Posology : מינונים

2        DOSAGE AND ADMINISTRATION

2.1      Administration Precautions
Hydration
Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. Consider hydration with both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). If needed, give an additional 250 mL to 500 mL of intravenous fluids following Kyprolis administration.
Continue oral and/or intravenous hydration, as needed, in subsequent cycles.


Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure [see Warnings and Precautions (5.1, 5.3)].

Electrolyte Monitoring
Monitor serum potassium levels regularly during treatment with Kyprolis [see Adverse Reactions (6.1)].

Premedications and Concomitant Medications

Premedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy [see Dosage and Administration (2.2)]. Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Kyprolis during Cycle 1 to reduce the incidence and severity of infusion-related reactions [see Warnings and Precautions (5.9)]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.

Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies [see Warnings and Precautions (5.8)].

Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation [see Adverse Reactions (6.1)].

Dose Calculation

For patients with body surface area (BSA) of 2.2 m2 or less, calculate the Kyprolis dose using actual BSA. Dose adjustments do not need to be made for weight changes of 20% or less.

For patients with a BSA greater than 2.2 m2, calculate the Kyprolis dose using a BSA of 2.2 m2.

2.2       Recommended Dosage

Kyprolis in Combination with Lenalidomide and Dexamethasone
Administer Kyprolis intravenously as a 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle in combination with lenalidomide and dexamethasone until Cycle 12 as shown in Table 1 [see Clinical Studies (14.1)]. The recommended starting dose of Kyprolis is 20 mg/m2 on Cycle 1, Days 1 and 2. If tolerated, escalate the dose to 27 mg/m2 on Cycle 1, Day 8. From Cycle 13, administer Kyprolis on Days 1, 2, 15, 16 until Cycle 18. Discontinue Kyprolis after Cycle 18. Continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity occurs. Refer to the Prescribing Information for lenalidomide and dexamethasone for additional dosage information.

Table 1: Kyprolis 20/27 mg/m2 Twice Weekly (10-Minute Infusion) in Combination with Lenalidomide and Dexamethasone

Cycle 1
Week 1                     Week 2                     Week 3                  Week 4 Days
Day      Day     Days     Day      Day     Days        Day     Day       17–    Day      Days 1        2      3–7       8        9      10–14       15      16         21    22       23-28 Kyprolis
(mg/m2)             20       20       -       27       27        -        27       27        -      -            - Dexamethason        40       -        -       40        -        -        40        -        -     40            - e(mg)
Lenalidomide                               25 mg daily on Days 1-21                                 -            - Cycles 2 to 12
Week 1                   Week 2                      Week 3                   Week 4 Da Days
Day      Day     Days     Day      Day      Days        Day   y    17–          Day      Days 1        2      3–7       8        9       10–14       15    16   21           22       23-28 Kyprolis
(mg/m2)             27       27       -       27       27         -        27       27       -      -            - Dexamethason        40       -        -       40        -         -        40           -    -     40            - e(mg)
Lenalidomide                      25 mg daily on Days 1-21                                          -            - Cycles 13 and latera
Week 1             Week 2                  Week 3                                Week 4 Da Days
Day Day Days Day Day            Days     Day     y    17–                       Day      Days 1   2     3–7    8      9     10–14      15     16   21                        22       23-28 Kyprolis
(mg/m2)             27       27       -        -        -         -        27       27       -      -            - Dexamethason        40       -        -       40        -         -        40           -    -     40            - e(mg)
Lenalidomide                               25 mg daily on Days 1-21
a   Kyprolis is administered through Cycle 18; lenalidomide and dexamethasone continue thereafter.

Kyprolis in Combination with Dexamethasone

Twice weekly 20/56 mg/m2 regimen by 30-minute infusion
Administer Kyprolis intravenously as a 30-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle in combination with dexamethasone until disease progression or unacceptable toxicity as shown in Table 2 [see Clinical Studies (14.2)]. The recommended starting dose of Kyprolis is 20 mg/m2 on Cycle 1, Days 1 and 2. If tolerated, escalate the dose to 56 mg/m2 on Cycle 1, Day 8. Administer dexamethasone 30 minutes to 4 hours before Kyprolis. Refer to the Prescribing Information for dexamethasone for additional dosage information

Table 2: Kyprolis 20/56 mg/m2 Twice Weekly (30-Minute Infusion) in Combination with Dexamethasone

Cycle 1
Week 1                Week 2                  Week 3                Week 4 Days                    Days
Da   Day      Days   Day   Day      10–      Day   Day      17–    Day   Day      Days y1    2       3–7     8     9        14      15    16        21     22    23      24-28 Kyprolis
(mg/m2)          20    20       -     56     56       -        56    56       -      -     -         - Dexamethason
e (mg)           20    20       -     20     20       -        20    20       -     20     20        - 
Cycles 2 and later
Week 1              Week 2              Week 3                      Week 4 Days                Days
Da   Day      Days   Day Day    10–     Day Day     17–            Day   Day      Days y1    2       3–7     8   9      14     15     16    21             22    23      24-28 Kyprolis                                                                                             - (mg/m2)          56    56       -     56     56       -        56    56       -      -     - Dexamethason
e (mg)           20    20       -     20     20       -        20    20       -     20     20        - 
Once weekly 20/70 mg/m2 regimen by 30-minute infusion

Administer Kyprolis intravenously as a 30-minute infusion on Days 1, 8, and 15 of each 28- day cycle in combination with dexamethasone until disease progression or unacceptable toxicity as shown in Table 3 [see Clinical Studies (14.2)]. The recommended starting dose of Kyprolis is 20 mg/m2 on Cycle 1, Day 1. If tolerated, escalate the dose to 70 mg/m2 on Cycle 1, Day 8. Administer dexamethasone 30 minutes to 4 hours before Kyprolis. Refer to Prescribing Information for dexamethasone for additional dosage information.


Table 3: Kyprolis 20/70 mg/m2 Once Weekly (30-Minute Infusion) in Combination with Dexamethasone

Cycle 1
Week 1                Week 2                   Week 3                Week 4 Days                     Days
Day    Day     Days   Day   Day       10–    Day     Day       17–   Day   Day      Days 1      2       3–7    8     9        14     15      16        21    22    23       24-28 Kyprolis
20      -       -     70      -        -      70        -      -      -      -        -
(mg/m2)
Dexamethason
40      -       -     40      -        -      40        -      -     40      -        -
e (mg)
Cycles 2 to 9
Week 1                Week 2                   Week 3                Week 4 Days                     Days
Day    Day     Days   Day   Day      10–     Day     Day      17–    Day   Day      Days 1      2      3–7     8     9        14     15      16        21    22    23       24-28 Kyprolis
70      -       -     70      -        -      70        -      -      -      -        - (mg/m2)
Dexamethason
40      -       -     40      -        -      40        -      -     40               -
e (mg)
Cycles 10 and later
Week 1                Week 2                   Week 3                Week 4 Days                     Days
Day    Day     Days   Day   Day      10–     Day     Day      17–    Day   Day      Days 1      2      3–7     8     9        14     15      16        21    22    23       24-28 Kyprolis
70      -       -     70      -        -      70        -      -      -      -        - (mg/m2)
Dexamethason
40      -       -     40      -        -      40        -      -      -      -        -
e (mg)

Kyprolis in Combination with Intravenous Daratumumab and Dexamethasone 
Twice weekly 20/56 mg/m2 regimen by 30-minute infusion

Administer Kyprolis intravenously as a 30-minute infusion on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle in combination the intravenous daratumumab and dexamethasone until disease progression or unacceptable toxicity as shown in Table 4 [see Clinical Studies (14.3)]. The recommended starting dose of Kyprolis is 20 mg/m2 on Cycle 1, Days 1 and 2.
If tolerated, escalate the dose to 56 mg/m2 on Cycle 1, Day 8 and thereafter. Administer dexamethasone 30 minutes to 4 hours before Kyprolis and 1 to 3 hours before intravenous 

daratumumab. Refer to the Prescribing Information for intravenous daratumumab and dexamethasone for additional dosage information.

Table 4: Kyprolis 20/56 mg/m2 Twice Weekly (30-Minute Infusion) in Combination with Intravenous Daratumumab and Dexamethasone

Cycle 1
Week 1                Week 2                     Week 3                 Week 4 Day    Day     Days   Day    Day      Days       Day    Day     Days    Day    Day       Days 1      2       3–7    8      9       10–14      15     16      17–21   22     23        24-28 Kyprolis
20     20      -     56      56        -         56      56      -      -      -          -
(mg/m2)
Dexamethasone
20     20      -     20      20        -         20      20      -     40      -          -
(mg)*
Daratumumab
8      8       -     16      -         -         16      -       -     16      -          - (mg/kg)
Cycle 2
Week 1                Week 2                     Week 3                 Week 4 Day    Day     Days   Day    Day      Days       Day    Day     Days    Day    Day       Days 1      2      3–7     8      9       10–14      15     16      17–21   22     23        24-28 Kyprolis
56     56      -     56      56        -         56      56      -      -      -          - (mg/m2)
Dexamethasone
20     20      -     20      20        -         20      20      -     40      -          -
(mg)*
Daratumumab
16     -       -     16      -         -         16      -       -     16      -          - (mg/kg)
Cycles 3-6
Week 1                Week 2                     Week 3                 Week 4 Day    Day     Days   Day    Day      Days       Day    Day     Days    Day    Day       Days 1      2      3–7     8      9       10–14      15     16      17–21   22     23        24-28 Kyprolis
56     56      -     56      56        -         56      56      -      -      -          - (mg/m2)
Dexamethasone
20     20      -     20      20        -         20      20      -     40      -          -
(mg)*
Daratumumab
16     -       -      -      -         -         16      -       -      -      -          - (mg/kg)
Cycles 7 and onwards
Week 1                Week 2                     Week 3                 Week 4 
Day    Day     Days   Day    Day      Days       Day    Day     Days    Day    Day       Days 1      2      3–7     8      9       10–14      15     16      17–21   22     23        24-28 Kyprolis
56     56      -     56      56        -         56      56      -      -      -          - (mg/m2)


Dexamethasone
20        20         -        20        20         -        20        20         -        40         -       - (mg)*
Daratumumab
16         -         -         -         -         -         -         -         -         -         -       - (mg/kg)
*For patients > 75 years of age, administer 20 mg of dexamethasone orally or intravenously weekly after the first week.

Once weekly 20/70 mg/m2 regimen by 30-minute infusion

Administer Kyprolis intravenously as a 30-minute infusion on Days 1, 8 and 15 of each 28- day cycle in combination with intravenous daratumumab and dexamethasone until disease progression or unacceptable toxicity as shown in Table 5 [see Clinical Studies (14.3)]. The recommended starting dose of Kyprolis is 20 mg/m2 on Cycle 1, Day 1. If tolerated, escalate the dose to 70 mg/m2 on Cycle 1, Day 8 and thereafter. Administer dexamethasone 30 minutes to 4 hours before Kyprolis and 1 to 3 hours before intravenous daratumumab. Refer to the Prescribing Information for intravenous daratumumab and dexamethasone for additional dosage information.

Table 5: Kyprolis 20/70 mg/m2 Once Weekly (30-Minute Infusion) in Combination with Intravenous Daratumumab and Dexamethasone


Cycle 1
Week 1                   Week 2                   Week 3                     Week 4 Days                     Days
Days
Day     Day               Day    Day      10–     Day     Day      17–     Day      Day      Days 1       2       3–7       8      9       14      15      16       21      22       23       24-28 Kyprolis
20       -        -       70      -        -      70       -        -     -          -        - (mg/m2)
Dexamethasone
20      20        -       20     20        -      20      20        -         20    20        - (mg)*
Daratumumab
8       8        -       16      -        -      16       -        -         16     -        - (mg/kg)
Cycle 2
Week 1                   Week 2                   Week 3                     Week 4 Days                     Days
Day     Day      Days     Day    Day     10–      Day     Day     17–      Day      Day      Days 1       2       3–7       8      9       14      15      16       21      22       23       24-28 Kyprolis
70       -        -       70      -        -      70       -        -         -      -        - (mg/m2)
Dexamethasone
20      20        -       20     20        -      20      20        -         20    20        - (mg)*
Daratumumab
16       -        -       16      -        -      16       -        -         16     -        - (mg/kg)
Cycles 3-6
Week 1                   Week 2                   Week 3                     Week 4 Days                     Days
Day     Day      Days     Day    Day     10–      Day     Day     17–      Day      Day      Days 1       2       3–7       8      9       14      15      16       21      22       23       24-28 Kyprolis
70       -        -       70      -        -      70       -        -         -      -        - (mg/m2)
Dexamethasone
20      20        -       40      -        -      20      20        -         40     -        - (mg)*
Daratumumab
16       -        -        -      -        -      16       -        -         -      -        - (mg/kg)
Cycles 7 and thereafter
Week 1                   Week 2                   Week 3                     Week 4 Days                     Days
Day     Day      Days     Day    Day     10–      Day     Day     17–      Day      Day      Days 1       2       3–7       8      9       14      15      16       21      22       23       24-28 Kyprolis
70       -        -       70      -        -      70       -        -         -      -        - (mg/m2)
Dexamethasone
20      20        -       40      -        -      40       -        -         40     -        - (mg)*
Daratumumab
16       -        -        -      -        -       -       -        -         -      -        - (mg/kg)
*For patients > 75 years of age, administer 20 mg of dexamethasone orally or intravenously weekly after the first week.

Kyprolis Monotherapy

20/27 mg/m2 twice weekly regimen by 10-minute infusion
Administer Kyprolis intravenously as a 10-minute infusion [see Clinical Studies (14.4)]. In Cycles 1 through 12, administer Kyprolis on Days 1, 2, 8, 9, 15 and 16 of each 28-day cycle as shown in Table 6. From Cycle 13, administer Kyprolis on Days 1, 2, 15 and 16 of each 28- day cycle. Premedicate with dexamethasone 4 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to minimize infusion-related
reactions [see Dosage and Administration (2.1)]. The recommended starting dose of Kyprolis is 20 mg/m2 in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 27 mg/m2 on Day 8 of Cycle 1 and thereafter. Continue Kyprolis until disease progression or unacceptable toxicity.

Table 6: Kyprolis Monotherapy 20/27 mg/m2 Twice Weekly (10-Minute Infusion) 
Cycle 1
Week 1                        Week 2                 Week 3         Week 4 Day Day    Days           Day     Day    Days      Day   Day    Days     Days 1   2     3–7             8       9     10–14     15     16    17–21   22–28 
Kyprolis (mg/m2)a          20      20        -       27     27        -      27     27      -       - Cycles 2 to 12
Week 1                     Week 2                 Week 3         Week 4 Day    Day    Days        Day     Day    Days      Day   Day    Days     Days 1      2     3–7          8       9     10–14     15     16    17–21   22–28 
Kyprolis (mg/m2)          27      27        -       27   27        -       27  27      -           - Cycles 13 and later
Week 1                     Week 2                Week 3             Week 4 Day  Da    Days            Day  Day     Days     Day Day    Days         Days 1   y     3–7              8    9      10–14     15  16    17–21       22–28 2
Kyprolis (mg/m2)          27      27        -         -        -        -   27     27      -       - a   Dexamethasone premedication is required for each Kyprolis dose in Cycle 1.


2.3         Dosage Modifications for Adverse Reactions
Recommended actions and dosage modifications for Kyprolis are presented in Table 7. Dose level reductions are presented in Table 9. See the lenalidomide, intravenous daratumumab, and dexamethasone Prescribing Information respectively for recommended dosage modifications associated with each product.

Table 7: Dosage Modifications for Adverse Reactionsa

Hematologic Toxicity
[see Warnings and Precautions (5.11)                          Recommended Action and Adverse Reactions (6.1)]
•    ANC less than 0.5 × 109/L             •   Withhold dose
•    If recovered to greater than or equal to 0.5 × 109/L,
continue at the same dose level
•   For subsequent drops to less than 0.5 × 109/L, follow the
same recommendations as above and consider 1 dose level
reduction when restarting Kyprolisa
•    Febrile neutropenia:                  •   Withhold dose
ANC less than 0.5 × 109/L and an          •    If ANC returns to baseline grade and fever resolves, oral temperature more than 38.5°C              resume at the same dose level or two consecutive readings of
more than 38.0°C for 2 hours
•    Platelets less than 10 × 109/L or     •   Withhold dose
evidence of bleeding with                 •    If recovered to greater than or equal to 10 × 109/L thrombocytopenia                               and/or bleeding is controlled, continue at the same dose level
•   For subsequent drops to less than 10 × 109/L, follow the
same recommendations as above and consider 1 dose level
reduction when restarting Kyprolisa
Renal Toxicity
Recommended Action
[see Warnings and Precautions (5.2)]
•    Serum creatinine greater than or      •    Withhold dose and continue monitoring renal function equal to 2 × baseline, or                  (serum creatinine or creatinine clearance) •    Creatinine clearance less                 • If attributable to Kyprolis, resume when renal function than 15 mL/min, or creatinine                  has recovered to within 25% of baseline; start at 1 dose clearance decreases to less than or            level reductiona
equal to 50% of baseline, or need         • If not attributable to Kyprolis, dosing may be resumed at for hemodialysis                               the discretion of the healthcare provider •    For patients on hemodialysis receiving Kyprolis, the dose is
to be administered after the hemodialysis procedure
Other Non-hematologic Toxicity
Recommended Action
[see Adverse Reactions (6.1)]
•    All other severe or life-             •   Withhold until resolved or returned to baseline threateningb non-hematological        •   Consider restarting the next scheduled treatment at 1 dose toxicities                                level reductiona
ANC = absolute neutrophil count
a See Table 8 for dose level reductions.
b Grade 3 and 4.


Table 8: Dose Level Reductions for Adverse Reactions

First Dose   Second Dose   Third Dose
Regimen                          Dose
Reduction     Reduction    Reduction
Kyprolis and Dexamethasone
OR
Kyprolis, Daratumumab and                 70 mg/m2            56 mg/m2      45 mg/m2     36 mg/m2a Dexamethasone (once weekly)

Kyprolis and Dexamethasone
OR
Kyprolis, Daratumumab, and
Dexamethasone                             56 mg/m2            45 mg/m2      36 mg/m2     27 mg/m2a (twice weekly)


Kyprolis, Lenalidomide, and
Dexamethasone
OR                                        27 mg/m2            20 mg/m2      15 mg/m2a       — Kyprolis Monotherapy (twice
weekly)
Note: Infusion times remain unchanged during dose reduction(s).
a If toxicity persists, discontinue Kyprolis treatment.


2.4       Recommended Dosage for End Stage Renal Disease

For patients with end stage renal disease who are on hemodialysis, administer Kyprolis after the hemodialysis procedure.

2.5       Preparation and Administration
Kyprolis vials contain no antimicrobial preservatives and are intended for single-dose only.
The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL.

Read the complete preparation instructions prior to reconstitution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Reconstitution/Preparation Steps:
1.        Remove vial from refrigerator just prior to use.
2.        Calculate the dose (mg/m2) and number of vials of Kyprolis required using the
patient’s BSA at baseline.
3.        Aseptically reconstitute each Kyprolis vial only with Sterile Water for Injection, USP using the volumes described in Table 9. Use a 21-gauge or larger needle (0.8 mm or smaller external diameter needle) to reconstitute each vial by slowly injecting Sterile Water for Injection, USP through the stopper and directing the Sterile Water for Injection, USP onto the INSIDE WALL OF THE VIAL to minimize foaming. There is no data to support the use of closed system transfer devices with Kyprolis.



Table 9: Reconstitution Volumes

Strength                   Amount of Sterile Water for Injection, USP required for reconstitution

10 mg vial                                        5 mL

30 mg vial                                       15 mL
60 mg vial                                       29 mL


4.   Gently swirl and/or invert the vial slowly for about 1 minute, or until complete
dissolution. DO NOT SHAKE to avoid foam generation. 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 discoloration prior to administration. The reconstituted product should be a clear, colorless solution and should not be administered if any discoloration or particulate matter is observed.
6.   Discard any unused portion left in the vial. DO NOT pool unused portions from the vials. DO NOT administer more than one dose from a vial.
7.   Administer Kyprolis directly by intravenous infusion or in a 50 mL to 100 mL intravenous bag containing 5% Dextrose Injection, USP. Do not administer as an intravenous push or bolus.
8.   When administering in an intravenous bag, use 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 50 mL or 100 mL intravenous bag containing only 5% Dextrose Injection, USP (based on the calculated total dose and infusion time).
9.            Flush the intravenous administration line with normal saline or 5% Dextrose Injection, USP immediately before and after Kyprolis administration.
10.           Do not mix Kyprolis with or administer as an infusion with other medicinal products.
The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 10.

Table 10: Stability of Reconstituted Kyprolis

Stabilitya per Container
Intravenous Bag
Storage Conditions of Reconstituted Kyprolis                      Vial              Syringe            (D5Wb) Refrigerated 2°C to 8°C                                            24 hours            24 hours           24 hours Room Temperature 15°C to 30°C                                       4 hours            4 hours           4 hours a   Total time from reconstitution to administration should not exceed 24 hours.
b   5% Dextrose Injection, USP.