KYPROLIS Powder for solution for infusion Ref.[6539] Active ingredients: Carfilzomib

Kyprolis treatment should be supervised by a physician experienced in the use of anti-cancer therapy.

Posology

The dose is calculated using the patient's baseline body surface area (BSA). Patients with a BSA greater than 2.2 m² should receive a dose based upon a BSA of 2.2 m². Dose adjustments do not need to be made for weight changes of less than or equal to 20%.

Kyprolis in combination with lenalidomide and dexamethasone

When combined with lenalidomide and dexamethasone, Kyprolis is administered intravenously as a 10 minute infusion, on two consecutive days, each week for three weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (days 17 to 28) as shown in table 1. Each 28-day period is considered one treatment cycle.

Kyprolis is administered at a starting dose of 20 mg/m² (maximum dose 44 mg) in cycle 1 on days 1 and 2. If tolerated, the dose should be increased on day 8 of cycle 1 to 27 mg/m² (maximum dose 60 mg). From cycle 13, the day 8 and 9 doses of Kyprolis are omitted.

Treatment may be continued until disease progression or until unacceptable toxicity occurs.

Treatment with Kyprolis combined with lenalidomide and dexamethasone for longer than 18 cycles should be based on an individual benefit/risk assessment, as the data on the tolerability and toxicity of carfilzomib beyond 18 cycles are limited (see section 5.1).

In combination with Kyprolis, lenalidomide is administered as 25 mg orally on days 1-21 and dexamethasone is administered as 40 mg orally or intravenously on days 1, 8, 15, and 22 of the 28-day cycles. Appropriate dose reduction for the starting dose of lenalidomide should be considered according to the recommendations in the current lenalidomide summary of product characteristics, for example for patients with baseline renal impairment. Dexamethasone should be administered 30 minutes to 4 hours before Kyprolis.

Table 1. Kyprolis in combination with lenalidomide and dexamethasone:

Kyprolis in combination with dexamethasone

When combined with dexamethasone, Kyprolis is administered intravenously as a 30 minute infusion on two consecutive days, each week for three weeks (days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period (days 17 to 28) as shown in table 2. Each 28-day period is considered one treatment cycle.

Kyprolis is administered at a starting dose of 20 mg/m² (maximum dose 44 mg) in cycle 1 on days 1 and 2. If tolerated, the dose should be increased on day 8 of cycle 1 to 56 mg/m² (maximum dose 123 mg).

Treatment may be continued until disease progression or until unacceptable toxicity occurs.

When Kyprolis is combined with dexamethasone alone, dexamethasone is administered as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23 of the 28-day cycles. Dexamethasone should be administered 30 minutes to 4 hours before Kyprolis.

Table 2. Kyprolis in combination with dexamethasone alone:

^a Infusion time is 30 minutes and remains consistent throughout the regimen

Kyprolis in combination with daratumumab and dexamethasone

When combined with daratumumab and dexamethasone, Kyprolis is administered intravenously as a 30-minute infusion on two consecutive days, each week for three weeks (days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period (days 17 to 28) as shown in table 3. Each 28-day period is considered one treatment cycle.

Kyprolis is administered at a starting dose of 20 mg/m² (maximum dose 44 mg) in cycle 1 on days 1 and 2. If tolerated, the dose should be increased on day 8 of cycle 1 to 56 mg/m² (maximum dose 123 mg).

Treatment may be continued until disease progression or until unacceptable toxicity occurs.

Dexamethasone is administered as 20 mg orally or intravenously on days 1, 2, 8, 9, 15 and 16 and 40 mg orally or intravenously on day 22 of each 28 day cycle. For patients >75 years of age, administer 20 mg of dexamethasone orally or intravenously weekly after the first week. Dexamethasone should be administered 30 minutes to 4 hours before Kyprolis.

Daratumumab can be administered intravenously or subcutaneously.

If given intravenously, daratumumab is given at a dose of 16 mg/kg actual body weight; with a split dose of 8 mg/kg in cycle 1 on days 1 and 2. Afterwards, daratumumab is administered as 16 mg/kg once weekly on days 8, 15 and 22 of cycle 1 and days 1, 8, 15 and 22 of cycle 2, then every 2 weeks for 4 cycles (cycles 3 to 6) and then every 4 weeks for the remaining cycles or until disease progression.

Alternatively, daratumumab can be given subcutaneously at a dose of 1800 mg on days 1, 8, 15 and 22 of cycle 1 and days 1, 8, 15 and 22 of cycle 2, then every 2 weeks for 4 cycles (cycles 3 to 6) and then every 4 weeks for the remaining cycles or until disease progression.

Refer to the daratumumab summary of product characteristics for additional information regarding the use of the subcutaneous formulation.

On days when more than one of these medicines is administered, the recommended order of administration is as follows: dexamethasone, pre-infusion medications for daratumumab (see section Concomitant medicinal products), carfilzomib, daratumumab, and post-infusion medications for daratumumab (see section Concomitant medicinal products).

Refer to the daratumumab and dexamethasone summary of product characteristics for additional details on administration.

Table 3. Kyprolis in combination with dexamethasone and daratumumab:

^a Infusion time is 30 minutes and remains consistent throughout the regimen
^b For patients >75 years of age, dexamethasone is administered as 20 mg orally or intravenously weekly after the first week.

Concomitant medicinal products

Antiviral prophylaxis should be considered in patients being treated with Kyprolis to decrease the risk of herpes zoster reactivation (see section 4.8).

Thromboprophylaxis is recommended in patients being treated with Kyprolis in combination with daratumumab and dexamethasone, with lenalidomide and dexamethasone, or with dexamethasone alone and should be based on an assessment of the patient's underlying risks and clinical status. For other concomitant medicinal products that may be required, such as the use of antacid prophylaxis, refer to the current lenalidomide and dexamethasone summary of product characteristics.

In patients being treated with Kyprolis in combination with daratumumab and dexamethasone, pre-infusion medications should be administered to reduce the risk of infusion-related reactions with daratumumab.

Refer to the daratumumab summary of product characteristics for additional details on concomitant medications including pre and post-infusion medications.

Hydration, fluid and electrolyte monitoring

Adequate hydration is required before dose administration in cycle 1, especially in patients at high risk of tumour lysis syndrome or renal toxicity. All patients should be monitored for evidence of volume overload and fluid requirements should be tailored to individual patient needs. The total volume of fluids may be adjusted as clinically indicated in patients with baseline cardiac failure or who are at risk for cardiac failure (see section 4.4).

Recommended hydration includes both oral fluids (30 mL/kg/day for 48 hours before day 1 of cycle 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid before each dose in cycle 1). Give an additional 250 mL to 500 mL of intravenous fluids as needed following Kyprolis administration in cycle 1. Oral and/or intravenous hydration should be continued, as needed, in subsequent cycles.

When given in combination with intravenous daratumumab, oral and/or intravenous hydration is not required on days when intravenous daratumumab is dosed.

Serum potassium levels should be monitored monthly, or more frequently during treatment with Kyprolis as clinically indicated and will depend on the potassium levels measured before the start of treatment, concomitant therapy used (e.g. medicinal products known to increase the risk of hypokalaemia) and associated comorbidities.

Recommended dose modifications

Dosing should be modified based on Kyprolis toxicity. Recommended actions and dose modifications are presented in table 4. Dose level reductions are presented in table 5.

Table 4. Dose modifications during Kyprolis treatment:

^a See table 5 for dose level reductions

Table 5. Dose level reductions for Kyprolis:

Note: Kyprolis infusion times remain unchanged during dose reduction(s)
^a If symptoms do not resolve, discontinue Kyprolis treatment

Special populations

Renal impairment

Patients with moderate or severe renal impairment were enrolled in Kyprolis-dexamethasone combination studies, but were excluded from Kyprolis-lenalidomide combination studies. Thus, there are limited data for Kyprolis in combination with lenalidomide and dexamethasone in patients with creatinine clearance (CrCL <50 mL/min). Appropriate dose reduction for the starting dose of lenalidomide in patients with baseline renal impairment should be considered according to the recommendations in the lenalidomide summary of product characteristics.

No starting dose adjustment for Kyprolis is recommended in patients with baseline mild, moderate, or severe renal impairment or patients on chronic dialysis based on available pharmacokinetic data (see section 5.2). However, in phase 3 clinical studies, the incidence of adverse events of acute renal failure was higher in patients with lower baseline creatinine clearance than that among patients with higher baseline creatinine clearance.

Renal function should be assessed at treatment initiation and monitored at least monthly or in accordance with accepted clinical practice guidelines, particularly in patients with lower baseline creatinine clearance (CrCL <30 mL/min). Appropriate dose modifications based on toxicity should be made (see table 4). There are limited efficacy and safety data on patients with baseline creatinine clearance <30 mL/min.

Since dialysis clearance of Kyprolis concentrations has not been studied, the medicinal product should be administered after the dialysis procedure.

Hepatic impairment

Patients with moderate or severe hepatic impairment were excluded from Kyprolis studies in combination with either lenalidomide and dexamethasone or dexamethasone alone.

The pharmacokinetics of Kyprolis has not been evaluated in patients with severe hepatic impairment. No starting dose adjustment is recommended in patients with mild or moderate hepatic impairment based on available pharmacokinetic data. However, higher subject incidence of hepatic function abnormalities, ≥ grade 3 adverse events and serious adverse events have been reported in patients with mild or moderate baseline hepatic impairment compared with patients with normal hepatic function (see sections 4.4 and 5.2). Liver enzymes and bilirubin should be assessed at treatment initiation and monitored monthly during treatment with carfilzomib, regardless of baseline values, and appropriate dose modifications based on toxicity should be made (see table 4). Special attention should be paid to patients with moderate and severe hepatic impairment in view of the very limited efficacy and safety data on this population.

Elderly patients

Overall, the subject incidence of certain adverse events (including cardiac failure) in clinical studies was higher for patients who were ≥75 years of age compared to patients who were <75 years of age (see section 4.4).

Paediatric population

The safety and efficacy of Kyprolis in paediatric patients have not been established. No data are available.

Method of administration

Kyprolis is to be administered by intravenous infusion. The 20/27 mg/m² dose is administered over 10 minutes. The 20/56 mg/m² dose must be administered over 30 minutes.

Kyprolis must not be administered as an intravenous push or bolus.

The intravenous administration line should be flushed with normal sodium chloride solution or 5% glucose solution for injection immediately before and after Kyprolis administration.

Do not mix Kyprolis with or administer as an infusion with other medicinal products.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

There is currently insufficient information to draw conclusions about the safety of doses higher than those evaluated in clinical studies. Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia and lymphopenia has been reported following a dose of 200 mg of Kyprolis administered in error.

There is no known specific antidote for carfilzomib overdose. In the event of an overdose, the patient should be monitored, specifically for the adverse reactions to Kyprolis listed in section 4.8.

Powder vial (unopened):

3 years.

Reconstituted solution:

Chemical and physical in-use stability of reconstituted solutions in the vial, syringe or intravenous bag has been demonstrated for 24 hours at 2°C - 8°C or for 4 hours at 25°C. The elapsed time from reconstitution to administration should not exceed 24 hours.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user and should not be longer than 24 hours at 2°C – 8°C.

Store in a refrigerator (2°C – 8°C).

Do not freeze.

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

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

Kyprolis 10 mg powder for solution for infusion:

10 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium seal with a light blue plastic flip off cap.

Kyprolis 30 mg powder for solution for infusion:

30 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium seal with an orange plastic flip off cap.

Kyprolis 60 mg powder for solution for infusion:

50 mL type I clear glass vial, closed with fluoropolymer laminated elastomeric stopper and aluminium seal with a purple plastic flip off cap.

Pack size of one vial.

General precautions

Carfilzomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of Kyprolis. Use of gloves and other protective equipment is recommended.

Reconstitution and preparation for intravenous administration

Kyprolis vials contain no antimicrobial preservatives and are intended for single use only. Proper aseptic technique must be observed.

The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution.

1. Calculate the dose (mg/m²) and number of vials of Kyprolis required using the patient's BSA at baseline. Patients with a BSA greater than 2.2 m² should receive a dose based upon a BSA of 2.2 m². Dose adjustments do not need to be made for weight changes of ≤20%.

2. Remove vial from refrigerator just prior to use.

3. Use only a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to aseptically reconstitute each vial by slowly injecting 5 mL (for 10 mg vial), 15 mL (for 30 mg vial) or 29 mL (for 60 mg vial) sterile water for injections through the stopper and directing the solution onto the INSIDE WALL OF THE VIAL to minimise foaming.

4. Gently swirl and/or invert the vial slowly for approximately 1 minute, or until complete dissolution. DO NOT SHAKE. If foaming occurs, allow the solution to settle in the vial until foaming subsides (approximately 5 minutes) and the solution is clear.

5. Visually inspect for particulate matter and discolouration prior to administration. The reconstituted product should be a clear, colourless to slightly yellow solution and should not be administered if any discolouration or particulate matter is observed.

6. Discard any unused portion left in the vial.

7. Kyprolis can be administered directly by intravenous infusion or optionally administered in an intravenous bag. Do not administer as an intravenous push or bolus.

8. When administering in an intravenous bag, use only a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to withdraw the calculated dose from the vial and dilute into a 50 or 100 mL intravenous bag containing 5% glucose solution for injection.

Disposal

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