Dosing and uses of Kyprolis (carfilzomib)
Adult dosage forms and strengths
injection, IV
- 60mg/vial
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
Pediatric dosage forms and strengths
<18 years: Safety and efficacy not established; use not recommended in children
Kyprolis (carfilzomib) adverse (side) 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
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 frequently
Fatal or serious cases of hemorrhage may occur, including gastrointestinal, pulmonary, and intracranial hemorrhage; promptly evaluate signs and symptoms of blood loss
Therapy can cause fetal harm; females of reproductive potential should avoid becoming pregnant while being treated
Cardiovascular risk
- 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
Pregnancy and 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.
Pharmacology of Kyprolis (carfilzomib)
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
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)
