Adverse reactions : תופעות לוואי

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)] 
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 1789 patients administered in combination with other drugs in ASPIRE, ENDEAVOR, A.R.R.O.W., and CANDOR. The most common adverse reactions occurring in at least 20% of patients who received Kyprolis in combination were anemia, diarrhea, fatigue, hypertension, pyrexia, upper respiratory tract infection, thrombocytopenia, cough, dyspnea, and insomnia.

Kyprolis in Combination with Lenalidomide and Dexamethasone

The safety of Kyprolis 20/27 mg/m2 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 11 summarizes the adverse reactions in the first 12 cycles in ASPIRE.

Table 11: Adverse Reactions (≥ 10%) Occurring in Cycles 1–12 in Patients Who Received KRd (20/27 mg/m2 Regimen) in ASPIRE

KRd                         Rd
(N = 392)                  (N = 389)
n (%)                      n (%)
Adverse Reactions              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) 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) 
KRd                                    Rd
(N = 392)                             (N = 389)
n (%)                                 n (%)
Adverse Reactions                  Any Grade         ≥ Grade 3       Any Grade          ≥ Grade 3 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: 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 12 describes Grade 3–4 laboratory abnormalities reported in ASPIRE.

Table 12: Grade 3–4 Laboratory Abnormalities (≥ 10%) in Cycles 1-12 in Patients Who Received KRd (20/27 mg/m2 Regimen) in ASPIRE

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) 

KRd                            Rd
(N = 392)                     (N = 389)
Laboratory Abnormality                             n (%)                         n (%) 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 

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/m2 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 13.

Table 13: Adverse Reactions (≥ 10%) Occurring in Months 1–6 in Patients Who Received Kd (20/56 mg/m2 Regimen) in ENDEAVOR

Kd                        Vd
(N = 463)                 (N = 456)
n (%)                     n (%)
Adverse Reactions                   Any Grade    Grade ≥ 3     Any Grade Grade ≥ 3 Blood and Lymphatic System Disorders
Anemia                                               161 (35)     57 (12)       112 (25)    43 (9) Thrombocytopeniaa                                    125 (27)     45 (10)       112 (25)    64 (14) Gastrointestinal Disorders
Diarrhea                                             117 (25)      14 (3)       149 (33)    27 (6) Nausea                                                70 (15)       4 (1)       68 (15)      3 (1) Constipation                                          60 (13)       1 (0)       113 (25)     6 (1) Vomiting                                              45 (10)       5 (1)        33 (7)      3 (1) General Disorders and Administration Site Conditions
Fatigue                                              116 (25)      14 (3)       126 (28)    25 (6) Pyrexia                                              102 (22)       9 (2)       52 (11)      3 (1) Asthenia                                              73 (16)       9 (2)       65 (14)     13 (3) Peripheral edema                                      62 (13)       3 (1)       62 (14)      3 (1) Infections
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                            Vd
(N = 463)                     (N = 456)
n (%)                         n (%)
Adverse Reactions                              Any Grade       Grade ≥ 3     Any Grade Grade ≥ 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: 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 14 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the Kd arm.

Table 14: Grade 3–4 Laboratory Abnormalities (≥ 10%)
in Months 1–6 in Patients Who Received Kd (20/56 mg/m2 Regimen) in ENDEAVOR 
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) a
Decreased creatinine clearance                    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.

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/m2 arm once weekly and 29.1 weeks in the Kd 20/27 mg/m2 twice weekly arm. 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 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/m2 arm versus 12% in the Kd 20/27 mg/m2 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/m2 arm versus 5.1% in the twice weekly Kd 20/27 mg/m2 arm.

Adverse reactions that occurred at a rate of 10% or greater in either Kd arm are presented in Table 15.

Table 15: Adverse Reactions in Patients Who Received Kd (≥ 10% in either Kd Arm) in A.R.R.O.W.

Once weekly Kd         Twice weekly Kd
20/70 mg/m2            20/27 mg/m2
(N = 238)               (N = 235)
n (%)                   n (%)
Adverse Reactions                    Any Grade   Grade ≥ 3   Any Grade Grade ≥ 3 Blood and Lymphatic System Disorders
Anemiaa                                              64 (27)     42 (18)     76 (32)    42 (18) b                                   53 (22)     26 (11)     41 (17)    27 (12) Thrombocytopenia
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) 
Once weekly Kd                  Twice weekly Kd
20/70 mg/m2                     20/27 mg/m2
(N = 238)                        (N = 235)
n (%)                            n (%)
Adverse Reactions                                  Any Grade        Grade ≥ 3       Any Grade Grade ≥ 3 Asthenia                                                               24 (10)           3 (1)         25 (11)           2 (1) Peripheral edema                                                       18 (8)            0 (0)         25 (11)           2 (1) Infections
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) Dyspneaf                                                              28 (12)          1 (< 1)         26 (11)           2 (1) 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: 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/m2 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 16 summarizes the adverse reactions in CANDOR.


Table 16: Adverse Reactions (≥ 15%) in Patients Who Received either DKd or Kd (20/56 mg/m2 Regimen) in CANDOR

Twice weekly DKd                   Twice weekly Kd
(N = 308)                         (N = 153)

All Grades       Grade 3 or       All Grades Grade 3 or 4
(%)            4 (%)              (%)       (%)
Adverse Reactions
General Disorders and Administration Site Conditions
Infusion-related reactiona                                41               12               28                5 Fatigueb                                                  32               11               28                8 Pyrexia                                                   20               1.9              15               0.7 Infections
Respiratory tract infectionc                              40g               7               29               3.3 Pneumonia                                                 18g              13               12                9 Bronchitis                                                17               2.6              12               1.3 Blood and lymphatic system disorders
Thrombocytopeniad                                         37               25               30               16 Anemiae                                                   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
Coughf                                                    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 DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone a 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, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd or Kd administration.
b
Fatigue includes fatigue and asthenia.
c
Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection.

d Thrombocytopenia    includes platelet count decreased and thrombocytopenia.
e Anemia  includes anemia, hematocrit decreased and hemoglobin decreased.
f Cough includes productive cough and cough.

g
Includes fatal adverse reactions.
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/m2 once weekly in combination with 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 17 summarizes the adverse reactions in EQUULEUS.
Table 17: Adverse Reactions (≥ 15%) in Patients Who Received DKd (20/70 mg/m2 Regimen) in EQUULEUS

Once weekly DKd
(N = 85)
All Grades         Grade 3 or 4
Adverse Reactions                        (%)               (%)
Blood and Lymphatic System Disorders
Thrombocytopeniaa                                          68                     32 Anemiab                                                    52                     21 c
Neutropenia                                                31                     21 Lymphopeniad                                               29                     25 

Once weekly DKd
(N = 85)
All Grades               Grade 3 or 4
Adverse Reactions                                        (%)                     (%) General Disorders and Administration Site Conditions
Fatiguee                                                                        54                       18 f
Infusion-related reaction                                                       53                       12 Pyrexia                                                                         37                       1.2 Infections
Respiratory tract infectiong                                                    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 h
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 DKd = Kyprolis, daratumumab, and dexamethasone; Kd = Kyprolis and dexamethasone a Thrombocytopenia includes platelet count decreased and thrombocytopenia.

b Anemia includes anemia, hematocrit decreased and hemoglobin decreased.

c Neutropenia includes neutrophil count decreased and neutropenia.
d Lymphopenia includes lymphocyte count decreased and lymphopenia

e Fatigue includes fatigue and asthenia.
f 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, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd administration.
g Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection.
h
Cough includes productive cough and cough.

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 Patients who Received Monotherapy

The safety of Kyprolis 20/27 mg/m2 as a 10-minute infusion was evaluated in clinical trials consisting of 598 patients with relapsed and/or refractory myeloma [see Clinical Studies (14.2)]. 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/m2 by 30-minute infusion was evaluated in a multicenter, open-label study in patients with relapsed and/or refractory multiple myeloma [see Clinical Studies (14.4)]. The patients received a median of 4 (range 1–10) prior regimens.

Adverse reactions occurring with Kyprolis monotherapy are presented in Table 18.

Table 18: 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)
All Grades       Grades 3-5   All Grades       Grades 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) Coughc                                8 (33)             0          134 (22)        2 (< 1) Vomiting                              8 (33)             0          104 (17)         4 (1) Lymphopenia                           8 (33)          8 (33)        85 (14)         73 (12) Insomnia                              7 (29)             0          75 (13)              0 Dizziness                             7 (29)             0          64 (11)          5 (1) Diarrhea                              6 (25)           1 (4)        160 (27)         8 (1) Blood creatinine increased            6 (25)           1 (4)        103 (17)        15 (3) Peripheral edema                      5 (21)             0          118 (20)        1 (< 1) 
20/56 mg/m2                             20/27 mg/m2
by 30-minute infusion               by 2- to 10-minute infusion
(N = 24)                                (N = 598)
All Grades      Grades 3-5             All Grades       Grades 3-5
Adverse Reactions                      n (%)            n (%)                 n (%)             n (%) 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: 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.

Table 19 describes Grade 3–4 laboratory abnormalities reported at a rate of > 10% for patients who received Kyprolis monotherapy.

Table 19: 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 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.

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 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.

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 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 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) and 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 the 2387 patients in clinical studies of Kyprolis, 51% were 65 years and older, while 14% were 75 years and older. The incidence of serious adverse reactions was 49% in patients < 65 years of age, 58% 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 <65 years of age, 14% of patients between 65 to 74 years of age, and 14% of patients ≥ 75 years of age [see Adverse Reactions (6.1)]. 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. 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) and 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)].