Special populations : אוכלוסיות מיוחדות

Geriatric Use
Of the total number of MDS patients exposed to Dacogen in the controlled clinical trial, 61 of 83 patients were age 65 and over, while 21 of 83 patients were age 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Method of Administration

DACOGEN is administered by intravenous infusion. A central venous catheter is not required. For instructions on reconstitution and dilution of the medicinal product before administration, see Section 6.6.


4.3 CONTRAINDICATIONS
- Hypersensitivity to decitabine or to any of the excipients, listed in section 6.1.
- Breast feeding (see warnings and precautions)

4.4 Special Warnings and Special Precautions for Use
Myelosuppresion
Myelosuppression and complications of myelosuppression, including infections and bleeding that occur in patients with MDS or AML may be exacerbated with DACOGEN treatment. Therefore patients are at increased risk for severe infections (due to any pathogen such as bacterial, fungal and viral), with potentially fatal outcome (see section 4.8). Patients should be monitored for signs and symptoms of infection and treated promptly.

In AML clinical studies, the majority of patients had baseline Grade 3/4 myelosuppression. In patients with baseline Grade 2 abnormalities, worsening of myelosuppression was seen in most patients and more 

frequently than in patients with baseline Grade 1 or 0 abnormalities. 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 and/or supportive measures instituted (see sections 4.2 and 4.8).

In MDS studies, Fatal and serious myelosuppression occurs in DACOGEN-treated patients. Myelosuppression (anemia, neutropenia, and thrombocytopenia) is the most frequent cause of DACOGEN dose reduction, delay, and discontinuation. Neutropenia of any grade occurred in 90% of DACOGEN-treated patients with grade 3 or 4 occurring in 87% of patients. Grade 3 or 4 febrile neutropenia occurred in 23% of patients. Thrombocytopenia of any grade occurred in 89% of patients with grade 3 or 4 occurring in 85% of patients. Anemia of any grade occurred in 82% of patients. Perform complete blood count with platelets at baseline, prior to each cycle, and as needed to monitor response and toxicity. Manage toxicity using dose-delay, dose-reduction, growth factors, and anti-infective therapies as needed [see Dosage and Administration (2.2)]. Myelosuppression and worsening neutropenia may occur more frequently in the first or second treatment cycles and may not necessarily indicate progression of underlying MDS.

Embryo-Fetal Toxicity
In MDS Based on findings from human data, animal studies and its mechanism of action, DACOGEN can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) and Preclinical Safety Data (5.31)]. In preclinical studies in mice and rats, decitabine caused adverse developmental outcomes including embryo-fetal lethality and malformations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving DACOGEN and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception while receiving treatment with DACOGEN and for 3 months following the last dose [see Fertility, Pregnancy and lactation 4.6)].


Respiratory, thoracic and mediastinal disorders
Cases of interstitial lung disease (ILD) (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving decitabine. Careful assessment of patients with an acute onset or unexplained worsening of pulmonary symptoms should be performed to exclude ILD. If ILD is confirmed, appropriate treatment should be initiated (see section 4.8).

Hepatic impairment
Use in patients with hepatic impairment has not been established. Caution should be exercised in the administration of Dacogen to patients with hepatic impairment and in patients who develop signs or symptoms of hepatic impairment. Liver function tests should be performed prior to initiation of therapy and prior to each treatment cycle, and as clinically indicated (see sections 4.2 and 5.2).



Renal impairment

Use in patients with severe renal impairment has not been studied. Caution should be exercised in the administration of DACOGEN to patients with severe renal impairment (Creatinine Clearance [CrCl] <30 ml/min) and these patients should be monitored closely (see section 4.2). Renal function tests should be performed prior to initiation of therapy and prior to each treatment cycle, and as clinically indicated (see section 4.2).


Cardiac disease
Patients with a history of severe congestive heart failure or clinically unstable cardiac disease were excluded from clinical studies and therefore the safety and efficacy of DACOGEN in these patients has not been established. Cases of cardiomyopathy with cardiac decompensation, in some cases reversible after treatment discontinuation, dose reduction or corrective treatment, have been reported in the postmarketing setting.
Patients, especially those with cardiac disease history, should be monitored for signs and symptoms of heart failure.

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving decitabine. Differentiation syndrome may be fatal (see section 4.8). Treatment with high-dose IV corticosteroids and haemodynamic monitoring should be considered at first onset of symptoms or signs suggestive of differentiation syndrome. Temporary discontinuation of Dacogen should be considered until resolution of symptoms and if resumed, caution is advised.

Excipients
This medicine contains 0.5 mmol potassium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicine contains less than 1 mmol (39 mg) of potassium per dose, i.e. essentially ‘potassium- free’

This medicine contains 0.29 mmol sodium per vial. After reconstitution and dilution of the solution for intravenous infusion, this medicine contains between 13.8 mg-138 mg (0.6-6 mmol) sodium per dose (depending on the infusion fluid for dilution), equivalent to 0.7-7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interactions with Other Medicinal Products and Other Forms of Interaction
No formal clinical drug interaction studies with decitabine have been conducted.

There is the potential for a drug-drug interaction with other agents 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). Therefore, caution should be exercised if these active substances are combined with DACOGEN.

Impact of co-administered medicinal products on decitabine


Cytochrome (CYP) 450-mediated metabolic interactions are not anticipated as decitabine metabolism is not mediated by this system but by oxidative deamination.

Impact of decitabine on co-administered medicinal products

Given its low in vitro plasma protein binding (<1%), decitabine is unlikely to displace co-administered medicinal products from their plasma protein binding.

Decitabine has been 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 medicinal products (see Section 5.2).

4.6 Fertility, Pregnancy and lactation
The use of Dacogen with hormonal contraceptives has not been studied.

Women of childbearing potential/Contraception in men and women
DACOGEN can cause fetal harm when administered to pregnant women. Due to the genotoxic potential of decitabine (see section 5.3), women of childbearing potential must use effective contraceptive measures and avoid becoming pregnant while being treated with Dacogen and for 6 months following completion of treatment Men should use effective contraceptive measures and be advised to not father a child while receiving Dacogen, and for 3 months following completion of treatment (see section 5.3).

Pregnancy
There are no adequate data on the use of Dacogen in pregnant women. Studies have shown that decitabine is teratogenic in rats and mice (see section 5.3). The potential risk for humans is unknown. Based on results from animal studies and its mechanism of action, Dacogen should not be used during pregnancy and in women of childbearing potential not using effective contraception. A pregnancy test should be performed on all women of childbearing potential before treatment is started. If Dacogen is used during pregnancy, or if a patient becomes pregnant while receiving this medicinal product, the patient should be apprised of the potential hazard to the foetus.

Breast-feeding
It is not known whether decitabine or its metabolites are excreted in breast milk. Dacogen is contraindicated during breast-feeding; therefore, if treatment with this medicine is required, breast-feeding must be discontinued (see section 4.3).

Fertility
No human data on the effect of decitabine on fertility are available. In non-clinical animal studies, decitabine alters male fertility and is mutagenic. Because of the possibility of infertility as a consequence of Dacogen therapy, men should seek advice on conservation of sperm and female patients of childbearing potential should seek consultation regarding oocyte cryopreservation prior to initiation of treatment with Dacogen.