riptan.
The relativebioavailabilityof TOSYMRA was 58% [90% CI 55 - 62] following 6 mg subcutaneousinjection of sumatriptan.
Absorption
Peak plasma concentration of sumatriptan was observed in a median time of 10 minutes (range 5to 23 minutes). After single nasal administration of the 10 mg dose, the mean (CV%) Cmax andAUC were 51.8 ng/mL (58%) and 60.70 ng-hr/mL (42%), respectively.
Distribution
Sumatriptan protein binding, determined by equilibrium dialysis over the concentration range of10 to 1,000 ng/mL, is low, approximately 14% to 21%. The effect of sumatriptan on theprotein binding of other drugs has not been eva luated.
Following a 6-mg subcutaneous injection into the deltoid area of the arm in 9 males (mean age:33 years, mean weight: 77 kg) the volume of distribution central compartment of sumatriptanwas 50 ± 8 liters and the distribution half-life was 15 ± 2 minutes.
Elimination
The elimination half-life of sumatriptan following administration of TOSYMRA is 2.44 ±1.00 hours.
Metabolism
In vitro studies with human microsomes suggest that sumatriptan is metabolized by MAO,predominantly the A isoenzyme. Most of a radiolabeled dose of sumatriptan excreted inthe urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both ofwhich are inactive.
Excretion
After a single 6-mg subcutaneous dose, 22% ± 4% was excreted in the urine as unchangedsumatriptan and 38% ± 7% as the IAA metabolite.
Following a 6-mg subcutaneous injection into the deltoid area of the arm, the systemicclearance of sumatriptan was 1,194 ± 149 mL/min and the terminal half-life was 115 ± 19minutes.
Specific Populations
Age
The pharmacokinetics of sumatriptan in the elderly (mean age: 72 years, 2 males and 4 females)and in subjects with migraine (mean age: 38 years, 25 males and 155 females) were similar tothat in healthy male subjects (mean age: 30 years).
Patients with Hepatic Impairment
The effect of hepatic disease on the pharmacokinetics of TOSYMRA has not been eva luated.
The effect of mild to moderate hepatic disease on the pharmacokinetics of subcutaneouslyadministered sumatriptan has been eva luated. There were no significant differences in thepharmacokinetics of subcutaneously administered sumatriptan in moderately hepaticallyimpaired subjects compared with healthy controls. The pharmacokinetics of subcutaneouslyadministered sumatriptan in patients with severe hepatic impairment has not been studied. Theuse of TOSYMRA in this population is contraindicated [see Contraindications (4)].
Racial Groups
The systemic clearance and Cmax of subcutaneous sumatriptan were similar in black (n=34)and Caucasian (n=38) healthy male subjects. TOSYMRA has not been eva luated for racedifferences.
Drug Interaction Studies
Monoamine Oxidase-A Inhibitors
In a trial of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearanceof subcutaneous sumatriptan, resulting in a 2-fold increase in the area under the sumatriptanplasma concentration-time curve (AUC), corresponding to a 40% increase in elimination halflife.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesisIn carcinogenicity studies in mouse and rat, sumatriptan was administered orally for 78 weeks
and 104 weeks, respectively, at doses up to 160 mg/kg/day (the highest dose in rat was reducedfrom |
