Kyprolis® (carfilzomib) for Injection, a proteasome inhibitor, is approved for the treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Currently, no data are available for Kyprolis that demonstrate an improvement in progression-free survival or overall survival.
Full Prescribing Information (pdf)
Important Safety Information Regarding Kyprolis® (carfilzomib) for Injection
Safety data have been eva luated in 526 patients with relapsed and/or refractory multiple myeloma who received single-agent carfilzomib. There were 37 deaths in the phase 2 studies, or 7% of patients. The most common causes of death, other than disease progression, were cardiac (5 patients), end-organ failure (4 patients), and infection (4 patients). Important warnings and precautions include cardiac arrest, congestive heart failure, myocardial ischemia; pulmonary hypertension, pulmonary complications, infusion reactions, tumor lysis syndrome, thrombocytopenia, hepatic toxicity and embryo-fetal toxicity.
Death due to cardiac arrest has occurred within a day of Kyprolis administration. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications.
Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with Kyprolis and was Grade 3 or greater in less than 1% of patients. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported.
Infusion reactions, characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina can occur immediately following or up to 24 hours after administration of Kyprolis. Administration of dexamethasone prior to Kyprolis reduces the incidence and severity of reactions. Tumor lysis syndrome (TLS) occurred following Kyprolis administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS.
Thrombocytopenia following Kyprolis administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with Kyprolis in < 1% of patients.
Cases of hepatic failure, including fatal cases, have been reported (< 1%). Kyprolis can cause elevations of serum transaminases and bilirubin.
There are no adequate and well-controlled studies in pregnant women using Kyprolis. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis.
The most common serious adverse reactions were pneumonia, acute renal failure, pyrexia, and congestive heart failure. The most common adverse reactions (incidence of 30% or greater) observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. Serious adverse reactions were reported in 45% of patients.
Manufacturer:
Onyx Pharmaceuticals
Pharmacological Class:
Proteasome inhibitor.
Active Ingredient(s):
Carfilzomib 60mg/vial; lyophilized pwd for IV inj after reconstitution; preservative-free.
Indication(s):
Treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy.
Pharmacology:
Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells.
Clinical Trials:
The safety and efficacy of Kyprolis were eva luated in a single-arm, multicenter clinical trial. Two hundred and sixty-six patients with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) were enrolled. Patients were enrolled in the trial whose disease had a ≤25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. Patients were excluded from the trial with total bilirubin levels ≥2 × upper limit of normal; CrCl <30mL/min; NYHA Class III to IV CHF; symptomatic cardiac ischemia; myocardial infarction (MI) within the last 6 months; peripheral neuropathy Grade 3 or 4, or peripheral neuropathy Grade 2 with pain; active infections requiring treatment; and pleural effusion.
Kyprolis was administered intravenously over 2–10 minutes on two consecutive days each week for three weeks, followed by a 12-day rest period (28-day treatment cycle), until disease progression, unacceptable toxicity, or for a maximum of 12 cycles. Patients received 20mg/m2 at each dose in Cycle 1, and 27mg/m2 in subsequent cycles. To reduce the incidence and severity of fever, rigors, chills, dyspnea, myalgia, and arthralgia, dexamethasone 4mg by mouth or by IV infusion was administered prior to all Kyprolis doses during the first cycle and prior to all Kyprolis doses during the first dose-escalation (27mg/m2) cycle. Dexamethasone premedication (4mg orally or intravenously) was reinstated if these symptoms reappeared during subsequent cycles.
The median number of cycles started was four.
The primary endpoint was the overall response rate (ORR) as determined by Independent Review Committee using International Myeloma Working Group criteria. The ORR (stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]) was 22.9% (95% CI: 18.0, 28.5) (N=266). The median duration of response was 7.8 months (95% CI: 5.6, 9.2).
Legal Classification:
Rx
Adults:
See literature. Premedicate with dexamethasone prior to all Cycle 1 doses, during 1st dose escalation and if infusion reactions occur. Give by IV over 2–10 minutes, on two consecutive days each week for 3 weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17–28). In Cycle 1: 20mg/m2 per each dose, if tolerated increase to 27mg/m2 starting in Cycle 2 and subsequent cycles; continue until disease progression or unacceptable toxicity occurs. On dialysis: give dose after session. Toxicity dose modification: see literature.
Children:
Not established.
Warnings/Precautions:
Risk of cardiac complications (eg, CHF, MI, pulmonary edema); monitor and manage promptly if occurs. Pulmonary hypertension; if suspected, withold therapy until resolved; may consider restarting after reeva luate. Monitor for dyspnea or tumor lysis syndrome, and manage promptly if occurs; interrupt therapy until resolved. Maintain adequate hydration. Monitor platelets frequently during therapy. Hepatic impairment (monitor enzymes). Pregnancy (Cat. D); avoid. Nursing mothers: not recommended.
Adverse Reaction(s):
Fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, pyrexia; cardiac events, pulmonary HTN, infusion reactions, tumor lysis syndrome, hepatic toxicity/failure.
How Supplied:
Single use vial—1
Last Updated:
7/30/2012
