Cisplatin FDA label changes

In 2013 we blogged about the controversy with the FDA labeling for cisplatin and its warning for TPMT variants and increased risk of ototoxicity in children. The 2012 label stated:

“Certain genetic variants in the thiopurine S-methyltransferase gene (e.g., TPMT*3B and TPMT*3C) are associated with an increased risk of ototoxicity in children administered conventional doses of cisplatin...Children who do not have one of these TPMT gene variants remain at risk for ototoxicity. All pediatric patients receiving cisplatin should have audiometric testing at baseline, prior to each subsequent dose, of drug and for several years post therapy.”

The label change appeared to be based on a single study from 2009.  Several years have passed and there is still very limited data in the public domain about TPMT and risk for cisplatin-induced ototoxicity: four papers comprising seven studies and a meta-analysis [PMID:19898482] [PMID:23820299] [PMID:23588304] [PMID:25551397]. The meta-analysis found no association with any of the TPMT variants and that the studies were significantly heterogeneous in terms of cancer types, ethnicities, age and co-treatments, all of which influence risk for ototoxicity.

The FDA has requested changes to the cisplatin label removing the whole Pharmacogenomics section, to now state :

“Genetic factors (e.g. variants in the thiopurine S-methyltransferase [TPMT] gene) may contribute to cisplatin-induced ototoxicity; although this association has not been consistent across populations and study designs.” 


This better reflects the current uncertainty about this gene-drug relationship and is more in line with the level of evidence we have assessed in our clinical annotations for the TPMT variants and cisplatin.