Azaturas 25 mg/mL Injection

AZATURAS 25 mg/mL is indicated for treatment of patients with myelodysplastic syndromes (MDS) including the following subtypes of the French-American-British classification:

• Refractory anaemia (RA) plus neutropenia or thrombocytopenia or requiring transfusions.
• Refractory anaemia with ringed sideroblasts (RARS) according to the FAB system, plus neutropenia or thrombocytopenia or requiring transfusions.
• Refractory anaemia with excess blasts (RAEB) according to the FAB system.
• Refractory anaemia with excess blasts in transformation (RAEB-T) according to the FAB system (or acute myeloid leukaemia with 20 u2013 30 % bone marrow blasts and multilineage dysplasia according to World Health Organisation (WHO) classification).
• AZATURAS 25 mg/mL is also indicated for treating adult patients with chronic myelomonocytic leukaemia (CMML) according to the FAB system.

Posology

AZATURAS 25 mg/mL treatment should be initiated and monitored under the supervision of a medical practitioner experienced in the use of chemotherapeutic medicine. Patients should be premedicated with anti-emetics for nausea and vomiting.

The recommended starting dose for the first treatment cycle, for all patients regardless of baseline haematology laboratory values, is 75 mg/m2 of body surface area, daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle). It is recommended that patients be treated for a minimum of 6 cycles. Treatment should be continued as long as the patient continues to benefit or until disease progression.

Patients should be monitored for haematological response/toxicity and renal toxicities (see section 4.8); a delay in starting the next cycle or a dose reduction as described below may be necessary.

Laboratory tests

Liver chemistries and serum creatinine should be obtained prior to initiation of therapy. 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 dosing cycle (see section 4.4).

Dosage adjustments due to haematological toxicity

Patients with baseline blood counts (i.e. white blood cells (WBC) > 3,0 x 109/L and absolute neutrophil count (ANC) > 1,5 x 109/L, and platelets > 75,0 x 109/L). If haematological toxicity is observed following AZATURAS 25 mg/mL treatment, the next cycle of AZATURAS 25 mg/mL 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.

Nadir counts % Dose in the next cycle, if recovery* is not achieved within 14 days ANC (x 109/L) Platelets (x 109/L) u2264 1,0 u2264 50,0 50 % > 1,0 > 50,0 100 % * Recovery = counts u2265 Nadir count + (0,5 x [baseline count u2013 Nadir count]).

Patients baseline blood counts (i.e. WBC < 3,0 x 109/L or ANC < 1,5 x 109/L or platelets < 75,0 x 109/L Following AZATURAS 25 mg/mL treatment, if the decrease in WBC or ANC or platelets from baseline is less than 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 be 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 AZATURAS 25 mg/mL 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 u2264 50 %, treatment should be delayed and the dose reduced according to the following table:

Bone marrow cellularity % Dose in the next cycle, if recovery is not achieved within 14 days Recovery* u2264 21 days Recovery > 21 days 15 u2013 50 % 100 % 50 % < 15 % 100 % 33 % * Recovery = counts u2265 Nadir count + (0,5 x [baseline count u2013 Nadir count]) Following dose modifications, the cycle duration should return to 28 days.

Special populations

Patients with renal impairment AZATURAS 25 mg/mL can be administered to patients with renal impairment without initial dose adjustments. If unexplained elevations of serum creatinine or blood urea occur, the next cycle should be delayed until values return to normal or baseline, and the dose should be reduced by 50 % on the next treatment course. Similarly, if unexplained reductions in serum bicarbonate levels to less than 20 mmol/L occur, the dosage should be reduced by 50 % on the next course.

Patients with hepatic impairment No studies have been conducted in patients with hepatic impairment. AZATURAS 25 mg/mL is contraindicated in patients with malignant hepatic tumours (see sections 4.3 and 4.4).

Elderly patients No specific dose adjustments are recommended for the elderly. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.

Paediatric population The safety and efficacy of AZATURAS 25 mg/mL in children and adolescents under 18 years of age has not been established.

Method of administration

Reconstituted AZATURAS 25 mg/mL should be injected subcutaneously. Rotate sites for injection (thigh, abdomen, or upper arm). New injections should be given at least 2,5 cm from an old site and never into areas where the site is tender, bruised, red or hard. For instructions on reconstitution of the medicine before administration, see section 6.6.

AZATURAS 25 mg/mL is contraindicated in the following:

• Patients with known hypersensitivity to azacitidine or to any of the excipients listed in section 6.1.
• Patients with malignant hepatic tumours (see section 4.4).
• Pregnancy and breastfeeding (see section 4.6).
• Patients must not receive live vaccines while being treated with AZATURAS 25 mg/mL.
• AZATURAS 25 mg/mL is not recommended for use in children and adolescents below the age of 18.

Haematological toxicity Treatment with AZATURAS 25 mg/mL 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 delayed based on nadir counts and haematological response (see section 4.2). Patients should be advised to promptly report febrile episodes. Patients and medical practitioners are also advised to be observant for signs and symptoms of bleeding (see section 4.2, u201cLaboratory testsu201d).

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 AZATURAS 25 mg/mL treatment, especially in such patients with baseline serum albumin < 30 g/L (see section 4.2, u201cSpecial populationsu201d). AZATURAS 25 mg/mL is contraindicated in patients with 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 AZATURAS 25 mg/mL in combination with other chemotherapeutic medicines. 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 subjects with chronic myelogenous leukaemia (CML) treated with azacitidine and etoposide (see section 4.2, u201cSpecial populationsu201d). If unexplained reductions in serum bicarbonate (< 20 mmol/L) or elevations of serum creatinine or BUN occur, the dosage should be reduced or administration delayed. Patients should be advised to report oliguria and anuria to the healthcare professional immediately. Patients with renal impairment should be closely monitored for toxicity, since AZATURAS 25 mg/mL and/or its metabolites are primarily excreted by the kidneys (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 initiation of therapy and as needed to monitor response and toxicity, but at a minimum, prior to each treatment cycle; see also sections 4.8 and 4.2.

Cardiac and pulmonary disease Patients with a history of severe congestive heart failure, clinically unstable cardiac disease or pulmonary disease were excluded from the clinical studies and therefore the safety and efficacy of azacitidine in these patients have not been established. 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 Necrotising fasciitis, including fatal cases, have been reported in patients treated with azacitidine. AZATURAS 25 mg/mL therapy should be discontinued in patients who develop necrotising fasciitis and appropriate treatment should be promptly initiated.

Tumour lysis syndrome 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.

Differentiation syndrome Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving injectable azacitidine. Differentiation syndrome may be fatal and symptoms and clinical findings include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary oedema, peripheral oedema, rapid weight gain, pleural effusions, pericardial effusions, hypotension and renal dysfunction (see section 4.8). Treatment with high-dose IV corticosteroids and haemodynamic monitoring should be considered at first onset of symptoms or signs suggestive of differentiation syndrome. Temporary discontinuation of injectable azacitidine should be considered until resolution of symptoms and if resumed, caution is advised.

Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450 isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulphotransferases (SULTs) and glutathione transferases (GSTs); interactions related to these metabolising 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 medicine interaction studies with azacitidine have been conducted.

Women of childbearing potential / contraception in males and females Women of childbearing potential should be advised to avoid pregnancy during treatment with AZATURAS 25 mg/mL and should use effective contraception during and up to 3 months after treatment.

Pregnancy AZATURAS 25 mg/mL is contraindicated in pregnancy (see section 4.3). AZATURAS 25 mg/mL may cause foetal harm when administered to a pregnant woman. Azacitidine was teratogenic in animals. If AZATURAS 25 mg/mL is used during pregnancy or if a patient becomes pregnant while receiving AZATURAS 25 mg/mL, the patient should be apprised of the potential hazard to the foetus. Female partners of male patients receiving AZATURAS 25 mg/mL should not become pregnant.

Breastfeeding Due to the potential serious adverse reactions in the nursing child, breastfeeding is contraindicated during azacitidine therapy.

Fertility 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.

AZATURAS 25 mg/mL has minor or moderate influence on the ability to drive and use machines. Fatigue has been reported with the use of AZATURAS 25 mg/mL. Therefore, caution is recommended when driving or operating machines.

a. Summary of the safety profile The most frequently reported adverse reactions were gastrointestinal (nausea, vomiting and diarrhoea), haematological (anaemia, thrombocytopenia, leukopenia/neutropenia), and injection site reactions (erythema and pain). In general, these events reflect the underlying nature of the disease and that AZATURAS 25 mg/mL is cytotoxic.

b. Tabulated summary of adverse reactions Post-marketing adverse reactions not seen in clinical trials are also included.

SYSTEM ORGAN CLASS FRQUENCY ADVERSE REACTIONS Infections and infestations Frequent: pneumonia* (including bacterial, viral and fungal), nasopharyngitis, 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 Frequency unknown: necrotising fasciitis Neoplasms benign, malignant and unspecified (including cysts and polyps) Frequency unknown: differentiation syndrome (see section 4.4) Blood and lymphatic system disorders Frequent: febrile neutropenia*, neutropenia, leukopenia, thrombocytopenia, anaemia, pancytopenia*, bone marrow failure, lymphadenopathy Less frequent: agranulocytosis Immune system disorders Less frequent: hypersensitivity reactions Metabolism and nutrition disorders Frequent: anorexia, decreased appetite, hypokalaemia, dehydration Less frequent: tumour lysis syndrome Psychiatric disorders Frequent: insomnia, confusional state, anxiety Nervous system disorders Frequent: dizziness, headache, intracranial haemorrhage*, syncope, somnolence, lethargy, burning sensation, hypaesthesia Eye disorders Frequent: eye haemorrhage, conjunctival haemorrhage Cardiac disorders Frequent: pericardial effusion Less frequent: pericarditis Vascular disorders Frequent: hypotension*, hypertension, orthostatic hypotension, haematoma, flushing, petechiae Respiratory, thoracic and mediastinal disorders Frequent: dyspnoea*, epistaxis, pleural effusion, exertional dyspnoea, pharyngolaryngeal pain, pharyngitis, haemoptysis, nasal congestion Less frequent: interstitial lung disease Gastrointestinal disorders Frequent: diarrhoea, vomiting, constipation, nausea, abdominal pain (includes upper and abdominal discomfort), gastrointestinal haemorrhage* (includes mouth haemorrhage), haemorrhoidal haemorrhage, stomatitis, gingival bleeding, dyspepsia, loose stools, oral mucosal petechiae, tongue ulceration Less frequent: perirectal abscess Hepatobiliary disorders Less frequent: hepatic failure*, progressive hepatic coma Skin and subcutaneous tissue disorders Frequent: petechiae, pruritus (includes generalised), rash, ecchymosis, purpura, alopecia, urticaria, erythema, macular rash, increased sweating rash Less frequent: acute febrile neutrophilic dermatosis, pyoderma gangrenosum Musculoskeletal and connective tissue disorders Frequent: arthralgia, musculoskeletal pain (includes back, bone and pain in extremity), muscle spasms, myalgia Renal and urinary disorders Frequent: renal failure*, haematuria, elevated serum creatinine, dysuria Less frequent: renal tubular acidosis General disorders and administration site conditions Frequent: pyrexia*, fatigue, asthenia, chest pain, injection site erythema, injection site pain, injection site reaction (unspecified), bruising, haematoma, induration, rash, pruritus, inflammation, discolouration, nodule and haemorrhage (at injection site), malaise, chills, catheter site haemorrhage, rigors Less frequent: injection site necrosis Investigations Frequent: decreased body mass, increased blood creatinine Injury, poisoning and procedural complications Frequent: post-procedural haemorrhage * = rarely fatal cases have been reported.

c. Description of selected adverse reactions Haematological adverse reactions The most frequently reported 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 lower 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 medicines, such as antihistamines, corticosteroids and nonsteroidal anti-inflammatory medicines (NSAIDs). These cutaneous reactions have to be distinguished from soft tissue infections, sometimes occurring at the 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, u201cInfections and infestationsu201d.

Gastrointestinal adverse reactions The most frequently reported gastrointestinal adverse reactions associated with azacitidine treatment included constipation, diarrhoea, nausea and vomiting. These adverse reactions were managed symptomatically with anti-emetics, antidiarrhoeals, and laxatives and/or stool softeners.

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 section 4.4).

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 section 4.4).

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 section 4.4).

e. Other special populations Elderly patients There is limited safety information available with azacitidine in patients u2265 85 years.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of AZATURAS 25 mg/mL is important. It allows continued monitoring of the benefit/risk balance of AZATURAS 25 mg/mL. Health care providers are requested to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform(who-umc-org) found on SAHPRA website.

In the event of overdosage, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for AZATURAS 25 mg/mL overdosage.