Onureg

Onureg treatment should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic medicinal products. Patients are to be treated with an anti-emetic 30 minutes prior to each dose of Onureg for the first 2 treatment cycles.

4). 3 Posology The recommended dose is 300 mg azacitidine orally once daily. Each repeated cycle consists of a treatment period of 14 days followed by a treatment free period of 14 days (28-day treatment cycle). Onureg treatment should be continued until no more than 15% blasts are observed in peripheral blood or bone marrow or until unacceptable toxicity (see dose schedule modification guidance for disease relapse).

Onureg should not be used interchangeably with injectable azacitidine due to differences in the exposure, dose and schedule of treatment. Healthcare professionals are recommended to verify the name of the medicinal product, dose and administration route.

Laboratory tests Complete blood counts should be performed prior to initiation of therapy. 4). Dose schedule modification for AML disease relapse In the case of disease relapse, with 5% to 15% blasts in peripheral blood or bone marrow, in conjunction with a clinical assessment, an extension of the dosing schedule from 14 to 21 days of repeated 28-day cycles should be considered.

Dosing should not exceed 21 days during any 28-day period. Onureg should be discontinued if more than 15% blasts are observed in either the peripheral blood or bone marrow or at the physician’s discretion. Dose adjustment for adverse reactions Dose modification guidelines for haematologic and non-haematologic adverse reactions are recommended based on clinical and laboratory findings (see Table 1).

4 Table 1: Dose adjustments for haematologic and non-haematologic adverse reactions Criteria* Recommended action Grade 4 neutropenia or Grade 3 neutropenia with fever First occurrence • Interrupt Onureg. Resume the treatment cycle at the same dose once neutrophils return to Grade 2 or lower.

4). Occurrence in 2 consecutive cycles • Interrupt Onureg. Resume the treatment cycle at a reduced dose of 200 mg after neutrophils return to Grade 2 or lower. • If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days.

• If the toxicity continues or re-occurs after dose and schedule reduction, discontinue Onureg. 4). Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding First occurrence • Interrupt Onureg. Resume the treatment cycle at the same dose once platelets return to Grade 2 or lower.

2%)1. 1% of patients receiving Onureg. 1%)1. 8% of patients. 3%). 4% of patients who received Onureg. 1%)4. Dose reductions due to an adverse reaction period occurred in 14% of patients who received Onureg. 7%). Tabulated list of adverse reactions Table 2 presents the frequency category of ADRs reported during clinical trials with Onureg and post- marketing use.

A total of 236 patients received Onureg in the pivotal Phase 3 study. 3 months) in the Onureg arm. Frequencies are defined as: 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 (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse reactions are presented in the table below according to the highest frequency observed.

Table 2:

Adverse drug reactions (ADRs) in AML patients receiving Onureg maintenance therapy System organ class All gradesa frequency Infections and infestations Very common Pneumonia1, 6 Respiratory tract infection2 Common Sepsis Influenza Urinary tract infection3 Bronchitis Rhinitis Uncommon Neutropenic sepsis Neoplasms benign, malignant and unspecified (incl.

0% higher frequency than the placebo arm. 1 Grouped terms include pneumonia, bronchopulmonary aspergillosis, lung infection, Pneumocystis jirovecii pneumonia, atypical pneumonia, pneumonia bacterial, and pneumonia fungal. 2 Grouped terms include upper respiratory tract infection, respiratory tract infection, and respiratory tract infection viral.

3 Grouped terms include urinary tract infection, urinary tract infection bacterial, Escherichia urinary tract infection, and cystitis. 4 Grouped terms include abdominal pain, abdominal pain upper, abdominal discomfort, and gastrointestinal pain.

8 for frequencies). Interruption, reduction or discontinuation of Onureg may be necessary to manage haematological toxicities. Patients should be advised to promptly report febrile episodes. Patients with low platelet counts should be advised to report early signs or symptoms of bleeding.

2 Table 1). Complete blood counts should be performed prior to initiation of therapy. Complete blood count monitoring is also recommended every other week for the first 2 cycles (56 days), every other week for the next 2 cycles after dose adjustment, and monthly thereafter, prior to the start of subsequent cycles of treatment.

2 Table 1). Differentiation syndrome Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving oral azacitidine. 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 oral azacitidine should be considered until resolution of symptoms and if resumed, caution is advised. 8). 2). Diarrhoea should be treated promptly at the onset of symptoms. 2). Women of childbearing potential/Contraception in males and females Women of childbearing potential have to use effective contraception during and up to 6 months after treatment.

6). Lactose intolerance Onureg tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Sodium content This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

1. 6).