"Today, the U.S. Food and Drug Administration approved Topamax (topiramate) for prevention (prophylaxis) of migraine headaches in adolescents ages 12 to 17. This is the first FDA approval of a drug for migraine prevention in this age group. The me"...
Mechanism Of Action
TREXIMET contains sumatriptan and naproxen.
Sumatriptan binds with high affinity to cloned 5-HT1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of neuropeptide release.
Naproxen is an NSAID with analgesic and antipyretic properties. The mechanism of action of naproxen, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.
In a randomized, double-blind, parallel group, active control trial, TREXIMET 85/500 mg administered intermittently over 6 months did not increase blood pressure in a normotensive adult population (n = 122). However, significant elevation in blood pressure has been reported with 5-HT1 agonists and NSAIDs in patients with and without a history of hypertension.
Absorption and Bioavailability
Sumatriptan, when given as TREXIMET 85/500 mg, has a mean Cmax similar to that of sumatriptan succinate 100 mg tablets alone. The median Tmax of sumatriptan, when given as TREXIMET 85/500 mg, was 1 hour (range: 0.3 to 4.0 hours), which is slightly different compared with sumatriptan succinate 100 mg tablets (median Tmax of 1.5 hours). Naproxen, when given as TREXIMET 85/500 mg, has a Cmax which is approximately 36% lower than naproxen sodium 550 mg tablets and a median Tmax of 5 hours (range: 0.3 to 12 hours), which is approximately 4 hours later than from naproxen sodium tablets 550 mg. AUC values for sumatriptan and for naproxen are similar for TREXIMET 85/500 mg compared with sumatriptan succinate 100 mg tablets or naproxen sodium 550 mg tablets, respectively. In a crossover trial in 16 subjects, the pharmacokinetics of both components administered as TREXIMET 85/500 mg were similar during a migraine attack and during a migraine-free period.
Bioavailability of sumatriptan is approximately 15%, primarily due to presystemic (first-pass) metabolism and partly due to incomplete absorption.
Naproxen is absorbed from the gastrointestinal tract with an in vivo bioavailability of 95%.
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 [see DOSAGE AND ADMINISTRATION].
Plasma protein binding is 14% to 21%. The effect of sumatriptan on the protein binding of other drugs has not been evaluated. The volume of distribution of sumatriptan is 2.7 L/kg.
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.
In vitro studies with human microsomes suggest that sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme. 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.
The elimination half-life of sumatriptan is approximately 2 hours. Radiolabeled 14C-sumatriptan administered orally is largely renally excreted (about 60%), with about 40% found in the feces. 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.
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.
The pharmacokinetics of TREXIMET in geriatric patients have not been studied. Elderly patients are more likely to have decreased hepatic function and decreased renal function [see Specific Populations].
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).
Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction, which represents < 1% of the total concentration, increased in the elderly (range of unbound trough naproxen from 0.12% to 0.19% in elderly subjects versus 0.05% to 0.075% in younger subjects).
A pharmacokinetic study compared 3 doses of TREXIMET in pediatric patients 12 to 17 years of age (n=24) with adults (n=26). The AUC and Cmax of sumatriptan were 50-60% higher following a single dose of TREXIMET 10/60 mg in pediatric patients 12 to 17 years of age (n=7) compared with adult subjects (n=8), and were 6-26% higher following a single dose of TREXIMET 30/180 mg or 85/500 mg in pediatrics than adults. Naproxen pharmacokinetic parameters were similar between pediatrics and adults.
The effect of renal impairment on the pharmacokinetics of TREXIMET has not been studied. 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 [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
The effect of hepatic impairment on the pharmacokinetics of TREXIMET has not been studied. In a study in patients with moderate hepatic impairment (n = 8) matched for sex, age, and weight with healthy subjects (n = 8), patients with hepatic impairment had an approximately 70% increase in AUC and Cmax of sumatriptan and a Tmax 40 minutes earlier compared to healthy subjects. The pharmacokinetics of sumatriptan in patients with severe hepatic impairment has not been studied.
In a pooled analysis of 5 pharmacokinetic trials, there was no effect of gender on the systemic exposure of TREXIMET.
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 white (n = 38) healthy male subjects.
Animal Toxicology And/Or Pharmacology
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 60week study. Earlier examinations for these toxicities were not conducted and no-effect doses were not established. The lowest dose tested is less than the MHDD (170 mg) of sumatriptan on a mg/m² basis.
The efficacy of TREXIMET in the acute treatment of migraine with or without aura in adults was demonstrated in 2 randomized, double-blind, multicenter, parallel-group trials utilizing placebo and each individual active component of TREXIMET 85/500 mg (sumatriptan and naproxen sodium) as comparison treatments (Study 1 and Study 2). Patients enrolled in these 2 trials were predominately female (87%) and white (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. No rescue medication was allowed within 2 hours postdose. 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 Study 1 and 2 are summarized in Table 3. In both trials, the percentage of patients achieving headache pain relief 2 hours after treatment was significantly greater among patients receiving TREXIMET 85/500 mg (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 85/500 mg (25% and 23%) compared with those who received placebo (8% and 7%) or either sumatriptan (16% and 14%) or naproxen sodium (10%) alone.
Table 3: Percentage of Adult Patients with 2-Hour Pain
Relief and Sustained Pain Free Following Treatmenta
|TREXIMET 85/500 mg||Sumatriptan 85 mg||Naproxen Sodium 500 mg||Placebo|
|2-Hour Pain Relief|
|n = 364||n = 361||n = 356||n = 360|
|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|
|aP values provided only for
bP < 0.05 versus placebo and sumatriptan.
cP < 0.01 versus placebo, sumatriptan, and naproxen sodium.
The percentage of patients achieving initial headache pain relief within 2 hours following treatment with TREXIMET 85/500 mg is shown in Figure 1.
Figure 1: Percentage of
Adult 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 85/500 mg. The estimated probability of taking a rescue medication over the first 24 hours is shown in Figure 2.
Figure 2: Estimated Probability of Adults Taking a
Rescue Medication over the 24 Hours following the First Dosea
a 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 85/500 mg was more effective than placebo regardless of the presence of aura; duration of headache prior to treatment; gender, age, or weight of the subject; or concomitant use of oral contraceptives or common migraine prophylactic drugs (e.g., beta-blockers, anti-epileptic drugs, tricyclic antidepressants).
Pediatric Patients 12 To 17 Years Of Age
The efficacy of TREXIMET in the acute treatment of migraine with or without aura in pediatric patients 12 to 17 years of age was demonstrated in a randomized, double-blind, multicenter, parallel-group, placebo-controlled, multicenter trial comparing 3 doses of TREXIMET and placebo (Study 3). Patients enrolled in this trial were mostly female (59%) and white (81%), with a mean age of 15 years.
Patients were required to have at least a 6-month history of migraine attacks with or without aura usually lasting 3 hours or more when untreated. Following a single-blind, placebo run-in phase, placebo nonresponders were randomized to receive a single dose of either TREXIMET 10/60 mg, 30/180 mg, 85/500 mg, or placebo. Patients were instructed to treat a single migraine attack with headache pain of moderate to severe intensity. No rescue medication was allowed within 2 hours postdose. Patients evaluated their headache pain 2 hours after taking 1 dose of study medication. Two-hour pain free was defined as a reduction in headache severity from moderate or severe pain to no pain at 2 hours postdose.
Results are summarized in Table 4. The percentage of patients who were pain free at 2 hours postdose was significantly greater among patients who received any of the 3 doses of TREXIMET compared with placebo.
Table 4: Percentage of
Pediatric Patients 12 to 17 Years of Age with 2-Hour Pain-Free Response
Following Treatment in Study 3a
|Endpoint||TREXIMET 10/60 mg
(n = 96)
|TREXIMET 30/180 mg
(n = 97)
|TREXIMET 85/500 mg
(n = 152)
(n = 145)
|2-Hour Pain Free||29%b||27% b||24% b||10%|
|aP values provided only for
bP < 0.01 versus placebo.
The percentage of pediatric patients who remained pain free without use of other medications 2 through 24 hours postdose was significantly greater after administration of a single dose of TREXIMET 85/500 mg compared with placebo. A greater percentage of pediatric patients who received a single dose of 10/60 mg or 30/180 mg remained pain free 2 through 24 hours postdose compared with placebo.
Compared with placebo, the incidence of photophobia and phonophobia was significantly decreased 2 hours after the administration of a single dose of 85/500 mg, whereas, the incidence of nausea was comparable. There was a decreased incidence of photophobia, phonophobia, and nausea 2 hours after single-dose administration of 10/60 mg or 30/180 mg compared with placebo.
Last reviewed on RxList: 9/10/2015
This monograph has been modified to include the generic and brand name in many instances.
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