TREXIMET is a formulation of 85 mg of sumatriptan (as sumatriptan succinate) and 500 mg of naproxen sodium with a distinct pharmacokinetic profile. Cmax (median, range) for sumatriptan following administration of TREXIMET occurs at approximately 1 hour (0.3 to 4.0 hours). Cmax (median, range) for naproxen following administration of TREXIMET occurs at approximately 5 hours (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® (sumatriptan succinate) 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.

Naproxen is rapidly and completely absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%.

Food Effects: Food had no significant effect on the bioavailability of sumatriptan or naproxen administered as TREXIMET, but slightly delayed the Tmax of sumatriptan by about 0.6 hour. These data indicate that TREXIMET may be administered without regard to food.

Distribution: The volume of distribution of sumatriptan is 2.4 L/kg. Plasma protein binding is 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated, but would be expected to be minor, given the low protein binding.

The volume of distribution of naproxen is 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin bound. At doses of naproxen greater than 500 mg/day, there is a less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses (average trough Css = 36.5, 49.2, and 56.4 mg/L with 500, 1,000, and 1,500 mg daily doses of naproxen, respectively). However, the concentration of unbound naproxen continues to increase proportionally to dose.

Metabolism: Most of a radiolabeled dose of sumatriptan excreted in the urine is the major metabolite indole acetic acid (IAA) or the IAA glucuronide, both of which are inactive. Three percent of the dose can be recovered as unchanged sumatriptan. In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme, and inhibitors of that enzyme may alter sumatriptan pharmacokinetics to increase systemic exposure (see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions: Monoamine Oxidase-A Inhibitors). No significant effect was seen with an MAO-B inhibitor.

Naproxen is extensively metabolized to 6-0-desmethyl naproxen, and both parent and metabolites do not induce metabolizing enzymes.

Elimination: Radiolabeled 14C-sumatriptan administered orally is largely renally excreted (about 60%), with about 40% found in the feces. The elimination half-life of sumatriptan is approximately 2 hours.

The clearance of naproxen is 0.13 mL/min/kg. Approximately 95% of the naproxen from any dose is excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%), or their conjugates (66% to 92%). The plasma half-life of the naproxen anion in humans is approximately 19 hours. The corresponding half-lives of both metabolites and conjugates of naproxen are shorter than 12 hours, and their rates of excretion have been found to coincide closely with the rate of naproxen disappearance from the plasma. In patients with renal failure, metabolites may accumulate (see PRECAUTIONS: Renal Effects).