CEPLENE Solution for injection Ref.[9699] Active ingredients: Histamine

Ceplene maintenance therapy should be administered following completion of consolidation therapy in patients concomitantly treated with IL-2 under the supervision of a physician experienced in the management of acute myeloid leukaemia.

Posology

For dosing instructions for Ceplene in combination with IL-2, see posology below.

Interleukin-2 (IL-2)

IL-2 is administered twice daily as a subcutaneous injection 1 to 3 minutes prior to the administration of Ceplene; each dose of IL-2 is 16 400 IU/kg (1 µg/kg).

Interleukin-2 (IL-2) is commercially available as a recombinant IL-2; aldesleukin. The dispensing and storage directions below are specific to aldesleukin.

Dispensing instructions for IL-2 (aldesleukin)

IL-2 (aldesleukin) should be aseptically reconstituted, diluted and dispensed in capped polypropylene tuberculin syringes by the pharmacy based on the individual patient’s weight (see administration chart for aldesleukin below) at the recommended dose of 16 400 IU/kg (1 µg/kg). Up to two weeks supply of pre-filled capped tuberculin syringes may be provided to patients for home administration, with instructions that the syringes be stored under refrigeration at 2°C–8°C prior to administration.

Studies have shown chemical stability and sterility of diluted aldesleukin (dispensed in capped polypropylene tuberculin syringes) for up to three weeks when prepared in a controlled aseptic environment and stored under refrigeration at 2°C–8°C.

NOTE: Dispensing of aldesleukin must be carried out under controlled aseptic conditions.

Dispensing of dilute IL-2 (Aldesleukin) for each patient

The diluted IL-2 (aldesleukin) is aseptically drawn up into sterile polypropylene tuberculin syringes and capped for each patient at 1 µg/kg dose, with a minimum standard dosage volume of 0.25 mL (50 µg) and a maximum dose of 0.5 mL (100 µg). Dosing volumes based on patient weight are provided in Table 1 below. This table also provides the volume required if a 20% dose reduction is prescribed.

Table 1. Administration chart for IL-2 (aldesleukin):

^* Injection volume rounded up to the nearest 0.05 mL
^** Injection volumes based on 20% reductions are rounded thus actual dose reductions vary from 15%-25%

Ceplene

0.5 mL solution is sufficient for a single dose (see section 6.6).

Ceplene is administered 1 to 3 minutes after each injection of IL-2. Each 0.5 mL Ceplene dose is injected slowly, over 5-15 minutes.

Treatment cycles

Ceplene and IL-2 are administered for 10 treatment cycles: each cycle consists of a treatment period of 21 days (3 weeks) followed by a three-week or six-week treatment-free period.

For cycles 1-3, each cycle consists of 3 weeks of treatment, followed by a 3-week treatment free period. For cycles 4-10, each cycle consists of 3 weeks of treatment, followed by a 6-week treatmentfree period.

The recommended dosing regimen is presented in Tables 2 and 3.

Table 2. For treatment cycles 1-3 with Ceplene and IL-2:

^* see dose modification for provisions for the modification to dose and dosage schedule

Table 3. For treatment cycles 4-10 with Ceplene and IL-2, same as for Table 1 above, with the exception of number of cycles and duration of rest periods:

^* see dose modification for provisions for the modification to dose and dosage schedule

Dose modification

Patients should be monitored for the expected symptomatic adverse reactions and laboratory changes associated with this treatment. Doses of Ceplene and IL-2 should be modified as necessary based on individual patient tolerance to treatment. It is recommended that dose modifications be addressed early in treatment. The dose reductions can be temporary or permanent. Should Ceplene related toxicities occur (such as hypotension, headache), the injection time can be increased from 5 minutes to a maximum duration of 15 minutes.

For patients experiencing grade 1 toxicity events:

No altered dose recommendations with the exception of grade 1 neurologic toxicity and grade 1 generalised toxic dermatitis. For the dose recommendations for these grade 1 toxicity events refer to the relevant sections below:

For patients experiencing grade 1-4 neurologic toxicity:

• for grade 1 to 3 toxicity, treatment should be discontinued until grade 0 toxicity event has been achieved. Treatment should then be resumed at a 20% dose reduction for both Ceplene and IL-2.
• for grade 4 toxicity, discontinuation of treatment should be considered.

For patients experiencing grade 1-4 generalised toxic dermatitis:

• for grade 1 toxicity, the treatment should be delayed for 48 hours or until all symptoms have been resolved. Treatment should then be resumed using the full dose of Ceplene, but reducing the IL-2 dose by 20%.
• for grade 2 toxicity, the IL-2 dose should be reduced 50% and only increased to full dose if the symptoms do not reappear. Ceplene and IL-2 doses should be separated by 60 minutes, which should be maintained throughout treatment.
• for grade 3 and 4 toxicity, treatment should be discontinued and not resumed until events have been resolved. Treatment should only be resumed after consideration of risk – benefit to the patient.

For patients experiencing grade 2 (including cardiac function, renal, hepatic) toxicity:

• treatment should be discontinued until the event has returned to grade 1
• the time of injection of the dose of Ceplene should be extended to a maximum of 15 minutes.
• for cardiac, hepatic or renal toxicities the dose should be reduced by 20% for both Ceplene and IL-2.

For patients experiencing grade 3 and 4 (including hypotension, arrhythmia) toxicities:

• treatment should be discontinued until the event is resolved. A maximum delay of one treatment cycle can be considered for the resolution of grade 3 and 4 events.

For persistent hypotension, headache, arrhythmia, cardiac, hepatic and renal toxicities:

• the time of injection of the dose of Ceplene should be extended to a maximum of 15 minutes.
• the dose amount of both Ceplene and IL-2 should be reduced by 20%.

Fever:

• IL-2 can be discontinued for 24 hours and then restarted at a 20% dose reduction level.

Abnormal WBC counts:

• the dose of IL-2 can be reduced by 20% for the remaining duration of the treatment course and if abnormal WBC counts re-occur during the following cycle a permanent IL-2 reduction is recommended.

Localised toxic dermatitis:

• treatment should be discontinued until symptoms resolved. Treatment can be resumed by administering Ceplene at the full dose and IL-2 at 50%.

Special populations

Renal impairment

Patients with renal impairment may be more sensitive to the blood pressure lowering effects of Ceplene. Although the degree of renal impairment has no demonstrable effect on the pharmacokinetic disposition of Ceplene, caution is warranted when Ceplene is administered to patients with severe renal impairment. However, no Ceplene dose reduction is normally required in renally impaired patients.

Hepatic impairment

Ceplene should be used with caution in patients with moderate to severe hepatic impairment (see section 5.2). Plasma Ceplene levels are higher in patients with moderate and severe liver impairment, and these patient groups tend to experience more tachycardia and lower blood pressure after Ceplene dosing than do patients with normal or mildly affected liver function. Plasma drug levels were not predictive of adverse effects, however, and effects did not correlate closely with drug exposure. Dose reduction of Ceplene is normally not required in hepatically impaired patients, but caution should be used in these patients.

Paediatric population

The safety and efficacy of Ceplene in children below 18 years of age have not yet been established. No data are available.

Method of administration

Ceplene is for subcutaneous use only.

One to 3 minutes after the subcutaneous administration of IL-2 has been completed, Ceplene should be administered by slow subcutaneous injection at a rate not to exceed 0.1 mL (0.1 mg histamine dihydrochloride) per minute. The usual time for administering a 0.5 mL Ceplene dose is 5 minutes. To reduce potential adverse reactions, the administration time may be lengthened to a maximum of 15 minutes, see below. Ceplene can be administered via an ambulatory infusion syringe pump or by controlled manual subcutaneous injection by syringe with a timer.

The first dose of Ceplene and IL-2 on day 1 of the initiation of the first cycle of treatment should be administered in the clinic under direct supervision by a physician. Patient monitoring on day 1 should include vital signs, including pulse, blood pressure and respiratory rate. If the patient experiences a significant change in vital signs, the physician should evaluate the status of the patient and continue to monitor vital signs; these patients should be monitored during subsequent treatments.

Subsequent injections of Ceplene may be self-administered at home by a patient who demonstrates a good understanding of necessary precautions and who has demonstrated adequate injection skills. Injections should be preferably administered in a supervised setting in the presence of an adult family member, friend, or other care provider who is capable of responding appropriately should signs or symptoms of hypotension occur.

The preferred injection areas are the thighs and the abdomen. Ceplene should not be injected into the same anatomic region as IL-2.

The twice daily dosing of IL-2 and Ceplene should be separated by a minimum of 6 hours. Patients should remain at rest for 20 minutes after injection of Ceplene.

For instructions on reconstitution and dilution of Interleukin-2 (aldesleukin) before administration, see section 6.6.

Administration of Ceplene or IL-2 by rapid infusion or into vascular spaces, at higher doses than the approved ones, may exaggerate the adverse reactions associated with Ceplene.

Unopened vials: 3 years.

Ceplene: Do not freeze.

Interleukin-2 (IL-2; aldesleukin): Diluted IL-2 (aldesleukin) dispensed in capped polypropylene tuberculin syringes is to be stored in the refrigerator (2°C–8°C).

2 mL type I glass vial, with bromobutyl rubber stopper and flip-off aluminium over seal, containing 0.5 mL of solution (0.70 mL including overfill).

Each carton contains 14 vials.

Ceplene

The vials contain 0.70 mL of solution (including overfill) to facilitate the dose extraction of a single 0.5 mL dose.

Patients should be provided with capped polypropylene syringes and instructed to extract 0.5 mL of solution into the syringe.

The solution should be visually inspected for particulate matter and discolouration prior to administration. The solution must be clear and colourless.

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

Interleukin-2 (IL-2; aldesleukin)

Dilute IL-2 dispensed in capped polypropylene tuberculin syringes is to be prepared by the pharmacy in a controlled aseptic environment and stored in a refrigerator at 2°C–8°C.

Initial reconstitution

Each vial of aldesleukin (1.3 mg/vial) is reconstituted aseptically with 1.2 mL water for injections (see commercially available aldesleukin SmPC). Direct the diluent against the side of the vial to avoid excessive foaming. Gently swirl to facilitate complete dissolution of the powder. Do NOT shake the vial during the entire reconstitution process. The resulting solution contains 22 × 10⁶ IU (1,300 µg) of aldesleukin per 1.2 mL.

Subsequent dilution to 200 µg/mL

The entire contents of the reconstituted vial (1.2 mL) is then further diluted aseptically with 5.3 mL dextrose 5%w/v solution for injection to a total volume of 6.5 mL providing a final concentration of 200 µg/mL (3.3 × 10⁶ IU/mL) of IL-2 (aldesleukin).

When reconstituted and diluted, stability of dilute IL-2 (aldesleukin) in capped polypropylene tuberculin syringes has been demonstrated for up to 21 days when stored at refrigerated temperatures (2°C–8°C).

Please see section 4.2 for IL-2 dispensing instructions.