ONUREG Film-coated tablet Ref.[28040] Active ingredients: Azacitidine

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).

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’.

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.

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.

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.

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 in the pivotal Phase 3 study with Onureg. A total of 236 patients received Onureg. The median treatment duration was 11.6 months (range: 0.5 to 74.3 months) for 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:

^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 national reporting system listed in Appendix V.

Not applicable.