Mechanism of Action: TREXIMET contains sumatriptan, a 5-HT₁ receptor agonist that mediates vasoconstriction of the human basilar artery and vasculature of human dura mater, which correlates with the relief of migraine headache. It also contains naproxen, an NSAID that inhibits the synthesis of inflammatory mediators. Therefore, sumatriptan and naproxen contribute to the relief of migraine through pharmacologically different mechanisms of action.

Sumatriptan is a 5-HT₁ receptor agonist that binds with high affinity to 5-HT_1B and 5-HT_1D receptors. Sumatriptan has only a weak affinity for 5-HT_1A, 5-HT_5A, and 5-HT₇ receptors and no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5-HT₂, 5-HT₃, or 5-HT₄ receptor subtypes or at alpha₁-, alpha₂-, or beta-adrenergic; dopamine₁; dopamine₂; muscarinic; or benzodiazepine receptors. In addition to causing vasoconstriction, experimental data from animal studies show that sumatriptan also activates 5-HT₁ receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels. Such an action may contribute to the antimigrainous effect of sumatriptan in humans. In the anesthetized dog, sumatriptan selectively reduces carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance.

Naproxen sodium is an NSAID with analgesic and antipyretic properties. The sodium salt of naproxen has been developed as a more rapidly absorbed formulation of naproxen for use as an analgesic. The mechanism of action of the naproxen anion, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.

Pharmacokinetics: TREXIMET is a formulation of 85 mg of sumatriptan (as sumatriptan succinate) and 500 mg of naproxen sodium with a distinct pharmacokinetic profile. Cmax for sumatriptan following administration of TREXIMET occurs at approximately 1 hour (median, range 0.3 to 4.0 hours). Cmax for naproxen following administration of TREXIMET occurs at approximately 5 hours (median, range 0.3 to 12 hours). The sumatriptan half-life is approximately 2 hours (15% to 43% CV) and the naproxen half-life is approximately 19 hours (13% to 15% CV). The mean Cmax for sumatriptan when given as TREXIMET is similar to that of sumatriptan when given as IMITREX Tablets 100 mg alone. The median sumatriptan Tmax is only slightly different (1 hour for TREXIMET and 1.5 hours for IMITREX). The Cmax for naproxen is approximately 36% lower, and the Tmax occurs approximately 4 hours later from TREXIMET than from ANAPROX® DS (naproxen sodium tablets) 550 mg. AUC values for sumatriptan and for naproxen are similar for TREXIMET compared to IMITREX or ANAPROX DS, respectively. In a crossover study in 16 patients, the pharmacokinetics of both components administered as TREXIMET were similar during a migraine attack and during a migraine-free period.

Absorption and Bioavailability: Bioavailability of sumatriptan is approximately 15%, primarily due to presystemic (first-pass) metabolism and partly due to incomplete absorption.

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