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

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.

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.

 

Dosage Adjustment due to haematological toxicity

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

Nadir Counts		% Dose in the next cycle, if 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 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. No data

are available.

 

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).

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 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.

 

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 and men have to use effective contraception during and up to

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). Men should be advised not to

father a child while receiving treatment and must use effective contraception during and up to

3 months after treatment. Before starting treatment, male patients should be advised to seek

counselling on sperm storage.

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

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: ADRs reported in patients with MDS or AML treated with azacitidine (clinical

studies and post- marketing)

 

 

 

 

    * = rarely fatal cases have been reported

 

Description of selected adverse reactions

Haematologic adverse reactions

The most commonly reported (≥ 10%) haematological adverse reactions associated with azacitidine

treatment include anaemia, thrombocytopenia, neutropenia, febrile neutropenia and leukopenia, and

were usually Grade 3 or 4. There is a greater risk of these events occurring during the first 2 cycles,

after which they occur with less frequency in patients with restoration of haematological function.

Most haematological adverse reactions were managed by routine monitoring of complete blood counts

and delaying azacitidine administration in the next cycle, prophylactic antibiotics and/or growth factor

support (e.g. G-CSF) for neutropenia and transfusions for anaemia or thrombocytopenia as required.

 

Infections

Myelosuppression may lead to neutropenia and an increased risk of infection. Serious adverse

reactions such as sepsis, including neutropenic sepsis, and pneumonia were reported in patients

receiving azacitidine, some with a fatal outcome. Infections may be managed with the use of antiinfectives plus growth factor support (e.g. G-CSF) for neutropenia.

 

Bleeding

Bleeding may occur with patients receiving azacitidine. Serious adverse reactions such as

gastrointestinal haemorrhage and intracranial haemorrhage have been reported. Patients should be

monitored for signs and symptoms of bleeding, particularly those with pre-existing or treatmentrelated

thrombocytopenia.

 

Hypersensitivity

Serious hypersensitivity reactions have been reported in patients receiving azacitidine. In case of an

anaphylactic-like reaction, treatment with azacitidine should be immediately discontinued and

appropriate symptomatic treatment initiated.

 

Skin and subcutaneous tissue adverse reactions

The majority of skin and subcutaneous adverse reactions were associated with the injection site. None

of these adverse reactions led to discontinuation of azacitidine, or reduction of azacitidine dose in the

pivotal studies. The majority of adverse reactions occurred during the first 2 cycles and tended to

decrease with subsequent cycles. Subcutaneous adverse reactions such as injection site

rash/inflammation/pruritus, rash, erythema and skin lesion may require management with concomitant

medicinal products, such as antihistamines, corticosteroids and non-steroidal anti-inflammatory

medicinal products (NSAIDs). These cutaneous reactions have to be distinguished from soft tissue

infections, sometimes occurring at injection site. Soft tissue infections, including cellulitis and

necrotising fasciitis in rare cases leading to death, have been reported with azacitidine in the post

marketing setting. 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 a statistically significant 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 in AZA-AML-001 study).

 

To report any side effect(s):

 

- The National Pharmacovigilance and Drug Safety Centre (NPC): ·         Fax: +966-11-205-7662 ·         Toll free phone: 19999 ·         E-mail: npc.drug@sfda.gov.sa ·         Website: www.sfda.gov.sa

 

 

 

 

 

One case of overdose with Azacitidine was reported during clinical trials. A patient experienced

diarrhea, nausea, and vomiting after receiving a single intravenous dose of approximately 290

mg/m2, almost 4 times the recommended starting dose. The event resolved without sequelae, and

the correct dose was resumed the following day.

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.

 

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

Mechanism of action

Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is believed to exert its 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 cancersuppressing

functions to cancer cells. The relative importance of DNA hypomethylation versus

cytotoxicity or other activities of azacitidine to clinical outcomes has not been established 5.2

 

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, multicenter, 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).

In the ITT analysis of 358 patients (179 azacitidine and 179 CCR), Vidaza treatment was associated

with a median survival of 24.46 months versus 15.02 months for those receiving CCR treatment, a

difference of 9.4 months, with a stratified log-rank p-value of 0.0001. The hazard ratio for the

treatment effect was 0.58 (95 % CI: 0.43, 0.77). The two-year survival rates were 50.8 % in patients

receiving azacitidine versus 26.2 % in patients receiving CCR (p < 0.0001).

 

KEY: AZA = azacitidine; CCR = conventional care regimens; CI = confidence interval;

HR = hazard ratio

The survival benefits of Vidaza were consistent regardless of the CCR treatment option (BSC alone,

low-dose cytarabine plus BSC or standard induction chemotherapy plus BSC) utilised in the

control arm.

When IPSS cytogenetic subgroups were analysed, similar findings in terms of median overall survival

were observed in all groups (good, intermediate, poor cytogenetics, including monosomy 7).

On analyses of age subgroups, an increase in median overall survival was observed for all groups

(< 65 years, ≥ 65 years and ≥ 75 years).

Vidaza treatment was associated with a median time to death or transformation to AML of

13.0 months versus 7.6 months for those receiving CCR treatment, an improvement of 5.4 months

with a stratified log-rank p-value of 0.0025.

Vidaza treatment was also associated with a reduction in cytopenias, and their related symptoms.

Vidaza treatment led to a reduced need for red blood cell (RBC) and platelet transfusions. Of the

patients in the azacitidine group who were RBC transfusion dependent at baseline, 45.0 % of these

patients became RBC transfusion independent during the treatment period, compared with 11.4 % of

the patients in the combined CCR groups (a statistically significant (p < 0.0001) difference of 33.6 %

(95 % CI: 22.4, 44.6). In patients who were RBC transfusion dependent at baseline and became

independent, the median duration of RBC transfusion independence was 13 months in the

azacitidine group.

 

Response was assessed by the investigator or by the Independent Review Committee (IRC). Overall

response (complete remission [CR] + partial remission [PR]) as determined by the investigator was

29 % in the azacitidine group and 12% in the combined CCR group (p = 0.0001). Overall response

(CR + PR) as determined by the IRC in AZA PH GL 2003 CL 001 was 7 % (12/179) in the azacitidine

group compared with 1 % (2/179) in the combined CCR group (p = 0.0113). The differences between

the IRC and investigator assessments of response were a consequence of the International Working

Group (IWG) criteria requiring improvement in peripheral blood counts and maintenance of these

improvements for a minimum of 56 days. A survival benefit was also demonstrated in patients that

had not achieved a complete/partial response following azacitidine treatment. Haematological

improvement (major or minor) as determined by the IRC was achieved in 49 % of patients receiving

azacitidine compared with 29 % of patients treated with combined CCR (p < 0.0001).

In patients with one or more cytogenetic abnormalities at baseline, the percentage of patients with a

major cytogenetic response was similar in the azacitidine and combined CCR groups. Minor

cytogenetic response was statistically significantly (p = 0.0015) higher in the azacitidine group (34 %)

compared with the combined CCR group (10 %).

 

Adult population aged 65 years or older with AML with > 30% marrow blasts

The results presented below represent the intent-to-treat population studied in AZA-AML-001 (see

section 4.1 for the approved indication).

 

The efficacy and safety of Vidaza was studied in an international, multicentre, controlled, open-label,

parallel group Phase 3 study in patients 65 years and older with newly diagnosed de novo or secondary

AML with >30% bone marrow blasts according to the WHO classification, who were not eligible for

HSCT. Vidaza plus BSC (n=241) was compared to CCR. CCR consisted of BSC alone (n=45), lowdose

cytarabine plus BSC (n=158), or standard intensive chemotherapy with cytarabine and

anthracycline plus BSC (n=44). Patients were pre-selected by their physician to 1 of the 3 CCRs prior

to randomization. Patients received the pre-selected regimen if not randomised to Vidaza. As part of

the inclusion criteria, patients were required to have an ECOG performance status of 0-2 and

intermediate- or poor-risk cytogenetic abnormalities. The primary endpoint of the study was

overall survival.

 

Vidaza was administered at a SC dose of 75mg/m2/day for 7 days, followed by a rest period of 21 days

(28 day treatment cycle), for a median of 6 cycles (range: 1 to 28), BSC- only patients for a median of

3 cycles (range: 1 to 20), low-dose cytarabine patients for a median of 4 cycles (range 1 to 25) and

standard intensive chemotherapy patients for a median of 2 cycles (range: 1 to 3, induction cycle plus

1 or 2 consolidation cycles).

 

The individual baseline parameters were comparable between the Vidaza and CCR groups. The

median age of the subjects was 75.0 years (range: 64 to 91 years), 75.2% were Caucasian and 59.0%

were male. At baseline 60.7% were classified as AML not otherwise specified, 32.4% AML with

myelodysplasia-related changes, 4.1% therapy-related myeloid neoplasms and 2.9% AML with

recurrent genetic abnormalities according to the WHO classification.

 

In the ITT analysis of 488 patients (241 Vidaza and 247 CCR), Vidaza treatment was associated with a

median survival of 10.4 months versus 6.5 months for those receiving CCR treatment, a difference of

3.8 months, with a stratified log-rank p-value of 0.1009 (two- sided). The hazard ratio for the

treatment effect was 0.85 (95% CI= 0.69, 1.03). The one-year survival rates were 46.5% in patients

receiving Vidaza versus 34.3% in patients receiving CCR.

 

 

The Cox PH model adjusted for pre-specified baseline prognostic factors defined a HR for Vidaza

versus CCR of 0.80 (95% CI= 0.66, 0.99; p = 0.0355).

 

In addition, although the study was not powered to demonstrate a statistically significant difference

when comparing azacitidine to the preselection CCR treatment groups, the survival of Vidaza treated

patients was longer when compared to CCR treatment options BSC alone, low-dose cytarabine plus

BSC and were similar when compared to standard intensive chemotherapy plus BSC.

 

In all pre- specified subgroups age [(< 75 years & ≥ 75 years), gender, race, ECOG performance status

(0 or 1 & 2) , baseline cytogenetic risk (intermediate & poor) , geographic region, WHO classification

of AML (including AML with myelodysplasia-related changes), baseline WBC count (≤ 5 x109/L &

>5 x 109/L), baseline bone marrow blasts (≤ 50% & > 50%) and prior history of MDS] there was a

trend in OS benefit in favour of Vidaza. In a few pre-specified subgroups, the OS HR reached

statistical significance including patients with poor cytogenetic risk, patients with AML with

myelodysplasia-related changes, patients < 75 years, female patients and white patients.

 

Haematologic and cytogenetic responses were assessed by the investigator and by the IRC with similar

results. Overall response rate (complete remission [CR] + complete remission with incomplete blood

count recovery [CRi]) as determined by the IRC was 27.8% in the Vidaza group and 25.1% in the

combined CCR group (p = 0.5384). In patients who achieved CR or CRi, the median duration of

remission was 10.4 months (95% CI = 7.2, 15.2) for the Vidaza subjects and 12.3 months (95%

CI = 9.0, 17.0) for the CCR subjects. A survival benefit was also demonstrated in patients that had not

achieved a complete response for Vidaza compared to CCR.

 

Vidaza treatment improved peripheral blood counts and led to a reduced need for RBC and platelet

transfusions. A patient was considered RBC or platelet transfusion dependent at baseline if the subject

had one or more RBC or platelet transfusions during the 56 days (8 weeks) on or prior to

randomization, respectively. A patient was considered RBC or platelet transfusion independent during

the treatment period if the subject had no RBC or platelet transfusions during any consecutive 56 days

during the reporting period, respectively.

 

Of the patients in the Vidaza group who were RBC transfusion dependent at baseline, 38.5%

(95% CI = 31.1, 46.2) of these patients became RBC transfusion independent during the treatment

period, compared with 27.6% of (95% CI = 20.9, 35.1) patients in the combined CCR groups. In

patients who were RBC transfusion dependent at baseline and achieved transfusion independence on

treatment, the median duration of RBC transfusion independence was 13.9 months in the Vidaza group

and was not reached in the CCR group.

 

Of the patients in the Vidaza group who were platelet transfusion dependent at baseline, 40.6%

(95% CI = 30.9, 50.8) of these patients became platelet transfusion independent during the treatment

period, compared with 29.3% of (95% CI = 19.7, 40.4) patients in the combined CCR groups. In

patients who were platelet transfusion dependent at baseline and achieved transfusion independence on

treatment, the median duration of platelet transfusion independence was 10.8 months in the Vidaza

group and 19.2 months in the CCR group.

Health- Related Quality of Life (HRQoL) was assessed using the European Organization for Research

and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). HRQoL data could

be analysed for a subset of the full trial population. While there are limitations in the analysis, the

available data suggest that patients do not experience meaningful deterioration in quality of life during

treatment with Vidaza.

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 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

Azacitidine is cleared rapidly from plasma with a mean elimination half-life (t½) after subcutaneous

administration of 41 ± 8 minutes. No accumulation occurs after subcutaneous administration of

75 mg/m2 azacitidine once daily for 7 days. Urinary excretion is the primary route of elimination of

azacitidine and/or its metabolites. Following intravenous and subcutaneous administration of

14C-azacitidine, 85 and 50 % of the administered radioactivity was recovered in urine respectively,

while < 1 % was recovered in faeces.

 

Special populations

The effects of hepatic impairment (see section 4.2), gender, age, or race on the pharmacokinetics of

azacitidine have not been formally studied.

 

Renal impairment

Renal impairment has no major effect on the pharmacokinetic exposure of azacitidine after single and

multiple subcutaneous administrations. Following subcutaneous administration of a single 75 mg/m2

dose, mean exposure values (AUC and Cmax) from subjects with mild, moderate and severe renal

impairment were increased by 11-21%, 15-27%, and 41-66%, respectively, compared to normal renal

function subjects. However, exposure was within the same general range of exposures observed for

subjects with normal renal function. Azacitidine can be administered to patients with renal impairment

without initial dose adjustment provided these patients are monitored for toxicity since azacitidine

and/or its metabolites are primarily excreted by the kidney.

 

Pharmacogenomics

The effect of known cytidine deaminase polymorphisms on azacitidine metabolism has not been

formally investigated.

Azacitidine induces both gene mutations and chromosomal aberrations in bacterial and mammalian

cell systems in vitro. The potential carcinogenicity of azacitidine was evaluated in mice and rats.

Azacitidine induced tumours of the haematopoietic system in female mice, when administered

intraperitoneally 3 times per week for 52 weeks. An increased incidence of tumours in the

lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine

administered intraperitoneally for 50 weeks. A tumorigenicity study in rats revealed an increased

incidence of testicular tumours.

 

Early embryotoxicity studies in mice revealed a 44 % frequency of intrauterine embryonal death

(increased resorption) after a single intraperitoneal injection of azacitidine during organogenesis.

Developmental abnormalities in the brain have been detected in mice given azacitidine on or before

closure of the hard palate. In rats, azacitidine caused no adverse reactions when given preimplantation,

but it was clearly embryotoxic when given during organogenesis. Foetal abnormalities

during organogenesis in rats included: CNS anomalies (exencephaly/encephalocele), limb anomalies

(micromelia, club foot, syndactyly, oligodactyly) and others (microphthalmia, micrognathia,

gastroschisis, oedema, and rib abnormalities).

 

Administration of azacitidine to male mice prior to mating with untreated female mice resulted in

decreased fertility and loss of offspring during subsequent embryonic and postnatal development.

Treatment of male rats resulted in decreased weight of the testes and epididymides, decreased sperm

counts, decreased pregnancy rates, an increase in abnormal embryos and increased loss of embryos in

mated females (see section 4.4).

 

Mannitol, Acetonitrile HP, Water for Injection

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Unopened powder vial: 2 years After reconstitution: After reconstitution: When Vidaza is reconstituted using water for injections that has not been refrigerated, chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated at 25 °C for 45 minutes and at 2 °C to 8 °C for 8 hours. The shelf life of the reconstituted medicinal product can be extended by reconstituting with refrigerated (2 °C to 8 °C) water for injections. When Vidaza is reconstituted using refrigerated (2 °C to 8 °C) water for injections, the chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated at 2 °C to 8 °C for 22 hours. From a microbiological point of view, the reconstituted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and must not be longer than 8 hours at 2 °C to 8 °C when reconstituted using water for injections that has not been refrigerated or not longer than 22 hours when reconstituted using refrigerated (2 °C to 8 °C) water for injections.

6.4 Special precautions for storage

Unopened vials

Do not store above 30C

Reconstituted suspension

For storage conditions after reconstitution of the medicinal product, see section 6.2.

USP type-1 clear molded glass vial

Recommendations for safe handling

Azacitidine is a cytotoxic medicinal product and, as with other potentially toxic compounds,

caution should be exercised when handling and preparing azacitidine suspensions. Procedures for

proper handling and disposal of anticancer medicinal products should be applied.

If reconstituted azacitidine comes into contact with the skin, immediately and thoroughly wash

with soap and water. If it comes into contact with mucous membranes, flush thoroughly with

water.

 

Reconstitution procedure

Vidaza should be reconstituted with water for injections. The shelf life of the reconstituted medicinal

product can be extended by reconstituting with refrigerated (2 °C to 8 °C) water for injections. Details

on storage of the reconstituted product are provided below.

1. The following supplies should be assembled:

Vial (s) of azacitidine; vial(s) of water for injections; non-sterile surgical gloves; alcohol wipes;

5 mL injection syringe(s) with needle(s).

2. 4 mL of water for injections should be drawn into the syringe, making sure to purge any air

trapped within the syringe.

3. The needle of the syringe containing the 4 mL of water for injections should be inserted through

the rubber top of the azacitidine vial followed by injection of the water for injections into

the vial.

4. Following removal of the syringe and needle, the vial should be vigorously shaken until a

uniform cloudy suspension is achieved. After reconstitution each mL of suspension will contain

25 mg of azacitidine (100 mg/4 mL). The reconstituted product is a homogeneous, cloudy

suspension, free of agglomerates. The product should be discarded if it contains large particles

or agglomerates. Do not filter the suspension after reconstitution since this could remove the

active substance. It must be taken into account that filters are present in some adaptors, spikes

and closed systems; therefore such systems should not be used for administration of the

medicinal product after reconstitution.

5. The rubber top should be cleaned and a new syringe with needle inserted into the vial. The vial

should then be turned upside down, making sure the needle tip is below the level of the liquid.

The plunger should then be pulled back to withdraw the amount of medicinal product required

for the proper dose, making sure to purge any air trapped within the syringe. The syringe with

needle should then be removed from the vial and the needle disposed of.

6. A fresh subcutaneous needle (recommended 25-gauge) should then be firmly attached to the

syringe. The needle should not be purged prior to injection, in order to reduce the incidence of

local injection site reactions.

7. When more than 1 vial is needed all the above steps for preparation of the suspension should be

repeated. For doses requiring more than 1 vial, the dose should be equally divided e.g., dose

150 mg = 6 mL, 2 syringes with 3 mL in each syringe. Due to retention in the vial and needle, it

may not be feasible to withdraw all of the suspension from the vial.

8. The contents of the dosing syringe must be re-suspended immediately prior to administration.

The syringe filled with reconstituted suspension should be allowed up to 30 minutes prior to

administration to reach a temperature of approximately 20 °C-25 °C. If the elapsed time is

longer than 30 minutes, the suspension should be discarded appropriately and a new dose

prepared. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy

suspension is achieved. The product should be discarded if it contains large particles or

agglomerates.

Storage of the reconstituted product

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Calculation of an individual dose

The total dose, according to the body surface area (BSA) can be calculated as follows:

Total dose (mg) = Dose (mg/m2) x BSA (m2)

The following table is provided only as an example of how to calculate individual azacitidine doses

based on an average BSA value of 1.8 m2.

 

Method of administration

Reconstituted Vidaza should be injected subcutaneously (insert the needle at a 45-90o angle) using a

25-gauge needle into the upper arm, thigh or abdomen.

Doses greater than 4 mL should be injected into two separate sites.

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.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.