Elodyst 50 mg Powder for concentrate for solution for infusion

ELODYST is indicated for the treatment of adult patients (u2265 65 years) with newly diagnosed de novo or secondary acute myeloid leukaemia (AML), according to the World Health Organisation (WHO) classification.

Posology

Dosing regimen

A 5-Day dosing regimen in the treatment of AML is recommended. It is recommended that patients be treated for a minimum of 4 cycles; however, a response may take longer than 4 cycles to be obtained.

In the AML Phase 3 study, the median time to response (complete remission [CR] or CR with incomplete platelet recovery [CRp]) was 4,3 months. 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 patientu2019s haematological values (e.g., platelet counts or absolute neutrophil count), 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 should be considered to be a non-responder and alternative therapeutic options to ELODYST should be considered. Pre-medication for the prevention of nausea and vomiting is not routinely recommended but may be administered if required.

Treatment Regimen

In a treatment cycle, ELODYST is administered at a dose of 20 mg/m2 body surface area by intravenous infusion over 1 hour repeated daily for 5 consecutive days (i.e., a total of 5 doses per treatment cycle). The total daily dose must not exceed 20 mg/m2 and the total dose per treatment cycle must not exceed 100 mg/m2. The cycle should be repeated every 4 weeks depending on the patient's clinical response and observed toxicity. If a dose is missed, treatment should be resumed as soon as possible. It is possible to use this regimen in an outpatient setting.

Myelosuppression and associated complications

Myelosuppression and adverse events related to myelosuppression (thrombocytopaenia, anaemia, neutropaenia, and febrile neutropaenia) are common in both treated and untreated patients. Complications of myelosuppression include infections and bleeding. Treatment may be modified in patients experiencing myelosuppression and associated complications as described below:

• Febrile neutropaenia (temperature u2265 38,5 u00b0C and absolute neutrophil count < 1 000/u03bcL).
• Active viral, bacterial or fungal infection (i.e., requiring intravenous anti-infectives or extensive supportive care).
• Haemorrhage (gastrointestinal, genito-urinary, pulmonary with platelets < 25 000/u03bcL or any central nervous system haemorrhage).

Treatment with ELODYST may be resumed once these conditions have improved or have been stabilised with adequate treatment (anti-infective therapy, transfusions, or growth factors). Dose reduction is not recommended.

Method of administration

ELODYST is for single use only. ELODYST is administered by intravenous infusion. A central venous catheter is not required.

• Known hypersensitivity to decitabine or to any of the excipients of ELODYST (see section 6.1).
• ELODYST is contraindicated in lactating women (see section 4.6).

Myelosuppresion

Myelosuppression and complications of myelosuppression, including infections and bleeding are likely to occur with ELODYST treatment. 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 ELODYST may be interrupted, the dose reduced, or supportive measures instituted as recommended (see section 4.2). Haematological adverse medicine reactions should be managed by routine monitoring of complete blood counts and 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 ELODYST administration should be delayed (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 ELODYST in these patients has not been established.

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).

Special populations

Hepatic impairment

Studies in patients with hepatic impairment have not been conducted. The need for dosage adjustment in patients with hepatic impairment has not been evaluated. Caution should be exercised in the administration of ELODYST to patients with hepatic impairment or in patients who develop signs or symptoms of hepatic impairment. Patients should be carefully monitored. (see sections 4.8 and 5.2).

Renal impairment

Studies in patients with renal impairment have not been conducted; however, data from clinical trials that included patients with mild-moderate impairment indicated no need for dosage adjustment. Patients with severe renal impairment were excluded from these trials (see section 5.2). The use of ELODYST in patients with severe renal impairment has not been studied. Caution should be exercised in the administration of ELODYST to patients with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) and these patients should be monitored closely (see section 4.2).

Paediatric population

Treatment of paediatric patients with AML is not recommended because ELODYST was not shown to be effective in this patient population.

No formal clinical medicine interaction studies with decitabine have been conducted. There is the potential for a medicine - medicine interaction with other medicines 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 medicines are combined with ELODYST.

Impact of co-administered medicines on ELODYST

CYP450-mediated metabolic medicine interactions are not anticipated as decitabine metabolism is not mediated by this system but by oxidative deamination. Displacement of ELODYST from its plasma protein binding by co-administered medicines is unlikely given the negligible in vitro plasma protein binding (< 1 %) of ELODYST. In vitro data indicated that ELODYST is a poor P-glycoprotein (P-gp) substrate and is therefore not prone to interaction with P-gp inhibitors.

Impact of ELODYST on co-administered medicines

Given its low in vitro plasma protein binding (< 1 %), ELODYST is unlikely to displace co-administered medicines from their plasma protein binding. In vitro studies show that ELODYST does not inhibit nor induce CYP 450 enzymes up to more than 20-fold of the therapeutic maximum observed plasma concentration (C max). Thus, CYP-mediated metabolic medicine interactions are not anticipated and is unlikely to interact with medicines metabolised through these pathways. ELODYST 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 medicines (see section 5.2).

Women of childbearing potential/contraception in males and females

Women of childbearing potential should be advised to use effective contraceptive measures and avoid becoming pregnant while being treated with ELODYST. The time period following treatment with ELODYST where it is safe to become pregnant is unknown.

Use in Males:

Men should be advised to not father a child while receiving ELODYST, and for 3 months following completion of treatment.

Pregnancy

There are no adequate data on the use of ELODYST in pregnant women. Studies have shown that ELODYST is teratogenic in rats and mice. The potential risk for humans is unknown. Based on results from animal studies and its mechanism of action, ELODYST should not be used during pregnancy. If this medicine is used during pregnancy, or if a patient becomes pregnant while receiving ELODYST, the patient should be apprised of the potential hazard to the foetus.

Breastfeeding

It is not known whether ELODYST or its metabolites are excreted in breast milk. ELODYST is contraindicated during lactation; therefore, if treatment with ELODYST is required, breastfeeding must be discontinued (see section 4.3).

Fertility

Female patients of childbearing potential should be advised to seek consultation regarding oocyte cryopreservation prior to initiation of treatment with ELODYST. Because of the possibility of infertility as a consequence of ELODYST therapy, men should seek advice on conservation of sperm prior to any treatment.

No studies of the effects on the ability to drive and use machines with ELODYST have been performed. 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.

a) Summary of the safety profile

The most important and frequently occurring adverse medicine reactions are myelosuppression and those occurring as a consequence of myelosuppression.

b) Tabulated list of adverse reactions

Infections and infestations

Frequent: Pneumonia*, urinary tract infection*, other infections (all viral, bacterial, fungal infections including fatal)* b , septic shock*, sepsis*, sinusitis

Blood and lymphatic system disorders

Frequent: Fibrile neutropaenia*, neutropaenia*, thrombocytopaenia c *, anaemia, leucopaenia, pancytopaenia*

Immune system disorders

Frequent: Hypersensitivity including anaphylactic reaction d

Metabolism and nutrition disorders

Frequency unknown: Hyperglycaemia

Nervous system disorders

Frequent: Headache

Cardiac disorders

Frequency unknown: Cardiomyopathy (including decreased ejection fraction)

Respiratory, thoracic and mediastinal disorders

Frequent: Epistaxis

Frequency unknown: interstitial lung disease

Gastrointestinal disorders

Frequent: Diarrhoea, vomiting, stomatitis, nausea

Frequency unknown: enterocolitis, including neutropaenic colitis, caecitis*

Hepato-biliary disorders

Frequency unknown: Abnormal hepatic function, hyperbilirubineamia

Skin and subcutaneous tissue disorders

Less frequent: Acute febrile neutrophilic dermatosis (Sweetu2019s Syndrome)

General disorders and administration site conditions

Frequent: Pyrexia

a Worst National Cancer Institute Common Terminology Criteria for Adverse Events Grade

b Excluding pneumonia, urinary tract infection, sepsis, septic shock and sinusitis

c Including haemorrhage associated with thrombocytopaenia, including fatal cases

d Including preferred terms hypersensitivity, drug hypersensitivity, anaphylactic reaction, anaphylactic shock

* Included events with fatal outcome

c) Description of selected adverse reactions

Haematologic adverse medicine reactions

The most commonly reported haematologic adverse medicine reactions associated with ELODYST treatment included febrile neutropaenia, thrombocytopaenia, neutropaenia, anaemia and leucopaenia. Serious infection-related adverse medicine reactions such as septic shock, sepsis, and pneumonia were reported in patients receiving ELODYST.

Serious bleeding-related adverse medicine reactions such as CNS haemorrhage (1 %) and gastrointestinal haemorrhage (2 %), in the context of severe thrombocytopaenia, were reported in patients receiving ELODYST.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za or to the Holder of certificate of registration through the mail: [email protected]

There is no direct experience of human overdose and no specific antidote. However, early clinical study data in published literature at doses greater than 20 times higher than the current therapeutic doses, reported increased myelosuppression including prolonged neutropaenia and thrombocytopaenia. Toxicity is likely to manifest as exacerbations of adverse reactions, primarily myelosuppression (see section 4.8). Treatment for overdose should be supportive.