Adverse reactions : תופעות לוואי

6     ADVERSE REACTIONS

The following clinically significant adverse reactions are discussed in greater detail in other sections of 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 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)]
•     Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients [see Warnings and Precautions (5.15)] 

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 medical practice.

Safety Experience with Kyprolis in Combination with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma

The safety of Kyprolis in combination with lenalidomide and dexamethasone (KRd) was evaluated in an open-label randomized study in patients with relapsed multiple myeloma.
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 45/392 (12%) patients compared with 42/389 (11%) 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 infection 12 (3%) versus 11 (3%), cardiac 10 (3%) versus 9 (2%), and other adverse reactions 23 (6%) versus 22 (6%). Serious adverse reactions were reported in 65% of the patients in the KRd arm and 57% of the patients in the Rd arm. The most common serious adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia (17% versus 13%), respiratory tract infection (4% versus 2%), pyrexia (4% versus 3%), and pulmonary embolism (3% versus 2%). In patients treated with Kyprolis, 47% were 65 and over and 11% were 75 years and over. The incidence of serious adverse events was 57% in patients < 65 years of age, 73% in patients 65 to 74 years of age, and 81% in patients ≥ 75 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].
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.

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 9.


Table 9: Most Common Adverse Reactions (≥ 10% in the KRd Arm)
Occurring in Cycles 1–12
2
(20/27 mg/m Regimen in Combination with Lenalidomide and Dexamethasone) 
KRd Arm                      Rd Arm
(N = 392)                   (N = 389) n (%)                       n (%)
Adverse Reactions by Body System        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                                    119 (30)          8 (2)    106 (27)       12 (3) 
KRd Arm                                Rd Arm
(N = 392)                             (N = 389) n (%)                                 n (%)
Adverse Reactions by Body System                   Any Grade         ≥ Grade 3       Any Grade          ≥ Grade 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 and Infestations
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) a
Pneumonia                                                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 neuropathiesb                                 43 (11)            7 (2)           39 (10)               4 (1) Psychiatric Disorders
Insomnia                                                 64 (16)            6 (2)           51 (13)               8 (2) Respiratory, Thoracic and Mediastinal Disorders
Coughc                                                   93 (24)            2 (1)           54 (14)               0 (0) d
Dyspnea                                                  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 eventse                           49 (13)           16 (4)            23 (6)               9 (2) f
Hypertension                                             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 includes 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%

•     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 and infestations: 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.

Laboratory Abnormalities

Table 10 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the KRd arm for patients who received combination therapy.

Table 10: Grade 3–4 Laboratory Abnormalities (≥ 10% in the KRd Arm) in Cycles 1-12
2
(20/27 mg/m Regimen in Combination with Lenalidomide and Dexamethasone) 
KRd                           Rd
(N = 392)                    (N = 389)
Laboratory Abnormality                              n (%)                        n (%) 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) KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone 

Safety Experience with Kyprolis in Combination with Dexamethasone in Patients with Multiple Myeloma

The safety of Kyprolis in combination with dexamethasone was evaluated in two open-label, randomized trials (ENDEAVOR and A.R.R.O.W.) [see Clinical Studies (14.2)].

ENDEAVOR evaluated patients with relapsed or refractory multiple myeloma. The study treatment is described in Section 14.2. Patients received treatment for a median duration of 48 weeks in the twice weekly Kyprolis/dexamethasone (Kd) 20/56 mg/m2 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%). In patients treated with Kyprolis, 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 69% in patients ≥ 75 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)]. 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%). The incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm.

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 11.

Table 11: Most Common Adverse Reactions (≥ 10% in the Kd Arm) Occurring in Months 1–6 (20/56 mg/m2 Regimen in Combination with Dexamethasone)

Kd                    Vd
(N = 463)             (N = 456) n (%)                 n (%)
Adverse Reactions by Body System            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) 
Kd                             Vd
(N = 463)                      (N = 456) n (%)                          n (%)
Adverse Reactions by Body System                        Any Grade ≥ Grade 3            Any Grade ≥ Grade 3 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 includes peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy.
c See Clinical Studies (14.2).
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%
•    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 and infestations: 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 
Laboratory Abnormalities

Table 12 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the Kd arm.

Table 12: Grade 3–4 Laboratory Abnormalities (≥ 10%) in Months 1–6 (20/56 mg/m2 Regimen in Combination with Dexamethasone) 
Kd                              Vd
(N = 463)                       (N = 456)
Laboratory Abnormality                   n (%)                           n (%) 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) 
Kd                       Vd
(N = 463)                (N = 456)
Laboratory Abnormality                          n (%)                    n (%) 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.


A.R.R.O.W. evaluated patients with relapsed and refractory multiple myeloma. The study treatment is described in Section 14.2. Patients received treatment for a median duration of 38 weeks in the once weekly Kd 20/70 mg/m2 arm and 29.1 weeks in the twice weekly Kd 20/27 mg/m2 arm of A.R.R.O.W.. The safety profile for the once weekly Kd 20/70 mg/m2 regimen was similar to the twice weekly Kd 20/27 mg/m2 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/m2 arm and 18/235 (8%) patients in the Kd 20/27 mg/m2 arm. The most frequent fatal adverse reactions occurring in patients (%) in the two arms (once weekly Kd 20/70 mg/m2 versus twice weekly Kd 20/27 mg/m2) 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/m2 arm and 41% of the patients in the Kd 20/27 mg/m2 arm. In both treatment arms, pneumonia was the most commonly reported serious adverse reaction (8% versus 7%). In patients treated with once weekly Kd 20/70 mg/m2, 57% were 65 and over and 19% were 75 and over. The incidence of serious adverse events was 37% in patients < 65 years of age, 50% in patients 65 to 74 years of age, and 44% in patients ≥ 75 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)]. Discontinuation due to any adverse reaction occurred in 13% in the Kd 20/70 mg/m2 arm versus 12% in the Kd 20/27 mg/m2 arm. The most common 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/m2 arm versus 5.1% in the twice weekly Kd 20/27 mg/m2 arm.

Common Adverse Reactions (≥ 10%)

Adverse reactions that occurred at a rate of 10% or greater in either Kd arm is presented in Table 13.

Table 13: Most Common Adverse Reactions (≥ 10% in either Kd Arm)

Once weekly Kd         Twice weekly Kd
20/70 mg/m2            20/27 mg/m2
(N = 238)               (N = 235) n (%)                   n (%)
Adverse Reactions by Body System          Any Grade   ≥ Grade 3   Any Grade ≥ Grade 3 Blood and Lymphatic System Disorders
Anemiaa                                              64 (27)     42 (18)     76 (32)    42 (18) Thrombocytopeniab                                    53 (22)     26 (11)     41 (17)    27 (12) Neutropeniac                                         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 and Infestations
Respiratory tract infectiond                         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
Coughe                                               37 (16)      2 (1)      31 (13)     0 (0) f                                         28 (12)     1 (< 1)     26 (11)     2 (1) Dyspnea


Once weekly Kd                  Twice weekly Kd
20/70 mg/m2                     20/27 mg/m2
(N = 238)                        (N = 235) n (%)                            n (%)
Adverse Reactions by Body System                          Any Grade         ≥ Grade 3       Any Grade ≥ Grade 3 Vascular Disorders
Hypertensiong                                                         51 (21)           13 (6)         48 (20)          12 (5) Kd = Kyprolis and dexamethasone a Anemia includes anemia, hematocrit decreased, and hemoglobin decreased.
 b Thrombocytopenia includes platelet count decreased and thrombocytopenia.
 c Neutropenia includes neutrophil count decreased and neutropenia.
d Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection,  and viral upper respiratory tract infection.
e Cough includes cough and productive cough.
 f Dyspnea includes dyspnea and dyspnea exertional.
g Hypertension includes hypertension and hypertensive crisis.



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 and infestations: 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 
Safety Experience with Kyprolis in Patients with Multiple Myeloma who Received Monotherapy

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, 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 [see Warnings and Precautions (5.1) and Use in Specific Populations (8.5)].

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 14.

Table 14: Most Common Adverse Reactions (≥ 20%) with Kyprolis Monotherapy 
20/56 mg/m2                        20/27 mg/m2 by 30-minute infusion          by 2- to 10-minute infusion
(N = 24)                           (N = 598)
Any Grade        Grade 3 - 5     Any Grade         Grade 3 - 5
Adverse Reactions          n (%)            n (%)           n (%)              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) Cough    c                              8 (33)             0            134 (22)           2 (< 1) 20/56 mg/m2                                  20/27 mg/m2 by 30-minute infusion                     by 2- to 10-minute infusion (N = 24)                                     (N = 598)
Any Grade        Grade 3 - 5                Any Grade         Grade 3 - 5 Adverse Reactions                         n (%)            n (%)                      n (%)              n (%) 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 dyspnea and dyspnea exertional.
b   Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency.
c   Cough includes cough and productive cough.

Adverse Reactions Occurring at a Frequency of < 20%
•     Blood and lymphatic system disorders: febrile neutropenia, leukopenia, neutropenia •     Cardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia
•     Ear and labyrinth disorders: tinnitus
•     Eye disorders: cataract, blurred vision
•     Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, gastrointestinal hemorrhage, toothache
•     General disorders and administration site conditions: asthenia, infusion site reaction, multi-organ failure, pain
•     Hepatobiliary disorders: hepatic failure
•     Infections and infestations: bronchitis, bronchopneumonia, influenza, lung infection, pneumonia, nasopharyngitis, respiratory tract infection, rhinitis, sepsis, urinary tract infection
•     Metabolism and nutrition disorders: hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome
•     Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, musculoskeletal chest pain, myalgia, pain in extremity
•     Nervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia, peripheral motor neuropathy, peripheral neuropathy, peripheral sensory neuropathy
•     Psychiatric disorders: anxiety
•     Renal and urinary disorders: acute renal failure, renal failure, renal impairment
•     Respiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary edema, pulmonary hemorrhage
•     Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash
•     Vascular disorders: embolic and thrombotic events, venous (including deep vein thrombosis and pulmonary embolism), hemorrhage, hypotension

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 Abnormalities

Table 15 describes Grade 3–4 laboratory abnormalities reported at a rate of > 10% for patients who received Kyprolis monotherapy.

Table 15: Grade 3–4 Laboratory Abnormalities (> 10%) with Kyprolis Monotherapy 
Kyprolis                  Kyprolis
20/56 mg/m2               20/27 mg/m2
Laboratory Abnormality                    (N = 24)                 (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 additional adverse reactions were reported in the postmarketing experience with 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), gastrointestinal perforation, pericarditis, and cytomegalovirus infection including chorioretinitis, pneumonitis, enterocolitis, and viremia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/ 
8     USE IN SPECIFIC POPULATIONS

8.1   Pregnancy
Risk Summary

Kyprolis can cause fetal harm based on findings from animal studies (see Data) and the drug’s mechanism of action [see Clinical Pharmacology (12.1)]. There are no studies with the use of Kyprolis in pregnant women to inform drug-associated risks of adverse developmental outcomes. Kyprolis caused embryo-fetal lethality in rabbits at doses lower than the clinical dose. Advise pregnant women of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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/m2 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 many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from Kyprolis is unknown, advise nursing 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 avoid pregnancy and use effective contraception during treatment with Kyprolis and for at least 6 months following the final dose.

Males

Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for at least 3 months following the final 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.
8.5     Geriatric Use

Of 1691 patients in clinical studies of Kyprolis, 50.4% were 65 and over, while 15.4% were 75 and over. The incidence of serious adverse events in patients 65 and over was higher than the incidence in younger patients. No overall differences in effectiveness were observed between older and younger patients.

8.6     Hepatic Impairment

Reduce the dose of Kyprolis by 25% in patients with mild (total bilirubin 1 to 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. Dosing recommendation cannot be made for patients with severe hepatic function [see Clinical Pharmacology (12.3)].

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%) [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)].