Vidaza

1.

NAME OF THE MEDICINAL PRODUCT

Vidaza 25 mg/ml powder for suspension for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 100 mg azacitidine. After reconstitution, each ml suspension contains 25 mg

azacitidine.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder for suspension for injection.

White lyophilised powder.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Vidaza is indicated for the treatment of adult patients who are not eligible for haematopoietic stem cell

transplantation 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.

4.2 Posology and method of administration

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/m 2 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.

Dose adjustment due to haematological toxicity

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

below 50.0 x 10 9 /l and/or absolute neutrophil count (ANC) below 1 x 10 9 /l.

2

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 10 9 /l and

ANC >1.5 x 10 9 /l, and platelets > 75.0 x 10 9 /l) prior to the first treatment

If haematological toxicity is observed following Vidaza treatment, 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,

the dose should be reduced according to the following table. Following dose modifications, the cycle

duration should return to 28 days.

% Dose in the next cycle,

if recovery* is not

achieved within 14 days

≤ 1.0 ≤ 50.0 50 %

> 1.0 > 50.0 100 %

*Recovery = counts ≥ Nadir count + (0.5 x [Baseline count – Nadir count])

Platelets (x 10 9 /l)

Patients with reduced baseline blood counts (i.e. WBC < 3.0 x 10 9 /l or ANC < 1.5 x 10 9 /l or platelets

< 75.0 x 10 9 /l) prior to the first treatment

Following Vidaza treatment, if the decrease in WBC or ANC or platelets from that prior to treatment

is less than 50 %, or greater than 50 % but with an improvement in any cell line differentiation, the

next cycle should not be delayed and no dose adjustment 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

Renal impairment: No formal studies have been conducted in patients with decreased renal function.

Patients with severe organ impairment should be carefully monitored for adverse events. No specific

modification to the starting dose is recommended in patients with renal impairment (e.g. baseline

serum creatinine or blood urea nitrogen [BUN] ≥ 2-fold above upper limit of normal [ULN] or serum

bicarbonate less than 20 mmol/l) prior to starting treatment; subsequent dose modifications should be

based on haematology and renal laboratory values. 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 BUN to ≥ 2-fold above baseline values and above 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).

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

3

Nadir counts

ANC (x 10 9 /l)

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).

Elderly: 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.

Children and adolescents: Vidaza is not recommended for use in children below 18 years due to

insufficient data on safety and efficacy.

Laboratory tests

Liver function tests and serum creatinine 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 .

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.

Detailed instructions for the reconstitution and administration procedure for Vidaza are provided in

section 6.6.

4.3 Contraindications

Known hypersensitivity to the active substance or to any of the excipients.

Advanced malignant hepatic tumours (see section 4.4).

Lactation (see section 4.6).

4.4 Special warnings and precautions for use

Haematological toxicity

Treatment with azacitidine is associated with anaemia, neutropenia and thrombocytopenia, particularly

during the first 2 cycles (see section 4.8). Complete blood counts should be performed as needed to

monitor response and toxicity, but at least prior to each treatment cycle . After administration of the

recommended dose for the first cycle, the dose for subsequent cycles should be reduced or its

administration delayed based on nadir counts and haematological response (see section 4.2). Patients

should be advised to promptly report febrile episodes. Patients and physicians are also advised to be

observant for signs and symptoms of bleeding.

Hepatic impairment

No formal studies have been conducted in patients with hepatic impairment. Patients with extensive

tumour burden due to metastatic disease have been rarely 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

rarely 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

4

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 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).

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 clinical study and therefore the safety and efficacy

of Vidaza in these patients has not been established.

4.5 Interaction with other medicinal products and other forms of interaction

Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450

isoenzymes (CYPs), UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), and

glutathione transferases (GSTs); interactions related to these metabolizing enzymes in vivo are

therefore considered unlikely.

Clinically significant inhibitory or inductive effects of azacitidine on cytochrome P450 enzymes are

unlikely (see section 5.2).

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

4.6 Pregnancy and lactation

Pregnancy

There are no adequate data on 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.

Men and women of childbearing potential must use effective contraception during and up to 3 months

after treatment.

Lactation

It is not known whether azacitidine or its metabolites are excreted in human milk. Due to the potential

serious adverse reactions in the nursing child, breastfeeding is contraindicated during azacitidine

therapy.

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). 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.

4.7 Effects on ability to drive and use machines

No studies of the effects on the ability to drive and use machines have been performed. Patients should

be advised that they may experience undesirable effects such as fatigue, during treatment. Therefore,

caution should be recommended when driving a car or operating machines.

4.8 Undesirable effects

Adverse reactions considered to be possibly or probably related to the administration of Vidaza have

occurred in 97 % of patients.

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).

The most common serious adverse reactions (> 2 %) noted from the pivotal study

(AZA PH GL 2003 CL 001) and also reported in the supporting studies (CALGB 9221 and

CALGB 8921) included febrile neutropenia (8.0 %) and anaemia (2.3 %). Other less frequently

reported serious adverse reactions (< 2 %) included neutropenic sepsis, pneumonia, thrombocytopenia

and haemorrhagic events (e.g. cerebral haemorrhage).

The table below contains the adverse reactions for which a causal relationship with azacitidine

treatment could reasonably be established. Frequencies given are based on the observations during the

pivotal clinical study or two supporting clinical studies.

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.

System Organ

Class

Very common

Common

Uncommon

Infections and

infestations

pneumonia,

nasopharyngitis

neutropenic sepsis, upper

respiratory tract infection,

urinary tract infection,

sinusitis, pharyngitis,

rhinitis, herpes simplex

Blood and

lymphatic

system disorders

febrile neutropenia,

neutropenia,

leukopenia,

thrombocytopenia,

anaemia

bone marrow failure,

pancytopenia

Immune system

disorders

hypersensitivity

reactions

Metabolism and

nutrition

disorders

anorexia

hypokalemia

Psychiatric

disorders

confusional state, anxiety,

insomnia

Nervous system

disorders

dizziness, headache

intracranial haemorrhage,

lethargy

Eye disorders

eye haemorrhage,

conjunctival haemorrhage

Vascular

disorders

hypertension, hypotension,

haematoma

Respiratory,

thoracic and

mediastinal

disorders

dyspnoea

dyspnoea exertional,

pharyngolaryngeal pain

Gastrointestinal

disorders

diarrhoea, vomiting,

constipation, nausea,

abdominal pain

gastrointestinal

haemorrhage,

haemorrhoidal

haemorrhage, stomatitis,

gingival bleeding,

dyspepsia

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System Organ

Class

Very common

Common

Uncommon

Skin and

subcutaneous

tissue disorders

petechiae, pruritus,

rash, ecchymosis

purpura, alopecia,

erythema, rash macular

Musculoskeletal,

and connective

tissue disorders

arthralgia

myalgia, musculoskeletal

pain

Renal and

urinary

disorders

haematuria

General

disorders and

administration

site conditions

fatigue, pyrexia, chest

pain, injection site

erythema, injection

site pain, injection site

reaction (unspecified)

injection site: bruising,

haematoma, induration,

rash, pruritus,

inflammation,

discoloration, nodule and

haemorrhage.

malaise

Investigations

weight decreased

Haematologic adverse reactions

The most commonly reported adverse reactions associated with azacitidine treatment were

haematological including thrombocytopenia, 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 thromobocytopenia as required.

Infections

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

such as neutropenic sepsis (0.8 %) and pneumonia (2.5 %) were reported in patients receiving

azacitidine. 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 (0.8 %) and intracranial haemorrhage (0.5 %) 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 (0.25 %) 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 temporary or permanent discontinuation of azacitidine, or reduction

of azacitidine dose in the pivotal study. 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 drugs (NSAIDs).

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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; antidiarrhoeals for diarrhoea, and

laxatives and/or stool softeners for constipation.

4.9 Overdose

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

diarrhoea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m 2 ,

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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agent, 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

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 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/m 2 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

8

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).

Log-Rank p = 0.0001

HR = 0.58 [95% CI: 0.43-0.77]

Deaths: AZA = 82, CCR = 113

months

Time (months) from Randomization

# at risk

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

9

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 %).

5.2 Pharmacokinetic properties

The pharmacokinetics of azacitidine were studied following single 75 mg/m 2 doses given by

subcutaneous and intravenous administration.

Absorption

Azacitidine was rapidly absorbed after subcutaneous administration with peak plasma azacitidine

concentrations of 750 ± 403 ng/ml occurring at 0.5 h (the first sampling point) after dosing. The

absolute bioavailability of azacitidine after subcutaneous relative to intravenous administration was

approximately 89 % based on area under the curve (AUC).

Distribution

Following intravenous administration, the mean volume of distribution was 76 ± 26 l, and systemic

clearance was 147 ± 47 l/h.

Metabolism

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).

Metabolism of azacitidine is by spontaneous hydrolysis and by deamination mediated by cytidine

deaminase. In human liver S9 fractions, formation of metabolites was independent of NADPH

implying any metabolism would be catalysed by cytosolic enzymes. 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

cytochrome P450 isoenzymes (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) incubated with

100 µM azacitidine, IC 50 values could not be determined, therefore, enzyme inhibition by azacitidine

at clinically achievable plasma concentrations is unlikely.

Excretion

Azacitidine is cleared rapidly from plasma with a mean elimination half-life (t ½ ) after subcutaneous

administration of 41 ± 8 minutes. Urinary excretion is the primary route of elimination of azacitidine

and/or its metabolites. Following intravenous and subcutaneous administration of 14 C-azacitidine,

50-85 % of the administered radioactivity was recovered in urine, while < 1 % was recovered in

faeces.

Special populations

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

pharmacokinetics of azacitidine have not been formally studied.

Pharmacogenomics

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

formally investigated.

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5.3 Preclinical safety data

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 effects when given pre-implantation,

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

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

(micromelia, club foot, syndactyly, oligodactyly) and others (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).

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol (E421)

6.2 Incompatibilities

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

section 6.6.

6.3 Shelf life

Unopened powder vial:

4 years

After reconstitution:

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.

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.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

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

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6.5 Nature and contents of container

Colourless type I 30 ml glass vial sealed with butyl elastomeric stopper and aluminium seal with

polypropylene plastic button.

Pack size: 1 vial of 100 mg azacitidine.

6.6 Special precautions for disposal and other handling

Recommendations for safe handling

Vidaza 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

1.

The following supplies should be assembled:

•

Vial(s) of azacitidine; vial(s) of water for injections; nonsterile surgical gloves;

2.

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

trapped within the syringe.

Alcohol wipes; 5 ml injection syringe(s) with needle(s).

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.

5.

The rubber top should be cleaned and a new syringe with needle inserted. 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.

If needed (doses over 100 mg) all the above steps for preparation of the suspension should be

repeated. For doses greater than 100 mg (4 ml), the dose should be equally divided into

2 syringes (e.g, dose 150 mg = 6 ml, 2 syringes with 3 ml in each syringe).

8.

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

The temperature of the suspension at the time of injection should be approximately 20ºC-25ºC.

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.

The Vidaza suspension should be prepared immediately before use and the reconstituted suspension

should be administered within 45 minutes. If elapsed time is greater than 45 minutes, the reconstituted

suspension should be discarded appropriately and a new dose prepared. Alternatively, if the product

needs to be reconstituted in advance of the administration, it must be placed in a refrigerator (2°C to

8°C) immediately after reconstitution, and kept in the refrigerator for a maximum of 8 hours. If the

elapsed time in the refrigerator is greater than 8 hours, the suspension should be discarded

appropriately and a new dose prepared. 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.

12

•

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/m 2 ) x BSA (m 2 )

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 m 2 .

Dose mg/m 2

(% of recommended

starting dose)

Total dose based on

BSA value of 1.8 m 2

Number of vials

required

Total volume of

reconstituted

suspension required

75 mg/m 2 (100 %)

135 mg

2 vials

5.4 ml

37.5 mg/m 2 (50 %)

67.5 mg

1 vial

2.7 ml

25 mg/m 2 (33 %)

45 mg

1 vial

1.8 ml

Method of administration

Reconstituted Vidaza should be injected subcutaneously (insert the needle at a 45-90 o 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 product or waste material should be disposed of in accordance with local requirements.

7.

MARKETING AUTHORISATION HOLDER

Celgene Europe Ltd

Riverside House

Riverside Walk

Windsor

SL4 1NA

United Kingdom

Tel: +44 1753 240600

Fax: +44 1753 240656

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/08/488/001

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

17/12/2008

10. DATE OF REVISION OF THE TEXT

13

ANNEX II

A. MANUFACTURING AUTHORISATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OF THE MARKETING AUTHORISATION

14

A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH

RELEASE

Name and address of the manufacturers responsible for batch release

Catalent UK Packaging Ltd.

Sedge Close

Headway, Great Oakley

Corby, Northhants NN18 8HS

United Kingdom

Baxter Oncology GmbH

Kantstrasse 2

33790 Halle/Westfalen

Germany

The printed package leaflet of the medicinal product must state the name and address of the

manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OF THE MARKETING AUTHORISATION

•

CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON

THE MARKETING AUTHORISATION HOLDER

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product

Characteristics, section 4.2).

•

CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT

Not applicable.

•

OTHER CONDITIONS

Pharmacovigilance system

The MAH must ensure that the system of pharmacovigilance, as described in version 7.0 presented in

Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and

whilst the product is on the market.

Risk Management Plan

The MAH commits to performing the studies and additional pharmacovigilance activities detailed in

the Pharmacovigilance Plan, as agreed in version 3.0 of the Risk Management Plan (RMP) presented

in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP

agreed by the CHMP.

As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the

updated RMP should be submitted at the same time as the next Periodic Safety Update Report

(PSUR).

In addition, an updated RMP should be submitted:

•

When new information is received that may impact on the current Safety Specification,

Pharmacovigilance Plan or risk minimisation activities

•

Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being

reached

•

At the request of the EMEA

15

ANNEX III

LABELLING AND PACKAGE LEAFLET

16

A. LABELLING

17

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON

1.

NAME OF THE MEDICINAL PRODUCT

Vidaza 25 mg/ml powder for suspension for injection

Azacitidine

2.

STATEMENT OF ACTIVE SUBSTANCE(S)

100 mg. After reconstitution, each ml suspension contains 25 mg azacitidine.

3.

LIST OF EXCIPIENTS

Also contains Mannitol.

4.

PHARMACEUTICAL FORM AND CONTENTS

Powder for suspension for injection.

1 vial – 100 mg

5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

For single use only. Shake the suspension vigorously before administration.

Subcutaneous use.

6.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7.

OTHER SPECIAL WARNING(S), IF NECESSARY

8.

EXPIRY DATE

EXP

After reconstitution: The suspension may be stored at 25°C for 45 minutes or at 2°C to 8°C for

8 hours.

18

9.

SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF

APPROPRIATE

Any unused product or waste material should be discarded according to the local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Celgene Europe Ltd

Riverside House

Riverside Walk

Windsor

SL4 1NA

United Kingdom

12. MARKETING AUTHORISATION NUMBER(S)

EU/1/08/488/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Justification for not including Braille accepted.

19

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL LABEL

1.

NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Vidaza 25 mg/ml powder for suspension for injection

Azacitidine

Subcutaneous use

2.

METHOD OF ADMINISTRATION

Read the package leaflet before use.

3.

EXPIRY DATE

EXP

4.

BATCH NUMBER

Lot

5.

CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

100 mg

6.

OTHER

20

B. PACKAGE LEAFLET

21

PACKAGE LEAFLET: INFORMATION FOR THE USER

Vidaza 25 mg/ml powder for suspension for injection

Azacitidine

Read all of this leaflet carefully before you are given this medicine.

-

Keep this leaflet. You may need to read it again.

-

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or nurse.

In this leaflet :

1.

What Vidaza is and what it is used for

3.

How to use Vidaza

4.

Possible side effects

5

How to store Vidaza

6.

Further information

1.

WHAT VIDAZA IS AND WHAT IT IS USED FOR

Vidaza contains the active substance azacitidine. It works by preventing the growth of cancer cells.

Vidaza is used in adults who are not eligible for stem cell transplantation to treat:

•

higher-risk myelodysplastic syndromes (MDS) a group of illnesses of the bone marrow resulting

in the production of too few blood cells.

•

chronic myelomonocytic leukaemia (CMML).

•

acute myeloid leukaemia (AML).

Talk to your doctor if you have any questions about how Vidaza works or why this medicine has been

prescribed for you.

2.

BEFORE YOU USE VIDAZA

Do not use Vidaza

•

if you are allergic (hypersensitive) to azacitidine or to any of the other ingredients of Vidaza

(see section 6).

•

if you have advanced liver cancer.

•

if you are breastfeeding.

Take special care with Vidaza

Check with your doctor or nurse before using this medicine if you have:

•

decreased counts of platelets, red or white blood cells.

•

kidney disease.

•

liver disease.

If you are not sure if any of the above applies to you, talk to your doctor or nurse before having

Vidaza.

Vidaza is not recommended for use in children and adolescents below the age of 18.

22

-

If you have any further questions, ask your doctor or pharmacist.

2.

Before you use Vidaza

You will have blood tests before you begin treatment with Vidaza and at the start of each period of

treatment (called a ‘cycle’). This is to check that you have enough blood cells and that your liver and

kidneys are working properly.

For men having Vidaza, please see the section “Pregnancy and breastfeeding” below.

Taking other medicines

Please tell your doctor or nurse if you are using or have recently used any other medicines including

medicines obtained without a prescription and herbal preparations. This is because Vidaza may affect

the way some other medicines work. Also, some other medicines may affect the way Vidaza works.

Pregnancy and breastfeeding

You should not use Vidaza during pregnancy as it may be harmful to the baby.

Use an effective method of contraception during and up to 3 months after treatment with Vidaza.

Tell your doctor straight away if you become pregnant during treatment with Vidaza.

You must not use Vidaza if you are breastfeeding. It is not known if Vidaza passes into the mother’s

milk and therefore you must not breastfeed your baby during treatment.

Men should not father a child while receiving treatment with Vidaza. Use an effective method of

contraception during and up to 3 months after treatment with Vidaza.

Talk to your doctor if you wish to conserve your sperm before starting this treatment.

Driving and using machines

No studies of the effects on the ability to drive and use machines have been performed. Some people

may feel tired after being given Vidaza. If this happens to you, do not drive or use any tools or

machines.

3.

HOW TO USE VIDAZA

Your doctor will give you another medicine to prevent nausea and vomiting at the start of each

treatment cycle, before giving you Vidaza.

•

The usual dose is 75 mg per m 2 body surface area. Your doctor will choose your dose of Vidaza,

depending on your general condition, height and weight. Your doctor will check your progress

and may change your dose if necessary.

•

Vidaza is given every day for one week, followed by a rest period of 3 weeks. This “treatment

cycle” will be repeated every 4 weeks. You will usually receive at least 6 treatment cycles.

Vidaza will be given to you as an injection under the skin (subcutaneously) by a doctor or nurse. It

may be given under the skin on your thigh, tummy or upper arm.

If you have any further questions on the use of this product, ask your doctor or nurse.

4.

POSSIBLE SIDE EFFECTS

Like all medicines, Vidaza can cause side effects, although not everybody gets them.

Tell your doctor straight away if you notice any of the following side effects:

•

A fever . This may be due to an infection as a result of having low levels of white blood cells.

•

Chest pain or shortness of breath which may be accompanied with a fever. This may be due

to an infection of the lung called “pneumonia”.

•

Bleeding. Such as blood in the stools due to bleeding in the stomach or gut.

23

•

Difficulty breathing, swelling of the lips, itching or rash. This may be due to an allergic

(hypersensitivity) reaction.

Side effects may occur with certain frequencies, which are defined as follows:

very common:

affects more than 1 user in 10

common:

affects 1 to 10 users in 100

uncommon:

affects 1 to 10 users in 1,000

rare:

affects 1 to 10 users in 10,000

very rare:

affects less than 1 user in 10,000

not known:

frequency cannot be estimated from the available data

Very common side effects

•

Reduced red blood count (anaemia). You may feel tired and pale.

•

Reduced white blood cell count. This may be accompanied by a fever. You are also more likely

to get infections.

•

A low blood platelet count (thrombocytopenia). You are more prone to bleeding and bruising.

•

Constipation, diarrhoea, nausea, vomiting.

•

Pneumonia.

•

Chest pain, being short of breath.

•

Tiredness (fatigue).

•

Injection site reaction including redness, pain or a skin reaction.

•

Loss of appetite.

•

Joint aches.

•

Bruising.

•

Rash.

•

Red or purple spots under your skin.

•

Pain in your belly (abdominal pain).

•

Itching.

•

Fever.

•

Sore nose and throat.

•

Dizziness.

•

Headache.

Common side effects

•

Bleeding inside your head.

•

An infection of the blood caused by bacteria (sepsis). This may be due to low levels of white

cells in your blood.

•

Bone marrow failure. This can cause low levels of red and white blood cells and platelets.

•

A type of anaemia where your red and white blood cells and platelets are reduced.

•

An infection in your urine.

•

A viral infection causing cold sores (herpes).

•

Bleeding gums, bleeding in the stomach or gut, bleeding from around your back passage due to

piles (haemorrhoidal haemorrhage), bleeding in your eye, bleeding under your skin, or into your

skin (haematoma).

•

Blood in your urine.

•

Ulcers of your mouth or tongue.

•

Changes to your skin at the injection site. These include swelling, a hard lump, bruising,

bleeding into your skin (haematoma), rash, itching and changes in the skin colour.

•

Redness of your skin.

•

An infection of the nose and throat, or sore throat.

•

Sore or runny nose or sinuses (sinusitis).

•

Low levels of potassium in your blood.

•

High or low blood pressure (hypertension or hypotension).

24

•

Being short of breath when you move.

•

Pain in your throat and voicebox.

•

Indigestion.

•

Weight loss.

•

Lethargy.

•

Feeling generally unwell.

•

Muscle aches.

•

Anxiety or having trouble sleeping (insomnia).

•

Being confused.

•

Hair loss.

Uncommon side effects

•

Allergic (hypersensitivity) reaction.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please

tell your doctor or nurse.

5.

HOW TO STORE VIDAZA

Keep out of the reach and sight of children.

Do not use Vidaza after the expiry date which is stated on the vial label and the carton. The expiry

date refers to the last day of that month.

This medicine does not require any special storage conditions.

The reconstituted suspension may be stored at 25°C for 45 minutes or at 2°C to 8°C for 8 hours.

Your doctor or pharmacist are responsible for storing Vidaza. They are also responsible for disposing

of any unused Vidaza correctly.

6.

FURTHER INFORMATION

What Vidaza contains

•

The active substance is azacitidine. 1 vial contains 100 mg azacitidine. After reconstitution with

4 ml of water for injections, the reconstituted suspension contains 25 mg/ml azacitidine .

•

The other ingredient is mannitol (E421).

What Vidaza looks like and contents of the pack

Vidaza is a white powder for suspension for injection and is supplied in a glass vial containing 100 mg

of azacitidine.

Marketing Authorisation Holder

Celgene Europe Ltd

Riverside House

Riverside Walk

Windsor

SL4 1NA

United Kingdom

Manufacturer

Baxter Oncology GmbH

Kantstrasse 2

33790 Halle/Westfalen

Germany

25

OR

Catalent UK Packaging Limited

Sedge Close

Headway

Great Oakley

Corby

Northamptonshire

NN18 8HS

United Kingdom

This leaflet was last approved in

Detailed information on this medicine is available on the European Medicines Agency (EMEA) web

site: http://www.emea.europa.eu . There are also links to other websites about rare diseases and

treatments.

<--------------------------------------------------------------------------------------------------------------------

The following information is intended for medical or healthcare professionals only:

Recommendations for safe handling

Vidaza 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.

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned

below “Reconstitution Procedure”.

Reconstitution procedure

1.

The following supplies should be assembled:

•

Vial(s) of azacitidine; vial(s) of water for injections; nonsterile surgical gloves;

2.

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

trapped within the syringe.

Alcohol wipes; 5 ml injection syringe(s) with needle(s).

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.

5.

The rubber top should be cleaned and a new syringe with needle inserted. 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.

If needed (doses over 100 mg) all the above steps for preparation of the suspension should be

repeated. For doses greater than 100 mg (4 ml), the dose should be equally divided into

2 syringes (e.g, dose 150 mg = 6 ml, 2 syringes with 3 ml in each syringe).

26

•