TORISEL Concentrate and solvent for solution for infusion Ref.[9095] Active ingredients: Temsirolimus

This medicinal product must be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products.

Posology

Patients should be given intravenous diphenhydramine 25 mg to 50 mg (or similar antihistamine) approximately 30 minutes before the start of each dose of temsirolimus (see section 4.4).

Treatment with Torisel should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Renal cell carcinoma

The recommended dose of temsirolimus for advanced RCC is 25 mg administered by intravenous infusion over a 30- to 60-minute period once a week.

Treatment of suspected adverse reactions may require temporary interruption and/or dose reduction of temsirolimus therapy. If a suspected reaction is not manageable with dose delays, then temsirolimus may be reduced by 5 mg/week decrements.

Mantle cell lymphoma

The recommended dosing regimen of temsirolimus for MCL is 175 mg, infused over a 30-60 minute period once a week for 3 weeks followed by weekly doses of 75 mg, infused over a 30-60 minute period. The starting dose of 175 mg was associated with a significant incidence of adverse events and required dose reductions/delays in the majority of patients. The contribution of the initial 175 mg doses to the efficacy outcome is currently not known.

Treatment of suspected adverse reactions may require temporary interruption and/or dose reduction of temsirolimus therapy according to the guidelines in the following tables. If a suspected reaction is not manageable with dose delays and/or optimal medical therapy, then the dose of temsirolimus should be reduced according to the dose reduction table below.

Dose reduction levels:

^a In the MCL clinical trial, up to two dose level reductions were allowed per patient.

Temsirolimus dose modifications based on weekly ANC and platelet counts:

^a Upon recovery to ANC ≥1.0 × 10⁹/l (1000 cells/mm³) and platelets to ≥50 × 10⁹/l (50,000 cells/mm³), the doses should be modified to the next lower dose level according to the table above. If the patient cannot maintain ANC >1.0 × 10⁹/l and platelets >50 × 10⁹/l on the new dose reduction level, then the next lower dose should be given once the counts have recovered.
Abbreviation: ANC = absolute neutrophil count.

Special populations

Elderly

No specific dose adjustment is necessary in elderly patients.

Renal impairment

No dose adjustment is recommended in patients with renal impairment. Temsirolimus should be used with caution in patients with severe renal impairment (see section 4.4).

Hepatic impairment

Temsirolimus should be used with caution in patients with hepatic impairment (see section 4.4).

No dose adjustment is recommended for patients with advanced-RCC and mild to moderate hepatic impairment. For patients with RCC and severe hepatic impairment, the recommended dose for patients who have baseline platelets ≥100 × 10⁹/l is 10 mg intravenous once a week infused over a 30-60 minute period (see section 5.2).

No dose adjustment is recommended for patients with MCL and mild hepatic impairment. Temsirolimus should not be used in patients with MCL and moderate or severe hepatic impairment (see section 4.3).

Paediatric population

There is no relevant use of temsirolimus in the paediatric population for the indications of RCC and MCL.

Temsirolimus should not be used in the paediatric population for the treatment of neuroblastoma, rhabdomyosarcoma or high-grade glioma, because of efficacy concerns based on the available data (see section 5.1).

Method of administration

Torisel is for intravenous use only. The diluted solution must be administered by intravenous infusion.

The vial of concentrate must first be diluted with 1.8 ml of the supplied solvent to achieve a concentration of temsirolimus of 10 mg/ml. The required amount of the temsirolimus-solvent mixture (10 mg/ml) must be withdrawn and then rapidly injected into sodium chloride 9 mg/ml (0.9%) solution for injection.

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

There is no specific treatment for temsirolimus overdose. While temsirolimus has been safely administered to patients with renal cancer with repeated intravenous doses as high as 220 mg/m², in MCL, two administrations of 330 mg temsirolimus/week in one patient resulted in Grade 3 rectal bleeding and Grade 2 diarrhoea.

Shelf life

Unopened vial: 3 years.

After first dilution of Torisel 30 mg concentrate with 1.8 ml of the supplied solvent: 24 hours when stored below 25°C and protected from light.

After further dilution of the concentrate-solvent mixture with sodium chloride 9 mg/ml (0.9%) solution for injection: 6 hours when stored below 25°C and protected from light.

Store in a refrigerator (2°C-8°C).

Do not freeze.

Keep the vials in the outer carton in order to protect from light.

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

Concentrate: Clear glass vial (type 1), with butyl rubber stopper and a plastic flip-top closure sealed with aluminum containing 1.2 ml of concentrate.

Solvent: Clear glass vial (type 1), with butyl rubber stopper and a plastic flip-top closure sealed with aluminum containing 2.2 ml of solvent.

Pack size: 1 vial of concentrate and 1 vial of solvent.

During handling and preparation of admixtures, Torisel should be protected from excessive room light and sunlight.

Torisel, when diluted, contains polysorbate 80 and therefore appropriate administration materials must be used (see sections 6.1 and 6.2).

Bags/containers that come in contact with Torisel must be made of glass, polyolefin, or polyethylene.

Torisel concentrate and solvent should be inspected visually for particulate matter and discolouration prior to administration.

Do not use if particulates are present, or if discoloured. Use a new vial.

Dilution

The concentrate for solution for infusion must be diluted with the supplied solvent before administration in sodium chloride 9 mg/ml (0.9%) solution for injection.

Note: For MCL, multiple vials will be required for each dose over 25 mg. Each vial of Torisel must be diluted according to the instructions below. The required amount of concentrate--solvent mixture from each vial must be combined in one syringe for rapid injection into 250 ml of sodium chloride 9 mg/ml (0.9%) solution for injection (see section 4.2).

The concentrate-solvent mixture should be inspected visually for particulate matter and discolouration.

Do not use if particulates are present, or if discoloured.

In preparing the solution, the following two-step process must be carried out in an aseptic manner according to local standards for handling cytotoxic/cytostatic medicinal products:

STEP 1: DILUTION OF THE CONCENTRATE FOR SOLUTION FOR INFUSION WITH THE SUPPLIED SOLVENT

• Withdraw 1.8 ml of the supplied solvent.
• Inject the 1.8 ml of solvent into the vial of Torisel 30 mg concentrate.
• Mix the solvent and the concentrate well by inversion of the vial. Sufficient time should be allowed for air bubbles to subside. The solution should be a clear to slightly turbid, colourless to light-yellow to yellow solution, essentially free from visual particulates.

One vial of Torisel concentrate contains 30 mg of temsirolimus: when the 1.2 ml concentrate is combined with 1.8 ml of the supplied solvent, a total volume of 3.0 ml is obtained, and the concentration of temsirolimus will be 10 mg/ml. The concentrate-solvent mixture is stable below 25°C for up to 24 hours.

STEP 2: ADMINISTRATION OF CONCENTRATE FOR SOLUTION FOR INFUSION-SOLVENT MIXTURE IN SODIUM CHLORIDE 9MG/ML (0.9%) SOLUTION FOR INJECTION

• Withdraw the required amount of concentrate-solvent mixture (containing temsirolimus 10 mg/ml) from the vial; i.e., 2.5 ml for a temsirolimus dose of 25 mg.
• Inject the withdrawn volume rapidly into 250 ml of sodium chloride 9 mg/ml (0.9%) solution for injection to ensure adequate mixing.

The admixture should be mixed by inversion of the bag or bottle, avoiding excessive shaking, as this may cause foaming.

The final diluted solution in the bag or bottle should be inspected visually for particulate matter and discolouration prior to administration. The admixture of Torisel in sodium chloride 9 mg/ml (0.9%) solution for injection should be protected from excessive room light and sunlight.

For MCL, multiple vials will be required for each dose over 25 mg.

Administration

• Administration of the final diluted solution should be completed within six hours from the time that Torisel is first added to sodium chloride 9 mg/ml (0.9%) solution for injection.
• Torisel is infused over a 30- to 60-minute period once a week. The use of an infusion pump is the preferred method of administration to ensure accurate delivery of the medicinal product.
• Appropriate administration materials must be used to avoid excessive loss of medicinal product and to decrease the rate of DEHP extraction. The administration materials must consist of non- DEHP, non-PVC tubing with appropriate filter. An in-line polyethersulfone filter with a pore size of not greater than 5 microns is recommended for administration to avoid the possibility of particles bigger than 5 microns being infused. If the administration set available does not have an in-line filter incorporated, a filter should be added at the end of the set (i.e., an end-filter) before the admixture reaches the vein of the patient. Different end-filters can be used ranging in filter pore size from 0.2 microns up to 5 microns. The use of both an in-line and end-filter is not recommended (see sections 6.1 and 6.2).
• Torisel, when diluted, contains polysorbate 80,and therefore appropriate administration materials must be used (see sections 6.1 and 6.2). It is important that the recommendations in section 4.2 be followed closely.

Disposal

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