4.1. Therapeutic indications

Onureg is indicated as maintenance therapy in adult patients with acute myeloid leukaemia (AML) who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment and who are not candidates for, including those who choose not to proceed to, hematopoietic stem cell transplantation (HSCT).

4.2. Posology and method of administration

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. Anti-emetic prophylaxis may be omitted after 2 cycles, if there has been no nausea and vomiting (see section 4.4).

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. 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 (see section 4.4).

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).

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.

• Use supportive care such as granulocyte colony stimulating factor (GCSF), as clinically indicated (see section 4.4).

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.

• Use supportive care such as GCSF, as clinically indicated (see section 4.4).

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.

Occurrence in 2 consecutive cycles

• Interrupt Onureg. Resume the treatment cycle at a reduced dose of 200 mg after platelets 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.

Grade 3 or higher nausea, vomiting or diarrhoea

• Interrupt Onureg. Resume the treatment cycle at the same dose once toxicity has resolved to Grade 1 or lower.

• Use supportive care such as anti-emetic therapy and treat diarrhoea at the onset of symptoms (see section 4.4).

• If event re-occurs, interrupt dose until resolved to Grade 1 or lower and reduce the dose to 200 mg.

• 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.

Other Grade 3 or higher non-haematological events

• Interrupt Onureg and provide medical support according to local recommendations. Resume the treatment cycle at the same dose once toxicity has resolved to Grade 1 or lower.

• If the toxicity re-occurs, interrupt Onureg until resolved to Grade 1 or lower and reduce dose to 200 mg.

• 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.

* Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.3 (NCI-CTCAE v4.3).

Missed or delayed doses

If a dose of Onureg is missed, or not taken at the usual time, the dose should be taken as soon as possible on the same day. Then, the next scheduled dose should be taken at the normal time the following day. Two doses should not be taken on the same day.

If a dose is vomited, another dose must not be taken on the same day. Instead return to the normal time of dose administration the following day.

Special populations

Elderly patients

No dose adjustments are recommended for patients over 65 years of age (see section 5.2).

Renal impairment

Onureg can be administered to patients with mild, moderate or severe renal impairment without initial dose adjustment (see section 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin (BIL) ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or BIL 1 to 1.5 × ULN and any AST) (see section 5.2).

Patients with moderate (BIL > 1.5 to 3 × ULN) and severe hepatic impairment (BIL > 3 × ULN) should be monitored more frequently for adverse reactions and appropriate dose adjustment should be made (see Table 1).

Paediatric population

The safety and efficacy of Onureg in children and adolescents below 18 years have not been established. No data are available.

Method of administration

Onureg is for oral use.

Onureg can be taken with or without food. The tablets should be swallowed whole with a glass of water at about the same time each day. They should not be split, crushed, dissolved or chewed (see section 6.6).

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

4.4. Special warnings and precautions for use

Haematological toxicity

Treatment with Onureg can be associated with neutropenia, thrombocytopenia and febrile neutropenia (see section 4.8 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. Supportive care such as antibiotics and/or antipyretics for management of infection/fever and GCSF for neutropenia should be provided based on individual patient characteristics, treatment response and according to the current clinical guidelines (see section 4.2 Table 1).

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving oral azacitidine. 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 (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 oral azacitidine should be considered until resolution of symptoms and if resumed, caution is advised.

Gastrointestinal toxicity

Gastrointestinal toxicities were the most frequent adverse reactions in patients treated with Onureg (see section 4.8). Patients should be administered prophylactic anti-emetic therapy for the first 2 cycles of Onureg treatment (see section 4.2). Diarrhoea should be treated promptly at the onset of symptoms. Interruption, reduction or discontinuation of Onureg may be necessary to manage gastrointestinal toxicities (see section 4.2).

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. Men have to use effective contraception during and up to 3 months after treatment (see section 4.6).

Lactose intolerance

Onureg tablets contain lactose. 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'.

4.5. Interaction with other medicinal products and other forms of interaction

No formal clinical drug-drug interaction studies with azacitidine have been conducted.

In case of concomitant administration with other antineoplastic agents, caution and monitoring is recommended as an antagonistic, additive, or synergistic pharmacodynamic effect cannot be excluded. These effects may be dependent on the dose, sequence and schedule of administration.

Onureg exposure was minimally affected when co-administered with a proton pump inhibitor (omeprazole). Therefore, dose modification is not required when Onureg is co-administered with proton pump inhibitors or other pH modifiers.

An in vitro study of azacitidine with human liver fractions indicated that azacitidine was not metabolised by cytochrome P450 isoforms (CYPs). Therefore, interactions with CYP inducers or inhibitors are considered unlikely (see section 5.2).

Clinically relevant inhibitory or inductive effects of azacitidine on the metabolism of cytochrome P450 substrates are unlikely (see section 5.2). No clinically relevant drug-drug interactions are expected when Onureg is co-administered with substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptides (OATP) OATP1B1 and OATP1B3, or organic cation transporter (OCT) OCT2.

Azacitidine is not a substrate of P-gp, therefore it is not expected to interact with P-gp inducers or inhibitors.

4.6. Fertility, pregnancy and lactation

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. Men should be advised not to father a child while receiving treatment and have to use effective contraception during and up to 3 months after treatment (see sections 4.4 and 5.3).

Pregnancy

There are no adequate data from the use of Onureg in pregnant women. Studies in mice and rats have shown reproductive and developmental toxicity (see section 5.3). The potential risk for humans is unknown. Based on results from animal studies and its mechanism of action, Onureg is not recommended during pregnancy (especially during the first trimester, unless clearly necessary) and in women of childbearing potential not using contraception. The advantages of treatment should be weighed against the possible risk for the foetus in every individual case. If a patient or partner becomes pregnant while taking Onureg, the patient should be informed of the potential risk to the foetus.

Breast-feeding

It is unknown whether azacitidine or its metabolites are excreted in human milk. Due to the potential serious adverse reactions in the breastfed child, breast-feeding is contraindicated during Onureg therapy (see section 4.3).

Fertility

There are no human data on the effect of azacitidine on fertility. In animals, adverse effects of azacitidine on male fertility have been documented (see section 5.3). Patients who wish to conceive a child should be advised to seek reproductive counselling and cryo-conservation of either the ovum or sperm prior to starting Onureg treatment.

4.7. Effects on ability to drive and use machines

Onureg has minor influence on the ability to drive and use machines. Fatigue has been reported with the use of Onureg. Therefore, caution is recommended when driving or operating machines.

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reactions are nausea (64.8%), vomiting (59.7%), diarrhoea (50.4%), neutropenia (44.5%), fatigue/asthenia (44.1%)5, constipation (38.6%), thrombocytopenia (33.5%), abdominal pain (21.6%)4, respiratory tract infection (17%)2, arthralgia (13.6%), decreased appetite (12.7%), febrile neutropenia (11.9%), back pain (11.9%), leucopenia (10.6%), pain in extremity (10.6%) and pneumonia (10.2%)1.

Serious adverse reactions occurred in 16.1% of patients receiving Onureg. The most common serious adverse reactions are febrile neutropenia (6.8%) and pneumonia (5.1%)1.

Permanent discontinuation of Onureg due to an adverse reaction occurred in 6.8% of patients. The most common adverse reactions requiring permanent discontinuation are nausea (2.1%), diarrhoea (1.7%), and vomiting (1.3%).

Dose interruptions due to an adverse reaction occurred in 36.4% of patients who received Onureg. Adverse reactions requiring dose interruption include neutropenia (19.9%), thrombocytopenia (8.5%), nausea (5.5%), diarrhoea (4.2%), vomiting (3.8%), pneumonia (3.4%)1, leucopenia (2.5%), febrile neutropenia (2.1%), and abdominal pain (2.1%)4.

Dose reductions due to an adverse reaction period occurred in 14% of patients who received Onureg. Adverse reactions requiring dose reduction included neutropenia (5.5%), diarrhoea (3.4%), thrombocytopenia (1.7%), and nausea (1.7%).

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. The median treatment duration was 11.6 months (range: 0.5 to 74.3 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

Influenza, urinary tract infection3, bronchitis, rhinitis

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Not known

Differentiation syndrome

Blood and lymphatic system disorders

Very common

Neutropenia, thrombocytopenia6, febrile neutropenia6, leucopenia

Metabolism and nutrition disorders

Very common

Decreased appetite

Psychiatric disorders

Common

Anxiety

Gastrointestinal disorders

Very common

Nausea, vomiting, diarrhoea, constipation, abdominal pain4

Musculoskeletal and connective tissue disorders

Very common

Arthralgia, back pain, pain in extremity

General disorders and administration site conditions

Very common

Fatigue / asthenia5

Investigations

Common

Weight decreased

a All AEs with at least 5.0% of patients in the Onureg arm and at least 2.0% 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.

5 Grouped terms include fatigue and asthenia.

6 Adverse reactions in which at least one was considered to be life threatening (if the outcome of the reaction was death, it is included with death cases).

Description of selected adverse reactions

Haematological toxicity

New or worsening Grade 3 or higher neutropenia (41.1%), thrombocytopenia (22.5%), or febrile neutropenia (11.4%) were commonly reported adverse reactions in patients treated with Onureg. The first occurrence of Grade 3 or 4 neutropenia, thrombocytopenia, or febrile neutropenia occurred within the first 2 cycles in 19.9%, 10.6%, and 1.7%, respectively in patients treated with Onureg. See section 4.2 for monitoring and management guidance.

Gastrointestinal toxicity

Gastrointestinal toxicities were the most frequent adverse reactions in patients treated with Onureg. Nausea (64.8%), vomiting (59.7%), and diarrhoea (50.4%) were reported in patients treated with Onureg. Grade 3 or higher diarrhoea occurred in 5.1% of patients and Grade 3 or higher vomiting and nausea occurred in 3.0% and 2.5%, respectively in patients treated with Onureg. The first occurrence of Grade 3 or 4 nausea, vomiting, or diarrhoea occurred within the first 2 cycles in 1.7%, 3.0%, and 1.3%, respectively, in patients treated with Onureg. See section 4.2 for monitoring and management guidance.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

In the event of overdose, the patient should be monitored with appropriate blood counts and supportive treatment should be provided, as necessary, according to local recommendations. There is no known specific antidote for an overdose with Onureg.