"March 11, 2014 - The U.S. Food and Drug Administration allowed marketing of the first device as a preventative treatment for migraine headaches. This is also the first transcutaneous electrical nerve stimulation (TENS) device specifically "...
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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-HT1B and 5-HT1D receptors. Sumatriptan has only a weak affinity for 5-HT1A, 5-HT5A, 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.
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.
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.
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.
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.
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).
TREXIMET is not recommended for use in patients with creatinine clearance less than 30 mL/min (see PRECAUTIONS: Renal Effects). The effect of renal impairment on the pharmacokinetics of TREXIMET has not been studied.
Minimal change in clinical effect would be expected with regard to sumatriptan as it is largely metabolized to an inactive substance.
Since naproxen and its metabolites and conjugates are primarily excreted by the kidney, the potential exists for naproxen metabolites to accumulate in the presence of renal insufficiency. Elimination of naproxen is decreased in patients with severe renal impairment.
Because TREXIMET is a fixed-dose combination that cannot be adjusted for this patient population, it is contraindicated in patients with hepatic impairment (see CONTRAINDICATIONS and PRECAUTIONS: Hepatic Effects). The effect of hepatic impairment on the pharmacokinetics of TREXIMET has not been studied. Sumatriptan is contraindicated in patients with severe hepatic impairment and the dose is limited to 50 mg in patients with liver disease.
The effect of age (elderly or pediatric patients) on the pharmacokinetics of TREXIMET has not been studied. Elderly patients are more likely to have decreased hepatic function and decreased renal function (see PRECAUTIONS: Geriatric Use).
The pharmacokinetics of oral sumatriptan in the elderly (mean age, 72 years; 2 males and 4 females) and in patients with migraine (mean age, 38 years; 25 males and 155 females) were similar to that in healthy male subjects (mean age, 30 years).
In a pooled analysis of 5 pharmacokinetic studies, there was no effect of gender on the systemic exposure of TREXIMET. In a study comparing the pharmacokinetics of sumatriptan in females and males, no differences were observed between genders for AUC, Cmax, Tmax, and T½ .
The effect of race on the pharmacokinetics of TREXIMET has not been studied. The systemic clearance and Cmax of sumatriptan were similar in black (n = 34) and Caucasian (n = 38) healthy male subjects.
No formal drug interaction studies have been conducted with TREXIMET.
Monoamine Oxidase Inhibitors
TREXIMET is contraindicated in patients taking MAOA inhibitors (see CONTRAINDICATIONS and PRECAUTIONS: DRUG INTERACTIONS). Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels. This interaction has not been seen with an MAO-B inhibitor.
The effect of alcohol consumption on the pharmacokinetics of TREXIMET has not been studied. Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the pharmacokinetics of sumatriptan.
The efficacy of TREXIMET in providing relief from migraine was demonstrated in 2 randomized, double-blind, multicenter, parallel-group trials utilizing placebo and each individual active component of TREXIMET (sumatriptan and naproxen sodium) as comparison treatments. Patients enrolled in these 2 trials were predominately female (87%) and Caucasian (88%), with a mean age of 40 years (range 18 to 65 years). Patients were instructed to treat a migraine of moderate to severe pain with 1 tablet. Patients evaluated their headache pain 2 hours after taking 1 dose of study medication; headache relief was defined as a reduction in headache severity from moderate or severe pain to mild or no pain. Associated symptoms of nausea, photophobia, and phonophobia were also evaluated. Sustained pain free was defined as a reduction in headache severity from moderate or severe pain to no pain at 2 hours postdose without a return of mild, moderate, or severe pain and no use of rescue medication for 24 hours postdose. The results from the 2 controlled clinical trials are summarized in Table 1. In both trials, the percentage of patients achieving headache pain relief 2 hours after treatment was significantly greater among patients receiving TREXIMET (65% and 57%) compared with those who received placebo (28% and 29%).
Further, the percentage of patients who remained pain free without use of other medications through 24 hours postdose was significantly greater among patients receiving a single dose of TREXIMET (25% and 23%) compared with those who received placebo (8% and 7%) or either sumatriptan (16% and 14%) or naproxen sodium (10%) alone.
Table 1: Percentage of Patients With 2-Hour Pain Relief and
Sustained Pain Free Following Treatment*
|TREXIMET||Sumatriptan 85 mg||Naproxen Sodium 500 mg||Placebo|
|2-Hour Pain Relief|
|Study 1 (all patients)||65%†
n = 364
n = 361
n = 356
n = 360
|Study 2 (all patients)||57%†
n = 362
n = 362
n = 364
n = 382
|Sustained Pain Free (2-24 Hours)|
n = 364
n = 361
n = 356
n = 360
n = 362
n = 362
n = 364
n = 382
|*p values provided only for prespecified
†p<0.05 versus placebo and sumatriptan.
‡p<0.01 versus placebo, sumatriptan, and naproxen sodium.
Note that comparisons of the performance of different drugs based upon results obtained in different clinical trials are never reliable. Because studies are generally conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.
The percentage of patients achieving initial headache pain relief within 2 hours following treatment with TREXIMET is shown in Figure 1.
Figure 1: Percentage of Patients With Initial Headache Pain
Relief Within 2 Hours
Compared with placebo, there was a decreased incidence of photophobia, phonophobia, and nausea 2 hours after the administration of TREXIMET. The estimated probability of taking a rescue medication over the first 24 hours is shown in Figure 2.
Figure 2: Estimated Probability of Taking a Rescue Medication
Over the 24 Hours Following the First Dose*
* Kaplan-Meier plot based on data obtained in the 2 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours. Plot also includes patients who had no response to the initial dose. No rescue medication was allowed within 2 hours postdose.
TREXIMET was more effective than placebo regardless of the presence of aura; duration of headache prior to treatment; gender, age, or weight of the patient; or concomitant use of oral contraceptives or common migraine prophylactic drugs (e.g., beta-blockers, anti-epileptic drugs, tricyclic antidepressants).
Dogs receiving oral sumatriptan developed corneal opacities and defects in the corneal epithelium. Corneal opacities were seen at the lowest dosage tested, 2 mg/kg/day, and were present after 1 month of treatment. Defects in the corneal epithelium were noted in a 60-week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established; the lowest dose tested is approximately 0.8 times the recommended human oral daily dose of 85 mg sumatriptan on a mg/m² basis. There was evidence of alterations in corneal appearance on the first day of intranasal dosing to dogs at all doses tested.
Last reviewed on RxList: 12/2/2011
This monograph has been modified to include the generic and brand name in many instances.
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