Dosing & Uses
Dosage Forms & Strengths
injection, lyophilized powder for reconstitution
- 10mg/vial
- 30mg/vial
- 60mg/vial
Multiple Myeloma
Indicated for relapsed or refractory multiple myeloma in patients who have received 1-3 prior lines of therapy as a dual regimen with dexamethasone
Also indicated as a single agent for relapsed or refractory multiple myeloma in patient who have received ≥1 line of therapy
Combination with dexamethasone (once weekly regimen)
- Each 28-day period is 1 treatment cycle
- Cycle 1
- 20 mg/m² in Cycle 1 on Day 1; if tolerated, escalate dose to 70 mg/m² on Day 8 of Cycle 1
- Administer carfilzomib on Days 1, 8, and 15
- Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22
- Administer dexamethasone 30 minutes to 4 hr before carfilzomib
- Cycle 2-9
- Administer carfilzomib on Days 1, 8, and 15
- Dexamethasone 40 mg PO or IV on Days 1, 8, 15, and 22
- Administer dexamethasone 30 minutes to 4 hr before carfilzomib
- Cycle 10 and thereafter
- 70 mg/m² on Day 1, 8, and 15
- Dexamethasone 40 mg PO or IV on Days 1, 8, and 15
- Administer dexamethasone 30 minutes to 4 hr before carfilzomib
- Continue until disease progression or unacceptable toxicity occurs
Combination with dexamethasone (twice weekly regimen)
- 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
- Cycle 1
- Administer carfilzomib on Days 1 and 2, Days 8 and 9, and Days 15 and 16
- 20 mg/² 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
- Continue until disease progression or unacceptable toxicity occurs
Combination with lenalidomide and dexamethasone
- 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
- 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 Day 8 and 9 doses of carfilzomib (administer on Days 1 and 2, and Days 15 and 16)
- Discontinue carfilzomib after Cycle 18
Monotherapy
- Each 28-day period is considered 1 treatment cycle
- 20/27 mg/m² twice weekly 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 Day 8 and 9 doses of carfilzomib (administer on Days 1 and 2, and Days 15 and 16)
- 20/56 mg/m² twice weekly 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 and dexamethasone (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 × 10^9/L, continue at same dose level
- For subsequent drops to <0.5 × 10^9/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 × 10^9/L and/or bleeding is controlled, continue at same dose level
- For subsequent drops to <10 × 10^9/L, followsame 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
<18 years: Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
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
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
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
Inform patient of the risk and symptoms of infusion reactions
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
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 ~34% of patients in clinical trials with carfilzomib
Hypertension, including hypertensive crisis and hypertensive emergency, has been observed
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
- 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
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
- 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
- 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
- Control hypertension prior to starting 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
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.
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)
Administration
Administration Precautions
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 dose of dexamethasone for monotherapy or recommended dexamethasone dose if on combination therapy (see prescribing information)
- Administer dexamethasone PO/IV at least 30 minutes, but not exceeding 4 hr before all cycle 1 doses, 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 IV hydration as needed in subsequent cycles Monitor for fluid overload
Dose for BSA >2.2 m²
- Calculated dose using 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
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 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
Reconstituted product should be a clear, colorless solution; if any discoloration or particulate matter is observed, do not use the reconstituted product
Can be administered 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
Administer IV over 10 or 30 minutes depending on the dose regimen
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
Storage
Unopened vial: Refrigerate at 2-8°C (36-46°F); retain in original package to protect from light
Reconstituted solution: Refrigerate for up to 24 hr at 2-8°C (36-46°F) or at room temperature up to 4 hr at 15-30°C (59-86°F)
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Patient Handout
Formulary
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