The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see WARNINGS AND PRECAUTIONS]
- Pulmonary Hypertension [see WARNINGS AND PRECAUTIONS]
- Pulmonary Complications [see WARNINGS AND PRECAUTIONS]
- Infusion Reactions [see WARNINGS AND PRECAUTIONS]
- Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
- Thrombocytopenia [see WARNINGS AND PRECAUTIONS]
- Hepatic Toxicity and Hepatic Failure [see WARNINGS AND PRECAUTIONS]
The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.
Clinical Trials Safety 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.
A total of 526 patients with relapsed and/or refractory multiple myeloma received KYPROLIS as monotherapy or with pre-dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg.
Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, cardiac disorder), end-organ failure in 4 patients (multi-organ failure, hepatic failure, renal failure), infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes.
Serious adverse reactions were reported in 45% patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each).
Adverse reactions occurring at a rate of 10% or greater are presented in Table 4.
Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated with KYPROLIS
| Event | Patients (N = 526) [n (%)] | ||
| All Gradesa | Grade 3 Events | Grade 4 Events | |
| Fatigue | 292 (55.5) | 38 (7.2) | 2 (0.4) |
| Anemia | 246 (46.8) | 111 (21.1) | 7 (1.3) |
| Nausea | 236 (44.9) | 7 (1.3) | 0 |
| Thrombocytopenia | 191 (36.3) | 69 (13.1) | 54 (10.3) |
| Dyspnea | 182 (34.6) | 25 (4.8) | 1 (0.2)b |
| Diarrhea | 172 (32.7) | 4 (0.8) | 1 (0.2) |
| Pyrexia | 160 (30.4) | 7 (1.3) | 2 (0.4) |
| Upper respiratory tract infection | 149 (28.3) | 17 (3.2) | 0 |
| Headache | 145 (27.6) | 7 (1.3) | 0 |
| Cough | 137 (26.0) | 1 (0.2) | 0 |
| Blood creatinine increased | 127 (24.1) | 13 (2.5) | 1 (0.2) |
| Lymphopenia | 126 (24.0) | 84 (16.0) | 11 (2.1) |
| Edema peripheral | 126 (24.0) | 3 (0.6) | 0 |
| Vomiting | 117 (22.2) | 5 (1.0) | 0 |
| Constipation | 110 (20.9) | 1 (0.2) | 0 |
| Neutropenia | 109 (20.7) | 50 (9.5) | 4 (0.8) |
| Back pain | 106 (20.2) | 15 (2.9) | 0 |
| Insomnia | 94 (17.9) | 0 | 0 |
| Chills | 84 (16.0) | 1 (0.2) | 0 |
| Arthralgia | 83 (15.8) | 7 (1.3) | 0 |
| Muscle spasms | 76 (14.4) | 2 (0.4) | 0 |
| Hypertension | 75 (14.3) | 15 (2.9) | 2 (0.4) |
| Asthenia | 73 (13.9) | 12 (2.3) | 1 (0.2) |
| Hypokalemia | 72 (13.7) | 14 (2.7) | 3 (0.6) |
| Hypomagnesemia | 71 (13.5) | 2 (0.4) | 0 |
| Leukopenia | 71 (13.5) | 27 (5.1) | 1 (0.2) |
| Pain in extremity | 70 (13.3) | 7 (1.3) | 0 |
| Pneumonia | 67 (12.7) | 52 (9.9) | 3 (0.6)b |
| Aspartate aminotransferase increased | 66 (12.5) | 15 (2.9) | 1 (0.2) |
| Dizziness | 66 (12.5) | 5 (1.0) | 1 (0.2) |
| Hypoesthesia | 64 (12.2) | 3 (0.6) | 0 |
| Anorexia | 63 (12.0) | 1 (0.2) | 0 |
| Pain | 63 (12.0) | 12 (2.3) | 1 (0.2) |
| Hyperglycemia | 62 (11.8) | 16 (3.0) | 3 (0.6) |
| Chest wall pain | 60 (11.4) | 3 (0.6) | 0 |
| Hypercalcemia | 58 (11.0) | 13 (2.5) | 8 (1.5) |
| Hypophosphatemia | 55 (10.5) | 24 (4.6) | 3 (0.6) |
| Hyponatremia | 54 (10.3) | 31 (5.9) | 3 (0.6) |
| aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0 bOne event was Grade 5 severity. |
|||
Description of Selected Adverse Drug Reactions
Renal Events
The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function [see DOSAGE AND ADMINISTRATION].
Peripheral Neuropathy
Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see DOSAGE AND ADMINISTRATION].
Herpes Virus Infection
Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection.