This communication is to inform members of the oncology community of recent changes in the measurement of serum creatinine which may have an impact on carboplatin dosing. Based on preliminary communications with the National Cancer Institute/Cancer Therapy Evaluation Program, a potential safety issue with carboplatin dosing has been identified. By the end of 2010, all clinical laboratories in the US will use the new standardized Isotope Dilution Mass Spectrometry (IDMS) method to measure serum creatinine. The IDMS method appears to underestimate serum creatinine values compared to older methods when the serum creatinine values are relatively low (e.g., ~0.7 mg/dL). Measurement of serum creatinine by the IDMS-method could result in an overestimation of the Glomerular Filtration Rate (GFR) in some patients with normal renal function. If the total carboplatin dose is calculated based on IDMS-measured serum creatinine using the Calvert formula, carboplatin dosing couldbe higher than desired and could result in increased drug-related toxicity.
The current label for carboplatin provides safe dosing instructions that are based on actual GFR measurements. Provided that actual GFR measurements are made to assess renal function, carboplatin can be safely dosed according to the instructions described in the label.
If a patient’s GFR is estimated based on serum creatinine measurements by the IDMS method, FDA recommends that physicians consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. Based on the Calvert formula described in the carboplatin label, the maximum doses can be calculated as:
Total Carboplatin Dose (mg) = (target AUC) x (GFR +25) [Calvert formula]
Maximum Carboplatin Dose (mg) = target AUC (mg·min/mL) x (150 mL/min)
The maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients with normal renal function. No higher estimated GFR values should be used.
For a target AUC = 6, the maximum dose is 6 x 150 = 900 mg
For a target AUC = 5, the maximum dose is 5 x 150 = 750 mg
For a target AUC = 4, the maximum dose is 4 x 150 = 600 mg
Principal investigators of ongoing clinical trials should assess whether carboplatin dosing in those trials should be adjusted according to the above information.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).