PRODUCT MONOGRAPH IMITREX DF IMITREX ... - GlaxoSmithKline

ACTION AND CLINICAL PHARMACOLOGYMechanism of ActionIMITREX DF ® and IMITREX ® have been shown to be effective in relieving migraineheadache. Sumatriptan is an agonist for a vascular 5-hydroxytryptamine 1D (5-HT 1D )receptor subtype (a member of the 5-HT 1 family), and has only weak affinity for 5-HT 1Areceptors and no significant activity (as measured using standard radioligand bindingassays) or pharmacological activity at 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 5A , or 5-HT 7 receptorsubtypes, or at alpha 1 -, alpha 2 -, or beta-adrenergic; dopamine 1 or dopamine 2 ; muscarinic;or benzodiazepine receptors.The therapeutic activity of IMITREX DF ® and IMITREX ® in migraine is generallyattributed to its agonist activity at 5-HT 1B /5-HT 1D receptors. Two current theories havebeen proposed to explain the efficacy of 5-HT 1 receptor agonists in migraine. One theorysuggests that activation of 5-HT 1 receptors located on intracranial blood vessels,including those on the arteriovenous anastomoses, leads to vasoconstriction, which isbelieved to be correlated with the relief of migraine headache. The other hypothesissuggests that activation of 5-HT 1 receptors on perivascular fibres of the trigeminal systemresults in the inhibition of pro-inflammatory neuropeptide release. These theories are notmutually exclusive.Experimental data from animal studies show that sumatriptan also activates 5-HT 1receptors on peripheral terminals of the trigeminal nerve, which innervates cranial bloodvessels. This causes the inhibition of neuropeptide release. It is thought that such anaction may contribute to the anti-migraine action of sumatriptan in humans.Cardiovascular EffectsIn vitro studies in human isolated epicardial coronary arteries suggest that thepredominant contractile effect of 5-HT is mediated via 5-HT 2 receptors. However, 5-HT 1receptors also contribute to some degree to the contractile effect seen. Transientincreases in systolic and diastolic blood pressure (up to 20 mmHg) of rapid onset (withinminutes), have occurred after intravenous administration of up to 64 μg/kg (3.2 mg for50 kg subject) to healthy volunteers. These changes were not dose related and returned tonormal within 10-15 minutes. Following oral administration of 200 mg or intranasaladministration of 40 mg, however, mean peak increases in blood pressure were smallerand of slower onset than after intravenous or subcutaneous administration.PharmacodynamicsSignificant relief begins about 10-15 minutes following subcutaneous injection,15 minutes following intranasal administration and 30 minutes following oraladministration.October 21, 2014Page 21 of 58