KYPROLIS ® (carfilzomib) for injection, for intravenous use
Brief Summary of Prescribing Information.
Please see the KYPROLIS package insert for full prescribing information.
INDICATIONS AND USAGE
• Kyprolis 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.
WARNINGS AND PRECAUTIONS
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. In clinical studies with Kyprolis, these events occurred throughout
the course of Kyprolis therapy. Death due to cardiac arrest has occurred within one day of Kyprolis
administration. In randomized, open-label, multicenter trials for combination therapies, the incidence of
cardiac failure events was 8%.
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac 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 Kyprolis at 1 dose level reduction based on a benefit/risk assessment.
While adequate hydration is required prior to each dose in Cycle 1, all patients should also be monitored
for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as
clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.
In patients ≥ 75 years of age, the risk of cardiac failure is increased compared to patients < 75 years of
age. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction,
conduction abnormalities, angina, or arrhythmias uncontrolled by medications were not eligible for
the clinical trials. These patients may be at greater risk for cardiac complications and should have a
comprehensive medical assessment (including blood pressure control and fluid management) prior to
starting treatment with Kyprolis and remain under close follow-up.
Acute Renal Failure
Cases of acute renal failure have occurred in patients receiving Kyprolis. Some of these events have been
fatal. Renal insufficiency adverse events (including renal failure) have occurred in approximately 11% of
patients treated with Kyprolis. Acute renal failure was reported more frequently in patients with advanced
relapsed and refractory multiple myeloma who received Kyprolis monotherapy. The risk of fatal renal failure
risk was greater in patients with a baseline reduced estimated creatinine clearance (calculated using
Cockcroft and Gault equation). 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 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. Consider uric acid-lowering drugs in patients at risk for TLS. Monitor for
evidence of TLS during treatment and manage promptly, including interruption of Kyprolis until TLS
is 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 in approximately 1% of
patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity,
discontinue Kyprolis.
Pulmonary Hypertension
Pulmonary arterial hypertension was reported in approximately 1% of patients treated with Kyprolis and
was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as
indicated. Withhold Kyprolis for pulmonary hypertension until resolved or returned to baseline, and consider
whether to restart Kyprolis based on a benefit/risk assessment.
Dyspnea
Dyspnea was reported in 28% of patients treated with Kyprolis and was Grade 3 or greater in 4% of
patients. 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 Kyprolis based on a benefit/risk assessment.
Hypertension
Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis.
In a randomized, open-label, multicenter trial evaluating KRd versus Rd, the incidence of hypertension events
was 17% in the KRd arm versus 9% in the Rd arm. In a randomized, open-label, multicenter trial of Kd
versus Vd, the incidence of hypertension events was 34% in the Kd arm versus 11% in the Vd arm. Some
of these events have been fatal. It is recommended to control hypertension prior to starting Kyprolis. Monitor
blood pressure regularly in all patients while on Kyprolis. If hypertension cannot be adequately controlled,
withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.
Venous Thrombosis
Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been
observed with Kyprolis. In a randomized, open-label, multicenter trial evaluating KRd versus Rd (with
thromboprophylaxis used in both arms), the incidence of venous thromboembolic events in the first
12 cycles was 13% in the KRd arm versus 6% in the Rd arm. In a randomized, open-label, multicenter trial
of Kd versus Vd, the incidence of venous thromboembolic events in months 1–6 was 9% in the Kd arm versus
2% in the Vd arm. With Kyprolis monotherapy, the incidence of venous thromboembolic events was 2%.
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 oral contraceptives or a hormonal method of contraception associated with a risk of
thrombosis should consider an alternative method of effective contraception during treatment with Kyprolis
in combination with dexamethasone or lenalidomide plus dexamethasone.
Infusion Reactions
Infusion reactions, including life-threatening reactions, have occurred in patients receiving 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 of
symptoms and to contact a physician immediately if symptoms of an infusion reaction occur.
Hemorrhage
Fatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis. Hemorrhagic
events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. The bleeding
can be spontaneous, and intracranial hemorrhage has occurred without trauma. Hemorrhage has been
reported in patients having either low or normal platelet counts. Hemorrhage has also been reported in
patients who were not on antiplatelet therapy or anticoagulation. Promptly evaluate signs and symptoms of
blood loss. Reduce or withhold dose as appropriate.
Thrombocytopenia
Kyprolis causes thrombocytopenia with platelet nadirs observed between Day 8 and Day 15 of each 28-day
cycle, with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was
reported in approximately 32% of patients in clinical trials with Kyprolis. Monitor platelet counts frequently
during treatment with Kyprolis. Reduce or withhold dose as appropriate. Hemorrhage may occur.
Hepatic Toxicity and Hepatic Failure
Cases of hepatic failure, including fatal cases, have been reported (< 1%) during treatment with Kyprolis.
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), have been reported in patients who received Kyprolis. Some of these events have been
fatal. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Kyprolis and evaluate.
If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy
in patients previously experiencing TTP/HUS is not known.
Posterior Reversible Encephalopathy Syndrome
Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving
Kyprolis. PRES, formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is a
neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered
consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis
is confirmed by neuro-radiological imaging (MRI). Discontinue Kyprolis if PRES is suspected and evaluate.
The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES 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 955 transplant-ineligible patients with newly diagnosed multiple myeloma randomized
to Kyprolis (20/36 mg/m 2 by 30-minute infusion twice weekly for four of each six-week cycle), melphalan,
and prednisone (KMP) or bortezomib, melphalan, and prednisone (VMP), a higher incidence of fatal adverse
reactions (7% versus 4%) and serious adverse reactions (50% versus 42%) were observed in the KMP arm
compared to patients in the VMP arm, respectively. Patients in the KMP arm were observed to have a
higher incidence of any grade adverse reactions involving cardiac failure (11% versus 4%), hypertension
(25% versus 8%), acute renal failure (14% versus 6%), and dyspnea (18% versus 9%). This study did
not meet its primary outcome measure of superiority in progression-free survival (PFS) for the KMP arm.
Kyprolis in combination with melphalan and prednisone is not indicated for transplant-ineligible patients
with newly diagnosed multiple myeloma.
Embryo‑Fetal Toxicity
Based on the mechanism of action and findings in animals, Kyprolis can cause fetal harm when
administered to a pregnant woman. Carfilzomib administered intravenously to pregnant rabbits during
organogenesis at a dose approximately 40% of the clinical dose of 27 mg/m 2 based on body surface area
caused post-implantation loss and a decrease in fetal weight.
Females of reproductive potential should avoid becoming pregnant while being treated with Kyprolis. Advise
females of reproductive potential that they must use contraception during treatment with Kyprolis and for
6 months following the final dose. Advise males with female sexual partners of reproductive potential that
they must use contraception during treatment with Kyprolis and for 3 months following the final dose. If
Kyprolis is used during pregnancy or if the patient becomes pregnant during Kyprolis treatment, the patient
should be apprised of the potential risk to the fetus.
ADVERSE REACTIONS
The following adverse reactions have been discussed above and can be found in the Warnings and
Precautions section of the prescribing information. They include Cardiac Toxicities, Acute Renal
Failure, TLS, Pulmonary Toxicity, Pulmonary Hypertension, Dyspnea, Hypertension, Venous Thrombosis,
Infusion Reactions, Hemorrhage, Thrombocytopenia, Hepatic Toxicity and Hepatic Failure, Thrombotic
Microangiopathy, PRES, and Increased Fatal and Serious Toxicities in Combination with Melphalan and
Prednisone in Newly Diagnosed Transplant-Ineligible Patients.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may
not reflect the rates observed in medical practice.
Safety Experience with Kyprolis in Combination with Lenalidomide and Dexamethasone in Patients with
Multiple Myeloma
The safety of Kyprolis in combination with lenalidomide and dexamethasone (KRd) was evaluated in an
open-label randomized study in patients with relapsed multiple myeloma. The median number of cycles
initiated was 22 cycles for the KRd arm and 14 cycles for the Rd arm.
Deaths due to adverse reactions within 30 days of the last dose of any therapy in the KRd arm occurred in
45/392 (12%) patients compared with 42/389 (11%) patients who died due to adverse reactions within
30 days of the last dose of any Rd therapy. The most common cause of deaths occurring in patients (%)
in the two arms (KRd versus Rd) included infection 12 (3%) versus 11 (3%), cardiac 10 (3%) versus 9
(2%), and other adverse reactions 23 (6%) versus 22 (6%). Serious adverse reactions were reported in
65% of the patients in the KRd arm and 57% of the patients in the Rd arm. The most common serious
adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia (17% vs. 13%),
respiratory tract infection (4% vs. 2%), pyrexia (4% vs. 3%), and pulmonary embolism (3% vs. 2%). In
patients treated with Kyprolis, 47% were 65 and over and 11% were 75 years and over. The incidence of
serious adverse events was 57% in patients < 65 years of age, 73% in patients 65 to 74 years of age, and
81% in patients ≥ 75 years of age. Discontinuation due to any adverse reaction occurred in 33% in the KRd
arm versus 30% in the Rd arm. Adverse reactions leading to discontinuation of Kyprolis occurred in 12% of
patients and the most common reactions included pneumonia (1%), myocardial infarction (0.8%), and upper
respiratory tract infection (0.8%). The incidence of cardiac failure events was 7% in the KRd arm versus 4%
in the Rd arm.