Carfilzomib

5 WARNINGS AND PRECAUTIONS Cardiac Toxicities : Monitor for signs and symptoms of cardiac failure or ischemia. Withhold Kyprolis and evaluate promptly. ( 5.1 ) Acute Renal Failure : Monitor serum creatinine regularly. ( 5.2 ) Tumor Lysis Syndrome (TLS) : Administer pre-treatment hydration. (2.1 ) Monitor for TLS, including uric acid levels and treat promptly. ( 5.3 ) Pulmonary Toxicity, including Acute Respiratory Distress Syndrome, Acute Respiratory Failure, and Acute Diffuse Infiltrative Pulmonary Disease : Withhold Kyprolis and evaluate promptly. ( 5.4 ) Pulmonary Hypertension : Withhold Kyprolis and evaluate. ( 5.5 ) Dyspnea : For severe or life-threatening dyspnea, withhold Kyprolis and evaluate. ( 5.6 ) Hypertension, including Hypertensive Crisis : Monitor blood pressure regularly. If hypertension cannot be controlled, interrupt treatment with Kyprolis. ( 5.7 ) Venous Thrombosis : Thromboprophylaxis is recommended. ( 5.8 ) Infusion-related Reactions : Premedicate with dexamethasone. ( 2.1 , 5.9 ) Hemorrhage : Fatal or serious cases of hemorrhage may occur, including gastrointestinal, pulmonary, and intracranial hemorrhage. Promptly evaluate signs and symptoms of blood loss. ( 5.10 ) Thrombocytopenia : Monitor platelet counts; interrupt or reduce Kyprolis dosing as clinically indicated. ( 2.3 , 5.11 ) Hepatic Toxicity and Hepatic Failure : Monitor liver enzymes regularly. Withhold Kyprolis if suspected. ( 5.12 ) Thrombotic Microangiopathy : Monitor for signs and symptoms. Discontinue Kyprolis if suspected. ( 5.13 ) Posterior Reversible Encephalopathy Syndrome (PRES) : Consider neuro-radiological imaging (MRI) for onset of visual or neurological symptoms; discontinue Kyprolis if suspected. ( 5.14 ) Progressive Multifocal Leukoencephalopathy : Consider PML if new or worsening neurologic manifestations. Discontinue Kyprolis in patients who develop PML. ( 5.15 ) Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients ( 5.16 ) Embryo-Fetal Toxicity : Kyprolis can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of potential risk to a fetus and to use effective contraception. ( 5.17 , 8.1 ) 5.1 Cardiac Toxicities New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), 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% and that of arrythmias was 8% (majority of which were atrial fibrillation and sinus tachycardia) [see Adverse Reactions (6.1) ]. 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 reactions until recovery and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment [see Dosage and Administration (2.3) ] . While adequate hydration is required prior to each dose in Cycle 1, monitor all patients 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 [see Dosage and Administration (2.1) ] . In patients ≥ 75 years of age, the risk of cardiac failure is increased compared to younger patients. 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; for these patients, complete a comprehensive medical assessment (including blood pressure control and fluid management) prior to starting treatment with Kyprolis and remain under close follow-up [see Use in Specific Populations (8.5) ] . 5.2 Acute Renal Failure Cases of acute renal failure have occurred in patients receiving Kyprolis. Some of these events have been fatal. Renal insufficiency (including renal failure) has occurred in approximately 9% of patients who received 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-Gault equation). Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3) ] . 5.3 Tumor Lysis Syndrome Cases of 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. Administer oral and intravenous fluids 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 TLS during treatment and manage promptly, including interruption of Kyprolis until TLS is resolved [see Dosage and Administration (2.1) ] . 5.4 Pulmonary Toxicity Acute Respiratory Distress Syndrome (ARDS) and acute respiratory failure have occurred in approximately 2% of patients who received Kyprolis. In addition, acute diffuse infiltrative pulmonary disease, such as pneumonitis and interstitial lung disease, occurred in approximately 2% of patients who received Kyprolis. Some events were fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis. 5.5 Pulmonary Hypertension Pulmonary arterial hypertension was reported in approximately 2% of patients who received Kyprolis, with Grade 3 or greater in less than 1%. 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. 5.6 Dyspnea Dyspnea was reported in 25% of patients treated with Kyprolis, with Grade 3 or greater in 4%. 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 [see Warnings and Precautions (5.1 , 5.4) and Adverse Reactions (6.1) ] . 5.7 Hypertension Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. In ASPIRE, the incidence of hypertension events was 17% in the KRd arm versus 9% in the Rd arm. In ENDEAVOR, the incidence of hypertension events was 34% in the Kd arm versus 11% in the Vd arm. In CANDOR, the incidence of hypertension events was 31% in the DKd arm versus 28% in the Kd arm. Some of these events have been fatal. Optimize blood pressure 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. 5.8 Venous Thrombosis Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In ASPIRE, 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 ENDEAVOR, 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% [see Adverse Reactions (6.1) ] . Provide thromboprophylaxis for patients being treated with Kyprolis in combination with lenalidomide and dexamethasone; with dexamethasone; or with intravenous daratumumab and dexamethasone. Select the thromboprophylaxis regimen based on the patient’s underlying risks. For patients using oral contraceptives or hormonal contraception associated with a risk of thrombosis, consider non-hormonal contraception during treatment when Kyprolis is administered in combination [see Use in Specific Populations (8.3) ] . 5.9 Infusion-Related Reactions Infusion-related reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal 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-related reactions [see Dosage and Administration (2.1 , 2.2) , Adverse Reactions (6.1) ] . 5.10 Hemorrhage Fatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis [see Adverse Reactions (6.1) ] . 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 [see Dosage and Administration (2.3) ] . 5.11 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 [see Adverse Reactions (6.1) ] . Thrombocytopenia was reported in approximately 32% of patients in clinical trials with Kyprolis. Hemorrhage may occur [see Adverse Reactions (6.1) , Warnings and Precautions (5.10) ] . Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3) ] . 5.12 Hepatic Toxicity and Hepatic Failure Cases of hepatic failure, including fatal cases, have been reported (2%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases [see Adverse Reactions (6.1) ] . Monitor liver enzymes regularly, regardless of baseline values. Reduce or withhold dose as appropriate [see Dosage and Administration (2.3) ] . 5.13 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. 5.14 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. 5.15 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), which can be fatal, has been reported with Kyprolis. In addition to Kyprolis, other possible contributory factors include prior or concurrent immunosuppressive therapy that may cause immunosuppression. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue Kyprolis and initiate evaluation for PML including neurology consultation. 5.16 Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients In CLARION, 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. 5.17 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 BSA caused post-implantation loss and a decrease in fetal weight. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for 6 months following the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the last dose [see Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cardiac Toxicities [see Warnings and Precautions (5.1) ] Acute Renal Failure [see Warnings and Precautions (5.2) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.3) ] Pulmonary Toxicity [see Warnings and Precautions (5.4) ] Pulmonary Hypertension [see Warnings and Precautions (5.5) ] Dyspnea [see Warnings and Precautions (5.6) ] Hypertension [see Warnings and Precautions (5.7) ] Venous Thrombosis [see Warnings and Precautions (5.8) ] Infusion-Related Reactions [see Warnings and Precautions (5.9) ] Hemorrhage [see Warnings and Precautions (5.10) ] Thrombocytopenia [see Warnings and Precautions (5.11) ] Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions (5.12) ] Thrombotic Microangiopathy [see Warnings and Precautions (5.13) ] Posterior Reversible Encephalopathy Syndrome [see Warnings and Precautions (5.14) ] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.15) ] The most common adverse reactions occurring in at least 20% of patients treated with Kyprolis in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, dyspnea, diarrhea, headache, cough, edema peripheral. ( 6 ) The most common adverse reactions occurring in at least 20% of patients treated with Kyprolis in the combination therapy trials: anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, cough, dyspnea, and insomnia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 practice. The pooled safety population described in the Warnings and Precautions reflect exposure to Kyprolis in 2,239 patients administered in combination with other drugs in ASPIRE, ENDEAVOR, A.R.R.O.W., CANDOR, IKEMA, EQUULEUS, and PLEIADES. The most common adverse reactions occurring in at least 20% of patients who received Kyprolis in combination were anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, cough, dyspnea, and insomnia. Kyprolis in Combination with Lenalidomide and Dexamethasone The safety of Kyprolis 20/27 mg/m 2 twice weekly in combination with lenalidomide and dexamethasone (KRd) was evaluated in ASPIRE [see Clinical Studies (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 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 frequent 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 frequent serious adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia (17% versus 13%), respiratory tract infection (4% versus 2%), pyrexia (4% versus 3%), and pulmonary embolism (3% versus 2%). 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. Table 8 summarizes the adverse reactions in the first 12 cycles in ASPIRE. Table 8: Adverse Reactions (≥ 10%) Occurring in Cycles 1–12 in Patients Who Received KRd (20/27 mg/m 2 Regimen) in ASPIRE Adverse Reactions KRd (N = 392) n (%) Rd (N = 389) n (%) Any Grade ≥ Grade 3 Any Grade ≥ Grade 3 KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone 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 119 (30) 8 (2) 106 (27) 12 (3) Constipation 68 (17) 0 (0) 55 (14) 1 (0) Nausea 63 (16) 1 (0) 43 (11) 3 (1) General Disorders and Administration Site Conditions Fatigue 113 (29) 23 (6) 107 (28) 20 (5) Pyrexia 93 (24) 5 (1) 64 (17) 1 (0) Edema peripheral 59 (15) 3 (1) 48 (12) 2 (1) Asthenia 54 (14) 11 (3) 49 (13) 7 (2) Infections Upper respiratory tract infection 87 (22) 7 (2) 54 (14) 4 (1) Bronchitis 55 (14) 5 (1) 40 (10) 2 (1) Viral upper respiratory tract infection 55 (14) 0 (0) 44 (11) 0 (0) Pneumonia Pneumonia includes pneumonia and bronchopneumonia. 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 92 (24) 3 (1) 75 (19) 3 (1) Back pain 41 (11) 4 (1) 54 (14) 6 (2) Nervous System Disorders Peripheral neuropathies Peripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. 43 (11) 7 (2) 39 (10) 4 (1) Psychiatric Disorders Insomnia 64 (16) 6 (2) 51 (13) 8 (2) Respiratory, Thoracic and Mediastinal Disorders Cough Cough includes cough and productive cough. 93 (24) 2 (1) 54 (14) 0 (0) Dyspnea Dyspnea includes dyspnea and dyspnea exertional. 71 (18) 8 (2) 61 (16) 6 (2) Skin and Subcutaneous Tissue Disorders Rash 45 (12) 5 (1) 54 (14) 5 (1) Vascular Disorders Embolic and thrombotic events Embolic and thrombotic events, venous includes deep vein thrombosis, pulmonary embolism, thrombophlebitis superficial, thrombophlebitis, venous thrombosis limb, post thrombotic syndrome, venous thrombosis. 49 (13) 16 (4) 23 (6) 9 (2) Hypertension Hypertension includes hypertension, hypertensive crisis. 41 (11) 12 (3) 15 (4) 4 (1) 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% Blood and lymphatic system disorders: febrile neutropenia, lymphopenia Cardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, pericardial effusion Ear and labyrinth disorders: deafness, tinnitus Eye disorders: cataract, vision blurred Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache General disorders and administration site conditions: chills, infusion site reaction, multi-organ failure, pain Infections: clostridium difficile colitis, influenza, lung infection, rhinitis, sepsis, urinary tract infection, viral infection Metabolism and nutrition disorders: dehydration, hyperkalemia, hyperuricemia, hypoalbuminemia, hyponatremia, tumor lysis syndrome Musculoskeletal and connective tissue disorders: muscular weakness, myalgia Nervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia Psychiatric disorders: anxiety, delirium Renal and urinary disorders: renal failure, renal failure acute, renal impairment Respiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary embolism, pulmonary edema, pulmonary hemorrhage Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus Vascular disorders: deep vein thrombosis, hemorrhage, hypotension 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. Table 9 describes Grade 3–4 laboratory abnormalities reported in ASPIRE. Table 9: Grade 3–4 Laboratory Abnormalities (≥ 10%) in Cycles 1-12 in Patients Who Received KRd (20/27 mg/m 2 Regimen) in ASPIRE Laboratory Abnormality KRd (N = 392) n (%) Rd (N = 389) n (%) KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone Decreased lymphocytes 182 (46) 119 (31) Decreased absolute neutrophil count 152 (39) 141 (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) Increased glucose 53 (14) 30 (8) Decreased potassium 41 (11) 23 (6) Kyprolis in Combination with Dexamethasone The safety of Kyprolis in combination with dexamethasone was evaluated in two open-label, randomized trials (ENDEAVOR and A.R.R.O.W.). ENDEAVOR The safety of Kyprolis 20/56 mg/m 2 twice weekly in combination with dexamethasone (Kd) was evaluated in ENDEAVOR [see Clinical Studies (14.2) ] . Patients received treatment for a median duration of 48 weeks in the 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 reactions 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 arms, pneumonia was the most frequently 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 frequent adverse reaction leading to discontinuation was cardiac failure in the Kd arm (n = 8, 2%) and peripheral neuropathy in the Vd arm (n = 22, 5%). The incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm. 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: Adverse Reactions (≥ 10% ) Occurring in Months 1–6 in Patients Who Received Kd (20/56 mg/m 2 Regimen) in ENDEAVOR Adverse Reactions Kd (N = 463) n (%) Vd (N = 456) n (%) Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone Blood and Lymphatic System Disorders Anemia 161 (35) 57 (12) 112 (25) 43 (9) Thrombocytopenia Thrombocytopenia includes platelet count decreased and thrombocytopenia. 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 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 neuropathies Peripheral neuropathies includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. , See Clinical Studies (14.2) . 56 (12) 7 (2) 170 (37) 23 (5) Psychiatric Disorders Insomnia 105 (23) 5 (1) 116 (25) 10 (2) Respiratory, Thoracic and Mediastinal Disorders Dyspnea Dyspnea includes dyspnea and dyspnea exertional. 128 (28) 23 (5) 69 (15) 8 (2) Cough Cough includes cough and productive cough. 97 (21) 0 (0) 61 (13) 2 (0) Vascular Disorders Hypertension Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency. 83 (18) 30 (7) 33 (7) 12 (3) 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% Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy, thrombotic thrombocytopenic purpura Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, tachycardia Ear and labyrinth disorders: tinnitus Eye disorders: cataract, vision blurred Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia Immune system disorders: drug hypersensitivity Infections: bronchopneumonia, gastroenteritis, influenza, lung infection, nasopharyngitis, pneumonia, rhinitis, sepsis, urinary tract infection, viral infection Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome Musculoskeletal and connective tissue disorders: muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia Nervous system disorders: cerebrovascular accident, dizziness, hypoesthesia, paresthesia, posterior reversible encephalopathy syndrome Psychiatric disorders: anxiety Renal and urinary disorders: renal failure, renal failure acute, renal impairment Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary embolism, pulmonary edema, pulmonary hypertension, wheezing Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash Vascular disorders: deep vein thrombosis, flushing, hypotension Table 11 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the Kd arm. Table 11: Grade 3–4 Laboratory Abnormalities (≥ 10%) in Months 1–6 in Patients Who Received Kd (20/56 mg/m 2 Regimen) in ENDEAVOR Laboratory Abnormality Kd (N = 463) n (%) Vd (N = 456) n (%) Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone Decreased lymphocytes 249 (54) 180 (40) Increased 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 clearance Calculated using the Cockcroft-Gault formula. 65 (14) 49 (11) Increased potassium 55 (12) 21 (5) A.R.R.O.W. The safety of Kyprolis in combination with dexamethasone was evaluated in A.R.R.O.W. [see Clinical Studies (14.2) ] . Patients received treatment for a median duration of 38 weeks in the Kd 20/70 mg/m 2 arm once weekly and 29.1 weeks in the Kd 20/27 mg/m 2 twice weekly arm. The safety profile for the once weekly Kd 20/70 mg/m 2 regimen was similar to the twice weekly Kd 20/27 mg/m 2 regimen. Deaths due to adverse reactions within 30 days of last study treatment occurred in 22/238 (9%) patients in the Kd 20/70 mg/m 2 arm and 18/235 (8%) patients in the Kd 20/27 mg/m 2 arm. The most frequent fatal adverse reactions occurring in patients (%) in the two arms (once weekly Kd 20/70 mg/m 2 versus twice weekly Kd 20/27 mg/m 2 ) were sepsis 2 (< 1%) versus 2 (< 1%), septic shock 2 (< 1%) versus 1 (< 1%), and infection 2 (< 1%) versus 0 (0%). Serious adverse reactions were reported in 43% of the patients in the Kd 20/70 mg/m 2 arm and 41% of the patients in the Kd 20/27 mg/m 2 arm. In both arms, pneumonia was the most frequently reported serious adverse reaction (8% versus 7%). Discontinuation due to any adverse reaction occurred in 13% in the Kd 20/70 mg/m 2 arm versus 12% in the Kd 20/27 mg/m 2 arm. The most frequent adverse reaction leading to discontinuation was acute kidney injury (2% versus 2%). The incidence of cardiac failure events was 3.8% in the once weekly Kd 20/70 mg/m 2 arm versus 5.1% in the twice weekly Kd 20/27 mg/m 2 arm. Adverse reactions that occurred at a rate of 10% or greater in either Kd arm are presented in Table 12. Table 12: Adverse Reactions in Patients Who Received Kd (≥ 10% in either Kd Arm) in A.R.R.O.W. Adverse Reactions Once weekly Kd 20/70 mg/m 2 (N = 238) n (%) Twice weekly Kd 20/27 mg/m 2 (N = 235) n (%) Any Grade Grade ≥ 3 Any Grade Grade ≥ 3 Kd = Kyprolis and dexamethasone Blood and Lymphatic System Disorders Anemia Anemia includes anemia, hematocrit decreased, and hemoglobin decreased. 64 (27) 42 (18) 76 (32) 42 (18) Thrombocytopenia Thrombocytopenia includes platelet count decreased and thrombocytopenia. 53 (22) 26 (11) 41 (17) 27 (12) Neutropenia Neutropenia includes neutrophil count decreased and neutropenia. 30 (13) 21 (9) 27 (12) 17 (7) Gastrointestinal Disorders Diarrhea 44 (19) 2 (1) 47 (20) 3 (1) Nausea 34 (14) 1 (< 1) 26 (11) 2 (1) General Disorders and Administration Site Conditions Pyrexia 55 (23) 2 (1) 38 (16) 4 (2) Fatigue 48 (20) 11 (5) 47 (20) 5 (2) Asthenia 24 (10) 3 (1) 25 (11) 2 (1) Peripheral edema 18 (8) 0 (0) 25 (11) 2 (1) Infections Respiratory tract infection Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection, and viral upper respiratory tract infection. 70 (29) 7 (3) 79 (34) 7 (3) Pneumonia 28 (12) 24 (10) 20 (9) 16 (7) Bronchitis 27 (11) 2 (1) 25 (11) 5 (2) Musculoskeletal and Connective Tissue Disorders Back pain 28 (12) 2 (1) 28 (12) 4 (2) Nervous System Disorders Headache 25 (11) 1 (< 1) 23 (10) 1 (< 1) Psychiatric Disorders Insomnia 35 (15) 2 (1) 47 (20) 0 (0) Respiratory, Thoracic and Mediastinal Disorders Cough Cough includes cough and productive cough. 37 (16) 2 (1) 31 (13) 0 (0) Dyspnea Dyspnea includes dyspnea and dyspnea exertional. 28 (12) 1 (< 1) 26 (11) 2 (1) Vascular Disorders Hypertension Hypertension includes hypertension and hypertensive crisis. 51 (21) 13 (6) 48 (20) 12 (5) Adverse Reactions Occurring at a Frequency of < 10% Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, pericardial effusion, tachycardia Ear and labyrinth disorders: tinnitus Eye disorders: cataract, vision blurred Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, toothache, vomiting General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia Infections: clostridium difficile colitis, gastroenteritis, influenza, lung infection, nasopharyngitis, rhinitis, sepsis, septic shock, urinary tract infection, viral infection Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome Musculoskeletal and connective tissue disorders: muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia Nervous system disorders: cerebrovascular accident, dizziness, paresthesia, peripheral neuropathy Psychiatric disorders: anxiety, delirium Renal and urinary disorders: acute kidney injury, renal failure, renal impairment Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary hemorrhage, pulmonary embolism, pulmonary hypertension, pulmonary edema, wheezing Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash Vascular disorders: deep vein thrombosis, flushing, hypotension Kyprolis in Combination with Intravenous Daratumumab and Dexamethasone The safety of Kyprolis in combination with intravenous daratumumab and dexamethasone was evaluated in two trials (CANDOR and EQUULEUS). CANDOR The safety of Kyprolis 20/56 mg/m 2 twice weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in CANDOR [see Clinical Studies (14.3) ] . Patients received Kyprolis for a median duration of 58 weeks in the DKd arm and 40 weeks in the Kd arm. Serious adverse reactions were reported in 56% of the patients in the DKd arm and 46% of the patients in the Kd arm. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (14% versus 9%), pyrexia (4.2% versus 2.0%), influenza (3.9% versus 1.3%), sepsis (3.9% versus 1.3%), anemia (2.3% versus 0.7%), bronchitis (1.9% versus 0%) and diarrhea (1.6% versus 0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients in the DKd arm compared with 5% of 153 patients in the Kd arm. The most frequent fatal adverse reaction (DKd versus Kd) was infection 4.5% versus 2.6%. Permanent discontinuation due to an adverse reaction in patients who received Kyprolis occurred in 21% of patients in the DKd arm versus 22% in the Kd arm. The most frequent adverse reactions leading to discontinuation of Kyprolis were cardiac failure (1.9%) and fatigue (1.9%) in the DKd arm and cardiac failure (2.0%), hypertension (2.0%) and acute kidney injury (2.0%) in the Kd arm. Interruption of Kyprolis due to adverse reactions occurred in 71% of patients in DKd arm versus 63% in the Kd arm. Dose reduction of Kyprolis due to adverse reactions occurred in 25% of patients in DKd arm versus 20% in the Kd arm. Infusion-related reactions that occurred following the first Kyprolis dose was 13% in the DKd arm versus 1% in the Kd arm. Table 13 summarizes the adverse reactions in CANDOR. Table 13: Adverse Reactions (≥ 15%) in Patients Who Received either DKd or Kd (20/56 mg/m 2 Regimen) in CANDOR Adverse Reactions Twice weekly DKd (N = 308) Twice weekly Kd (N = 153) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone General Disorders and Administration Site Conditions Infusion-related reaction The incidence of infusion related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd or Kd administration. 41 12 28 5 Fatigue Fatigue includes fatigue and asthenia. 32 11 28 8 Pyrexia 20 1.9 15 0.7 Infections Respiratory tract infection Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 40 Includes fatal adverse reactions. 7 29 3.3 Pneumonia 18 13 12 9 Bronchitis 17 2.6 12 1.3 Blood and Lymphatic System Disorders Thrombocytopenia Thrombocytopenia includes platelet count decreased and thrombocytopenia. 37 25 30 16 Anemia Anemia includes anemia, hematocrit decreased and hemoglobin decreased. 33 17 31 14 Gastrointestinal Disorders Diarrhea 32 3.9 14 0.7 Nausea 18 0 13 0.7 Vascular Disorders Hypertension 31 18 28 13 Respiratory, Thoracic and Mediastinal Disorders Cough Cough includes productive cough and cough. 21 0 21 0 Dyspnea 20 3.9 22 2.6 Psychiatric Disorders Insomnia 18 3.9 11 2.0 Musculoskeletal and Connective Tissue Disorders Back pain 16 1.9 10 1.3 Adverse Reactions Occurring at a Frequency of < 15% Blood and lymphatic system disorders: febrile neutropenia, thrombotic thrombocytopenic purpura Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiomyopathy, myocardial infarction, myocardial ischemia, tachycardia Eye disorders: cataract Gastrointestinal disorders: abdominal pain, gastrointestinal hemorrhage General disorders and administration site conditions: chest pain, malaise Infections: gastroenteritis, influenza, lung infection, nasopharyngitis, sepsis, septic shock, urinary tract infection, viral infection Investigations: alanine aminotransferase increased, blood creatinine increased, C-reactive protein increased, ejection fraction decreased Metabolism and nutrition disorders: dehydration, hyperglycemia, hyperkalemia, hypokalemia, hyponatremia, tumor lysis syndrome Musculoskeletal and connective tissue disorders: pain in extremity Nervous system disorders: cerebrovascular accident, intracranial hemorrhage, posterior reversible encephalopathy syndrome, peripheral neuropathy Psychiatric disorders: anxiety Renal and urinary disorders: acute kidney injury, renal failure, renal impairment Respiratory, thoracic and mediastinal disorders: acute respiratory failure, epistaxis, interstitial lung disease, pneumonitis, pulmonary embolism, pulmonary hypertension, pulmonary edema Skin and subcutaneous tissue disorders: rash Vascular disorders: deep vein thrombosis, hypertensive crisis EQUULEUS The safety of Kyprolis 20/70 mg/m 2 once weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in EQUULEUS [see Clinical Studies (14.3) ] . Patients received Kyprolis for a median duration of 66 weeks. Serious adverse reactions were reported in 48% of patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%) and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression. Discontinuation of Kyprolis occurred in 19% of patients. The most frequent adverse reaction leading to discontinuation was asthenia (2%). Interruption of Kyprolis due to adverse reactions occurred in 77% of patients. Dose reduction of Kyprolis due to adverse reactions occurred in 31% of patients in DKd. Infusion-related reactions that occurred following the first Kyprolis dose was 11%. Pulmonary hypertension adverse reactions were reported in 4.7% of patients in EQUULEUS. Table 14 summarizes the adverse reactions in EQUULEUS. Table 14: Adverse Reactions (≥ 15%) in Patients Who Received DKd (20/70 mg/m 2 Regimen) in EQUULEUS Adverse Reactions Once weekly DKd (N = 85) All Grades (%) Grade 3 or 4 (%) DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone Blood and Lymphatic System Disorders Thrombocytopenia Thrombocytopenia includes platelet count decreased and thrombocytopenia. 68 32 Anemia Anemia includes anemia, hematocrit decreased and hemoglobin decreased. 52 21 Neutropenia Neutropenia includes neutrophil count decreased and neutropenia. 31 21 Lymphopenia Lymphopenia includes lymphocyte count decreased and lymphopenia. 29 25 General Disorders and Administration Site Conditions Fatigue Fatigue includes fatigue and asthenia. 54 18 Infusion-related reaction The incidence of infusion related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd administration. 53 12 Pyrexia 37 1.2 Infections Respiratory tract infection Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. 53 3.5 Bronchitis 19 0 Nasopharyngitis 18 0 Influenza 17 3.5 Gastrointestinal Disorders Nausea 42 1.2 Vomiting 40 1.2 Diarrhea 38 2.4 Constipation 17 0 Respiratory, Thoracic and Mediastinal Disorders Dyspnea 35 3.5 Cough Cough includes productive cough and cough. 33 0 Vascular Disorders Hypertension 33 20 Psychiatric Disorders Insomnia 33 4.7 Nervous System Disorders Headache 27 1.2 Musculoskeletal and Connective Tissue Disorders Back pain 25 0 Pain in extremity 15 0 Adverse Reactions Occurring at a Frequency of < 15% Blood and lymphatic system disorders: febrile neutropenia, thrombotic microangiopathy Cardiac disorders: cardiac failure, myocardial ischemia Gastrointestinal disorders: abdominal pain General disorders and administration site conditions: multiple organ dysfunction syndrome Infections: pneumonia, sepsis, septic shock Metabolism and nutrition disorders: dehydration, hypercalcemia Renal and urinary disorders: acute kidney injury, renal failure, renal impairment Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary hypertension Vascular disorders: hypotension Kyprolis in Combination with Subcutaneous Daratumumab and Dexamethasone The safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone was evaluated in PLEIADES [see Clinical Studies (14.3) ] . PLEIADES The safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone (DKd) was evaluated in a single-arm cohort of PLEIADES . Patients received Kyprolis as a 30-minute IV infusion once weekly for three weeks (Days 1, 8, and 15), followed by a 13-day rest period (Days 16 to 28) and continued until disease progression or unacceptable toxicity (N=66) in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Among these patients, 77% were exposed for 6 months or longer and 27% were exposed for greater than one year. Serious adverse reactions occurred in 27% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Fatal adverse reactions occurred in 3% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Permanent discontinuation of Kyprolis due to an adverse reaction occurred in 6% of patients who received Kyprolis. Dosage interruptions due to an adverse reaction occurred in 46% of patients who received Kyprolis. The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea and edema peripheral. Table 15 summarizes the adverse reactions in patients who received Kyprolis with subcutaneous daratumumab and dexamethasone (DKd) in PLEIADES. Table 15: Adverse Reactions (≥10%) in Patients Who Received Kyprolis with Subcutaneous Daratumumab and Dexamethasone (DKd) in PLEIADES Adverse Reaction DKd (N=66) All Grades (%) Grade ≥3 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection, viral pharyngitis, and viral upper respiratory tract infection. 52 0 Bronchitis Bronchitis includes bronchitis, and bronchitis viral. 12 2 Only Grade 3 adverse reactions occurred. General disorders and administration site conditions Fatigue Fatigue includes asthenia, and fatigue. 39 2 Pyrexia 21 2 Edema peripheral Edema peripheral includes generalized edema, edema peripheral, and peripheral swelling. 20 0 Psychiatric disorders Insomnia 33 6 Vascular disorders Hypertension Hypertension includes blood pressure increased, and hypertension. 32 21 Gastrointestinal disorders Diarrhea 29 0 Nausea 21 0 Vomiting 15 0 Respiratory, thoracic and mediastinal disorders Cough Cough includes cough, and productive cough. 24 0 Dyspnea Dyspnea includes dyspnea, and dyspnea exertional. 23 2 Nervous system disorders Headache 23 0 Peripheral sensory neuropathy 11 0 Musculoskeletal and connective tissue disorders Back pain 17 2 Musculoskeletal chest pain 11 0 Clinically relevant adverse reactions in 5% of patients who received Isa-Kd were pneumonia (25%) and upper respiratory tract infections (9%). Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients in the Isa-Kd group (those occurring in more than 1% of patients were pneumonia occurring in 1.7% and cardiac failure in 1.1% of patients). Permanent treatment discontinuation due to an adverse reaction (grades 1-4) occurred in 8% of patients who received Isa-Kd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Kd were infections (2.8%). Dosage interruptions due to an adverse reaction occurred in 4% of patients who received Kyprolis in the Isa-Kd group. The most frequent adverse reactions requiring dosage interruption in patients who received Kyprolis in the Isa-Kd group were administration site extravasation (1.1%) and infusion site extravasation (1.1%). Dose reductions or omissions of Kyprolis due to an adverse reaction in the Isa-Kd group occurred in 67% of patients. Adverse reactions which required dose reductions or omissions in >10% of patients who received Kyprolis in the Isa-Kd group were upper respiratory tract infection (12.4%) and hypertension (11.9%). The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough and back pain. Table 17 summarizes the adverse reactions in IKEMA. Table 17: Adverse Reactions (≥10%) in Patients Who Received Kyprolis with Isatuximab and Dexamethasone (Isa-Kd) in IKEMA Adverse Reactions Isa-Kd (N = 177) Kd (N = 122) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Isa-Kd = Kyprolis, isatuximab, and dexamethasone Infections Upper respiratory tract infection Upper respiratory tract infection includes acute sinusitis, chronic sinusitis, H1N1 influenza, H3N2 influenza, influenza, laryngitis, laryngitis viral, nasal herpes, nasopharyngitis, pharyngitis, pharyngotonsillitis, respiratory syncytial virus infection, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, tracheitis, upper respiratory tract infection, viral rhinitis, respiratory tract infection, respiratory tract infection viral, influenza like illness, parainfluenzae virus infection, respiratory tract infection bacterial, and viral upper respiratory tract infection. 67 9 57 7 Pneumonia Pneumonia includes atypical pneumonia, lower respiratory tract infection, lower respiratory tract infection viral, pneumocystis jirovecii pneumonia, pneumonia, pneumonia influenzal, pneumonia legionella, pneumonia pneumococcal, pneumonia respiratory syncytial viral, pneumonia streptococcal, pneumonia viral, pulmonary sepsis, and pulmonary tuberculosis. 36 22 30 18 Bronchitis Bronchitis includes bronchitis, bronchitis viral, respiratory syncytial virus bronchitis, bronchitis chronic, and tracheobronchitis. 24 2.3 13 0.8 General Disorders and Administration Site Conditions Infusion-related reaction Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and hypersensitivity. 46 0.6 3.3 0 Fatigue Fatigue includes fatigue and asthenia. 42 5 32 3.3 Vascular Disorders Hypertension Hypertension includes hypertension, blood pressure increased, and hypertensive crisis. 37 21 32 20 Gastrointestinal Disorders Diarrhea 36 2.8 29 2.5 Vomiting 15 1.1 9 0.8 Respiratory, Thoracic and Mediastinal Disorders Dyspnea Dyspnea includes dyspnea and dyspnea exertional. 29 5 24 0.8 Cough Cough includes cough, productive cough, and allergic cough. 23 0 15 0 Table 18 summarizes the laboratory abnormalities in patients who received Kyprolis with isatuximab and dexamethasone versus Kyprolis with dexamethasone in IKEMA. Table 18: Hematology Laboratory Abnormalities During the Treatment Period in Patients Who Received Isa-Kd versus Kd in IKEMA Laboratory Abnormality Isa-Kd Denominator is based on the safety population. (N=177) Kd (N=122) All Grades (%) Grades 3-4 (%) All Grades (%) Grades 3-4 (%) Hemoglobin decreased 99 22 99 20 Lymphocytes decreased 94 69 95 57 Platelets decreased 94 30 88 24 Neutrophils decreased 55 20 43 8 Kyprolis in Patients who Received Monotherapy The safety of Kyprolis 20/27 mg/m 2 as a 10-minute infusion was evaluated in clinical trials consisting of 598 patients with relapsed and/or refractory myeloma [see Clinical Studies (14.5) ] . 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). 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. Serious adverse reactions were reported in 50% of patients in the pooled Kyprolis monotherapy studies (N = 598). The most frequent 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 FOCUS, 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/m 2 by 30-minute infusion was evaluated in a multicenter, open-label study in patients with relapsed and/or refractory multiple myeloma [see Clinical Studies (14.5) ] . The patients received a median of 4 (range 1–10) prior regimens. Adverse reactions occurring with Kyprolis monotherapy are presented in Table 19. Table 19: Adverse Reactions (≥ 20%) with Kyprolis Monotherapy Adverse Reactions 20/56 mg/m 2 by 30-minute infusion (N = 24) 20/27 mg/m 2 by 2- to 10-minute infusion (N = 598) All Grades n (%) Grades 3-5 n (%) All Grades n (%) Grades 3-5 n (%) Fatigue 14 (58) 2 (8) 238 (40) 25 (4) Dyspnea Dyspnea includes dyspnea and dyspnea exertional. 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) Hypertension Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency. 10 (42) 3 (13) 90 (15) 22 (4) Chills 9 (38) 0 73 (12) 1 (< 1) Headache 8 (33) 0 141 (24) 7 (1) Cough Cough includes cough and productive cough. 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) Adverse Reactions Occurring at a Frequency 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. Table 20 describes Grade 3–4 laboratory abnormalities reported at a rate of > 10% for patients who received Kyprolis monotherapy. Table 20: Grade 3–4 Laboratory Abnormalities (> 10%) with Kyprolis Monotherapy Laboratory Abnormality Kyprolis 20/56 mg/m 2 (N = 24) Kyprolis 20/27 mg/m 2 (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 (13) 71 (12) Decreased sodium 2 (8) 69 (12) Decreased absolute neutrophil count 2 (8) 67 (11) 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Kyprolis. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: hemolytic uremic syndrome (HUS), hepatitis B virus reactivation, gastrointestinal perforation, pericarditis, and cytomegalovirus infection, including chorioretinitis, pneumonitis, enterocolitis, viremia, intestinal obstruction, and acute pancreatitis.

8 USE IN SPECIFIC POPULATIONS Geriatric Use : In the Kyprolis clinical trials, the incidence of adverse reactions was greater in patients ≥ 75 years of age. ( 8.5 ) Hepatic Impairment : Reduce the dose of Kyprolis by 25% in patients with mild or moderate hepatic impairment. ( 2.4 ) Patients on Hemodialysis : Administer Kyprolis after the hemodialysis procedure. ( 2.1 ) Lactation : Advise women not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Kyprolis can cause fetal harm based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] . There are no available data on Kyprolis use in pregnant women to evaluate for drug-associated risks. Kyprolis caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (see Data ) . Advise pregnant women of the potential risk 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. Data Animal 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. 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/m 2 based on BSA. 8.2 Lactation Risk Summary There are no data on the presence of Kyprolis in human milk, the effects on the breastfed child, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with Kyprolis and for 2 weeks after treatment. 8.3 Females and Males of Reproductive Potential Based on its mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Conduct pregnancy testing on females of reproductive potential prior to initiating Kyprolis treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for 6 months following the last dose. Males Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the last dose. Infertility Based on the mechanism of action, Kyprolis may have an effect on either male or female fertility [see Clinical Pharmacology (12.1) , Nonclinical Toxicology (13.1) ] . There are no data on the effect of Kyprolis on human fertility. 8.4 Pediatric Use The safety and effectiveness of Kyprolis in pediatric patients have not been established. The safety and effectiveness of Kyprolis in combination with chemotherapy was evaluated, but not established in an open label trial (Study 20140106; NCT02303821) in 124 patients aged 1 to younger than 17 years with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) who have received prior targeted B-cell immune therapy or relapsed or refractory T-cell ALL. No new safety signals were observed in these pediatric patients. The systemic exposure of carfilzomib in these pediatric patients was within range of that observed in adults given the same dose based on body surface area. 8.5 Geriatric Use Of the 2,837 patients with relapsed or refractory multiple myeloma exposed to Kyprolis in monotherapy and combination therapy studies [see Clinical Studies (14.1 , 14.2 , 14.3 , 14.4 , 14.5) ] , 50% were 65 years and older, while 13% were 75 years and older. The incidence of serious adverse reactions was 50% in patients < 65 years of age, 60% in patients 65 to 74 years of age, and 63% in patients ≥ 75 years of age. Of the 308 patients in CANDOR who received DKd, 47% of patients were 65 years and older, while 9% were 75 years and older. Fatal adverse reactions in the DKd arm of CANDOR occurred in 6% of patients ULN) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. A recommended dosage of Kyprolis has not been established for patients with severe hepatic impairment (total bilirubin > 3 × ULN and any AST) [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] . The incidence of serious adverse reactions 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%) [see Warnings and Precautions (5.12) , Clinical Pharmacology (12.3) ] .