloid leukemias and myelodysplastic syndromes: past, present and future trends. Leukemia 1993; 7(suppl 1):51-60.
    16) Product Information: DACOGEN(R) injection, decitabine injection. Eisai, Inc, Woodcliff Lake, NJ, 2010.
    17) Product Information: LEUKINE(R) injection, sargramostim injection. Berlex, Seattle, WA, 2006.
    18) Product Information: NEUPOGEN(R) injection, filgrastim injection. Amgen,Inc, Thousand Oaks, CA, 2006.
    19) Product Information: decitabine intravenous injection lyophilized powder for solution, decitabine intravenous injection lyophilized powder for solution. Dr. Reddy’s Laboratories Limited (per DailyMed), Princeton, NJ, 2014.
    20) Sacchi S, Kantarjian H, O'Brien S, et al: Chronic myelogenous leukemia in nonlymphoid blastic phase. Cancer 1999; 86:2632-2641.
    21) Stull DM, Bilmes R, Kim H, et al: Comparison of sargramostim and filgrastim in the treatment of chemotherapy-induced neutropenia. Am J Health Syst Pharm 2005; 62(1):83-87.
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