Kyprolis

Kyprolis

carfilzomib

Manufacturer:

Amgen

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Carfilzomib.
Description
Each 60 mg vial contains 60 mg of carfilzomib, 3000 mg sulfobutylether beta-cyclodextrin sodium, 57.7 mg citric acid, and sodium hydroxide for pH adjustment (target pH 3.5).
Carfilzomib is a modified tetrapeptidyl epoxide, isolated as the crystalline free base. The chemical name for carfilzomib is (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide.
Carfilzomib is a crystalline substance with a molecular weight of 719.9. The molecular formula is C40H57N5O7. Carfilzomib is practically insoluble in water and very slightly soluble in acidic conditions.
Kyprolis is a sterile, white to off-white lyophilized powder and is available as a single-dose 60 mg vial.
Action
Pharmacology: Mechanism of Action: Carfilzomib is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors.
Pharmacodynamics: Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like (CT-L) activity when measured in blood 1 hour after the first dose. Doses of carfilzomib ≥ 15 mg/m2 with or without lenalidomide and dexamethasone induced a ≥ 80% inhibition of the CT-L activity of the proteasome. In addition, carfilzomib, 20 mg/m2 intravenously as a single agent, resulted in a mean inhibition of the low molecular mass polypeptide 2 (LMP2) and multicatalytic endopeptidase complex-like 1 (MECL1) subunits of the proteasome ranging from 26% to 32% and 41% to 49%, respectively. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing.
Clinical Studies: In Combination with Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma: ASPIRE (NCT01080391): ASPIRE was a randomized, open-label, multicenter superiority trial which evaluated the combination of Kyprolis with lenalidomide and dexamethasone (KRd) versus lenalidomide and dexamethasone alone (Rd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 lines of therapy (A line of therapy is a planned course of treatment [including sequential induction, transplantation, consolidation, and/or maintenance] without an interruption for lack of efficacy, such as for relapse or progressive disease). Patients who had the following were excluded from the trial: refractory to bortezomib in the most recent regimen, refractory to lenalidomide and dexamethasone in the most recent regimen, not responding to any prior regimen, creatinine clearance < 50 mL/min, ALT/AST > 3.5 × ULN and bilirubin > 2 × ULN, New York Heart Association Class III to IV congestive heart failure, or myocardial infarction within the last 4 months. In the KRd arm, Kyprolis was evaluated at a starting dose of 20 mg/m2, which was increased to 27 mg/m2 on Cycle 1, Day 8 onward. Kyprolis was administered as a 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle for Cycle 1 through 12. Kyprolis was dosed on Days 1, 2, 15, and 16 of each 28-day cycle from Cycle 13 through 18. Dexamethasone 40 mg was administered orally or intravenously on Days 1, 8, 15 and 22 of each cycle. Lenalidomide was given 25 mg orally on Days 1 to 21 of each 28-day cycle. The Rd treatment arm had the same regimen for lenalidomide and dexamethasone as the KRd treatment arm. Kyprolis was administered for a maximum of 18 cycles unless discontinued early for disease progression or unacceptable toxicity. Lenalidomide and dexamethasone administration could continue until progression or unacceptable toxicity. Concurrent use of thromboprophylaxis and a proton pump inhibitor were required for both arms, and antiviral prophylaxis was required for the KRd arm.
The 792 patients in ASPIRE were randomized 1:1 to the KRd or Rd arm. The demographics and baseline characteristics were well-balanced between the two arms (see Table 1). Only 53% of the patients had testing for genetic mutations; a high-risk genetic mutation was identified for 12% of patients in the KRd arm and in 13% in the Rd arm. (See Table 1).

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Patients in the KRd arm demonstrated improved PFS compared with those in the Rd arm (HR = 0.69, with 2-sided P-value = 0.0001) as determined using standard International Myeloma Working Group (IMWG)/European Blood and Marrow Transplantation (EBMT) response criteria by an Independent Review Committee (IRC).
The median PFS was 26.3 months in the KRd arm versus 17.6 months in the Rd arm (see Table 2 and Figure 1).
A pre-planned overall survival (OS) analysis was performed after 246 deaths in the KRd arm and 267 deaths in the Rd arm. The median follow-up was approximately 67 months. A statistically significant advantage in OS was observed in patients in the KRd arm compared to patients in the Rd arm (see Table 2 and Figure 2). (See Table 2.)

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The median duration of response (DOR) was 28.6 months (95% CI: 24.9, 31.3) for the 345 patients achieving a response in the KRd arm and 21.2 months (95% CI: 16.7, 25.8) for the 264 patients achieving a response in the Rd arm. The median time to response was 1 month (range 1 to 14 months) in the KRd arm and 1 month (range 1 to 16 months) in the Rd arm. (See Figures 1 and 2).

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In Combination with Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma: ENDEAVOR (NCT01568866): ENDEAVOR was a randomized, open-label, multicenter superiority trial of Kyprolis plus dexamethasone (Kd) versus bortezomib plus dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma who had received 1 to 3 lines of therapy. A total of 929 patients were enrolled and randomized (464 in the Kd arm; 465 in the Vd arm). Randomization was stratified by prior proteasome inhibitor therapy (yes versus no), prior lines of therapy (1 versus 2 or 3), current International Staging System stage (1 versus 2 or 3), and planned route of bortezomib administration. Patients were excluded if they had less than PR to all prior regimens; creatinine clearance < 15 mL/min; hepatic transaminases ≥ 3 × ULN; or left-ventricular ejection fraction < 40% or other significant cardiac conditions. This trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 56 mg/m2 on Cycle 1, Day 8 onward. Kyprolis was administered twice weekly as a 30-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle. In the Vd arm, bortezomib was dosed at 1.3 mg/m2 intravenously or subcutaneously on Days 1, 4, 8, and 11 of a 21-day cycle, and dexamethasone 20 mg was administered orally or intravenously on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle.
Concurrent use of thromboprophylaxis was optional, and prophylaxis with an antiviral agent and proton pump inhibitor was required. Of the 465 patients in the Vd arm, 381 received bortezomib subcutaneously. Treatment continued until disease progression or unacceptable toxicity.
The demographics and baseline characteristics are summarized in Table 3. (See Table 3).

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The efficacy of Kyprolis was evaluated by PFS as determined by an IRC using IMWG response criteria. The trial showed a median PFS of 18.7 months in the Kd arm versus 9.4 months in the Vd arm (see Table 4 and Figure 3). (See Figure 3.)

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Other endpoints included OS and overall response rate (ORR).
A pre-planned OS analysis was performed after 189 deaths in the Kd arm and 209 deaths in the Vd arm. The median follow-up was approximately 37 months. A significantly longer OS was observed in patients in the Kd arm compared to patients in the Vd arm (HR = 0.79; 95% CI: 0.65, 0.96; P-value = 0.01) (see Table 4 and Figure 4).
ORR was 77% for patients in the Kd arm and 63% for patients in the Vd arm (see Table 4). (See Table 4 and Figure 4.)

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The median DOR in subjects achieving PR or better was 21.3 months (95% CI: 21.3, not estimable) in the Kd arm and 10.4 months (95% CI: 9.3, 13.8) in the Vd arm. The median time to response was 1 month (range < 1 to 8 months) in both arms.
A.R.R.O.W. (NCT02412878): A.R.R.O.W. was a randomized, open-label, multicenter superiority trial of Kyprolis plus dexamethasone (Kd) once-weekly (20/70 mg/m2) versus Kd twice-weekly (20/27 mg/m2) in patients with relapsed and refractory multiple myeloma who had received 2 to 3 prior lines of therapy. Patients were excluded if they had less than PR to at least one prior line; creatinine clearance < 30 mL/min; hepatic transaminases ≥ 3 × ULN; or left-ventricular ejection fraction < 40% or other significant cardiac conditions. A total of 478 patients were enrolled and randomized (240 in 20/70 mg/m2 arm; 238 in 20/27 mg/m2 arm). Randomization was stratified by current International Staging System stage (stage 1 versus stages 2 or 3), refractory to bortezomib treatment (yes versus no), and age (< 65 versus ≥ 65 years). Arm 1 of this trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 70 mg/m2 on Cycle 1, Day 8 onward. Arm 1 Kyprolis was administered once weekly as a 30-minute infusion on Days 1, 8 and 15, of each 28-day cycle. Arm 2 of this trial evaluated Kyprolis at a starting dose of 20 mg/m2, which was increased to 27 mg/m2 on Cycle 1, Day 8 onward. Arm 2 Kyprolis was administered twice weekly as a 10-minute infusion on Days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. In both regimens, dexamethasone 40 mg was administered orally or intravenously on Days 1, 8, 15 for all cycles and on Day 22 for cycles 1 to 9 only. Concurrent use of thromboprophylaxis was optional, prophylaxis with an antiviral agent was recommended, and prophylaxis with a proton pump inhibitor was required. Treatment continued until disease progression or unacceptable toxicity.
The demographics and baseline characteristics are summarized in Table 5. (See Table 5.)

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The efficacy of Kyprolis was evaluated by PFS using IMWG response criteria. The trial showed a median PFS of 11.2 months in the once weekly Kd 20/70 mg/m2 arm versus 7.6 months in the twice weekly Kd 20/27 mg/m2 arm (see Table 6 and Figure 5). (See Figure 5.)

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Other endpoints included ORR. ORR was 62.9% for patients in the Kd 20/70 mg/m2 once-weekly arm and 40.8% for patients in the Kd 20/27 mg/m2 twice-weekly arm (see Table 6).

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The median DOR in subjects achieving PR or better was 15 months (95% CI: 12.2, not estimable) in the Kd 20/70 mg/m2 arm and 13.8 months (95% CI: 9.5, not estimable) in the Kd 20/27 mg/m2 arm. The median time to response was 1.1 months in the Kd 20/70 mg/m2 arm and 1.9 months in the Kd 20/27 mg/m2 arm.
Kyprolis is not approved for twice-weekly 20/27 mg/m2 administration in combination with dexamethasone alone.
Kyprolis monotherapy in patients with relapsed and refractory multiple myeloma: Additional clinical experience has been generated with Kyprolis monotherapy in patients with relapsed and refractory multiple myeloma. Study PX-171-011 was an open-label randomised phase 3 study (N = 315; exposure to ≥ 3 prior therapies required). Patients enrolled to study PX-171-011 were more heavily pre-treated with lower organ and marrow function as compared to those enrolled in Study 1. PX-171-011 evaluated Kyprolis monotherapy versus a control arm (corticosteroids and cyclophosphamide). The study did not meet its primary efficacy endpoint of demonstrating superiority of Kyprolis monotherapy over the active control arm in overall survival (HR = 0.975 [95% CI: 0.760-1.249]). PX-171-003A1 was a single-arm phase 2 study (N = 266; exposure to ≥ 2 prior therapies required), which met its primary efficacy endpoint of IRC-assessed ORR (22.9%).
Pharmacokinetics: Carfilzomib at doses between 20 mg/m2 and 70 mg/m2 administered as a 30-minute infusion resulted in dose-dependent increases in maximum plasma concentrations (Cmax) and area under the curve over time to infinity (AUCinf) in patients with multiple myeloma. A dose-dependent increase in Cmax and AUCinf was also observed between carfilzomib 20 mg/m2 and 56 mg/m2 as a 2- to 10-minute infusion in patients with relapsed or refractory multiple myeloma. A 30-minute infusion resulted in a similar AUCinf, but 2- to 3-fold lower Cmax than that observed with a 2- to 10-minute infusion at the same dose. There was no evidence of carfilzomib accumulation following repeated administration of carfilzomib 70 mg/m2 as a 30-minute once weekly infusion or 15 and 20 mg/m2 as a 2- to 10-minute twice weekly infusion.
Table 7 lists the estimated mean average daily area under the curve in the first cycle (AUCC1,avg), average daily area under the curve at steady-state (AUCss) and Cmax at the highest dose in the first cycle (Cmax,C1) for the different dosing regimens. (See Table 7.)

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Distribution: The mean steady-state volume of distribution of a 20 mg/m2 dose of carfilzomib was 28 L. Carfilzomib is 97% bound to human plasma proteins over the concentration range of 0.4 to 4 micromolar in vitro.
Elimination: Carfilzomib has a half-life of ≤ 1 hour on Day 1 of Cycle 1 following intravenous doses ≥ 15 mg/m2. The half-life was similar when administered either as a 30-minute infusion or a 2- to 10-minute infusion. The systemic clearance ranged from 151 to 263 L/hour.
Metabolism: Carfilzomib is rapidly metabolized by peptidase cleavage and epoxide hydrolysis were the principal pathways of metabolism. Cytochrome P450 (CYP)-mediated mechanisms contribute a minor role in overall carfilzomib metabolism.
Excretion: Approximately 25% of the administered dose of carfilzomib was excreted in urine as metabolites in 24 hours. Urinary and fecal excretion of the parent compound was negligible (0.3% of total dose).
Specific Populations: Age (35-89 years), sex, race or ethnicity (80% White, 11% Black, 6% Asians, 3% Hispanics), and mild to severe renal impairment (creatinine clearance 15-89 mL/min) did not have clinically meaningful effects on the pharmacokinetics of carfilzomib.
Patients with Hepatic Impairment: Compared to patients with normal hepatic function, patients with mild (total bilirubin 1 to 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) and moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment had approximately 50% higher carfilzomib AUC. The pharmacokinetics of carfilzomib has not been evaluated in patients with severe hepatic impairment (total bilirubin > 3 × ULN and any AST).
Patients with Renal Impairment: Relative to patients with normal renal function, ESRD patients on hemodialysis showed 33% higher carfilzomib AUC. Since hemodialysis clearance of Kyprolis concentrations has not been studied, the drug should be administered after the hemodialysis procedure.
Drug Interaction Studies: Clinical Studies: Effect of Carfilzomib on Sensitive CYP3A Substrate: Midazolam (a sensitive CYP3A substrate) pharmacokinetics was not affected by concomitant administration of carfilzomib.
In Vitro Studies: Effect of Carfilzomib on Cytochrome P450 (CYP) Enzymes: Carfilzomib showed direct and time-dependent inhibition of CYP3A but did not induce CYP1A2 and CYP3A4 in vitro.
Effect of Transporters on Carfilzomib: Carfilzomib is a P-glycoprotein (P-gp) substrate in vitro.
Effect of Carfilzomib on Transporters: Carfilzomib inhibits P-gp in vitro. However, given that Kyprolis is administered intravenously and is extensively metabolized, the pharmacokinetics of Kyprolis is unlikely to be affected by P-gp inhibitors or inducers.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies have not been conducted with carfilzomib.
Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay.
Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28-day repeat-dose rat and monkey toxicity studies or in 6-month rat and 9-month monkey chronic toxicity studies.
Animal Toxicology and/or Pharmacology: Cardiovascular Toxicity: Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on BSA) experienced hypotension, increased heart rate, and increased serum levels of troponin-T.
Chronic Administration: Repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on BSA. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on BSA.
Indications/Uses
Relapsed or Refractory Multiple Myeloma: Kyprolis is indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
Dosage/Direction for Use
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. The recommended hydration includes both oral fluids (30 mL per kg at least 48 hours before Cycle 1, Day 1) and intravenous fluids (250 mL to 500 mL of appropriate intravenous fluid prior to each dose in Cycle 1). 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 [see Cardiac Toxicities and Tumor Lysis Syndrome under Precautions].
Electrolyte Monitoring: Monitor serum potassium levels regularly during treatment with Kyprolis.
Premedications: Premedicate with the recommended dexamethasone dose for combination therapy [see Recommended Dosage as follows]. 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 [see Infusion-Related Reactions under Precautions]. Reinstate dexamethasone premedication if these symptoms occur during subsequent cycles.
Administration: Kyprolis can be administered in a 50 mL or 100 mL intravenous bag of 5% Dextrose Injection, USP. Infuse over 10 or 30 minutes depending on the Kyprolis dose regimen [see Recommended Dosage as follows]. Administer as an intravenous infusion. Flush the intravenous administration line with normal saline or 5% Dextrose Injection, USP immediately before and after Kyprolis administration. Do not mix Kyprolis with or administer as an infusion with other medicinal products.
Dose Calculation: Calculate the Kyprolis dose [see Recommended Dosage as follows] using the patient's actual body surface area (BSA) at baseline. In patients with a BSA greater than 2.2 m2, calculate the dose based upon a BSA of 2.2 m2.
Thromboprophylaxis: Thromboprophylaxis is recommended for patients being treated with the combination of Kyprolis with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient's underlying risks [see Venous Thrombosis under Precautions].
Infection Prophylaxis: Consider antiviral prophylaxis for patients being treated with Kyprolis to decrease the risk of herpes zoster reactivation.
Patients on Hemodialysis: Administer Kyprolis after the hemodialysis procedure.
Recommended Dosage:
Kyprolis in Combination with Dexamethasone: For the combination regimen with dexamethasone alone, administer Kyprolis intravenously once weekly or twice weekly as a 30-minute infusion as described in Table 8 & 9 as follows.
Once weekly 20/70 mg/m2 regimen by 30-minute infusion: Kyprolis is administered intravenously as a 30-minute infusion once weekly for three weeks followed by a 13-day rest period as shown in Table 8. Each 28-day period is considered one treatment cycle. Administer Kyprolis at a starting dose of 20 mg/m2 in Cycle 1 on Day 1. If tolerated, escalate the dose to 70 mg/m2 on Day 8 of Cycle 1. Dexamethasone 40 mg is taken by mouth or intravenously on Days 1, 8, and 15 of all cycles and on Day 22 of Cycles 1 to 9. Administer dexamethasone 30 minutes to 4 hours before Kyprolis. (See Table 8.)

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Treatment may be continued until disease progression or unacceptable toxicity occurs [see Dosage Modifications for Adverse Reactions as follows]. Refer to the dexamethasone Prescribing Information for other information on that product.
Twice weekly 20/56 mg/m2 regimen by 30-minute infusion: Kyprolis is administered intravenously as a 30-minute infusion on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 9. Each 28-day period is considered one treatment cycle. Administer Kyprolis at a starting dose of 20 mg/m2 in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 56 mg/m2 on Day 8 of Cycle 1.
Dexamethasone 20 mg is taken by mouth or intravenously on Days 1, 2, 8, 9, 15, 16, 22, and 23 of each 28-day cycle. Administer dexamethasone 30 minutes to 4 hours before Kyprolis. (See Table 9.)

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Treatment may be continued until disease progression or unacceptable toxicity occurs [see Dosage Modifications for Adverse Reactions as follows]. Refer to the dexamethasone Prescribing Information for other information on that product.
Kyprolis in Combination with Lenalidomide and Dexamethasone: For the combination regimen with lenalidomide and dexamethasone, administer Kyprolis intravenously as a 10-minute infusion on two consecutive days, each week for three weeks followed by a 12-day rest period as shown in Table 10. Each 28-day period is considered one treatment cycle. The recommended starting dose of Kyprolis is 20 mg/m2 in Cycle 1 on Days 1 and 2. If tolerated, escalate the dose to 27 mg/m2 on Day 8 of Cycle 1. From Cycle 13, omit the Day 8 and 9 doses of Kyprolis. Discontinue Kyprolis after Cycle 18. Lenalidomide 25 mg is taken orally on Days 1-21 and dexamethasone 40 mg by mouth or intravenously on Days 1, 8, 15, and 22 of the 28-day cycles. (See Table 10.)

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Continue treatment until disease progression or unacceptable toxicity occurs [see Dosage Modifications for Adverse Reactions as follows]. Refer to the lenalidomide and dexamethasone Prescribing Information for other concomitant medications, such as the use of anticoagulant and antacid prophylaxis, that may be required with those agents.
Dose Modifications for Adverse Reactions: Recommended actions and dosage modifications for Kyprolis are presented in Table 11. Dose level reductions are presented in Table 12. See the lenalidomide and dexamethasone Prescribing Information respectively for dosage recommendations. (See Tables 11 and 12.)

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Dosage Modifications for Use in 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%. Dosing recommendation cannot be made in patients with severe hepatic impairment [see Hepatic Impairment under Precautions, Pharmacology: Pharmacokinetics under Actions].
Recommended Dosage in Patients with End Stage Renal Disease: For patients with end stage renal disease who are on hemodialysis, administer Kyprolis after the hemodialysis procedure.
Reconstitution and Preparation for Intravenous Administration: Kyprolis vials contain no antimicrobial preservatives and are intended for single-dose only. Unopened vials of Kyprolis are stable until the date indicated on the package when stored in the original package at 2°C to 8°C. 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: 1. Remove vial from refrigerator just prior to use.
2. Calculate the dose (mg/m2) and number of vials of Kyprolis required using the patient's BSA at baseline. Patients with a BSA greater than 2.2 m2 should receive a dose based upon a BSA of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.
3. Aseptically reconstitute each Kyprolis vial only with Sterile Water for Injection, USP using the volumes described in Table 13. 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, USP through the stopper and directing the Sterile Water for Injection, USP 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.

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4. 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.
5. Visually inspect for particulate matter and discoloration prior to administration. The reconstituted product should be a clear, colorless solution and should not be administered if any discoloration or particulate matter is observed.
6. 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.
7. Kyprolis can be administered directly by intravenous infusion or optionally, administered in a 50 mL to 100 mL intravenous bag containing 5% Dextrose Injection, USP. Do not administer as an intravenous push or bolus.
8. 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 [see as previously mentioned] from the vial and dilute into 50 mL or 100 mL intravenous bag containing only 5% Dextrose Injection, USP (based on the calculated total dose and infusion time).
The stabilities of reconstituted Kyprolis under various temperature and container conditions are shown in Table 14.

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Overdosage
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, the patient should be monitored, specifically for the side effects and/or adverse reactions listed in Adverse Reactions.
Contraindications
None.
Special Precautions
Cardiac Toxicities: New onset or worsening of pre-existing cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Some events occurred in patients with normal baseline ventricular function. In clinical studies with Kyprolis, these events occurred throughout the course of Kyprolis therapy. Death due to cardiac arrest has occurred within one day of Kyprolis administration. In randomized, open-label, multicenter trials for combination therapies, the incidence of cardiac failure events was 8% [see Clinical Trials Experience under Adverse Reactions].
Monitor patients for clinical signs or symptoms of cardiac failure or cardiac ischemia. Evaluate promptly if cardiac toxicity is suspected. Withhold Kyprolis for Grade 3 or 4 cardiac adverse reactions until recovery and consider whether to restart Kyprolis at 1 dose level reduction based on a benefit/risk assessment [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
While adequate hydration is required prior to each dose in Cycle 1, monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure [see Administration Precautions under Dosage & Administration].
In patients ≥ 75 years of age, the risk of cardiac failure is increased compared to patients < 75 years of age. The risk of cardiac failure is also increased in Asian patients. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, conduction abnormalities, angina, or arrhythmias uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications and should have a comprehensive medical assessment (including blood pressure control and fluid management) prior to starting treatment with Kyprolis and remain under close follow-up [see Use in Elderly as follows].
Acute Renal Failure: Cases of acute renal failure have occurred in patients receiving Kyprolis. Some of these events have been fatal. Renal insufficiency (including renal failure) has occurred in approximately 11% of patients treated with Kyprolis. The risk of fatal renal failure was greater in patients with a baseline reduced estimated creatinine clearance (calculated using Cockcroft-Gault equation). Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Tumor Lysis Syndrome: Cases of tumor lysis syndrome (TLS), including fatal outcomes, have been reported in patients who received Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Ensure that patients are well hydrated before administration of Kyprolis in Cycle 1, and in subsequent cycles as needed [see Administration Precautions under Dosage & Administration]. Consider uric acid-lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly, including interruption of Kyprolis until TLS is resolved [see Administration Precautions under Dosage & Administration].
Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in approximately 1% of patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Pulmonary Hypertension: Pulmonary arterial hypertension was reported in approximately 1% of patients treated with Kyprolis and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for pulmonary hypertension until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Dyspnea: Dyspnea was reported in 28% of patients treated with Kyprolis and was Grade 3 or greater in 4% of patients. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment [see Dosage Modifications for Adverse Reactions under Dosage & Administration, Cardiac Toxicities and Pulmonary Toxicity as previously mentioned, and Clinical Trials Experience under Adverse Reactions].
Hypertension: Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. In a randomized, open-label, multicenter trial evaluating KRd versus Rd, the incidence of hypertension events was 17% in the KRd arm versus 9% in the Rd arm. In a randomized, open-label, multicenter trial of Kd versus Vd, the incidence of hypertension events was 34% in the Kd arm versus 11% in the Vd arm. Some of these events have been fatal. It is recommended to control hypertension prior to starting Kyprolis. Monitor blood pressure regularly in all patients while on Kyprolis. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment [see Dosage & Administration].
Venous Thrombosis: Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. In a randomized, open-label, multicenter trial evaluating KRd versus Rd (with thromboprophylaxis used in both arms), the incidence of venous thromboembolic events in the first 12 cycles was 13% in the KRd arm versus 6% in the Rd arm. In a randomized, open-label, multicenter trial of Kd versus Vd, the incidence of venous thromboembolic events in months 1-6 was 9% in the Kd arm versus 2% in the Vd arm.
Thromboprophylaxis is recommended for patients being treated with the combination of Kyprolis with dexamethasone or with lenalidomide plus dexamethasone. The thromboprophylaxis regimen should be based on an assessment of the patient's underlying risks.
Patients using oral contraceptives or a hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with Kyprolis in combination with dexamethasone or lenalidomide plus dexamethasone [see Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Infusion-Related Reactions: Infusion-related reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Signs and symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, laryngeal edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Administer dexamethasone prior to Kyprolis to reduce the incidence and severity of infusion-related reactions [see Dosage & Administration]. Inform patients of the risk and of symptoms and to contact a healthcare provider immediately if symptoms of an infusion-related reaction occur.
Hemorrhage: Fatal or serious cases of hemorrhage have been reported in patients treated with Kyprolis. Hemorrhagic events have included gastrointestinal, pulmonary, and intracranial hemorrhage and epistaxis. The bleeding can be spontaneous, and intracranial hemorrhage has occurred without trauma. Hemorrhage has been reported in patients having either low or normal platelet counts. Hemorrhage has also been reported in patients who were not on antiplatelet therapy or anticoagulation. Promptly evaluate signs and symptoms of blood loss. Reduce or withhold dose as appropriate [see Dosage Modification for Adverse Reactions under Dosage & Administration and Clinical Trials Experience under Adverse Reactions].
Thrombocytopenia: Kyprolis causes thrombocytopenia with platelet nadirs observed between Day 8 and Day 15 of each 28-day cycle with recovery to baseline platelet count usually by the start of the next cycle [see Clinical Trials Experience under Adverse Reactions]. Thrombocytopenia was reported in approximately 32% of patients in clinical trials with Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate [see Dosage Modification for Adverse Reactions under Dosage & Administration]. Hemorrhage may occur [see Clinical Trials Experience under Adverse Reactions and Hemorrhage as previously mentioned].
Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%) during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly, regardless of baseline values. Reduce or withhold dose as appropriate [see Dosage Modification for Adverse Reactions under Dosage & Administration and Clinical Trials Experience under Adverse Reactions].
Thrombotic Microangiopathy: Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received Kyprolis. Some of these events have been fatal. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Kyprolis and evaluate. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known [see Dosage Modification for Adverse Reactions under Dosage & Administration].
Posterior Reversible Encephalopathy Syndrome: Cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving Kyprolis. PRES, formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS), is a neurological disorder which can present with seizure, headache, lethargy, confusion, blindness, altered consciousness, and other visual and neurological disturbances, along with hypertension, and the diagnosis is confirmed by neuro-radiological imaging (MRI). Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.
Progressive Multifocal Leukoencephalopathy: Progressive multifocal leukoencephalopathy (PML), which can be fatal, has occurred with Kyprolis. In addition to Kyprolis, other possible contributary factors include prior or concurrent immunosuppressive therapy that may cause immunosuppression. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue Kyprolis and initiate evaluation for PML including neurology consultation.
Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients: In a clinical trial of 955 transplant-ineligible patients with newly diagnosed multiple myeloma randomized to Kyprolis (20/36 mg/m2 by 30-minute infusion twice weekly for four of each six-week cycle), melphalan and prednisone (KMP) or bortezomib, melphalan and prednisone (VMP), a higher incidence of fatal adverse reactions (7% versus 4%) and serious adverse reactions (50% versus 42%) were observed in the KMP arm compared to patients in the VMP arm, respectively. Patients in the KMP arm were observed to have a higher incidence of any grade adverse reactions involving cardiac failure (11% versus 4%), hypertension (25% versus 8%), acute renal failure (14% versus 6%), and dyspnea (18% versus 9%). This study did not meet its primary outcome measure of superiority in progression-free survival (PFS) for the KMP arm. Kyprolis in combination with melphalan and prednisone is not indicated for transplant-ineligible patients with newly diagnosed multiple myeloma.
Embryo-Fetal Toxicity: Based on the mechanism of action and findings in animals, Kyprolis can cause fetal harm when administered to a pregnant woman. Carfilzomib administered intravenously to pregnant rabbits during organogenesis at a dose approximately 40% of the clinical dose of 27 mg/m2 based on BSA caused post-implantation loss and a decrease in fetal weight [see Pregnancy under Use in Pregnancy & Lactation].
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Kyprolis and for 6 months following the final dose. Advise males with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the final dose [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation, and Pharmacology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions].
Hepatic Impairment: Reduce the dose of Kyprolis by 25% in patients with mild (total bilirubin 1 to 1.5 × ULN and any AST or total bilirubin ≤ ULN and AST > ULN) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. Dosing recommendation cannot be made for patients with severe hepatic function [see Dosage Modifications for Use in Hepatic Impairment under Dosage & Administration, Pharmacology: Pharmacokinetics under Actions].
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 Hepatic Toxicity and Hepatic Failure as previously mentioned, Pharmacology: Pharmacokinetics under Actions].
Use in Children: The safety and effectiveness of Kyprolis in pediatric patients have not been established.
Use in Elderly: Of 1691 patients in clinical studies of Kyprolis, 50.4% were 65 and over, while 15.4% were 75 and over. The incidence of serious adverse reactions in patients 65 and over was higher than the incidence in younger patients. No overall differences in effectiveness were observed between older and younger patients.
Use In Pregnancy & Lactation
Pregnancy: Risk Summary: Kyprolis can cause fetal harm based on findings from animal studies (see Data as follows) and the drug's mechanism of action [see Pharmacology: Mechanism of Action under Actions]. There are no studies with the use of Kyprolis in pregnant women to inform drug-associated risks of adverse developmental outcomes.
Kyprolis caused embryo-fetal lethality in rabbits at doses lower than the clinical dose. Advise pregnant women of the potential risk to the fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Data: Animal Data: Carfilzomib administered intravenously to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to 2 mg/kg/day in rats and 0.8 mg/kg/day in rabbits. In rabbits, there was an increase in pre-implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post-implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on BSA.
Lactation: Risk Summary: There are no data on the presence of Kyprolis in human milk, the effects on the breastfed child, or the effects of the drug on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from Kyprolis is unknown, advise women not to breastfeed during treatment with Kyprolis and for 2 weeks after treatment.
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 Pregnancy as previously mentioned].
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 Pharmacology: Mechanism of Action under Actions, Pharmacology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility under Actions]. There are no data on the effect of Kyprolis on human fertility.
Adverse Reactions
The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Cardiac Toxicities [see Cardiac Toxicities under Precautions]; Acute Renal Failure [see Acute Renal Failure under Precautions]; Tumor Lysis Syndrome [see Tumor Lysis Syndrome under Precautions]; Pulmonary Toxicity [see Pulmonary Toxicity under Precautions]; Pulmonary Hypertension [see Pulmonary Hypertension under Precautions]; Dyspnea [see Dyspnea under Precautions]; Hypertension [see Hypertension under Precautions]; Venous Thrombosis [see Venous Thrombosis under Precautions]; Infusion-Related Reactions [see Infusion-Related Reactions under Precautions]; Hemorrhage [see Hemorrhage under Precautions]; Thrombocytopenia [see Thrombocytopenia under Precautions]; Hepatic Toxicity and Hepatic Failure [see Hepatic Toxicity and Hepatic Failure under Precautions]; Thrombotic Microangiopathy [see Thrombotic Microangiopathy under Precautions]; Posterior Reversible Encephalopathy Syndrome [see Posterior Reversible Encephalopathy Syndrome under Precautions]; Progressive Multifocal Leukoencephalopathy [see Progressive Multifocal Leukoencephalopathy under Precautions]; Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients [see Increased Fatal and Serious Toxicities in Combination with Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Patients under Precautions].
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 [see Pharmacology: Pharmacodynamics: Clinical Studies: In Combination with Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma under Actions]. 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 common cause of deaths occurring in patients (%) in the two arms (KRd versus Rd) included infection 12 (3%) versus 11 (3%), cardiac 10 (3%) versus 9 (2%), and other adverse reactions 23 (6%) versus 22 (6%). Serious adverse reactions were reported in 65% of the patients in the KRd arm and 57% of the patients in the Rd arm. The most common serious adverse reactions reported in the KRd arm as compared with the Rd arm were pneumonia (17% versus 13%), respiratory tract infection (4% versus 2%), pyrexia (4% versus 3%), and pulmonary embolism (3% versus 2%). In patients treated with Kyprolis, 47% were 65 and over and 11% were 75 years and over. The incidence of serious adverse reactions was 57% in patients < 65 years of age, 73% in patients 65 to 74 years of age, and 81% in patients ≥ 75 years of age [see Cardiac Toxicities under Precautions and Use in Elderly under Precautions]. Discontinuation due to any adverse reaction occurred in 33% in the KRd arm versus 30% in the Rd arm. Adverse reactions leading to discontinuation of Kyprolis occurred in 12% of patients and the most common reactions included pneumonia (1%), myocardial infarction (0.8%), and upper respiratory tract infection (0.8%). The incidence of cardiac failure events was 7% in the KRd arm versus 4% in the Rd arm.
Common Adverse Reactions (≥ 10%): The adverse reactions in the first 12 cycles of therapy that occurred at a rate of 10% or greater in the KRd arm are presented in Table 15. (See Table 15).

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There were 274 (70%) patients in the KRd arm who received treatment beyond Cycle 12. There were no new clinically relevant adverse reactions that emerged in the later treatment cycles.
Adverse Reactions Occurring at a Frequency of < 10%: Blood and lymphatic system disorders: febrile neutropenia, lymphopenia.
Cardiac disorders: cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, pericardial effusion.
Ear and labyrinth disorders: deafness, tinnitus.
Eye disorders: cataract, vision blurred.
Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache.
General disorders and administration site conditions: chills, infusion site reaction, multi-organ failure, pain.
Infections and infestations: Clostridium difficile colitis, influenza, lung infection, rhinitis, sepsis, urinary tract infection, viral infection.
Metabolism and nutrition disorders: dehydration, hyperkalemia, hyperuricemia, hypoalbuminemia, hyponatremia, tumor lysis syndrome.
Musculoskeletal and connective tissue disorders: muscular weakness, myalgia.
Nervous system disorders: hypoesthesia, intracranial hemorrhage, paresthesia.
Psychiatric disorders: anxiety, delirium.
Renal and urinary disorders: renal failure, renal failure acute, renal impairment.
Respiratory, thoracic and mediastinal disorders: dysphonia, epistaxis, oropharyngeal pain, pulmonary embolism, pulmonary edema, pulmonary hemorrhage.
Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus.
Vascular disorders: deep vein thrombosis, hemorrhage, hypotension.
Grade 3 and higher adverse reactions that occurred during Cycles 1-12 with a substantial difference (≥ 2%) between the two arms were neutropenia, thrombocytopenia, hypokalemia, and hypophosphatemia.
Laboratory Abnormalities: Table 16 describes Grade 3-4 laboratory abnormalities reported at a rate of ≥ 10% in the KRd arm for patients who received combination therapy. (See Table 16.)

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Safety Experience with Kyprolis in Combination with Dexamethasone in Patients with Multiple Myeloma: The safety of Kyprolis in combination with dexamethasone was evaluated in two open-label, randomized trials (ENDEAVOR and A.R.R.O.W.).
ENDEAVOR evaluated patients with relapsed or refractory multiple myeloma [see Pharmacology: Pharmacodynamics: Clinical Studies: In Combination with Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma under Actions]. Patients received treatment for a median duration of 48 weeks in the twice weekly Kyprolis/dexamethasone (Kd) 20/56 mg/m2 arm and 27 weeks in the bortezomib/dexamethasone (Vd) arm.
Deaths due to adverse reactions within 30 days of last study treatment occurred in 32/463 (7%) patients in the Kd arm and 21/456 (5%) patients in the Vd arm. The causes of death occurring in patients (%) in the two arms (Kd versus Vd) included cardiac 4 (1%) versus 5 (1%), infections 8 (2%) versus 8 (2%), disease progression 7 (2%) versus 4 (1%), pulmonary 3 (1%) versus 2 (< 1%), renal 1 (< 1%) versus 0 (0%), and other adverse 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 treatment arms, pneumonia was the most commonly reported serious adverse reaction (8% versus 9%). In patients treated with Kyprolis, 52% were 65 and over and 17% were 75 and over. The incidence of serious adverse reactions was 54% in patients < 65 years of age, 60% in patients 65 to 74 years of age, and 69% in patients ≥ 75 years of age [see Cardiac Toxicities under Precautions and Use in Elderly under Precautions]. Discontinuation due to any adverse reaction occurred in 29% in the Kd arm versus 26% in the Vd arm. The most common reaction leading to discontinuation was cardiac failure in the Kd arm (n = 8, 2%) and peripheral neuropathy in the Vd arm (n = 22, 5%). The incidence of cardiac failure events was 11% in the Kd arm versus 3% in the Vd arm.
Common Adverse Reactions (≥ 10%): Adverse reactions in the first 6 months of therapy that occurred at a rate of 10% or greater in the Kd arm are presented in Table 17. (See Table 17).

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The event rate of ≥ Grade 2 peripheral neuropathy in the Kd arm was 7% (95% CI: 5, 9) versus 35% (95% CI: 31, 39) in the Vd arm.
Adverse Reactions Occurring at a Frequency of < 10%: Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy, thrombotic thrombocytopenic purpura.
Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, tachycardia.
Ear and labyrinth disorders: tinnitus.
Eye disorders: cataract, vision blurred.
Gastrointestinal disorders: abdominal pain, abdominal pain upper, dyspepsia, gastrointestinal hemorrhage, toothache.
General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain.
Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia.
Immune system disorders: drug hypersensitivity.
Infections and infestations: bronchopneumonia, gastroenteritis, influenza, lung infection, nasopharyngitis, pneumonia, rhinitis, sepsis, urinary tract infection, viral infection.
Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome.
Musculoskeletal and connective tissue disorders: muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia.
Nervous system disorders: cerebrovascular accident, dizziness, hypoesthesia, paresthesia, posterior reversible encephalopathy syndrome.
Psychiatric disorders: anxiety.
Renal and urinary disorders: renal failure, renal failure acute, renal impairment.
Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis, pulmonary embolism, pulmonary edema, pulmonary hypertension, wheezing.
Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash.
Vascular disorders: deep vein thrombosis, flushing, hypotension.
Laboratory Abnormalities: Table 18 describes Grades 3-4 laboratory abnormalities reported at a rate of ≥ 10% in the Kd arm. (See Table 18.)

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A.R.R.O.W. evaluated patients with relapsed and refractory multiple myeloma [see Pharmacology: Pharmacodynamics: Clinical Studies: In Combination with Dexamethasone for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma under Actions]. Patients received treatment for a median duration of 38 weeks in the once weekly Kd 20/70 mg/m2 arm and 29.1 weeks in the twice weekly Kd 20/27 mg/m2 arm of A.R.R.O.W. The safety profile for the once weekly Kd 20/70 mg/m2 regimen was similar to the twice weekly Kd 20/27 mg/m2 regimen.
Deaths due to adverse reactions within 30 days of last study treatment occurred in 22/238 (9%) patients in the Kd 20/70 mg/m2 arm and 18/235 (8%) patients in the Kd 20/27 mg/m2 arm. The most frequent fatal adverse reactions occurring in patients (%) in the two arms (once weekly Kd 20/70 mg/m2 versus twice weekly Kd 20/27 mg/m2) were sepsis 2 (< 1%) versus 2 (< 1%), septic shock 2 (< 1%) versus 1 (< 1%), and infection 2 (< 1%) versus 0 (0%). Serious adverse reactions were reported in 43% of the patients in the Kd 20/70 mg/m2 arm and 41% of the patients in the Kd 20/27 mg/m2 arm. In both treatment arms, pneumonia was the most commonly reported serious adverse reaction (8% versus 7%). In patients treated with once weekly Kd 20/70 mg/m2, 57% were 65 and over and 19% were 75 and over. The incidence of serious adverse reactions was 37% in patients < 65 years of age, 50% in patients 65 to 74 years of age, and 44% in patients ≥ 75 years of age [see Cardiac Toxicities under Precautions and Use in Elderly under Precautions]. Discontinuation due to any adverse reaction occurred in 13% in the Kd 20/70 mg/m2 arm versus 12% in the Kd 20/27 mg/m2 arm. The most common reaction leading to discontinuation was acute kidney injury (2% versus 2%). The incidence of cardiac failure events was 3.8% in the once weekly Kd 20/70 mg/m2 arm versus 5.1% in the twice weekly Kd 20/27 mg/m2 arm.
Common Adverse Reactions (≥ 10%): Adverse reactions that occurred at a rate of 10% or greater in either Kd arm is presented in Table 19. (See Table 19.)

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Adverse Reactions Occurring at a Frequency of < 10%: Blood and lymphatic system disorders: febrile neutropenia, leukopenia, lymphopenia, neutropenia, thrombotic microangiopathy.
Cardiac disorders: atrial fibrillation, cardiac arrest, cardiac failure, cardiac failure congestive, myocardial infarction, myocardial ischemia, palpitations, pericardial effusion, tachycardia.
Ear and labyrinth disorders: tinnitus.
Eye disorders: cataract, vision blurred.
Gastrointestinal disorders: abdominal pain, abdominal pain upper, constipation, dyspepsia, toothache, vomiting.
General disorders and administration site conditions: chest pain, chills, influenza like illness, infusion site reactions (including inflammation, pain, and erythema), malaise, pain.
Hepatobiliary disorders: cholestasis, hepatic failure, hyperbilirubinemia.
Infections and infestations: Clostridium difficile colitis, gastroenteritis, influenza, lung infection, nasopharyngitis, rhinitis, sepsis, septic shock, urinary tract infection, viral infection.
Metabolism and nutrition disorders: decreased appetite, dehydration, hypercalcemia, hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, tumor lysis syndrome.
Musculoskeletal and connective tissue disorders: muscle spasms, muscular weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia.
Nervous system disorders: cerebrovascular accident, dizziness, paresthesia, peripheral neuropathy.
Psychiatric disorders: anxiety, delirium.
Renal and urinary disorders: acute kidney injury, renal failure, renal impairment.
Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, dysphonia, epistaxis, interstitial lung disease, oropharyngeal pain, pneumonitis pulmonary hemorrhage, pulmonary embolism, pulmonary hypertension, pulmonary edema, wheezing.
Skin and subcutaneous tissue disorders: erythema, hyperhidrosis, pruritus, rash.
Vascular disorders: deep vein thrombosis, flushing, hypotension.
Postmarketing Experience: The following adverse reactions have been identified during post approval 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, and viremia.
Storage
Unopened vials should be stored refrigerated 2°C to 8°C. Retain in original package to protect from light.
Patient Counseling Information
Discuss the following with patients prior to treatment with Kyprolis: Cardiac Toxicities: Advise patients of the risks and symptoms of cardiac failure and ischemia [see Cardiac Toxicities under Precautions].
Dehydration: Counsel patients to avoid dehydration, since patients receiving Kyprolis therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dehydration [see Tumor Lysis Syndrome under Precautions].
Respiratory: Advise patients that they may experience cough or shortness of breath (dyspnea) during treatment with Kyprolis. This most commonly occurs within a day of dosing. Advise patients to contact their healthcare provider if they experience shortness of breath [see Dyspnea under Precautions].
Venous Thrombosis: Inform patients of the risk of venous thromboembolism and discuss the options for prophylaxis. Advise patients to seek immediate medical attention for symptoms of venous thrombosis or embolism [see Venous Thrombosis under Precautions].
Infusion-Related Reactions: Advise patients of the risk of infusion-related reactions, and discuss the common signs and symptoms of infusion-related reactions with the patients [see Infusion-Related Reactions under Precautions].
Bleeding: Inform patients that they may bruise or bleed more easily or that it may take longer to stop bleeding and to report to their healthcare provider any prolonged, unusual or excessive bleeding. Instruct patients on the signs of occult bleeding [see Hemorrhage under Precautions].
Hepatic: Inform patients of the risk of developing hepatic failure. Advise patients to contact their healthcare provider for symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Hepatic Toxicity and Hepatic Failure under Precautions].
Other: Inform patients to contact their healthcare provider if they experience neurologic symptoms such as headaches, confusion, dizziness or loss of balance, difficulty talking or walking, decreased strength or weakness on one side of the body, seizures, or visual loss [see Precautions and Adverse Reactions].
Driving/Operating Machines: Advise patients that Kyprolis may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms [see Clinical Trials Experience under Adverse Reactions].
Embryo-Fetal Toxicity: Advise females of the potential risk to the fetus. Advise females of reproductive potential to inform their healthcare provider immediately of a known or suspected pregnancy. Advise female patients to use effective contraceptive during treatment with Kyprolis and for 6 months following the final dose. Advise male patients with female sexual partners of reproductive potential to use effective contraception during treatment with Kyprolis and for 3 months following the final dose [see Embryo-Fetal Toxicity under Precautions, Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Lactation: Advise patients to avoid breastfeeding while receiving Kyprolis and for 2 weeks after the final dose [see Lactation under Use in Pregnancy & Lactation].
Concomitant Medications: Advise patients to discuss with their healthcare provider any medication they are currently taking prior to starting treatment with Kyprolis, or prior to starting any new medication(s) during treatment with Kyprolis.
ATC Classification
L01XG02 - carfilzomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.
Presentation/Packing
Powd for infusion (vial) (white to off-white lyophilized cake or powder) 60 mg x 1's.
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