KYPROLIS
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KYPROLIS (KYPROLIS).
Carfilzomib is an irreversible inhibitor of the proteasome, a large protease complex that degrades ubiquitinated proteins. By blocking proteasome function, carfilzomib disrupts protein homeostasis, leading to accumulation of misfolded proteins, activation of the unfolded protein response, endoplasmic reticulum stress, and ultimately apoptosis, particularly in myeloma cells with high protein turnover.
| Metabolism | Carfilzomib is extensively metabolized via peptidase cleavage and epoxide hydrolysis, with minor contributions from CYP450 enzymes (primarily CYP3A4/5). The major metabolic pathways are non-CYP mediated, involving rapid degradation to metabolites that are inactive. |
| Excretion | Primarily hepatic metabolism; less than 2% of the dose is excreted unchanged in urine and feces combined |
| Half-life | Terminal elimination half-life of 1.3 to 2.1 hours (mean 1.5 hours), supporting continuous infusion scheduling |
| Protein binding | Approximately 97% bound to human plasma proteins, primarily to serum albumin and alpha-1-acid glycoprotein |
| Volume of Distribution | Mean volume of distribution is approximately 5 L/kg (range 3–10 L/kg), indicating extensive extravascular distribution and tissue binding |
| Bioavailability | Not applicable; KYPROLIS is administered intravenously only, thus bioavailability is 100% |
| Onset of Action | Intravenous: measurable proteasome inhibition within 1 hour of infusion start |
| Duration of Action | Proteasome inhibition persists for approximately 48 hours after a 30-minute infusion; clinical dosing is on days 1, 2, 8, 9, 15, 16 of a 28-day cycle |
| Action Class | Proteasome inhibitor |
| Brand Substitutes | Carfilnat Injection, Carzomib 60mg Injection |
20 mg/m² IV over 30 minutes on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle; increase to 27 mg/m² on day 8 of cycle 1 if tolerated.
| Dosage form | POWDER |
| Renal impairment | CrCl 15-49 mL/min: reduce dose by 25%. CrCl <15 mL/min or dialysis: not recommended. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 25%. Child-Pugh C: not recommended. |
| Pediatric use | Safety and efficacy not established; no recommended dose. |
| Geriatric use | No specific dose adjustment; monitor for toxicity and renal function as older patients may have decreased renal reserve. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for KYPROLIS (KYPROLIS).
| Breastfeeding | No human data on presence in breast milk. M/P ratio unknown. Due to potential for serious adverse reactions, advise not to breastfeed during treatment and for 2 weeks after last dose. |
| Teratogenic Risk | Pregnancy Category D. Embryofetal toxicity including malformations and death observed in animal studies at doses below clinical exposure. Avoid use in pregnancy unless benefit outweighs risk. |
| Fetal Monitoring |
■ FDA Black Box Warning
Cardiac toxicity: Fatal or serious cardiac events (e.g., cardiac failure, ischemia, arrhythmia) have occurred, especially in patients with pre-existing cardiac risk factors. Monitor for signs/symptoms of cardiac failure, ischemia, and arrhythmias, and interrupt or discontinue therapy accordingly.
| Serious Effects |
["Hypersensitivity to carfilzomib or any component of the formulation."]
| Precautions | ["Cardiac toxicity: Includes cardiac failure, ischemia, and arrhythmias. Monitor cardiac function and manage risk factors.","Pulmonary toxicity: Acute respiratory distress syndrome, pneumonitis, interstitial lung disease, and pulmonary hypertension have been reported.","Infusion reactions: May include fever, chills, hypotension, dyspnea, and other symptoms. Premedicate with dexamethasone.","Tumor lysis syndrome: Monitor patients at high risk and provide appropriate prophylaxis.","Thrombotic microangiopathy: Cases of thrombotic microangiopathy (including hemolytic uremic syndrome) have been reported.","Hepatotoxicity: Has been associated with elevations in liver enzymes and hepatic failure.","Posterior reversible encephalopathy syndrome (PRES): Rare but can occur; manage with discontinuation."] |
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| Monitor complete blood counts (CBC) for cytopenias, liver function tests, serum creatinine, and cardiac function (echocardiogram) for pulmonary hypertension. Assess fetal growth via ultrasound if exposed. |
| Fertility Effects | Animal studies show impaired fertility in males and females. May cause reduced sperm count and ovarian dysfunction. Data on human fertility effects are lacking. |