carfilzomib (Rx)

>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

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

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.

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)

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)