May 1, 2016
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Kyprolis

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Kyprolis

Indications
Dosage
How Supplied

INDICATIONS

Combination Therapy

Kyprolis in combination with lenalidomide and dexamethasone is indicated for the treatment of patients with relapsed multiple myeloma who have received one to three prior lines of therapy [see Clinical Studies].

Monotherapy

Kyprolis is indicated as a single agent for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy [see Clinical Studies]. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

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].
  • Premedications - Premedicate with dexamethasone 4 mg for monotherapy (or the recommended dexamethasone dose if on combination therapy [see Recommended Dosing]) 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 minutes. 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 Dosingf] using the patient's actual body surface area at baseline. Patients with a body surface area greater than 2.2 m² should receive a dose based upon a body surface area of 2.2 m².
  • Thromboprophylaxis - Thromboprophylaxis is recommended for patients being treated with the combination of Kyprolis, lenalidomide, and 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 in 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, 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 to a target dose of 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 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 40 mg - - 40 mg - - 40 mg - - 40 mg -
Lenalidomide 25 mg daily - -
  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 40 mg - - 40 mg - - 40 mg - - 40 mg -
Lenalidomide 25 mg daily - -
  Cycles 13 ona
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 - - -
Dexamethasone 40 mg - - 40 mg - - 40 mg - - 40 mg -
Lenalidomide 25 mg daily
a Kyprolis is administered through Cycle 18, lenalidomide and dexamethasone continue thereafter.

Continue treatment until disease progression or unacceptable toxicity occurs. 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 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. The recommended starting dose of Kyprolis is 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate to a target dose of 27 mg/m² on Day 8 of Cycle 1. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis. Continue treatment until disease progression or unacceptable toxicity occurs.

Table 2: Kyprolis Monotherapy

  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 Days 22-28
Kyprolis (mg/m²): 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 10-14 Day 15 Day 16 Days 17-21 Days 22-28
Kyprolis (mg/m²): 27 27 - 27 27 - 27 27 - -
  Cycles 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 Days 22-28
Kyprolis (mg/m²): 27 27 - - - - 27 27 - -

Dose Modifications Based On Toxicities

Modify dosing based on toxicity. Recommended actions and dose modifications for Kyprolis are presented in Table 3. See the lenalidomide and dexamethasone Prescribing Information respectively for dosing recommendations.

Table 3: Dose Modifications for Toxicitya during Kyprolis Treatment

Hematologic Toxicity Recommended Action
  • Absolute neutrophil count < 0.5 x109/L
  • Withhold dose
  • If recovered to ≥ 0.5 x109/L, continue at the same dose level
  • For subsequent drops to < 0.5 x109/L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolisa
Platelets < 10 x109/L or evidence of bleeding with thrombocytopenia [see WARNINGS AND PRECAUTIONS]
  • Withhold dose
  • If recovered to ≥ 10 x109/L and/or bleeding is controlled, continue at the same dose level
  • For subsequent drops to < 10 x109 /L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolisa
Renal Toxicity Recommended Action
  • Serum creatinine ≥ 2 x baseline, or
  • Creatinine clearance < 15 mL/min, or creatinine clearance decreases 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
a From 27 mg/m² to 20 mg/m² or from 20 mg/m² to 15 mg/m² is considered 1 dose level reduction.
b CTCAE Grades 3 and 4

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. Caution should be used 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%.
    1. 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.
  3. KYPROLIS® (carfilzomib) Figure  Illustration
  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.
  7. Optionally, Kyprolis can be administered in an intravenous bag.
  8. When administering in an intravenous bag, withdraw the calculated dose [see Recommended Dosing] from the vial and dilute into 50 mL intravenous bag containing 5% Dextrose Injection, USP.

The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 4.

Table 4: 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

Kyprolis single-dose vial contains 60 mg of carfilzomib as a sterile, white to off-white lyophilized cake or powder.

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 U.S.A. Revised: July 2015

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

Last reviewed on RxList: 9/14/2015

Indications
Dosage
How Supplied

Report Problems to the Food and Drug Administration

 

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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