July 26, 2016
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Kyprolis

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Kyprolis

Indications
Dosage
How Supplied

INDICATIONS

Relapsed Or Refractory Multiple Myeloma

  • Kyprolis is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy [see Clinical Studies].
  • Kyprolis is indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy [see Clinical Studies].

DOSAGE AND ADMINISTRATION

Administration Precautions

  • Hydration -Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high risk of tumor lysis syndrome 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].
  • 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 Recommended Dosing]. 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]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.
  • Administration -Infuse over 10 or 30 minutes depending on the Kyprolis dose regimen [see Recommended Dosing]. Do not administer as a bolus. 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 Recommended Dosing] using the patient's actual body surface area at baseline. In patients with a body surface area greater than 2.2 m², calculate the dose based upon a body surface area 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].
  • Infection Prophylaxis -Consider antiviral prophylaxis for patients being treated with Kyprolis to decrease the risk of herpes zoster reactivation.

Recommended Dosing

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 1. 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 1: Kyprolis (10-Minute Infusion) 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
Kyprolis (mg/m²) 20 20 - 27 27 - 27 27 - - -
Dexamethasone (mg) 40 - - 40 - - 40 - - 40 -
Lenalidomide 25 mg daily on Days 1-21 - -
  Cycles 2 to 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
Kyprolis (mg/m²) 27 27 - 27 27 - 27 27 - - -
Dexamethasone (mg) 40 - - 40 - - 40 - - 40 -
Lenalidomide 25 mg daily on Days 1-21 - -
  Cycles 13 and latera
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 2 3-28
Kyprolis (mg/m²) 27 27 - - - - 27 27 - - -
Dexamethasone (mg) 40 - - 40 - - 40 - - 40 -
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 Dose Modifications Based on Toxicities]. 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 In Combination With Dexamethasone

For the combination regimen with dexamethasone, administer Kyprolis 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 by 30-minute infusion 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 (30-Minute Infusion) in Combination with 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 Day 23 Days 2428
Kyprolis (mg/m²) 20 20 - 56 56 - 56 56 - - - -
Dexamethasone (mg) 20 20 - 20 20 - 20 20 - 20 20 -
  Cycles 2 and later
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 Day 23 Days 2428
Kyprolis (mg/m²) 56 56 - 56 56 - 56 56 - - - -
Dexamethasone (mg) 20 20 - 20 20 - 20 20 - 20 20 -

Treatment may be continued until disease progression or unacceptable toxicity occurs [see Dose Modifications Based on Toxicities]. Refer to the dexamethasone Prescribing Information for other concomitant medications.

Kyprolis Monotherapy

For monotherapy, administer Kyprolis intravenously as a 10-minute or 30-minute infusion depending on the regimen as described below.

20/27 mg/m² Regimen by 10-minute Infusion

For monotherapy using the 20/27 mg/m² regimen, administer Kyprolis intravenously as a 10-minute infusion [see Clinical Studies]. 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 3. Each 28-day period is considered one treatment cycle. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis (see Table 3). 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 Administration Precautions]. 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 3: Kyprolis Monotherapy (10-Minute Infusion)

  Cycle 1
Week 1 Week 2 Week 3 Week 4
Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 1014 Day 15 Day 16 Days 1721 Days 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 1 Day 2 Days 3-7 Day 8 Day 9 Days 1014 Day 15 Day 16 Days 1721 Days 22-28
Kyprolis (mg/m²) 27 27 - 27 27 - 27 27 - -
  Cycles 13 and later
Week 1 Week 2 Week 3 Week 4
Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 1014 Day 15 Day 16 Days 1721 Days 22-28
Kyprolis (mg/m²) 27 27 - - - - 27 27 - -
a Dexamethasone premedication is required for each Kyprolis dose in Cycle 1.

20/56 mg/m² Regimen by 30-minute Infusion

For monotherapy using the 20/56 mg/m² regimen, administer Kyprolis intravenously as a 30-minute infusion [see Clinical Studies]. 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 8 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 Administration Precautions]. The recommended starting dose of Kyprolis is 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. Treatment may continue until disease progression or unacceptable toxicity occurs.

Table 4: Kyprolis Monotherapy (30-Minute Infusion)

  Cycle 1
Week 1 Week 2 Week 3 Week 4
Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 1014 Day 15 Day 16 Days 1721 Days 22-28
Kyprolis (mg/m²)a 20 20 - 56 56 - 56 56 - -
  Cycles 2 to 12
Week 1 Week 2 Week 3 Week 4
Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 1014 Day 15 Day 16 Days 1721 Days 22-28
Kyprolis (mg/m²) 56 56 - 56 56 - 56 56 - -
  Cycles 13 and later
Week 1 Week 2 Week 3 Week 4
Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 1014 Day 15 Day 16 Days 1721 Days 22-28
Kyprolis (mg/m²) 56 56 - - - - 56 56 - -
a Dexamethasone premedication is required for each Kyprolis dose in Cycle 1.

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 x 109/L
  • Withhold dose
  • If recovered to greater than or equal to 0.5 x 109/L, continue at the same dose level
  • For subsequent drops to less than 0.5 x 109/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolisa
  • Febrile neutropenia ANC less than 0.5 x 109/L and an oral temperature more than 38.5°C or two consecutive readings of more than 38.0°C for 2 hours
  • Withhold dose
  • If ANC returns to baseline grade and fever resolves, resume at the same dose level.
  • Platelets less than 10 x 109/L or evidence of bleeding with thrombocytopenia [see WARNINGS AND PRECAUTIONS]
  • Withhold dose
  • If recovered to greater than or equal to 10 x 109/L and/or bleeding is controlled, continue at the same dose level
  • For subsequent drops to less than 10 x 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 equal to 2 x baseline, or
  • Creatinine clearance less than 15 mL/min, or creatinine clearance decreases to less than or equal to 50% of baseline, or need for dialysis [see WARNINGS AND PRECAUTIONS]
  • Withhold dose and continue monitoring renal function (serum creatinine or creatinine clearance)
  • If attributable to Kyprolis, resume when renal function has recovered to within 25% of baseline; start at 1 dose level reductiona
  • If not attributable to Kyprolis, dosing may be resumed at the discretion of the physician
  • For patients on dialysis receiving Kyprolis, the dose is to be administered after the dialysis procedure
Other Non-hematologic Toxicity Recommended Action
  • All other severe or life-threateningb non-hematological toxicities
  • Withhold until resolved or returned to baseline
  • Consider restarting the next scheduled treatment at 1 dose 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

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

Reconstitution And Preparation For Intravenous Administration

Kyprolis vials contain no antimicrobial preservatives and are intended for single use 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 (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. The quantity of Kyprolis contained in one single-dose vial (60 mg carfilzomib) may exceed the required dose. Use caution in calculating the quantity delivered to prevent overdosing. 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 body surface area (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 vial by slowly injecting 29 mL Sterile Water for Injection, USP, through the stopper and directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming
  4. Direct the solution onto the INSIDE WALL OF THE VIAL -  Illustration
  5. 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.
  6. 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.
  7. Discard any unused portion left in the vial. DO NOT pool unused portions from the vials.
  8. Optionally, Kyprolis can be administered in an intravenous bag.
  9. When administering in an intravenous bag, withdraw the calculated dose from the vial and dilute into 50 mL or 100 mL intravenous bag containing 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 7.

Table 7: Stability of Reconstituted Kyprolis

Storage Conditions of Reconstituted Kyprolis Stabilitya per Container
Vial Syringe Intravenous Bag (D5Wb)
Refrigerated (2°C to 8°C; 36°F to 46°F) 24 hours 24 hours 24 hours
Room Temperature (15°C to 30°C; 59°F to 86°F) 4 hours 4 hours 4 hours
a Total time from reconstitution to administration should not exceed 24 hours.
b 5% Dextrose Injection, USP.

HOW SUPPLIED

Dosage Forms And Strengths

For injection: 60 mg lyophilized cake or powder in single-dose vial for reconstitution

Kyprolis (carfilzomib) is supplied as an individually cartoned single-dose vial containing a dose of 60 mg of carfilzomib as a white to off-white lyophilized cake or powder.

NDC 76075-101-01, 60 mg carfilzomib per vial

Storage And Handling

Unopened vials should be stored refrigerated (2°C to 8°C; 36°F to 46°F). Retain in original package to protect from light.

Manufactured for: Onyx Pharmaceuticals, Inc. Thousand Oaks, CA 91320-1799. Revised: May 2016

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 6/7/2016

Indications
Dosage
How Supplied

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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


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