Carfilzomib

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.

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.

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 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 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.

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 (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.

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 (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, 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.

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 (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. Concurrent drug therapy issues:

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.

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. Dosage form specific issues:

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).