PRODUCT MONOGRAPH IMITREX DF IMITREX ... - GlaxoSmithKline

Chronic toxicity studies were carried out for 24 weeks and 72 weeks in rats and 26 and60 weeks in dogs.In both the 24-week and 72-week studies in rats receiving sumatriptan doses of 5, 50 and500 mg/kg/day orally, clinical signs were similar to those seen in previous oral toxicitystudies in rats and were mild and transient in nature.Animals of each sex receiving 50 and 500 mg/kg/day gained weight more rapidly thancontrols. This was considered to be related to increased food consumption.Small reductions in cholesterol levels were frequently noted at 500 mg/kg/day. As well,dose-related increases in urine-specific gravity were seen throughout the 72-week studyat 500 mg/kg/day. These increases were of no toxicological significance. Cessation oftreatment showed good evidence of recovery.There were no macroscopic or histological treatment-related findings in any of the organsin either study.A long term repeat-dose subcutaneous toxicity study of 24 weeks’ duration wasperformed in RH rats receiving sumatriptan at doses of 1, 8 and 64 mg/kg/day.There was occasional temporary appearance of masses at the injection sites in the animalsreceiving the highest dose of sumatriptan. Evidence of injection site injury was alsoapparent in the recovery animals. Rats in this group showed signs of neutrophilia andlymphocytosis.Injection site reactions in animals in the high-dose group were similar to those reportedduring previous toxicity studies.Studies of 26 and 60 weeks at oral doses of 2, 10 and 50 mg/kg/day were performed inBeagle dogs.A moderate increase in heart rate was observed in the intermediate (10 mg/kg/day) dosegroup (60 week study) and in the high (50 mg/kg/day) dose group (26 and 60 weekstudies). The increase lasted for up to 7 hours after dosing and a dose related decrease inheart rate was evident 24 hours after dosing, at 10 and 50 mg/kg/day. There were nochanges in rhythm. Animals of either sex receiving 50 mg/kg/day showed slightreductions in body weight gain in both studies.In the 60-week study, a dose-related incidence of transient changes was noted on thesurface of the cornea. However, these changes were not considered to be treatmentrelatedas evidenced by microscopic examination.Organ weight analyses revealed significantly increased heart weights in all groups oftreated females in the 26-week study. There were no treatment-related effects on organweights in the 60-week study.October 21, 2014Page 35 of 58