Evoltra 1mg/ml concentrate for solution for infusion Ref.[2669] Active ingredients: Clofarabine

Therapy must be initiated and supervised by a physician experienced in the management of patients with acute leukaemias.

Posology

Adult population (including the elderly)

There are currently insufficient data to establish the safety and efficacy of clofarabine in adult patients (see section 5.2).

Paediatric population

The recommended dose is 52 mg/m² of body surface area administered by intravenous infusion over 2 hours daily for 5 consecutive days. Body surface area must be calculated using the actual height and weight of the patient before the start of each cycle. Treatment cycles should be repeated every 2 to 6 weeks (from the starting day of the previous cycle) following recovery of normal haematopoiesis (i.e. ANC ≥ 0.75 × 109/l) and return to baseline organ function. A 25% dose reduction may be warranted in patients experiencing significant toxicities (see below). There is currently limited experience of patients receiving more than 3 treatment cycles (see section 4.4).

The majority of patients who respond to clofarabine achieve a response after 1 or 2 treatment cycles (see section 5.1). Therefore, the potential benefit and risks associated with continued therapy in patients who do not show haematological and/or clinical improvement after 2 treatment cycles should be assessed by the treating physician (see section 4.4).

Children (weighing < 20 kg): An infusion time of > 2 hours should be considered to help reduce symptoms of anxiety and irritability, and to avoid unduly high maximum concentrations of clofarabine (see section 5.2).

Children (< 1 year old): There are no data on the pharmacokinetics, safety or efficacy of clofarabine in infants. Therefore, a safe and effective dosage recommendation for patients (< 1 year old) has yet to be established.

Patients with renal insufficiency: The limited data available indicate that clofarabine may accumulate in patients with decreased creatinine clearance (see sections 4.4 and 5.2). Clofarabine is contraindicated in patients with severe renal insufficiency (see section 4.3) and should be used with caution in patients with mild to moderate renal insufficiency (see section 4.4).

Patients with moderate renal impairment (creatinine clearance 30 — <60 ml/min) require a 50% dose reduction (see section 5.2).

Patients with hepatic impairment: There is no experience in patients with hepatic impairment (serum bilirubin > 1.5 x ULN plus AST and ALT > 5 x ULN) and the liver is a potential target organ for toxicity. Therefore, clofarabine is contraindicated in patients with severe hepatic impairment (see section 4.3) and should be used with caution in patients with mild to moderate hepatic impairment (see section 4.4).

Dose reduction for patients experiencing haematological toxicities: If the ANC does not recover by 6 weeks from the start of a treatment cycle, a bone marrow aspirate / biopsy should be performed to determine possible refractory disease. If persistent leukaemia is not evident, it is recommended that the dose for the next cycle be reduced by 25% of the previous dose following recovery of ANC to ≥ 0.75 × 109/l. Should patients experience an ANC < 0.5 × 109/l for more than 4 weeks from the start of the last cycle, it is recommended that the dose for the next cycle be reduced by 25%.

Dose reduction for patients experiencing non-haematological toxicities:

Infectious events: If a patient develops a clinically significant infection, clofarabine treatment may be withheld until the infection is clinically controlled. At this time, treatment may be reinitiated at the full dose. In the event of a second clinically significant infection, clofarabine treatment should be withheld until the infection is clinically controlled and may be reinitiated at a 25% dose reduction.

Non-infectious events: If a patient experiences one or more severe toxicities (US National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Grade 3 toxicities excluding nausea and vomiting), treatment should be delayed until the toxicities resolve to baseline parameters or to the point where they are no longer severe and the potential benefit of continued treatment with clofarabine outweighs the risk of such continuation. It is then recommended that clofarabine be administered at a 25% dose reduction.

Should a patient experience the same severe toxicity on a second occasion, treatment should be delayed until the toxicity resolves to baseline parameters or to the point where it is no longer severe and the potential benefit of continued treatment with clofarabine outweighs the risk of such continuation. It is then recommended that clofarabine be administered at a further 25% dose reduction.

Any patient who experiences a severe toxicity on a third occasion, a severe toxicity that does not recover within 14 days (see above for exclusions), or a life-threatening or disabling toxicity (US NCI CTC Grade 4 toxicity) should be withdrawn from treatment with clofarabine (see section 4.4).

Method of administration

For instructions on dilution of the medicinal product before administration, see section 6.6. The recommended dosage should be administered by intravenous infusion although it has been administered via a central venous catheter in ongoing clinical trials. Evoltra must not be mixed with or concomitantly administered using the same intravenous line as other medicinal products (see section 6.2).

No case of overdose has been reported. However, possible symptoms of overdose are expected to include nausea, vomiting, diarrhoea and severe bone marrow suppression. To date, the highest daily dose administered to human beings is 70 mg/m² for 5 consecutive days (2 paediatric ALL patients). The toxicities observed in these patients included vomiting, hyperbilirubinaemia, elevated transaminase levels and maculo-papular rash.

No specific antidotal therapy exists. Immediate discontinuation of therapy, careful observation and initiation of appropriate supportive measures are recommended.

3 years.

The diluted concentrate is chemically and physically stable for 3 days at 2°C to 8°C and at room temperature. From a microbiological point of view, it should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C unless dilution has taken place under controlled and validated aseptic conditions.

Do not freeze.

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

Type I glass vial with bromobutyl rubber stopper, polypropylene flip-off cap and aluminium overseal. The vials contain 20 ml concentrate for solution for infusion and are packaged in a box. Each box contains 1, 3, 4, 10 or 20 vials.

Not all pack sizes may be marketed.

Evoltra 1 mg/ml concentrate for solution for infusion must be diluted prior to administration. It should be filtered through a sterile 0.2 micrometre syringe filter and then diluted with sodium chloride 9 mg/ml (0.9%) intravenous infusion to produce a total volume according to the examples given in the table below. However, the final dilution volume may vary depending on the patient’s clinical status and physician discretion. (If the use of a 0.2 micrometre syringe filter is not feasible, the concentrate should be pre-filtered with a 5 micrometre filter, diluted and then administered through a 0.22 micrometre in-line filter.)

* Each ml of concentrate contains 1 mg of clofarabine. Each 20 ml vial contains 20 mg of clofarabine. Therefore, for patients with a body surface area ≤ 0.38 m², the partial contents of a single vial will be required to produce the recommended daily dosage of clofarabine. However, for patients with a body surface area > 0.38 m², the contents of between 1 to 7 vials will be required to produce the recommended daily dosage of clofarabine.

The diluted concentrate should be a clear, colourless solution. It should be visually inspected for particulate matter and discolouration prior to administration.

Evoltra is for single use only. Any unused product must be discarded.

Procedures for proper handling of antineoplastic agents should be observed. Cytotoxic medicinal products should be handled with caution.

The use of disposable gloves and protective garments is recommended when handling Evoltra. If the product comes into contact with eyes, skin or mucous membranes, rinse immediately with copious amounts of water.

Evoltra should not be handled by pregnant women.

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