Kyprolis Dosage/Direction for Use

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 Cardiac Toxicities and Tumor Lysis Syndrome under Precautions].
Electrolyte Monitoring: Monitor serum potassium levels regularly during treatment with Kyprolis [see Clinical Trials Experience under Adverse Reactions].
Premedications and Concomitant Medications: Premedicate with dexamethasone administered as part of the combination therapy [see Recommended Dosage as follows]. 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 Infusion-Related Reactions under Precautions]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.
Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies [see Venous Thrombosis under Precautions].
Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation [see Clinical Trials Experience under Adverse Reactions].
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.
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 12 [see Pharmacology: Clinical Studies: In Combination with Lenalidomide and Dexamethasone for Relapse or Refractory Multiple Myeloma under Actions]. 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. (See Table 12.)

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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 13 [see Pharmacology: Clinical Studies: In Combination with Dexamethasone for Relapsed or Refractory Multiple Myeloma under Actions]. 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. (See Table 13.)

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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 14 [see Pharmacology: Clinical Studies: In Combination with Dexamethasone for Relapsed or Refractory Multiple Myeloma under Actions]. 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. (See Table 14.)

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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 with intravenous daratumumab and dexamethasone until disease progression or unacceptable toxicity as shown in Table 15 [see Pharmacology: Clinical Studies: In Combination with Intravenous Daratumumab and Dexamethasone for Relapsed or Refractory Multiple Myeloma under Actions]. 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. (See Table 15.)

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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 15 [see Pharmacology: Clinical Studies: In Combination with Intravenous Daratumumab and Dexamethasone for Relapsed or Refractory Multiple Myeloma under Actions]. 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. (See Table 16.)

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Dosage Modifications for Adverse Reactions: Recommended actions and dosage modifications for Kyprolis are presented in Table 17. Dose level reductions are presented in Table 18. See the lenalidomide, intravenous daratumumab, and dexamethasone Prescribing Information respectively for recommended dosage modifications associated with each product. (See Table 17 and Table 18.)

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Dosage Modifications for Hepatic Impairment: For patients with mild (total bilirubin > 1 to 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment, reduce the dose of Kyprolis by 25% [see Hepatic Impairment under Precautions, Pharmacology: Pharmacokinetics under Actions].
Recommended Dosage for End Stage Renal Disease: For patients with end stage renal disease who are on hemodialysis, administer Kyprolis after the hemodialysis procedure.
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 19. 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. (See Table 19.)

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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 20. (See Table 20.)

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