Active Ingredient: Carfilzomib
Carfilzomib in combination with lenalidomide and dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy.
For this indication, competent medicine agencies globally authorize below treatments:
For:
Intravenous
20 - 27 mg per m² of body surface area (BSA)
From 10 To 13.5 mg per m² of body surface area (BSA) 2 time(s) per day every 7 day(s)
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, carfilzomib 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.
Carfilzomib 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 carfilzomib are omitted.
Treatment may be continued until disease progression or until unacceptable toxicity occurs.
Treatment with carfilzomib 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.
In combination with carfilzomib, 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 carfilzomib.
Table 1. Carfilzomib in combination with lenalidomide and dexamethasone:
| Cycle 1 | |||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | ||||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Day 22 | Days 23-28 | |
| Carfilzomib (mg/m²)a | 20 | 20 | - | 27 | 27 | - | 27 | 27 | - | - | - |
| Dexamethasone (mg) | 40 | - | - | 40 | - | - | 40 | - | - | 40 | - |
| Lenalidomide | 25 mg daily | - | - | ||||||||
| Cycles 2-12 | |||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | ||||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Day 22 | Days 23-28 | |
| Carfilzomib (mg/m²)a | 27 | 27 | - | 27 | 27 | - | 27 | 27 | - | - | - |
| Dexamethasone (mg) | 40 | - | - | 40 | - | - | 40 | - | - | 40 | - |
| Lenalidomide | 25 mg daily | - | - | ||||||||
| Cycle 13 on | |||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | ||||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Day 22 | Days 23-28 | |
| Carfilzomib (mg/m²)a | 27 | 27 | - | - | - | - | 27 | 27 | - | - | - |
| Dexamethasone (mg) | 40 | - | - | 40 | - | - | 40 | - | - | 40 | - |
| Lenalidomide | 25 mg daily | - | - | ||||||||
Antiviral prophylaxis should be considered in patients being treated with carfilzomib to decrease the risk of herpes zoster reactivation.
Thromboprophylaxis is recommended in patients being treated with carfilzomib in combination with lenalidomide and dexamethasonee 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.
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 carfilzomib 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 carfilzomib 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 carfilzomib toxicity. Recommended actions and dose modifications are presented in table 2. Dose level reductions are presented in table 3.
Table 2. Dose modifications during carfilzomib treatment:
| Haematologic toxicity | Recommended action |
| • Absolute neutrophil count <0.5 × 109/L | • Stop dose - If recovered to ≥0.5 × 109/L, continue at same dose level • For subsequent drops to <0.5 × 109/L, follow the same recommendations as above and consider 1 dose level reduction when restarting carfilzomiba |
| • Febrile neutropenia • Absolute neutrophil count <0.5 × 109/L and an oral temperature >38.5°C or two consecutive readings of >38.0°C for 2 hours | • Stop dose • If absolute neutrophil count returns to baseline grade and fever resolves, resume at the same dose level |
| • Platelet count <10 × 109/L or evidence of bleeding with thrombocytopenia | • Stop dose - If recovered to ≥10 × 109/L and/or bleeding is controlled continue at same dose level • For subsequent drops to <10 × 109/L, follow the same recommendations as above and consider 1 dose level reduction when restarting carfilzomiba |
| Non-haematologic toxicity (renal) | Recommended action |
| • Serum creatinine equal to or greater than 2 × baseline; or • Creatinine clearance <15 mL/min (or creatinine clearance decreases to ≤50% of baseline) or need for dialysis | • Stop dose and continue monitoring renal function (serum creatinine or creatinine clearance) - carfilzomib should be resumed when renal function has recovered to within 25% of baseline; consider resuming at 1 dose level reductiona • For patients on dialysis receiving carfilzomib, the dose is to be administered after the dialysis procedure |
| Other non-haematologic toxicity | Recommended action |
| • All other grade 3 or 4 non-haematologic toxicities | • Stop until resolved or returned to baseline • Consider restarting the next scheduled treatment at 1 dose level reductiona |
a See table 3 for dose level reductions
Table 3. Dose level reductions for carfilzomib:
| Regimen | Carfilzomib Dose | First carfilzomib dose reduction | Second carfilzomib dose reduction | Third carfilzomib dose reduction |
| Carfilzomib, lenalidomide, and dexamethasone | 27 mg/m² | 20 mg/m² | 15 mg/m²a | — |
Note: Carfilzomib infusion times remain unchanged during dose reduction(s)
a If symptoms do not resolve, discontinue carfilzomib treatment
Carfilzomib is to be administered by intravenous infusion. The 20/27 mg/m² dose is administered over 10 minutes.
Carfilzomib 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 carfilzomib administration.
Do not mix carfilzomib with or administer as an infusion with other medicinal products.
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