Xpreza Adverse Reactions

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 for injection 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%]). 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 3 as follows 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); 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 as follows according to the highest frequency observed in any of the main clinical studies. (See Table 3.)

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Description of selected adverse reactions: Haematologic adverse reactions: The most commonly reported (≥ 10%) haematological adverse reactions associated with azacitidine treatment include anaemia, thrombocytopenia, neutropenia, febrile neutropenia and leukopenia, and were usually Grade 3 or 4. There is a greater risk of these events occurring during the first 2 cycles, after which they occur with less frequency in patients with restoration of haematological function. Most haematological adverse reactions were managed by routine monitoring of complete blood counts and delaying azacitidine administration in the next cycle, prophylactic antibiotics and/or growth factor support (e.g. G-CSF) for neutropenia and transfusions for anaemia or thrombocytopenia as required
Infections: Myelosuppression may lead to neutropenia and an increased risk of infection. Serious adverse reactions such as sepsis, including neutropenic sepsis, and pneumonia were reported in patients receiving azacitidine, some with a fatal outcome. Infections may be managed with the use of anti-infectives plus growth factor support (e.g. G-CSF) for neutropenia.
Bleeding: Bleeding may occur with patients receiving azacitidine. Serious adverse reactions such as gastrointestinal haemorrhage and intracranial haemorrhage have been reported. Patients should be monitored for signs and symptoms of bleeding, particularly those with pre-existing or treatment-related thrombocytopenia.
Hypersensitivity: Serious hypersensitivity reactions have been reported in patients receiving azacitidine. In case of an anaphylactic-like reaction, treatment with azacitidine should be immediately discontinued and appropriate symptomatic treatment initiated.
Skin and subcutaneous tissue adverse reactions: The majority of skin and subcutaneous adverse reactions were associated with the injection site. None of these adverse reactions led to discontinuation of azacitidine, or reduction of azacitidine dose in the pivotal studies. The majority of adverse reactions occurred during the first 2 cycles of treatment and tended to decrease with subsequent cycles. Subcutaneous adverse reactions such as injection site rash/inflammation/pruritus, rash, erythema and skin lesion may require management with concomitant medicinal products, such as antihistamines, corticosteroids and non-steroidal anti-inflammatory medicinal products (NSAIDs).
These cutaneous reactions have to be distinguished from soft tissue infections, sometimes occurring at injection site. Soft tissue infections, including cellulitis and necrotising fasciitis in rare cases leading to death, have been reported with azacitidine in the post marketing setting. For clinical management of infectious adverse reactions, see Infections as previously mentioned.
Gastrointestinal adverse reactions: The most commonly reported gastrointestinal adverse reactions associated with azacitidine treatment included constipation, diarrhoea, nausea and vomiting. These adverse reactions were managed symptomatically with anti-emetics for nausea and vomiting; anti-diarrhoeals for diarrhoea, and laxatives and/or stool softeners for constipation.
Renal adverse reactions: Renal abnormalities, ranging from elevated serum creatinine and haematuria to renal tubular acidosis, renal failure and death were reported in patients treated with azacitidine (see Precautions).
Hepatic adverse reactions: Patients with extensive tumour burden due to metastatic disease have been reported to experience hepatic failure, progressive hepatic coma and death during azacitidine treatment (see Precautions).
Cardiac events: Data from a clinical study allowing enrolment of patients with known history of cardiovascular or pulmonary disease showed an increase in cardiac events in patients with newly diagnosed AML treated with azacitidine (see Precautions).
Elderly population: There is limited safety information available with azacitidine in patients ≥ 85 years (with 14 [5.9%] patients ≥ 85 years treated in Study AZA-AML-001).
Paediatric population: In Study AZA-JMML-001, 28 paediatric patients (1 month to less than 18 years of age) were treated with azacitidine for MDS (n = 10) or juvenile myelomonocytic leukaemia (JMML) (n = 18) (see Pharmacology: Pharmacodynamics under Actions).
All 28 patients experienced at least 1 adverse event and 17 (60.7%) experienced at least 1 treatment related event. The most commonly reported adverse events in the overall paediatric population were pyrexia, haematologic events including anaemia, thrombocytopenia and febrile neutropenia, and gastrointestinal events including constipation and vomiting.
Three (3) subjects experienced a treatment emergent event leading to drug discontinuation (pyrexia, disease progression and abdominal pain).
In Study AZA-AML-004, 7 paediatric patients (aged 2 to 12 years) were treated with Azacitidine for injection for AML in molecular relapse after first complete remission [CR1] (see Pharmacology: Pharmacodynamics under Actions).
All 7 patients experienced at least 1 treatment-related adverse event. The most commonly reported adverse events were neutropenia, nausea, leukopenia, thrombocytopenia, diarrhoea and increased alanine aminotransferase (ALT). Two patients experienced a treatment-related event leading to dose interruption (febrile neutropenia, neutropenia).
No new safety signals were identified in the limited number of paediatric patients treated with Azacitidine for injection during the course of the clinical study. The overall safety profile was consistent with that of the adult population.