Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia, and lymphopenia has been reported following a dose of 200 mg of Kyprolis administered in error.
There is no known specific antidote for Kyprolis overdosage. In the event of overdose, the patient should be monitored, specifically for the side effects and/or adverse reactions listed in ADVERSE REACTIONS.
None.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
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 MyelomaThe safety of Kyprolis in combination with lenalidomide and dexamethasone (KRd) was evaluated in an open-label randomized study in patients with relapsed multiple myeloma. Â Details of the study treatment are described in Section 14.1. 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 27/392 (7%) patients compared with 27/389 (7%) patients who died due to adverse events 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 cardiac 10 (3%) versus 7 (2%), infection 9 (2%) versus 10 (3%), renal 0 (0%) versus 1 (< 1%), and other adverse reactions 9 (2%) versus 10 (3%). Serious adverse reactions were reported in 60% of the patients in the KRd arm and 54% 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 (14% versus 11%), respiratory tract infection (4% versus 1.5%), pyrexia (4% versus 2%), and pulmonary embolism (3% versus 2%). Discontinuation due to any adverse reaction occurred in 26% in the KRd arm versus 25% 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%).
Common Adverse Reactions (≥ 10%)The adverse reactions in the first 12 cycles of therapy that occurred at a rate of 10% or greater in the KRd arm are presented in Table 8.
Table 8: Most Common Adverse Reactions (≥ 10% in
the KRd Arm) Occurring in Cycles 1–12 (20/27 mg/m² Regimen In Combination with
Lenalidomide and Dexamethasone)
| Adverse Reactions by Body System | KRd Arm (N = 392) n (%) |
Rd Arm (N = 389) n (%) |
||
| Any Grade | ≥ Grade 3 | Any Grade | ≥ Grade 3 | |
| Blood and Lymphatic System Disorders | ||||
| Anemia | 138 (35) | 53 (14) | 127 (33) | 47 (12) |
| Neutropenia | 124 (32) | 104 (27) | 115 (30) | 89 (23) |
| Thrombocytopenia | 100 (26) | 58 (15) | 75 (19) | 39 (10) |
| Gastrointestinal Disorders | ||||
| Diarrhea | 115 (29) | 7 (2) | 105 (27) | 12 (3) |
| Constipation | 68 (17) | 0 | 53 (14) | 1 (0) |
| Nausea | 60 (15) | 1 (0) | 39 (10) | 3 (1) |
| General Disorders and Administration Site Conditions | ||||
| Fatigue | 109 (28) | 21 (5) | 104 (27) | 20 (5) |
| Pyrexia | 93 (24) | 5 (1) | 64 (17) | 1 (0) |
| Edema peripheral | 63 (16) | 2 (1) | 57 (15) | 2 (1) |
| Asthenia | 53 (14) | 11 (3) | 46 (12) | 7 (2) |
| Infections and Infestations | ||||
| Upper respiratory tract infection | 85 (22) | 7 (2) | 52 (13) | 3 (1) |
| Nasopharyngitis | 63 (16) | 0 | 43 (11) | 0 |
| Bronchitis | 54 (14) | 5 (1) | 39 (10) | 2 (1) |
| Pneumoniaa | 54 (14) | 35 (9) | 43 (11) | 27 (7) |
| Metabolism and Nutrition Disorders | ||||
| Hypokalemia | 78 (20) | 22 (6) | 35 (9) | 12 (3) |
| Hypocalcemia | 55 (14) | 10 (3) | 39 (10) | 5 (1) |
| Hyperglycemia | 43 (11) | 18 (5) | 33 (9) | 15 (4) |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Muscle spasms | 88 (22) | 3 (1) | 73 (19) | 3 (1) |
| Nervous System Disorders | ||||
| Peripheral neuropathiesb | 43 (11) | 7 (2) | 37 (10) | 4 (1) |
| Psychiatric Disorders | ||||
| Insomnia | 63 (16) | 6 (2) | 50 (13) | 8 (2) |
| Respiratory, Thoracic, and Mediastinal Disorders | ||||
| Coughc | 91 (23) | 2(1) | 52(13) | 0 |
| Dyspnead | 70 (18) | 9 (2) | 58 (15) | 6 (2) |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rash | 45 (12) | 5 (1) | 53 (14) | 5 (1) |
| Vascular Disorders | ||||
| Embolic and thrombotic events venouse | 49 (13) | 16 (4) | 22 (6) | 9 (2) |
| Hypertensionf | 41 (11) | 12 (3) | 15 (4) | 4 (1) |
| KRd = Kyprolis, lenalidomide, and dexamethasone; Rd =
lenalidomide and dexamethasone a Pneumonia includes pneumonia and bronchopneumonia. b Peripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. c Cough includes cough and productive cough. d Dyspnea includes dyspnea and dyspnea exertional. e Embolic and thrombotic events, venous include deep vein thrombosis, pulmonary embolism, thrombophlebitis superficial, thrombophlebitis, venous thrombosis limb, post thrombotic syndrome, venous thrombosis. f Hypertension includes hypertension, hypertensive crisis. |
||||
There were 274 (70%) patients in the KRd arm who received treatment beyond Cycle 12.
There were no new clinically relevant adverse reactions that emerged in the later treatment cycles.
Adverse Reactions Occurring At A Frequency Of < 10%Grade 3 and higher adverse reactions that occurred during Cycles 1–12 with a substantial difference (≥ 2%) between the two arms were neutropenia, thrombocytopenia, hypokalemia, and hypophosphatemia.
Laboratory AbnormalitiesTable 9 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the KRd arm for patients who received combination therapy.
Table 9: Grade 3–4 Laboratory Abnormalities (≥
10% in the KRd Arm) in Cycles 1–12 (20/27 mg/m² Regimen In Combination with
Lenalidomide and Dexamethasone)
| Laboratory Abnormality | KRd (N = 392) n (%) |
Rd (N = 389) n (%) |
| Decreased lymphocytes | 182 (46) | 119 (31) |
| Decreased absolute neutrophil count | 152 (39) | 140 (36) |
| Decreased phosphorus | 122 (31) | 106 (27) |
| Decreased platelets | 101 (26) | 59 (15) |
| Decreased total white blood cell count | 97 (25) | 71 (18) |
| Decreased hemoglobin | 58 (15) | 68 (18) |
| Decreased potassium | 41 (11) | 23 (6) |
| KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone |
The safety of Kyprolis in combination with dexamethasone was evaluated in an open-label, randomized trial of patients with relapsed multiple myeloma. The study treatment is described in Section 14.2. Patients received treatment for a median duration of 48 weeks in the Kyprolis/dexamethasone (Kd) arm and 27 weeks in the bortezomib/dexamethasone (Vd) arm.
Deaths due to adverse reactions within 30 days of last study treatment occurred in 32/463 (7%) patients in the Kd arm and 21/456 (5%) patients in the Vd arm. The causes of death occurring in patients (%) in the two arms (Kd versus Vd) included cardiac 4 (1%) versus 5 (1%), infections 8 (2%) versus 8 (2%), disease progression 7 (2%) versus 4 (1%), pulmonary 3 (1%) versus 2 (< 1%), renal 1 (< 1%) versus 0 (0%), and other adverse events 9 (2%) versus 2 (< 1%). Serious adverse reactions were reported in 59% of the patients in the Kd arm and 40% of the patients in the Vd arm. In both treatment arms, pneumonia was the most commonly reported serious adverse reaction (8% versus 9%). Discontinuation due to any adverse reaction occurred in 29% in the Kd arm versus 26% in the Vd arm. The most common reaction leading to discontinuation was cardiac failure in the Kd arm (n = 8, 2%) and peripheral neuropathy in the Vd arm (n = 22, 5%).
Common Adverse Reactions (≥ 10%)Adverse reactions in the first 6 months of therapy that occurred at a rate of 10% or greater in the Kd arm are presented in Table 10.
Table 10: Most Common Adverse Reactions (≥ 10%
in the Kd Arm) Occurring in Months 1–6 (20/56 mg/m² Regimen In Combination with
Dexamethasone)
| Adverse Reaction by Body System | Kd (N = 463) n (%) |
Vd (N = 456) n (%) |
||
| Any Grade | ≥ Grade 3 | Any Grade | ≥ Grade 3 | |
| Blood and Lymphatic System Disorders | ||||
| Anemia | 161 (35) | 57 (12) | 112 (25) | 43 (9) |
| Thrombocytopeniaa | 125 (27) | 45 (10) | 112 (25) | 64 (14) |
| Gastrointestinal Disorders | ||||
| Diarrhea | 117(25) | 14 (3) | 149 (33) | 27 (6) |
| Nausea | 70(15) | 4 (1) | 68(15) | 3 (1) |
| Constipation | 60(13) | 1 (0) | 113 (25) | 6(1) |
| Vomiting | 45 (10) | 5 (1) | 33 (7) | 3 (1) |
| General Disorders and Administration Site Conditions | ||||
| Fatigue | 116(25) | 14(3) | 126 (28) | 25 (6) |
| Pyrexia | 102 (22) | 9 (2) | 52 (11) | 3 (1) |
| Asthenia | 73 (16) | 9 (2) | 65 (14) | 13 (3) |
| Peripheral edema | 62(13) | 3 (1) | 62 (14) | 3 (1) |
| Infections and Infestations | ||||
| Upper respiratory tract infection | 67(15) | 4 (1) | 55 (12) | 3 (1) |
| Bronchitis | 54 (12) | 5 (1) | 25 (6) | 2 (0) |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Muscle spasms | 70(15) | 1 (0) | 23 (5) | 3 (1) |
| Back pain | 64 (14) | 8(2) | 61 (13) | 10(2) |
| Nervous System Disorders | ||||
| Headache | 67(15) | 4 (1) | 39(9) | 2 (0) |
| Peripheral neuropathiesb,c | 56 (12) | 7 (2) | 170 (37) | 23 (5) |
| Psychiatric Disorders | ||||
| Insomnia | 105 (23) | 5 (1) | 116(25) | 10 (2) |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Dyspnead | 128 (28) | 23 (5) | 69(15) | 8 (2) |
| Coughe | 97 (21) | 0 (0) | 61 (13) | 2 (0) |
| Vascular Disorders | ||||
| Hypertensionf | 83 (18) | 30(7) | 33 (7) | 12 (3) |
| Kd = Kyprolis and dexamethasone; Vd = bortezomib and
dexamethasone a Thrombocytopenia includes platelet count decreased and thrombocytopenia. b Peripheral neuropathies include peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. c See Clinical Studies. d Dyspnea includes dyspnea and dyspnea exertional. e Cough includes cough and productive cough. f Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency. |
||||
The event rate of ≥ Grade 2 peripheral neuropathy in the Kd arm was 7% (95% CI: 5, 9) versus 35% (95% CI: 31, 39) in the Vd arm.
Adverse Reactions Occurring At A Frequency Of < 10%Table 11 describes Grades 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the Kd arm.
Table 11: Grades 3–4 Laboratory Abnormalities (≥
10%) in Months 1–6 (20/56 mg/m² Regimen In Combination with Dexamethasone)
| Laboratory Abnormality | Kd (N = 463) n (%) |
Vd (N = 456) n (%) |
| Decreased lymphocytes | 249 (54) | 180 (40) |
| Increase uric acid | 244 (53) | 198 (43) |
| Decreased hemoglobin | 79 (17) | 68 (15) |
| Decreased platelets | 85 (18) | 77 (17) |
| Decreased phosphorus | 74 (16) | 61 (13) |
| Decreased creatinine clearancea | 65 (14) | 49 (11) |
| Increased potassium | 55 (12) | 21 (5) |
| Kd = Kyprolis and dexamethasone; Vd = bortezomib and
dexamethasone a Calculated using the Cockcroft-Gault formula. |
The safety of Kyprolis, dosed at 20/27 mg/m² by up to 10-minute infusion, was evaluated in clinical trials in which 598 patients with relapsed and/or refractory myeloma received Kyprolis monotherapy starting with the 20 mg/m² dose in Cycle 1, Day 1 and escalating to 27 mg/m² on Cycle 1, Day 8 or Cycle 2, Day 1. Premedication with dexamethasone 4 mg was required before each dose in Cycle 1 and was optional for subsequent cycles. The median age was 64 years (range 32–87), and approximately 57% were male. The patients received a median of 5 (range 1–20) prior regimens. The median number of cycles initiated was 4 (range 1–35).
Serious adverse reactions, regardless of causality, were reported in 50% of patients in the pooled Kyprolis monotherapy studies (N = 598). The most common serious adverse reactions were: pneumonia (8%), acute renal failure (5%), disease progression (4%), pyrexia (3%), hypercalcemia (3%), congestive heart failure (3%), multiple myeloma (3%), anemia (2%), and dyspnea (2%). In patients treated with Kyprolis, the incidence of serious adverse reactions was higher in those ≥ 65 years old and those ≥ 75 years old.
Deaths due to adverse reactions within 30 days of the last dose of Kyprolis occurred in 30/598 (5%) patients receiving Kyprolis monotherapy. These adverse reactions were related to cardiac disorders in 10 (2%) patients, infections in 8 (1%) patients, renal disorders in 4 (< 1%) patients, and other adverse reactions in 8 (1%) patients. In a randomized trial comparing Kyprolis as a single agent versus corticosteroids with optional oral cyclophosphamide for patients with relapsed and refractory multiple myeloma, mortality was higher in the patients treated with Kyprolis in comparison to the control arm in the subgroup of 48 patients ≥ 75 years of age. The most common cause of discontinuation due to an adverse reaction was acute renal failure (2%).
Safety of Kyprolis monotherapy dosed at 20/56 mg/m² by 30-minute infusion was evaluated in a multicenter, open-label study in patients with relapsed and/or refractory multiple myeloma. The study treatment is described in Section 14.3. The patients received a median of 4 (range 1–10) prior regimens.
The common adverse reactions occurring at a rate of 20% or greater with Kyprolis monotherapy are presented in Table 12.
Table 12: Most Common Adverse Reactions (≥ 20%)
with Kyprolis Monotherapy
| Adverse Reaction | 20/56 mg/m² by 30-minute infusion (N = 24) |
20/27 mg/m² by 2- to 10-minute infusion (N = 598) |
||
| Any Grade n (%) | Grades 3-5 n (%) | Any Grade n (%) | Grades 3-5 n (%) | |
| Fatigue | 14 (58) | 2 (8) | 238 (40) | 25(4) |
| Dyspneaa | 14 (58) | 2 (8) | 202 (34) | 21(4) |
| Pyrexia | 14 (58) | 0 | 177 (30) | 11(2) |
| Thrombocytopenia | 13 (54) | 13 (54) | 220 (37) | 152 (25) |
| Nausea | 13 (54) | 0 | 211 (35) | 7(1) |
| Anemia | 10 (42) | 7 (29) | 291 (49) | 141 (24) |
| Hypertensionb | 10 (42) | 3 (13) | 90 (15) | 22 (4) |
| Chills | 9 (38) | 0 | 73 (12) | 1 (<1) |
| Headache | 8 (33) | 0 | 141 (24) | 7 (1) |
| Coughc | 8 (33) | 0 | 134 (22) | 2 (<1) |
| Vomiting | 8 (33) | 0 | 104 (17) | 4 (1) |
| Lymphopenia | 8 (33) | 8 (33) | 85 (14) | 73 (12) |
| Insomnia | 7 (29) | 0 | 75 (13) | 0 |
| Dizziness | 7 (29) | 0 | 64 (11) | 5 (1) |
| Diarrhea | 6 (25) | 1 (4) | 160 (27) | 8 (1) |
| Blood creatinine increased | 6 (25) | 1 (4) | 103 (17) | 15 (3) |
| Peripheral edema | 5 (21) | 0 | 118 (20) | 1 (<1) |
| Back pain | 5 (21) | 1 (4) | 115 (19) | 19 (3) |
| Upper respiratory tract infection | 5(21) | 1 (4) | 112 (19) | 15 (3) |
| Decreased appetite | 5 (21) | 0 | 89 (15) | 2 (<1) |
| Muscle spasms | 5 (21) | 0 | 62 (10) | 2 (<1) |
| Chest pain | 5 (21) | 0 | 20 (3) | 1 (<1) |
| a Dyspnea includes preferred terms of dyspnea
and dyspnea exertional. b Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency. c Cough includes cough and productive cough. |
Grade 3 and higher adverse reactions occurring at an incidence of > 1% include febrile neutropenia, cardiac arrest, cardiac failure congestive, pain, sepsis, urinary tract infection, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hyponatremia, hypophosphatemia, renal failure, renal failure acute, renal impairment, pulmonary edema, and hypotension.
Laboratory AbnormalitiesTable 13 describes Grade 3–4 laboratory abnormalities reported at a rate of > 10% for patients who received Kyprolis monotherapy.
Table 13: Grade 3–4 Laboratory Abnormalities (>
10%) with Kyprolis Monotherapy
| Laboratory Abnormality | Kyprolis 20/56 mg/m² (N = 24) |
Kyprolis 20/27 mg/m² (N = 598) |
| Decreased lymphocytes | 15 (63) | 151 (25) |
| Decreased platelets | 11 (46) | 184 (31) |
| Decreased hemoglobin | 7 (29) | 132 (22) |
| Decreased total white blood cell count | 3 |
Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like (CT-L) activity when measured in blood 1 hour after the first dose. Doses of carfilzomib ≥ 15 mg/m² with or without lenalidomide and dexamethasone induced a ≥ 80% inhibition of the CT-L activity of the proteasome. In addition, carfilzomib, 20 mg/m² intravenously as a single agent, resulted in a mean inhibition of the low molecular mass polypeptide 2 (LMP2) and multicatalytic endopeptidase complex-like 1 (MECL1) subunits of the proteasome ranging from 26% to 32% and 41% to 49%, respectively. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing.
The mean (CV%) Cmax and AUC following a 2- to 10-minute intravenous infusion of 27 mg/m² of carfilzomib were 4232 ng/mL (49%) and 379 ng•hr/mL (25%), respectively. Following repeated doses of carfilzomib at 15 and 20 mg/m², systemic exposure (AUC) and half-life were similar on Days 1 and 15 or 16 of Cycle 1, suggesting there was no systemic carfilzomib accumulation.
Following a 30-minute infusion of the 56 mg/m² dose, the mean (CV%) AUC of 948 ng•hr/mL (34%) was approximately twice that observed following a 2- to 10-minute infusion at the 27 mg/m² dose with a mean (CV%) of 379 ng•hr/mL (25%). The mean (CV%) Cmax of 2079 ng/mL (44%) following a 30-minute infusion of the 56 mg/m² dose was lower compared to that of 27 mg/m² over the 2- to 10-minute infusion with a mean (CV%) of 4232 ng/mL (49%).
At doses between 20 and 56 mg/m², there was a dose-dependent increase in exposure at either infusion duration.
DistributionThe mean steady-state volume of distribution of a 20 mg/m² dose of carfilzomib was 28 L. When tested in vitro, the binding of carfilzomib to human plasma proteins averaged 97% over the concentration range of 0.4 to 4 micromolar.
MetabolismCarfilzomib was rapidly and extensively metabolized. The predominant metabolites measured in human plasma and urine, and generated in vitro by human hepatocytes, were peptide fragments and the diol of carfilzomib, suggesting that peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome P450-mediated mechanisms played a minor role in overall carfilzomib metabolism. The metabolites have no known biologic activity.
EliminationFollowing intravenous administration of doses ≥ 15 mg/m², carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1. The systemic clearance ranged from 151 to 263 L/hour, and exceeded hepatic blood flow, suggesting that carfilzomib was largely cleared extrahepatically. In 24 hours, approximately 25% of the administered dose of carfilzomib was excreted in urine as metabolites. Urinary and fecal excretion of the parent compound was negligible (0.3% of total dose).
Kyprolis can cause fetal harm based on findings from animal studies and the drug's mechanism of action. 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. Males of reproductive potential should be advised to avoid fathering a child while being treated with Kyprolis. Consider the benefits and risks of Kyprolis and possible risks to the fetus when prescribing Kyprolis to a pregnant woman. If Kyprolis is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.
DataAnimal Data
Carfilzomib administered intravenously to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day in rats and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre-implantation loss at ≥0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m² based on body surface area.
Kyprolis is supplied as follows:
Kyprolis (carfilzomib) is supplied as:
An individually packaged single-dose vial containing 30 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-102-01.
An individually packaged single-dose vial containing 60 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-101-01.
Storage And HandlingUnopened vials should be stored refrigerated (2°C to 8°C; 36°F to 46°F). Retain in original package to protect from light.
Manufactured for: Onyx Pharmaceuticals, Inc. Thousand Oaks, CA 91320-1799 U.S.A. Revised: Jan 2018
Included as part of the PRECAUTIONS section.
PRECAUTIONS Cardiac ToxicitiesNew 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 a randomized, open-label, multicenter trial evaluating Kyprolis in combination with lenalidomide and dexamethasone (KRd) versus lenalidomide/dexamethasone (Rd), the incidence of cardiac failure events was 6% in the KRd arm versus 4% in the Rd arm. In a randomized, open-label, multicenter trial of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd), the incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm.
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 FailureCases 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 10% 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 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 SyndromeCases 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 ToxicityAcute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in less than 1% of patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.
Pulmonary HypertensionPulmonary 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.
DyspneaDyspnea was reported in 31% of patients treated with Kyprolis and was Grade 3 or greater in 5% 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.
HypertensionHypertension, 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 16% in the KRd arm versus 8% 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 ThrombosisVenous 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 ReactionsInfusion 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.
HemorrhageFatal 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.
ThrombocytopeniaKyprolis 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 34% 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 FailureCases 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 MicroangiopathyCases 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 SyndromeCases 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 PatientsIn a clinical trial of 955 transplant-ineligible patients with newly diagnosed multiple myeloma randomized to Kyprolis (20/36 mg/m² 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 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 ToxicityKyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using Kyprolis.
Advise females of reproductive potential to avoid becoming pregnant while being treated with Kyprolis. Advise males of reproductive potential to avoid fathering a child while being treated with Kyprolis. Advise women who use Kyprolis during pregnancy or become pregnant during treatment with Kyprolis of the potential hazard to the fetus.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityCarcinogenicity studies have not been conducted with carfilzomib.
Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay.
Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies.
Use In Specific Populations Pregnancy Risk SummaryKyprolis can cause fetal harm based on findings from animal studies and the drug's mechanism of action. 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. Males of reproductive potential should be advised to avoid fathering a child while being treated with Kyprolis. Consider the benefits and risks of Kyprolis and possible risks to the fetus when prescribing Kyprolis to a pregnant woman. If Kyprolis is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.
DataAnimal Data
Carfilzomib administered intravenously to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day in rats and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre-implantation loss at ≥0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m² based on body surface area.
Lactation Risk SummaryThere is no information regarding the presence of Kyprolis in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Kyprolis and any potential adverse effects on the breastfed infant from Kyprolis or from the underlying maternal condition.
Females And Males Of Reproductive Potential ContraceptionKyprolis can cause fetal harm. Advise female patients of reproductive potential to use effective contraceptive measures or abstain from sexual activity to prevent pregnancy during treatment with Kyprolis and for at least 30 days following completion of therapy. Advise male patients of reproductive potential to use effective contraceptive measures or abstain from sexual activity to prevent pregnancy during treatment with Kyprolis and for at least 90 days following completion of therapy.
Pediatric UseThe safety and effectiveness of Kyprolis in pediatric patients have not been established.
Geriatric UseOf 598 patients in clinical studies of Kyprolis monotherapy dosed at 20/27 mg/m² by up to 10-minute infusion, 49% were 65 and over, while 16% were 75 and over. The incidence of serious adverse events was 44% in patients < 65 years of age, 55% in patients 65 to 74 years of age, and 56% in patients ≥ 75 years of age. In a single-arm, multicenter clinical trial of Kyprolis monotherapy dosed at 20/27 mg/m² (N = 266), no overall differences in effectiveness were observed between older and younger patients.
Of 392 patients treated with Kyprolis in combination with lenalidomide and dexamethasone, 47% were 65 and over and 11% were 75 years and over. The incidence of serious adverse events was 50% in patients < 65 years of age, 70% in patients 65 to 74 years of age, and 74% in patients ≥ 75 years of age. No overall differences in effectiveness were observed between older and younger patients.
Of 463 patients treated with Kyprolis dosed at 20/56 mg/m² by 30-minute infusion in combination with dexamethasone, 52% were 65 and over and 17% were 75 and over. The incidence of serious adverse events was 54% in patients < 65 years of age, 60% in patients 65 to 74 years of age, and 70% in patients ≥ 75 years of age. No overall differences in effectiveness were observed between older and younger patients.
Hepatic ImpairmentReduce the dose of Kyprolis by 25% in patients with mild or moderate hepatic impairment. Dosing recommendation cannot be made for patients with severe hepatic function.
The pharmacokinetics and safety of Kyprolis were evaluated in patients with advanced malignancies who had either normal hepatic function, or mild (bilirubin > 1 to 1.5 × ULN or AST > ULN), moderate (bilirubin > 1.5 to 3 × ULN), or severe (bilirubin > 3 × ULN) hepatic impairment. The AUC of carfilzomib increased by approximately 50% in patients with mild and moderate hepatic impairment compared to patients with normal hepatic function. PK data were not collected in patients with severe hepatic impairment. The incidence of serious adverse events was higher in patients with mild, moderate, and severe hepatic impairment combined (22/35 or 63%) than in patients with normal hepatic function (3/11 or 27%).
Monitor liver enzymes regularly, regardless of baseline values, and modify dose based on toxicity.
Renal ImpairmentNo starting dose adjustment is required in patients with baseline mild, moderate, or severe renal impairment or patients on chronic hemodialysis. The pharmacokinetics and safety of Kyprolis were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic hemodialysis. In addition, a pharmacokinetic study was conducted in patients with normal renal function and end-stage renal disease (ESRD).
In these studies, the pharmacokinetics of Kyprolis was not influenced by the degree of baseline renal impairment, including the patients on hemodialysis. Since dialysis clearance of Kyprolis concentrations has not been studied, the drug should be administered after the hemodialysis procedure.
Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high risk of tumor lysis syndrome or renal toxicity. The recommended hydration includes both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous 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.
Electrolyte MonitoringMonitor serum potassium levels regularly during treatment with Kyprolis.
PremedicationsPremedicate with the recommended dose of dexamethasone fo  monotherapy or the recommended dexamethasone dose if on 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.
AdministrationKyprolis can be administered in a 50 mL or 100 mL intravenous bag of 5% Dextrose Injection, USP. Infuse over 10 or 30 minutes depending on the Kyprolis dose regimen. Do not administer as a bolus. Flush the intravenous administration line with normal saline or 5% dextrose injection, USP immediately before and after Kyprolis administration. Do not mix Kyprolis with or administer as an infusion with other medicinal products.
Dose CalculationCalculate the Kyprolis dose using the patient's actual body surface area at baseline. In patients with a body surface area greater than 2.2 m², calculate the dose based upon a body surface area of 2.2 m².
ThromboprophylaxisThromboprophylaxis 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.
Infection ProphylaxisConsider antiviral prophylaxis for patients being treated with Kyprolis to decrease the risk of herpes zoster reactivation.
Patients On HemodialysisAdminister Kyprolis after the hemodialysis procedure.
Recommended Dosing Kyprolis In Combination With Lenalidomide And DexamethasoneFor the combination regimen with lenalidomide and dexamethasone, administer Kyprolis intravenously as a 10-minute infusion on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 1. Each 28-day period is considered one treatment cycle. The recommended starting dose of Kyprolis is 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 27 mg/m² on Day 8 of Cycle 1. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis. Discontinue Kyprolis after Cycle 18. Lenalidomide 25 mg is taken orally on Days 1–21 and dexamethasone 40 mg by mouth or intravenously on Days 1, 8, 15, and 22 of the 28-day cycles.
Table 1: Kyprolis (10-Minute Infusion) in Combination
with Lenalidomide and Dexamethasone
| Cycle 1 | |||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | ||||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Day 22 | Days 23-28 | |
| Kyprolis (mg/m²) | 20 | 20 | - | 27 | 27 | - | 27 | 27 | - | - | - |
| Dexamethasone (mg) | 40 | - | - | 40 | - | - | 40 | - | - | 40 | - |
| Lenalidomide | 25 mg daily on Days 1-21 | - | - | ||||||||
| Cycles 2 to 12 | |||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | ||||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Day 22 | Days 23-28 | |
| Kyprolis (mg/m²) | 27 | 27 | - | 27 | 27 | - | 27 | 27 | - | - | - |
| Dexamethasone (mg) | 40 | - | - | 40 | - | - | 40 | - | - | 40 | - |
| Lenalidomide | 25 mg daily on Days 1-21 | - | - | ||||||||
| Cycles 13 and latera | |||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | ||||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Day 22 | Days 23-28 | |
| Kyprolis (mg/m²) | 27 | 27 | - | - | - | - | 27 | 27 | - | - | - |
| Dexamethasone (mg) | 40 | - | - | 40 | - | - | 40 | - | - | 40 | - |
| Lenalidomide | 25 mg daily on Days 1-21 | - | - | ||||||||
| a Kyprolis is administered through Cycle 18; lenalidomide and dexamethasone continue thereafter. |
Continue treatment until disease progression or unacceptable toxicity occurs. Refer to the lenalidomide and dexamethasone Prescribing Information for other concomitant medications, such as the use of anticoagulant and antacid prophylaxis, that may be required with those agents.
Kyprolis In Combination With DexamethasoneFor the combination regimen with dexamethasone, administer Kyprolis intravenously as a 30-minute infusion on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 2. Each 28-day period is considered one treatment cycle. Administer Kyprolis by 30-minute infusion at a starting dose of 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 56 mg/m² on Day 8 of Cycle 1. Dexamethasone 20 mg is taken by mouth or intravenously on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. Administer dexamethasone 30 minutes to 4 hours before Kyprolis.
Table 2: Kyprolis (30-Minute Infusion) in Combination
with Dexamethasone
| Cycle 1 | ||||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | |||||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Day 22 | Day 23 | Days 24-28 | |
| Kyprolis (mg/m²) | 20 | 20 | - | 56 | 56 | - | 56 | 56 | - | - | - | - |
| Dexamethasone (mg) | 20 | 20 | - | 20 | 20 | - | 20 | 20 | - | 20 | 20 | - |
| Cycles 2 and later | ||||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | |||||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Day 22 | Day 23 | Days 24-28 | |
| Kyprolis (mg/m²) | 56 | 56 | - | 56 | 56 | - | 56 | 56 | - | - | - | - |
| Dexamethasone (mg) | 20 | 20 | - | 20 | 20 | - | 20 | 20 | - | 20 | 20 | - |
Treatment may be continued until disease progression or unacceptable toxicity occurs. Refer to the dexamethasone Prescribing Information for other concomitant medications.
Kyprolis MonotherapyFor monotherapy, administer Kyprolis intravenously as a 10-minute or 30-minute infusion depending on the regimen as described below.
20/27 mg/m² Regimen By 10-Minute Infusion
For monotherapy using the 20/27 mg/m² regimen, administer Kyprolis intravenously as a 10-minute infusion. In Cycles 1 through 12, administer Kyprolis on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 3. Each 28-day period is considered one treatment cycle. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis (see Table 3). Premedicate with dexamethasone 4 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to help prevent infusion reactions. The recommended starting dose of Kyprolis is 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 27 mg/m² on Day 8 of Cycle 1. Treatment may continue until disease progression or unacceptable toxicity occurs.
Table 3: Kyprolis Monotherapy (10-Minute
Infusion)
| Cycle 1 | ||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | |||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Days 22-28 | |
| Kyprolis (mg/m²)a | 20 | 20 | - | 27 | 27 | - | 27 | 27 | - | - |
| Cycles 2 to 12 | ||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | |||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Days 22-28 | |
| Kyprolis (mg/m²) | 27 | 27 | - | 27 | 27 | - | 27 | 27 | - | - |
| Cycles 13 and later | ||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | |||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Days 22-28 | |
| Kyprolis (mg/m²) | 27 | 27 | - | - | - | - | 27 | 27 | - | - |
| a Dexamethasone premedication is required for each Kyprolis dose in Cycle 1. |
20/56 mg/m² Regimen By 30-Minute Infusion
For monotherapy using the 20/56 mg/m² regimen, administer Kyprolis intravenously as a 30-minute infusion. In Cycles 1 through 12, administer Kyprolis on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 4. Each 28-day period is considered one treatment cycle. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis (see Table 4). Premedicate with dexamethasone 8 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to help prevent infusion reactions. The recommended starting dose of Kyprolis is 20 mg/m² in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 56 mg/m² on Day 8 of Cycle 1. Treatment may continue until disease progression or unacceptable toxicity occurs.
Table 4: Kyprolis Monotherapy (30-Minute
Infusion)
| Cycle 1 | ||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | |||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Days 22-28 | |
| Kyprolis (mg/m²)a | 20 | 20 | - | 56 | 56 | - | 56 | 56 | - | - |
| Cycles 2 to 12 | ||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | |||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Days 22-28 | |
| Kyprolis (mg/m²) | 56 | 56 | - | 56 | 56 | - | 56 | 56 | - | - |
| Cycles 13 and later | ||||||||||
| Week 1 | Week 2 | Week 3 | Week 4 | |||||||
| Day 1 | Day 2 | Days 3-7 | Day 8 | Day 9 | Days 10-14 | Day 15 | Day 16 | Days 17-21 | Days 22-28 | |
| Kyprolis (mg/m²) | 56 | 56 | - | - | - | - | 56 | 56 | - | - |
| a Dexamethasone premedication is required for each Kyprolis dose in Cycle 1. |
Modify dosing based on toxicity. Recommended actions and dose modifications for Kyprolis are presented in Table 5. Dose level reductions are presented in Table 6. See the lenalidomide and dexamethasone Prescribing Information respectively for dosing recommendations.
Table 5: Dose Modifications for Toxicitya during
Kyprolis Treatment
| Hematologic Toxicity | Recommended Action |
|
|
|
|
|
|
| Renal Toxicity | Recommended Action |
|
|
| Other Non-hematologic Toxicity | Recommended Action |
|
|
| ANC = absolute neutrophil count a See Table 6 for dose level reductions. b CTCAE Grades 3 and 4. |
|
Table 6: Dose Level Reductions for Kyprolis
| Regimen | Dose | First Dose Reduction | Second Dose Reduction | Third Dose Reduction |
| Kyprolis, Lenalidomide, and Dexamethasone, or Monotherapy (20/27 mg/m²) | 27 mg/m² | 20 mg/m² | 15 mg/m²a | - |
| Kyprolis and Dexamethasone, or Monotherapy (20/56 mg/m²) | 56 mg/m² | 45 mg/m² | 36 mg/m² | 27 mg/m²a |
| Note: Infusion times remain unchanged during dose
reduction(s). a If toxicity persists, discontinue Kyprolis treatment. |
For patients with mild or moderate hepatic impairment, reduce the dose of Kyprolis by 25%. Dosing recommendation cannot be made in patients with severe hepatic impairment.
Dosing In Patients With End Stage Renal DiseaseFor patients with end stage renal disease who are on dialysis, administer Kyprolis after the hemodialysis procedure.
Reconstitution And Preparation For Intravenous AdministrationKyprolis vials contain no antimicrobial preservatives and are intended for single use 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). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL.
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.
Reconstitution/Preparation Steps
The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 7.
Table 7: Stability of Reconstituted Kyprolis
| Storage Conditions of Reconstituted Kyprolis | Stabilitya per Container | ||
| Vial | Syringe | Intravenous Bag (D5Wb) | |
| 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 |
| a Total time from reconstitution to
administration should not exceed 24 hours. b 5% Dextrose Injection, USP. |
Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs.
Cytochrome P450In an in vitro study using human liver microsomes, carfilzomib showed modest direct (Ki = 1.7 micromolar) and time-dependent inhibition (Ki = 11 micromolar) of human cytochrome CYP3A4/5. In vitro studies indicated that carfilzomib did not induce human CYP1A2 and CYP3A4 in cultured fresh human hepatocytes. Cytochrome P450-mediated mechanisms play a minor role in the overall metabolism of carfilzomib. A clinical trial of 17 patients using oral midazolam as a CYP3A probe demonstrated that the pharmacokinetics of midazolam were unaffected by concomitant carfilzomib administration. Kyprolis is not expected to inhibit CYP3A4/5 activities and/or affect the exposure to CYP3A4/5 substrates.
P-gpCarfilzomib is a P-glycoprotein (P-gp) substrate. In vitro, carfilzomib inhibited the efflux transport of P-gp substrate digoxin by 25% in a Caco-2 monolayer system. However, given that Kyprolis is administered intravenously and is extensively metabolized, the pharmacokinetics of Kyprolis is unlikely to be affected by P-gp inhibitors or inducers.
