ting the greater frequency of decreased hepatic, renal, or cardiacfunction and of concomitant disease or other drug therapy.
A cardiovascular eva luation is recommended for geriatric patients who have other cardiovascularrisk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD) priorto receiving TOSYMRA [see Warnings and Precautions (5.1)].
10 OVERDOSAGE
Coronary vasospasm was observed after intravenous administration of sumatriptan injection[see Contraindications (4)]. Overdoses would be expected from animal data (dogs at 0.1 g/kg,rats at 2 g/kg) to possibly cause convulsions, tremor, inactivity, erythema of the extremities,reduced respiratory rate, cyanosis, ataxia, mydriasis, injection site reactions (desquamation,hair loss, and scab formation), and paralysis.
The elimination half-life of sumatriptan is about 2 hours [see Clinical Pharmacology (12.3)],and therefore monitoring of patients after overdose with TOSYMRA should continue for atleast 10 hours or while symptoms or signs persist.
It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrationsof sumatriptan.
11 DESCRIPTION
TOSYMRA contains sumatriptan, a selective 5-HT1B/1D receptor agonist. Sumatriptan ischemically designated as 1-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-Nmethylmethanesulfonamide,and it has the following structure:
The empirical formula is C14H21N3O2S, representing a molecular weight of 295.40. Sumatriptanis a white to pale yellow powder that is very slightly soluble in water.
TOSYMRA nasal spray is a clear, pale yellow to yellow colored liquid. Each 100 uL ofTOSYMRA contains 10 mg of sumatriptan in single-dose aqueous buffered solution
containing citric acid monohydrate, n-Dodecyl beta-D-maltoside, potassium phosphatemonobasic, sodium chloride, and sodium phosphate dibasic anhydrous in water for injection.
The pH range of solution is approximately 5.0 to 6.0 and the osmolality is between 270 to 330mOsmol.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Sumatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. Sumatriptanpresumably exerts its therapeutic effects in the treatment of migraine headache through agonisteffects at the 5-HT1B/1D receptors on intracranial blood vessels and sensory nerves of thetrigeminal system, which result in cranial vessel constriction and inhibition of pro-inflammatoryneuropeptide release.
12.2 Pharmacodynamics
Blood Pressure
Significant elevation in blood pressure, including hypertensive crisis, has been reported inpatients with and without a history of hypertension [see Warnings and Precautions (5.8)].
Peripheral (Small) Arteries
In healthy volunteers (N = 18), a trial eva luating the effects of sumatriptan on peripheral (smallvessel) arterial reactivity failed to detect a clinically significant increase in peripheral resistance.
Heart Rate
Transient increases in blood pressure observed in some subjects in clinical trials carried outduring sumatriptan’s development as a treatment for migraine were not accompanied by anyclinically significant changes in heart rate.
12.3 Pharmacokinetics
Following nasal administration of 10 mg TOSYMRA in 73 healthy subjects, the relativebioavailabilityof TOSYMRA was approximately 87% [90% confidence interval (CI) 82 - 94]of that obtained following 4 mg subcutaneous injection of sumat |
