Indications
  • KYPROLIS® (carfilzomib) 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.
  • 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.
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Administration and dose modifications

Dosing reference guide

3 easy steps to determine your patient's KYPROLIS® priming and therapeutic dose amounts1:

This tool provides assistance only. It is not designed or intended to replace the physician’s clinical judgment in determining the appropriate dose for his or her patient.

  • At initiation of therapy, the patient’s body surface area (BSA) should always be used when calculating the KYPROLIS® dose.
    • 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 calculated for weight changes of less than or equal to 20%
  • To calculate the priming and therapeutic dose, multiply the patient’s BSA by the KYPROLIS® dose for the specific treatment regimen:
    • Patient’s body surface area (BSA; m2) x dose (mg/m2)
    • Example: Calculate the correct Kd once-weekly dose for a patient with a BSA of 1.8 m2
      • Priming dose: 1.8 m2 x 20 mg/m2 = 36 mg
      • Therapeutic dose: 1.8 m2 x 70 mg/m2 = 126 mg

Step 1: Select dosing regimen

Complete previous steps to continue
m2
Complete previous steps to continue
Priming Dose

mg
Therapeutic Dose

mg
For more information on dosing, please review the or refer to the full Prescribing Information.

Reconstitution and preparation

Follow these steps to reconstitute and prepare KYPROLIS®

Step 1

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

Step 2

Remove vial from refrigerator just prior to use.1

Step 3

Aseptically reconstitute each KYPROLIS® vial only with Sterile Water for Injection, USP using the volumes described in the Reconstitution Table below. 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®.1

Reconstitution volumes1
StrengthAmount of Sterile Water for Injection, USP required for reconstitution
10 mg vial5 mL
30 mg vial15 mL
60 mg vial29 mL
Step 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.1

Step 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.1

Step 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.1

Step 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.1

Step 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).1

KYPROLIS#[sup ®] Dosing and Administration: Reconstitution and Preparation

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.1

Administration and storage

Precautions for administration of KYPROLIS®1

The quantity of KYPROLIS® (carfilzomib) contained in one single-dose vial (30 mg or 60 mg) may exceed the recommended dose. Caution should be used in calculating the quantity delivered to prevent overdosing.

  • KYPROLIS® 56 mg/m2 is infused intravenously over 30 minutes
  • KYPROLIS® 27 mg/m2 is infused intravenously for 10 minutes

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.

Storage1

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 (36°F to 46°F). Retain in original package to protect from light. The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL.

Stability of reconstituted KYPROLIS®1
Storage conditions of reconstituted KYPROLIS®Stability per container*
VialSyringeIntravenous bag (D5W)
Refrigerated 2°C to 8°C (36°F to 46°F)24 hours24 hours24 hours
Room temperature 15°C to 30°C (59°F to 86°F)4 hours4 hours4 hours

Additional dosing considerations

Hydration management1
Additional dosing considerations: Hydration management

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 IV fluids (250 mL to 500 mL of appropriate IV 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

Hydration requirements for KYPROLIS® prior to Cycle 11

Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high risk of TLS.

  • Cases of TLS, including fatal outcomes, have been reported in patients who received KYPROLIS®
  • Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS
  • Ensure that patients are well hydrated before administration of KYPROLIS® in Cycle 1, and in subsequent cycles as needed
  • Uric acid lowering drugs should be considered in patients at risk for TLS
  • Monitor for evidence of TLS during treatment and manage promptly
  • Interrupt KYPROLIS® until TLS is resolved

Infusion reactions1

  • Infusion reactions, including life‑threatening reactions, have been reported in patients who received KYPROLIS®
  • Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina
  • These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS®. Administer dexamethasone prior to KYPROLIS® to reduce the incidence and severity of infusion reactions
  • Inform patients of the risk and symptoms and to contact a physician immediately if symptoms of an infusion reaction occur
Premedications and concomitant medications1
Additional dosing considerations: premedications and concomitant medications
  • Premedicate with the recommended dose of dexamethasone for monotherapy or the recommended dexamethasone dose if on combination therapy. 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. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles
  • Consider antiviral prophylaxis for patients being treated with KYPROLIS® to decrease the risk of herpes zoster reactivation
  • Advise patients to discuss any medication they are currently taking prior to starting treatment with KYPROLIS®, or prior to starting any new medication(s) during treatment with KYPROLIS®
  • 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
  • Refer to the dexamethasone Prescribing Information for other concomitant medications. If treating with lenalidomide, refer to that Prescribing Information for other concomitant medications

Dose modifications

Dose modifications for toxicity during KYPROLIS® treatment1
Hematologic toxicityRecommended action
  • Absolute neutrophil count (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 KYPROLIS®*
  • 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
  • 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 KYPROLIS®*
Renal toxicityRecommended action
  • Serum creatinine greater than or equal to 2 × 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 hemodialysis
  • 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 reduction*
  • If not attributable to KYPROLIS®, dosing may be resumed at the discretion of the physician
  • For patients on hemodialysis receiving KYPROLIS®, the dose is to be administered after the hemodialysis procedure
Other non-hematologic toxicityRecommended action
  • All other severe or life-threatening (CTCAE Grade 3 or 4) non-hematological toxicities
  • Withhold until resolved or returned to baseline
  • Consider restarting the next scheduled treatment at 1 dose level reduction (see table below for dose level reductions)

CTCAE = Common Terminology Criteria for Adverse Events.

Dose modifications for use in hepatic impairment1

For patients with mild or moderate hepatic impairment, reduce the dose of KYPROLIS® by 25%. Dosing recommendation cannot be made in patients with severe hepatic impairment.

Dosing in patients with end stage renal disease1

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

Dose level reductions for KYPROLIS®1
RegimenDoseFirst dose reductionSecond dose reductionThird dose reduction
KYPROLIS®, lenalid-
omide, and dexa-
methasone, or mono-
therapy (20/27 mg/m2)
27 mg/m220 mg/m215 mg/m2
KYPROLIS® and dexa-
methasone, or mono-
therapy (20/56 mg/m2)
56 mg/m245 mg/m236 mg/m227 mg/m2,*
KYPROLIS® and dexa-
methasone (20/70 mg/m2)
70 mg/m256 mg/m245 mg/m236 mg/m2

Note: Infusion times remain unchanged during dose reduction(s).

REFERENCES

1. KYPROLIS® (carfilzomib) prescribing information, Onyx Pharmaceuticals Inc., an Amgen Inc. subsidiary.

IMPORTANT SAFETY INFORMATION FOR KYPROLIS

Cardiac Toxicities

  • New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of KYPROLIS. Some events occurred in patients with normal baseline ventricular function. Death due to cardiac arrest has occurred within one day of administration.
  • Monitor patients for signs or symptoms of cardiac failure or ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold KYPROLIS for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart at 1 dose level reduction based on a benefit/risk assessment.
  • While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate.
  • For patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias may be at greater risk for cardiac complications and should have a comprehensive medical assessment prior to starting treatment with KYPROLIS and remain under close follow-up with fluid management.

Acute Renal Failure

  • Cases of acute renal failure, including some fatal renal failure events, and renal insufficiency adverse events (including renal failure) have occurred. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received KYPROLIS monotherapy. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Tumor Lysis Syndrome

  • Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred. Patients with a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly, and withhold until resolved.

Pulmonary Toxicity

  • Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue KYPROLIS.

Pulmonary Hypertension

  • Pulmonary arterial hypertension (PAH) was reported. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for PAH until resolved or returned to baseline and consider whether to restart based on a benefit/risk assessment.

Dyspnea

  • Dyspnea was reported in patients treated with KYPROLIS. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop KYPROLIS for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart based on a benefit/risk assessment.

Hypertension

  • Hypertension, including hypertensive crisis and hypertensive emergency, has been observed, some fatal. Control hypertension prior to starting KYPROLIS. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold KYPROLIS and evaluate. Consider whether to restart based on a benefit/risk assessment.

Venous Thrombosis

  • Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed. 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.
  • Patients using hormonal contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment.

Infusion Reactions

  • Infusion reactions, including life-threatening reactions, have occurred. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms and seek immediate medical attention if they occur.

Hemorrhage

  • Fatal or serious cases of hemorrhage have been reported. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate.

Thrombocytopenia

  • KYPROLIS causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Monitor platelet counts frequently during treatment. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure

  • Cases of hepatic failure, including fatal cases, have occurred. KYPROLIS can cause increased serum transaminases. Monitor liver enzymes regularly regardless of baseline values. Reduce or withhold dose as appropriate.

Thrombotic Microangiopathy

  • Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), including fatal outcome, have occurred. Monitor for signs and symptoms of TTP/HUS. Discontinue if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, KYPROLIS may be restarted. The safety of reinitiating KYPROLIS is not known.

Posterior Reversible Encephalopathy Syndrome (PRES)

  • Cases of PRES have occurred in patients receiving KYPROLIS. If PRES is suspected, discontinue and evaluate with appropriate imaging. The safety of reinitiating KYPROLIS is not known.

Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-ineligible Patients

  • In a clinical trial of transplant-ineligible patients with newly diagnosed multiple myeloma comparing KYPROLIS, melphalan, and prednisone (KMP) vs bortezomib, melphalan, and prednisone (VMP), a higher incidence of serious and fatal adverse events was observed in patients in the KMP arm. KMP is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.

Embryo-fetal Toxicity

  • KYPROLIS can cause fetal harm when administered to a pregnant woman.
  • Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS and for 6 months following the final dose. Males of reproductive potential should be advised to avoid fathering a child while being treated with KYPROLIS and for 3 months following the final dose. If this drug is used during pregnancy, or if pregnancy occurs while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions

  • The most common adverse reactions in the combination therapy trials: anemia, neutropenia, diarrhea, dyspnea, fatigue, thrombocytopenia, pyrexia, insomnia, muscle spasm, cough, upper respiratory tract infection, hypokalemia.
  • The most common adverse reactions in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.

Please see full Prescribing Information.

INDICATIONS

  • KYPROLIS® (carfilzomib) 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.
  • 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.