Consumer medicine information

Azacitidine Accord

Azacitidine

BRAND INFORMATION

Brand name

Azacitidine Accord

Active ingredient

Azacitidine

Schedule

SUMMARY CMI

AZACITIDINE ACCORD

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Azacitidine Accord?

Azacitidine Accord contains the active ingredient azacitidine. Azacitidine Accord is used 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.

For more information, see Section 1. Why am I using Azacitidine Accord? in the full CMI.

2. What should I know before I use Azacitidine Accord?

Do not use if you have ever had an allergic reaction to azacitidine or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Azacitidine Accord? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Azacitidine Accord and affect how it works.

See Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Azacitidine Accord?

Azacitidine Accord is an injection and will be given to you by your doctor or nurse.

More instructions can be found in Section 4. How do I use Azacitidine Accord? in the full CMI.

5. What should I know while using Azacitidine Accord?

Things you should do

Tell any other doctors, dentists, and pharmacists who are treating you that you are being treated with Azacitidine Accord
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 effect

Driving or using machines

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

For more information, see Section 5. What should I know while using Azacitidine Accord? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

Some of the common and serious side effects are included in full below in the CMI. Speak to your doctor if you have any of these common or serious side effects and they worry you.

The very serious side effects are:

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.
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.
Fever; chills; shortness of breath; cough; phlegm; or occasionally coughing up blood.
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.
Vomiting blood or material that looks like coffee grounds; bleeding from the back passage; black sticky bowel motions (stools); or bloody diarrhoea.
Fever, cough, difficulty breathing, rash, decreased urine, low blood pressure (hypotension), swelling of the arms or legs and rapid weight gain. These could be symptoms of a serious immune reaction (differentiation syndrome).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

FULL CMI

AZACITIDINE ACCORD

Active ingredient: azacitidine

Consumer Medicine Information (CMI)

This leaflet provides important information about using Azacitidine Accord. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Azacitidine Accord.

Where to find information in this leaflet:

1. Why am I using Azacitidine Accord?
2. What should I know before I use Azacitidine Accord?
3. What if I am taking other medicines?
4. How do I use Azacitidine Accord?
5. What should I know while using Azacitidine Accord?
6. Are there any side effects?
7. Product details

1. Why am I using Azacitidine Accord?

Azacitidine Accord contains the active ingredient azacitidine. Azacitidine is an anti-cancer agent. It is used to prevent the growth of cancer cells.

Azacitidine Accord is used 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.

2. What should I know before I use Azacitidine Accord?

Warnings

Do not use Azacitidine Accord if:

you are allergic to azacitidine or any of the ingredients listed at the end of this leaflet
always check the ingredients to make sure you can use this medicine

Check with your doctor if you have or have had:

advanced liver cancer
severe problems with your kidney function
heart problems or lung disease
allergies to any other medicines, foods, preservatives or dyes.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Women: Avoid becoming pregnant while receiving Azacitidine Accord but if you do, tell your doctor immediately.

Use an effective method of contraception during treatment with Azacitidine Accord and for up to six months after discontinuation of Azacitidine Accord.

Do not breast-feed while you are receiving Azacitidine Accord but if you do, tell your doctor immediately.

It is not known if Azacitidine Accord is excreted in human milk.

Men: Do not father a child while receiving treatment with Azacitidine Accord.

Use barrier methods of contraception (e.g. condoms) during treatment and for up to three months after discontinuation of Azacitidine Accord, if your partner is of childbearing potential.

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

3. What if I am taking other medicines?

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Azacitidine Accord.

4. How do I use Azacitidine Accord?

How much to use

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

Your doctor will decide what dose of Azacitidine Accord, the 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 Azacitidine Accord per metre squared of body surface area.

Azacitidine Accord 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 Azacitidine Accord.

When to use Azacitidine Accord

It is very important that you continue to receive Azacitidine Accord for as long as your doctor prescribes it.

You will have blood tests before you begin treatment with Azacitidine Accord 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.

Initially, Azacitidine Accord will be given daily for 7 days. 21 days later, you will have Azacitidine Accord 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.

If you are older than 65 years, your doctor will give you regular blood tests described above but may also check your kidney function during your treatment with other tests.

If you use too much Azacitidine Accord

It is unlikely that you will receive an overdose of Azacitidine Accord because a trained nurse or doctor will give it. If you think that you have been given too much Azacitidine Accord, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre (by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Azacitidine Accord?

Things you should do

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

Driving or using machines

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

Looking after your medicine

The hospital will store Azacitidine Accord under the correct conditions.

Getting rid of any unwanted medicine

Your doctor or pharmacist will dispose of any Azacitidine Accord that may be left over.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Common side effects

Common side effects

What to do

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

Speak to your doctor if you have any of these common side effects and they worry you.

Serious side effects

Serious side effects

What to do

Bleeding (including nosebleeds) or bruising in the absence of injury, or you are more tired than usual. Azacitidine Accord 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 to bleeding in your eyes.
Blood in the urine.

Call your doctor straight away or go straight to the Emergency Department at your nearest hospital

Very Serious side effects

Very Serious side effects

What to do

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 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.
Fever, cough, difficulty breathing, rash, decreased urine, low blood pressure (hypotension), swelling of the arms or legs and rapid weight gain. These could be symptoms of a serious immune reaction (differentiation syndrome).

Call your doctor straight away or go straight to the Emergency Department at your nearest hospital

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Azacitidine Accord contains

Active ingredient (main ingredient)	azacitidine
Other ingredients (inactive ingredients)	mannitol

Do not take this medicine if you are allergic to any of these ingredients.

What Azacitidine Accord looks like

Azacitidine Accord is a white powder supplied in glass vials. (100 mg Aust R 265774).

Who distributes Azacitidine Accord

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

This leaflet was prepared in August 2022.

Published by MIMS October 2022

BRAND INFORMATION

Brand name

Azacitidine Accord

Active ingredient

Azacitidine

Schedule

1 Name of Medicine

Azacitidine.

2 Qualitative and Quantitative Composition

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

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 azacitidine injection contain white sterile lyophilised powder or cake.

4 Clinical Particulars

4.1 Therapeutic Indications

Azacitidine injection 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

Injectable azacitidine should not be used interchangeably with oral azacitidine due to differences in the exposure, dose and schedule of treatment (see Section 5.2 Pharmacokinetic Properties). Healthcare professionals are recommended to verify drug name, dose, and administration route.
Azacitidine Accord 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.
Azacitidine Accord is for single use in one patient only. Discard any residue.

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.
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 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 Azacitidine Accord treatment (as defined by: Platelets < 50.0 x 10⁹/L and/or ANC < 1 x 10⁹/L) the next cycle of Azacitidine Accord 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 Azacitidine Accord 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).

Preparation of Azacitidine Accord.

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

Azacitidine Accord 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 Azacitidine Accord 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 (25°C) 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.
When Azacitidine Accord 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 Azacitidine Accord 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.

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 Azacitidine Accord 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 Azacitidine Accord 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.
See Section 6.2 Incompatibilities.

Intravenous administration.

Azacitidine Accord 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 Azacitidine Accord vial.

4.3 Contraindications

Azacitidine injection 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 Special Warnings and Precautions for Use);
pregnancy;
patients with severe renal impairment (creatinine clearance < 30 mL/min).

4.4 Special Warnings and Precautions for Use

Haematology.

Treatment with azacitidine injection 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).

Renal toxicity.

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).

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.

Differentiation syndrome.

Cases of differentiation syndrome (also known as retinoic acid syndrome) have been reported in patients receiving injectable azacitidine. Differentiation syndrome may be fatal, and symptoms and clinical findings include respiratory distress, pulmonary infiltrates, fever, rash, pulmonary oedema, peripheral oedema, rapid weight gain, pleural effusions, pericardial effusions, hypotension and renal dysfunction (see Section 4.8 Adverse Effects (Undesirable Effects)). Treatment with high-dose IV corticosteroids and haemodynamic monitoring should be considered at first onset of symptoms or signs suggestive of differentiation syndrome. Temporary discontinuation of injectable azacitidine should be considered until resolution of symptoms and if resumed, caution is advised.

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.

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). Advise females of reproductive potential to use an effective method of contraception during treatment with azacitidine and for at least 6 months after the last dose.

Use in male patients.

Men should be advised not to father a child while receiving treatment and for at least 3 months after the last dose. 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; differentiation syndrome.

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.
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.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

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 injection 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 injection 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 injection. The primary endpoint of the study was overall survival. Azacitidine injection 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 injection 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 injection 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 injection treatment arm (< 65 years, ≥ 65 years and ≥ 75 years). Azacitidine injection 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 injection treatment was also associated with a reduction in cytopenias, and their related symptoms. Azacitidine injection treatment led to a reduced need for red blood cell and platelet transfusions. Of the patients in the azacitidine injection 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

Intravenous solution incompatibility.

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Azacitidine Accord 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

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

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.
Molecular formula: C₈H₁₂N₄O₅.
Molecular weight: 244.20.
Chemical name: 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one.

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