Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands
Kyprolis in combination with either lenalidomide and dexamethasone or dexamethasone alone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy (see section 5.1).
Kyprolis treatment should be supervised by a physician experienced in the use of anti-cancer therapy.
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%.
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 dexamethasonea:
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 alonea:
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 dexamethasone or with lenalidomide and dexamethasone, 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.
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.
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.
Dosing should be modified based on Kyprolis toxicity. Recommended actions and dose modifications are presented in table 3. Dose level reductions are presented in table 4.
Table 3. Dose modifications during Kyprolis treatment:
Table 4. Dose level reductions for Kyprolis:
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 3). 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.
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 3). 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.
Overall, the subject incidence of certain adverse events (including cardiac failure) in clinical trials was higher for patients who were ≥75 years of age compared to patients who were <75 years of age (see section 4.4).
The safety and efficacy of Kyprolis in paediatric patients have not been established. No data are available.
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.
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.
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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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