CARFILZOMIB
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CARFILZOMIB (CARFILZOMIB).
Irreversible proteasome inhibitor; selectively binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome, leading to inhibition of chymotrypsin-like activity and accumulation of polyubiquitinated proteins, resulting in cell cycle arrest and apoptosis in multiple myeloma cells.
| Metabolism | Primarily metabolized via peptidase and epoxide hydrolase activities, with minor contributions from cytochrome P450 enzymes (CYP1A2, CYP2C19, and CYP3A4); the major metabolite is a ring-opened alcohol derivative, which is inactive. |
| Excretion | Primarily hepatic metabolism, with less than 2% of the dose excreted unchanged in urine and approximately 25% excreted in feces (as metabolites). |
| Half-life | Terminal elimination half-life of approximately 1 hour (range 0.3–2 hours); rapid clearance necessitates twice-weekly dosing. |
| Protein binding | Approximately 97–98% bound to human plasma proteins, predominantly albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Mean Vd at steady state is approximately 11 L/m² (about 0.3 L/kg), indicating limited extravascular distribution. |
| Bioavailability | Not applicable; carfilzomib is administered only intravenously due to extensive first-pass metabolism. |
| Onset of Action | Intravenous: Clinical response (e.g., reduction in serum free light chains) may be observed within 1–2 weeks of starting treatment. |
| Duration of Action | Duration of proteasome inhibition in blood cells is transient, with recovery within 24 hours; clinical duration of response depends on regimen and tumor sensitivity. |
20 mg/m2 intravenously over 10 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle; increase to 27 mg/m2 from cycle 2 if tolerated. Administered with dexamethasone and lenalidomide or cyclophosphamide.
| Dosage form | POWDER |
| Renal impairment | For CrCl 15-29 mL/min: no dose adjustment required; but for patients on hemodialysis, administer after dialysis. If CrCl <15 mL/min: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose to 20 mg/m2. Child-Pugh C: not recommended. |
| Pediatric use | Not established for patients <18 years. Safety and efficacy not determined. |
| Geriatric use | No specific dose adjustment required; consider monitoring for cardiac and renal function due to increased sensitivity. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for CARFILZOMIB (CARFILZOMIB).
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. Due to potential serious adverse reactions, breastfeeding is not recommended during therapy and for at least 2 weeks after last dose. M/P ratio unknown. |
| Teratogenic Risk | Carfilzomib is embryolethal and teratogenic in animal studies. There are no adequate human data. Use is contraindicated in pregnancy due to risk of fetal harm. First trimester: high risk of malformations. Second and third trimesters: potential for fetal growth restriction, oligohydramnios, and neonatal toxicity. |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
["Hypersensitivity to carfilzomib or any of its components (including severe reactions such as anaphylaxis)"]
| Precautions | ["Cardiac toxicity: Fatal or serious cardiac adverse events including cardiac arrest, congestive heart failure, myocardial ischemia, and arrhythmias; monitor cardiac function and manage appropriately.","Pulmonary toxicity: Acute respiratory distress syndrome (ARDS), pneumonitis, pulmonary hypertension, and pulmonary edema; interrupt or discontinue therapy.","Hepatic toxicity: Hepatic failure and hepatitis; monitor hepatic enzymes and bilirubin.","Posterior reversible encephalopathy syndrome (PRES): Monitor for hypertension, headache, seizures, visual disturbances; discontinue if suspected.","Tumor lysis syndrome: Monitor patients at risk and manage with hydration and uric acid-lowering agents.","Thrombotic microangiopathy (TMA): Including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome; discontinue if suspected.","Infusion reactions: Reactions may include hypotension, dyspnea, fever, chills; premedicate with corticosteroids and antihistamines.","Thrombocytopenia: Monitor platelet counts and adjust dosing as needed.","Hepatitis B virus (HBV) reactivation: Screen and monitor in patients at risk.","Embryo-fetal toxicity: Can cause fetal harm; advise females of reproductive potential and males with female partners to use effective contraception."] |
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| Fetal Monitoring |
| Monitor complete blood count, hepatic function, renal function (serum creatinine, BUN), cardiac function (echocardiogram, blood pressure), and pulmonary status (for dyspnea, pulmonary hypertension). Fetal monitoring via ultrasound for growth and amniotic fluid volume. |
| Fertility Effects | Carfilzomib may impair fertility in males and females based on animal studies showing reduced spermatogenesis, ovarian effects, and embryolethality. Human fertility effects unknown. |
| Food/Dietary | Avoid grapefruit and grapefruit juice, as they may increase drug levels. No specific food restrictions otherwise. |
| Clinical Pearls | Carfilzomib is a proteasome inhibitor used in multiple myeloma. It can cause cardiotoxicity including heart failure, hypertension, and arrhythmias; assess cardiac function before and during treatment. Infusion reactions are common; premedicate with dexamethasone. Monitor for tumor lysis syndrome, especially in high tumor burden. Dose reduction required for moderate hepatic impairment. Not a substrate of CYP450, but caution with strong CYP3A4 inducers or inhibitors. |
| Patient Advice | Take exactly as prescribed; do not skip doses. · Report any chest pain, shortness of breath, or swelling of ankles immediately. · Hydrate well before and after infusion to prevent kidney damage. · Avoid grapefruit and Seville oranges during treatment. · Use effective contraception; do not breastfeed. · Inform doctor of all medications, including herbal supplements. · You may experience fatigue, nausea, or low blood counts; report severe symptoms. |