Decitabine

Decitabine is an antineoplastic agent belonging to the pharmacological class of demethylation agents, specifically DNA Methylation inhibitors.

Decitabine has been approved by the FDA for treating myelodysplastic syndromes (MDS).

When Decitabine is infused intravenously, absorption occurs quickly and fully. It distributes widely throughout the body, entering different tissues, and has an apparent volume of distribution of 4.59 ± 1.42 L/kg. The kidneys remove the medication after hepatic metabolism, mostly mediated by cytidine deaminase.

The most common side effects of Decitabine include nausea, vomiting, diarrhea, headache, fever and lung infection.

Decitabine is available as a powder for injection.

The molecule is available in India, the United States, Canada, countries within the European Union, Australia, Japan and South Korea.

Decitabine is an antineoplastic agent belonging to the pharmacological class of demethylation agents, specifically DNA Methylation inhibitors.

After phosphorylation, direct incorporation into DNA, and inhibition of DNA methyltransferase, Decitabine is considered to exert its antineoplastic effects. This results in hypomethylation of DNA, cellular differentiation, or apoptosis. At concentrations that do not significantly suppress DNA synthesis, Decitabine inhibits DNA methylation in vitro.

Decitabine-induced hypomethylation in cancerous cells may return the normal function of genes essential for regulating cellular proliferation and differentiation. The creation of covalent adducts between DNA methyltransferase and Decitabine integrated into DNA may also be responsible for the cytotoxicity of Decitabine in rapidly dividing cells. Decitabine has comparatively little effect on non-proliferating cells.

Powder for injection: To be administered parenterally as applicable.

The physician recommends taking this medication once daily for five days, with or without food.

• Myelodysplastic syndrome
• Blood cancer

Parenterally: It is not recommended to administer Decitabine as an intravenous push or bolus; instead, it should be given as an intravenous infusion over a period of one to three hours. The treatment cycle should be repeated every six weeks, with one infusion administered once daily for three days in a row. The injection must be administered slowly and with a specific intravenous line. Preparing and handling the medication with appropriate aseptic techniques is essential to maintain the medication's integrity and avoid contamination.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Decitabine is available as a powder for injection.

Dose Adjustment in Adult Patients:

Myelodysplastic Syndromes

First regimen: At least four cycles of a three-day regimen consisting of a 15 mg/m² IV infusion over three hours, repeated q8 hours for 3 days; repeat every six weeks; a complete or partial response may take longer than four cycles; delay and reduce dose for hematologic toxicity.

Second regimen: 5 days of treatment: IV infusion of 20 mg/m² every hour. After hematologic recovery (ANC at least 1,000/μL and platelets at least 50,000/μL), repeat the cycle every four weeks for a minimum of four cycles. A complete or partial response may require more time than four cycles.

Follow the dietary guidelines while taking Decitabine: Consume foods high in protein, whole grains, healthy fats, and vitamins. Emphasize plant-based proteins like nuts, seeds, beans, and legumes. Maintain a healthy weight through regular low-strain exercises and a balanced diet that is rich in green leafy vegetables, citrus fruits, fatty fish, berries, yoghurt, apples, peaches, cauliflower, cabbage, broccoli, beans, and herbs. Refrain from smoking and alcohol consumption.

The dietary restriction should be individualized as per patient requirements.

• Hypersensitivity to Decitabine or any of its excipients
• Lactation

Exercise caution in renal/hepatic impairment.

• Treated patients face fatal myelosuppression, the leading cause of dose adjustments and discontinuation. Manage using dose delays, reductions, and supportive therapies; initial cycles may see increased myelosuppression without disease progression.
• Administering this therapy during pregnancy can harm the fetus by altering DNA synthesis, causing adverse reproductive effects. Men with fertile partners should avoid fathering a child during treatment and for 3 months after the last dose. Female patients of childbearing potential should use effective contraception during this period.
• Potential dose adjustment may be required in case bone marrow suppression may occur.

The adverse reactions related to Decitabine can be categorized as:

• Common Adverse Effects: Myelosuppression (anemia, neutropenia, and thrombocytopenia)
• Less Common Adverse Effects: Gastrointestinal disturbances, fatigue, and fever.
• Rare Adverse Effects: Renal and hepatic toxicity.

Postmarketing Reports:

Acute febrile neutrophilic dermatosis (also known as Sweet's syndrome)

Interstitial lung disease

Differentiation syndrome

The clinically relevant drug interactions of Decitabine are briefly summarized here.

• Drug Interactions: Adalimumab, baricitinib, leflunomide, and other medications used to treat psoriatic and rheumatoid arthritis, as well as vaccinations such as the dengue, BCG, and yellow fever vaccines, and antipsychotic drugs such as clozapine, may interact with Decitabine.
• Drug-Disease Interactions: Decitabine may interact with several medical disorders, such as liver, kidney, and haematological toxicities (low platelet count, low count of a particular kind of white blood cell).

• Pregnancy

Pregnancy Category D (FDA): Use in cases where no safer medication is available and life is in danger. Positive evidence of prenatal risk in humans.

Pregnant women who receive therapy may experience harm to their fetus due to findings from animal studies, human data, and the mechanism of action. Very little information about its use during the first trimester of pregnancy has been published, and it describes adverse developmental outcomes, such as significant congenital disabilities (structural abnormalities), and alerts expectant mothers to possible fetal risk.

Decitabine's effects on male fertility have been shown in animals; however, it is unknown whether or not these effects can be reversed.

Before starting treatment, have women who are capable of becoming pregnant tested.

Advise women who are capable of becoming pregnant to refrain from getting pregnant and to use effective contraception for the six months after their last treatment.

Explain effective contraception to female partners who are capable of having children both during treatment and for three months after the last dose.

animal data

Decitabine caused adverse developmental outcomes and was teratogenic, fetotoxic, and embryotoxic when given to pregnant mice and rats during organogenesis in animal reproduction studies. These effects started at about 7% of the recommended human dose on a mg/m2 basis.

• Nursing Mothers

It is advised that nursing mothers avoid breastfeeding during treatment and for at least one week following the last dose due to the fact that many drugs are excreted in human milk and may cause severe adverse reactions in a nursing child. There is no data regarding the presence of drugs or their metabolites in human milk, their effects on a breastfed child, or their production of milk.

• Pediatric Use

As per the FDA, the safety and efficacy of Decitabine have not been specifically studied in pediatric patients.

Dose Adjustment in Kidney Impairment Patients:

Mild-moderate impairment indicated: No need for dosage adjustment.

Severe: Not studied; use caution.

Dose Adjustment in Hepatic Impairment Patients:

Mild, moderate and severe hepatic impairment: Not studied; use caution.

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Decitabine.

Signs and Symptoms

Overconsumption of Decitabine could lead to myelosuppression, including prolonged neutropenia and thrombocytopenia.

Management

There is no specific antidote for Decitabine overdosage. Healthcare providers should manage Decitabine overdose through supportive measures, addressing complications such as myelosuppression and infections. Based on the clinical situation, they may consider hematopoietic growth factors and blood products. It is recommended to closely monitor hematologic parameters and renal and hepatic function and provide symptomatic treatment if required.

Pharmacodynamic

Both in vitro and in vivo, Decitabine has been demonstrated to cause hypomethylation. However, studies on the pharmacokinetic parameters and hypomethylation caused by Decitabine have yet to be conducted.

Pharmacokinetics

• Absorption: Decitabine is administered via intravenous infusion, achieving rapid and complete absorption.
• Distribution: Decitabine distributes itself effectively throughout the body, entering different tissues, with an apparent volume of distribution of 4.59 ± 1.42 L/kg. It barely binds to plasma proteins (<1%).
• Metabolism: Decitabine is metabolized in the liver by cytidine deaminase-mediated pathways, including oxidation and deamination. Numerous metabolites are produced by this metabolic breakdown.
• Elimination: The majority of the dose is eliminated through the kidneys, where urine accounts for 90% of the total amount eliminated. The function of unchanged drug excretion is negligible, and the elimination half-life is 30-35 minutes.

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• US Food and Drug Administration (FDA) [Internet]. Maryland. USA; Package leaflet information for the user; Dacogen® (decitabine)
• https://www.ncbi.nlm.nih.gov/books/NBK548668/
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021790s021lbl.pdf