Kyprolis Drug Information

Relapsed or Refractory Multiple Myeloma Kyprolis is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with: Lenalidomide and dexamethasone; or Dexamethasone; or Daratumumab and dexamethasone; or Daratumumab and hyaluronidase-fihj and dexamethasone; or Isatuximab and dexamethasone. Kyprolis is indicated as a single agent for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

Administration Precautions Hydration

Adequate hydration is required prior to dosing in Cycle 1, especially in patients at high-risk of tumor lysis syndrome (TLS) or renal toxicity. If needed, give an additional 250 mL to 500 mL of intravenous fluids following Kyprolis administration. Continue oral and/or intravenous hydration, as needed, in subsequent cycles.

Monitor patients for evidence of volume overload and adjust hydration to individual patient needs, especially in patients with or at risk for cardiac failure. Electrolyte Monitoring Monitor serum potassium levels regularly during treatment with Kyprolis. Premedications and Concomitant Medications Premedicate with the recommended dose of dexamethasone for monotherapy or dexamethasone administered as part of the combination therapy.

Administer dexamethasone orally or intravenously at least 30 minutes but no more than 4 hours prior to all doses of Kyprolis during Cycle 1 to reduce the incidence and severity of infusion-related reactions. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles. Provide thromboprophylaxis for patients being treated with Kyprolis in combination with other therapies.

Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation. Dose Calculation For patients with body surface area (BSA) of 2.2 m 2 or less, calculate the Kyprolis dose using actual BSA. Dose adjustments do not need to be made for weight changes of 20% or less.

For dosage instructions of combination agents with Kyprolis, see Clinical Studies sections 14.2 (Kd) and 14.3 (DKd). Refer to the Prescribing Information for dexamethasone, intravenous daratumumab, and subcutaneous daratumumab and hyaluronidase-fihj for additional dosage information. Table 1: Kyprolis (30-minute infusion) Kyprolis twice weekly 20/56 mg/m 2 administered as monotherapy or in combination with dexamethasone (Kd), daratumumab plus dexamethasone (DKd), daratumumab and hyaluronidase-fihj plus dexamethasone (DKd), or isatuximab plus dexamethasone (Isa-Kd).

Administer Kyprolis intravenously as a 30-minute infusion on Days of each 28-day cycle as shown in Table 2 until disease progression or unacceptable toxicity. If given as monotherapy, administer 8 mg dexamethasone orally or intravenously 30 minutes to 4 hours before Kyprolis then as needed to minimize infusion-related reactions. Kyprolis given as monotherapy may be omitted on Days 8 and 9 of cycle 13 onward.

Table 2: Kyprolis (10-minute infusion) Kyprolis twice weekly 20/27 mg/m 2 is administered as monotherapy or in combination with lenalidomide and dexamethasone (KRd). Administer Kyprolis intravenously as a 10-minute infusion. In Cycles 1 through 12, administer Kyprolis on Days of each 28-day cycle as shown in Table 3.

From Cycle 13, administer Kyprolis on Days of each 28-day cycle. Continue Kyprolis with the regimens shown in Table 3 until disease progression or unacceptable toxicity occurs. When combined with lenalidomide and dexamethasone, discontinue Kyprolis after Cycle 18 and continue lenalidomide and dexamethasone until disease progression or unacceptable toxicity occurs.

For dosage instructions of combination agents with Kyprolis, see Clinical Studies sections 14.1 (KRd) and 14.5 (Monotherapy). Table 3: Kyprolis Modifications for Adverse Reactions Recommended actions and dosage modifications for Kyprolis are presented in Table 4. Dose level reductions are presented in Table 5.

See the lenalidomide, intravenous daratumumab, subcutaneous daratumumab and hyaluronidase-fihj, isatuximab, and dexamethasone Prescribing Information respectively for recommended dosage modifications associated with each product. Table 4: Dosage Modifications for Adverse Reactions See Table 10 for dose level reductions. Modifications for Hepatic Impairment For 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, reduce the dose of Kyprolis by 25%.

Recommended Dosage for End Stage Renal Disease

For patients with end stage renal disease who are on hemodialysis, administer Kyprolis after the hemodialysis procedure.

Preparation and Administration

Kyprolis vials contain no antimicrobial preservatives and are intended for single-dose only. The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Reconstitution/Preparation Steps: Remove vial from refrigerator just prior to use. Calculate the dose (mg/m 2 ) and number of vials of Kyprolis required using the patient's BSA at baseline.

Aseptically reconstitute each Kyprolis vial only with Sterile Water for Injection, USP using the volumes described in Table 6. Use a 21-gauge or larger needle (0.8 mm or smaller external diameter needle) to reconstitute each vial by slowly injecting Sterile Water for Injection through the stopper and directing the Sterile Water for Injection onto the INSIDE WALL OF THE VIAL to minimize foaming. There is no data to support the use of closed system transfer devices with Kyprolis.

Table 6: Reconstitution Volumes Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow the solution to settle in the vial until foaming subsides (approximately 5 minutes) and the solution is clear.

The reconstituted product should be a clear, colorless solution and should not be administered if any discoloration or particulate matter is observed. Discard any unused portion left in the vial. DO NOT pool unused portions from the vials.

DO NOT administer more than one dose from a vial. Administer Kyprolis directly by intravenous infusion or in a 50 mL to 100 mL intravenous bag containing 5% Dextrose Injection. Do not administer as an intravenous push or bolus.

When administering in an intravenous bag, use a 21-gauge or larger gauge needle (0.8 mm or smaller external diameter needle) to withdraw the calculated dose from the vial and dilute into 50 mL or 100 mL intravenous bag containing only 5% Dextrose Injection (based on the calculated total dose and infusion time). Flush the intravenous administration line with 0.9% Sodium Chloride Injection or 5% Dextrose Injection immediately before and after Kyprolis administration. Do not mix Kyprolis with or administer as an infusion with other medicinal products.

The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 7. Table 7: Stability of Reconstituted Kyprolis Figure

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the Warnings and Precautions reflect exposure to Kyprolis in 2,239 patients administered in combination with other drugs in ASPIRE, ENDEAVOR, A.R.R.O.W., CANDOR, IKEMA, EQUULEUS, and PLEIADES. The most common adverse reactions occurring in at least 20% of patients who received Kyprolis in combination were anemia, diarrhea, hypertension, fatigue, upper respiratory tract infection, thrombocytopenia, pyrexia, cough, dyspnea, and insomnia.

Kyprolis in Combination with Lenalidomide and Dexamethasone The safety of Kyprolis 20/27 mg/m 2 twice weekly in combination with lenalidomide and dexamethasone (KRd) was evaluated in ASPIRE. The median number of cycles initiated was 22 cycles for the KRd arm and 14 cycles for the Rd arm. Serious adverse reactions were reported in 65% of the patients in the KRd arm and 57% of the patients in the Rd arm.

Discontinuation due to any adverse reaction occurred in 33% in the KRd arm versus 30% in the Rd arm. The incidence of cardiac failure events was 7% in the KRd arm versus 4% in the Rd arm. There were no new clinically relevant adverse reactions that emerged in the later treatment cycles.

Adverse Reactions Occurring at a Frequency of < 10% Blood and lymphatic system disorders: febrile neutropenia, lymphopenia Cardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, pericardial effusion Ear and labyrinth disorders: deafness, tinnitus Eye disorders: cataract, vision blurred Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache General disorders and administration site conditions: chills, infusion site reaction, multi-organ failure, pain Infections: clostridium difficile colitis, influenza, lung infection, rhinitis, sepsis, urinary tract infection, viral infection Metabolism and nutrition disorders: dehydration, hyperkalemia, hyperuricemia, hypoalbuminemia, hyponatremia, tumor lysis syndrome Musculoskeletal and connective tissue disorders: muscular weakness, myalgia Nervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia Psychiatric disorders: anxiety, delirium Renal and urinary disorders: renal failure, renal failure acute, renal impairment Respiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary embolism, pulmonary edema, pulmonary hemorrhage Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus Vascular disorders: deep vein thrombosis, hemorrhage, hypotension Grade 3 and higher adverse reactions that occurred during Cycles 1–12 with a substantial difference (≥ 2%) between the two arms were neutropenia, thrombocytopenia, hypokalemia, and hypophosphatemia. Table 9 describes Grade 3–4 laboratory abnormalities reported in ASPIRE. Table 9: Grade 3–4 Laboratory Abnormalities ≥ Kyprolis in Combination with Dexamethasone The safety of Kyprolis in combination with dexamethasone was evaluated in two open-label, randomized trials (ENDEAVOR and A.R.R.O.W.).

ENDEAVOR The safety of Kyprolis 20/56 mg/m 2 twice weekly in combination with dexamethasone (Kd) was evaluated in ENDEAVOR. Patients received treatment for a median duration of 48 weeks in the Kd arm and 27 weeks in the bortezomib/dexamethasone (Vd) arm. 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 incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm.

Adverse reactions in the first 6 months of therapy that occurred at a rate of 10% or greater in the Kd arm are presented in Table 10. Table 10: Adverse Reactions (≥ 10% ) Occurring in Months 1–6 in Patients Who Received Kd The event rate of ≥ Grade 2 peripheral neuropathy in the Kd arm was 7% % Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy, thrombotic thrombocytopenic purpura Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, tachycardia Ear and labyrinth disorders: tinnitus Eye disorders: cataract, vision blurred Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia Immune system disorders: drug hypersensitivity Infections: bronchopneumonia, gastroenteritis, influenza, lung infection, nasopharyngitis, pneumonia, rhinitis, sepsis, urinary tract infection, viral infection Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome Musculoskeletal and connective tissue disorders: muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia Nervous system disorders: cerebrovascular accident, dizziness, hypoesthesia, paresthesia, posterior reversible encephalopathy syndrome Psychiatric disorders: anxiety Renal and urinary disorders: renal failure, renal failure acute, renal impairment Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary embolism, pulmonary edema, pulmonary hypertension, wheezing Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash Vascular disorders: deep vein thrombosis, flushing, hypotension Table 11 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥ 10% in the Kd arm. The most frequent adverse reaction leading to discontinuation was acute kidney injury (2% versus 2%).

Adverse reactions that occurred at a rate of 10% or greater in either Kd arm are presented in Table % Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, pericardial effusion, tachycardia Ear and labyrinth disorders: tinnitus Eye disorders: cataract, vision blurred Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, toothache, vomiting General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia Infections: clostridium difficile colitis, gastroenteritis, influenza, lung infection, nasopharyngitis, rhinitis, sepsis, septic shock, urinary tract infection, viral infection Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome Musculoskeletal and connective tissue disorders: muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia Nervous system disorders: cerebrovascular accident, dizziness, paresthesia, peripheral neuropathy Psychiatric disorders: anxiety, delirium Renal and urinary disorders: acute kidney injury, renal failure, renal impairment Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary hemorrhage, pulmonary embolism, pulmonary hypertension, pulmonary edema, wheezing Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash Vascular disorders: deep vein thrombosis, flushing, hypotension Kyprolis in Combination with Intravenous Daratumumab and Dexamethasone The safety of Kyprolis in combination with intravenous daratumumab and dexamethasone was evaluated in two trials (CANDOR and EQUULEUS). CANDOR The safety of Kyprolis 20/56 mg/m 2 twice weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in CANDOR. 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 ( % versus 0%) and diarrhea (1.6% versus 0%). 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. Interruption of Kyprolis due to adverse reactions occurred in 71% of patients in DKd arm versus 63% in the Kd arm. Dose reduction of Kyprolis due to adverse reactions occurred in 25% of patients in DKd arm versus 20% in the Kd arm.

Infusion-related reactions that occurred following the first Kyprolis dose was 13% in the DKd arm versus 1% in the Kd arm. Table 13 summarizes the adverse reactions in CANDOR. Table 13: Adverse Reactions (≥ 15%) in Patients Who Received either DKd or Kd % Blood and lymphatic system disorders: febrile neutropenia, thrombotic thrombocytopenic purpura Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiomyopathy, myocardial infarction, myocardial ischemia, tachycardia Eye disorders: cataract Gastrointestinal disorders: abdominal pain, gastrointestinal hemorrhage General disorders and administration site conditions: chest pain, malaise Infections: gastroenteritis, influenza, lung infection, nasopharyngitis, sepsis, septic shock, urinary tract infection, viral infection Investigations: alanine aminotransferase increased, blood creatinine increased, C-reactive protein increased, ejection fraction decreased Metabolism and nutrition disorders: dehydration, hyperglycemia, hyperkalemia, hypokalemia, hyponatremia, tumor lysis syndrome Musculoskeletal and connective tissue disorders: pain in extremity Nervous system disorders: cerebrovascular accident, intracranial hemorrhage, posterior reversible encephalopathy syndrome, peripheral neuropathy Psychiatric disorders: anxiety Renal and urinary disorders: acute kidney injury, renal failure, renal impairment Respiratory, thoracic and mediastinal disorders: acute respiratory failure, epistaxis, interstitial lung disease, pneumonitis, pulmonary embolism, pulmonary hypertension, pulmonary edema Skin and subcutaneous tissue disorders: rash Vascular disorders: deep vein thrombosis, hypertensive crisis EQUULEUS The safety of Kyprolis 20/70 mg/m 2 once weekly in combination with intravenous daratumumab and dexamethasone (DKd) was evaluated in EQUULEUS.

Serious adverse reactions were reported in 48% of patients. 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.

Pulmonary hypertension adverse reactions were reported in 4.7% of patients in EQUULEUS. Table 14 summarizes the adverse reactions in EQUULEUS. Table % Blood and lymphatic system disorders: febrile neutropenia, thrombotic microangiopathy Cardiac disorders: cardiac failure, myocardial ischemia Gastrointestinal disorders: abdominal pain General disorders and administration site conditions: multiple organ dysfunction syndrome Infections: pneumonia, sepsis, septic shock Metabolism and nutrition disorders: dehydration, hypercalcemia Renal and urinary disorders: acute kidney injury, renal failure, renal impairment Respiratory, thoracic and mediastinal disorders: pulmonary embolism, pulmonary hypertension Vascular disorders: hypotension Kyprolis in Combination with Subcutaneous Daratumumab and Dexamethasone The safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone was evaluated in PLEIADES.

PLEIADES The safety of Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone (DKd) was evaluated in a single-arm cohort of PLEIADES. Patients received Kyprolis as a 30-minute IV infusion once weekly for three weeks (Days 1, 8, and 15), followed by a 13-day rest period (Days 16 to 28) and continued until disease progression or unacceptable toxicity (N=66) in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Among these patients, 77% were exposed for 6 months or longer and 27% were exposed for greater than one year.

Serious adverse reactions occurred in 27% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Fatal adverse reactions occurred in 3% of patients who received Kyprolis in combination with daratumumab and hyaluronidase-fihj and dexamethasone. Dosage interruptions due to an adverse reaction occurred in 46% of patients who received Kyprolis.

The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, insomnia, hypertension, diarrhea, cough, dyspnea, headache, pyrexia, nausea and edema peripheral. Table 15 summarizes the adverse reactions in patients who received Kyprolis with subcutaneous daratumumab and dexamethasone (DKd) in PLEIADES. Table 16: Select Laboratory Abnormalities (≥30%) Worsening from Baseline in Patients Who Received DKd in PLEIADES 5 Kyprolis in Combination with Isatuximab and Dexamethasone The safety of Kyprolis in combination with isatuximab and dexamethasone was evaluated in IKEMA, a randomized, open-label clinical trial in patients with previously treated multiple myeloma.

Patients received Kyprolis 20/56 mg/m 2 twice weekly in combination with isatuximab and dexamethasone (Isa-Kd) (n=177) or Kyprolis and dexamethasone (Kd) (n=122). Among patients receiving Isa-Kd, the median exposure to Kyprolis was 65 weeks. Serious adverse reactions occurred in 59% of patients receiving Isa-Kd.

The most frequent serious adverse reactions in >5% of patients who received Isa-Kd were pneumonia (25%) and upper respiratory tract infections (9%). Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients in the Isa-Kd group (those occurring in more than 1% of patients were pneumonia occurring in 1.7% and cardiac failure in 1.1% of patients). Permanent treatment discontinuation due to an adverse reaction (grades 1-4) occurred in 8% of patients who received Isa-Kd.

The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Kd were infections (2.8%). The most frequent adverse reactions requiring dosage interruption in patients who received Kyprolis in the Isa-Kd group were administration site extravasation (1.1%) and infusion site extravasation (1.1%). Dose reductions or omissions of Kyprolis due to an adverse reaction in the Isa-Kd group occurred in 67% of patients.

Adverse reactions which required dose reductions or omissions in >10% of patients who received Kyprolis in the Isa-Kd group were upper respiratory tract infection (12.4%) and hypertension (11.9%). The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough and back pain. Table 17 summarizes the adverse reactions in IKEMA.

Table 18: Hematology Laboratory Abnormalities During the Treatment Period in Patients Who Received Isa-Kd versus Kd in IKEMA 8 Kyprolis in Patients who Received Monotherapy The safety of Kyprolis 20/27 mg/m 2 as a 10-minute infusion was evaluated in clinical trials consisting of 598 patients with relapsed and/or refractory myeloma. 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.

Serious adverse reactions were reported in 50% of patients in the pooled Kyprolis monotherapy studies (N = 598). In FOCUS, a randomized trial comparing Kyprolis as a single agent versus corticosteroids with optional oral cyclophosphamide for patients with relapsed and refractory multiple myeloma, mortality was higher in the patients treated with Kyprolis in comparison to the control arm in the subgroup of 48 patients ≥ 75 years of age. The most common cause of discontinuation due to an adverse reaction was acute renal failure (2%).

Safety of Kyprolis monotherapy dosed at 20/56 mg/m 2 by 30-minute infusion was evaluated in a multicenter, open-label study in patients with relapsed and/or refractory multiple myeloma. The patients received a median of 4 (range 1–10) prior regimens. Adverse reactions occurring with Kyprolis monotherapy are presented in Table % 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 20 describes Grade 3–4 laboratory abnormalities reported at a rate of > 10% for patients who received Kyprolis monotherapy. Table

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.

Pregnancy Risk Summary Kyprolis can cause fetal harm based on findings from animal studies and its mechanism of action. There are no available data on Kyprolis use in pregnant women to evaluate for drug-associated risks. Kyprolis caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (see Data ).

Advise pregnant women of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. Data Animal Data Carfilzomib administered intravenously to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day in rats and 0.8 mg/kg/day in rabbits.

In rabbits, there was an increase in pre-implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day.

Pediatric Use The safety and effectiveness of Kyprolis in pediatric patients have not been established. The safety and effectiveness of Kyprolis in combination with chemotherapy was evaluated, but not established in an open label trial (Study 20140106; NCT02303821) in 124 patients aged 1 to younger than 17 years with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) who have received prior targeted B-cell immune therapy or relapsed or refractory T-cell ALL. No new safety signals were observed in these pediatric patients.

The systemic exposure of carfilzomib in these pediatric patients was within range of that observed in adults given the same dose based on body surface area.

Acute onset of chills, hypotension, renal insufficiency, thrombocytopenia, and lymphopenia has been reported following a dose of 200 mg of Kyprolis administered in error. There is no known specific antidote for Kyprolis overdosage. In the event of overdose, monitor patients for adverse reactions and provide supportive care as appropriate.