DATA SHEET

Vidaza® (azacitidine) 100 mg Powder for Injection

i) NAME OF THE MEDICINE

Approved Name: azacitidine
Molecular formula: C8H12N4O5
Molecular weight: 244
The CAS number: 320-67-2
Chemical name: 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one.
Chemical structure:
NH2

N N

HO N
O
O

OH OH

ii) DESCRIPTION
Azacitidine is a white to off-white solid. It is insoluble in acetone, ethanol, and methyl
ethyl ketone. Azacitidine is slightly soluble in ethanol/water (50/50) and propylene
glycol; it is sparingly soluble in water (13.8 mg/mL, 5% glucose in water and in
normal saline.

The finished product is supplied in a sterile form for reconstitution as a suspension for
subcutaneous injection or reconstitution as a solution with further dilution for
intravenous infusion. Vials of Vidaza contain 100 mg of azacitidine and 100 mg
mannitol as a white to off-white, sterile lyophilised powder.

iii) PHARMACOLOGY
Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, antimetabolites, pyrimidine

analogues, ATC code: L01BC07

Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation

of DNA and direct cytotoxicity on abnormal haematopoietic cells in the bone marrow.

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DNA hypomethylation may allow for the re-expression of genes involved in normal
cell cycle regulation and differentiation. The cytotoxic effects of azacitidine may be
due in part to its incorporation into RNA with subsequent inhibition of protein
synthesis and/or its ability to activate DNA damage pathways leading to apoptosis.
In vitro, non-proliferating cells are relatively insensitive to azacitidine.

Pharmacokinetic properties

The effects of renal or hepatic impairment, gender, age, or race on the

pharmacokinetics of azacitidine have not been formally studied.

Absorption and distribution

The pharmacokinetics of azacitidine were studied following single 75 mg/m2 SC and

IV doses. Azacitidine was rapidly absorbed after SC administration with peak plasma
azacitidine concentrations of 687 ng/mL (geometric mean) occurring at 0.5 hour (the
first sampling point) after dosing. Azacitidine disappeared from plasma rapidly with a
mean half-life after SC administration of 41 ± 8 minutes. The absolute bioavailability
of SC azacitidine relative to IV azacitidine was approximately 89% based on area
under the curve. Following IV dosing, the mean volume of distribution was 76 ± 26 L,
systemic clearance was 147 ± 47 L/hr, and Cmax was 2580 ng/mL. The differences in
Cmax after SC and IV administration are consistent with higher maximum exposure
expected following IV versus extravascular drug administration.

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.

In vitro studies of azacitidine with cultured human hepatocytes indicate that at

concentrations of 1.0 µM to 100 µM, azacitidine does not induce cytochrome P450
1A2, 2C19, or 3A4/5. In studies to assess inhibition of a series of P450 isoenzymes
(1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) incubated with azacitidine
concentrations of up to 100 µM, azacitidine did not produce inhibition at clinically
achievable plasma concentrations. Therefore, CYP enzyme induction or inhibition by
azacitidine is unlikely.

Excretion

Urinary excretion is the primary route of elimination of azacitidine and/or its

metabolites. Following IV and SC administration of 14C-azacitidine, 85% and 50% of
the dose-administered radioactivity was recovered in urine, respectively, while < 1%
was recovered in faeces.

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iv) CLINICAL TRIALS
The efficacy and safety of Vidaza were demonstrated in an international, multicenter,
controlled, open-label, randomized, parallel-group, Phase 3 comparative study (AZA-
PH-GL 2003-CL 001) in patients with: Intermediate-2 and High-risk MDS according
to IPSS, RAEB, RAEB-T and mCMMoL according to the French American British
(FAB) classification system. RAEB-T patients (21-30% blasts) are now considered to
be AML under the WHO classification system. Vidaza plus Best Supportive Care
(BSC) was compared to Conventional Care Regimens (CCR). CCR consisted of BSC
(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 randomization. Patients received this pre-selected regimen if not
randomized to Vidaza. The primary endpoint of the study was overall survival. Vidaza
was administered at a subcutaneous (SC) dose of 75 mg/m2 daily for 7 days every 28
days for a median of 9 cycles (range = 1-39).

In the Intent to Treat analysis of 358 patients (179 azacitidine and 179 CCR), Vidaza
treatment was associated with a median survival of 24.5 months versus 15 months for
those receiving CCR treatment, an improvement of 9.4 months with a stratified log-
rank p-value of 0.0001. The hazard ratio describing this treatment effect was 0.58
(95% CI: 0.43, 0.77). The two year survival rates were 50.8% versus 26.2% for
patients receiving azacitidine versus CCR (p < 0.0001). The survival benefit was
apparent from as early as 3.5 months.

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 chemotherapy plus
BSC) utilized in the control arm.

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When IPSS cytogenetic subgroups were analysed, similar findings in terms of median
overall survival were observed in all groups (good, intermediate, and poor
cytogenetics).

On analyses of age subgroups, an increase in median overall survival was observed for
all groups in the Vidaza treatment arm (< 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 and platelet
transfusions. Of the patients in the Vidaza 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]).

v) INDICATIONS

Vidaza is indicated for the treatment of patients with:

• Intermediate-2 and High-risk Myelodysplastic Syndromes (MDS) according to
the International Prognostic Scoring System (IPSS),
• Chronic Myelomonocytic Leukemia (CMMoL [10%-29% marrow blasts
without Myeloproliferative Disorder]),
• Acute Myeloid Leukemia (AML) with 20-30% blasts and multi-lineage
dysplasia, according to World Health Organisation Classification (WHO),
in whom allogenic stem cell transplantation is not indicated.

vi) CONTRAINDICATIONS
Vidaza is contraindicated in the following patients:

- patients with known hypersensitivity to azacitidine or to any of the excipients

- patients with advanced malignant hepatic tumours (see “PRECAUTIONS”)
- pregnancy
- patients with severe renal impairment (creatinine clearance < 30 mLs/min).

vii) PRECAUTIONS
1. Effects on Fertility
Azacitidine had adverse effects on male fertility in rodents. Administration of
azacitidine to male mice at 9.9 mg/m2 IP (well below the recommended human daily
dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice
resulted in decreased fertility and increased pre- and post-implantation loss.

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Treatment of male rats three times per week for 6-11 weeks at doses well below the
recommended human daily dose on a mg/m2 basis, resulted in decreased weight of the
testes and epididymides, decreased sperm counts accompanied by decreased
pregnancy rates and increased loss of embryos in mated females, and an increase in
abnormal embryos in mated females when examined on day 2 of gestation (see “Use
in male patients”). There have been no animal studies which have examined the effects
of azacitidine on female fertility.

2. Use in Pregnancy (Category X)

There are no adequate data on the use of azacitidine in pregnant women. Studies in
animals have shown reproductive toxicity including teratogenic effects at relatively
low doses. Azacitidine must not be used during pregnancy.

Increased foetal resorptions were observed in mice treated with azacitidine (6 mg/m2
IP, well below the recommended human daily dose) on single days during gestation
(days 10-14). In pregnant rats given azacitidine on gestation days 4-8 at doses well
below the recommended human dose, foetal survival and foetal weights were
decreased.

Azacitidine caused multiple foetal abnormalities in rats after administration of a single

IP dose of 3 to 12 mg/m2 (well below the recommended human daily dose) on
gestation day 9, 10, 11 or 12. Foetal abnormalities included CNS abnormalities
(exencephaly/encephalocele), limb abnormalities (micromelia, club foot, syndactyly,
oligodactyly) and others (microphthalmia, micrognathia, gastroschisis, oedema, and
rib abnormalities). Azacitidine also caused multiple foetal abnormalities in mice after
administration of a single IP dose of 6 mg/m2 (well below the recommended human
daily dose) on gestation day 10, 11 or 12. Foetal abnormalities included: CNS
abnormalities (exencephaly), limb abnormalities (malformed limbs, polydactyly,
syndactyly, oligodactyly) and others (cleft palate, skull bone defects and rib
abnormalities).

Women of childbearing potential should be advised to avoid becoming pregnant while

receiving treatment with azacitidine. If a patient becomes pregnant while taking this
drug, the patient should be appraised for the potential hazard to the foetus (see
CONTRINDICATIONS).

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

3. Use in male patients

Men should be advised not to father a child while receiving treatment. Contraceptive
measures are recommended. Before starting treatment, men are advised to seek
counselling on sperm storage. Female partners of male patients receiving azacitidine
should not become pregnant (see “Effects on Fertility”).

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4. Use in Lactation
It is not known whether azacitidine or its metabolites are excreted in human milk. The
safety of azacitidine has not been investigated in lactating animals. Given the serious
toxicity (severe target organ toxicity, genotoxicity and carcinogenicity) observed in
other animal studies and the potential for serious adverse effects on the nursing child,
breastfeeding must be discontinued during azacitidine therapy.

5. Paediatric use
The safety and efficacy of azacitidine in children and adolescents under 18 years of
age has not been established.

6. Use in the 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.

7. Genotoxicity
Azacitidine was mutagenic, as assessed in Salmonella typhimurium, L5178Y mouse
lymphoma cells and human lymphoblast TK6 cells. Azacitidine was clastogenic in the
in vitro micronucleus assays in Syrian hamster embryo fibroblasts and L5178Y mouse
lymphoma cells. Azacitidine induced morphological transformation in Syrian hamster
kidney and embryo fibroblasts. No in vivo tests have been conducted with azacitidine.

8. Carcinogenicity
Azacitidine has been shown to be carcinogenic when administered by the
intraperitoneal route 2 or 3 times weekly for 50-52 weeks in mice at doses of 7-
13 mg/m2 and for 8-36 weeks in rats at doses of 16-60 mg/m2. These doses are well
below the recommended human daily dose (when compared on a mg/m2 basis).
Tumour types included lung, testicular, mammary gland, and skin tumours,
lymphomas and tumours of the haematopoietic system.

9. Haematology
Treatment with Vidaza is associated with anaemia, neutropenia and thrombocytopenia,
particularly during the first 2 cycles. Complete blood counts should be performed as
needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle.
After administration of the recommended dose for the first cycle, in the presence of
cytopenias, the dose for subsequent cycles should be reduced or delayed based on
nadir counts and haematologic response as described in DOSAGE AND
ADMINISTRATION.

10. Use in Patients with Hepatic Impairment

No formal studies have been conducted in patients with hepatic impairment (see
“Pharmacokinetic properties”). The pivotal safety and efficacy study excluded patients
with bilirubin > 1.5 times the upper limit of normal, or with aspartate aminotransferase
(AST) or alanine aminotransferase (ALT) > 2.0 times the upper limit of normal. The
safety of azacitidine in such patients has therefore not been established.

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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 “CONTRAINDICATIONS”).

11. Renal Toxicity and Use in Patients with Renal Impairment

Renal abnormalities ranging from elevated serum creatinine to renal failure and death
were reported rarely in patients treated with intravenous (IV) 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 leukemia (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 delayed as described in
“DOSAGE AND ADMINISTRATION”.

No formal studies have been conducted in patients with renal impairment. Since
azacitidine and/or its metabolites are primarily excreted by the kidneys, patients with
mild or moderate renal impairment should be monitored closely and the dose adjusted
based on haematology and renal laboratory values (see “DOSAGE AND
ADMINISTRATION”). There are inadequate pharmacokinetic or safety data to
support the use of azacitidine in patients with severe renal impairment (creatinine
clearance < 30 mLs/min – see “CONTRAINDICATIONS”).

Patients should be advised to report oliguria and anuria to the healthcare provider
immediately.

12. 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 azacitidine in these patients has not been
established.

13. 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 as needed to monitor response and

toxicity, but at a minimum, prior to each treatment cycle.

14. Effects on ability to drive and use machines

While no studies on the effects of azacitidine on the ability to drive and use machines
have been performed, patients should be advised that they may experience undesirable
effects such as dizziness during treatment. Therefore caution should be recommended
when driving a car or operating machinery.

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 15. 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.

viii) INTERACTIONS WITH OTHER MEDICINES

No formal clinical drug interaction studies with azacitidine have been conducted. It is
not known whether azacitidine metabolism is affected by microsomal enzyme
inhibitors or inducers. Concomitant administration of medications known to be strong
metabolising enzyme inducers or inhibitors is not recommended. Where such
medications are considered essential, alternatives that are not strong inducers or
inhibitors of metabolising enzymes should be sought.

ix) ADVERSE EFFECTS

The most commonly reported adverse events with azacitidine treatment were
haematological (thrombocytopenia, neutropenia and leukopenia [usually Grade 3-4],
and anaemia [usually Grade 1-2]), or those associated with administration (nausea,
vomiting and injection site reactions, usually Grade 1-2). Adverse reactions associated
with intravenously administered azacitidine were similar in frequency and severity
compared with subcutaneously administered azacitidine. This assessment was mostly
based on cross-study comparisons, with studies of differing design (including
considerably longer IV infusion of azacitidine than is now recommended) and
differing patient populations. The most common adverse reactions by IV route also
included petechiae, rigors, weakness and hypokalemia.

The following Table 1 shows the adverse events that occurred at a frequency of greater
than or equal to 10% in the azacitidine group in the pivotal clinical study.

Table 1: Most frequently reported adverse events (≥ 10% in the azacitidine

treatment arm) from the pivotal clinical study (AZA PH GL 2003 CL 001 –
subcutaneous route of administration)

System Organ Class Number (%) of Patients

Preferred Term Azacitidine BSC
(N = 175) (N = 102)
All Grades Grade 3 or 4 All Grades Grade 3 or 4
Blood and lymphatic system disorders
Thrombocytopenia 122 (69.7) 102 (58.3) 35 (34.3) 29 (28.4)
Neutropenia 115 (65.7) 107 (61.1) 29 (28.4) 22 (21.6)
Anaemia 90 (51.4) 24 (13.7) 45 (44.1) 9 (8.8)
Leukopenia 32 (18.3) 26 (14.9) 2 (2.0) 1 (1.0)
Febrile Neutropenia 24 (13.7) 22 (12.6) 10 (9.8) 7 (6.0)

Gastrointestinal Disorders
Constipation 88 (50.3) 2 (1.1) 8 (7.8) 0
Nausea 84 (48.0) 3 (1.7) 12 (11.8) 0
Vomiting 47 (26.9) 0 7 (6.9) 0
Diarrhoea 38 (21.7) 1 (0.6) 18 (17.6) 1 (1.0)
Abdominal Pain 22 (12.6) 7 (4.0) 7 (6.9) 0

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System Organ Class Number (%) of Patients
Preferred Term Azacitidine BSC
(N = 175) (N = 102)
All Grades Grade 3 or 4 All Grades Grade 3 or 4
General Disorders and Administration Site
Conditions
Injection/catheter site erythema 75 (42.9) 0 0 0
Pyrexia 53 (30.3) 8 (4.6) 18 (17.6) 1 (1.0)
Injection site reaction 51 (29.1) 1 (0.6) 0 0
Fatigue 42 (24.0) 6 (3.4) 12 (11.8) 2 (2.0)
Injection site pain 33 (18.9) 0 0 0
Asthenia 28 (16.0) 4 (2.3) 15 (14.7) 2 (2.0)
Oedema Peripheral 23 (13.1) 0 13 (12.7) 0
Infections and infestations
Nasopharyngitis 33 (18.9) 2 (1.1) 13 (12.7) 0
Pneumonia 22 (12.6) 18 (10.3) 12 (11.8) 8 (7.8)
Bronchitis 17 (9.7) 0 8 (7.8) 0
Injury, poisoning and procedural
complications
Transfusion reaction 21 (12.0) 4 (2.3) 5 (4.9) 1 (1.0)
Metabolism and nutrition disorders
Anorexia 25 (14.3) 3 (1.7) 9 (8.8) 0
Neoplasms benign, malignant and
unspecified (including cysts and polyps)
Acute myeloid leukaemia 30 (17.1) 28 (16.0) 36 (35.3) 32 (31.4)
Nervous system disorders
Headache 25 (14.3) 0 8 (7.8) 0
Dizziness 17 (9.7) 1 (0.6) 7 (6.9) 0
Respiratory, Thoracic and mediastinal
disorders
Cough 34 (19.4) 1 (0.6) 15 (14.7) 0
Epistaxis 29 (16.6) 9 (5.1) 16 (15.7) 7 (6.9)
Dyspnoea 26 (14.9) 6 (3.4) 5 (4.9) 2 (2.0)
Skin and subcutaneous tissue disorders
Pruritus 21 (12.0) 0 2 (2.0) 0
Petechiae 20 (11.4) 2 (1.1) 4 (3.9) 0
Rash 18 (10.3) 0 1 (1.0) 0
Vascular disorders
Haematoma 21 (12.0) 0 10 (9.8) 0
Multiple reports of the same preferred term for a patient are counted only once within each treatment
group. Preferred terms were coded using the MedDRA Version 10.0. The severity of the adverse events
is graded according to NCI CTC Version 2.0. Grade 3 = severe; Grade 4 = life threatening.
BSC = Best supportive care.

The adverse reactions for which a causal relationship with azacitidine treatment could
reasonably be established are listed below. 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 (≥ 1/1000 to < 1/100). Within each frequency grouping, undesirable
effects are presented in order of decreasing seriousness.

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Adverse Drug Reactions (ADRs) observed in patients treated with azacitidine:

Infections and infestations

Very Common: pneumonia, nasopharyngitis
Common: neutropenic sepsis, upper respiratory tract infection, urinary tract
infection, sinusitis, pharyngitis, rhinitis, herpes simplex

Blood and lymphatic system disorders

Very Common: febrile neutropenia, neutropenia, leukopenia, thrombocytopenia,
anaemia
Common: bone marrow failure, pancytopenia

Immune system disorders

Uncommon: hypersensitivity reactions

Metabolism and nutrition disorders

Very Common: anorexia
Common: hypokalemia

Psychiatric disorders
Common: confusional state, anxiety, insomnia

Nervous system disorders

Very Common: dizziness, headache
Common: intracranial haemorrhage, lethargy

Eye disorders
Common: eye haemorrhage, conjunctival haemorrhage

Vascular disorders
Common: hypertension, hypotension, haematoma

Respiratory, thoracic and mediastinal disorders

Very Common: dyspnoea
Common: dyspnoea exertional, pharyngolaryngeal pain

Gastrointestinal disorders
Very Common: diarrhoea, vomiting, constipation, nausea, abdominal pain
Common: gastrointestinal haemorrhage, haemorrhoidal haemorrhage,
stomatitis, gingival bleeding, dyspepsia

Skin and subcutaneous tissue disorders

Very Common: petechiae, pruritus, rash, ecchymosis
Common: purpura, alopecia, erythema, rash macular

Musculoskeletal and connective tissue disorders

Very Common: arthralgia
Common: myalgia, musculoskeletal pain

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Renal and urinary disorders
Common: haematuria

General disorders and administration site conditions

Very Common: fatigue, pyrexia, chest pain, injection site erythema, injection site
pain, injection site reaction (unspecified)
Common: injection site: bruising, haematoma, induration, rash, pruritus,
inflammation, discoloration, nodule and haemorrhage, malaise

Investigations
Common: weight decreased

Haematologic Events
The most commonly reported adverse events associated with azacitidine treatment
were haematological including: thrombocytopenia, neutropenia and leukopenia
(usually Grade 3 or 4), and anaemia (usually Grade 1 or 2). 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. Blood
transfusions were provided for anaemia or thrombocytopenia and prophylactic
antibiotics and/or growth factor support for neutropenia as required.

Thrombocytopenia may lead to bleeding and patients should be monitored for signs
and symptoms of bleeding, particularly those with pre-existing or treatment-related
thrombocytopenia. Infections as a result of neutropenia may be managed with the use
of anti-infectives plus growth factor support (e.g. G-CSF).

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, erythema and skin lesion may require management with
concomitant medicinal products, such as antihistamines, corticosteroids and non-
steroidal anti inflammatory drugs (NSAIDs).

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

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vomiting, antidiarrhoeals for diarrhoea, and laxatives and/or stool softeners for
constipation.

Renal adverse reactions

Renal abnormalities, ranging from elevated serum creatinine to renal tubular acidosis,
renal failure and death were reported rarely in patients treated with azacitidine (see
Precautions).

Hepatic adverse reactions

Patients with extensive tumour burden due to metastatic disease have been rarely
reported to experience progressive hepatic coma and death during azacitidine
treatment (see Precautions).

Post-marketing Data
The following events have been reported in the post-marketing setting:
• Interstitial lung disease
• Tumour Lysis Syndrome
• Injection Site Necrosis
• Cellulitis
• Necrotizing fasciitis
• Acute febrile neutrophilic dermatosis
• Pyoderma gangrenosum.

x) DOSAGE AND ADMINISTRATION

Vidaza treatment should only be administered under the supervision of a physician
experienced in the use of cancer chemotherapeutic agents. Patients should be
premedicated for nausea and vomiting.

Recommended Dosage in Adults:

First Treatment Cycle

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 given
subcutaneously or by intravenous infusion, daily for seven days, followed by a rest
period of 21 days (28-day treatment cycle).

Subsequent Treatment Cycles

Cycles should be repeated every 28 days. It is recommended that patients be treated
for a minimum of 6 cycles. However, complete or partial response may require more
than 6 treatment cycles. Treatment may be continued as long as the patient continues
to benefit or until disease progression.

Patients should be monitored for haematological response and renal toxicities, and a
dose delay or reduction as described below may be necessary.

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With subcutaneous injection, rotate sites for injection (thigh, abdomen, or upper arm).
New injections should be given at least 2.5 cm or one inch from the previous site and
never into areas where the site is tender, bruised, red, or hard.

Dosage Adjustment based on Haematology Laboratory Values:

Patients without reduced baseline blood counts (i.e. WBC ≥ 3.0 x 109/L and ANC
≥ 1.5 x 109/L, and platelets ≥ 75.0 x 109/L prior to treatment
If haematological toxicity is observed following Vidaza treatment (as defined by:
Platelets < 50.0 x 109/L and/or ANC < 1 x 109/L), 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. If recovery has not been
achieved within 14 days, the dose should be reduced according to the following table.
Following dose modifications, the cycle duration should return to 28 days.

Nadir counts % Dose in the next cycle if

recovery* is not achieved
ANC (x 109/L) Platelets (x 109/L) within 14 days
≤ 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, ANC
< 1.5 x 109/L, or platelets < 75.0 x 109/L prior to 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
{counts ≥ Nadir Count + (0.5 x [Baseline Count – Nadir Count])} and, if recovery has
not been achieved within 14 days, bone marrow cellularity must be determined. If the
bone marrow cellularity is > 50% no dose adjustments should be made. If bone
marrow cellularity is ≤ 50%, delay treatment and reduce the dose 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.

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Dose adjustment based on renal function and serum electrolytes:
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. Similarly, if unexplained and
clinically significant elevations of serum creatinine or blood urea nitrogen (BUN)
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
‘PRECAUTIONS’).

Preparation of Vidaza:
Vidaza is a cytotoxic drug and, as with other potentially toxic compounds, caution
should be exercised when handling and preparing Vidaza suspensions. Procedures for
proper handling and disposal of anticancer drugs should be applied.

If reconstituted Vidaza 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.

The Vidaza vial is single-use and does not contain any preservatives. Unused portions
of each vial should be discarded in accordance with local requirements for disposal of
cytotoxic compounds.

Instructions for Subcutaneous Administration:

Vidaza must be reconstituted with water for injections to form a uniform suspension
prior to administration as follows. Aseptically add 4 mL of sterilised water for
injections slowly into the vial. Vigorously shake the vial until a uniform, cloudy
suspension is achieved. No filters, and no adaptors, spikes or closed systems that
contain filters, should be used after reconstitution since these could remove the active
substance. The suspension contains azacitidine 25 mg/mL. The maximum recovery of
azacitidine is 96% per vial following reconstitution.

Suspension stability
To reduce microbiological hazard, use as soon as practicable after reconstitution.

Reconstituted Vidaza suspension may be stored for up to:

• 1 hour at 25°C, or
• 8 hours between 2°C and 8°C, or
• 22 hours between 2°C and 8°C when reconstituted with refrigerated (2°C-8°C)
water for injections.

Preparation for Immediate Subcutaneous Administration:

Doses greater than 4 mL should be divided equally into two syringes and injected into
two separate sites. The product may be held at room temperature (25ºC) for up to
1 hour, but must be administered within 1 hour after reconstitution.

Preparation for Delayed Subcutaneous Administration:

The reconstituted product may be kept in the vial or drawn into a syringe. Doses
greater than 4 mL should be divided equally into two syringes. The product must be
refrigerated immediately.
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 • When Vidaza is reconstituted using water for injections that has not been
refrigerated, the product may be held under refrigerated conditions (2ºC-8ºC)
for up to 8 hours.
• When Vidaza is reconstituted using refrigerated (2°C-8°C) water for injections,
the product may be stored under refrigerated conditions (2ºC-8ºC) for up to
22 hours.

After removal from refrigerated conditions, the suspension may be allowed to

equilibrate to room temperature for up to 30 minutes prior to administration.

Subcutaneous Administration:
The contents of the dosing syringe must be re-suspended immediately prior to
administration. To re-suspend, vigorously roll the syringe between the palms until a
uniform, cloudy suspension is achieved.

Doses greater than 4 mL should be divided equally into 2 syringes and injected into 2
separate sites. Rotate sites for each injection (thigh, abdomen, or upper arm). New
injections should be given at least 2.5 cm or one inch from an old site and never into
areas where the site is tender, bruised, red, or hard.

Instructions for Intravenous Administration:

Preparation for intravenous administration
Reconstitute the appropriate number of Vidaza vials to achieve the desired dose as
follows:

Reconstitute each vial with 10 mL sterile water for injection. Vigorously shake or roll
the vial until all solids are dissolved. The resulting solution will contain azacitidine
10 mg/mL. The solution should be clear. Do not filter the solution as this could
remove any undissolved active substance.

Withdraw the required amount of Vidaza solution to deliver the desired dose and
inject into a 50-100 mL infusion bag of either 0.9% Sodium Chloride Injection or
Lactated Ringer’s Injection.

Intravenous Solution Incompatibility

Vidaza is incompatible with 5% dextrose solution, volulyte or solutions that contain
bicarbonate. These solutions have the potential to increase the rate of degradation of
Vidaza and should therefore be avoided.

Intravenous Administration:
Vidaza solution is administered as an intravenous infusion. Administer the total dose
over a period of 10-40 minutes. The intravenous administration must be completed
within 45 minutes of reconstitution of the Vidaza vial.

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xi) OVERDOSAGE
In the event of overdosage, the patient should be monitored with appropriate blood
counts and should receive supportive treatment, as necessary. There is no known
specific antidote for azacitidine overdosage. In New Zealand, contact the National
Poison Centre on 0800 POISON or 0800 764 766 for advice on management. In
Australia, contact the Poisons Advisory Centre on 13 11 26 for advice on
management.

One case of overdose with azacitidine was reported during clinical trials. A patient
experienced diarrhoea, nausea, and vomiting after receiving a single IV dose of
approximately 290 mg/m2, almost 4 times the recommended starting dose. The events
resolved without sequelae, and the correct dose was resumed the following day.

xii) PRESENTATION AND STORAGE CONDITIONS

Each vial contains 100 mg azacitidine and 100 mg mannitol.

Vidaza is supplied in a colourless single use Type I glass vial sealed with butyl rubber
stopper and aluminium seal with plastic button.

Pack sizes: 1 vial

Storage
Powder for injection: Store below 25°C.

xiii) MEDICINE SCHEDULE

Schedule 4 (Prescription only medicine)

xiv) NAME AND ADDRESS OF THE SPONSOR

Sponsored in Australia by:
Celgene Pty Limited
Level 15, 60 City Road
Southbank VIC 3006
Australia.
Telephone: 1800 CELGENE (1800 235 4363)

Sponsored in New Zealand by:

Celgene Limited
PO Box 3035
Wellington
New Zealand.
Phone: 0800 526 529

xv) DATE OF PREPARATION

13 September 2016

Vidaza® (azacitidine) 100 mg Powder for Injection – NZ Data Sheet

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