Description of Decitabine

Decitabine is a pyrimidine antimetabolite. It is indicated for the treatment of adult patients with myelodysplastic syndrome. Severe myelosuppression has been reported with decitabine therapy; monitor complete blood counts during therapy.

Mechanism of Action of Decitabine

Decitabine is an antimetabolite that can replace cytosine in DNA but, unlike cytosine, it cannot be methylated. The exact mechanism of decitabine activity has not been determined and may involve multiple pathways. Decitabine is thought to primarily act by correcting DNA methylation, a major mechanism for gene expression.

In some cancer cells, hypermethylation blocks the activity of tumor suppressor genes, which regulate cell division and differentiation to prevent malignant transformation. When suppressor gene activity is blocked, cell division becomes unregulated, leading to the formation of neoplastic cells.

Decitabine regulates DNA methylation (specifically targets methyltransferase), effectively demethylating and reactivating different tumor suppressor genes. Because hypermethylation occurs early in the malignant transformation of cells, decitabine may have activity in chemoprevention.

Other possible mechanisms for decitabine activity include cytotoxicity due to incorporation into DNA similar to other antimetabolites, methylation-independent induction of gene expression, and degradation of DNA methyltransferase 1.

Pharmacokinetics

Decitabine is administered by intravenous (IV) infusion. Plasma protein binding of decitabine is less than 1%. In a pharmacokinetic evaluation, the mean clearance values were 125 L/hour/m² (coefficient of variance (CV), 53%) and 210 L/hour/m2 (CV, 47%) in 11 patients who received 15 mg/m² IV over 3 hours every 8 hours for 3 days (option 1) and 14 patients who received 20 mg/m² IV over 1 hour daily for 5 days (option 2), respectively. The half-life values were 0.62 hour (CV, 49%) and 0.54 hour (CV, 43%) with option 1 and option 2, respectively.

Decitabine appears to be eliminated via deamination by cytidine deaminase, which is found intracellularly in the liver, granulocytes, intestinal epithelium, and whole blood. Decitabine is unlikely to inhibit or induce cytochrome P450 enzymes.

Route-Specific Pharmacokinetics

Intravenous Route
Pharmacokinetic (PK) parameters were evaluated in 11 patients who received 15 mg/m² IV over 3 hours every 8 hours for 3 days (option 1) and 14 patients who received 20 mg/m² IV over 1 hour daily for 5 days (option 2). The Cmax values were 73.8 ng/mL (CV, 66%) and 147 ng/mL (CV, 49%) with option 1 and 2, respectively. Plasma concentration-time profiles following the decitabine infusion showed a biexponential decline.

Systemic accumulation of decitabine or significant changes in PK parameters did not occur with repeat doses. The cumulative decitabine AUC value per cycle was 2.3-fold lower with option 2 (570 ng/mL X hour) compared with option 1 (1,332 ng/mL X hour).

• Decitabine

• Dacogen

• Antimetabolite
• Antineoplastic Agent

• Myelodysplastic syndrome: Adult

Common Effects

• Cardiovascular: Edema (5% to 18% ), Heart murmur (16% ), Peripheral edema (25% to 27% )
• Dermatologic: Cellulitis (9% to 12% ), Ecchymosis (9% to 22% ), Erythema (5% to 14% ), Pallor (23% ), Petechiae (12% to 39% ), Pruritus (9% to 11% ), Rash (11% to 19% ), Skin lesion (5% to 11% )
• Endocrine metabolic: Hyperglycemia (6% to 33% ), Hyperkalemia (13% ), Hypoalbuminemia (24% ), Hypokalemia (12% to 22% ), Hypomagnesemia (5% to 24% ), Hyponatremia (19% ), Serum bicarbonate level abnormal (11% )
• Gastrointestinal: Abdominal pain (14% ), Constipation (30% to 35% ), Decrease in appetite (8% to 16% ), Diarrhea (17% to 34% ), Indigestion (10% to 12% ), Loss of appetite (16% to 23% ), Nausea (40% to 42% ), Petechiae, Oral Mucosal (13% ), Stomatitis (7% to 12% ), Vomiting (16% to 25% )
• Hematologic: Leukopenia (6% to 28% )
• Hepatic: Alkaline phosphatase raised (11% ), Ascites (10% ), Hyperbilirubinemia (14% ), Increased liver aminotransferase level (10% )
• Immunologic: Candidiasis (10% ), Lymphadenopathy (12% )
• Musculoskeletal: Arthralgia (17% to 20% ), Backache (17% to 18% ), Pain in limb (18% to 19% )
• Neurologic: Asthenia (15% ), Dizziness (18% to 21% ), Headache (23% to 28% ), Hypoesthesia (11% ), Insomnia (14% to 28% ), Lethargy (12% ), Shivering (16% ), Shivering or rigors (22% )
• Psychiatric: Anxiety (9% to 11% ), Confusion (8% to 12% )
• Renal: Finding of frequency of urination (5% ), Serum blood urea nitrogen raised (10% )
• Respiratory: Bleeding from nose (13% ), Cough (27% to 40% ), Decreased breath sounds (10% ), Hypoxia (10% ), Pharyngitis (16% ), Upper respiratory infection (10% )
• Other: Fatigue (46% ), Fever (27% to 85% ), Pain (5% to 13% ), Tenderness (11% )

Serious Effects

• Cardiovascular: Atrial fibrillation, Cardiac arrest, Congestive heart failure (5% ), Myocardial infarction
• Dermatologic: Sweet’s syndrome
• Hematologic: Anemia (31% to 82% ), Febrile neutropenia (20% to 68% ), Myelosuppression, Neutropenia (38% to 90% ), Thrombocytopenia (27% to 89% )
• Immunologic: Bacteremia (5% ), Infection due to Mycobacterium avium, Infectious disease (14% to 46% ), Sepsis (11% )
• Neurologic: Cerebral hemorrhage, Intracranial hemorrhage
• Respiratory: Pleural effusion (5% ), Pneumonia (20% to 22% ), Pulmonary edema (6% )

• NIOSH Group 1 Antineoplastics
• NIOSH: In the preparation and administration of injections, NIOSH recommends the use of double gloves and a protective gown. Prepare in a biological safety cabinet or a compounding aseptic containment isolator; eye/face and respiratory protection may be needed. Prepare compounds in a closed system drug transfer device. During administration, if there is a potential that the substance could splash or if the patient may resist, use eye/face protection. Administer certain dosage forms via a closed system drug transfer device .
• Use caution when handling and preparing decitabine, a cytotoxic agent .
• Intravenous: Reconstitute with 10 mL of room temperature (20 to 25 degrees C) sterile water for injection to a concentration of 5 mg/mL
• Intravenous: If administration is within 15 minutes of preparation: Dilute the reconstituted solution with room temperature (20 to 25 degrees C) NS or D5W to a final concentration of 0.1 to 1 mg/mL
• Intravenous: If administration is to be delayed longer than 15 minutes from preparation: Dilute the reconstituted solution with cold (2 to 8 degrees C) NS or D5W to a final concentration of 0.1 to 1 mg/mL. Store at 2 to 8 degrees C for up to 4 hours. Diluted stored solution must be used within 4 hours from the time of preparation .
• Intravenous: (3-day regimen) Infuse each dose IV over 3 hours
• Intravenous: (5-day regimen) Infuse each dose IV over 1 hours

• Dacogen: Intravenous Powder for Solution: 50 MG
• Decitabine Novaplus: Intravenous Powder for Solution: 50 MG
• PremierPro Rx Decitabine: Intravenous Powder for Solution: 50 MG

• Intravenous Powder for Solution: 50 MG

• Important Note: Perform baseline testing (CBC with platelets, serum hepatic panel, and serum creatinine) .
• Important Note: Orphan drug designation: Treatment of myelodysplastic syndromes
• Acute myeloid leukemia: 20 mg/m(2) IV infusion over 1 hour daily for 5 days every 4 weeks was used in a clinical trial (n=485)
• Myelodysplastic syndrome: Premedication, consider premedicating for nausea with antiemetics (FDA dosage)
• Myelodysplastic syndrome: (3-day regimen) 15 mg/m(2) IV over 3 hours every 8 hours for 3 days repeated every 6 weeks upon hematologic recovery (ANC of 1000/mcL or greater and platelets of 50,000/mcL or greater) for a minimum of 4 cycles (FDA dosage)
• Myelodysplastic syndrome: (5-day regimen) 20 mg/m(2)/day IV over 1 hour for 5 days repeated every 4 weeks upon hematologic recovery (ANC of 1000/mcL or greater and platelets of 50,000/mcL or greater) for a minimum of 4 cycles (FDA dosage)
• Myelodysplastic syndrome: (Low dose regimen) 20 mg/m(2) IV over 1 hour daily for 3 consecutive days of a 4-week cycle (off-label dosage)
• Myelodysplastic syndrome: (Low dose regimen) Induction phase, 0.2 mg/kg/day subQ on 2 consecutive days per week for 4 weeks; maintenance phase, 0.2 mg/kg/day subQ on 2 consecutive days per week, continue indefinitely; reinduction phase, increase treatment frequency (off-label dosage)

• Important Note: Perform baseline testing (CBC with platelets, serum hepatic panel, and serum creatinine) .
• Important Note: Orphan drug designation: Treatment of myelodysplastic syndromes
• General Dosage Information: Safety and efficacy not established in pediatric patients

• Tmax, IV route: 1 hour