PRODUCT MONOGRAPH IMITREX DF IMITREX ... - GlaxoSmithKline

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local damage at the injection sites, there were no macroscopic or microscopic changesnoted in any tissue (Table 11).Table 11Results from Acute Toxicity (LD50) Studies in Mice, Rats and DogsSPECIES/STRAIN ROUTE APPROX. LD 50(mg/kg)MNLD(mg/kg)MLD(mg/kg)Mouse: CRHMouse: CRHOralIntravenous1500>15, 1200> 15> 1200< 20Rat: RHRat: SDOralOral> 2000> 2000> 2000> 2000> 2000> 2000Rat: RH Intravenous > 40 > 20 < 32Rat: SD Subcutaneous 1200 (M) 1400 (F) > 500 < 1000Dog: BeagleOral> 500> 500> 500Dog: BeagleSubcutaneous> 100> 100> 100Key: MNLD - Maximum non-lethal doseMLD - Minimum lethal dose(M) - Male(F) - FemaleLong Term StudiesSubacute toxicity studies were conducted for periods up to 6 weeks in RH rats.Sumatriptan was given orally (by gavage) at doses up to 500 mg/kg/day and givensubcutaneously at doses up to 81 mg/kg/day.Clinical signs observed following oral administration were generally minor and transientin nature and occurred predominantly at 500 mg/kg/day. These signs included postdosingerythema, mydriasis, ataxia, salivation, subdued temperament, postural changesand moist eyes.Reactions were similar in subcutaneous studies in rats receiving doses of sumatriptan upto 81 mg/kg/day. Local irritation at the injection site was accompanied by a markedinflammatory response, local necrosis, hemorrhage, infiltration, granulation tissueformation and local muscle degeneration and repair. These reactions were dosedependent.In dogs administered oral sumatriptan (1-100 mg/kg/day) in studies up to 6 weeks,clinical signs observed included head shaking, scratching, salivation, trembling, agitatedbehaviour, vocalization, mydriasis and vasodilation. These effects were dose-related.The dogs also developed tachycardia lasting for several hours, often followed bybradycardia. No changes in ECG were detected.Subcutaneous administration of sumatriptan (1-16 mg/kg/day) up to 6 weeks in dogscaused injection site reactions similar to the reactions described in rats.October 21, 2014Page 34 of 58
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
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