MYLOTARG Powder for concentrate for solution for infusion Ref.[8921] Active ingredients: Gemtuzumab ozogamicin

MYLOTARG should be administered under the supervision of a physician experienced in the use of anticancer medicinal products and in an environment where full resuscitation facilities are immediately available.

MYLOTARG should be used only in patients eligible to receive intensive induction chemotherapy.

Premedication with a corticosteroid, antihistamine, and acetaminophen (or paracetamol) is recommended 1 hour prior to dosing to help ameliorate infusion-related symptoms (see section 4.4).

Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia, such as hydration, administration of antihyperuricemic or other agents for treatment of hyperuricaemia should be taken (see section 4.4).

Posology

Induction

The recommended dose of MYLOTARG is 3 mg/m²/dose (up to a maximum of one 5 mg vial) infused over a 2-hour period on Days 1, 4, and 7 in combination with DNR 60 mg/m²/day infused over 30 minutes on Day 1 to Day 3, and AraC 200 mg/m²/day by continuous infusion on Day 1 to Day 7.

If a second induction is required, MYLOTARG should not be administered during second induction therapy. Only DNR and AraC should be administered during the second induction cycle, at the following recommended dosing: DNR 35 mg/m²/day on Days 1 and 2, and AraC 1 g/m² every 12 hours, on Day 1 to Day 3.

Consolidation

For patients experiencing a complete remission (CR) following induction, defined as fewer than 5% blasts in a normocellular marrow and an absolute neutrophil count (ANC) of more than 1.0 × 10⁹ cells/L with a platelet count of 100 × 10⁹/L or more in the peripheral blood in the absence of transfusion, up to 2 consolidation courses of intravenous DNR (60 mg/m² for 1 day [first course] or 2 days [second course]) in combination with intravenous AraC (1 g/m² per 12 hours, infused over 2 hours on Day 1 to Day 4) with intravenous MYLOTARG (3 mg/m²/dose infused over 2 hours up to a maximum dose of one 5 mg vial on Day 1) are recommended.

Table 1. Dosing regimens for MYLOTARG in combination with chemotherapy:

^a See Table 3 and Table 4 for dose modification information.
^b For patients experiencing a complete remission (CR) following induction.

Dose and schedule modifications

Schedule modification for hyperleukocytosis

In patients with hyperleukocytic (leukocyte count ≥30,000/mm³) AML, cytoreduction is recommended either with leukapheresis, oral hydroxyurea or AraC with or without hydroxyurea to reduce the peripheral white blood cell (WBC) count 48 hours prior to administration of MYLOTARG.

If AraC is used for leukoreduction with or without hydroxyurea in patients with previously untreated, de novo hyperleukocytic AML receiving MYLOTARG in combination therapy, apply the following modified schedule (Table 2).

Table 2. Schedule modification for the treatment of hyperleukocytosis with cytarabine:

See Table 1 for dose recommendations for consolidation course.
^a See Table 3 and Table 4 for additional dose modification information.

Dose modification for adverse reactions

Dose modification of MYLOTARG is recommended based on individual safety and tolerability (see section 4.4). Management of some adverse reactions may require dose interruptions or permanent discontinuation of MYLOTARG (see sections 4.4 and 4.8).

Tables 3 and 4 show the dose modification guidelines for haematological and non-haematological toxicities, respectively.

Table 3. Dose modifications for haematological toxicities:

Abbreviations: AML=acute myeloid leukaemia; AraC=cytarabine; BMA=bone marrow aspirate, DNR=daunorubicin.

Table 4. Dose modifications for non-haematological toxicities:

Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; SOS=sinusoidal obstruction syndrome; ULN=upper limit of normal; VOD=venoocclusive disease.

Special populations

Use in patients with hepatic impairment

No adjustment of the starting dose is required in patients with hepatic impairment defined by total bilirubin ≤2 × upper limit of normal (ULN) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5 × ULN. Postpone MYLOTARG until recovery of total bilirubin to ≤2 × ULN and AST and ALT to ≤2.5 × ULN prior to each dose (see Table 4, sections 4.4 and 5.2).

Use in patients with renal impairment

No dose adjustment is required in patients with mild to moderate renal impairment. MYLOTARG has not been studied in patients with severe renal impairment. MYLOTARG does not undergo renal clearance, the pharmacokinetics in patients with severe renal impairment is unknown (see section 5.2).

Elderly patients

No dose adjustment is required in elderly patients (≥65 years) (see section 5.2).

Paediatric population

The safety and efficacy of MYLOTARG in patients less than 15 years of age has not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made. Method of administration MYLOTARG is for intravenous use and must be reconstituted and diluted before administration (see section 6.6). When reconstituted to a 1 mg/mL concentration, the extractable content of one vial is 4.5 mg (4.5 mL). The reconstituted and diluted solution should be administered intravenously by infusion over a 2-hour period under close clinical monitoring, including pulse, blood pressure, and temperature. MYLOTARG should not be administered as an intravenous push or bolus (see section 6.6).

For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

No cases of overdose with MYLOTARG were reported in clinical experience. Single doses higher than 9 mg/m² in adults were not tested. Treatment of MYLOTARG overdose should consist of general supportive measures.

Shelf life

Unopened vial: 5 years.

Reconstituted and diluted solution: Following reconstitution and dilution, the solution should be protected from light and should be used immediately. If the product cannot be used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2°C–8°C) from the time of initial vial puncture with not more than 6 hours at room temperature (below 25°C). This includes the time required for reconstitution, dilution, and administration.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Store the vial in the original carton to protect from light.

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

Amber Type 1 glass vial, with butyl rubber stopper and crimp seal with flip-off cap containing 5 mg gemtuzumab ozogamicin.

Each carton contains 1 vial.

Use appropriate aseptic technique for the reconstitution and dilution procedures. MYLOTARG is light sensitive and should be protected from ultraviolet light during reconstitution, dilution, and administration.

Reconstitution:

• Calculate the dose (mg) of MYLOTARG required.
• Prior to reconstitution, allow the vial to reach room temperature (below 25°C) for approximately 5 minutes. Reconstitute each 5 mg vial with 5 mL of water for injections to obtain a single-use solution of 1 mg/mL of gemtuzumab ozogamicin.
• Gently swirl the vial to aid dissolution. Do not shake.
• Inspect the reconstituted solution for particulates and discolouration. The reconstituted solution may contain small white to off-white, opaque to translucent, and amorphous to fibre-like particles.
• MYLOTARG contains no bacteriostatic preservatives.
• If the reconstituted solution cannot be used immediately, it may be stored in the original vial for up to 6 hours in a refrigerator (2°C-8°C) with not more than 3 hours at room temperature (below 25°C). Protect from light and do not freeze.

Dilution:

• Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to patient body surface area. Withdraw this amount from the vial using a syringe. Mylotarg vials contain 5 mg of drug product with no overfill. When reconstituted to a 1 mg/mL concentration as directed, the extractable content of the vial is 4.5 mg (4.5 mL). Protect from light. Discard any unused reconstituted solution left in the vial.
• Doses must be mixed to a concentration between 0.075 mg/mL to 0.234 mg/mL according to the following instructions:
  • Doses less than 3.9 mg must be prepared for administration by syringe. Add the reconstituted MYLOTARG solution to a syringe with sodium chloride 9 mg/mL (0.9%) solution for injection to a final concentration between 0.075 mg/mL to 0.234 mg/mL. Protect from light.
  • Doses greater than or equal to 3.9 mg are to be diluted in a syringe or an IV bag in an appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection to ensure a final

concentration between 0.075 mg/mL to 0.234 mg/mL. Protect from light.

• Gently invert the infusion container to mix the diluted solution. Do not shake.
• Following dilution with sodium chloride 9 mg/mL (0.9%) solution for injection, MYLOTARG solution should be infused immediately. If not used immediately, store at room temperature (below 25°C) for up to 6 hours, which includes the 2-hour infusion time and 1 hour, if needed, to allow the refrigerated diluted solution to equilibrate to room temperature (below 25°C). The diluted solution can be refrigerated at 2°C-8°C for up to 12 hours. Protect from light and do not freeze.
• It is recommended that the infusion container be made of polyvinyl chloride (PVC) with DEHP, or polyolefin (polypropylene and/or polyethylene).

Administration:

• Filtration of the diluted solution is required. An in-line, low protein-binding 0.2 micron polyethersulphone (PES) filter must be used for infusion of MYLOTARG.
• Doses administered by syringe must utilize small bore infusion lines (microbore) with an in-line, low protein-binding 0.2 micron polyethersulphone (PES) filter.
• During the infusion, the intravenous bag or syringes needs to be protected from light using a light (including ultraviolet light) blocking cover. The infusion line does not need to be protected from light.
• Infuse the diluted solution for 2 hours. Infusion lines made of PVC (DEHP- or non DEHP-containing), or polyethylene are recommended.

Do not mix MYLOTARG with, or administer as an infusion with, other medicinal products.

See also section 6.3 for dilution, storage, and infusion information.

Disposal: Toxic waste disposal procedures prescribed for anticancer medicinal products must be used.