DACOGEN Powder for concentrate for solution for infusion Ref.[9063] Active ingredients: Decitabine

Myelosuppression

Myelosuppression and complications of myelosuppression, including infections and bleeding that occur in patients with 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 clinical studies, the majority of patients had baseline Grade ¾ 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).

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). 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 (6.67 mg) 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.

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 metabolised by enzymes implicated in the inactivation of decitabine (e.g., cytidine deaminase). Therefore, caution should be exercised if these active substances are combined with decitabine.

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).

Women of childbearing potential/Contraception in males and females

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).

The use of decitabine with hormonal contraceptives has not been studied.

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.

Dacogen has moderate influence on the ability to drive and use machines. Patients should be advised that they may experience undesirable effects such as anaemia during treatment. Therefore, caution should be recommended when driving a car or operating machines.

Summary of the safety profile

The most common adverse drug reactions (≥35%) reported are pyrexia, anaemia and thrombocytopaenia.

The most common Grade ¾ adverse drug reactions (≥20%) included pneumonia, thrombocytopaenia, neutropaenia, febrile neutropaenia and anaemia.

In clinical studies, 30% of patients treated with Dacogen and 25% of patients treated in the comparator arm had adverse events with an outcome of death during treatment or within 30 days after the last dose of study drug.

In the Dacogen treatment group, there was a higher incidence of treatment discontinuation due to adverse events in women compared to men (43% versus 32%).

Tabulated list of adverse drug reactions

Adverse drug reactions reported in 293 AML patients treated with Dacogen are summarised in Table 1. The following table reflects data from AML clinical studies and from post-marketing experience. The adverse drug reactions are listed by frequency category. Frequency categories are defined as follows: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

Table 1. Adverse drug reactions identified with Dacogen:

^a Worst National Cancer Institute Common Terminology Criteria for Adverse Events Grade.
^b Excluding pneumonia, urinary tract infection, sepsis, septic shock and sinusitis.
^c The most frequently reported “other infections” in study DACO-016 were: oral herpes, oral candidiasis, pharyngitis, upper respiratory tract infection, cellulitis, bronchitis, nasopharyngitis.
^d Including enterocolitis infectious.
^e Including haemorrhage associated with thrombocytopaenia, including fatal cases.
^f Including preferred terms hypersensitivity, drug hypersensitivity, anaphylactic reaction, anaphylactic shock, anaphylactoid reaction, anaphylactoid shock.
^g In clinical studies in AML and myelodysplastic syndrome (MDS), the reporting frequency for hyperbilirubinaemia was 11% for All Grades and 2% for Grade 3-4.
* Includes events with a fatal outcome.
NA = Not applicable

Description of selected adverse drug reactions

Haematologic adverse drug reactions

The most commonly reported haematologic adverse drug reactions associated with Dacogen treatment included febrile neutropaenia, thrombocytopaenia, neutropaenia, anaemia and leukopaenia.

Serious bleeding-related adverse drug reactions, some of which lead to a fatal outcome, such as central nervous system (CNS) haemorrhage (2%) and gastrointestinal (GI) haemorrhage (2%), in the context of severe thrombocytopaenia, were reported in patients receiving decitabine.

Haematological adverse drug reactions should be managed by routine monitoring of complete blood counts and early administration of supportive treatments as required. Supportive treatments include, administration of prophylactic antibiotics and/or growth factor support (e.g., G-CSF) for neutropaenia and transfusions for anaemia or thrombocytopaenia according to institutional guidelines. For situations where decitabine administration should be delayed, see section 4.2.

Infections and infestations adverse drug reactions

Serious infection-related adverse drug reactions, with potentially fatal outcome, such as septic shock, sepsis, pneumonia, and other infections (viral, bacterial and fungal) were reported in patients receiving decitabine.

Gastrointestinal disorders

Occurrences of enterocolitis, including neutropaenic colitis, caecitis have been reported during treatment with decitabine. Enterocolitis may lead to septic complications and may be associated with fatal outcome.

Respiratory, thoracic and mediastinal disorders

Cases of interstitial lung disease (including pulmonary infiltrates, organising pneumonia and pulmonary fibrosis) without signs of infectious aetiology have been reported in patients receiving decitabine.

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving decitabine. Differentiation syndrome may be fatal and symptoms and clinical findings include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary oedema, peripheral oedema, rapid weight gain, pleural effusions, pericardial effusions, hypotension and renal dysfunction. Differentiation syndrome may occur with or without concomitant leucocytosis. Capillary leak syndrome and coagulopathy can also occur (see section 4.4).

Paediatric population

The safety assessment in paediatric patients is based on the limited safety data from a Phase I/II study to evaluate pharmacokinetics, safety and efficacy of Dacogen in paediatric patients (aged 1 to 14 years) with relapsed or refractory AML (n=17) (see section 5.1). No new safety signal was observed in this paediatric study.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.