Decitabine

Decitabine (5-aza-2′-deoxycytidine) is a cytidine deoxynucleoside analogue. At low doses it selectively inhibits DNA methyltransferases, so that gene promoters become hypomethylated. This can reactivate tumour suppressor genes and induce cellular differentiation or senescence, followed by programmed cell death. Decitabine is a prodrug: cells must take it up and phosphorylate it before it is active.

Mechanism of Action

• Activation: inside the cell, deoxycytidine kinase, nucleotide monophosphate kinase and nucleotide diphosphate kinase phosphorylate decitabine in sequence to its active triphosphate.
• Incorporation into DNA: DNA polymerase builds the triphosphate into newly synthesised DNA. DNA methyltransferases (mainly DNMT1) that meet the analogue are trapped on the DNA by an irreversible covalent bond, because the ring carries nitrogen instead of carbon at position 5.
• Dose effect: at low concentrations this depletes the methyltransferases and causes global DNA hypomethylation. At high concentrations it also causes double-strand breaks and cell death.
• Therapeutic hypothesis: hypomethylation is thought to restore the expression of previously silent tumour suppressor genes and so reduce the proliferation of leukaemic cells. Effects on transcription factors, histone modification and chromatin structure, and activation of DNA damage response pathways, have also been proposed.
• Unincorporated drug: decitabine that is not built into DNA is deaminated by cytidine deaminase and degraded further before excretion.

Pharmacokinetics

• Disposition: the SmPC’s population analysis (45 patients with AML or myelodysplastic syndrome on the 5-day regimen) describes a linear two-compartment model after a 1-hour infusion, with rapid elimination from the central compartment and slower distribution from the peripheral compartment. Steady-state concentrations are reached within 0.5 hour, with no change from cycle to cycle and no accumulation.
• Typical patient (70 kg, 1.73 m², 20 mg/m² daily for 5 days): peak concentration about 107 ng/mL, cumulative exposure about 580 ng·h/mL per cycle, half-life about 68 minutes, volume of distribution at steady state about 116 L and clearance about 298 L/h.
• Distribution: plasma protein binding is negligible (below 1%). The large volume of distribution indicates spread into peripheral tissues.
• Metabolism: the cytochrome P450 system is not involved. The main route of breakdown is probably deamination by cytidine deaminase in the liver, kidney, intestinal epithelium and blood. Unchanged decitabine accounted for about 2.4% of plasma radioactivity in the human mass-balance study, and the major circulating metabolites are not believed to be pharmacologically active.
• Elimination: less than 1% of an administered dose appears in the urine.
• Special populations: the population analysis found no dependence on age, creatinine clearance, total bilirubin or disease type. Studies in patients with hepatic or renal impairment have not been conducted.

• Acute myeloid leukaemia (AML): adults with newly diagnosed de novo or secondary AML, according to the World Health Organisation (WHO) classification, who are not candidates for standard induction chemotherapy.

• Hypersensitivity to decitabine or to any of the excipients.
• Breast-feeding.

The most common reactions (≥35% of patients) are pyrexia, anaemia and thrombocytopenia, and the most common grade 3 or 4 reactions (≥20%) are pneumonia, thrombocytopenia, neutropenia, febrile neutropenia and anaemia. The groups below come from 293 patients with AML treated with Dacogen and from post-marketing experience.

Very common (≥1/10): pneumonia, urinary tract infection, other viral, bacterial and fungal infections (for example oral herpes, oral candidiasis, pharyngitis, upper respiratory tract infection, cellulitis, bronchitis, nasopharyngitis), febrile neutropenia, neutropenia, thrombocytopenia, anaemia, leukopenia, hyperglycaemia, headache, epistaxis, diarrhoea, vomiting, nausea, abnormal hepatic function, pyrexia.

Common (≥1/100 to <1/10): sepsis, septic shock, sinusitis, hypersensitivity (including anaphylactic reaction), stomatitis, hyperbilirubinaemia.

Uncommon (≥1/1,000 to <1/100): pancytopenia, cardiomyopathy, acute febrile neutrophilic dermatosis (Sweet’s syndrome).

Not known: differentiation syndrome, interstitial lung disease, enterocolitis (including neutropenic colitis and caecitis).

Fatal outcomes have been reported with infections (including pneumonia, sepsis and septic shock), febrile neutropenia, neutropenia, thrombocytopenia (including haemorrhage), pancytopenia and enterocolitis. In clinical studies, 30% of patients on Dacogen and 25% in the comparator arm had an adverse event with a fatal outcome during treatment or within 30 days of the last dose, and more women than men stopped treatment because of adverse events (43% versus 32%). Serious bleeding, some of it fatal, occurred in the setting of severe thrombocytopenia (central nervous system haemorrhage 2%, gastrointestinal haemorrhage 2%). Enterocolitis may lead to septic complications. Differentiation syndrome may be fatal; its signs include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary and peripheral oedema, rapid weight gain, pleural and pericardial effusions, hypotension and renal dysfunction, with or without leucocytosis, and capillary leak syndrome and coagulopathy can also occur. In 17 children aged 1 to 14 years with relapsed or refractory AML (phase I/II study), no new safety signal was seen.

No formal clinical interaction studies have been conducted.

• Medicines activated by sequential phosphorylation or inactivated by the same enzymes (for example cytidine deaminase): a drug-drug interaction is possible, so caution is advised when such substances are combined with decitabine.
• Cytochrome P450: metabolic interactions are not expected, because decitabine is inactivated by oxidative deamination rather than by the P450 system.
• Protein binding and P-glycoprotein: with negligible protein binding (below 1%), displacement of other medicines is unlikely. Decitabine is a weak inhibitor of P-glycoprotein-mediated transport in vitro and is not expected to affect the transport of other medicines.
• Hormonal contraceptives: use together with decitabine has not been studied.

Treatment must be started under the supervision of physicians experienced in the use of chemotherapeutic medicinal products. Dacogen is given by intravenous infusion; a central venous catheter is not required. The powder is reconstituted with 10 mL of water for injections, and the concentrate is then diluted with cold infusion fluid (see section 6.6 of the SmPC for the full instructions).

Recommended Dose

• 20 mg/m² body surface area by intravenous infusion over 1 hour, once daily for 5 consecutive days (5 doses per treatment cycle).
• The total daily dose must not exceed 20 mg/m², and the total dose per cycle must not exceed 100 mg/m².
• The cycle is repeated every 4 weeks, depending on the patient’s clinical response and observed toxicity.
• A minimum of 4 cycles is recommended, although a complete or partial remission may take longer. Treatment can continue as long as the patient responds, continues to benefit or has stable disease, that is, in the absence of overt progression.
• If after 4 cycles the blood counts (for example platelets or absolute neutrophil count) have not returned to pre-treatment levels, or the disease progresses (rising peripheral blast counts or worsening bone marrow blast counts), the patient may be considered a non-responder and other treatment options should be considered.
• Premedication to prevent nausea and vomiting is not routinely recommended but may be given if required.

Managing Myelosuppression

• Myelosuppression and related events (thrombocytopenia, anaemia, neutropenia, febrile neutropenia) are common in both treated and untreated patients with AML. Their complications include infections and bleeding.
• Treatment may be delayed, at the treating physician’s discretion, for febrile neutropenia (temperature ≥38.5 °C and absolute neutrophil count below 1,000/µL), for an active viral, bacterial or fungal infection that needs intravenous anti-infectives or extensive supportive care, and for haemorrhage (gastrointestinal, genito-urinary, pulmonary with platelets below 25,000/µL, or any central nervous system haemorrhage).
• Treatment can be resumed once these conditions have improved or been stabilised with adequate treatment (anti-infective therapy, transfusions or growth factors).
• About one third of patients in the clinical studies needed a dose delay. Dose reduction is not recommended.

Special Populations

• Elderly: the pivotal study enrolled patients with a median age of 73 years (range 64 to 91), and the population analysis found no dependence of pharmacokinetics on age.
• Hepatic impairment: not studied, and the need for dose adjustment has not been evaluated. Patients should be carefully monitored if hepatic function worsens.
• Renal impairment: not studied, and the need for dose adjustment has not been evaluated.
• Children and adolescents: Dacogen should not be used in children with AML under 18 years of age, because efficacy was not established.

Missed Dose

If a dose is missed, treatment should be resumed as soon as possible.

Myelosuppression and Infections

Myelosuppression and its complications, including infections and bleeding, may be worsened by Dacogen, so patients are at increased risk of severe infection with any pathogen (bacterial, fungal or viral), with a potentially fatal outcome. Patients should be monitored for signs and symptoms of infection and treated promptly. Most patients in the studies already had grade 3 or 4 myelosuppression at baseline, and those with grade 2 abnormalities worsened more often than those with grade 0 or 1. The myelosuppression caused by Dacogen is reversible. Complete blood and platelet counts should be checked regularly, as clinically indicated, and before each treatment cycle; treatment may be interrupted and supportive measures started when myelosuppression or its complications occur.

Interstitial Lung Disease

Interstitial lung disease (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infection has been reported. Patients with an acute onset or unexplained worsening of lung symptoms should be assessed carefully to exclude it, and appropriate treatment started if it is confirmed.

Differentiation Syndrome

Differentiation syndrome (also known as retinoic acid syndrome) has been reported and may be fatal. At the first signs or symptoms suggestive of it, treatment with high-dose intravenous corticosteroids and haemodynamic monitoring should be considered. Temporary discontinuation of Dacogen should be considered until the symptoms resolve, and caution is advised if treatment is resumed.

Cardiac Disease

Patients with a history of severe congestive heart failure or clinically unstable cardiac disease were excluded from the clinical studies, so safety and efficacy in them have not been established. Cardiomyopathy with cardiac decompensation, in some cases reversible after stopping treatment, reducing the dose or corrective treatment, has been reported after marketing. Patients, especially those with a history of cardiac disease, should be monitored for signs and symptoms of heart failure.

Hepatic and Renal Impairment

Use in patients with hepatic impairment has not been established; caution is needed in these patients and in those who develop signs or symptoms of hepatic impairment. Liver function tests should be done before treatment starts, before each cycle and as clinically indicated. Use in severe renal impairment (creatinine clearance below 30 mL/min) has not been studied, and caution is needed; renal function tests should be done before treatment starts, before each cycle and as clinically indicated.

Pregnancy, Breastfeeding and Fertility

• Contraception: because decitabine is genotoxic, women of childbearing potential must use effective contraception and avoid pregnancy during treatment and for 6 months after the last dose. Men should use effective contraception and not father a child during treatment and for 3 months after. Use together with hormonal contraceptives has not been studied.
• Pregnancy: there are no adequate data. Decitabine is teratogenic in rats and mice, and the risk to humans is unknown. It should not be used during pregnancy or in women of childbearing potential who are not using effective contraception. A pregnancy test should be done in all women of childbearing potential before treatment starts. A patient who is treated during pregnancy, or who becomes pregnant during treatment, should be told of the potential hazard to the foetus.
• Breastfeeding: it is not known whether decitabine or its metabolites pass into breast milk. Dacogen is contraindicated during breast-feeding, so breast-feeding must be stopped if treatment is needed.
• Fertility: there are no human data. In animal studies decitabine alters male fertility and is mutagenic.

Potassium and Sodium

Each vial contains 0.5 mmol potassium; after reconstitution and dilution, each dose contains less than 1 mmol (39 mg) of potassium, that is, it is essentially ‘potassium-free’. Each vial contains 0.29 mmol (6.67 mg) sodium; after reconstitution and dilution, each dose contains between 13.8 mg and 138 mg (0.6 to 6 mmol) of sodium, depending on the infusion fluid, equivalent to 0.7–7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Effect on Driving

Dacogen has a moderate influence on the ability to drive and use machines. Patients may experience undesirable effects such as anaemia during treatment, so caution is advised when driving or operating machines.

Do not store above 25 °C. The unopened vial does not need refrigeration. The infusion solution is prepared by reconstituting the powder with 10 mL of water for injections and, within 15 minutes, diluting the concentrate with cold (2–8 °C) infusion fluid. The diluted solution can be stored at 2–8 °C for up to 3 hours, followed by up to 1 hour at room temperature (20–25 °C) before administration. The user is responsible for observing these times and for reconstitution under aseptic conditions. Dacogen is supplied as one 50 mg vial (20 mL clear Type I glass vial with a butyl rubber stopper and aluminium seal) per pack.

Unopened vial: 3 years. Reconstituted and diluted solution: as described under Storage Conditions, at most 3 hours at 2–8 °C followed by up to 1 hour at room temperature (20–25 °C) before administration.

Prescription only (Rx). Dacogen is subject to restricted medical prescription, and treatment is started under the supervision of physicians experienced in the use of chemotherapeutic medicinal products. It is given as an intravenous infusion, so it is supplied to the hospital or clinic that administers it.