Posology : מינונים

4.2        Posology and method of administration

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

The vial of Torisel concentrate must first be diluted with 1.8 ml of diluent withdrawn from the supplied vial to achieve a concentration of temsirolimus of 10 mg/ml.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

For instructions on preparation and to help ensure correct dosing, see section 6.6.

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 Torisel for advanced renal cell carcinoma administered intravenously is 25 mg infused over a 30 to 60 minute period once a week (see section 6.6 for instructions on dilution,
administration and disposal).

Management 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 Torisel for mantle cell lymphoma is 175 mg, infused over a 30 to 60 minute period once a week for 3 weeks followed by weekly doses of 75 mg, infused over a 30 to 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.

Management 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
Starting dose                     Continuing dosea
Dose reduction level                    175 mg                              75 mg -1                                75 mg                              50 mg -2                                 50 mg                              25 mg 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 ANC                           Platelets               Dose of temsirolimus ≥1.0 x 109/l                       ≥50 x 109/l                    100% of planned dose <1.0 x 109/l                       <50 x 109/l                            Holda a
Upon recovery to ANC ≥1.0 x 109/l (1000 cells/mm3) and platelets to ≥50 x 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 x 109/l and platelets >50 x 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 of temsirolimus 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 of temsirolimus is recommended for patients with advanced renal cell carcinoma (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 x 109/l is 10 mg intravenous once a week infused over a 30to 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 indication: treatment of renal cell carcinoma and mantle cell lymphoma.
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 must be administered by intravenous infusion.
For instructions on dilution and preparation of the medicinal product before administration, see section 6.6.

Renal cell carcinoma

The recommended dose of Torisel for advanced renal cell carcinoma administered intravenously is 25 mg infused over a 30- to 60-minute period once a week (see section 6.6 for instructions on dilution,
administration and disposal).

Mantle cell lymphoma

The recommended dose of Torisel for mantle cell lymphoma 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 (see section 6.6 for instructions on dilution, administration and disposal).