azacitidine: prescribing information – dosing, contraindications, interactions, side effects

Onureg is indicated as maintenance therapy in adult patients with acute myeloid leukaemia (AML) who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following induction therapy with or without consolidation treatment and who are not candidates for, including those who choose not to proceed to, hematopoietic stem cell transplantation (HSCT).

Onureg treatment should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic medicinal products.

Patients are to be treated with an anti-emetic 30 minutes prior to each dose of Onureg for the first 2 treatment cycles. Anti-emetic prophylaxis may be omitted after 2 cycles, if there has been no nausea and vomiting (see section 4.4).

Posology

The recommended dose is 300 mg azacitidine orally once daily. Each repeated cycle consists of a treatment period of 14 days followed by a treatment free period of 14 days (28-day treatment cycle).

Onureg treatment should be continued until no more than 15% blasts are observed in peripheral blood or bone marrow or until unacceptable toxicity (see dose schedule modification guidance for disease relapse).

Onureg should not be used interchangeably with injectable azacitidine due to differences in the exposure, dose and schedule of treatment. Healthcare professionals are recommended to verify the name of the medicinal product, dose and administration route.

Laboratory tests

Complete blood counts should be performed prior to initiation of therapy. Complete blood count monitoring is also recommended every other week for the first 2 cycles (56 days), every other week for the next 2 cycles after dose adjustment, and monthly thereafter, prior to the start of subsequent cycles of treatment (see section 4.4).

Dose schedule modification for AML disease relapse

In the case of disease relapse, with 5% to 15% blasts in peripheral blood or bone marrow, in conjunction with a clinical assessment, an extension of the dosing schedule from 14 to 21 days of repeated 28-day cycles should be considered. Dosing should not exceed 21 days during any 28-day period. Onureg should be discontinued if more than 15% blasts are observed in either the peripheral blood or bone marrow or at the physician’s discretion.

Dose adjustment for adverse reactions

Dose modification guidelines for haematologic and non-haematologic adverse reactions are recommended based on clinical and laboratory findings (see Table 1).

Table 1:
Dose adjustments for haematologic and non-haematologic adverse reactions
Criteria*
Recommended action
Grade 4 neutropenia or
Grade 3 neutropenia with fever
First occurrence
- Interrupt Onureg. Resume the treatment cycle at the same dose once neutrophils return to Grade 2 or lower.
- Use supportive care such as granulocyte colony stimulating factor (GCSF), as clinically indicated (see section 4.4).
Occurrence in 2 consecutive cycles
- Interrupt Onureg. Resume the treatment cycle at a reduced dose of 200 mg after neutrophils return to Grade 2 or lower.
- If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days.
- If the toxicity continues or re-occurs after dose and schedule reduction, discontinue Onureg.
- Use supportive care such as GCSF, as clinically indicated (see section 4.4).
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding
First occurrence
- Interrupt Onureg. Resume the treatment cycle at the same dose once platelets return to Grade 2 or lower.
Occurrence in 2 consecutive cycles
- Interrupt Onureg. Resume the treatment cycle at a reduced dose of 200 mg after platelets return to Grade 2 or lower.
- If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days.
- If the toxicity continues or re-occurs after dose and schedule reduction, discontinue Onureg.
Grade 3 or higher nausea, vomiting or diarrhoea

- Interrupt Onureg. Resume the treatment cycle at the same dose once toxicity has resolved to Grade 1 or lower.
- Use supportive care such as anti-emetic therapy and treat diarrhoea at the onset of symptoms (see section 4.4).
- If event re-occurs, interrupt dose until resolved to Grade 1 or lower and reduce the dose to 200 mg.
- If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days.
- If the toxicity continues or re-occurs after dose and schedule reduction, discontinue Onureg.
Other Grade 3 or higher non-haematological events
- Interrupt Onureg and provide medical support according to local recommendations. Resume the treatment cycle at the same dose once toxicity has resolved to Grade 1 or lower.
- If the toxicity re-occurs, interrupt Onureg until resolved to
Grade 1 or lower and reduce dose to 200 mg.
- If a patient continues to experience the toxicity after dose reduction, reduce the treatment duration by 7 days.
- If the toxicity continues or re-occurs after dose and schedule reduction, discontinue Onureg.
* Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening. Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.3 (NCI- CTCAE v4.3).

Missed or delayed doses
If a dose of Onureg is missed, or not taken at the usual time, the dose should be taken as soon as possible on the same day. Then, the next scheduled dose should be taken at the normal time the following day. Two doses should not be taken on the same day.

If a dose is vomited, another dose must not be taken on the same day. Instead return to the normal time of dose administration the following day.

Special populations

Elderly patients
No dose adjustments are recommended for patients over 65 years of age (see section 5.2).

Renal impairment
Onureg can be administered to patients with mild, moderate or severe renal impairment without initial dose adjustment (see section 5.2).

Hepatic impairment
No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin (BIL) ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN, or BIL 1 to 1.5 × ULN and any AST) (see section 5.2).

Patients with moderate (BIL > 1.5 to 3 × ULN) and severe hepatic impairment (BIL > 3 × ULN) should be monitored more frequently for adverse reactions and appropriate dose adjustment should be made (see Table 1).

Paediatric population
The safety and efficacy of Onureg in children and adolescents below 18 years have not been established. No data are available.

Method of administration

Onureg is for oral use.

Onureg can be taken with or without food. The tablets should be swallowed whole with a glass of water at about the same time each day. They should not be split, crushed, dissolved or chewed (see section 6.6).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

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%), leukopenia (10.6%), pain in extremity (10.6%) and pneumonia (10.2%)1.

Serious adverse reactions occurred in 16.1% of patients receiving Onureg. The most common serious adverse reactions are febrile neutropenia (6.8%) and pneumonia (5.1%)1.

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

Tabulated list of adverse reactions

Table 2 presents the frequency category of ADRs reported during clinical trials with Onureg and post- marketing use. A total of 236 patients received Onureg in the pivotal Phase 3 study. The median treatment duration was 11.6 months (range: 0.5 to 74.3 months) in the Onureg 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.

Table 2:
Adverse drug reactions (ADRs) in AML patients receiving Onureg maintenance therapy System organ class All gradesa frequency Infections and infestations Very common Pneumonia1, 6 Respiratory tract infection2

Common
Sepsis
Influenza
Urinary tract infection3
Bronchitis
Rhinitis

Uncommon
Neutropenic sepsis
Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
Not known
Differentiation syndrome
Blood and lymphatic system disorders Very common
Neutropenia
Thrombocytopenia6
Febrile neutropenia6
Leukopenia
Metabolism and nutrition disorders
Very common
Decreased appetite
Psychiatric disorders
Common
Anxiety

System organ class
All gradesa frequency
Gastrointestinal disorders
Very common
Nausea
Vomiting
Diarrhoea
Constipation
Abdominal pain4
Musculoskeletal and connective tissue disorders
Very common
Arthralgia
Back pain
Pain in extremity
General disorders and administration site conditions
Very common
Fatigue / asthenia5
Investigations
Common
Weight decreased a All AEs with at least 5.0% of patients in the Onureg 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 Onureg. 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 Onureg (see section 4.2).

Gastrointestinal toxicity
Gastrointestinal toxicities were the most frequent adverse reactions in patients treated with Onureg.
Nausea (64.8%), vomiting (59.7%), and diarrhoea (50.4%) were reported in patients treated with Onureg. 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 Onureg. 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 Onureg (see section 4.2).

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 national reporting system listed in Appendix V.

Haematological toxicity

Treatment with Onureg can be associated with neutropenia, thrombocytopenia and febrile neutropenia (see section 4.8 for frequencies). Interruption, reduction or discontinuation of Onureg may be necessary to manage haematological toxicities. Patients should be advised to promptly report febrile episodes. Patients with low platelet counts should be advised to report early signs or symptoms of bleeding. Supportive care such as antibiotics and/or antipyretics for management of infection/fever and GCSF for neutropenia should be provided based on individual patient characteristics, treatment response and according to the current clinical guidelines (see section 4.2 Table 1).

Complete blood counts should be performed prior to initiation of therapy. Complete blood count monitoring is also recommended every other week for the first 2 cycles (56 days), every other week for the next 2 cycles after dose adjustment, and monthly thereafter, prior to the start of subsequent cycles of treatment.

Patients with moderate (BIL > 1.5 to 3 × ULN) and severe hepatic impairment (BIL > 3 × ULN) should be monitored more frequently for adverse reactions and appropriate dose adjustment should be made (see section 4.2 Table 1).

Differentiation syndrome

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving oral 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 oral azacitidine should be considered until resolution of symptoms and if resumed, caution is advised.

Gastrointestinal toxicity

Gastrointestinal toxicities were the most frequent adverse reactions in patients treated with Onureg (see section 4.8). Patients should be administered prophylactic anti-emetic therapy for the first 2 cycles of Onureg treatment (see section 4.2). Diarrhoea should be treated promptly at the onset of symptoms.
Interruption, reduction or discontinuation of Onureg may be necessary to manage gastrointestinal toxicities (see section 4.2).

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 have to use effective contraception during and up to 3 months after treatment (see section 4.6).

Lactose intolerance

Onureg tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

No formal clinical drug-drug interaction studies with azacitidine have been conducted.

In case of concomitant administration with other antineoplastic agents, caution and monitoring is recommended as an antagonistic, additive, or synergistic pharmacodynamic effect cannot be excluded.
These effects may be dependent on the dose, sequence and schedule of administration.

Onureg exposure was minimally affected when co-administered with a proton pump inhibitor (omeprazole). Therefore, dose modification is not required when Onureg is co-administered with proton pump inhibitors or other pH modifiers.

An in vitro study of azacitidine with human liver fractions indicated that azacitidine was not metabolised by cytochrome P450 isoforms (CYPs). Therefore, interactions with CYP inducers or inhibitors are considered unlikely (see section 5.2).
Clinically relevant inhibitory or inductive effects of azacitidine on the metabolism of cytochrome P450 substrates are unlikely (see section 5.2). No clinically relevant drug-drug interactions are

expected when Onureg is co-administered with substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptides (OATP) OATP1B1 and OATP1B3, or organic cation transporter (OCT) OCT2.

Azacitidine is not a substrate of P-gp, therefore it is not expected to interact with P-gp inducers or inhibitors.

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 (see sections 4.4 and 5.3).

Pregnancy

There are no adequate data from the use of Onureg in pregnant women. Studies in mice and rats have shown reproductive and developmental toxicity (see section 5.3). The potential risk for humans is unknown. Based on results from animal studies and its mechanism of action, Onureg 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 Onureg, the patient should be informed of the potential risk to the foetus.

Breast-feeding

It is unknown whether azacitidine or its metabolites are excreted in human milk. Due to the potential serious adverse reactions in the breastfed child, breast-feeding is contraindicated during Onureg therapy (see section 4.3).

Fertility

There are no human data on the effect of azacitidine on fertility. In animals, adverse effects of azacitidine on male fertility have been documented (see section 5.3). 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 Onureg treatment.

Onureg has minor influence on the ability to drive and use machines. Fatigue has been reported with the use of Onureg. Therefore, caution is recommended when driving or operating machines.

In the event of overdose, the patient should be monitored with appropriate blood counts and supportive treatment should be provided, as necessary, according to local recommendations. There is no known specific antidote for an overdose with Onureg.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, pyrimidine analogues, ATC code:
L01BC07

Mechanism of action

Azacitidine is a DNA methyltransferase inhibitor and epigenetic modifier. Azacitidine is incorporated into DNA and RNA following cellular uptake and enzymatic biotransformation to nucleotide triphosphates. Incorporation of azacitidine into the DNA of AML cells, modified epigenetic pathways through the inhibition of DNA methyltransferases, and reduction of DNA methylation. This led to alteration of gene expression, including re-expression of genes regulating tumour suppression, immune pathways, cell cycle, and cell differentiation. Incorporation of azacitidine into the RNA of AML cells, inhibited RNA methyltransferase, reduced RNA methylation, decreased RNA stability, and decreased protein synthesis.

Clinical efficacy and safety

The efficacy and safety of Onureg was studied in a multi-centre, placebo-controlled, Phase 3 study QUAZAR AML-001 (CC-486-AML-001) with a double-blind, randomised, parallel-group design which evaluated Onureg versus placebo as maintenance therapy in AML patients. Patients were enrolled with de novo AML, AML secondary to prior diagnosis of myelodysplastic syndromes (MDS), or chronic myelomonocytic leukaemia (CMML); the patients were aged ≥ 55 years, and had achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) within 4 months (+/- 7 days) after intensive induction chemotherapy with or without consolidation therapy. Patients were not eligible for HSCT at the time of randomisation, which included patients who did not have a transplant donor, or who chose not to proceed to HSCT.

Patients in both treatment arms received best supportive care as deemed necessary by the investigator.
Best supportive care included, but was not limited to, treatment with red blood cell (RBC) transfusions, platelet transfusions, use of erythropoiesis stimulating agent, antibiotic, antiviral and/or antifungal therapy, GCSF, anti-emetic therapy, and nutritional support.

Patients who achieved a CR/CRi after completion of intensive induction therapy with or without consolidation were administered Onureg 300 mg (N = 236) or placebo (N = 233) once daily on Days 1 through 14 of each 28-day cycle. In the event of disease relapse (5% to 15% blasts in peripheral blood or bone marrow), the dose schedule was extended to 21 days of repeated 28-day treatment cycles per medical discretion. Treatment continued until disease progression (more than 15% blasts were observed in peripheral blood or bone marrow) or until unacceptable toxicity.

Absorption

Exposure was generally linear with dose-proportional increases in systemic exposure; high intersubject variability was observed. The geometric mean (coefficient of variation [%CV]) Cmax and AUC values after oral administration of a 300 mg single dose were 145.1 ng/mL (63.7) and 241.6 ng h/mL (64.5), respectively. Multiple dosing at the recommended dose regimen did not result in drug accumulation.
Absorption of azacitidine was rapid, with a median Tmax of 1 hour post dose. Mean oral bioavailability relative to subcutaneous (SC) administration was approximately 11%.

Time (months) from randomisation
Number at risk
Median RFS: 4.8
Median RFS: 10.2
Survival probability
Stratified HR:

Vidaza 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 10-29% marrow blasts without myeloproliferative disorder,
- acute myeloid leukaemia (AML) with 20-30% blasts and multi-lineage dysplasia, according to World Health Organisation (WHO) classification,
- AML with > 30% marrow blasts according to the WHO classification.

Vidaza 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.

Vidaza 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 x 109/L and/or absolute neutrophil count (ANC) ≤ 1 x 109/L.

Recovery is defined as an increase of cell line(s) where haematological toxicity was observed of at least half of the absolute 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 x 109/l and ANC ≥ 1.5 x 109/l, and platelets ≥ 75.0 x 109/l) prior to the first treatment If haematological toxicity is observed following Vidaza 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 (x 109/L)
Platelets (x 109/L)
≤ 1.0
≤ 50.0
50%
> 1.0
> 50.0
100%
*Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count])

Patients with reduced 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) prior to the first treatment Following Vidaza 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 Vidaza 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 x [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. Vidaza is contraindicated in patients with advanced malignant hepatic tumours (see sections 4.3 and 4.4).

Paediatric population
The safety and efficacy of Vidaza in children aged 0-17 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
Reconstituted Vidaza 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.

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).

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 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).

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 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

System Organ
Class
Very common
Common
Uncommon
Rare
Not Known
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, pharyngolarynge al 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

System Organ
Class
Very common
Common
Uncommon
Rare
Not Known
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 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).

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 Vidaza 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 Vidaza 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 Vidaza 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 national reporting system listed in Appendix V.

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 study 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 Vidaza. Vidaza 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), 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/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 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.

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.

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.

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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, pyrimidine analogues; ATC code: L01BC07

Mechanism of action
Azacitidine is believed to exert its antineoplastic effects by multiple mechanisms including cytotoxicity on abnormal haematopoietic cells in the bone marrow and hypomethylation of DNA. The cytotoxic effects of azacitidine may result from multiple mechanisms, including inhibition of DNA, RNA and protein synthesis, incorporation into RNA and DNA, and activation of DNA damage pathways. Non-proliferating cells are relatively insensitive to azacitidine. Incorporation of azacitidine into DNA results in the inactivation of DNA methyltransferases, leading to hypomethylation of DNA.
DNA hypomethylation of aberrantly methylated genes involved in normal cell cycle regulation, differentiation and death pathways may result in gene re-expression and restoration of cancer- suppressing functions to cancer cells. The relative importance of DNA hypomethylation versus cytotoxicity or other activities of azacitidine to clinical outcomes has not been established.

Clinical efficacy and safety

Adult population (MDS, CMML and AML [20-30% marrow blasts])
The efficacy and safety of Vidaza were studied in an international, multicentre, controlled, open-label, randomised, parallel-group, Phase 3 comparative study (AZA PH GL 2003 CL 001) in adult patients with: intermediate-2 and high-risk MDS according to the International Prognostic Scoring System (IPSS), refractory anaemia with excess blasts (RAEB), refractory anaemia with excess blasts in transformation (RAEB-T) and modified chronic myelomonocytic leukaemia (mCMML) according to the French American British (FAB) classification system. RAEB-T patients (21-30% blasts) are now considered to be AML patients under the current WHO classification system. Azacitidine plus best supportive care (BSC) (n = 179) was compared to conventional care regimens (CCR). CCR consisted of BSC alone (n = 105), low-dose cytarabine plus BSC (n = 49) or standard induction chemotherapy plus BSC (n = 25). Patients were pre-selected by their physician to 1 of the 3 CCR prior to randomisation. Patients received this pre-selected regimen if not randomised to Vidaza. As part of the inclusion criteria, patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients with secondary MDS were excluded from the study. The primary endpoint of the study was overall survival. Vidaza was administered at a subcutaneous dose of 75 mg/m2 daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle) for a median of 9 cycles (range = 1-39) and a mean of 10.2 cycles. Within the Intent to Treat population (ITT), the median age was 69 years (range 38 to 88 years).

Absorption
Following subcutaneous administration of a single 75 mg/m2 dose, azacitidine was rapidly absorbed with peak plasma concentrations of 750 ± 403 ng/mL occurring at 0.5 h after dosing (the first sampling point). The absolute bioavailability of azacitidine after subcutaneous relative to intravenous administration (single 75 mg/m2 doses) was approximately 89% based on the area under the curve (AUC).

Area under the curve and maximum plasma concentration (Cmax) of subcutaneous admiminstration of azacitidine were approximately proportional within the 25 to 100 mg/m2 dose range.

Distribution
Following intravenous administration, the mean volume of distribution was 76 ± 26 L, and systemic clearance was 147 ± 47 L/h.

Biotransformation
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).

Azacitidine undergoes spontaneous hydrolysis and deamination mediated by cytidine deaminase. In human liver S9 fractions, formation of metabolites was independent of NADPH implying that azacitidine metabolism was not mediated by cytochrome P450 isoenzymes. An in vitro study of azacitidine with cultured human hepatocytes indicates that at concentrations of 1.0 µM to 100 µM (i.e.
up to approximately 30-fold higher than clinically achievable concentrations), azacitidine does not induce CYP 1A2, 2C19, or 3A4 or 3A5. In studies to assess inhibition of a series of P450 isoenzymes (CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) azacitidine up to 100 μM did not produce inhibition. Therefore, CYP enzyme induction or inhibition by azacitidine at clinically achievable plasma concentrations is unlikely.

Elimination