Procesamiento de la Información

Once the reconstituted MylotargTM _{is diluted in 100 ml sodium chloride 0.9% for} infusion, the resulting solution should be infused over 2 hours. Prior to infusion inspect visually for particulate matter and discoloration. A separate IV line equipped with a low protein-binding 1.2-micron terminal filter must be used for administration of the drug (see note1_{). MYLOTARG}TM _{may be given peripherally or} through a central line. Premedication, consisting of an antihistamine (such as

chlorphenamine), should be given before each infusion to reduce the incidence of a post-infusion symptom complex. Vital signs should be monitored during infusion and for four hours following infusion

Instructions for Use, Handling and for Disposal:

Procedures for handling and disposal of cytotoxic drugs should be applied. Cautions

Hepatic Insufficiency: Patients with hepatic impairment will not be included in the clinical studies.

Renal Insufficiency: Patients with renal impairment will not be included in the clinical studies.

Note1

The recommended in-line filter for Mylotarg administration is a 1.2-micron polyether sulfone (PES) filter, e.g. “intrapurlipid” (Braun product number 4099702). If that filter is not available, the following filters may be used: 0.22 micron PES, 0.20 micron cellulose acetate, 0.8 to 1.2 micron cellulose acetate/cellulose nitrate (mixed ester), or 1.2 micron acrylic copolymer.

Adverse Events

The most important serious adverse event may be hepatotoxicity or myelosuppression. These should be reported to the Chief Investigator as described in Section 18. Other events which have been reported in at least 10% of recipients of single agent Mylotarg include fever, nausea, chills, vomiting, headache, dyspneoa, hypotension, hypertension, and hyperglycaemia. It is not necessary to report these events.

CLOFARABINE (EvoltraTM_{; Bioenvision Limited)}

Clofarabine is a purine nucleoside anti-metabolite. It is formulated as a 1 mg/ml sterile concentrate solution for infusion. It is a clear, practically colourless solution with a pH of 4.5 to 7.5 and an osmolarity of 270 to 310 mOsm/l.

Clofarabine is supplied in 20 ml, Type I glass vials with bromobutyl rubber stopper, polypropylene flip-off cap and aluminium overseal. The vials contain 20 ml sterile concentrate and are packaged in boxes of 4 vials.

Each 20 ml vial contains 20 mg of clofarabine and 180 mg of sodium chloride. The latter is equivalent to 3.08 mmol (or 70.77 mg) of sodium and should be taken into consideration for patients on a controlled sodium diet.

Posology and method of administration

The dose per protocol (mg/m2_{) is administered by intravenous infusion in 100 to} 250ml of N saline over 1 hour 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.

Clofarabine 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 as required. If the use of a 0.2 micrometre syringe filter is not feasible, the sterile concentrate should be pre-filtered with a 5 micrometre filter, diluted and then administered through a 0.22 micrometre in-line filter. The diluted sterile concentrate should be a clear, colourless solution. Visually inspect for particulate matter and discolouration prior to administration.

The recommended dosage should be administered by intravenous infusion. Clofarabine should not be mixed with or concomitantly administered using the same intravenous line as other medicinal products.

Patients with renal insufficiency: There is no experience in patients with renal insufficiency (serum creatinine ≥ 2 x ULN for age) and clofarabine is predominately excreted via the kidneys. In AML16, clofarabine is contraindicated in patients with serum creatinine levels above the normal range.

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 and should be used with caution in patients with mild to moderate hepatic impairment.

For detailed information on product, refer to Investigator Brochure. Storage

Vials should not be frozen. The diluted sterile concentrate is chemically and physically stable for 72 hours at 2 – 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 – 8°_{C unless} dilution has taken place under controlled and validated aseptic conditions.

AZACYTIDINE (VidazaTM _{) (Pharmion Corporation)}

Azacytidine is a pyridine nucleoside analogue of Cytidine (C2 H12 N4 O5 ) is supplied for injectable suspension as a lyophilized powder in 100mg single vials for single use which should be stored at 15 – 30°_{C. Procedures for the proper handling of} chemotherapy should be applied. In this trial it will be used in a dose of 75 mg/m2 daily for 5 days by subcutaneous injection, which may be subject to dose reduction.

The main side effects are gastrointestinal and myelosuppression. Patients should be pre-medicated with an anti-emetic (e.g. ondansentron).

Azacytidine is reconstituted in 4 ml of water for injection. The diluent should be injected slowly into the vial which will then contain 25 mg/ml. If a larger dose is required the sc injection should be given in two sites. The suspension should be gently mixed and can be kept a room temperature for up to one hour or kept refrigerated at 4 – 8°_{C for up to 8 hours. After removal from refrigeration the} suspension should be injected within 30 minutes. If more than one vial is required to achieve the dose the dose should be equally divided between two syringes and injected into two sites.

Cautions

There is no experience of treating patients with pre-existing hepatic or renal dysfunction, so no recommendations are available, however such patients should be observed carefully after treatment. Azacytidine is contraindicated in patients with an allergy to mannitol.

ARSENIC TRIOXIDE (TrisenoxTM_{) (Cephalon Inc.)}

Trisenox is 1 mg/ml concentrate for solution for infusion (arsenic trioxide). It is presented as a sterile, clear, aqueous solution in a single use 10 ml ampoule. ATO is a trivalent inorganic arsenical. The active substance is a white crystalline powder that is very poorly soluble in water.

Trisenox must be diluted with 100 – 250 ml of glucose (5%) injection or sodium chloride 9 mg/ml (0.9%) injection immediately after withdrawal from the ampoule and must not be mixed with or concomitantly administered in the same intravenous line with other medicinal products.

Aseptic technique must be strictly observed throughout the handling of Trisenox since no preservation is present.

After dilution in intravenous solutions, Trisenox is chemically and physically stable for 24 hours at 15 – 30°_{C and 48 hours at refrigerated temperatures (2 – 8}°_C). From a microbiological point of view, the product must 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 – 8°_{C, unless dilution has taken place in controlled and validated aseptic conditions.}

Trisenox is given as a slow infusion over 1 – 2 hours. The daily infusions may be given on an inpatient basis, but investigators should ensure that serum potassium and magnesium levels are within the normal range at the start of each treatment week. Trisenox should not be mixed with other medications.