Class: Antineoplastic Agents
- Proteasome Inhibitors
VA Class: AN900
Chemical Name: (αS)-α-[(4-Morpholinylacetyl)amino]benzenebutanoyl-l-leucyl-N-[(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]-l-phenylalaninamide
Molecular Formula: C40H57N5O7
CAS Number: 868540-17-4
Antineoplastic agent; inhibitor of the 20S proteasome.
Uses for Carfilzomib
Treatment of multiple myeloma (as monotherapy) in patients who have received ≤2 prior therapies, including bortezomib and an immunomodulatory agent (e.g., lenalidomide, thalidomide) and demonstrated disease progression ≤60 days following completion of their last therapy (designated an orphan drug by FDA for this use).
Longer-term maintenance therapy (i.e., more than 12 cycles) was effective and well tolerated in an extension study.
Overall tolerability profile compares favorably with that of other drugs used in multiple myeloma treatment (e.g., bortezomib, lenalidomide, thalidomide). Appears less likely than bortezomib and thalidomide to cause peripheral neuropathy. Has also been well tolerated in multiple myeloma patients with preexisting peripheral neuropathy. Incidence of thrombocytopenia appears similar between carfilzomib and bortezomib; carfilzomib causes minimal neutropenia.
Carfilzomib Dosage and Administration
Obtain carfilzomib through select specialty distributors and wholesalers. For specific information, visit [Web].
To minimize risk of nephrotoxicity and tumor lysis syndrome, hydrate patients. Maintain adequate fluid volume status throughout therapy; closely monitor blood chemistries. (See Tumor Lysis Syndrome under Cautions.)
In cycle 1, administration of 250–500 mL of 0.9% sodium chloride injection or other appropriate IV fluid recommended prior to each dose. If needed, administer an additional 250–500 mL of IV fluids following administration of carfilzomib.
In subsequent cycles, continue IV hydration as needed.
Monitor patients for fluid overload.
To minimize incidence and/or severity of infusion-related reactions, premedicate with dexamethasone 4 mg orally or IV prior to each carfilzomib dose in cycle 1 and prior to each dose during the first cycle of dosage escalation to 27 mg/m2; restart dexamethasone premedication if an infusion-related reaction develops or reappears during subsequent cycles. (See Infusion Reactions under Cautions.)
Routine antiemetic and antidiarrheal prophylaxis not necessary.
Risk of herpes zoster reactivation. Consider antiviral prophylaxis (e.g., acyclovir) in patients with a history of herpes zoster infection.
For solution compatibility information, see Compatibility under Stability.
Administer IV. Do not administer by rapid IV injection (e.g., IV push or bolus).
Carfilzomib powder for injection must be reconstituted and may be further diluted prior to administration. Use within 24 hours following reconstitution. (See Storage under Stability.)
Do not admix with or administer as an IV infusion with any other drug.
Reconstitute vial containing 60 mg of carfilzomib with 29 mL of sterile water for injection to provide a solution containing 2 mg/mL; direct diluent toward the wall of the vial. Gently swirl and/or slowly invert vial to ensure complete dissolution. Do not shake reconstituted solution.
Reconstituted solution should be clear, colorless, and free of visible particulates.
Dilute appropriate dose in 50 mL of 5% dextrose injection. Discard any partially used vial.
Rate of Administration
Administer by IV injection or infusion over 2–10 minutes.
Calculate dosage based on actual BSA at baseline. If BSA >2.2 m2, calculate dosage based on BSA of 2.2 m2. Dosage adjustment not necessary for weight changes of ≤20%.
Cycle 1: 20 mg/m2 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).
Subsequent cycles (if 20 mg/m2 dosage is tolerated in previous cycle): 27 mg/m2 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).
Continue therapy until disease progression or unacceptable toxicity occurs. In principal efficacy study, therapy was continued for a maximum of 12 cycles. (See Dosage Modification for Toxicity under Dosage and Administration.)
Because amount of carfilzomib contained in one 60-mg, single-use vial may exceed the single dose required, use caution calculating the dose to prevent overdosage.
Dosage Modification for Toxicity
Some adverse effects require temporary interruption of therapy and/or dosage reduction. If dosage reduction from 27 mg/m2 is necessary, recommended dosage is 20 mg/m2. If further dosage reduction is required, recommended dosage is 15 mg/m2.
Monitor platelet counts frequently during therapy.
If grade 3 or 4 neutropenia or grade 4 thrombocytopenia occurs, withhold therapy.
If full recovery occurs prior to next scheduled dose, resume therapy at same dosage level. If toxicity resolves to grade 2 neutropenia or grade 3 thrombocytopenia, reduce dosage by one dose level. If reduced dosage is tolerated, may escalate dosage back to previous dosage at the discretion of the clinician. (See Thrombocytopenia under Cautions.)
If grade 3 or 4 new-onset or worsening CHF, decreased left ventricular function, or myocardial ischemia occurs, withhold therapy until toxicity resolves or returns to baseline.
Following resolution, consider whether resuming therapy at a reduced dosage is appropriate based on a benefit/risk assessment. If reduced dosage is tolerated, may escalate dosage back to previous dosage at the discretion of the clinician. (See Cardiac Effects under Cautions.)
If pulmonary arterial hypertension (PAH) occurs, withhold therapy until toxicity resolves or returns to baseline.
Consider whether resuming therapy at previous or reduced dosage is appropriate based on a benefit/risk assessment. If reduced dosage is tolerated, may escalate dosage back to previous dosage at the discretion of the clinician. (See Pulmonary Hypertension under Cautions.)
If grade 3 or 4 pulmonary complications (e.g., dyspnea) occur, withhold therapy until toxicity resolves or returns to baseline.
Consider resuming therapy at a reduced dosage. If reduced dosage is tolerated, may escalate dosage back to previous dosage at the discretion of the clinician. (See Pulmonary Complications under Cautions.)
If grade 3 or 4 elevations of serum aminotransferases (ALT or AST), bilirubin, or other liver abnormalities occur, withhold therapy until toxicity resolves or returns to baseline.
If appropriate, consider resuming therapy at a reduced dosage and frequently monitor liver function tests. If reduced dosage is tolerated, may escalate dosage back to previous dosage at the discretion of the clinician. (See Hepatic Toxicity and Hepatic Failure under Cautions.)
If Scr elevations ≥2 times the baseline value occur, withhold therapy until renal function recovers to grade 1 or baseline and monitor renal function.
If attributable to carfilzomib, resume therapy at reduced dosage. If not attributable to carfilzomib, may resume therapy at the dosage used prior to the event. If reduced dosage is tolerated, may escalate dosage back to previous dosage at the discretion of the clinician.
If grade 3 or 4 peripheral neuropathy occurs, withhold therapy until toxicity resolves or returns to baseline.
May resume therapy at the dosage used prior to the event or at a reduced dosage. If reduced dosage is tolerated, may escalate dosage back to previous dosage at the discretion of the clinician.
Other Nonhematologic Toxicity
If other grade 3 or 4 nonhematologic toxicity occurs, withhold therapy until toxicity resolves or returns to baseline.
Consider resuming therapy at a reduced dosage. If reduced dosage is tolerated, may escalate dosage back to previous dosage at the discretion of the clinician.
No specific dosage recommendations.
No dosage adjustment required.
Dialysis: Not studied; administer after dialysis session. (See Renal Impairment under Cautions.)
No dosage adjustment required. (See Geriatric Use under Cautions.)
Cautions for Carfilzomib
Manufacturer states none known.
Death from cardiac arrest within a day of administration reported.
New onset or worsening of preexisting CHF with decreased left ventricular function or myocardial ischemia also reported. Heart failure-related events (e.g., CHF, pulmonary edema, decreased left ventricular ejection fraction) occurred in 7% of carfilzomib-treated patients.
Patients with NYHA class III or IV heart failure, history of MI in the preceding 6 months, or conduction abnormalities not controlled by medication may be at greater risk for cardiac complications.
Monitor for cardiac complications and manage promptly if they occur. If grade 3 or 4 cardiac toxicity occurs, withhold therapy until toxicity resolves or returns to baseline; may resume therapy at reduced dosage if benefit outweighs risk. (See Dosage Modification for Toxicity under Dosage and Administration.)
PAH reported in 2% of patients. Evaluate patients for PAH using cardiac imaging and/or other tests as indicated.
If PAH is suspected, withhold therapy until signs and symptoms resolve or return to baseline; may resume therapy at previous or reduced dosage if benefit outweighs risk. (See Dosage Modification for Toxicity under Dosage and Administration.)
Dyspnea reported in approximately 35% of patients. Grade 3 dyspnea occurred in 5% of patients; no grade 4 cases and one fatal case reported. Generally occurs early in therapy and is transient; risk does not increase with cumulative exposure and is not associated with progressive lung injury.
Monitor patients for dyspnea and manage immediately. If grade 3 or 4 pulmonary toxicity (i.e., dyspnea) occurs, withhold therapy until toxicity resolves or returns to baseline; may resume therapy at reduced dosage if benefit outweighs risk. (See Dosage Modification for Toxicity under Dosage and Administration.)
Infusion-related reactions (e.g., pyrexia, chills, arthralgia, myalgia, flushing, facial edema, emesis, weakness, dyspnea, hypoxia, hypotension, syncope, chest tightness, angina) reported; may occur immediately following or up to 24–48 hours following IV administration.
To minimize incidence and severity of infusion-related reactions, administer premedication with dexamethasone. (See Premedication under Dosage and Administration and also see Advice to Patients.)
Tumor Lysis Syndrome
Tumor lysis syndrome reported rarely. Increased risk in patients with multiple myeloma and high tumor burden.
Hydrate well prior to administration. Some clinicians also concurrently administer allopurinol to reduce risk. Monitor for manifestations of tumor lysis syndrome during therapy; if present, manage promptly. Interrupt carfilzomib therapy until tumor lysis syndrome resolves. (See Hydration under Dosage and Administration.)
Thrombocytopenia, usually transient and rarely requiring dosage reduction or discontinuance, reported. Nadir platelet count occurs around day 8 of each 4-week cycle; recovery to baseline typically occurs by start of subsequent cycle.
Monitor platelet counts frequently during therapy. If thrombocytopenia occurs, reduce dosage or interrupt therapy as clinically indicated. (See Dosage Modification for Toxicity under Dosage and Administration.)
Hepatic Toxicity and Hepatic Failure
Hepatic failure, including fatal cases, reported rarely. Elevated serum aminotransferase (ALT or AST) and bilirubin concentrations also reported.
Monitor liver function tests frequently. If grade 3 or greater elevations of liver function tests occur, withhold therapy until toxicity resolves or returns to baseline; may resume therapy at reduced dosage if appropriate. (See Dosage Modification for Toxicity under Dosage and Administration.)
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; embryotoxicity and fetotoxicity demonstrated in animals.
Avoid pregnancy during therapy. If used during pregnancy or if the patient becomes pregnant during therapy, apprise of potential fetal hazard. (See Advice to Patients.)
Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Not known whether carfilzomib is distributed into human milk. Discontinue nursing or the drug.
Safety and efficacy not established.
No clinically important differences in safety and efficacy relative to younger adults. (See Absorption: Special Populations, under Pharmacokinetics.)
Efficacy, safety, and pharmacokinetics not studied in patients with baseline hepatic impairment. Patients with baseline ALT or AST concentrations ≥3 times ULN or bilirubin concentrations ≥2 times ULN were excluded from clinical trials.
Pharmacokinetics (i.e., clearance, exposure) and safety not affected by baseline mild to severe renal impairment, including chronic hemodialysis; no dosage adjustment necessary. Because dialysis clearance not specifically studied to date, administer carfilzomib after the hemodialysis session.
Pharmacokinetics (e.g., AUC, peak plasma concentrations) not affected by gender.
Common Adverse Effects
Fatigue, anemia, nausea, dyspnea, diarrhea, pyrexia.
Laboratory abnormalities: Anemia, thrombocytopenia, increased Scr, lymphopenia, neutropenia, hypokalemia, hypomagnesemia, leukopenia, increased AST concentrations, hyperglycemia, hypercalcemia, hypophosphatemia, hyponatremia.
Interactions for Carfilzomib
Metabolism appears to occur primarily by extrahepatic peptidase cleavage and epoxide hydrolysis. CYP-mediated mechanisms play a minor role in overall metabolism.
Has modest inhibitory effect on CYP3A4/5 in vitro.
Does not induce CYP1A2 or CYP3A4 in human hepatocytes in vitro.
Substrate of P-glycoprotein (P-gp). Has shown marginal inhibitory effects on P-gp in a Caco-2 monolayer system.
Drugs Affecting Hepatic Microsomal Enzymes
CYP inhibitors or inducers: Clinically important pharmacokinetic interactions unlikely.
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP3A4/5: Clinically important pharmacokinetic interactions not expected.
Drugs Affecting the P-glycoprotein Transport System
P-gp inhibitors or inducers: Clinically important pharmacokinetic interactions not expected.
No change in pharmacokinetics of midazolam
AUC is dose-proportional over the dose range of 20–36 mg/m2.
Proteasome inhibition maintained in blood for ≥48 hours following initial dose for each week of dosing. Duration of proteasome inhibition is longer for carfilzomib than for bortezomib (another proteasome inhibitor), presumably due to carfilzomib's irreversible mechanism of action.
No clinically important difference in exposure between patients ≥65 years of age and younger adults.
Mild to severe renal impairment, including chronic hemodialysis, does not affect exposure.
Gender does not substantially affect AUC and peak plasma concentrations.
Not known whether distributed into human milk.
Plasma Protein Binding
Rapidly and extensively metabolized; main metabolites were peptide fragments and the diol of carfilzomib, suggesting that peptidase cleavage and epoxide hydrolysis are main metabolic pathways.
CYP-mediated mechanisms have a minor role in overall metabolism.
Metabolites have no known pharmacologic activity.
Not clearly elucidated in humans. Appears to be principally eliminated extrahepatically.
≤1 hour following initial IV doses of ≥15 mg/m2.
Effect of hepatic impairment on pharmacokinetics of carfilzomib not elucidated.
Mild to severe renal impairment, including chronic hemodialysis, does not affect clearance.
Powder for Injection
2–8°C in original package to protect from light.
May store reconstituted drug in vial or syringe at 2–8°C or 15–30°C; use within 24 or 4 hours, respectively, of reconstitution.
May store infusion solution at 2–8°C or 15–30°C; use within 24 or 4 hours, respectively, of reconstitution.
For information on systemic interactions resulting from concomitant use, see Interactions.
Dextrose 5% in water
Tetrapeptide epoxyketone proteasome inhibitor.
Selectively and irreversibly inhibits the 20S proteolytic core particle within the 26S proteasome (a large protein complex that degrades ubiquitinated proteins), which prevents targeted proteolysis and causes proteotoxic stress resulting in cell death.
Has antiproliferative and proapoptotic activity in solid and hematologic tumor cells in vitro, including in some bortezomib-resistant cell lines.
In animal studies, inhibits proteasome activity in blood and tissue and delays tumor growth in models of multiple myeloma, hematologic, and solid tumors.
Mechanism by which carfilzomib overcomes bortezomib-resistant cell line models and clinical samples not fully elucidated; however, studies suggest that carfilzomib produces more selective, potent, and durable proteasome inhibition than bortezomib.
Mechanism for peripheral neuropathy resulting from proteasome inhibitor therapy not fully elucidated; however, carfilzomib's selectivity for the 26S proteasome and weak activity on other protease classes may help explain the lower incidence of neurotoxicity observed in animal and clinical studies.
Advice to Patients
Importance of informing clinician if fever, chills, rigors, chest pain, cough, or swelling of the feet or legs occurs.
Risk of fatigue, dizziness, syncope, and/or hypotension; importance of advising patients to avoid driving or operating machinery if these effects occur.
Risk of dyspnea, which generally occurs within a day of dosing. Importance of informing clinician if shortness of breath occurs.
Importance of avoiding dehydration since carfilzomib may cause vomiting and/or diarrhea. Importance of informing a clinician if dizziness, lightheadedness, or fainting spells occur.
Risk of fetal harm. Necessity of advising women to avoid pregnancy and use effective methods of contraception while receiving therapy. Importance of women informing their clinicians immediately if they are pregnant. If pregnancy occurs, advise of potential risk to fetus.
Importance of advising women to avoid breast-feeding while receiving carfilzomib therapy. If patient wishes to resume breast-feeding following therapy, importance of discussing appropriate timing with clinician.
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., CHF, history of MI, conduction abnormalities).
Importance of informing patients of other important precautionary information. (See Cautions.)
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.
Commercially available through select specialty distributors and wholesalers. For specific information, visit [Web].
For injection, for IV use only
AHFS DI Essentials™. © Copyright 2021, Selected Revisions September 19, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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