Dacogen

/ Janssen

Dacogen must be administered under the supervision of physicians experienced in the treatment of MDS.
Pre-medication for the prevention of nausea and vomiting is not routinely recommended but may be administered if required. There are two regimens for Dacogen administration. With either regimen It is recommended that patients be treated for a minimum of 4 cycles; however, a complete or partial remission may take longer than 4 cycles to be obtained. In Phase 3 study, the median time to response (complete and partial remission) according to the International Working Group criteria (IWG 2000), which includes transfusion independence, was 3 treatment cycles. Treatment may be continued as long as the patient shows response, continues to benefit or exhibits stable disease, i.e., in the absence of overt progression. If after 4 cycles, the patient’s hematological values (e.g., platelet counts or absolute neutrophil count [ANC]), have not returned to pre-treatment levels or if disease progression occurs (peripheral blast counts are increasing or bone marrow blast counts are worsening), the patient may be considered to be a nonresponder and alternative therapeutic options to Dacogen should be considered. Complete blood counts and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of treatment.
For full details see prescribing information.

Treatment of 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.

– Dacogen is contraindicated in patients with a known hypersensitivity to decitabine or any of the excipients.
– Pregnancy (see Special precautions)
– Breast feeding (see Special precautions)

Myelosuppression and complications of myelosuppression that occur in patients with MDS may be exacerbated with Dacogen treatment. Myelosuppression caused by Dacogen is reversible. Complete blood and platelet counts should be performed regularly, as clinically indicated and prior to each treatment cycle. In the presence of myelosuppression or its complications, treatment with DACOGEN may be interrupted or the dose reduced as recommended in Section dosage and administration. The use of Dacogen in patients with renal or hepatic impairment has not been established. Caution should be exercised in the administration of Dacogen to patients with hepatic or renal impairment and patients should be monitored closely for signs of toxicity.
Neutropenia and Thrombocytopenia: Treatment with Dacogen is associated with neutropenia and thrombocytopenia. Complete blood and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, treatment for subsequent cycles should be adjusted (see Dosage). Clinicians should consider the need for early institution of growth factors and/or antimicrobial agents for the prevention or treatment of infections in patients with MDS. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles, and may not necessarily indicate progression of underlying MDS.
Use in Pregnancy: Dacogen can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, Dacogen is expected to result in adverse reproductive effects. In preclinical studies in mice and rats, decitabine was teratogenic, fetotoxic, and embryotoxic. There are no adequate and well-controlled studies of Dacogen in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking Dacogen.
Use in Women of Childbearing Potential: Women of childbearing potential should be advised to avoid becoming pregnant while receiving Dacogen and for 1 month following completion of treatment. Women of childbearing potential should be counseled to use effective contraception during this time. Based on its mechanism of action, Dacogen can cause fetal harm if used during pregnancy. Decitabine is teratogenic in rats and mice. There are no adequate and well-controlled studies from the use of DACOGEN in pregnant women. DACOGEN is contraindicated during pregnancy. If women become pregnant while receiving DACOGEN, treatment should stop immediately, and the patient should be apprised of the potential hazard to the fetus.
Use in Men: Men should be advised not to father a child while receiving treatment with Dacogen, and for 2 months following completion of treatment. Men with female partners of childbearing potential should use effective contraception during this time. Based on its mechanism of action, Dacogen alters DNA synthesis and can cause fetal harm. Because of the possibility of infertility as a consequence of Dacogen therapy, men should seek advice on conservation of sperm prior to any treatment.
Treatment is associated with neutropenia and thrombocytopenia. Complete blood and platelet counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, treatment for subsequent cycles should be adjusted.
Pediatric use: The safety and effectiveness have not been established.
Geriatric use: No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
Renal/hepatic impairment: Caution should be exercised and patients should be monitored closely for signs of toxicity.
See prescribing information for full details.

Clinical Studies Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most Commonly Occurring Adverse Reactions: neutropenia, thrombocytopenia, anemia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, and hyperglycemia.
Adverse Reactions Most Frequently (≥ 1%) Resulting in Clinical Intervention in the Phase 3 Trial in the Dacogen Arm:
– Discontinuation: thrombocytopenia, neutropenia, pneumonia, Mycobacterium avium complex infection, cardio-respiratory arrest, increased blood bilirubin, intracranial hemorrhage, abnormal liver function tests.
– Dose Delayed: neutropenia, pulmonary edema, atrial fibrillation, central line infection, febrile neutropenia.
– Dose Reduced: neutropenia, thrombocytopenia, anemia, lethargy, edema, tachycardia, depression, pharyngitis.
See prescribing information for full details.

Impact of co-administered drugs on decitabine: Displacement of decitabine from its plasma protein binding by co-administered drugs is unlikely given the negligible in vitro plasma protein binding (< 1%) of decitabine. There is the potential for a pharmacokinetic drug-drug interaction with other agents, such as cytarabine, which are also activated by sequential phosphorylation (via intracellular phosphokinase activities) and/or metabolized by enzymes implicated in the inactivation of decitabine (e.g., cytidine deaminase). In vitro data indicated that decitabine is a poor Pglycoprotein (P-gp) substrate and is therefore not prone to interaction with P-gp inhibitors.
Impact of decitabine on co-administered drugs: Given its low in vitro plasma protein binding (< 1%), decitabine is unlikely to displace co-administered drugs from their plasma protein binding. Decitabine is a weak inhibitor of the major human cytochrome P450 enzymes (CYP): in vitro IC50 values towards inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 were in excess of 5700 ng/mL. In each case, these IC50-values are much higher than the maximum plasma concentrations of decitabine achieved in patients (plasma Cmax-values < 100 ng/mL) treated as described in Section 4.2. Similarly, decitabine does not induce major CYPs (CYP1A2, 2B6, 2C9, and 3A4/5) in vitro at concentrations of decitabine up to 2280 ng/mL; i.e., a concentration that substantially exceeds clinical plasma Cmax-values at the proposed clinical dose. Decitabine, at concentrations up to 2280 ng/mL, was also shown to be a weak inhibitor of P-gp mediated transport in vitro and is therefore also not expected to affect P-gp mediated transport of co-administered drugs.
See prescribing information for full details.

Pregnancy: Dacogen can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of Dacogen in pregnant women. The developmental toxicity of decitabine was examined in mice exposed to single IP (intraperitoneal) injections (0, 0.9 and 3.0 mg/m², approximately 2% and 7% of the recommended daily clinical dose, respectively) over gestation days 8, 9, 10 or 11. No maternal toxicity was observed but reduced fetal survival was observed after treatment at 3 mg/m² and decreased fetal weight was observed at both dose levels. The 3 mg/m² dose elicited characteristic fetal defects for each treatment day, including supernumerary ribs (both dose levels), fused vertebrae and ribs, cleft palate, vertebral defects, hind-limb defects and digital defects of fore- and hindlimbs. In rats given a single IP injection of 2.4, 3.6 or 6 mg/m² (approximately 5, 8, or 13% the daily recommended clinical dose, respectively) on gestation days 9-12, no maternal toxicity was observed. No live fetuses were seen at any dose when decitabine was injected on gestation day 9. A significant decrease in fetal survival and reduced fetal weight at doses greater than 3.6 mg/m2 was seen when decitabine was given on gestation day 10. Increased incidences of vertebral and rib anomalies were seen at all dose levels, and induction of exophthalmia, exencephaly, and cleft palate were observed at 6.0 mg/m2. Increased incidence of foredigit defects was seen in fetuses at doses greater than 3.6 mg/m2. Reduced size and ossification of long bones of the fore-limb and hindlimb were noted at 6.0 mg/m2. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child bearing potential should be advised to avoid becoming pregnant while taking Dacogen.
Lactation: It is not known whether decitabine or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from Dacogen in
nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. DACOGEN is contraindicated during lactation; therefore if treatment with DACOGEN is required, breastfeeding must be discontinued.
Pediatric Use: The safety and effectiveness of Dacogen in pediatric patients have not been established.

There is no known antidote for overdose with Dacogen. Higher doses are associated with increased myelosuppression including prolonged neutropenia and thrombocytopenia. Standard supportive measures should be taken in the event of an overdose.