KYPROLIS

Carfilzomib is an injectable antineoplastic agent (Intravenous only).

Chemically, it is a modified tetrapeptidyl epoxide and an analog of epoxomicin.

It is also a selective proteasome inhibitor.

FDA approved carfilzomib in

July for the treatment of adults with relapsed or refractory multiple myeloma as monotherapy or combination therapy.

Carfilzomib 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.

It is also indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. 3,

Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like activity when measured in blood 1 hour after the first dose.

On Day of

Cycle 1, proteasome inhibition in peripheral blood mononuclear cells (PBMCs) ranged from 79% to 89% at 15 mg/m2, and from 82% to 83% at 20 mg/m2.

In addition, carfilzomib administration resulted in inhibition of the LMP2 and MECL1 subunits of the immunoproteasome ranging from 26% to 32% and 41% to 49%, respectively, at 20 mg/m2.

Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing.

Resistance against carfilzomib has been observed and although the mechanism has not been confirmed, it is thought that up-regulation of P-glycoprotein may be a contributing factor.

Furthermore, studies suggest that carfilzomib is more potent than bortezomib.

Proteasome subunit beta type-5 Inhibitor Proteasome subunit beta type-8 Inhibitor Proteasome subunit beta type-1 Inhibitor + 3 more targets.

Cmax, single Intravenous dose of 27 mg/m^2 = 4232 ng/mL AUC, single Intravenous dose of 27 mg/m^2 = 379 ng•hr/mL Carfilzomib does not accumulation in the systemic.

At doses between and 36 mg/m2, there was a dose-dependent increase in exposure.

Carfilzomib was rapidly and extensively metabolized by the liver.

The predominant metabolites were the peptide fragments and the diol of carfilzomib which suggests that the main metabolic pathways are peptidase cleavage and epoxide hydrolysis.

The cytochrome

P450 enzyme system is minimally involved in the metabolism of carfilzomib.

All metabolites are inactive.

Following intravenous administration of doses ≥ 15 mg/m^2, carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day of Cycle 1.

Systemic clearance = 151-263 L/hour.

As this value exceeds hepatic blood flow, it suggests that carfilozmib is cleared extrahepatically.

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Most commonly reported adverse reactions (incidence ≥ 30%) are fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia.

The two dose limiting toxicities are thrombocytopenia and febrile neutropenia.

Hydrate prior to and following

Kyprolis as needed.

Premedicate prior to all

Cycle 1 doses and if infusion-related reactions develop or reappear.

The recommended dosing regimens are as follows.

Information for additional dosage information.

Regimen Dosage Infusion Time Kyprolis and

Dexamethasone (Kd) or Kyprolis, Daratumumab and Dexamethasone (DKd) or Kyprolis, Daratumumab and hyaluronidase-fihj and Dexamethasone (DKd) 20/70 mg/m 2 once weekly 30 minutes Kyprolis and Dexamethasone (Kd) or Kyprolis, Daratumumab and Dexamethasone (DKd) or Kyprolis, Daratumumab and hyaluronidase-fihj and Dexamethasone (DKd) or Kyprolis, Isatuximab and Dexamethasone (Isa-Kd) or Kyprolis Monotherapy 20/56 mg/m 2 twice weekly 30 minutes Kyprolis, Lenalidomide and Dexamethasone (KRd) or Kyprolis Monotherapy 20/27 mg/m 2 twice weekly 10 minutes 2.1 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.

Consider hydration with 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.

Monitor serum potassium levels regularly during treatment with Kyprolis.

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 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.

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 patients with a

BSA greater than 2.2 m 2, calculate the Kyprolis dose using a BSA of 2.2 m 2. 2.2 Recommended Dosage Once Weekly 20/70 mg/m 2 (30-minute infusion) Kyprolis once weekly 20/70 mg/m 2 administered in combination with dexamethasone (Kd), daratumumab plus dexamethasone (DKd), or daratumumab and hyaluronidase-fihj plus dexamethasone (DKd).

The recommended starting dosage of

Kyprolis is 20 mg/m on Cycle 1, Day 1.

If tolerated, escalate the dose to 70 mg/m on Cycle 1, Day 8.

Kyprolis intravenously as a 30-minute infusion on Days 1, 8, and of each 28-day cycle until disease progression or unacceptable toxicity as shown in Table 1.

Administer dexamethasone 30 minutes to 4 hours before Kyprolis and to 3 hours before daratumumab or daratumumab and hyaluronidase-fihj.

For dosage instructions of combination agents with Kyprolis, see Clinical Studies sections 14.2 (Kd) and 14.3 (DKd) .

Information for dexamethasone, intravenous daratumumab, and subcutaneous daratumumab and hyaluronidase-fihj for additional dosage information.

Table 1: Kyprolis 20/70 mg/m 2 Once Weekly (30-Minute Infusion) Cycle 1 Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 10-14 Day 15 Day 16 Days 17-21 Day 22 Day 23 Days 24-28 Kyprolis (mg/m 2 ) 20.

• Cycles and later Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 10-14 Day 15 Day 16 Days 17-21 Day 22 Day 23 Days 24-28 Kyprolis (mg/m 2 ) 70.

• Twice Weekly 20/56 mg/m 2 (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).

Kyprolis is 20 mg/m on Cycle 1, Days and 2.

If tolerated, escalate the dose to 56 mg/m on Cycle 1, Day 8.

Kyprolis intravenously as a 30-minute infusion on Days 1, 2, 8, 9, 15, and 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 and 9 of cycle 13 onward.

For dosage instructions of combination agents administered with Kyprolis, see Clinical Studies sections 14.2 (Kd) , 14.3 (DKd) , 14.4 (Isa-Kd) , and 14.5 (Monotherapy) .

Information for dexamethasone, intravenous daratumumab, subcutaneous daratumumab and hyaluronidase-fihj, and isatuximab for additional dosage information.

Table 2: Kyprolis 20/56 mg/m 2 Twice Weekly (30-Minute Infusion) Cycle 1 Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 10-14 Day 15 Day 16 Days 17-21 Day 22 Day 23 Days 24-28 Kyprolis As monotherapy, dexamethasone premedication is required for each Kyprolis dose in Cycle 1. (mg/m 2 ) 20 20.

• Cycles and later Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 10-14 Day 15 Day 16 Days 17-21 Day 22 Day 23 Days 24-28 Kyprolis (mg/m 2 ) 56 56.

• Twice Weekly 20/27 mg/m 2 (10-minute infusion) Kyprolis twice weekly 20/27 mg/m is administered as monotherapy or in combination with lenalidomide and dexamethasone (KRd).

Kyprolis is 20 mg/m in Cycle on Days and 2.

If tolerated, escalate the dose to 27 mg/m on Day of Cycle and thereafter.

Kyprolis intravenously as a 10-minute infusion.

In Cycles 1 through 12, administer Kyprolis on Days and 16 of each 28-day cycle as shown in Table 3.

Cycle 13, administer Kyprolis on Days and 16 of each 28-day cycle.

If given as monotherapy, premedicate with dexamethasone 4 mg orally or intravenously 30 minutes to 4 hours before each Kyprolis dose in Cycle 1, then as needed to minimize infusion-related reactions.

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 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) .

Information for dexamethasone and lenalidomide for additional dosage information.

Table 3: Kyprolis 20/27 mg/m 2 Twice Weekly (10-Minute Infusion) Cycle 1 Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 10-14 Day 15 Day 16 Days 17-21 Days 22-28 Kyprolis (mg/m 2 ) Dexamethasone premedication is required for each Kyprolis dose in Cycle 1. 20 20.

• Cycles to 12 Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 10-14 Day 15 Day 16 Days 17-21 Days 22-28 Kyprolis (mg/m 2 ) 27 27.

• Cycles and later When administered in combination with lenalidomide and dexamethasone, discontinue Kyprolis after Cycle 18.

Week 1 Week 2 Week 3 Week 4 Day 1 Day 2 Days 3-7 Day 8 Day 9 Days 10-14 Day 15 Day 16 Days 17-21 Days 22-28 Kyprolis (mg/m 2 ) 27 27.

• 2.3 Dosage 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 for dose level reductions.

ANC = absolute neutrophil count Hematologic Toxicity Recommended Action ANC less than 0.5 × 10 9 /L Withhold dose If recovered to greater than or equal to 0.5 × 10 9 /L, continue at the same dose level For subsequent drops to less than 0.5 × 10 9 /L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolis Febrile neutropenia: ANC less than 0.5 × 10 9 /L and an oral temperature more than 38.5°C or two consecutive readings of more than 38.0°C for 2 hours Withhold dose If ANC returns to baseline grade and fever resolves, resume at the same dose level Platelets less than 10 × 10 9 /L or evidence of bleeding with thrombocytopenia Withhold dose If recovered to greater than or equal to 10 × 10 9 /L and/or bleeding is controlled, continue at the same dose level For subsequent drops to less than 10 × 10 9 /L, follow the same recommendations as above and consider 1 dose level reduction when restarting Kyprolis Renal Toxicity Recommended Action Serum creatinine greater than or equal to 2 × baseline, or Creatinine clearance less than 15 mL/min, or creatinine clearance decreases to less than or equal to 50% of baseline, or need for hemodialysis Withhold dose and continue monitoring renal function (serum creatinine or creatinine clearance) If attributable to Kyprolis, resume when renal function has recovered to within 25% of baseline; start at 1 dose level reduction If not attributable to Kyprolis, dosing may be resumed at the discretion of the healthcare provider For patients on hemodialysis receiving Kyprolis, the dose is to be administered after the hemodialysis procedure Other Non-hematologic Toxicity.

Recommended Action All other severe or life-threatening Grade and 4. non-hematological toxicities Withhold until resolved or returned to baseline Consider restarting the next scheduled treatment at 1 dose level reduction Table 5: Dose Level Reductions for Adverse Reactions Regimen Kyprolis Frequency Dose First Dose Reduction Second Dose Reduction Third Dose Reduction Note: Infusion times remain unchanged during dose reduction(s).

Kyprolis, Daratumumab, and Dexamethasone Once weekly 70 mg/m 2 56 mg/m 2 45 mg/m 2 36 mg/m 2 If toxicity persists, discontinue Kyprolis treatment.

Kyprolis, Daratumumab, and Dexamethasone OR Kyprolis, Isatuximab, and Dexamethasone OR Kyprolis Monotherapy Twice weekly 56 mg/m 2 45 mg/m 2 36 mg/m 2 27 mg/m 2 Kyprolis, Lenalidomide, and Dexamethasone OR Kyprolis Monotherapy Twice weekly 27 mg/m 2 20 mg/m 2 15 mg/m 2 — 2.4 Dosage Modifications for Hepatic Impairment For patients with mild (total bilirubin 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% . 2.5 Recommended Dosage for End Stage Renal Disease For patients with end stage renal dise.

Kyprolis (carfilzomib) for Injection is supplied as: An individually packaged single-dose vial containing 10 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-103-01, NDC 76075-103-21.

An individually packaged single-dose vial containing 30 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-102-01, NDC 76075-102-21.

An individually packaged single-dose vial containing 60 mg of carfilzomib as a white to off-white lyophilized cake or powder: NDC 76075-101-01, NDC 76075-101-21.

Unopened vials should be stored refrigerated 2°C to 8°C (36°F to 46°F).

Retain in original package to protect from light.

Unopened vials should be stored refrigerated 2°C to 8°C (36°F to 46°F).

Retain in original package to protect from light.

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.

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.

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/m 2 based on BSA.

The safety and effectiveness of

Kyprolis in pediatric patients have not been established.

Kyprolis in combination with chemotherapy was evaluated, but not established in an open label trial (Study 20140106; NCT02303821) in 124 patients aged 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.

Of the 2,837 patients with relapsed or refractory multiple myeloma exposed to Kyprolis in monotherapy and combination therapy studies, 50% were 65 years and older, while 13% were 75 years and older.

The incidence of serious adverse reactions was 50% in patients < 65 years of age, 60% in patients to 74 years of age, and 63% in patients ≥ 75 years of age.

Of the 308 patients in CANDOR who received DKd, 47% of patients were 65 years and older, while 9% were 75 years and older.

Fatal adverse reactions in the DKd arm of CANDOR occurred in 6% of patients < 65 years of age, 14% of patients between to 74 years of age, and 14% of patients ≥ 75 years of age.

No overall differences in effectiveness were observed between older and younger patients.