Tolterodine's Safety Profile in Children Remains Reassuring

ROCKVILLE, MD. — No new safety concerns were raised in a review of pediatric adverse event reports for the muscarinic receptor antagonist tolterodine, according to the Food and Drug Administration.

Tolterodine is marketed as Detrol and Detrol LA (the extended-release formulation). Among the drug's indications is treatment of overactive bladder in both neurologically impaired and neurologically intact children.

Dr. Larry Grylack, a medical officer in the FDA's division of pediatric drug development, Rockville, Md., presented data before the FDA's Pediatric Advisory Committee from pediatric exclusivity studies in neurologically impaired and intact children with overactive bladder, as well as data from other studies by Pfizer.

The three 12-week, open-label studies of neurologically impaired children enrolled 34 patients aged 1 month to 15 years, who received different doses of Detrol immediate release syrup or Detrol LA capsules. The urodynamic data were inconsistent within and across trials, and there was a “lack of dose response trends” across studies, Dr. Grylack told the panel. The two phase III studies of neurologically intact patients with overactive bladder, aged 5–10, found no significant differences in the number of weekly incontinence episodes during waking hours in the 486 children on Detrol LA (2 mg/day), compared with the 224 on placebo.

In these and the other Pfizer studies, of 917 pediatric patients taking tolterodine, 20 patients reported 24 serious adverse events, including four lower urinary tract infections (UTIs) and three cases of pyelonephritis. There were no deaths. There also were reports of aggressive and/or abnormal behavior in 18 patients, which were called nonserious adverse events, Dr. Grylack said. The Detrol LA label already includes information on the excess number of UTIs and episodes of abnormal behavior in patients treated with tolterodine, compared with those on placebo, he noted.

The adverse event reporting system database entries from 1998, when Detrol was approved, through February 2005 included 29 unduplicated pediatric adverse event reports (25 for Detrol and 4 for Detrol LA). Nine were anticholinergic events, including lethargy, urine retention, constipation, dry mouth, and blurred vision, as listed on the labels. But events also included overheating, confusion, and flushing.

There also were eight reports of CNS stimulation: These included reports of aggression and hyperactivity, which are not listed in the Detrol label but are on the Detrol LA label; and irritability and insomnia, which are not on either label. There were two reports of UTIs, three of medication errors, and five classified as “other.”