Azacitidine Other names: Azacytidine

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.

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.

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.

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. 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.

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.

Treatment with azacitidine is associated with anaemia, neutropenia and thrombocytopenia, particularly during the first 2 cycles. 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. Patients should be advised to promptly report febrile episodes. Patients and physicians are also advised to be observant for signs and symptoms of bleeding.

Dose adjustment due to haematological toxicity

Haematological toxicity is defined as the lowest count reached in a given cycle (nadir) if platelets ≤50.0 × 10⁹/l and/or absolute neutrophil count (ANC) ≤1 × 10⁹/l.

Recovery is defined as an increase of cell line(s) where haematological toxicity was observed of at least half of the difference of nadir and the baseline count plus the nadir count (i.e. blood count at recovery ≥ nadir count + (0.5 x [baseline count – nadir count]).

Patients without reduced baseline blood counts (i.e. White Blood Cells (WBC) ≥3.0 × 10⁹/l and ANC ≥1.5 × 10⁹/l, and platelets ≥75.0 × 10⁹/l) prior to the first treatment

If haematological toxicity is observed following azacitidine treatment, the next cycle of the therapy should be delayed until the platelet count and the ANC have recovered. If recovery is achieved within 14 days, no dose adjustment is necessary. However, if recovery has not been achieved within 14 days, the dose should be reduced according to the following table. Following dose modifications, the cycle duration should return to 28 days.

* Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count])

Patients with reduced baseline blood counts (i.e. WBC <3.0 × 10⁹/l or ANC <1.5 × 10⁹/l or platelets <75.0 × 10⁹/l) prior to the first treatment

Following azacitidine treatment, if the decrease in WBC or ANC or platelets from that prior to treatment is ≤50%, or greater than 50% but with an improvement in any cell line differentiation, the next cycle should not be delayed and no dose adjustment made.

If the decrease in WBC or ANC or platelets is greater than 50% from that prior to treatment, with no improvement in cell line differentiation, the next cycle of azacitidine therapy should be delayed until the platelet count and the ANC have recovered. If recovery is achieved within 14 days, no dose adjustment is necessary. However, if recovery has not been achieved within 14 days, bone marrow cellularity should be determined. If the bone marrow cellularity is >50%, no dose adjustments should be made. If bone marrow cellularity is ≤50%, treatment should be delayed and the dose reduced according to the following table:

* Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count])

Following dose modifications, the cycle duration should return to 28 days.

Necrotising fasciitis, including fatal cases, have been reported in patients treated with azacitidine. Azacitidine therapy should be discontinued in patients who develop necrotising fasciitis and appropriate treatment should be promptly initiated.

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. It is therefore advised to exercise caution when prescribing azacitidine to these patients. Cardiopulmonary assessment before and during the treatment should be considered.

There are no adequate data from the use of azacitidine in pregnant women. Studies in mice and rats have shown reproductive and developmental toxicity.

The potential risk for humans is unknown. Based on results from animal studies and its mechanism of action, azacitidine 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, the patient should be informed of the potential risk to the foetus.

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.

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.

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. 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. 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 treatment.

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.

Subcutaneous administration

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%])).

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).

List of adverse reactions

The list 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 list below according to the highest frequency observed in any of the main clinical studies.

ADRs reported in patients with MDS or AML treated with azacitidine (clinical studies and post-marketing):

Infections and infestations

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*

Blood and lymphatic system disorders

Very common: febrile neutropenia*, neutropenia, leukopenia, thrombocytopenia, anaemia

Common: pancytopenia*, bone marrow failure

Immune system disorders

Uncommon: hypersensitivity reactions

Metabolism and nutrition disorders

Very common: anorexia, decreased appetite, hypokalemia

Common: dehydration

Rare: tumour lysis syndrome

Psychiatric disorders

Very common: insomnia

Common: confusional state, anxiety

Nervous system disorders

Very common: dizziness, headache

Common: intracranial haemorrhage*, syncope, somnolence, lethargy

Eye disorders

Common: eye haemorrhage, conjunctival haemorrhage

Cardiac disorders

Common: pericardial effusion

Uncommon: pericarditis

Vascular disorders

Common: hypotension*, hypertension, orthostatic hypotension, haematoma

Respiratory, thoracic and mediastinal disorders

Very common: dyspnoea, epistaxis

Common: pleural effusion, dyspnoea exertional, pharyngolaryngeal pain

Rare: interstitial lung disease

Gastrointestinal disorders

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

Hepatobiliary disorders

Uncommon: hepatic failure*, progressive hepatic coma

Skin and subcutaneous tissue disorders

Very common: petechiae, pruritus (includes generalized), rash, ecchymosis

Common: purpura, alopecia, urticaria, erythema, rash macular

Uncommon: acute febrile neutrophilic dermatosis, pyoderma gangrenosum

Musculoskeletal and connective tissue disorders

Very common: arthralgia, musculoskeletal pain (includes back, bone and pain in extremity)

Common: muscle spasms, myalgia

Renal and urinary disorders

Common: renal failure*, haematuria, elevated serum creatinine

Uncommon: renal tubular acidosis

General disorders and administration site conditions

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)

Investigations

Very common: weight decreased

^* rarely fatal cases have been reported

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 antiinfectives 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 treatmentrelated 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 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.

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.

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.

Cardiac events

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.

Elderly population

There is limited safety information available with azacitidine in patients ≥85 years (with 14 [5.9%] patients ≥85 years in AZA-AML-001 study).

Oral administration

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. The most common serious adverse reactions are febrile neutropenia (6.8%) and pneumonia (5.1%)¹.

Permanent discontinuation of azacitidine 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. 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. Adverse reactions requiring dose reduction included neutropenia (5.5%), diarrhoea (3.4%), thrombocytopenia (1.7%), and nausea (1.7%).

Tabulated list of adverse reactions

The following table presents the frequency category of ADRs reported in the pivotal Phase 3 study with azacitidine. A total of 236 patients received azacitidine. The median treatment duration was 11.6 months (range: 0.5 to 74.3 months) for azacitidine 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.

Adverse drug reactions (ADRs) in AML patients receiving azacitidine maintenance therapy:

^a All AEs with at least 5.0% of patients in the azacitidine 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 azacitidine. 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 azacitidine. See section 4.2 for monitoring and management guidance.

Gastrointestinal toxicity

Gastrointestinal toxicities were the most frequent adverse reactions in patients treated with azacitidine. Nausea (64.8%), vomiting (59.7%), and diarrhoea (50.4%) were reported in patients treated with azacitidine. 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 azacitidine. 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 azacitidine. See section 4.2 for monitoring and management guidance.