July 25, 2016
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Kyprolis

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Kyprolis

Side Effects
Interactions

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

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 27/392 (7%) patients compared with 27/389 (7%) patients who died due to adverse events within 30 days of the last dose of any Rd therapy. The most common cause of deaths occurring in patients (%) in the two arms (KRd versus Rd) included cardiac 10 (3%) versus 7 (2%), infection 9 (2%) versus 10 (3%), renal 0 (0%) versus 1 ( < 1%), and other adverse reactions 9 (2%) versus 10 (3%). Serious adverse reactions were reported in 60% of the patients in the KRd arm and 54% of the patients in the Rd arm. The most common serious adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia (14% versus 11%), respiratory tract infection (4% versus 1.5%), pyrexia (4% versus 2%), and pulmonary embolism (3% versus 2%). Discontinuation due to any adverse reaction occurred in 26% in the KRd arm versus 25% in the Rd arm. Adverse reactions leading to discontinuation of Kyprolis occurred in 12% of patients and the most common reactions included pneumonia (1%), myocardial infarction (0.8%), and upper respiratory tract infection (0.8%).

Common Adverse Reactions ( ≥ 10%)

The adverse reactions in the first 12 cycles of therapy that occurred at a rate of 10% or greater in the KRd arm are presented in Table 8.

Table 8: Most Common Adverse Reactions ( ≥ 10% in the KRd Arm) Occurring in Cycles 1–12 (20/27 mg/m² Regimen In Combination with Lenalidomide and Dexamethasone)

Adverse Reactions by Body System KRd Arm
(N = 392) n (%)
Rd Arm
(N = 389) n (%)
Any Grade ≥ Grade 3 Any Grade ≥ Grade 3
Blood and Lymphatic System Disorders
  Anemia 138 (35) 53 (14) 127 (33) 47 (12)
  Neutropenia 124 (32) 104 (27) 115 (30) 89 (23)
  Thrombocytopenia 100 (26) 58 (15) 75 (19) 39 (10)
Gastrointestinal Disorders
  Diarrhea 115 (29) 7 (2) 105 (27) 12 (3)
  Constipation 68 (17) 0 53 (14) 1 (0)
  Nausea 60 (15) 1 (0) 39 (10) 3 (1)
General Disorders and Administration Site Conditions
  Fatigue 109 (28) 21 (5) 104 (27) 20 (5)
  Pyrexia 93 (24) 5 (1) 64 (17) 1 (0)
  Edema peripheral 63 (16) 2 (1) 57 (15) 2 (1)
  Asthenia 53 (14) 11 (3) 46 (12) 7 (2)
Infections and Infestations
  Upper respiratory tract infection 85 (22) 7 (2) 52 (13) 3 (1)
  Nasopharyngitis 63 (16) 0 43 (11) 0
  Bronchitis 54 (14) 5 (1) 39 (10) 2 (1)
  Pneumoniaa 54 (14) 35 (9) 43 (11) 27 (7)
Metabolism and Nutrition Disorders
  Hypokalemia 78 (20) 22 (6) 35 (9) 12 (3)
  Hypocalcemia 55 (14) 10 (3) 39 (10) 5 (1)
  Hyperglycemia 43 (11) 18 (5) 33 (9) 15 (4)
Musculoskeletal and Connective Tissue Disorders
  Muscle spasms 88 (22) 3 (1) 73 (19) 3 (1)
Nervous System Disorders
  Peripheral neuropathiesb 43 (11) 7 (2) 37 (10) 4 (1)
Psychiatric Disorders
  Insomnia 63 (16) 6 (2) 50 (13) 8 (2)
Respiratory, Thoracic, and Mediastinal Disorders
  Cough 85 (22) 1 (0) 46 (12) 0
  Dyspneac 70 (18) 9 (2) 58 (15) 6 (2)
Skin and Subcutaneous Tissue Disorders
  Rash 45 (12) 5 (1) 53 (14) 5 (1)
Vascular Disorders
  Embolic and thrombotic events venousd 49 (13) 16 (4) 22 (6) 9 (2)
  Hypertensione 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 Dyspnea includes dyspnea and dyspnea exertional.
d Embolic and thrombotic events, venous include deep vein thrombosis, pulmonary embolism, thrombophlebitis superficial, thrombophlebitis, venous thrombosis limb, post thrombotic syndrome, venous thrombosis.
e Hypertension includes hypertension, hypertensive crisis.

There were 274 (70%) patients in the KRd arm who received treatment beyond Cycle 12.

There were no new clinically relevant adverse reactions that emerged in the later treatment cycles.

Adverse Reactions Occurring At A Frequency of < 10%

Grade 3 and higher adverse reactions that occurred during Cycles 1–12 with a substantial difference ( ≥ 2%) between the two arms were neutropenia, thrombocytopenia, hypokalemia, and hypophosphatemia.

Laboratory Abnormalities

Table 9 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the KRd arm for patients who received combination therapy.

Table 9: Grade 3–4 Laboratory Abnormalities ( ≥ 10% in the KRd Arm) in Cycles 1–12 (20/27 mg/m² Regimen In Combination with Lenalidomide and Dexamethasone)

Laboratory Abnormality KRd
(N = 392)
n (%)
Rd
(N = 389)
n (%)
Decreased lymphocytes 182 (46) 119 (31)
Decreased absolute neutrophil count 152 (39) 140 (36)
Decreased phosphorus 122 (31) 106 (27)
Decreased platelets 101 (26) 59 (15)
Decreased total white blood cell count 97 (25) 71 (18)
Decreased hemoglobin 58 (15) 68 (18)
Decreased potassium 41 (11) 23 (6)
KRd = Kyprolis, lenalidomide, and dexamethasone; Rd = lenalidomide and dexamethasone

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

The safety of Kyprolis in combination with dexamethasone was evaluated in an open-label, randomized trial of patients with relapsed multiple myeloma. The study treatment is described in Section 14.2. Patients received treatment for a median duration of 40 weeks in the Kyprolis/dexamethasone (Kd) arm and 27 weeks in the bortezomib/dexamethasone (Vd) arm.

Deaths due to adverse reactions within 30 days of last study treatment occurred in 22/463 (5%) 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 7 (2%) versus 5 (1%), infections 5 (1%) versus 8 (2%), disease progression 6 (1%) versus 4 (1%), pulmonary 3 (1%) versus 2 ( < 1%), renal 1 ( < 1%) versus 0 (0%), and other adverse events 2 ( < 1%) versus 2 ( < 1%). Serious adverse reactions were reported in 48% of the patients in the Kd arm and 36% of the patients in the Vd arm. In both treatment arms, pneumonia was the most commonly reported serious adverse reaction (6% versus 9%). Discontinuation due to any adverse reaction occurred in 20% in the Kd arm versus 21% in the Vd arm. The most common reaction leading to discontinuation was cardiac failure in the Kd arm (n = 6, 1.3%) and peripheral neuropathy in the Vd arm (n = 19, 4.2%).

Common Adverse Reactions ( ≥ 10%)

Adverse reactions in the first 6 months of therapy that occurred at a rate of 10% or greater in the Kd arm are presented in Table 10.

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

Adverse Reaction by Body System Kd
(N = 463) n (%)
Vd
(N = 456) n (%)
Any Grade ≥ Grade 3 Any Grade ≥ Grade 3
Blood and Lymphatic System Disorders
  Anemia 160 (35) 57 (12) 112 (25) 43 (9)
  Thrombocytopeniaa 127 (27) 46 (10) 112 (25) 65 (14)
Gastrointestinal Disorders
  Diarrhea 111 (24) 14 (3) 150 (33) 26 (6)
  Nausea 69 (15) 4 (1) 66 (15) 3 (1)
  Constipation 58 (13) 1 (0) 109 (24) 6 (1)
  Vomiting 45 (10) 5 (1) 32 (7) 3 (1)
General Disorders and Administration Site Conditions
  Fatigue 112 (24) 13 (3) 124 (27) 25 (6)
  Pyrexia 102 (22) 9 (2) 52 (11) 3 (1)
  Peripheral edema 75 (16) 3 (1) 73 (16) 3 (1)
  Asthenia 71 (15) 9 (2) 66 (14) 13 (3)
Infections and Infestations
  Upper respiratory tract infection 66 (14) 4 (1) 54 (12) 3 (1)
  Bronchitis 54 (12) 5 (1) 26 (6) 2 (0)
  Nasopharyngitis 45 (10) 0 (0) 42 (9) 1 (0)
Musculoskeletal and Connective Tissue Disorders
  Muscle spasms 66 (14) 1 (0) 22 (5) 3 (1)
  Back pain 58 (13) 7 (2) 60 (13) 8 (2)
Nervous System Disorders
  Headache 68 (15) 4 (1) 38 (8) 2 (0)
  Peripheral neuropathiesb,c 54 (12) 7 (2) 167 (37) 23 (5)
Psychiatric Disorders
  Insomnia 103 (22) 5 (1) 113 (25) 10 (2)
Respiratory, Thoracic and Mediastinal Disorders
  Dyspnead 123 (27) 23 (5) 66 (15) 8 (2)
  Cough 77 (17) 0 (0) 55 (12) 1 (0)
Vascular Disorders
  Hypertensione 80 (17) 29 (6) 33 (7) 12 (3)
Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone
a Thrombocytopenia includes platelet count decreased and thrombocytopenia.
b Peripheral neuropathies include peripheral neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy.
c See Clinical Studies.
d Dyspnea includes dyspnea and dyspnea exertional.
e Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency.

The event rate of ≥ Grade 2 peripheral neuropathy in the Kd arm was 6% (95% CI: 4, 8) versus 32% (95% CI: 28, 36) 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
  • Eye disorders: cataract, vision blurred
  • Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, toothache
  • General disorders and administration site conditions: chest pain, chills, infusion site reactions (including inflammation, pain, and erythema), pain
  • Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia
  • Immune system disorders: drug hypersensitivity
  • Infections and infestations: bronchopneumonia, influenza, pneumonia, 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 11 describes Grades 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the Kd arm.

Table 11: Grades 3–4 Laboratory Abnormalities ( ≥ 10%) in Months 1–6 (20/56 mg/m² Regimen In Combination with Dexamethasone)

Laboratory Abnormality Kd
(N = 463)
n (%)
Vd
(N = 456)
n (%)
Decreased lymphocytes 248 (54) 180 (40)
Increase uric acid 243 (53) 198 (43)
Decreased hemoglobin 79 (17) 68 (15)
Decreased platelets 85 (18) 77 (17)
Decreased phosphorus 73 (16) 61 (13)
Decreased creatinine clearancea 65 (14) 49 (11)
Increased potassium 55 (12) 21 (5)
Kd = Kyprolis and dexamethasone; Vd = bortezomib and dexamethasone
a Calculated using the Cockcroft-Gault formula.

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, the incidence of serious adverse reactions was higher in those ≥ 65 years old and those ≥ 75 years old [see Geriatric Use].

Deaths due to adverse reactions within 30 days of the last dose of Kyprolis occurred in 30/598 (5%) patients receiving Kyprolis monotherapy. These adverse reactions were related to cardiac disorders in 10 (2%) patients, infections in 8 (1%) patients, renal disorders in 4 ( < 1%) patients, and other adverse reactions in 8 (1%) patients. In a randomized trial comparing Kyprolis as a single agent versus corticosteroids with optional oral cyclophosphamide for patients with relapsed and refractory multiple myeloma, mortality was higher in the patients treated with Kyprolis in comparison to the control arm in the subgroup of 48 patients ≥ 75 years of age. The most common cause of discontinuation due to an adverse reaction was acute renal failure (2%).

Safety of Kyprolis monotherapy dosed at 20/56 mg/m² by 30-minute infusion was evaluated in a multicenter, open-label study in patients with relapsed and/or refractory multiple myeloma. The study treatment is described in Section 14.3. The patients received a median of 4 (range 1–10) prior regimens.

The common adverse reactions occurring at a rate of 20% or greater with Kyprolis monotherapy are presented in Table 12.

Table 12: Most Common Adverse Reactions ( ≥ 20%) with Kyprolis Monotherapy

Adverse Reaction 20/56 mg/m² by 30-minute infusion
(N = 24)
20/27 mg/m² by 2- to 10-minute infusion
(N = 598)
Any Grade
n (%)
Grades 3 - 5
n (%)
Any Grade
n (%)
Grades 3 - 5
n (%)
Fatigue 14 (58) 2 (8) 238 (40) 25 (4)
Dyspneaa 14 (58) 2 (8) 202 (34) 21 (4)
Pyrexia 14 (58) 0 177 (30) 11 (2)
Thrombocytopenia 13 (54) 13 (54) 220 (37) 152 (25)
Nausea 13 (54) 0 211 (35) 7 (1)
Anemia 10 (42) 7 (29) 291 (49) 141 (24)
Hypertensionb 10 (42) 3 (13) 90 (15) 22 (4)
Chills 9 (38) 0 73 (12) 1 ( < 1)
Headache 8 (33) 0 141 (24) 7 (1)
Vomiting 8 (33) 0 104 (17) 4 (1)
Lymphopenia 8 (33) 8 (33) 85 (14) 73 (12)
Cough 7 (29) 0 120 (20) 2 ( < 1)
Insomnia 7 (29) 0 75 (13) 0
Dizziness 7 (29) 0 64 (11) 5 (1)
Diarrhea 6 (25) 1 (4) 160 (27) 8 (1)
Blood creatinine increased 6 (25) 1 (4) 103 (17) 15 (3)
Peripheral edema 5 (21) 0 118 (20) 1 ( < 1)
Back pain 5 (21) 1 (4) 115 (19) 19 (3)
Upper respiratory tract infection 5 (21) 1 (4) 112 (19) 15 (3)
Decreased appetite 5 (21) 0 89 (15) 2 ( < 1)
Muscle spasms 5 (21) 0 62 (10) 2 ( < 1)
Chest pain 5 (21) 0 20 (3) 1 ( < 1)
a Dyspnea includes preferred terms of dyspnea and dyspnea exertional.
b Hypertension includes hypertension, hypertensive crisis, and hypertensive emergency.

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
  • Eye disorders: cataract, blurred vision
  • Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, 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, pneumonia, nasopharyngitis, respiratory tract infection, 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, 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
  • Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash
  • Vascular disorders: embolic and thrombotic events, venous (including deep vein thrombosis and pulmonary embolism), 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 13 describes Grade 3–4 laboratory abnormalities reported at a rate of > 10% for patients who received Kyprolis monotherapy.

Table 13: Grade 3–4 Laboratory Abnormalities ( > 10%) with Kyprolis Monotherapy

Laboratory Abnormality Kyprolis 20/56 mg/m²
(N = 24)
Kyprolis 20/27 mg/m²
(N = 598)
Decreased lymphocytes 15 (63) 151 (25)
Decreased platelets 11 (46) 184 (31)
Decreased hemoglobin 7 (29) 132 (22)
Decreased total white blood cell count 3 (13) 71 (12)
Decreased sodium 2 (8) 69 (12)
Decreased absolute neutrophil count 2 (8) 67 (11)

Postmarketing Experience

The following additional adverse reactions were reported in the post-marketing 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.

Read the Kyprolis (carfilzomib) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs [see CLINICAL PHARMACOLOGY].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 6/7/2016

Side Effects
Interactions

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