VIDAZA Powder for suspension for injection Ref.[6341] Active ingredients: Azacitidine

Vidaza treatment should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic agents. Patients should be premedicated with anti-emetics for nausea and vomiting.

Posology

The recommended starting dose for the first treatment cycle, for all patients regardless of baseline haematology laboratory values, is 75 mg/m² of body surface area, injected subcutaneously, daily for 7 days, followed by a rest period of 21 days (28-day treatment cycle).

It is recommended that patients be treated for a minimum of 6 cycles. Treatment should be continued as long as the patient continues to benefit or until disease progression.

Patients should be monitored for haematologic response/toxicity and renal toxicities (see section 4.4); a delay in starting the next cycle or a dose reduction as described below may be necessary.

Laboratory tests

Liver function tests, serum creatinine and serum bicarbonate should be determined prior to initiation of therapy and prior to each treatment cycle. Complete blood counts should be performed prior to initiation of therapy and as needed to monitor response and toxicity, but at a minimum, prior to each treatment cycle.

Dose adjustment due to haematological toxicity

Haematological toxicity is defined as the lowest count reached in a given cycle (nadir) if platelets ≤ 50.0 × 10^9^/l and/or absolute neutrophil count (ANC) ≤ 1 × 10^9^/l.

Recovery is defined as an increase of cell line(s) where haematological toxicity was observed of at least half of the difference of nadir and the baseline count plus the nadir count (i.e. blood count at recovery ≥ nadir count + (0.5 x [baseline count – nadir count]).

Patients without reduced baseline blood counts (i.e. White Blood Cells (WBC) ≥ 3.0 × 10^9^/l and ANC ≥ 1.5 × 10^9^/l, and platelets ≥ 75.0 × 10^9^/l) prior to the first treatment

If haematological toxicity is observed following Vidaza treatment, the next cycle of the therapy should be delayed until the platelet count and the ANC have recovered. If recovery is achieved within 14 days, no dose adjustment is necessary. However, if recovery has not been achieved within 14 days, the dose should be reduced according to the following table. Following dose modifications, the cycle duration should return to 28 days.

* Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count])

Patients with reduced baseline blood counts (i.e. WBC < 3.0 × 10^9^/l or ANC < 1.5 × 10^9^/l or platelets < 75.0 × 10^9^/l) prior to the first treatment

Following Vidaza treatment, if the decrease in WBC or ANC or platelets from that prior to treatment is ≤50 , or greater than 50 but with an improvement in any cell line differentiation, the next cycle should not be delayed and no dose adjustment made.

If the decrease in WBC or ANC or platelets is greater than 50 % from that prior to treatment, with no improvement in cell line differentiation, the next cycle of Vidaza therapy should be delayed until the platelet count and the ANC have recovered. If recovery is achieved within 14 days, no dose adjustment is necessary. However, if recovery has not been achieved within 14 days, bone marrow cellularity should be determined. If the bone marrow cellularity is >50%, no dose adjustments should be made. If bone marrow cellularity is ≤50%, treatment should be delayed and the dose reduced according to the following table:

* Recovery = counts ≥ nadir count + (0.5 x [baseline count – nadir count])

Following dose modifications, the cycle duration should return to 28 days.

Special populations

Elderly patients

No specific dose adjustments are recommended for the elderly. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.

Patients with renal impairment

Azacitidine can be administered to patients with renal impairment without initial dose adjustment (see section 5.2). If unexplained reductions in serum bicarbonate levels to less than 20 mmol/l occur, the dose should be reduced by 50 % on the next cycle. If unexplained elevations in serum creatinine or blood urea nitrogen (BUN) to ≥ 2-fold above baseline values and above upper limit of normal (ULN) occur, the next cycle should be delayed until values return to normal or baseline and the dose should be reduced by 50 % on the next treatment cycle (see section 4.4).

Patients with hepatic impairment

No formal studies have been conducted in patients with hepatic impairment (see section 4.4). Patients with severe hepatic organ impairment should be carefully monitored for adverse events. No specific modification to the starting dose is recommended for patients with hepatic impairment prior to starting treatment; subsequent dose modifications should be based on haematology laboratory values. Vidaza is contraindicated in patients with advanced malignant hepatic tumours (see sections 4.3 and 4.4).

Paediatric population

The safety and efficacy of Vidaza in children aged 0-17 years have not yet been established. No data are available.

Method of administration

Reconstituted Vidaza should be injected subcutaneously into the upper arm, thigh or abdomen. Injection sites should be rotated. New injections should be given at least 2.5 cm from the previous site and never into areas where the site is tender, bruised, red, or hardened.

After reconstitution, the suspension should not be filtered. For instructions on reconstitution of the medicinal product before administration, see section 6.6.

One case of overdose with azacitidine was reported during clinical trials. A patient experienced diarrhoea, nausea, and vomiting after receiving a single intravenous dose of approximately 290 mg/m², almost 4 times the recommended starting dose.

In the event of overdose, the patient should be monitored with appropriate blood counts and should receive supportive treatment, as necessary. There is no known specific antidote for azacitidine overdose.

Unopened powder vial: 4 years.

After reconstitution:

When Vidaza is reconstituted using water for injections that has not been refrigerated, chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated at 25°C for 45 minutes and at 2°C to 8°C for 8 hours.

The shelf life of the reconstituted medicinal product can be extended by reconstituting with refrigerated (2°C to 8°C) water for injections. When Vidaza is reconstituted using refrigerated (2°C to 8°C) water for injections, the chemical and physical in-use stability of the reconstituted medicinal product has been demonstrated at 2°C to 8°C for 22 hours.

From a microbiological point of view, the reconstituted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and must not be longer than 8 hours at 2°C to 8°C when reconstituted using water for injections that has not been refrigerated or not longer than 22 hours when reconstituted using refrigerated (2°C to 8°C) water for injections.

Unopened vials: This medicinal product does not require any special storage conditions.

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

Colourless type I glass vial sealed with butyl elastomeric stopper and aluminium seal with polypropylene plastic button, containing 100 mg of azacitidine.

Pack size: 1 vial.

Recommendations for safe handling

Vidaza is a cytotoxic medicinal product and, as with other potentially toxic compounds, caution should be exercised when handling and preparing azacitidine suspensions. Procedures for proper handling and disposal of anticancer medicinal products should be applied. If reconstituted azacitidine comes into contact with the skin, immediately and thoroughly wash with soap and water. If it comes into contact with mucous membranes, flush thoroughly with water.

Reconstitution procedure

Vidaza should be reconstituted with water for injections. The shelf life of the reconstituted medicinal product can be extended by reconstituting with refrigerated (2°C to 8°C) water for injections. Details on storage of the reconstituted product are provided below.

1. The following supplies should be assembled: Vial (s) of azacitidine; vial(s) of water for injections; non-sterile surgical gloves; alcohol wipes; 5 mL injection syringe(s) with needle(s).
2. 4 mL of water for injections should be drawn into the syringe, making sure to purge any air trapped within the syringe.
3. The needle of the syringe containing the 4 mL of water for injections should be inserted through the rubber top of the azacitidine vial followed by injection of the water for injections into the vial.
4. Following removal of the syringe and needle, the vial should be vigorously shaken until a uniform cloudy suspension is achieved. After reconstitution each mL of suspension will contain 25 mg of azacitidine (100 mg/4 mL). The reconstituted product is a homogeneous, cloudy suspension, free of agglomerates. The product should be discarded if it contains large particles or agglomerates. Do not filter the suspension after reconstitution since this could remove the active substance. It must be taken into account that filters are present in some adaptors, spikes and closed systems; therefore such systems should not be used for administration of the medicinal product after reconstitution.
5. The rubber top should be cleaned and a new syringe with needle inserted into the vial. The vial should then be turned upside down, making sure the needle tip is below the level of the liquid. The plunger should then be pulled back to withdraw the amount of medicinal product required for the proper dose, making sure to purge any air trapped within the syringe. The syringe with needle should then be removed from the vial and the needle disposed of.
6. A fresh subcutaneous needle (recommended 25-gauge) should then be firmly attached to the syringe. The needle should not be purged prior to injection, in order to reduce the incidence of local injection site reactions.
7. When more than 1 vial is needed all the above steps for preparation of the suspension should be repeated. For doses requiring more than 1 vial, the dose should be equally divided e.g., dose 150 mg = 6 mL, 2 syringes with 3 mL in each syringe. Due to retention in the vial and needle, it may not be feasible to withdraw all of the suspension from the vial.
8. The contents of the dosing syringe must be re-suspended immediately prior to administration. The syringe filled with reconstituted suspension should be allowed up to 30 minutes prior to administration to reach a temperature of approximately 20°C-25°C. If the elapsed time is longer than 30 minutes, the suspension should be discarded appropriately and a new dose prepared. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy suspension is achieved. The product should be discarded if it contains large particles or agglomerates.

Storage of the reconstituted product

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

Calculation of an individual dose

The total dose, according to the body surface area (BSA) can be calculated as follows: Total dose (mg) = Dose (mg/m²) x BSA (m²) The following table is provided only as an example of how to calculate individual azacitidine doses based on an average BSA value of 1.8 m².

Method of administration

Reconstituted Vidaza should be injected subcutaneously (insert the needle at a 45-90° angle) using a 25-gauge needle into the upper arm, thigh or abdomen.

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

Injection sites should be rotated. New injections should be given at least 2.5 cm from the previous site and never into areas where the site is tender, bruised, red, or hardened.

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