Usage
Decitabine is a nucleoside metabolic inhibitor primarily used to treat adult patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia), and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. It is also used in some cases for acute myeloid leukemia (AML).
It is classified as an antineoplastic antimetabolite.
Decitabine’s mechanism of action involves hypomethylation of DNA. It incorporates into DNA and inhibits DNA methyltransferases, leading to gene re-expression and potentially inducing cell differentiation and apoptosis in abnormal hematopoietic cells.
Alternate Names
- 5-Aza-2’-deoxycytidine
- Dacogen (brand name)
How It Works
Pharmacodynamics: Decitabine’s primary effect is the hypomethylation of DNA by inhibiting DNA methyltransferase, primarily DNMT1. Hypomethylation can lead to the reactivation of tumor suppressor genes and altered gene expression, which may contribute to the differentiation and/or apoptosis of malignant cells.
Pharmacokinetics: Decitabine is administered intravenously and is rapidly metabolized by cytidine deaminase, primarily in the liver and also in the intestinal tract and blood. It exhibits dose-proportional pharmacokinetics. Peak plasma concentration is achieved at the end of infusion. Decitabine has low plasma protein binding (<1%). Elimination occurs through metabolism and renal excretion of inactive metabolites.
Mode of action: Decitabine incorporates into DNA, where it inhibits DNA methyltransferases by trapping them. This leads to hypomethylation of genomic DNA.
Elimination pathways: Primarily hepatic via cytidine deaminase; Renally excreted as inactive metabolites.
Dosage
Standard Dosage
Adults:
- 3-day regimen: 15 mg/m² IV infusion over 3 hours repeated every 8 hours for 3 days; repeat cycle every 6 weeks.
- 5-day regimen: 20 mg/m² IV infusion over 1 hour daily for 5 days; repeat cycle every 4 weeks.
Minimum of 4 cycles recommended, although response may take longer. Hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL) should be achieved before repeating cycles.
Children:
Safety and efficacy not established in pediatric patients.
Special Cases:
- Elderly Patients: No specific dose adjustment recommended.
- Patients with Renal Impairment: Use with caution; dose adjustment may be necessary.
- Patients with Hepatic Dysfunction: Use with caution; dose adjustment may be necessary.
- Patients with Comorbid Conditions: Monitor closely; dose adjustments may be necessary based on individual patient conditions.
Clinical Use Cases
Decitabine is primarily indicated for MDS and AML. Dosing in these scenarios follows the standard adult regimens mentioned above. Specific dosage modifications may apply based on individual patient factors and tolerability. There are no specific dose recommendations for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Hematologic Toxicity:
- Recovery >6 to <8 weeks: Delay the next cycle up to 2 weeks and reduce dose to 11 mg/m² every 8 hours for 3 days upon restarting.
- Recovery >8 to <10 weeks: Assess for disease progression; If no progression, delay up to 2 more weeks and reduce dose to 11 mg/m² every 8 hours for 3 days, then maintain or increase in subsequent cycles as clinically indicated.
Side Effects
Common Side Effects
Neutropenia, thrombocytopenia, anemia, pyrexia, nausea, vomiting, diarrhea, constipation, fatigue, cough, myalgia, arthralgia, bruising at the injection site.
Rare but Serious Side Effects
Severe myelosuppression, bleeding, infections, allergic reactions (including rash, dyspnea, facial swelling), interstitial lung disease, acute respiratory distress syndrome.
Long-Term Effects
Prolonged myelosuppression, secondary malignancies, pulmonary fibrosis.
Adverse Drug Reactions (ADR)
Severe neutropenia, febrile neutropenia, severe thrombocytopenia with bleeding, anaphylaxis.
Contraindications
Hypersensitivity to decitabine. Breast-feeding.
Drug Interactions
- Drugs metabolized by cytidine deaminase (e.g., cytarabine, gemcitabine): potential for increased toxicity of these medications.
- Medications primarily cleared by renal excretion: Concurrent use might enhance their potential toxicities.
Pregnancy and Breastfeeding
Decitabine is contraindicated in pregnancy (Pregnancy Category D) and during breastfeeding. It is teratogenic in animals. Females of reproductive potential should use effective contraception during treatment and for 6 months after the last dose. Males should use effective contraception during treatment and for 3 months after the last dose.
Drug Profile Summary
- Mechanism of Action: DNA hypomethylating agent, inhibiting DNA methyltransferase.
- Side Effects: Myelosuppression, fatigue, nausea, vomiting, diarrhea, infection risk.
- Contraindications: Hypersensitivity to decitabine, breastfeeding.
- Drug Interactions: Drugs metabolized by cytidine deaminase, some antineoplastics.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Varies; see detailed dosage section.
- Monitoring Parameters: Complete blood counts, including ANC and platelets, liver and renal function tests, pulmonary function tests if indicated.
Popular Combinations
Decitabine may be used in combination with other chemotherapy agents in certain treatment protocols for AML; however, it is frequently used as monotherapy for MDS.
Precautions
- Myelosuppression: Monitor blood counts regularly.
- Infections: Prophylactic antibiotics may be considered in patients with severe neutropenia.
- Pulmonary toxicity: Evaluate patients with new or worsening respiratory symptoms.
- Patients with hepatic or renal dysfunction should be monitored for increased drug exposure.
- Pregnancy: Contraindicated.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Decitabine?
A: Adults: 15 mg/m² IV over 3 hours every 8 hours for 3 days repeated every 6 weeks OR 20 mg/m² IV over 1 hour daily for 5 days repeated every 4 weeks. Pediatric: Not established.
Q2: What are the most common side effects?
A: Myelosuppression (neutropenia, thrombocytopenia, anemia), pyrexia, fatigue, nausea, vomiting, and diarrhea.
Q3: What are the serious side effects?
A: Severe myelosuppression, bleeding, infections, allergic reactions, interstitial lung disease.
Q4: Can Decitabine be used during pregnancy?
A: No, Decitabine is contraindicated during pregnancy due to its teratogenic effects.
Q5: What should be monitored during Decitabine therapy?
A: Complete blood counts, including ANC and platelets, liver and renal function, and pulmonary function if indicated.
Q6: How does Decitabine work?
A: It incorporates into DNA and inhibits DNA methyltransferases, leading to hypomethylation and affecting gene expression.
Q7: What are the major drug interactions?
A: Drugs metabolized by cytidine deaminase, resulting in potential increased toxicity for those medications.
Q8: Are there any dose adjustments for renal or hepatic impairment?
A: Use with caution in patients with renal or hepatic impairment. Dosage adjustments may be necessary.
Q9: How is Decitabine administered?
A: Intravenous infusion.
Q10: What is the duration of treatment with Decitabine?
A: A minimum of 4 cycles is recommended, but treatment may continue as long as the patient benefits or until disease progression.
