Carfilzomib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous:

Kyprolis: 10 mg (1 ea); 30 mg (1 ea); 60 mg (1 ea)

Pharmacology

Mechanism of Action

Carfilzomib inhibits proteasomes, which are responsible for intracellular protein homeostasis. Specifically, it is a potent, selective, and irreversible inhibitor of chymotrypsin-like activity of the 20S proteasome, leading to cell cycle arrest and apoptosis.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: 28 L (based on a 20 mg/m² dose); penetrates all tissues extensively except the brain (Kortuem 2013)

Metabolism

Rapid and extensive; peptidase cleavage and epoxide hydrolysis; minimal metabolism through cytochrome P450-mediated mechanisms

Excretion

Urine (~25% as metabolites; <1% as parent drug); feces (<1% as parent drug)

Half-Life Elimination

Doses ≥15 mg/m²: ≤1 hour on day 1 of cycle 1

Protein Binding

97%; to human plasma proteins

Use in Specific Populations

Special Populations: Renal Function Impairment

Patients with relapsed or progressive advanced malignancies with ESRD requiring hemodialysis had a 33% higher AUC compared to patients with normal renal function.

Special Populations: Hepatic Function Impairment

Patients with mild (total bilirubin 1 to 1.5 times ULN and any AST or total bilirubin ≤ULN and AST >ULN) or moderate (bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment had an approximately 50% higher AUC compared to patients with normal hepatic function.

Use: Labeled Indications

Multiple myeloma, relapsed/refractory: Treatment (monotherapy) of relapsed or refractory multiple myeloma in patients who have received 1 or more lines of therapy; treatment of relapsed or refractory multiple myeloma (in combination with dexamethasone or with lenalidomide plus dexamethasone) in patients who have received 1 to 3 prior lines of therapy

Use: Off Label

Multiple myeloma (newly diagnosed)b

Data from a small open-label phase II trial support the use of carfilzomib (in combination with cyclophosphamide and dexamethasone) in the management of newly diagnosed multiple myeloma in patients ≥65 years of age or who are ineligible for autologous stem cell transplant Bringhen 2014.

Waldenström macroglobulinemiab

Data from a small phase II trial support the use of carfilzomib (in combination with rituximab and dexamethasone) in the management of Waldenström macroglobulinemia in patients who have not previously received bortezomib or rituximab Treon 2014.

Contraindications

There are no contraindications listed in the manufacturer's US labeling

Canadian labeling: Hypersensitivity to carfilzomib or any component of the formulation

Dosage and Administration

Dosing: Adult

Note: Hydrate with oral fluids (30 mL/kg) at least 48 hours prior to initiating cycle 1, as well as with 250 to 500 mL normal saline (or other appropriate IV fluid) before dosing (recommended) and after (if needed) administration during cycle 1 (continue oral and/or IV hydration in subsequent cycles if necessary); monitor for evidence of volume overload and adjust hydration based on individual needs. Consider antiviral prophylaxis for patients with a history of herpes zoster infection. Thromboprophylaxis is recommended when administering in combination with dexamethasone or with lenalidomide plus dexamethasone. When administering in combination with dexamethasone, antacids may be recommended.

Premedication: When administering as monotherapy, premedicate with dexamethasone 4 mg orally or IV when infusing carfilzomib over 10 minutes or with dexamethasone 8 mg orally or IV when infusing carfilzomib over 30 minutes. When using combination therapy, administer the recommended dexamethasone dose (refer to prescribing information). Premedicate 30 minutes to 4 hours prior to all doses in cycle 1, and as needed with future cycles to reduce the incidence and severity of infusion reaction.

Note: Calculate dose using actual body surface area (BSA) at baseline. Patients with a BSA >2.2 m² should be dosed based upon a maximum BSA of 2.2 m². Dose adjustments for weight changes of ≤20% are not necessary, per manufacturer labeling.

Multiple myeloma, newly diagnosed (off-label use): Adults ≥65 years or ineligible for autologous transplant: IV:

Induction:

Cycle 1: 20 mg/m² over 30 minutes on days 1 and 2, and 36 mg/m² over 30 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle (in combination with cyclophosphamide and dexamethasone) (Bringhen 2014).

Cycles 2 to 9: 36 mg/m² over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle (in combination with cyclophosphamide and dexamethasone) (Bringhen 2014).

Maintenance: 36 mg/m² on days 1, 2, 15, and 16 of a 28-day treatment cycle (as a single-agent) until disease progression or unacceptable toxicity (Bringhen 2014).

Multiple myeloma, relapsed/refractory (single-agent; 20/27 mg/m² regimen [twice-weekly dosing]): IV:

Cycle 1: 20 mg/m² over 10 minutes on days 1 and 2; if tolerated, increase dose to 27 mg/m² over 10 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle

Cycles 2 to 12: 27 mg/m² over 10 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle

Cycle 13 and beyond: 27 mg/m² over 10 minutes on days 1, 2, 15, and 16 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity

Multiple myeloma, relapsed/refractory (single-agent; 20/56 mg/m² regimen [twice-weekly dosing]): IV:

Cycle 1: 20 mg/m² over 30 minutes on days 1 and 2; if tolerated, increase dose to 56 mg/m² over 30 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle.

Cycles 2 to 12: 56 mg/m² over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle.

Cycle 13 and beyond: 56 mg/m² over 30 minutes on days 1, 2, 15, and 16 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity.

Multiple myeloma, relapsed/refractory (in combination with lenalidomide and dexamethasone; 20/27 mg/m² regimen [twice-weekly dosing]) (Stewart 2015): IV:

Cycle 1: 20 mg/m² over 10 minutes on days 1 and 2; if tolerated, increase dose to 27 mg/m² over 10 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle.

Cycles 2 to 12: 27 mg/m² over 10 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle.

Cycles 13 to 18: 27 mg/m² over 10 minutes on days 1, 2, 15, and 16 of a 28-day treatment cycle; discontinue carfilzomib after cycle 18; beginning with cycle 19, lenalidomide and dexamethasone may be continued until disease progression or unacceptable toxicity.

Multiple myeloma, relapsed/refractory (in combination with dexamethasone; 20/56 mg/m² regimen [twice-weekly dosing]) (Dimopoulos 2016a): IV:

Cycle 1: 20 mg/m² over 30 minutes on days 1 and 2; if tolerated, increase dose to 56 mg/m² over 30 minutes on days 8, 9, 15, and 16 of a 28-day treatment cycle.

Cycle 2 and beyond: 56 mg/m² over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity.

Multiple myeloma, relapsed/refractory (in combination with dexamethasone; 20/70 mg/m² regimen [once-weekly dosing]) (Moreau 2018): IV:

Cycle 1: 20 mg/m² over 30 minutes on day 1; increase dose to 70 mg/m² over 30 minutes on days 8 and 15 of a 28-day treatment cycle.

Cycle 2 and beyond: 70 mg/m² over 30 minutes on days 1, 8, and 15 of a 28-day treatment cycle; continue until disease progression or unacceptable toxicity.

Waldenström macroglobulinemia (off-label use): IV:

Induction (Treon 2014):

Cycle 1: 20 mg/m² over 20 minutes on days 1, 2, 8, and 9 of a 21-day treatment cycle (in combination with dexamethasone and rituximab)

Cycles 2 to 6: 36 mg/m² over 30 minutes on days 1, 2, 8, and 9 of a 21-day treatment cycle (in combination with dexamethasone and rituximab)

Maintenance (started 8 weeks after completion of induction therapy in patients with stable disease or better response): 36 mg/m² on days 1 and 2 every 8 weeks for 8 cycles (in combination with dexamethasone and rituximab) (Treon 2014).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Carfilzomib dose level reductions for toxicity:

If initial dose is 27 mg/m²:

First dose reduction: 20 mg/m²

Second dose reduction: 15 mg/m²; if toxicity persists on 15 mg/m² dose, discontinue carfilzomib

If initial dose is 56 mg/m²:

First dose reduction: 45 mg/m²

Second dose reduction: 36 mg/m²

Third dose reduction: 27 mg/m²; if toxicity persists on 27 mg/m² dose, discontinue carfilzomib

If initial dose is 70 mg/m²:

First dose reduction: 56 mg/m²

Second dose reduction: 45 mg/m²

Third dose reduction: 36 mg/m²; if toxicity persists on 36 mg/m² dose, discontinue carfilzomib

Hematologic toxicity:

ANC <500/mm³: Withhold dose; continue at same dose level if ANC recovers to ≥500/mm³. For subsequent ANC levels <500/mm³, withhold dose and consider reducing dose by 1 dose level when ANC ≥500/mm³.

Neutropenic fever (ANC <500/mm³ with an oral temperature >38.5°C or 2 consecutive readings of >38°C for 2 hours): Withhold dose; if ANC recovers to baseline and fever resolves, resume at the same dose level.

Platelets: <10,000/mm³ or evidence of bleeding with thrombocytopenia: Withhold dose; continue at same dose level if platelets recover to ≥10,000/mm³ and bleeding is controlled. For subsequent platelet levels <10,000/mm³, withhold dose and consider reducing dose by 1 dose level when platelets ≥10,000/mm³.

Nonhematologic toxicity:

Grade 3 or 4 nonhematologic toxicities: Withhold dose until resolved or at baseline. After resolution, consider restarting the next scheduled treatment at 1 dose level reduction.

Cardiac: Grade 3 or 4, new-onset or worsening of heart failure, decreased left ventricular function, or myocardial ischemia: Withhold dose until resolved or at baseline. After resolution, if considered appropriate to reinitiate, consider restarting at 1 dose level reduction.

Hemorrhage or symptoms of blood loss: Reduce dose or withhold treatment as clinically appropriate.

Hypertension, severe or life-threatening: If hypertension cannot be adequately controlled, withhold dose and evaluate. After resolution, consider if appropriate to reinitiate based on risk versus benefit.

Pulmonary toxicity

Acute respiratory distress syndrome, acute respiratory failure, and acute diffuse infiltrative pulmonary disease (drug-induced): Discontinue therapy.

Pulmonary hypertension: Withhold dose until resolved or at baseline. After resolution, consider if appropriate to reinitiate based on risk versus benefit.

Grade 3 or 4 dyspnea: Withhold dose until resolved or at baseline. After resolution, consider if appropriate to reinitiate based on risk versus benefit.

Tumor lysis syndrome: Interrupt treatment until resolved.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: In general, utilize patient's actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012). Note: According to the manufacturer, patients with a body surface area (BSA) >2.2 m² should be dosed based upon a maximum BSA of 2.2 m²; dose adjustments for weight changes of ≤20% are not necessary.

Reconstitution

Reconstitute the 60 mg vial with 29 mL, the 30 mg vial with 15 mL, and the 10 mg vial with 5 mL of sterile water for injection using a 21-gauge or larger needle (0.8 mm or smaller external diameter needle), to a concentration of 2 mg/mL (directing solution onto the inside wall of the vial to avoid foaming). Gently invert and/or swirl vial slowly for ~1 minute to mix; do not shake. If foaming results, allow solution to sit for ~5 minutes until foaming resolves. Reconstituted solution should be clear and colorless. May administer directly, or may further dilute dose by using a 21-gauge or larger needle (0.8 mm or smaller external diameter needle) to transfer the reconstituted solution into 50 or 100 mL (depending on dose and infusion duration) of D5W. Discard unused portion of the vial (do not pool unused solution from the vials).

Administration

IV: Administer over 10 or 30 minutes depending on the carfilzomib dose regimen (see Dosing). Do not administer as an IV push or bolus. Hydrate with oral fluids (30 mL/kg) at least 48 hours prior to initiating cycle 1, as well as with 250 to 500 mL NS (or other appropriate IV fluid) prior to (recommended) and after (if needed) each dose in cycle 1; continue oral and/or IV hydration in subsequent cycles (if necessary). Flush line immediately before and after carfilzomib with NS or D₅W. Do not administer with other medications.

When administering as monotherapy, premedicate with dexamethasone 4 mg orally or IV when infusing carfilzomib over 10 minutes or with dexamethasone 8 mg orally or IV when infusing carfilzomib over 30 minutes. When using combination therapy, administer the recommended dexamethasone dose (refer to prescribing information). Premedicate 30 minutes to 4 hours prior to all doses in cycle 1, and as needed with future cycles to reduce the incidence and severity of infusion reaction.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Store in original carton until use to protect from light. Reconstituted drug (in the vial or in a syringe) and preparations diluted for infusion in D5W are stable for 4 hours at room temperature or for 24 hours refrigerated at 2°C to 8°C (36°F to 46°F).

Drug Interactions

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Estrogen Derivatives (Contraceptive): Carfilzomib may enhance the thrombogenic effect of Estrogen Derivatives (Contraceptive). Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib. Consider therapy modification

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Avoid combination

Lumacaftor and Ivacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor and Ivacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Progestins (Contraceptive): Carfilzomib may enhance the thrombogenic effect of Progestins (Contraceptive). Management: Consider alternative, non-hormonal methods of contraception in patients requiring therapy with carfilzomib. Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Ranolazine: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

Adverse Reactions

≥10%:

Cardiovascular: Hypertension (15% to 42%), peripheral edema (20% to 21%), chest pain (3% to 21%)

Central nervous system: Fatigue (40% to 58%), chills (12% to 38%), headache (24% to 33%), insomnia (13% to 29%), dizziness (11% to 29%), hypoesthesia (Siegel 2013), peripheral neuropathy (Siegel 2012)

Gastrointestinal: Nausea (35% to 54%), vomiting (17% to 33%), diarrhea (25% to 27%), anorexia (15% to 21%), constipation (Siegel 2013)

Hematologic & oncologic: Thrombocytopenia (32% to 54%; ≥ grade 3: 25% to 54%), anemia (42% to 49%, ≥ grade 3: 24% to 29%), lymphocytopenia (14% to 33%; ≥ grade 3: 12% to 33%), leukopenia (Siegel 2013), neutropenia (Siegel 2013)

Neuromuscular & skeletal: Back pain (19% to 21%), muscle spasm (10% to 21%)

Renal: Increased serum creatinine (17% to 25%)

Respiratory: Dyspnea (34% to 58%), cough (22% to 33%), upper respiratory tract infection (19% to 21%), pneumonia (Siegel 2013)

Miscellaneous: Fever (30% to 58%)

1% to 10%:

Cardiovascular: Deep vein thrombosis (≤2%), pulmonary embolism (≤2%), pulmonary hypertension (1%), ischemic heart disease (Siegel 2013)

Central nervous system: Paresthesia (Siegel 2013), peripheral sensory neuropathy (Siegel 2013)

Endocrine & metabolic: Hypercalcemia (Siegel 2013), hyponatremia (Siegel 2012), hypophosphatemia (Siegel 2012)

Hematologic & oncologic: Febrile neutropenia

Renal: Renal insufficiency (10%), acute renal failure (more common in patients with advanced relapsed and refractory multiple myeloma [Siegel 2013]), renal failure syndrome (Siegel 2013)

Respiratory: Acute respiratory distress syndrome (≤1%), acute respiratory failure (≤1%), interstitial pulmonary disease (≤1%), pneumonitis (≤1%)

Frequency not defined:

Cardiovascular: Cardiac failure, hypertensive crisis, hypotension, thromboembolic complications

Central nervous system: Anxiety, intracranial hemorrhage, pain, voice disorder

Dermatologic: Erythema of skin, hyperhidrosis, pruritus, skin rash

Endocrine & metabolic: Hyperglycemia, hyperkalemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypokalemia, hypomagnesemia

Gastrointestinal: Abdominal pain, dyspepsia, gastrointestinal hemorrhage, toothache, upper abdominal pain

Genitourinary: Urinary tract infection

Hematologic & oncologic: Hemorrhage, pulmonary hemorrhage

Hepatic: Hepatic failure, increased serum transaminases

Infection: Influenza, sepsis

Local: Infusion site reaction

Neuromuscular & skeletal: Arthralgia, asthenia, limb pain, musculoskeletal chest pain, musculoskeletal pain, myalgia

Ophthalmic: Blurred vision, cataract

Respiratory: Bronchitis, bronchopneumonia, epistaxis, nasopharyngitis, oropharyngeal pain, pulmonary edema, pulmonary infection, respiratory tract infection, rhinitis

Miscellaneous: Multiorgan failure

<1%, postmarketing, and/or case reports: Acute myocardial infarction (Siegel 2012), cardiomyopathy (restrictive), cytomegalovirus disease, gastrointestinal perforation, hemolytic-uremic syndrome, immune thrombocytopenia, pericarditis, peripheral motor neuropathy (Siegel 2013), pulmonary disease, reversible posterior leukoencephalopathy syndrome, tumor lysis syndrome (Siegel 2012)

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Thrombocytopenia (including grade 4) was observed in patients receiving carfilzomib, with platelet nadirs occurring between day 8 and day 15 of each 28-day treatment cycle, and recovery to baseline by the start of the next cycle. Monitor platelets closely and adjust dose or withhold therapy if necessary. Hemorrhage due to thrombocytopenia may occur. Anemia, lymphopenia, leukopenia, and neutropenia were also observed.
• Cardiovascular effects: Death caused by cardiac arrest has occurred within 24 hours of administration. Carfilzomib has been associated with new-onset or worsening of heart failure (HF), pulmonary edema, decreased left ventricular ejection fraction (LVEF), restrictive cardiomyopathy, myocardial ischemia, and MI (including fatalities). Some events occurred in patients with normal ventricular function at baseline. Cardiac events typically were observed throughout the course of therapy. Patients ≥75 years of age have an increased risk of heart failure. Monitor closely for cardiac complications and for volume overload (due to pretreatment hydration), particularly in patients at risk for HF; withhold carfilzomib therapy for grade 3 or 4 cardiac events until recovery. Patients with New York Heart Association Class III and IV heart failure, recent MI (within 3 to 6 months), and conduction abnormalities, angina, or arrhythmias not managed by medication were excluded from clinical trials and may be at increased risk for cardiac complications; evaluate with a comprehensive medical assessment prior to initiation and closely monitor.
• Hemorrhage: Serious or fatal cases of hemorrhage have been reported, including GI, intracranial, and pulmonary hemorrhage and epistaxis. Bleeding may be spontaneous; intracranial hemorrhage has occurred without trauma. Hemorrhage has been reported in patients with and without low platelets and has also been reported in patients who were not receiving anticoagulation or antiplatelet therapy. Monitor for signs/symptoms of hemorrhage and promptly evaluate symptoms of blood loss. Reduce dose or withhold treatment as clinically indicated.
• Hepatic effects: Hepatic failure, including fatal cases, has been reported rarely. Increased transaminases and hyperbilirubinemia have also been observed. Interrupt therapy with grade 3 or higher hepatic toxicity until resolved or recovered to baseline (may require dose reduction if appropriate to reinitiate); monitor liver enzymes regularly.
• Hypertension: Hypertension has occurred with use; hypertensive crisis and hypertensive emergency have also been reported (some events were fatal). Control hypertension prior to initiating carfilzomib. Monitor blood pressure regularly throughout therapy; if hypertension cannot be adequately controlled, interrupt carfilzomib therapy and evaluate; assess risks versus benefits when determining to restart treatment.
• Infusion reactions: May occur immediately following or within 24 hours of carfilzomib infusion; may be life-threatening. Symptoms have included fever, chills, arthralgia, myalgia, flushing, facial edema, vomiting, weakness, dyspnea, hypotension, syncope, chest tightness, or angina. To lessen the incidence and intensity of infusion reactions, administer dexamethasone prior to drug administration.
• Posterior reversible encephalopathy syndrome: Posterior reversible encephalopathy syndrome (PRES) has been reported rarely with use; symptoms include seizure, headache, lethargy, confusion, blindness, altered consciousness, hypertension, and other visual/neurological disturbances. Discontinue therapy if PRES diagnosis is suspected; the safety of reinitiating therapy after PRES diagnosis is not known.
• Pulmonary toxicities: Acute respiratory distress syndrome (ARDS), acute respiratory failure, and acute diffuse-infiltrative pulmonary disease (eg, pneumonitis and interstitial lung disease) have occurred in a small number of patients (some events were fatal); discontinue therapy if any of these drug-induced pulmonary toxicities occur. In clinical trials, pulmonary arterial hypertension (PAH) was observed (including grade 3 or higher events); perform cardiac imaging or other testing as appropriate, and withhold carfilzomib until PAH is resolved or returns to baseline. Dyspnea (including grade 3 or higher events) has been reported; monitor closely. Withhold carfilzomib for grade 3 or 4 dyspnea until pulmonary symptom resolution or return to baseline.
• Renal toxicity: Renal toxicity (eg, renal insufficiency, acute renal failure, renal failure) has been reported with carfilzomib; some events have been fatal. Acute renal failure was observed more frequently in patients receiving carfilzomib monotherapy for advanced relapsed/refractory multiple myeloma; renal failure risk is greater when patients have a baseline reduced CrCl. Monitor renal function closely; may require therapy interruption or dose reduction.
• Thrombotic microangiopathy: Thrombotic microangiopathy, including cases of thrombocytopenic thrombotic purpura/hemolytic uremic syndrome (TTP/HUS) has been reported (some fatal); monitor for signs/symptoms. Interrupt therapy if TTP/HUS diagnosis is suspected and manage appropriately (eg, plasma exchange as clinically necessary). If TTP/HUS diagnosis is excluded, may consider reinitiating therapy; the safety of restarting carfilzomib after a TTP/HUS diagnosis is not known.
• Thromboembolic events: Venous thromboembolism (eg, deep vein thrombosis and pulmonary embolism) has been observed, particularly when used as part of combination therapy with dexamethasone or with lenalidomide plus dexamethasone. Thromboprophylaxis is recommended with combination therapy, and should be based on patients’ underlying risk factors, treatment regimen, and clinical status. Due to risk of thrombosis with hormonal contraception, consider an alternative method of effective contraception during combination treatment of carfilzomib with dexamethasone or lenalidomide plus dexamethasone.
• Tumor lysis syndrome: Tumor lysis syndrome (TLS), including fatalities, has been observed. TLS risk is increased in multiple myeloma patients with a high tumor burden. Adequately hydrate patients prior to carfilzomib therapy and monitor closely for signs and symptoms of TLS; consider use of antihyperuricemic agents. If TLS occurs, interrupt treatment until resolved.

Disease-related concerns:

• Hepatic impairment: The incidence of serious adverse events is higher in patients with baseline hepatic impairment (compared to patients with normal hepatic function). Dose reductions are recommended at treatment initiation in patients with mild or moderate hepatic impairment.

Concurrent drug therapy issues:

• Combination therapy toxicity: An increased incidence of serious and fatal adverse events was observed in a clinical trial comparing the combination of carfilzomib, melphalan, and prednisone (KMP) to bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed multiple myeloma (MM) in transplant-ineligible patients. Cardiac failure, hypertension, acute renal failure, and dyspnea were observed more frequently in the KMP arm. KMP is not an approved carfilzomib combination regimen.
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: The incidence of serious adverse events is higher in patients ≥65 years of age (compared to younger patients).

Dosage form specific issues:

• Injection: Vials contain the excipient cyclodextrin (sulfobutyl ether beta-cyclodextrin), which may accumulate in patients with renal insufficiency, although the clinical significance of this finding is uncertain (Luke 2010).

Monitoring Parameters

CBC with differential and platelets (monitor frequently throughout therapy), serum potassium levels regularly during treatment, renal function, pulmonary function (with new or worsening pulmonary symptoms), liver function tests, blood pressure (regularly during treatment in all patients). Pregnancy test (prior to treatment initiation) in females of reproductive potential. Signs/symptoms of infusion-related reactions, congestive heart failure, tumor lysis syndrome, peripheral neuropathy, posterior reversible encephalopathy syndrome, thrombocytopenic thrombotic purpura/hemolytic uremic syndrome, and venous thromboembolic events. Monitor for evidence of volume overload due to pre- and posthydration.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action and findings from animal reproduction studies, carfilzomib may cause fetal harm if administered to a pregnant female.

Conduct pregnancy testing prior to treatment initiation in females of reproductive potential. Females of reproductive potential should avoid pregnancy during carfilzomib treatment and use effective contraception during treatment and for at least 6 months after the final carfilzomib dose. Males with female partners of reproductive potential should use effective contraception during treatment and for at least 3 months after the final carfilzomib dose.

Carfilzomib may impair fertility in males and females (based on the mechanism of action).

Patient Education

What is this drug used for?

• It is used to treat multiple myeloma.
• It may be given to you for other reasons. Talk with the doctor.
• If you have just been diagnosed with multiple myeloma and cannot have a transplant, talk with your doctor. A study showed that these patients taking this drug with certain other drugs (melphalan and prednisone) had more very bad and sometimes deadly side effects compared to a certain other drug.

Frequently reported side effects of this drug

• Diarrhea
• Constipation
• Muscle spasm
• Lack of appetite
• Back pain
• Trouble sleeping
• Nausea
• Vomiting
• Common cold symptoms
• Fatigue
• Loss of strength and energy

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infusion reaction
• Infection
• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache
• Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome like bruising or bleeding, loss of strength and energy, dark urine or yellow skin, pale skin, change in amount of urine passed, vision changes, change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or fever
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums, abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish
• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out
• Kidney problems like unable to pass urine, blood in urine, change in amount of urine passed, or weight gain
• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Severe pulmonary disorder like lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse
• Flushing
• Muscle pain
• Joint pain
• Dizziness
• Vision changes
• Passing out
• Severe headache
• Burning or numbness feeling
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.