carfilzomib (Rx)

Brand and Other Names:Kyprolis
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injection, lyophilized powder for reconstitution

  • 10mg/vial
  • 30mg/vial
  • 60mg/vial

Multiple myeloma

Indicated for relapsed or refractory multiple myeloma in adults who have received 1-3 lines of therapy in combination with dexamethasone, lenalidomide plus dexamethasone, or daratumumab plus dexamethasone

Also indicated as a single agent for relapsed or refractory multiple myeloma in adults who received ≥1 lines

Combination with dexamethasone (once weekly regimen)

  • Each cycle is 28 days
  • Administer dexamethasone 30 min - 4 hr before carfilzomib; refer to prescribing information for dexamethasone for additional dosage information
  • Cycle 1
    • Carfilzomib 20 mg/m2 IV Day 1; if tolerated escalate dose to 70 mg/m2 on Days 8 and 15 PLUS  
    • Dexamethasone 40 mg PO/IV on Days 1, 8, 15, 22
  • Cycle 2-9

    • Carfilzomib 70 mg/m2 IV on Days 1, 8, 15 PLUS
    • Dexamethasone 40 mg PO/IV on Days 1, 8, 15, 22
  • Cycle 10 and thereafter
    • Carfilzomib 70 mg/m2 IV on Days 1, 8, 15 PLUS
    • Dexamethasone 40 mg PO/IV on Days 1, 8, 15
    • Continue until disease progression or unacceptable toxicity occurs

Combination with dexamethasone (twice weekly regimen)

  • Each cycle is 28 days
  • Administer dexamethasone 30 min - 4 hr before carfilzomib; refer to prescribing information for dexamethasone for additional dosage information
  • Cycle 1
    • Carfilzomib 20 mg/m2 IV Days 1 and 2; if tolerated escalate dose to 56 mg/m2 on Days 8, 9, 15, 16 PLUS  
    • Dexamethasone 20 mg PO/IV on Days 1, 2, 8, 9, 15, 16, 22, 23
  • Cycles 2 and thereafter
    • Carfilzomib 56 mg/m2 IV on Days 1, 2, 8, 9, 15, 16 PLUS
    • Dexamethasone 20 mg PO/IV on Days 1, 2, 8, 9, 15, 16, 22, 23
    • Continue until disease progression or unacceptable toxicity occurs

Combination with lenalidomide and dexamethasone

  • Each cycle is 28 days
  • Administer dexamethasone 30 min - 4 hr before carfilzomib; refer to prescribing information for lenalidomide and dexamethasone for additional dosage information
  • Cycle 1
    • Carfilzomib 20 mg/m2 IV Days 1 and 2; if tolerated escalate dose to 27 mg/m2 on Days 8, 9, 15, 16 PLUS  
    • Lenalidomide 25 mg PO on Days 1–21 PLUS
    • Dexamethasone 40 mg PO/IV on Days 1, 8, 15, 22
  • Cycles 2-12
    • Carfilzomib 27 mg/m2 IV on Days 1, 2, 8, 9, 15, 16 PLUS
    • Lenalidomide 25 mg PO on Days 1–21 PLUS
    • Dexamethasone 40 mg PO/IV on Days 1, 8, 15, 22
  • Cycles 13 -18
    • Carfilzomib 27 mg/m2 IV on Days 1, 2, 15, 16 PLUS
    • Lenalidomide 25 mg PO on Days 1–21 PLUS
    • Dexamethasone 40 mg PO/IV on Days 1, 8, 15, 22
  • Cycles 19 and thereafter
    • Lenalidomide 25 mg PO on Days 1–21 PLUS
    • Dexamethasone 40 mg PO or IV on Days 1, 8, 15, 22
    • Continue until disease progression or unacceptable toxicity

Combination with daratumumab and dexamethasone (once weekly regimen)

  • Each cycle is 28 days
  • Administer dexamethasone 30 min - 4 hr before carfilzomib and 1-3 hr before IV daratumumab; refer to prescribing information for daratumumab IV and dexamethasone for additional dosage information
  • Patients aged >75 years administer dexamethasone 20 mg PO/IV after the first week
  • Cycle 1
    • Carfilzomib 20 mg/m2 IV Day 1; if tolerated escalate dose to 70 mg/m2 on Days 8 and 15 PLUS  
    • Daratumumab 8 mg/kg IV Days 1 and 2; if tolerated escalated dose to 16 mg/kg on Days 8, 15, 22, PLUS
    • Dexamethasone 20 mg PO/IV on Days 1, 2, 8, 9, 15, 16, 22, 23
  • Cycle 2
    • Carfilzomib 70 mg/m2 IV on Days 1, 8, 15, PLUS
    • Daratumumab 16 mg/kg IV on Days 1, 8, 15, 22, PLUS
    • Dexamethasone 20 mg PO/IV on Days 1, 2, 8, 9, 15, 16, 22, 23
  • Cycles 3-6
    • Carfilzomib 70 mg/m2 IV on Days 1, 8, 15, PLUS
    • Daratumumab 16 mg/kg IV on Days 1 and 15, PLUS
    • Dexamethasone 20 mg PO/IV on Days 1, 2; then 40 mg on Day 8; then 20 mg on Days 15, 16; then 40 mg on Day 22
  • Cycles 7 and thereafter
    • Carfilzomib 70 mg/m2 IV on Days 1, 8, 15 PLUS
    • Daratumumab 16 mg/kg IV on Day 1, PLUS
    • Dexamethasone 20 mg PO/IV on Days 1, 2; then 40 mg PO/IV on Day 8, 15, 22
    • Continue until disease progression or unacceptable toxicity occurs

Combination with daratumumab and dexamethasone (twice weekly regimen)

  • Each cycle is 28 days
  • Administer dexamethasone 30 min - 4 hr before carfilzomib and 1-3 hr before IV daratumumab; refer to prescribing information for daratumumab IV and dexamethasone for additional dosage information
  • Cycle 1
    • Carfilzomib 20 mg/m2 IV Days 1 and 2; if tolerated escalate dose to 56 mg/m2 on Days 8, 9, 15, 16, PLUS  
    • Daratumumab 8 mg/kg IV Days 1 and 2; if tolerated escalated dose to 16 mg/kg on Days 8, 15, 22, PLUS
    • Dexamethasone 20 mg PO/IV on Days 1, 2, 8, 9, 15, 16; then 40 mg PO/IV on Day 22
  • Cycle 2
    • Carfilzomib 56 mg/m2 IV on Days 1, 2, 8, 9, 15, 16, PLUS
    • Daratumumab 16 mg/kg IV on Days 1, 8, 15, 22, PLUS
    • Dexamethasone 20 mg PO/IV on Days 1, 2, 8, 9, 15, 16; then 40 mg PO/IV on Day 22
  • Cycles 3-6
    • Carfilzomib 56 mg/m2 IV on Days 1, 2, 8, 9, 15, 16, PLUS
    • Daratumumab 16 mg/kg IV on Days 1 and 15, PLUS
    • Dexamethasone 20 mg PO/IV on Days 1, 2, 8, 9, 15, 16; then 40 mg PO/IV on Day 22
  • Cycles 7 and thereafter
    • Carfilzomib 56 mg/m2 IV on Days 1, 2, 8, 9, 15, 16, PLUS
    • Daratumumab 16 mg/kg IV on Day 1 PLUS
    • Dexamethasone 20 mg PO/IV on Days 1, 2, 8, 9, 15, 16; then 40 mg PO/IV on Day 22
    • Continue until disease progression or unacceptable toxicity occurs

Monotherapy

Each cycle is 28 days

20/27 mg/m2 twice weekly regimen (10-min infusion)
  • Cycle 1: Carfilzomib 20 mg/m2 IV on Days 1 and 2; if tolerated, escalate to a escalate dose to 27 mg/m2 on Days 8, 9, 15, 16  
  • Cycles 2-12: Carfilzomib 27 mg/m2 IV on Days 1, 2, 8, 9, 15, and 16
  • Cycles 13 and thereafter: Carfilzomib 27 mg/m2 IV on Days 1, 2, 15, and 16; continue until disease progression or unacceptable toxicity
20/56 mg/m2 twice weekly regimen (30-min infusion)
  • Cycle 1: Carfilzomib 20 mg/m2 IV on Days 1 and 2; if tolerated, escalate to a escalate dose to 56 mg/m2 on Days 8, 9, 15, 16
  • Cycles 2-12: Carfilzomib 56 mg/m2 IV on Days 1, 2, 8, 9, 15, and 16
  • Cycles 13 and thereafter: Carfilzomib 56 mg/m2 IV on Days 1, 2, 15, and 16; continue until disease progression or unacceptable toxicity

Dosage Modifications

Dose level reductions

  • Carfilzomib and dexamethasone with or without daratumumab (once weekly)
    • For target dose of 70 mg/m2
    • First dose reduction: 56 mg/m2
    • Second dose reduction: 45 mg/m2
    • Third dose reduction: 36 mg/m2; if toxicity persists, discontinue
  • Carfilzomib, lenalidomide, and dexamethasone, or monotherapy (twice weekly
    • For target dose of 27 mg/m2
    • First dose reduction: 20 mg/m2
    • Second dose reduction: 15 mg/m2
    • Third dose reduction: If toxicity persists, discontinue
  • Carfilzomib and dexamethasone, or monotherapy (twice weekly)
    • For target dose of 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

  • ANC <0.5 x 10^9/L
    • Withhold dose; if recovered to ≥0.5 × 109/L, continue at same dose level
    • For subsequent drops to <0.5 × 109/L, follow same recommendations as above and consider 1 dose level reduction when restarting carfilzomib
  • Febrile neutropenia ANC <0.5 × 10^9/L and an oral temperature >38.5°C or 2 consecutive readings of >38°C for 2 hr
    • Withhold dose; if ANC returns to baseline grade and fever resolves, resume at same dose level
  • Platelets <10 × 10^9/L or evidence of bleeding with thrombocytopenia
    • Withhold dose; if recovered to ≥10 × 109/L and/or bleeding is controlled, continue at same dose level
    • For subsequent drops to <10 × 109/L, follow same recommendations as above and consider 1 dose level reduction when restarting carfilzomib

Renal toxicity

  • Serum creatinine >2x baseline or CrCl <15 mL/min, or CrCl decreases to ≤50% of baseline, or need for hemodialysis
    • Withhold until renal function has recovered to Grade 1 or to baseline and monitor renal function
    • If attributable to carfilzomib, resume to within 25% of baseline; start at 1 dose level reduction
    • If not attributable to carfilzomib, resume at the discretion of the physician
    • For patients on hemodialysis, administer dose after hemodialysis

All other severe or life-threatening non-hematological toxicities

  • Withhold until resolved or returned to baseline
  • Consider restarting next scheduled treatment at 1 dose level reduction

Renal impairment

  • Baseline mild, moderate, severe, or patients on chronic hemodialysis: No starting dose adjustment required
  • Patients with end stage renal disease who are on dialysis: Administer dose after hemodialysis procedure

Hepatic impairment

  • Mild or moderate (bilirubin >1 to 3x ULN): Reduce dose by 25%
  • Severe: Not evaluated; dose recommendation cannot be made

Dosing Considerations

See Administration

Dosage calculation based on body surface area

Hydration required before each dose

Premedication recommended before each dose

Thromboembolism and infection prophylaxis recommended

Dose calculation

  • Patients with BSA ≤2.2 m2: Calculate dose using actual BSA; no dose adjustments for weight changes ≤20%
  • Patients with a BSA >2.2 m2: Calculate dose using a BSA of 2.2 m2

<18 years: Safety and efficacy not established

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Interactions

Interaction Checker

and carfilzomib

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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             activity indicator 

            Contraindicated (0)

              Serious - Use Alternative (5)

              • erdafitinib

                erdafitinib will increase the level or effect of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If coadministration unavoidable, separate administration by at least 6 hr before or after administration of P-gp substrates with narrow therapeutic index.

              • lasmiditan

                lasmiditan increases levels of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.

              • palifermin

                palifermin increases toxicity of carfilzomib by Other (see comment). Avoid or Use Alternate Drug. Comment: Palifermin should not be administered within 24 hr before, during infusion of, or within 24 hr after administration of antineoplastic agents. Coadministration of palifermin within 24 hr of chemotherapy resulted in increased severity and duration of oral mucositis.

              • sotorasib

                sotorasib will decrease the level or effect of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If use is unavoidable, refer to the prescribing information of the P-gp substrate for dosage modifications.

              • tepotinib

                tepotinib will increase the level or effect of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If concomitant use unavoidable, reduce the P-gp substrate dosage if recommended in its approved product labeling.

              Monitor Closely (12)

              • berotralstat

                berotralstat will increase the level or effect of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor or titrate P-gp substrate dose if coadministered.

              • dichlorphenamide

                dichlorphenamide and carfilzomib both decrease serum potassium. Use Caution/Monitor.

              • elagolix

                elagolix will increase the level or effect of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • eliglustat

                eliglustat increases levels of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the P-gp substrate and titrate to clinical effect.

              • fostamatinib

                fostamatinib will increase the level or effect of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Concomitant use of fostamatinib may increase concentrations of P-gp substrates. Monitor for toxicities of the P-gp substrate drug that may require dosage reduction when given concurrently with fostamatinib.

              • glecaprevir/pibrentasvir

                glecaprevir/pibrentasvir will increase the level or effect of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

              • istradefylline

                istradefylline will increase the level or effect of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of P-gp substrates in clinical trials. Consider dose reduction of sensitive P-gp substrates.

              • ponesimod

                ponesimod and carfilzomib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

              • sarecycline

                sarecycline will increase the level or effect of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Monitor for toxicities of P-gp substrates that may require dosage reduction when coadministered with P-gp inhibitors.

              • siponimod

                siponimod and carfilzomib both increase immunosuppressive effects; risk of infection. Use Caution/Monitor. Caution if coadministered because of additive immunosuppressive effects during such therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

              • stiripentol

                stiripentol will increase the level or effect of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing the dose of P-glycoprotein (P-gp) substrates, if adverse reactions are experienced when administered concomitantly with stiripentol.

              • tucatinib

                tucatinib will increase the level or effect of carfilzomib by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.

              Minor (0)

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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

                Febrile neutropenia

                Thrombotic microangiopathy

                Atrial fibrillation

                Cardiac failure congestive

                Myocardial infarction

                Palpitations

                Pericardial effusion

                Tachycardia

                Cataract

                Blurred vision

                Dyspepsia

                Toothache

                Cholestasis

                Hyperbilirubinemia

                Septic shock

                Decreased appetite

                Dehydration

                Cerebrovascular

                Postmarketing Reports

                Gastrointestinal hemorrhage

                Lung infection

                Rhinitis

                Intracranial hemorrhage

                Hemorrhage

                Influenza like illness

                Malaise

                Bronchopneumonia

                Gastroenteritis

                Influenza

                Nasopharyngitis

                Sepsis

                Urinary tract infection

                Viral infection

                Ear and labyrinth disorders: Deafness, tinnitus

                Infections and infestations: Clostridium difficile colitis, influenza

                Cytomegalovirus infection (chorioretinitis, pneumonitis, enterocolitis, and viremia)

                Hemolytic uremic syndrome (HUS)

                Hepatitis B virus reactivation

                Gastrointestinal perforation

                Progressive multifocal leukoencephalopathy (PML)

                Acute pancreatitis

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                Warnings

                Contraindications

                None

                Cautions

                Also see Dosage Modifications

                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)

                Tumor lysis syndrome, including fatal outcomes, reported; patients with multiple myeloma and a high tumor burden are at greater risk; ensure adequate hydration and consider uric acid-lowering drugs

                Acute respiratory distress syndrome (ARDS) and acute respiratory failure reported; acute diffuse infiltrative pulmonary disease, such as pneumonitis and interstitial lung disease also reported

                Monitor for pulmonary hypertension and other pulmonary complications (eg, ARDS) during and after treatment completion; dyspnea reported in 31% of patients

                Dyspnea reported; evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes

                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

                Cases of hepatic failure, including fatal cases, reported; 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; bleeding can be spontaneous; intracranial hemorrhage has occurred without trauma; also reported in patients having either low or normal platelet counts and in patients who were not on antiplatelet therapy or anticoagulation; evaluate signs and symptoms or blood loss promptly; withhold or reduce dose as necessary

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

                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; thrombocytopenia reported in ~32% of patients in clinical trials with carfilzomib

                Infusion-related reactions, including life-threatening reactions reported; 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; may occur immediately following or up to 24 hours after administration; administer dexamethasone prior to therapy to reduce incidence and severity of infusion-related reactions; inform patients of risk and of symptoms and to contact a healthcare provider immediately if symptoms of an infusion-related reaction occur

                Progressive multifocal leukoencephalopathy (PML), which can be fatal, reported; 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 therapy and initiate evaluation for PML including neurology consultation

                Hypertension, including hypertensive crisis and hypertensive emergency, has been observed; optimize blood pressure prior to starting treatment; monitor blood pressure regularly in all patients while on therapy; if hypertension cannot be adequately controlled, withhold therapy and evaluate; consider whether to restart therapy based on a benefit/risk assessment

                Can cause fetal harm (see Pregnancy)

                Acute renal failure

                • Acute renal failure reported, including some fatalities
                • Renal insufficiency adverse events (including renal failure) reported in ~11%; acute renal failure reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received carfilzomib monotherapy
                • Reduce or interrupt dosage as described for toxicities accordingly (see Dosage Modification)

                Thromboembolic events

                • Venous thromboembolic events (VTE) reported
                • Cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), reported; some cases have been fatal; monitor for signs and symptoms of TTP/HUS; discontinue therapy if suspected; if diagnosis of TTP/HUS is excluded, therapy may be restarted
                • 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

                Cardiovascular risk

                • New onset or worsening of pre-existing cardiac failure (eg, congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of carfilzomib; some events occurred in patients with normal baseline ventricular function; monitor for signs and symptoms of cardiac failure or ischemia; withhold therapy and evaluate promptly
                • 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
                • 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
                • Death due to cardiac arrest has occurred within a day of carfilzomib 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
                • Optimize blood pressure prior to starting therapy; if blood pressure cannot be controlled withhold therapy and evaluate; assess benefit/risk when considering whether to restart therapy; monitor blood pressure regularly in all patients receiving therapy
                • 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

                Can cause fetal harm based on findings from animal studies and the drug’s mechanism of action

                Females of reproductive potential should be advised to avoid becoming pregnant while being treated

                Males of reproductive potential should be advised to avoid fathering a child while being treated

                Animal data

                • Carfilzomib administered IV 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
                • Drug reported to cause embryo-fetal lethality in rabbits at doses lower than the clinical dose; in rabbits, there was an increase in pre-implantation loss at ≥0.4 mg/kg/day and an increase in early resorptions and postimplantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day; doses of 0.4 and 0.8 mg/kg/day in rabbits are ~20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area

                Contraception

                • Advise females of reproductive potential to use contraception during treatment and for 6 months following final dose; if drug used during pregnancy or if patient becomes pregnant during treatment, patient should be apprised of potential risk to fetus
                • Advise male patients with female sexual partners to use effective contraceptive measures or abstain from sexual activity to prevent pregnancy during treatment and for at least 90 days following completion of therapy

                Lactation

                There are no data on presence of drug in human milk, effects on breastfed child, or on milk production; because many drugs are excreted in human milk and potential for serious adverse reactions in breastfed child unknown, advise nursing women not to breastfeed during treatment and for 2 weeks after treatment

                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 (27 mg/m²); 2079 ng/mL (56 mg/m²)

                AUC: 379 ng·hr/mL (27 mg/m²); 948 ng•hr/mL (56 mg/m²)

                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: ≤1 hr (Day 1 of Cycle 1)

                Clearance: 151-263 L/hr

                Excretion: Urine, metabolites (~25%)

                Urinary and fecal excretion of the parent compound was negligible (0.3% of total dose)

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                Administration

                IV Incompatibilities

                Do not mix with or administer as an infusion with other medicinal products

                IV Compatibilities

                Dextrose 5% (D5W)

                Thromboprophylaxis and 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 recommended dexamethasone dose if on combination therapy (see prescribing information)

                Monotherapy and combination with daratumumab and dexamethasone: Premedicate with dexamethasone 8 mg PO/IV 30 min

                Administer dexamethasone PO/IV at least 30 minutes to 4 hr each dose in Cycle 1, during 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 closely monitor blood chemistries

                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 oral or IV hydration as needed in subsequent cycles

                Monitor for fluid overload

                IV Preparation

                Remove vial from refrigerator prior to use

                Reconstitute each vial by slowly injecting 29 mL (60-mg vial) or 15 mL (30-mg vial) or 5 mL (10-mg vial) sterile water for injection, direct solution onto the inside wall of the vial to minimize foaming; resulting concentration of reconstituted vial is 2 mg/mL

                There is no data to support use of closed system transfer devices with carfilzomib

                Gently swirl and/or invert vial slowly for about 1 min, 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 min, until foaming subsides

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

                Administer directly by slow IV infusion or optionally, may dilute further by adding calculated dose to 50-100 mL D5W IV bag

                When administering in an IV bag, use ≥21-gauge needle (≤0.8 mm external diameter needle) to withdraw calculated dose

                Immediately discard vial containing unused portion

                IV Administration

                Do not administer by IV push or bolus

                Flush IV live with 0.9% NaCl or D5W immediately before and after carfilzomib administration

                Do not mix with or administer as an infusion with other medicinal products

                Infuse over 10 min

                • Monotherapy (20/27 mg/m2 twice weekly regimen)
                • Combination with lenalidomide and dexamethasone

                Infuse over 30 min

                • Combination with dexamethasone (once or twice weekly)
                • Combination with dexamethasone and IV daratumumab (once or twice weekly)
                • Monotherapy (20/56 mg/m2 twice weekly regimen)

                Storage

                Unopened vial: Refrigerate at 2-8ºC (36-46ºF); retain in original package to protect from light

                Reconstituted solution: Refrigerate for up to 24 hr at 2-8ºC (36-46ºF) or at room temperature up to 4 hr at 15-30ºC (59-86ºF)

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                Images

                BRAND FORM. UNIT PRICE PILL IMAGE
                Kyprolis intravenous
                -
                10 mg vial
                Kyprolis intravenous
                -
                60 mg vial

                Copyright © 2010 First DataBank, Inc.

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                Patient Handout

                Patient Education
                carfilzomib intravenous

                CARFILZOMIB - INJECTION

                (kar-FILZ-oh-mib)

                COMMON BRAND NAME(S): Kyprolis

                USES: This medication is used to treat a certain type of cancer (multiple myeloma). It works by helping to slow the growth and spread of cancer cells.

                HOW TO USE: This medication is given by injection into a vein by a health care professional. It is given as directed by your doctor, usually over 10 minutes or over 30 minutes. The dosage is based on your body size, lab tests, medical condition, and response to treatment.This medication can sometimes cause a serious reaction during and up to 24 hours after the injection. Tell your doctor right away if you develop symptoms such as chills, fever, flushing, trouble breathing, joint/muscle pain, chest pain, or fainting. Your doctor may prescribe other medications (such as dexamethasone) before each dose to help prevent serious side effects. Carefully follow your doctor's directions.

                SIDE EFFECTS: See also How to Use section.Dizziness, lightheadedness, nausea, vomiting, diarrhea, constipation, and tiredness may occur. If any of these effects last or get worse, tell your doctor or pharmacist promptly.To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.People using this medication may have serious side effects. However, you have been prescribed this drug because your doctor has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.Tell your doctor right away if you have any serious side effects, including: easy bruising/bleeding, numbness/tingling of arms/legs, fainting, fast/irregular heartbeat, symptoms of heart failure (such as shortness of breath, swelling ankles/feet, unusual tiredness, unusual/sudden weight gain), signs of liver disease (such as nausea/vomiting that doesn't stop, loss of appetite, stomach/abdominal pain, yellowing eyes/skin, dark urine), mental/mood changes (such as confusion), severe/persistent headache.This medication may raise your blood pressure. Check your blood pressure regularly and tell your doctor if the results are high. Your doctor may control your blood pressure with medication.Carfilzomib sometimes causes side effects due to the rapid destruction of cancer cells (tumor lysis syndrome). To lower your risk, your doctor may add a medication and tell you to drink plenty of fluids. Tell your doctor right away if you have symptoms such as: low back/side pain (flank pain), signs of kidney problems (such as painful urination, pink/bloody urine, change in the amount of urine), muscle spasms/weakness.This medication may increase your risk of getting a rare but very serious (possibly fatal) brain infection (progressive multifocal leukoencephalopathy-PML). Get medical help right away if you have any of these side effects: clumsiness, loss of coordination/balance, weakness, sudden change in your thinking (such as confusion, difficulty concentrating, memory loss), difficulty talking/walking, seizure, vision changes.Get medical help right away if you have any very serious side effects, including: sudden pain/swelling/redness in the legs, chest/jaw/left arm pain, trouble breathing, weakness on one side of the body, trouble speaking, black/bloody stools, vomit that looks like coffee grounds.This medication may lower your ability to fight infections. This may make you more likely to get a serious (rarely fatal) infection or make any infection you have worse. Tell your doctor right away if you have any signs of infection (such as fever, chills, persistent sore throat, cough).A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

                PRECAUTIONS: Before taking carfilzomib, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart disease (such as heart failure, heart attack, heart rhythm problems), high blood pressure, kidney disease, liver disease (such as hepatitis B), certain viral infections (herpes, shingles).Carfilzomib can make you more likely to get infections or may worsen any current infections. Avoid contact with people who have infections that may spread to others (such as chickenpox, measles, flu). Consult your doctor if you have been exposed to an infection or for more details.Do not have immunizations/vaccinations without the consent of your doctor. Avoid contact with people who have recently received live vaccines (such as flu vaccine inhaled through the nose).To lower the chance of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.This drug may make you dizzy. Alcohol or marijuana (cannabis) can make you more dizzy. Do not drive, use machinery, or do anything that needs alertness until you can do it safely. Limit alcoholic beverages. Talk to your doctor if you are using marijuana (cannabis).Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).Older adults may be more sensitive to the side effects of this drug, especially heart problems.Tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while using carfilzomib. Carfilzomib may harm an unborn baby. Females should use reliable forms of birth control during and for 6 months after treatment with carfilzomib. Males and their female partner should use reliable forms of birth control during and for 3 months after treatment with carfilzomib. If you or your partner become pregnant, talk to your doctor right away about the risks and benefits of this medication.It is unknown if this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding is not recommended while using this drug and for 2 weeks after stopping treatment. Consult your doctor before breast-feeding.

                DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.Some products that may interact with this drug are: other drugs that weaken the immune system/increase the risk of infection (such as natalizumab, rituximab).

                OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

                NOTES: Lab and/or medical tests (such as kidney/liver function tests, blood potassium level, blood pressure, complete blood count including platelets) should be done while you are using this medication. Keep all medical and lab appointments.

                MISSED DOSE: It is important to get each dose of this medication as scheduled. If you miss a dose, ask your doctor or pharmacist right away for a new dosing schedule.

                STORAGE: Not applicable. This medication is given in a clinic and will not be stored at home.

                MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-888-633-4298 (US) or 1-800-668-1507 (Canada).

                Information last revised September 2021. Copyright(c) 2021 First Databank, Inc.

                IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

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                Formulary

                FormularyPatient Discounts

                Adding plans allows you to compare formulary status to other drugs in the same class.

                To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.

                Adding plans allows you to:

                • View the formulary and any restrictions for each plan.
                • Manage and view all your plans together – even plans in different states.
                • Compare formulary status to other drugs in the same class.
                • Access your plan list on any device – mobile or desktop.

                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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                Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.