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. The recommended hydration includes 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.
•     Premedications - Premedicate with the recommended dose of dexamethasone for monotherapy or the recommended dexamethasone dose if on 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 reactions [see Warnings and Precautions (5.9)]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.
•     Administration - Kyprolis can be administered in a 50 mL or 100 mL intravenous bag of 5% Dextrose Injection, USP. Infuse over 10 or 30 minutes depending on the Kyprolis dose regimen [see Dosage and Administration (2.2)]. Administer as an intravenous infusion. Flush the intravenous administration line with normal saline or 5% Dextrose Injection, USP immediately before and after Kyprolis administration. Do not mix Kyprolis with or administer as an infusion with other medicinal products.
•     Dose Calculation - Calculate the Kyprolis dose [see Dosage and Administration (2.2)] using the patient’s actual body surface area (BSA) at baseline. In patients with a BSA greater than 2.2 m2, calculate the dose based upon a BSA of 2.2 m2.
•     Thromboprophylaxis - Thromboprophylaxis is recommended for patients being treated with the combination of Kyprolis with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks [see Warnings and Precautions (5.8)].
•     Infection Prophylaxis - Consider antiviral prophylaxis for patients being treated with Kyprolis to decrease the risk of herpes zoster reactivation.
•     Patients on Hemodialysis - Administer Kyprolis after the hemodialysis procedure.

2.2     Recommended Dosing

Kyprolis in Combination with Dexamethasone
For the combination regimen with dexamethasone alone, administer Kyprolis intravenously once weekly or twice weekly as a 30-minute infusion as described in Table 1 & 2 below.

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

Kyprolis is administered intravenously as a 30-minute infusion once weekly for three weeks followed by a 13-day rest period as shown in Table 1. Each 28-day period is considered one treatment cycle. Administer Kyprolis at a starting dose of 20 mg/m2 in Cycle 1 on Day 1. If tolerated, escalate the dose to 70 mg/m2 on Day 8 of Cycle 1. Dexamethasone 40 mg is taken by mouth or intravenously on Days 1, 8, and 15 of all cycles and on Day 22 of Cycles 1 to 9.
Administer dexamethasone 30 minutes to 4 hours before Kyprolis.

Table 1: Kyprolis 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)


Treatment may be continued until disease progression or unacceptable toxicity occurs [see 
Dosage and Administration (2.3)]. Refer to the dexamethasone Prescribing Information for other information on that product.

Twice weekly 20/56 mg/m2 regimen by 30-minute infusion
Kyprolis is administered intravenously as a 30-minute infusion on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 2. Each 28-day period is considered one treatment cycle. Administer Kyprolis at a starting dose of
20 mg/m2 in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 56 mg/m2 on Day 8 of Cycle 1. Dexamethasone 20 mg is taken by mouth or intravenously on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. Administer dexamethasone 30 minutes to 4 hours before Kyprolis.

Table 2: Kyprolis Twice 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     20       -     56     56       -        56    56       -      -      -        -
(mg/m2)
Dexamethasone
20     20       -     20     20       -        20    20       -     20     20        -
(mg)
Cycles 2 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                                                                                                - 56     56       -     56     56       -        56    56       -      -      - (mg/m2)
Dexamethasone
20     20       -     20     20       -        20    20       -     20     20        -
(mg)

Treatment may be continued until disease progression or unacceptable toxicity occurs [see Dosage and Administration (2.3)]. Refer to the dexamethasone Prescribing Information for other information on that product.


Kyprolis in Combination with Lenalidomide and Dexamethasone

For the combination regimen with lenalidomide and dexamethasone, administer Kyprolis intravenously as a 10-minute infusion on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 3. Each 28-day period is considered one treatment cycle. 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. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis. Discontinue Kyprolis after Cycle 18.
Lenalidomide 25 mg is taken orally on Days 1–21 and dexamethasone 40 mg by mouth or intravenously on Days 1, 8, 15, and 22 of the 28-day cycles.

Table 3: Kyprolis 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
20       20        -        27       27         -       27        27           -    -            - (mg/m2)
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 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
27       27        -        27       27         -         27       27          -    -            - (mg/m2)
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 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
27       27        -         -        -         -         27       27          -    -            - (mg/m2)
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.


Continue treatment until disease progression or unacceptable toxicity occurs [see Dosage and Administration (2.3)]. Refer to the lenalidomide and dexamethasone Prescribing Information for other concomitant medications, such as the use of anticoagulant and antacid prophylaxis, that may be required with those agents.

Kyprolis Monotherapy

For monotherapy, administer Kyprolis intravenously as a 10-minute infusion [see Clinical Studies (14.3)]. In Cycles 1 through 12, administer Kyprolis on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 4. Each 28-day period is considered one treatment cycle. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis (see Table 4). Premedicate with dexamethasone 4 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to help prevent infusion 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. Treatment may continue until disease progression or unacceptable toxicity occurs.

Table 4: Kyprolis Monotherapy Twice Weekly (10-Minute Infusion)

Cycle 1
Week 1                        Week 2                  Week 3         Week 4 Day Day    Days            Da     Day    Days      Day    Day    Days     Days 1   2     3–7              y      9     10–14      15     16    17–21   22–28 8
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         Da     Day     Days      Day   Day    Days     Days 1      2     3–7           y       9     10–14      15    16    17–21   22–28 8
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     Dose Modifications Based on Toxicities

Modify dosing based on toxicity. Recommended actions and dose modifications for Kyprolis are presented in Table 5. Dose level reductions are presented in Table 6. See the lenalidomide and dexamethasone Prescribing Information respectively for dosing recommendations.

Table 5: Dose Modifications for Toxicitya during Kyprolis Treatment

Hematologic Toxicity                                   Recommended Action •      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 [see Warnings and Precautions (5)]                    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 •    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 physician [see Warnings and Precautions (5)]         •    For patients on hemodialysis receiving Kyprolis, the dose is to be administered after the hemodialysis procedure
Other Non-hematologic Toxicity                              Recommended Action •      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 6 for dose level reductions.
b CTCAE Grades 3 and 4.


Table 6: Dose Level Reductions for Kyprolis Toxicity

First Dose   Second Dose   Third Dose
Regimen                          Dose
Reduction     Reduction    Reduction
Kyprolis and Dexamethasone
70 mg/m2           56 mg/m2      45 mg/m2     36 mg/m2a
(once weekly)
Kyprolis and Dexamethasone
56 mg/m2           45 mg/m2      36 mg/m2     27 mg/m2a
(twice weekly)
Kyprolis, Lenalidomide, and
Dexamethasone or Monotherapy                  27 mg/m2           20 mg/m2      15 mg/m2a       — (twice weekly)
Note: Infusion times remain unchanged during dose reduction(s).
a If toxicity persists, discontinue Kyprolis treatment.



2.4   Dosing in Patients with End Stage Renal Disease

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

2.5   Reconstitution and Preparation for Intravenous Administration
Kyprolis vials contain no antimicrobial preservatives and are intended for single-dose only.
Unopened vials of Kyprolis are stable until the date indicated on the package when stored in the original package at 2°C to 8°C. 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. 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%.
3.   Aseptically reconstitute each Kyprolis vial only with Sterile Water for Injection, USP using the volumes described in Table 7. 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 7: 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.   Kyprolis can be administered directly by intravenous infusion or optionally, administered 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 [see      Dosage and Administration (2)] 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).

The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 8.

Table 8: Stability of Reconstituted Kyprolis

Stabilitya per Container
Intravenous
Storage Conditions of Reconstituted Kyprolis                   Vial        Syringe        Bag (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.