PROLEUKIN Powder for solution for injection or infusion Ref.[6108] Active ingredients: Aldesleukin

Proleukin should be administered intravenously by continuous infusion or by subcutaneous injection. The following dosage regimen is recommended to treat adult patients with metastatic renal cell carcinoma.

Continuous intravenous infusion

18 × 10⁶ IU per m² per 24-hours is administered as a continuous infusion for 5 days, followed by 2-6 days without Proleukin therapy, an additional 5 days of intravenous Proleukin as a continuous infusion and 3 weeks without Proleukin therapy. This constitutes one induction cycle. After the 3-weeks without Proleukin therapy period of the first cycle, a second induction cycle should be given.

Maintenance: Up to four maintenance cycles (18 × 10⁶ IU per m² as continuous infusion for 5 days) may be given with 4-week intervals to patients who respond or have disease stabilization.

Subcutaneous injection

18 × 10⁶ IU as subcutaneous (s.c.) injection is administered every day for 5 days, followed by 2 days without Proleukin therapy. For the following 3 weeks, 18 × 10⁶ IU s.c. is administered on days 1 and 2 of each week followed by 9 × 10⁶ IU on days 3-5. On days 6 and 7 no treatment is administered. After 1 week without Proleukin therapy this 4-week cycle should be repeated.

Maintenance: The same cycle as described above may be given to patients who respond or have disease stabilisation.

If a patient does not tolerate the recommended dosage regimen, the dose should be reduced or the administration interrupted until the toxicity has moderated. It is not known to what extent dose reduction affects response rates and median survival.

Renal or hepatic impairment

No formal studies have been conducted to evaluate the pharmacokinetics, safety and tolerability of Proleukin in patients with pre-existing renal or hepatic impairment (see section 4.4).

Elderly patients

No formal clinical trials were conducted to compare the pharmacokinetics, efficacy or safety of Proleukin in geriatric patients to those in younger patients. There were a very small number of patients aged 65 and over in clinical trials of Proleukin. Clinicians should exercise caution in prescribing Proleukin to geriatric patients since decline in renal and hepatic function may occur with increasing age. Hence, elderly patients may be more susceptible to the side effects of Proleukin (see section 5.1 and 5.2).

Paediatric population

The safety and efficacy of Proleukin in children and in adolescents have not yet been established.

Adverse reactions following the use of Proleukin are dose-related. Therefore patients can be expected to experience these events in an exaggerated fashion when the recommended dose is exceeded.

Adverse reactions generally will reverse when the medicinal product is stopped. Any continuing symptoms should be treated supportively. Life-threatening toxicities may be ameliorated by the intravenous administration of dexamethasone, which may also result in loss of the therapeutic effects of Proleukin.

Shelf life: 45 months.

After reconstitution: 24 hours.

Diluted Proleukin should be used within 48 hours after reconstitution, which includes the time taken for infusion.

Store at 2°C to 8°C (in a refrigerator). Do not freeze.

Store in the original package in order to protect from light.

When reconstituted or reconstituted and diluted according to the directions, chemical and physical in-use stability has been demonstrated for up to 48 hours when stored at refrigerated and room temperatures (2°C to 30°C).

From a microbiological point of view, the reconstituted product 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 reconstitution/dilution has taken place in controlled and validated aseptic conditions.

Proleukin is supplied in 5 ml single-use clear Type I glass vials with a stopper of synthetic rubber. The product is supplied in carton boxes of 1 or 10 vials.

Not all pack sizes may be marketed.

Reconstitution of Proleukin powder for solution for injection or infusion:

Vials (which contain 22 million IU aldesleukin) must be reconstituted with 1.2 ml of Water for Injections. After reconstitution the obtained solution contains 18 million IU aldesleukin per millilitre. The reconstituted solution has a pH of 7.5 (range 7.2–7.8).

Using sterilised injection syringe and injection needle, inject 1.2 ml Water for Injections into the vial of Proleukin. Direct the diluent against the side of the vial to avoid excessive foaming. Swirl gently to facilitate complete dissolution of the powder. Do not shake. The appropriate dose can then be withdrawn with a sterile injection syringe and injected subcutaneously or diluted for continuous intravenous infusion.

As for all parenteral medicinal products, inspect the reconstituted solution visually for particulate matter and discoloration prior to administration. The solution may be slightly yellow.

The product should be brought to room temperature prior to administration.

Dilution directions for continuous intravenous infusion:

The total daily dose of reconstituted aldesleukin should be diluted as necessary up to 500 ml with glucose 50 mg/ml (5%) solution for infusion containing 1 mg/ml (0.1%) human albumin, and infused over a 24-hour period.

Order of addition: human albumin should be added and mixed with the glucose solution prior to the addition of the reconstituted aldesleukin. Human albumin is added to protect against loss of bioactivity.

For single use only. Any unused solution, the vial, and the syringe used for the reconstituted solution should be adequately disposed of, in accordance with local requirements for the handling of biohazardous waste.