EMPLICITI Powder for concentrate for solution for infusion Ref.[8967] Active ingredients: Elotuzumab

Elotuzumab therapy should be initiated and supervised by physicians experienced in the treatment of multiple myeloma.

Premedication for prevention of infusion reaction

Patients must be administered with the following premedications 45-90 minutes prior to Empliciti infusion (see section 4.4):

• Dexamethasone 8 mg intravenous
• H1 blocker: diphenhydramine (25-50 mg orally or intravenous) or equivalent H1 blocker.
• H2 blocker: ranitidine (50 mg intravenous or 150 mg orally) or equivalent H2 blocker.
• Paracetamol (650-1000 mg orally).

Management of infusion reaction

If a ≥ Grade 2 infusion reaction occurs during Empliciti administration, the infusion must be interrupted. Upon resolution to ≤ Grade 1, Empliciti should be restarted at 0.5 mL/min and may be gradually increased at a rate of 0.5 mL/min every 30 minutes as tolerated to the rate at which the infusion reaction occurred. If there is no recurrence of the infusion reaction, the escalation can be resumed (see Tables 3 and 4).

In patients who experience an infusion reaction, vital signs should be monitored every 30 minutes for 2 hours after the end of the Empliciti infusion. If the infusion reaction recurs, the Empliciti infusion must be stopped and not restarted on that day (see section 4.4). Very severe infusion reactions (≥ Grade 3) may require permanent discontinuation of Empliciti therapy and emergency treatment.

Posology for administration with lenalidomide and dexamethasone

The length of each treatment cycle is 28 days, see Table 1 for the dosing schedule. Treatment should continue until disease progression or unacceptable toxicity.

The recommended dose of Empliciti is 10 mg/kg administered intravenously every week, on days 1, 8, 15, and 22 for the first two treatment cycles and every 2 weeks thereafter on days 1 and 15.

The recommended dose of lenalidomide is 25 mg orally once daily on days 1-21 of repeated 28-day cycles, and at least 2 hours after Empliciti infusion when administered on the same day.

The administration of dexamethasone is as follows:

• On days that Empliciti is administered, dexamethasone should be given as 28 mg orally once daily between 3 and 24 hours before Empliciti plus 8 mg intravenously between 45 and 90 minutes before Empliciti on days 1, 8, 15, and 22 of repeated 28-day cycles.
• On days that Empliciti is not administered but a dose of dexamethasone is scheduled (Days 8 and 22 of cycle 3 and all subsequent cycles), dexamethasone should be given 40 mg orally.

Table 1. Recommended dosing schedule of Empliciti in combination with lenalidomide and dexamethasone:

For additional information concerning lenalidomide and dexamethasone, see the corresponding Summary of Product Characteristics.

Posology for administration with pomalidomide and dexamethasone

The length of each treatment cycle is 28 days, see Table 2 for the dosing schedule. Treatment should continue until disease progression or unacceptable toxicity.

The recommended dose of Empliciti is 10 mg/kg administered intravenously every week on days 1, 8, 15, and 22 of each treatment cycle for the first two cycles and then 20 mg/kg administered on day 1 of each treatment cycle thereafter.

The recommended dose of pomalidomide is 4 mg orally once daily on days 1-21 of repeated 28-day cycles, and at least 2 hours after Empliciti infusion when administered on the same day.

The administration of dexamethasone is as follows:

• On days that Empliciti is administered, patients ≤75 years old give dexamethasone 28 mg orally between 3 and 24 hours before Empliciti plus 8 mg intravenously between 45 and 90 minutes before Empliciti and for patients >75 years old give dexamethasone 8 mg orally between 3 and 24 hours before Empliciti plus 8 mg intravenously between 45 and 90 minutes before Empliciti.
• On days that Empliciti is not administered but a dose of dexamethasone is scheduled (Days 8, 15 and 22 of cycle 3 and all subsequent cycles), give 40 mg orally to patients ≤75 years old and 20 mg orally to patients >75 years old.

Table 2. Recommended dosing schedule of Empliciti in combination with pomalidomide and dexamethasone:

For additional information concerning pomalidomide and dexamethasone, see the corresponding Summary of Product Characteristics.

See Method of administration below for instruction on infusion rates.

Dose delay, interruption, or discontinuation

If the dose of one medicine in the regimen is delayed, interrupted, or discontinued, the treatment with the other medicinal products may continue as scheduled. However, if oral or intravenous dexamethasone is delayed or discontinued, the administration of Empliciti should be based on clinical judgment (e.g. risk of hypersensitivity) (see section 4.4).

Special populations

Paediatric population

There is no relevant use of Empliciti in the paediatric population for the indication of multiple myeloma.

Elderly

No dose adjustment is required for Empliciti in patients over 65 years of age (see section 5.2). Data on the efficacy and safety of Empliciti in patients ≥ 85 years of age are very limited.

Renal impairment

No dose adjustment of Empliciti is required for patients with mild (CrCl = 60-89 mL/min), moderate (CrCl = 30-59 mL/min), severe (CrCl <30 mL/min) renal impairment or end stage renal disease requiring dialysis (see section 5.2).

Hepatic impairment

No dose adjustment for Empliciti is required for patients with mild hepatic impairment (total bilirubin [TB] ≤ to the upper limit of normal [ULN] and AST > ULN or TB <1 to 1.5 × ULN and any AST). Empliciti has not been studied in patients with moderate (TB >1.5 to 3 × ULN and any AST) or severe (TB >3 × ULN and any AST) hepatic impairment (see section 5.2).

Method of administration

Empliciti is for intravenous use only.

Infusion rate for Empliciti 10 mg/kg

The administration of the reconstituted and diluted solution must be initiated at an infusion rate of 0.5 mL/min. If the infusion is well tolerated the infusion rate may be increased in a stepwise fashion as described in Table 3. The maximum infusion rate should not exceed 5 mL/min.

Table 3. Infusion rate for Empliciti 10 mg/kg:

* Continue this rate until infusion is completed.

Infusion rate for Empliciti 20 mg/kg

The administration of reconstituted and diluted solution must be initiated at an infusion rate of 3 mL/min. If the infusion is well tolerated, the infusion rate maybe increased in a stepwise fashion as described in Table 4. The maximum infusion rate should not exceed 5 mL/min. Patients who have escalated to 5 mL/min at 10 mg/kg dose must decrease the rate to 3 mL/min at the first infusion at 20 mg/kg.

Table 4. Infusion rate for Empliciti 20 mg/kg:

* Continue this rate until infusion is completed.

For instructions on reconstitution and dilution of Empliciti before administration, see section 6.6.

One patient was reported to be overdosed with 23.3 mg/kg of elotuzumab in combination with lenalidomide and dexamethasone. The patient had no symptoms, did not require any treatment for the overdose, and was able to continue on elotuzumab therapy.

In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted.

Shelf life

Unopened vial: 3 years.

After reconstitution and dilution: The reconstituted solution should be transferred from the vial into the infusion bag immediately.

Chemical and physical in use stability of the reconstituted and diluted solution has been demonstrated for 24 hours at 2°C-8°C and protected from light.

From a microbiological point of view, the solution for infusion 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-8°C protected from light. Do not freeze the reconstituted or diluted solution. The solution for infusion may be stored for a maximum of 8 hours of the total 24 hours at 20°C-25°C and room light. This 8-hour period should be inclusive of the product administration period.

Store in a refrigerator (2°C-8°C).

Do not freeze.

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

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

20 ml Type I glass vial, closed with a grey butyl stopper and sealed with aluminium crimp seal with a polypropylene flip off button, containing either 300 mg or 400 mg elotuzumab. The flip-off seal button colour is ivory for the 300 mg presentation and blue for the 400 mg presentation. Pack size of 1 vial.

Calculating the dose

Calculate the dose (mg) and determine the number of vials needed for the dose (10 mg/kg or 20 mg/kg) based on patient weight. More than one vial of Empliciti may be needed to give the total dose for the patient.

• The total elotuzumab dose in mg equals the patient’s weight in kg multiplied by the elotuzumab dose (10 or 20 mg/kg, see section 4.2).

Reconstitution of vials

Aseptically reconstitute each Empliciti vial with a syringe of adequate size and an 18 gauge or smaller needle as shown in Table 12. A slight back pressure may be experienced during administration of the water for injections, which is considered normal.

Table 12. Reconstitution instructions:

Hold the vial upright and swirl the solution by rotating the vial to dissolve the lyophilised cake. Then invert the vial a few times in order to dissolve any powder that may be present on top of the vial or the stopper. Avoid vigorous agitation, DO NOT SHAKE. The lyophilised powder should dissolve in less than 10 minutes.

After the remaining solids are completely dissolved, allow the reconstituted solution to stand for 5 to 10 minutes. The reconstituted solution is colourless to slightly yellow, and clear to very opalescent. Empliciti should be inspected visually for particulate matter and discolouration prior to administration. Discard the solution if any particulate matter or discolouration is observed.

Preparation of the solution for infusion

The reconstituted solution should be diluted with sodium chloride 9 mg/mL (0.9%) solution for injection or 5% glucose injection to obtain a final infusion concentration range between 1 mg/mL and 6 mg/mL. The volume of sodium chloride 9 mg/mL (0.9%) solution for injection or 5% glucose injection should be adjusted so as to not exceed 5 mL/kg of patient weight at any given dose of Empliciti.

Calculate the volume (mL) of diluent (either sodium chloride 9 mg/mL (0.9%) solution for injection or 5% glucose injection) needed to make up the solution for infusion for the patient.

Withdraw the necessary volume for the calculated dose from each vial, up to a maximum of 16 mL from 400 mg vial and 12 mL from 300 mg vial. Each vial contains a slight overfill to ensure sufficient extractable volume.

Transfer the withdrawn volumes of all vials needed according to the calculated dose for this patient into one single infusion bag made of polyvinyl chloride or polyolefin containing the calculated volume of diluent. Gently mix the infusion by manual rotation. Do not shake. Empliciti is for single use only. Discard any unused portion left in the vial.

Administration

The entire Empliciti infusion should be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 µm) using an automated infusion pump.

Empliciti infusion is compatible with:

• PVC and polyolefin containers
• PVC infusion sets
• polyethersulfone and nylon in-line filters with pore sizes of 0.2 μm to 1.2 μm.

Empliciti should be initiated at an infusion rate of 0.5 mL/min for 10 mg/kg dose and 3 mL/min for 20 mg/kg dose. If well tolerated, the infusion rate may be increased stepwise as described in Tables 3 and 4 (see section 4.2 Method of administration). The maximum infusion rate should not exceed 5 mL/min.

The Empliciti infusion solution 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-8°C protected from light. Do not freeze the reconstituted or diluted solution. The solution for infusion may be stored for a maximum of 8 hours of the total 24 hours at 20°C-25°C and room light. This 8-hour period should be inclusive of the product administration period.

Disposal

Do not store any unused portion of the infusion solution for reuse. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.