Azacitidine Accord · 4.4 Special warnings and precautions for use · 2

HOS-287827 · has-adverse-reaction-information · PDF-Seite 27

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 Azacitidine Accord. The most common serious adverse reactions are febrile neutropenia (6.8%) and pneumonia (5.1%)1. Permanent discontinuation of Azacitidine Accord 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 Azacitidine Accord. 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 Azacitidine Accord. 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 Azacitidine Accord. A total of 236 patients received Azacitidine Accord. The median treatment duration was 11.6 months (range: 0.5 to 74.3 months) for Azacitidine Accord 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 Azacitidine Accord maintenance therapy System organ class All gradesa frequency Infections and infestations Very common Pneumonia1, 6, respiratory tract infection2

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HOS-287821 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile Adult population with MDS, CMML and AML (20-30% marrow blasts) Adverse reactions considered to be possibly or probably related to the administration of azacitidine have occurred in 97 % of patients. The most common serious adverse reactions noted from the pivotal study (AZA PH GL 2003 CL 001) included febrile neutropenia (8.0 %) and anaemia (2.3 %), which were also reported in the supporting studies (CALGB 9221 and CALGB 8921). Other serious adverse reactions from these 3 studies included infections such as neutropenic sepsis (0.8%) and pneumonia (2.5%) (some with fatal outcome), thrombocytopenia (3.5%), hypersensitivity reactions (0.25%) and haemorrhagic events (e.g. cerebral haemorrhage [0.5%], gastrointestinal haemorrhage [0.8%] and intracranial haemorrhage [0.5%])). 6 The most commonly reported adverse reactions with azacitidine treatment were haematological reactions (71.4 %) including thrombocytopenia, neutropenia and leukopenia (usually Grade 3-4), gastrointestinal events (60.6 %) including nausea, vomiting (usually Grade 1-2) or injection site reactions (77.1 %; usually Grade 1-2). Adult population aged 65 years or older with AML with > 30% marrow blasts The most common serious adverse reactions (≥10%) noted from AZA-AML-001 within the azacitidine treatment arm included febrile neutropenia (25.0%), pneumonia (20.3%), and pyrexia (10.6%). Other less frequently reported serious adverse reactions in the azacitidine treatment arm included sepsis (5.1%), anaemia (4.2%), neutropenic sepsis (3.0%), urinary tract infection (3.0%), thrombocytopenia (2.5%), neutropenia (2.1%), cellulitis (2.1%), dizziness (2.1%) and dyspnoea (2.1%). The most commonly reported (≥ 30%) adverse reactions with azacitidine treatment were gastrointestinal events, including constipation (41.9%), nausea (39.8%), and diarrhoea (36.9%; usually Grade 1-2), general disorders and administration site conditions including pyrexia (37.7%; usually Grade 1-2) and haematological events, including febrile neutropenia (32.2%) and neutropenia (30.1%; usually Grade 3-4). Tabulated list of adverse reactions Table 1 below contains adverse reactions associated with azacitidine treatment obtained from the main clinical studies in MDS and AML and post marketing surveillance. 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);

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HOS-287817 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Advanced malignant hepatic tumours (see section 4.4). Breast-feeding (see section 4.6).

HOS-287823 · has-contraindication-information · PDF-Seite 25

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 Breast-feeding (see section 4.6).

HOS-287816 · has-indication-information · PDF-Seite 2

Azacitidine Accord is indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell transplantation (HSCT) with: - Intermediate-2 and high-risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS), - chronic myelomonocytic leukaemia (CMML) with 10-29 % marrow blasts without myeloproliferative disorder, - acute myeloid leukaemia (AML) with 20-30 % blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification, - AML with >30% marrow blasts according to the WHO classification.

HOS-287822 · has-indication-information · PDF-Seite 22

Azacitidine Accord 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).

HOS-287825 · has-interaction-information · PDF-Seite 25

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. 25 Azacitidine Accord exposure was minimally affected when co-administered with a proton pump inhibitor (omeprazole). Therefore, dose modification is not required when Azacitidine Accord 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 Azacitidine Accord 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.

HOS-287819 · has-interaction-information · PDF-Seite 6

Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450 isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and glutathione transferases (GSTs); interactions related to these metabolizing enzymes in vivo are therefore considered unlikely. Clinically significant inhibitory or inductive effects of azacitidine on cytochrome P450 enzymes are unlikely (see section 5.2). No formal clinical drug interaction studies with azacitidine have been conducted.

HOS-287826 · has-pregnancy-information · PDF-Seite 26

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 Azacitidine Accord 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, Azacitidine Accord 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 Azacitidine Accord, 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 Azacitidine Accord 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 Azacitidine Accord treatment.

HOS-287820 · has-pregnancy-information · PDF-Seite 6

Women of childbearing potential / Contraception in males and females Women of childbearing potential have to use effective contraception during and for at least 6 months after treatment. Men should be advised not to father a child while receiving treatment and must use effective contraception during and for at least 3 months after treatment. Pregnancy There are no adequate data from the use of azacitidine in pregnant women. Studies in mice have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Based on results from animal studies and its mechanism of action, azacitidine should not be used during pregnancy, especially during the first trimester, unless clearly necessary. The advantages of treatment should be weighed against the possible risk for the foetus in every individual case. Breast-feeding It is unknown whether azacitidine/metabolites are excreted in human milk. Due to the potential serious adverse reactions in the nursing child, breast-feeding is contraindicated during azacitidine therapy. Fertility There are no human data on the effect of azacitidine on fertility. In animals, adverse reactions with azacitidine use on male fertility have been documented (see section 5.3). Before starting treatment, male patients should be advised to seek counselling on sperm storage.

HOS-287818 · has-warning-information · PDF-Seite 4

Haematological toxicity Treatment with azacitidine is associated with anaemia, neutropenia and thrombocytopenia, particularly during the first 2 cycles (see section 4.8). Complete blood counts should be performed as needed to monitor response and toxicity, but at least prior to each treatment cycle. After administration of the recommended dose for the first cycle, the dose for subsequent cycles should be reduced or its administration delayed based on nadir counts and haematological response (see section 4.2). Patients should be advised to promptly report febrile episodes. Patients and physicians are also advised to be observant for signs and symptoms of bleeding. 4 Hepatic impairment No formal studies have been conducted in patients with hepatic impairment. Patients with extensive tumour burden due to metastatic disease have been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline serum albumin < 30 g/L. Azacitidine is contraindicated in patients with advanced malignant hepatic tumours (see section 4.3). Renal impairment Renal abnormalities ranging from elevated serum creatinine to renal failure and death were reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to < 20 mmol/L in association with an alkaline urine and hypokalaemia (serum potassium < 3 mmol/L) developed in 5 subjects with chronic myelogenous leukaemia (CML) treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate (< 20 mmol/L) or elevations of serum creatinine or BUN occur, the dose should be reduced or administration delayed (see section 4.2). Patients should be advised to report oliguria and anuria to the health care provider immediately. Although no clinically relevant differences in the frequency of adverse reactions were noted between subjects with normal renal function compared to those with renal impairment, patients with renal impairment should be closely monitored for toxicity since azacitidine and/or its metabolites are primarily excreted by the kidney (see section 4.2). Laboratory tests Liver function tests, serum creatinine and serum bicarbonate should be determined prior to initiation of therapy and prior to each treatment cycle. Complete blood counts should be performed prior to init

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HOS-287824 · has-warning-information · PDF-Seite 25

Haematological toxicity Treatment with Azacitidine Accord can be associated with neutropenia, thrombocytopenia and febrile neutropenia (see section 4.8 for frequencies). Interruption, reduction or discontinuation of Azacitidine Accord 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 Azacitidine Accord (see section 4.8). Patients should be administered prophylactic anti-emetic therapy for the first 2 cycles of Azacitidine Accord treatment (see section 4.2). Diarrhoea should be treated promptly at the onset of symptoms. Interruption, reduction or discontinuation of Azacitidine Accord 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 Azacitidine Accord 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'.