Administration and dose modifications

Dosing reference guide
Preparation
Administration
Additional considerations
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.

For patients with a body surface area (BSA) of 2.2 m² or less, calculate the dose using actual BSA
- 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 doses, 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

Step 2: Select patient BSA (m²)

Complete previous steps to continue

m²

Step 3: Dose

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.

Using the patient’s total dose calculated in Step 3, refer to the full Prescribing Information to determine the appropriate number of vials required for administration. KYPROLIS^® is supplied in 60-mg, 30-mg, and 10-mg single-dose vials for reconstitution

Reconstitution and preparation

Follow these steps to reconstitute and prepare KYPROLIS^®

Step 1

Remove vial from refrigerator just prior to use.¹

Step 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

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

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

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

Administer KYPROLIS^® directly by intravenous infusion or optionally, administer 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

Step 9

Flush the intravenous administration line with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS^® administration.¹

Step 10

Do not mix KYPROLIS^® with or administer as an infusion with other medicinal products.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.

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*
Storage conditions of reconstituted KYPROLIS^®		Vial	Syringe	Intravenous bag (D5W^†)
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

Additional dosing considerations

Hydration management¹

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 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-related reactions¹

Infusion-related 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

Premedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the 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
Provide thromboprophylaxis for patients being treated with KYPROLIS^® in combination with other therapies
Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation
Advise patients to discuss with their healthcare provider any medication they are currently taking prior to starting treatment with KYPROLIS^®, or prior to starting any new medication(s) during treatment with KYPROLIS^®
Refer to the dexamethasone Prescribing Information for other concomitant medications. If treating with lenalidomide, refer to that Prescribing Information for other concomitant medications. If treating with Darzalex^® (daratumumab), refer to that Prescribing Information for other concomitant medications

IV = intravenous.

Dose modifications

Dose modifications for adverse reactions¹

Hematologic toxicity	Recommended 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 toxicity	Recommended 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 healthcare provider For patients on hemodialysis receiving KYPROLIS^®, the dose is to be administered after the hemodialysis procedure

Renal toxicity

Recommended 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 healthcare provider
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-threatening (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)

Dose modifications for use in hepatic impairment¹

For patients with mild or moderate hepatic impairment, reduce the dose of KYPROLIS^® by 25%.

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

Regimen	Dose	First dose reduction	Second dose reduction	Third dose reduction
KYPROLIS^®, dara- tumumab, and dexa- methasone (20/70 mg/m² once weekly) OR KYPROLIS^® and dexa- methasone (20/70 mg/m² once weekly)	70 mg/m²	56 mg/m²	45 mg/m²	36 mg/m²*
KYPROLIS^®, dara- tumumab, and dexa- methasone (20/56 mg/m² twice weekly) OR KYPROLIS^® and dexa- methasone, OR mono- therapy (20/56 mg/m² twice weekly)	56 mg/m²	45 mg/m²	36 mg/m²	27 mg/m²*
KYPROLIS^®, lenalid- omide, and dexa- methasone, OR mono- therapy (20/27 mg/m² twice weekly)	27 mg/m²	20 mg/m²	15 mg/m²*	—

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

*If toxicity persists, discontinue KYPROLIS^® treatment.¹

REFERENCE

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), 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 reactions 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 (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. Provide thromboprophylaxis for patients being treated with the combination of KYPROLIS with dexamethasone or with lenalidomide plus dexamethasone or with daratumumab and dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks.
For patients using hormonal contraception associated with a risk of thrombosis, consider an alternative method of effective contraception during treatment.

Infusion-Related Reactions

Infusion-related 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-related reactions.

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.

Progressive Multifocal Leukoencephalopathy (PML)

Cases of PML, including fatal cases, have occurred. In addition to KYPROLIS, other contributary factors may include prior or concurrent use of immunosuppressive therapy. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue and initiate evaluation for PML including neurology consultation.

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 reactions 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.
Advise pregnant women of the potential risk to a fetus. Females of reproductive potential should use effective contraception during treatment with KYPROLIS and for 6 months following the final dose. Males of reproductive potential should use effective contraception during treatment with KYPROLIS and for 3 months following the final dose.

Adverse Reactions

The most common adverse reactions occurring in at least 20% of patients taking KYPROLIS in the combination therapy trials: anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, cough, dyspnea, and insomnia.
The most common adverse reactions occurring in at least 20% of patients taking KYPROLIS in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral.

Please see accompanying full Prescribing Information.

INDICATIONS

KYPROLIS^® (carfilzomib) is indicated in combination with dexamethasone, or with lenalidomide plus dexamethasone, or with daratumumab plus dexamethasone, or with daratumumab plus hyaluronidase-fihj plus dexamethasone, or with isatuximab plus dexamethasone for the treatment of adult 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.