4.1. Therapeutic indications

Azacitidine betapharm 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 % to 29 % marrow blasts without myeloproliferative disorder,

• acute myeloid leukaemia (AML) with 20 % to 30 % blasts and multi-lineage dysplasia, according to World Health Organization (WHO) classification,

• AML with > 30 % marrow blasts according to the WHO classification.

4.2. Posology and method of administration

Azacitidine betapharm treatment should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic agents. Patients should be premedicated with anti-emetics for nausea and vomiting.

Posology

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, injected subcutaneously, 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 for as long as the patient continues to benefit or until disease progression.

Patients should be monitored for haematologic response/toxicity and renal toxicities (see section 4.4); a delay in starting the next cycle or a dose reduction as described below may be necessary.

Azacitidine betapharm should not be used interchangeably with oral azacitidine. Due to differences in the exposure, the dose and schedule recommendations for oral azacitidine are different from those for injectable azacitidine. Healthcare professionals are recommended to verify the name of the medicinal product, dose and administration route.

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.

Dose adjustment due to haematological toxicity

Haematological toxicity is defined as the lowest count reached (nadir) in a given cycle 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 × [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 betapharm 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.

Cycle Nadir count

Dose in the next cycle, if recovery* is not achieved within 14 days (%)

ANC (× 109/L)

Platelets (× 109/L)

≤ 1.0

≤ 50.0

50 %

> 1.0

> 50.0

100 %

*Recovery = counts ≥ nadir count + (0.5 × [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 betapharm 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 betapharm 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:

Bone marrow cellularity

Dose in the next cycle if recovery is not achieved within 14 days(%)

Recovery* ≤ 21 days

Recovery* > 21 days

15-50 %

100 %

50 %

< 15 %

100 %

33 %

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

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

Special populations

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.

Patients with renal impairment

Azacitidine can be administered to patients with renal impairment without initial dose adjustment (see section 5.2). If unexplained reductions in serum bicarbonate levels to less than 20 mmol/L occur, the dose should be reduced by 50 % on the next cycle. If unexplained elevations in serum creatinine or blood urea nitrogen (BUN) to ≥ 2-fold above baseline values and above upper limit of normal (ULN) 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 cycle (see section 4.4).

Patients with hepatic impairment

No formal studies have been conducted in patients with hepatic impairment (see section 4.4). Patients with severe hepatic organ impairment should be carefully monitored for adverse events. No specific modification to the starting dose is recommended for patients with hepatic impairment prior to starting treatment; subsequent dose modifications should be based on haematology laboratory values. Azacitidine betapharm is contraindicated in patients with advanced malignant hepatic tumours (see sections 4.3 and 4.4).

Paediatric population

The safety and efficacy of Azacitidine betapharm in children aged 0 to 17 years have not yet been established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.

Method of administration

Azacitidine betapharm is for subcutaneous use. Reconstituted Azacitidine betapharm should be injected subcutaneously into the upper arm, thigh or abdomen. Injection sites should be rotated. New injections should be given at least 2.5 cm from the previous site and never into areas where the site is tender, bruised, red, or hardened.

After reconstitution, the suspension should not be filtered. For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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.

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 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.

Cardiac and pulmonary disease

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

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.

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.

4.5. Interaction with other medicinal products and other forms of interaction

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 performed.

4.6. Fertility, pregnancy and lactation

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 or adequete 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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

Adult population with MDS, CMML and AML (20 % to 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 to 4), gastrointestinal events (60.6 %) including nausea, vomiting (usually Grade 1 to 2) or injection site reactions (77.1 %; usually Grade 1 to 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 to 2), general disorders and administration site conditions including pyrexia (37.7 %; usually Grade 1 to 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); 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: Adverse reactions reported in patients with MDS or AML treated with azacitidine (clinical studies and post- marketing)

System organ class

Very common

Common

Uncommon

Rare

Not known

Infections and infestations

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

necrotising fasciitis *

Neoplasms benign, malignant and unspecified (including cysts and polyps)

differentiation syndrome*,a

Blood and lymphatic system disorders

febrile neutropenia*, neutropenia, leukopenia, thrombocytopenia, anaemia

pancytopenia*, bone marrow failure

Immune system disorders

hypersensitivity reactions

Metabolism and nutrition disorders

anorexia, decreased appetite, hypokalemia

dehydration

tumour lysis syndrome

Psychiatric disorders

insomnia

confusional state, anxiety

Nervous system disorders

dizziness, headache

intracranial haemorrhage*, syncope, somnolence, lethargy

Eye disorders

eye haemorrhage, conjunctival haemorrhage

Cardiac disorders

pericardial effusion

pericarditis

Vascular disorders

hypotension*, hypertension, orthostatic hypotension, haematoma

Respiratory, thoracic and mediastinal disorders

dyspnoea, epistaxis

pleural effusion, dyspnoea exertional, pharyngolaryngeal pain

interstitial lung disease

Gastrointestinal disorders

diarrhoea, vomiting, constipation, nausea, abdominal pain (includes upper and abdominal discomfort)

gastrointestinal haemorrhage* (includes mouth haemorrhage), haemorrhoidal haemorrhage, stomatitis, gingival bleeding, dyspepsia

Hepatobiliary disorders

hepatic failure*, progressive hepatic coma

Skin and subcutaneous tissue disorders

petechiae, pruritus (includes generalized), rash, ecchymosis

purpura, alopecia, urticaria, erythema, rash macular

acute febrile neutrophilic dermatosis, pyoderma gangrenosum

cutaneous vasculitis

Musculoskeletal and connective tissue disorders

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

muscle spasms, myalgia

Renal and urinary disorders

renal failure*, haematuria, elevated serum creatinine

renal tubular acidosis

General disorders and administration site conditions

pyrexia*, fatigue, asthenia, chest pain, injection site erythema, injection site pain, injection site reaction (unspecified)

bruising, haematoma, induration, rash, pruritus, inflammation, discoloration, nodule and haemorrhage (at injection site), malaise, chills, catheter site hemorrhage

injection site necrosis (at injection site)

Investigations

weight decreased

* = rarely fatal cases have been reported

a = see section 4.4

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 section 4.8 infections.

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 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 trial 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).

Elderly population

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

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 section 5.1).

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 AML in molecular relapse after first complete remission [CR1] (see section 5.1).

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 during the course of the clinical study. The overall safety profile was consistent with that of the adult population.

Reporting of suspected adverse reactions

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 Yellow Card Scheme website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

One case of overdose with azacitidine was reported during clinical studies. A patient experienced diarrhoea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m2, almost 4 times the recommended starting dose.

In the event of overdose, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for azacitidine overdose.