Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Celgene Europe B.V., Winthontlaan 6 N, 3526 KV Utrecht, Netherlands
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).
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.
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 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).
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 initiation of therapy and as needed to monitor response and toxicity, but at a minimum, prior to each treatment cycle, see also section 4.8.
Patients with a history of severe congestive heart failure, clinically unstable cardiac disease or pulmonary disease were excluded from the pivotal registration studies (AZA PH GL 2003 CL 001 and AZA-AML-001) and therefore the safety and efficacy of azacitidine in these patients has not been established. Recent data from a clinical trial in patients with a known history of cardiovascular or pulmonary disease showed a significantly increased incidence of cardiac events with azacitidine (see section 4.8). It is therefore advised to exercise caution when prescribing azacitidine to these patients. Cardiopulmonary assessment before and during the treatment should be considered.
Necrotising fasciitis, including fatal cases, have been reported in patients treated with Vidaza. Vidaza therapy should be discontinued in patients who develop necrotising fasciitis and appropriate treatment should be promptly initiated.
The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
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.
Women of childbearing potential and men have to use effective contraception during and up to 3 months after treatment.
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.
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.
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). Men should be advised not to father a child while receiving treatment and must use effective contraception during and up to 3 months after treatment. Before starting treatment, male patients should be advised to seek counselling on sperm storage.
Azacitidine has minor or moderate influence on the ability to drive and use machines. Fatigue has been reported with the use of azacitidine. Therefore, caution is recommended when driving or operating machines.
Adverse reactions considered to be possibly or probably related to the administration of Vidaza 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).
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).
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); 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 in any of the main clinical studies.
Table 1. ADRs reported in patients with MDS or AML treated with azacitidine (clinical studies and post-marketing):
Very common: pneumonia* (including bacterial, viral and fungal), nasopharyngitis
Common: sepsis* (including bacterial, viral and fungal), neutropenic sepsis*, respiratory tract infection (includes upper and bronchitis), urinary tract infection, cellulitis, diverticulitis, oral fungal infection, sinusitis, pharyngitis, rhinitis, herpes simplex, skin infection
Not Known: necrotising fasciitis*
Very common: febrile neutropenia*, neutropenia, leukopenia, thrombocytopenia, anaemia
Common: pancytopenia*, bone marrow failure
Uncommon: hypersensitivity reactions
Very common: anorexia, decreased appetite, hypokalemia
Common: dehydration
Rare: tumour lysis syndrome
Very common: insomnia
Common: confusional state, anxiety
Very common: dizziness, headache
Common: intracranial haemorrhage*, syncope, somnolence, lethargy
Common: eye haemorrhage, conjunctival haemorrhage
Common: pericardial effusion
Uncommon: pericarditis
Common: hypotension*, hypertension, orthostatic hypotension, haematoma
Very common: dyspnoea, epistaxis
Common: pleural effusion, dyspnoea exertional, pharyngolaryngeal pain
Rare: interstitial lung disease
Very common: diarrhoea, vomiting, constipation, nausea, abdominal pain (includes upper and abdominal discomfort)
Common: gastrointestinal haemorrhage* (includes mouth haemorrhage), haemorrhoidal haemorrhage, stomatitis, gingival bleeding, dyspepsia
Uncommon: hepatic failure*, progressive hepatic coma
Very common: petechiae, pruritus (includes generalized), rash, ecchymosis
Common: purpura, alopecia, urticaria, erythema, rash macular
Uncommon: acute febrile neutrophilic dermatosis, pyoderma gangrenosum
Very common: arthralgia, musculoskeletal pain (includes back, bone and pain in extremity)
Common: muscle spasms, myalgia
Common: renal failure*, haematuria, elevated serum creatinine
Uncommon: renal tubular acidosis
Very common: pyrexia*, fatigue, asthenia, chest pain, injection site erythema, injection site pain, injection site reaction (unspecified)
Common: bruising, haematoma, induration, rash, pruritus, inflammation, discoloration, nodule and haemorrhage (at injection site), malaise, chills, catheter site hemorrhage
Rare: injection site necrosis (at injection site)
Very common: weight decreased
* rarely fatal cases have been reported
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.
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 antiinfectives plus growth factor support (e.g. G-CSF) for neutropenia.
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 treatmentrelated thrombocytopenia.
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.
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 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 section 4.8 Infections.
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 abnormalities, ranging from elevated serum creatinine and haematuria to renal tubular acidosis, renal failure and death were reported in patients treated with azacitidine (see section 4.4).
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 section 4.4).
Data from a clinical trial allowing enrolment of patients with known history of cardiovascular or pulmonary disease showed a statistically significant increase in cardiac events in patients with newly diagnosed AML treated with azacitidine (see section 4.4).
There is limited safety information available with azacitidine in patients ≥85 years (with 14 [5.9%] patients ≥85 years in AZA-AML-001 study).
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.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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