Consumer medicine information

Celazadine

Azacitidine

BRAND INFORMATION

Brand name

Celazadine

Active ingredient

Azacitidine

Schedule

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Celazadine.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Celazadine against the benefits this medicine is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

WHAT IS CELAZADINE USED FOR

Celazadine is an anti-cancer agent. This product contains a medicine called azacitidine which prevents the growth of cancer cells. Celazadine has been prescribed by your doctor for the treatment of myelodysplastic syndrome (MDS). Myelodysplastic syndrome is a blood disorder in which the bone marrow is not working normally and does not produce enough mature blood cells. This causes a lack of healthy blood cells that can function properly in the body.

Ask your doctor if you have any questions about how this medicine works, or why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

Celazadine will only be prescribed to you by a doctor who has experience in medicines to treat cancers of the blood.

BEFORE YOU ARE GIVEN CELAZADINE

When you must not be given Celazadine

Tell your doctor:

If you are allergic to azacitidine or any of the other ingredients of the product listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:
- shortness of breath
- wheezing or difficulty breathing
- swelling of the face, lips, tongue or other parts of the body
- rash, itching or hives on the skin.

If you have advanced liver cancer.
If you are pregnant.
If you have severe problems with your kidney function.

Before you are given Celazadine

1. Use by women

Avoid becoming pregnant while receiving this medicine but, if you do, tell your doctor immediately.
Use an effective method of contraception during treatment with this medicine and for up to three (3) months after discontinuation of the medicine.
Do not breast-feed while you are receiving Celazadine but, if you do, tell your doctor immediately.
It is not known if azacitidine is excreted in human milk.

2. Use by men

Do not father a child while receiving treatment with Celazadine.
Use barrier methods of contraception (e.g. condoms) during treatment and for up to three (3) months after discontinuation of this medicine, if your partner is of childbearing potential.
Talk to your doctor if you wish to conserve your sperm before having this treatment.

3. Use by all patients

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.
Do not give Celazadine to children (under 18 years).
Before receiving this medicine, tell your doctor if you have had any heart problems or lung disease.
You will have blood tests before you begin treatment with Celazadine 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.
If you are older than 65 years, your doctor will give you the regular blood tests described above but may also check your kidney function during your treatment with other tests.

Taking other medicines

Tell your doctor if you are taking any other medicines or have recently taken any other medicines, including any medicines that you buy without a prescription from a pharmacy, supermarket or health food shop.

HOW YOU WILL BE GIVEN CELAZADINE

Celazadine will be given to you as an injection under the skin (subcutaneously i.e. under the skin on your thigh, abdomen or upper arm) or as an intravenous infusion by a doctor or nurse.

Your doctor will choose the correct dose of this medicine for you.

Your dose will depend on your general condition and your height and weight.
Your dose will be calculated based on your body surface area, with the usual dose of 75 mg Celazadine per m² of body surface.
Initially, this medicine will be given daily for 7 days. 21 days later, you will have Celazadine for another 7 days. This is called a cycle. The cycle is repeated every 28 days for a minimum of 6 cycles.
Your doctor will check your progress and may change your dose if necessary.

Celazadine can cause nausea and vomiting. To stop you from getting sick (nausea and vomiting), your doctor may give you another medicine at the start of each treatment cycle with Celazadine.

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

WHILE YOU ARE BEING TREATED WITH CELAZADINE

Things you must do

Tell any other doctors, dentists, and pharmacists who are treating you that you are being treated with Celazadine.

Tell your doctor immediately if you stop passing urine or if you are passing less urine than normal.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being treated with this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Keep all your doctor's appointments so that your progress can be checked. Your doctor will do some tests e.g. blood tests, at regular intervals to make sure the medicine is working and to prevent any unwanted side effects.

Things to be careful of

Be careful driving or operating machinery until you know how Celazadine affects you.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are receiving Celazadine.

Like all medicines, this medicine can have side effects, although not everybody gets them. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

Sore throat or trouble swallowing; feeling of tension in the nose, cheeks or behind your eyes; runny or blocked nose.
Trouble sleeping; feeling tired or lacking energy; dizziness; headache; anxiety; or feeling confused.
Loss of appetite, decreased weight, constipation, stomach pain, indigestion.
Cold sores or bleeding from the gums.
Red or purple, flat, pinhead spots under the skin; itching; rash; bruising, redness of the skin; soreness and swelling at the injection site; unusual hair loss or thinning.
Muscle or joint pain.
Chest pain.

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible if you notice any of the following:

Bleeding (including nose-bleeds) or bruising in the absence of injury, or you are more tired than usual.
Celazadine can reduce the number of red blood cells that carry oxygen around the body and can also reduce the number of platelets, which are responsible for making the blood clot appropriately.
Pain in one or both eyes, changes in vision.
This could be due bleeding in your eyes.
Blood in the urine.

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

Shortness of breath; wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash; itching; or hives on the skin.
These could be symptoms of an allergic reaction.
A sudden severe headache; weakness or numbness in the face, arm or leg; changes in vision; trouble speaking or understanding speech; or loss of coordination.
These could be signs of bleeding in the brain (a type of stroke).
Fever; chills; shortness of breath; cough; phlegm; or occasionally coughing up blood.
These could be the symptoms of pneumonia (a serious lung infection).
Fever; severe chills; hot, tender and red skin; rapid breathing; rapid pulse; confusion; nausea; vomiting; diarrhoea; pain or burning when you urinate; sore mouth or throat; or mouth ulcers.
These could be symptoms of sepsis (blood infection) or other frequent infections.
Vomiting blood or material that looks like coffee grounds; bleeding from the back passage; black sticky bowel motions (stools); or bloody diarrhoea.
These could be signs of bleeding in your gut.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects (for example, high blood pressure) can only be found when your doctor does tests from time to time to check your progress.

AFTER BEEN GIVEN CELAZADINE

Storage

Your doctor or pharmacist is responsible for storing Celazadine. They are also responsible for disposing of any unused product correctly.

PRODUCT DESCRIPTION

What this medicine looks like

Celazadine is a white powder for suspension for injection and is supplied in a glass vial containing 100 mg of azacitidine.

Ingredients

The active substance is azacitidine.
The other ingredient is mannitol.

This medicine does not contain lactose.

Supplier

Celazadine is supplied in Australia by:

Celgene Pty Limited
Level 15, 60 City Road
Southbank VIC 3006.

Distributed in Australia by:

Juno Pharmaceuticals Pty Ltd
42 Kelso Street
Cremorne, VIC 3121
Australia
For medical enquires telephone: 1800 620 076.

In New Zealand:

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

® = Registered Trademark

This leaflet was updated in July 2020.

Australian Registration Number: 216327

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Celazadine

Active ingredient

Azacitidine

Schedule

Notes

Distributed by Juno Pharmaceuticals Pty Ltd

1 Name of Medicine

Australian approved name: azacitidine.

2 Qualitative and Quantitative Composition

Each vial contains 100 mg azacitidine.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

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 Celazadine contain 100 mg of azacitidine and 100 mg mannitol as a white to off-white, sterile lyophilised powder.
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.

4 Clinical Particulars

4.1 Therapeutic Indications

Celazadine 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.

4.2 Dose and Method of Administration

Azacitidine 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.

Dose.

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.
With subcutaneous injection, rotate sites for injection (thigh, abdomen, or upper arm). 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 hard.

Dosage modification or interruption.

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 the first treatment.

If haematological toxicity is observed following Celazadine treatment (as defined by: Platelets < 50.0 x 10⁹/L and/or ANC < 1 x 10⁹/L) the next cycle of Celazadine 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 Table 1. Following dose modifications, the cycle duration should return to 28 days.

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 the first 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 Celazadine 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 Table 2.

Following dose modifications, the cycle duration should return to 28 days.
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 Section 4.4 Special Warnings and Precautions for Use).

Method of administration.

Celazadine is a cytotoxic drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Celazadine suspensions. Procedures for proper handling and disposal of anticancer drugs should be applied.
If reconstituted Celazadine 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 Celazadine 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. Celazadine 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 reconstituted product may be kept in the vial or drawn into a syringe (see Immediate/ Delayed subcutaneous administration below).
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.
When more than 1 vial is needed, all of the above steps for preparation of the suspension should be repeated.
The suspension contains azacitidine 25 mg/mL. The maximum recovery of azacitidine is 96% per vial following reconstitution.
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. 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) and injected into two separate sites.

Suspension stability.

To reduce microbiological hazard, use as soon as practicable after reconstitution.
Reconstituted Celazadine 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.

Immediate subcutaneous administration.

The reconstituted product may be drawn into a syringe and held at room temperature (25°C), but must be administered within 1 hour after reconstitution.

Delayed subcutaneous administration.

The reconstituted product may be kept in the vial or drawn into a syringe. The reconstituted product must be refrigerated immediately.
When Celazadine is reconstituted using water for injections that has not been refrigerated, the product may be held under refrigerated conditions (2°C-8°C) for up to 8 hours.
When Celazadine is reconstituted using refrigerated (2°C-8°C) water for injections, the product may be stored under refrigerated conditions (2°C-8°C) 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.
Instructions for intravenous administration.

Preparation for intravenous administration.

Reconstitute the appropriate number of Celazadine 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 Celazadine 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.

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

Intravenous administration.

Celazadine 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 Celazadine vial.

4.3 Contraindications

Celazadine is contraindicated in the following:
patients with known hypersensitivity to azacitidine or to any of the excipients;
patients with advanced malignant hepatic tumours (see Section 4.4);
pregnancy;
patients with severe renal impairment (creatinine clearance < 30 mL/min).

4.4 Special Warnings and Precautions for Use

Identified precautions.

Haematological toxicity.

Treatment with azacitidine 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, see Section 4.2 Dose and Method of Administration.

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.

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.

Use in hepatic impairment.

No formal studies have been conducted in patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties). The pivotal safety and efficacy study excluded patients with bilirubin > 1.5 times the upper limit of normal, or with AST or ALT > 2.0 times the upper limit of normal. The safety of azacitidine in such patients has therefore not been established.
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 Contraindications).

Use in 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 (see Section 4.2 Dose and Method of 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 Section 4.2 Dose and Method of Administration). There are inadequate pharmacokinetic or safety data to support the use of azacitidine in patients with severe renal impairment (creatinine clearance < 30 mL/min - see Section 4.3 Contraindications).
Patients should be advised to report oliguria and anuria to the health care provider immediately.

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.

Paediatric use.

The safety and efficacy of azacitidine in children and adolescents under 18 years of age have not been established.

Effects on 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 are not recommended. Where such medications are considered essential, alternatives that are not strong inducers or inhibitors of metabolising enzymes should be sought.

4.6 Fertility, Pregnancy and Lactation

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.
Treatment of male rats three times per week for 6 to 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.
(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 the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the foetus (see Section 4.3 Contraindications).
Men and women of childbearing potential must use effective contraception during and up to 3 months after treatment.

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).
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.

4.7 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.

4.8 Adverse Effects (Undesirable 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 hypokalaemia.
Table 3 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.
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 (≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

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.

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 reactions associated with azacitidine treatment were haematological including: thrombocytopenia, neutropenia and leucopenia (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 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 Section 4.4 Special Warnings and Precautions for Use).

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 Section 4.4 Special Warnings and Precautions for Use).

Post-marketing data.

The following events have been reported in post-marketing setting: interstitial lung disease; tumour lysis syndrome; injection site necrosis; cellulitis; necrotizing fasciitis; acute febrile neutrophilic dermatosis; pyoderma gangrenosum.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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 Australia, contact the Poisons Information Centre on 13 11 26 for advice on management.
In New Zealand, contact the National Poison Centre on 0800 POISON or 0800 764 766 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.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: antineoplastic agents, antimetabolites, pyrimidine analogues, ATC code: L01BC07.

Mechanism of action.

Azacitidine is believed to exert its antineoplastic effects by causing hypomethylation of DNA and direct cytotoxicity on abnormal haematopoietic cells in the bone marrow.
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.

Clinical trials.

The efficacy and safety of azacitidine 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. Azacitidine 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 azacitidine. The primary endpoint of the study was overall survival. Azacitidine 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), azacitidine 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. See Figure 1.

The survival benefits of azacitidine 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.
When IPSS cytogenetic subgroups were analysed, similar findings in terms of median overall survival were observed in all groups (good, intermediate, poor cytogenetics).
On analyses of age subgroups, an increase in median overall survival was observed for all groups in the azacitidine treatment arm (< 65 years, ≥ 65 years and ≥ 75 years). Azacitidine 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.
Azacitidine treatment was also associated with a reduction in cytopenias, and their related symptoms. Azacitidine treatment led to a reduced need for red blood cell 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)).

5.2 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 nanogram/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 C_max was 2580 nanogram/mL. The differences in C_max 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 microM to 100 microM, 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 microM, 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.

5.3 Preclinical Safety Data

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.

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each vial contains 100 mg mannitol.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Unopened powder vial.

4 years.

6.4 Special Precautions for Storage

Powder for injection: Store below 25°C.

6.5 Nature and Contents of Container

Celazadine 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.

6.6 Special Precautions for Disposal

6.7 Physicochemical Properties

Chemical Name: 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one.

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