Carfilzomib, an inhibitor of the 20S proteasome, is an antineoplastic agent.1, 2, 6, 7, 8, 21, 22, 23, 24
Carfilzomib is used alone for the treatment of multiple myeloma in patients who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent (e.g., lenalidomide, thalidomide) and have demonstrated disease progression during or within 60 days following completion of their last therapy.1, 2, 14, 16, 17 Carfilzomib is designated an orphan drug by the US Food and Drug Administration (FDA) for use in multiple myeloma.4 The current indication is based on overall response rate; there currently are no clinical trials demonstrating a clinical benefit (e.g., improvement in disease-related symptoms, increased survival).1
The current indication for carfilzomib is based principally on the results of an open-label, noncomparative, multicenter, phase 2 study in 266 adults with relapsed multiple myeloma who had received at least 2 prior therapies, including bortezomib and an immunomodulatory agent (e.g., lenalidomide, thalidomide, pomalidomide).1, 2 Other prior therapies included high-dose corticosteroids, alkylating agents, anthracyclines, and stem cell transplantation.2 Patients were enrolled if their disease was refractory to their most recent therapy (i.e., response of no more than 25% or disease progression during or within 60 days following completion of their most recent therapy).1, 2 Patients received IV carfilzomib on 2 consecutive days each week for 3 weeks followed by a 12-day rest period (28-day treatment cycle) until disease progression, unacceptable toxicity, or for a maximum of 12 cycles.1, 2 Treatment consisted of carfilzomib 20 mg/m2 for each dose during the first cycle and 27 mg/m2 in subsequent cycles.1, 2 The primary end point of this study was overall response rate, which was assessed according to the International Myeloma Working Group Uniform Response criteria; secondary end points included progression-free survival, overall survival, clinical benefit rate, and duration of response.1, 2
The median age of enrolled patients in this study was 63 years, and patients had received a median of 5 prior therapies for multiple myeloma.1, 2 All except one of the enrolled patients had previously received bortezomib; a majority of these patients were refractory to bortezomib in any prior line of therapy and 45% were refractory to bortezomib in their most recent therapy.2 The overall response rate with carfilzomib was 22.9% with a median duration of response of 7.8 months; one patient (0.4%) achieved a complete response.1 In 257 response-evaluable patients, median progression-free survival and overall survival were 3.7 and 15.6 months, respectively; median overall survival was slightly shorter in patients refractory or intolerant to both bortezomib and lenalidomide and in those refractory to both drugs (13.2 and 11.9 months, respectively).2
Longer-term maintenance therapy (i.e., more than 12 cycles) with carfilzomib has been shown to be effective and well tolerated in patients with relapsed and/or refractory multiple myeloma in an extension study.18
The overall tolerability profile of carfilzomib appears to compare favorably with that of other drugs used in the treatment of multiple myeloma (e.g., bortezomib, lenalidomide, thalidomide).2, 15, 18, 21, 22, 23 In particular, carfilzomib appears to be less likely than bortezomib and thalidomide to cause peripheral neuropathy; the incidence of new-onset or worsening peripheral neuropathy in the carfilzomib-treated patients in the main efficacy study was 12.4%.2, 15, 18, 21, 22, 23 In addition, carfilzomib appears to be well tolerated when used in multiple myeloma patients with preexisting peripheral neuropathy.2, 21 (See Description.) The incidence of thrombocytopenia appears to be similar between carfilzomib and bortezomib, and carfilzomib appears to cause minimal neutropenia; however, additional studies, including comparative trials, are needed to confirm these initial findings.1, 2, 23
To minimize the risk of nephrotoxicity and tumor lysis syndrome associated with carfilzomib treatment, patients should be hydrated.1 Adequate fluid volume status should be maintained throughout therapy and blood chemistries should be monitored closely.1 The manufacturer recommends that 250-500 mL of 0.9% sodium chloride injection or other appropriate IV fluid be given prior to each dose of carfilzomib in cycle 1.1 An additional 250-500 mL of IV fluids may be given as needed following administration of the drug.1 In subsequent cycles, IV hydration may be continued as needed.1 Patients also should be monitored for fluid overload during this period.1 (See Tumor Lysis Syndrome under Cautions: Warnings/Precautions.)
To reduce the incidence and/or severity of infusion-related reactions, patients should be premedicated with dexamethasone 4 mg orally or IV prior to each dose of carfilzomib in cycle 1 and prior to each dose during the first cycle of dosage escalation to 27 mg/m2.1 If an infusion-related reaction develops or reappears during subsequent cycles, dexamethasone premedication (4 mg orally or IV) should be reinstated.1 (See Infusion Reactions under Cautions: Warnings/Precautions.)
Because reactivation of herpes zoster was reported in 2% of carfilzomib-treated patients, the manufacturer and some clinicians recommend that antiviral prophylaxis (e.g., acyclovir) be considered in patients receiving the drug who have a history of herpes zoster infection.1, 22
Routine antiemetic and antidiarrheal prophylaxis is not necessary in patients receiving carfilzomib therapy.6, 7
Carfilzomib is currently available through select specialty distributors and wholesalers.20 Specific information regarding distribution of the drug is available from the manufacturer at [Web].20
Carfilzomib is administered IV over 2-10 minutes.1 The drug should not be administered by rapid IV injection, such as IV push or bolus.1 Immediately prior to and following carfilzomib administration, the IV administration line should be flushed with 0.9% sodium chloride injection or 5% dextrose injection.1
Unreconstituted carfilzomib powder for injection should be stored in unopened vials at 2-8°C.1 Unopened vials should be retained in the original package for protection from light.1
Prior to administration, commercially available carfilzomib powder for injection must be reconstituted and the reconstituted solution of the drug may be diluted using proper aseptic technique.1 The powder is reconstituted by adding 29 mL of sterile water for injection to a vial labeled as containing 60 mg of the drug to provide a solution containing 2-mg/mL.1 The diluent should be directed toward the inside wall of the vial to minimize foaming.1 The vial should then be gently swirled and/or inverted for approximately 1 minute, or until complete dissolution of the cake or powder occurs, and inspected visually for particulate matter and discoloration prior to dilution and administration.1 The resulting solution should not be shaken.1 If foaming occurs, the solution should be allowed to stand for about 2-5 minutes until foaming subsides.1 The solution should be clear, colorless, and free of visible particulates.1
The desired dose of the carfilzomib reconstituted solution may be given by IV injection or may be further diluted with 5% dextrose injection for IV infusion.1 The reconstituted solution is diluted by adding an appropriate volume of carfilzomib 2-mg/mL solution to a 50-mL infusion bag containing 5% dextrose injection.1 Reconstituted and diluted solutions of the drug are stable for up to 4 or 24 hours at room temperature (15-30°C) or under refrigeration (2-8°C), respectively, regardless of container (e.g., vial, syringe, IV bag).1
Carfilzomib should not be admixed with or administered as an infusion with any other drug.1 Commercially available carfilzomib for injection contains no preservatives and is intended for single use; vials containing the unused portion of the reconstituted solution should be immediately discarded.1
Carfilzomib dosage is calculated according to the patient's actual body surface area (BSA) at baseline.1 In patients with a BSA greater than 2.2 m2, dosage of carfilzomib should be based on a BSA of 2.2 m2.1 No dosage adjustment is necessary for weight changes of 20% or less.1
For the treatment of multiple myeloma following failure of 2 or more chemotherapy regimens including bortezomib and an immunomodulatory agent and disease progression during or within 60 days following completion of the last therapy, the recommended adult dosage of carfilzomib during cycle 1 is 20 mg/m2 administered IV over 2-10 minutes on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) followed by a 12-day rest period (days 17 through 28) of a 28-day cycle.1 If the dosage in cycle 1 is tolerated, the recommended dosage for cycle 2 and subsequent cycles is 27 mg/m2.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 In the principal efficacy study, therapy was continued for a maximum of 12 cycles.2
The amount of carfilzomib contained in one 60-mg, single-use vial may exceed the single dose required.1 Caution should therefore be exercised in calculating the dose to prevent overdosage.1
Dosage Modification for Toxicity
Dosage Modification for Hematologic Toxicity
Platelet counts should be monitored frequently during carfilzomib therapy.1 If grade 3 or 4 neutropenia or grade 4 thrombocytopenia occurs, carfilzomib therapy should be withheld.1 If full recovery occurs prior to the next scheduled dose, carfilzomib may be resumed at the same dosage level.1 If the toxicity resolves to grade 2 neutropenia or grade 3 thrombocytopenia, the dosage of carfilzomib may be reduced by one dose level (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2).1 If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician.1 (See Thrombocytopenia under Cautions: Warnings/Precautions.)
Dosage Modification for Cardiac Toxicity
If grade 3 or 4 new onset or worsening of congestive heart failure, decreased left ventricular function, or myocardial ischemia occurs, carfilzomib therapy should be withheld until the toxicity resolves or returns to baseline.1 Following resolution, it should be considered whether resuming carfilzomib therapy at a reduced dosage (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2) is appropriate based on assessment of potential risks and benefits.1 If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician.1 (See Cardiac Effects under Cautions: Warnings/Precautions.)
Dosage Modification for Pulmonary Hypertension
If pulmonary arterial hypertension (PAH) occurs, carfilzomib therapy should be withheld until the toxicity resolves or returns to baseline.1 Following resolution, therapy may then be resumed at either the previous dosage or at a dosage reduced by one dose level (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2) at the discretion of the clinician.1 If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician.1 (See Pulmonary Hypertension under Cautions: Warnings/Precautions.)
Dosage Modification for Pulmonary Complications
If grade 3 or 4 pulmonary complications (e.g., dyspnea) occur, carfilzomib therapy should be withheld until the toxicity resolves or returns to baseline.1 Resumption of therapy at a dosage reduced by one dose level (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2) may then be considered.1 If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician.1 (See Pulmonary Complications under Cautions: Warnings/Precautions.)
Dosage Modification for Hepatic Toxicity
In patients who develop grade 3 or 4 elevations of serum aminotransferases (ALT or AST), bilirubin, or other liver abnormalities, carfilzomib therapy should be withheld until the toxicity resolves or returns to baseline.1 Following resolution, it should be considered whether resuming therapy is appropriate.1 Therapy may be resumed at a reduced dosage (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2) with frequent monitoring of liver function tests.1 If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician.1 (See Hepatic Toxicity and Hepatic Failure under Cautions: Warnings/Precautions.)
Dosage Modification for Nephrotoxicity
In patients who develop elevated serum creatinine concentrations of 2 or more times the baseline value, carfilzomib therapy should be withheld until renal function recovers to grade 1 or baseline and renal function should be monitored.1 If nephrotoxicity is attributable to carfilzomib, therapy may then be resumed at a reduced dosage (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2).1 If nephrotoxicity is not attributable to carfilzomib, therapy may be resumed at the dosage used prior to the event.1 If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician.1
Dosage Modification for Peripheral Neuropathy
If grade 3 or 4 peripheral neuropathy occurs, carfilzomib therapy should be withheld until the condition resolves or returns to baseline.1 Therapy may then be resumed at the dosage used prior to the event or at a reduced dosage (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2).1 If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician.1
Dosage Modification for Other Nonhematologic Toxicity
If other grade 3 or 4 nonhematologic toxicity occurs, carfilzomib therapy should be withheld until the toxicity resolves or returns to baseline.1 Resumption of therapy at a dosage reduced by one dose level (i.e., a dose of 27 mg/m2 reduced to 20 mg/m2; a dose of 20 mg/m2 reduced to 15 mg/m2) may then be considered.1 If the reduced dosage is tolerated, the dosage may be escalated back to the previous dosage at the discretion of the clinician.1
Carfilzomib has not been studied in patients with preexisting hepatic impairment.1 The manufacturer does not provide specific dosage recommendations for such patients.1 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
The pharmacokinetics and safety of carfilzomib are not influenced by the degree of preexisting renal impairment; therefore, dosage adjustment is not necessary in patients with renal impairment.1, 19 However, because clearance of carfilzomib by hemodialysis has not been studied, the drug should be administered after the dialysis procedure.1 (See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)
Dosage adjustment is not necessary in geriatric patients.1 (See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
The manufacturer states there are no known contraindications to the use of carfilzomib.1
Death from cardiac arrest has occurred within 24 hours of carfilzomib administration.1, 2 New onset or worsening of preexisting congestive heart failure with decreased left ventricular function or myocardial ischemia also has been reported following administration of the drug.1, 2 Heart failure-related events (e.g., congestive heart failure, pulmonary edema, decreased left ventricular ejection fraction) have been reported in 7% of patients receiving carfilzomib.1 Patients with New York Heart Association (NYHA) class III or IV heart failure, history of myocardial infarction in the preceding 6 months, or conduction abnormalities not controlled by medication were excluded from clinical trials; these patients may be at greater risk for cardiac complications.1
Patients receiving carfilzomib should be monitored for the development of cardiac complications and managed promptly if they occur.1 If grade 3 or 4 cardiac toxicity occurs, therapy should be withheld until the toxicity resolves or returns to baseline.1 If resumption of therapy is considered appropriate based on assessment of potential risks and benefits, therapy may be resumed at a reduced dosage.1 (See Dosage Modification for Cardiac Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Pulmonary arterial hypertension (PAH) has been reported in 2% of patients receiving carfilzomib in clinical trials, and was grade 3 or greater in less than 1% of patients.1 Patients should be evaluated for PAH using cardiac imaging and/or other tests as indicated.1 If PAH is suspected, carfilzomib therapy should be withheld until signs and symptoms resolve or return to baseline.1 If resumption of therapy is considered appropriate based on assessment of potential risks and benefits, therapy may be resumed at either the previous dosage or at a reduced dosage.1 (See Dosage Modification for Pulmonary Hypertension under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Dyspnea was reported in approximately 35% of patients receiving carfilzomib in clinical trials.1, 2, 6 Grade 3 dyspnea occurred in 5% of patients; no grade 4 cases and one fatal case of dyspnea were reported.1, 2, 6 In the main clinical trial, dyspnea generally occurred early in therapy and was transient, did not increase with cumulative exposure to the drug, and was not associated with progressive lung injury.2, 6
Patients should be monitored for dyspnea during carfilzomib therapy, and dyspnea should be managed immediately if it occurs.1 If grade 3 or 4 pulmonary toxicity (i.e., dyspnea) occurs, carfilzomib therapy should be withheld until the symptoms resolve or return to baseline; resumption of therapy at a reduced dosage may then be considered.1 (See Dosage Modification for Pulmonary Complications under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Infusion-related reactions characterized by a spectrum of systemic symptoms, including pyrexia, chills, arthralgia, myalgia, flushing, facial edema, emesis, weakness, dyspnea, hypoxia, hypotension, syncope, chest tightness, or angina, have been reported in patients receiving carfilzomib.1, 5 These reactions can occur immediately following or up to 24-48 hours following IV administration of the drug.1, 5
To minimize the incidence and/or severity of infusion reactions, patients should be premedicated with dexamethasone prior to each dose of carfilzomib in cycle 1 and prior to each dose during the first cycle of dosage escalation to 27 mg/m2.1 (See Dosage and Administration: General and also see Advice to Patients.)
Tumor lysis syndrome has been reported rarely in patients receiving carfilzomib.1, 2 In the principal phase 2 clinical trial, tumor lysis syndrome occurred in one patient (0.4%) who received the drug.2 Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for the syndrome.1 Patients should be well hydrated prior to administration of carfilzomib.1 Some clinicians also administer allopurinol to reduce the risk of tumor lysis syndrome.22 The manufacturer states that patients should be monitored for signs and symptoms of tumor lysis syndrome during carfilzomib therapy and, if present, they should be managed promptly.1 Carfilzomib therapy should be interrupted until tumor lysis syndrome has resolved.1 (See Dosage and Administration: General.)
Thrombocytopenia, which in rare cases has required dosage reduction or discontinuance of therapy, has been reported in patients receiving carfilzomib.1, 2 Among patients receiving carfilzomib for multiple myeloma, thrombocytopenia occurred in 36% of patients, including grade 4 thrombocytopenia in 10% of patients.1 Thrombocytopenia associated with the drug usually is transient; the nadir platelet count occurs around day 8 of each 4-week cycle, and recovery to baseline typically occurs by the start of the subsequent cycle.1, 2
The manufacturer states that platelet counts should be monitored frequently in patients receiving carfilzomib therapy.1 If thrombocytopenia occurs, the dosage of carfilzomib should be reduced or treatment interrupted as clinically indicated.1 (See Dosage Modification for Hematologic Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Hepatic Toxicity and Hepatic Failure
Hepatic failure, including fatal cases, has been reported in less than 1% of patients receiving carfilzomib.1, 2, 5, 6 The drug also may cause elevations in serum aminotransferase (ALT or AST) and bilirubin concentrations.1, 6 In the phase 2 clinical trial, 2 patients with normal baseline aminotransferase concentrations died from hepatic failure following carfilzomib therapy; aminotransferase elevations were reversible in the other patients in this study.2, 5
Liver enzymes should be monitored frequently in patients receiving carfilzomib.1 In patients who develop grade 3 or greater elevations of liver function tests, including serum aminotransferase or bilirubin concentrations, therapy with the drug should be withheld until the toxicity resolves or returns to baseline.1 Following resolution, it should be considered whether resuming carfilzomib therapy is appropriate.1 (See Dosage Modification for Hepatic Toxicity under Dosage: Dosage Modification for Toxicity, in Dosage and Administration.)
Fetal/Neonatal Morbidity and Mortality
Carfilzomib may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 There are no adequate and well-controlled studies in humans.1 The drug has been shown to be embryotoxic and fetotoxic in animals.1 Pregnancy should be avoided during carfilzomib therapy.1 Women of childbearing potential should use effective contraception while receiving the drug.1 If carfilzomib is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential fetal hazard.1 (See Advice to Patients.)
Category D.1 (See Users Guide and see Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)
It is not known whether carfilzomib is distributed into human milk.1 Because many drugs are distributed into human milk and because of the potential for serious adverse reactions to carfilzomib in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1
Safety and efficacy of carfilzomib have not been established in pediatric patients.1
In a population pharmacokinetic analysis, carfilzomib exposure in patients 65 years of age and older did not differ substantially from that in adult patients younger than 65 years of age following a single 20-mg/m2 IV dose of the drug.1 In clinical studies, no clinically important differences in safety or efficacy were observed between patients 65 years of age and older and younger adults.1 (See Dosage and Administration: Special Populations.)
The efficacy, safety, and pharmacokinetics of carfilzomib have not been studied in patients with baseline hepatic impairment.1 Patients with baseline serum aminotransferase (e.g., ALT, AST) concentrations 3 or more times the upper limit of normal (ULN) or bilirubin concentrations 2 or more times the ULN were excluded from carfilzomib clinical trials.1, 2 (See Dosage and Administration: Special Populations.)
In a phase 2 study evaluating the pharmacokinetics and safety of carfilzomib in multiple myeloma patients with normal renal function and those with mild, moderate, and severe renal impairment, including patients on chronic hemodialysis, patients were treated with the drug for an average of 5.5 cycles in a dosage of 15 mg/m2 in cycle 1, 20 mg/m2 in cycle 2, and 27 mg/m2 in cycle 3 and beyond.1, 19 The pharmacokinetics and safety of carfilzomib were not affected by the degree of baseline renal impairment, including in patients who were receiving hemodialysis.1, 19 However, because dialysis clearance of carfilzomib has not been specifically studied, the drug should be administered after the hemodialysis session.1 (See Dosage and Administration: Special Populations.)
A population pharmacokinetic analysis indicated that the area under the plasma concentration-time curve (AUC) and peak plasma concentrations of carfilzomib were not substantially affected by gender.1
Adverse effects reported in 30% or more of multiple myeloma patients receiving carfilzomib include fatigue,1, 2 anemia,1, 2 nausea,1, 2 dyspnea,1, 2 diarrhea,1, 2 and pyrexia.1, 2 Serious adverse effects occurred in 45% of patients, and included pneumonia,1, 2 acute renal failure,1, 2 pyrexia,1 and congestive heart failure.1, 2
Laboratory abnormalities reported in 10% or more of patients receiving carfilzomib include anemia,1, 2 thrombocytopenia,1, 2 increased creatinine concentrations,1, 2 lymphopenia,1, 2 neutropenia,1, 2 hypokalemia,1 hypomagnesemia,1 leukopenia,1, 2 increased AST concentrations,1 hyperglycemia,1 hypercalcemia,1 hypophosphatemia,1 and hyponatremia.1
Carfilzomib appears to be metabolized principally by extrahepatic peptidase cleavage and epoxide hydrolysis.1, 26 Cytochrome P-450 (CYP)-mediated mechanisms play a minor role in the drug's overall metabolism.1 In an in vitro study, carfilzomib demonstrated a modest inhibitory effect on CYP3A4/5.1, 26 The drug does not induce CYP1A2 and CYP3A4 in human hepatocytes in vitro.1 Carfilzomib is a substrate of P-glycoprotein (P-gp).1 The drug has shown marginal inhibitory effects on P-gp in a Caco-2 monolayer system.1
Drugs Affecting Hepatic Microsomal Enzymes
Clinically important pharmacokinetic interactions with CYP inhibitors and inducers are unlikely.1, 26
Drugs Metabolized by Hepatic Microsomal Enzymes
Clinically important pharmacokinetic interactions are not expected with concurrent use of drugs metabolized by CYP3A4/5.1
When the CYP3A substrate midazolam was administered concomitantly with carfilzomib, the pharmacokinetics of midazolam were not affected.1
Drugs Affecting the P-glycoprotein Transport System
Carfilzomib is a substrate of P-gp and has demonstrated marginal inhibitory effects on P-gp.1 However, because carfilzomib is administered IV and extensively metabolized, the pharmacokinetics of carfilzomib are unlikely to be substantially affected by concurrent use of either P-gp inhibitors or inducers.1
Carfilzomib, a tetrapeptide epoxyketone proteasome inhibitor, is an antineoplastic agent.1, 2, 6, 7, 8, 21, 22, 23, 24 The drug selectively and irreversibly binds to the NH2-terminal threonine active sites of the 20S proteolytic core particle within the 26S proteasome.1, 2, 6, 7, 8, 21 The 26S proteasome is a large protein complex composed of the 20S proteolytic core, which contains the proteolytic active sites, and 19S regulatory complexes.9, 12 Ubiquitinated proteins targeted for degradation by the 19S regulatory particles are cleaved by catalytic activities in the 20S proteolytic core;9, 12 major catalytic activities of the 20S proteolytic core include chymotrypsin-like activity, trypsin-like activity, and caspase-like activity.6, 10, 11, 21 The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells; cancer cells appear to be particularly dependent on proteasome-mediated homeostatic pathways.7, 9, 10, 11, 21 Carfilzomib potently and selectively inhibits chymotrypsin-like activity of the 20S proteasome, which results in accumulation of ubiquitinated proteins and causes proteotoxic stress and leads to cell cycle arrest and apoptosis.6, 7 In vitro studies indicate that carfilzomib has antiproliferative and proapoptotic activities in solid and hematologic tumor cells, including in some bortezomib-resistant cell lines.1, 6, 8, 21, 27 In animal studies, carfilzomib inhibits proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.1
Carfilzomib differs structurally from bortezomib;7, 13, 14 unlike bortezomib, carfilzomib contains an epoxyketone pharmacophore which is selective for the NH2-terminal threonine active sites unique to the 20S proteolytic core of the 26S proteasome.7, 8, 13 The mechanism by which carfilzomib maintains activity in some bortezomib-resistant tumor cells has not been fully elucidated; however, studies suggest that carfilzomib produces more selective, potent, and durable proteasome inhibition than bortezomib.6, 7, 10, 12, 14, 21, 27 Although the exact mechanism for peripheral neuropathy resulting from proteasome inhibitor therapy has not been fully elucidated, it has been suggested that the selectivity of carfilzomib for the 26S proteasome and its weak activity on other protease classes may explain the lower incidence of neurotoxicity observed with the drug in animal and clinical studies.2, 6, 8, 12, 13 Neurodegeneration independent of proteasome inhibition also has been proposed as a mechanism for this class adverse effect associated with proteasome inhibitors; despite equivalent levels of proteasome inhibition with carfilzomib and bortezomib in vitro, only bortezomib reduced neurite length and neuronal cell survival.6, 13
Carfilzomib is approximately 97-98% bound to plasma proteins.1, 26 Metabolism is thought to occur primarily by extrahepatic peptidase cleavage and epoxide hydrolysis to inactive metabolites;1, 6, 26 peptide fragments of carfilzomib (i.e., M14, M15) and carfilzomib diol (M16) are the major metabolites found in plasma and urine.6 Following initial IV doses of carfilzomib of 15 mg/m2 or more, carfilzomib was rapidly cleared from plasma with an elimination half-life of no more than 1 hour.1, 7
Importance of informing clinician if fever, chills, rigors, chest pain, cough, or swelling of the feet or legs occurs.1
Risk of fatigue, dizziness, syncope, and/or hypotension; importance of advising patients to avoid driving or operating machinery if these effects occur.1
Risk of dyspnea, which generally occurs within a day of dosing.1 Importance of informing clinician if shortness of breath occurs.1
Importance of advising patients to avoid dehydration since carfilzomib therapy may cause vomiting and/or diarrhea.1 Importance of advising patients to inform a clinician if dizziness, lightheadedness, or fainting spells occur.1
Risk of fetal harm.1 Necessity of advising women of childbearing potential to avoid pregnancy and to use effective methods of contraception while receiving carfilzomib therapy.1 Importance of women informing clinicians immediately if they become pregnant during therapy.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1
Importance of advising women to avoid breast-feeding while receiving carfilzomib therapy.1 If patient wishes to resume breast-feeding following therapy, importance of discussing the appropriate timing with clinician.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., congestive heart failure, history of myocardial infarction, conduction abnormalities).1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Carfilzomib is currently available through select specialty distributors and most wholesalers.20 Specific information regarding distribution of carfilzomib is available from the manufacturer at [Web].20
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions April 6, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Onyx Pharmaceuticals, Inc. Kyprolis® (carfilzomib) for injection prescribing information. South San Francisco, CA; 2012 Jul.
2. Siegel DS, Martin T, Wang M et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood . 2012; 120:2817-25. [PubMedCentral][PubMed 22833546]
4. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P. L. 97-414). Rockville, MD. From FDA website. Accessed 2012 Nov 12. [Web]
5. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 202714: Summary review. 2011 Sep 27. From FDA website. [Web]
6. Onyx Pharmaceuticals, Inc. NDA 202,714: Kyprolis (carfilzomib for injection) briefing document. 2012 Jun 20. From FDA website.
7. O'Connor OA, Stewart AK, Vallone M et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res . 2009; 15:7085-91. [PubMedCentral][PubMed 19903785]
8. Demo SD, Kirk CJ, Aujay MA et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res . 2007; 67:6383-91. [PubMed 17616698]
9. da Fonseca PC, Morris EP. Structure of the human 26S proteasome: subunit radial displacements open the gate into the proteolytic core. J Biol Chem . 2008; 283:23305-14. [PubMedCentral][PubMed 18534977]
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