carfilzomib (Rx)

Brand and Other Names:Kyprolis
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, IV

  • 60mg/vial
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Multiple Myeloma

Dual combination therapy

  • Indicated for relapsed or refractory multiple myeloma in patients who have received 1-3 prior lines of therapy as a dual regimen with dexamethasone
  • Each 28-day period is considered 1 treatment cycle
  • Dexamethasone: 20 mg PO or IV on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each cycle; administer dexamethasone 30 minutes to 4 hr before carfilzomib
  • Treatment may be continued until disease progression or unacceptable toxicity occurs
  • Note: Thromboprophylaxis is recommended for patients treated with combination therapy; the thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks
  • Cycle 1
    • Administer carfilzomib on Days 1 and 2, Days 8 and 9, and Days 15 and 16 20 mg/m² IV infused over 30 minutes, on Days 1 and 2
    • If tolerated, escalate to a target dose of 56 mg/m² starting on Day 8 of Cycle 1
  • Cycle 2 and thereafter
    • 56 mg/m² IV infused over 30 minutes on Days 1 and 2, Days 8 and 9, and Days 15 and 16
    • Treatment may be continued until disease progression or unacceptable toxicity occurs

Triple combination therapy

  • Indicated for relapsed or refractory multiple myeloma in patients who have received 1-3 prior lines of therapy as a triple regimen in combination with dexamethasone plus lenalidomide
  • Each 28-day period is considered 1 treatment cycle
  • Lenalidomide: 25 mg PO on Days 1–21 of each cycle
  • Dexamethasone: 40 mg PO or IV on Days 1, 8, 15, and 22 of each cycle
  • Note: Thromboprophylaxis is recommended for patients treated with combination therapy; the thromboprophylaxis regimen should be based on an assessment of the patient’s underlying risks
  • Cycle 1
    • Administer carfilzomib on Days 1 and 2, Days 8 and 9, and Days 15 and 16
    • 20 mg/m² IV infused over 10 minutes, on Days 1 and 2
    • If tolerated, escalate to a target dose of 27 mg/m² starting on Day 8 of Cycle 1
  • Cycles 2-12
    • Administer carfilzomib on Days 1 and 2, Days 8 and 9, and Days 15 and 16
  • Cycles 13 and thereafter
    • From Cycle 13, omit the Day 8 and 9 doses of carfilzomib (administer on Days 1 and 2, and Days 15 and 16)
    • Discontinue carfilzomib after Cycle 18

Monotherapy

  • Indicated for relapsed or refractory multiple myeloma in patients who have received ≥1 prior lines of therapy
  • Each 28-day period is considered 1 treatment cycle
  • 20/27 mg/m² regimen (10-minute infusion)
    • Cycle 1: 20 mg/m² on Days 1 and 2; if tolerated, escalate to a target dose of 27 mg/m² starting on day 8 of cycle 1; continue with tolerated dose on Days 9 and Days 15 and 16
    • Cycles 2-12: Administer carfilzomib on Days 1 and 2, Days 8 and 9, and Days 15 and 16
    • Cycles 13 and thereafter: Omit the Day 8 and 9 doses of carfilzomib (administer on Days 1 and 2, and Days 15 and 16)
  • 20/56 mg/m² regimen (30-minute infusion)
    • Cycle 1: 20 mg/m² on Days 1 and 2; if tolerated, escalate to a target dose of 56 mg/m² starting on day 8 of cycle 1; continue with tolerated dose on Days 9 and Days 15 and 16
    • Cycle 2-12: Administer carfilzomib on Days 1 and 2, Days 8 and 9, and Days 15 and 16
    • Cycle 13 and thereafter: Administer carfilzomib on Days 1, 2, 15, and 16

Dosage Modifications

Dose level reductions

  • Carfilzomib, lenalidomide, and dexamethasone, or monotherapy (dose 27 mg/m²)
    • First dose reduction: 20 mg/m²
    • Second dose reduction: 20 mg/m²; if toxicity persists, discontinue
  • Carfilzomib and dexamethasone, or monotherapy (dose 56 mg/m²)
    • First dose reduction: 45 mg/m²
    • Second dose reduction: 36 mg/m²
    • Third dose reduction: 27 mg/m²; if toxicity persists, discontinue

Hematologic toxicity

  • Grade 3 or 4 neutropenia or grade 4 thrombocytopenia
  • Withhold dose
    • If fully recovered before next scheduled dose, continue at same dose level
    • If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by 1 dose level
    • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician

Cardiac toxicity

  • Grade 3 or 4, new onset or worsening of CHF, decreased LVF, or myocardial ischemia
  • Withhold until resolved or returned to baseline
    • After resolution, consider if restarting at a reduced dose is appropriate
    • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician

Pulmonary hypertension

  • Withhold until resolved or returned to baseline
  • Restart at the dose used prior to the event or reduced dose, at the discretion of the physician
  • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician

Pulmonary complications

  • Grade 3 or 4
    • Withhold until resolved or returned to baseline
    • Consider restarting at the next scheduled treatment with one dose level reduction
    • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician

Hepatic toxicity

  • Grade 3 or 4 elevation of transaminases, bilirubin, or other liver abnormalities
    • Withhold until resolved or returned to baseline
    • After resolution, consider if restarting is appropriate; may be reinitiated at a reduced dose with frequent monitoring of liver function
    • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician

Renal toxicity

  • Serum creatinine >2 × baseline
    • Withhold until renal function has recovered to Grade 1 or to baseline and monitor renal function
    • If attributable to carfilzomib, restart at the next scheduled treatment at a reduced dose
    • If not attributable to carfilzomib, restart at the dose used prior to the event
    • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician

Peripheral neuropathy

  • Grade 3 or 4
    • Withhold until resolved or returned to baseline
    • Restart at the dose used prior to the event or reduced dose, at the discretion of the physician
    • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician

Other

  • Grade 3 or 4 nonhematological toxicities
    • Withhold until resolved or returned to baseline
    • Consider restarting at the next scheduled treatment with one dose level reduction
    • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician

Renal & Hepatic Impairment

Renal impairment

  • No dose adjustment required if elevated serum creatinine not attributed to carfilzomib
  • Dialysis: Clearance during dialysis not studied; administer after dialysis procedure

Hepatic impairment

  • Efficacy and safety not yet established; avoid use in severe hepatic impairment

<18 years: Safety and efficacy not established; use not recommended in children

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Interactions

Interaction Checker

and carfilzomib

No Results

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    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Fatigue (55.5%)

            Anemia (46.8%)

            Nausea (44.9%)

            Thrombocytopenia (36.3%)

            Dyspnea (34.6%)

            Diarrhea (32.7%)

            Pyrexia (30.4%)

            Upper respiratory tract infection (28.3%)

            Headache (27.6%)

            Cough (26%)

            Increase in blood creatinine (24.1%)

            Lymphopenia (24%)

            Peripheral Edema (24%)

            Vomiting (22.2%)

            Constipation (20.9%)

            Neutropenia (20.7%)

            Back pain (20.2%)

            Insomnia (17.9%)

            Chills (16%)

            Arthralgia (15.8%)

            Muscle spasms (14.4%)

            Hypertension (14.3%)

            Asthenia (13.9%)

            Hypokalemia (13.7%)

            Hypomagnesemia (13.5%)

            Leukopenia (13.5%)

            Pain in extremity (13.3%)

            Pneumonia (12.7%)

            Increase in aspartate aminotransferase (12.5%)

            Dizziness (12.5%) Hypoesthesia (12.2%)

            Anorexia (12%) Pain (12%)

            Hyperglycemia (11.8%)

            Chest wall pain (11.4%)

            Hypercalcemia (11%)

            Hypophosphatemia (10.5%)

            Hyponatremia (10.3%)

            1-10%

            Pneumonia (10%)

            Acute renal failure (4%)

            Pyrexia (3%)

            Congestive heart failure (3%)

            Frequency Not Reported

            Cardiac arrest

            Myocardial ischemia

            Pulmonary hypertension

            Pulmonary complications

            Infusion reactions

            Tumor-lysis syndrome

            Thrombocytopenia

            Hepatic toxicity

            Hepatic failure

            Postmarketing Reports

            Gastrointestinal hemorrhage

            Lung infection

            Rhinitis

            Intracranial hemorrhage

            Hemorrhage

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            Warnings

            Contraindications

            None

            Cautions

            Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) and premedicate to avoid infusion reactions; maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely (see Administration)

            Reduce or interrupt dosage as described for toxicities accordingly (see Dosage Modification)

            Monitor for pulmonary hypertension and other pulmonary complications during and after treatment completion

            Inform patient of the risk and symptoms of infusion reactions

            Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS); monitor for signs and symptoms of TTP/HUS; discontinue therapy if suspected

            Venous thromboembolic events (VTE), including DVT and PE, were observed in clinical trials; in the combination study, VTE incidence in the first 12 cycles was 13% in the carfilzomib combination arm vs 6 % in the control arm; with monotherapy, the incidence of VTE was 2%; patients using oral contraceptives or hormonal method of contraception associated with a risk of thrombosis should consider an alternative method of effective contraception during treatment with carfilzomib in combination with dexamethasone or lenalidomide plus dexamethasone

            Thromboprophylaxis is recommended for patients being treated in combination with dexamethasone or with lenalidomide plus dexamethasone; thromboprophylaxis regimen should be based on assessment of patient’s underlying risks

            Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), reported; some cases have been fatal; monitor for signs and symptoms; discontinue therapy if suspected

            Consider neuroradiological imaging (MRI) for onset of visual or neurological symptoms of posterior reversible encephalopathy syndrome (PRES); discontinue therapy if suspected

            Monitor platelet counts; interrupt or reduce dosing as clinically indicated if thrombocytopenia occurs

            For severe or life threatening dyspnea, withhold therapy and evaluate

            Monitor for evidence of TLS during and after treatment completion

            Monitor for thrombocytopenia and reduce dose as needed

            Monitor liver enzymes regularly, regardless of baseline values, and modify dose based on toxicity

            Fatal or serious cases of hemorrhage may occur, including gastrointestinal, pulmonary, and intracranial hemorrhage; promptly evaluate signs and symptoms of blood loss

            Advise males of reproductive potential to avoid fathering a child while on therapy

            Increased fatal and serious toxicities reported in combination with melphalan and prednisone in newly diagnosed transplant-ineligible patients

            Advise women on therapy during pregnancy or become pregnant during treatment of potential hazard to fetus; therapy can cause fetal harm; females of reproductive potential should avoid becoming pregnant while being treated

            Cardiovascular risk

            • Patients experiencing cardiac failure or ischemia may be at greater risk for cardiac complications; perform comprehensive medical assessment, including blood pressure and fluid management, prior to initiating treatment and continue close follow-up
            • Death due to cardiac arrest has occurred within a day of carfilzomib administration
            • New onset or worsening of pre-existing CHF with decreased LVF or myocardial ischemia have occurred following administration
            • Cardiac failure events (eg, cardiac failure congestive, pulmonary edema, decreased ejection fraction) were reported in 7% of patients; monitor for signs and symptoms of cardiac failure or ischemia; withhold therapy and evaluate promptly
            • Monitor for cardiac complications and manage promptly
            • Patients with New York Heart Association Class III and IV heart failure, MI in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials; these patients may be at greater risk for cardiac complications
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            Pregnancy & Lactation

            Pregnancy Category: D; Based on mechanism of action and findings in animals, can cause fetal harm

            Lactation: Unknown whether distributed in human milk; avoid use in nursing mothers

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            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; has antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells

            Absorption

            Peak Plasma Concentration: 4232 ng/mL

            AUC: 379 ng⋅hr/mL

            Distribution

            Protein Bound: 97%

            Vd: 28 L

            Metabolism

            Rapidly and extensively metabolized

            Principal pathways of metabolism: peptidase cleavage and epoxide hydrolysis

            The metabolites have no known biologic activity

            Elimination

            Half-life: <20 hr

            Clearance: 151 to 263 L/hr

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            Administration

            Thromboprophylaxis & Infection Prophylaxis

            Thromboprophylaxis: Recommended for patients being treated with combination therapy (with dexamethasone or lenalidomide plus dexamethasone); base thromboprophylaxis regimen on assessment of the patient's underlying risks

            Infection prophylaxis: Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation

            Premedication

            Premedicate with dexamethasone 4 mg PO/IV before all cycle 1 doses, during the first cycle of dose escalation, and if infusion reaction symptoms develop or reappear

            Modify dose according to toxicity (see Dosage Modifications)

            Hydration

            Hydration required before and following administration to reduce risk for renal toxicity and tumor lysis syndrome

            Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely

            Prior to each dose in cycle 1, give 250-500 mL IV of 0.9% NaCl or other appropriate IV fluid

            Give an additional 250-500 mL of IV fluids as needed following administration

            Continue IV hydration as needed in subsequent cycles Monitor for fluid overload

            Dose for BSA >2.2 m²

            Calculated dose using the patient’s actual body surface area (BSA) at baseline

            If BSA exceeds 2.2 m², calculate dose based upon BSA of 2.2 m²

            Dose adjustments do not need to be made for weight changes of <20%

            IV Incompatibilities

            Due to potential for chemical incompatibility, do not mix or inject in IV administration lines containing other drugs, medicinal products (eg, blood, albumin), or TPN

            IV Preparation

            Remove vial from refrigerator just prior to use

            Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the inside wall of the vial to minimize foaming

            Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs

            Do not shake to avoid foam generation; if foaming occurs, allow solution to rest in vial for about 2-5 minutes, until foaming subsides

            Resulting concentration of reconstituted vial is 2 mg/mL

            The reconstituted product should be a clear, colorless solution; if any discoloration or particulate matter is observed, do not use the reconstituted product

            When administering in an intravenous bag, withdraw the calculated dose from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag

            Immediately discard the vial containing the unused portion

            Storage

            Unopened vial containing lyophilized powder: Store refrigerated: between 2-8°C (36-46°F); retain in original package to protect from light

            Reconstituted solution: Stable when refrigerated up to 24 hr (2-8°C; 36-46°F) or at room temperature up to 4 hr (15-30°C; 59-86°F)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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