Brand Name: Treximet^®

Generic Name: Sumatriptan Succinate/Naproxen Sodium

Manufacturer: GlaxoSmithKline

Drug Class: Anti-migraine

Uses:

Labeled: Acute migraine attack with or without aura¹

Unlabled: None

Mechanism of Action:

Treximet contains sumatriptan succinate, a 5-HT₁ receptor agonist and naproxen sodium, a non-steroidal anti-inflammatory drug (NSAID) which act through different mechanisms of action to produce migraine relief.  Sumatriptan mediates vasoconstriction of the human basilar artery and vasculature of human dura mater.  This vasoconstriction correlates with migraine relief.  Sumatriptan binds with high affinity to 5-HT_1B and 5-HT_1D receptors, while it has only weak affinity for 5-HT_1A, 5-HT_5A, and 5-HT₇ receptors, and no significant affinity or pharmacological activity at 5-HT₂, 5-HT₃, or 5-HT₄ receptor subtypes, alpha₁-, alpha₂-, or beta-adrenergic; dopamine₁; dopamine₂; muscarinic; or benzodiazepine receptors.² Naproxen has both analgesic and anti-pyretic properties through inhibition of both cylcooxygenase (COX) isoenzymes, COX-1 and COX-2 by blocking arachidonate binding.  This results in the inhibition of prostaglandin formation and subsequent pain and inflammation relief.  Naproxen has been formulated as the sodium salt in order to achieve more rapid absorption and faster onset of analgesia.  The mechanism of action of the naproxen anion, like that of other NSAIDs is not completely understood, but is possibly related to prostaglandin synthestase inhibition. 

Pharmacokinetics:

            Metabolism:

Sumatriptan is metabolized by monoamine oxidase (MAO), predominantly the A isoenzyme.  Most of a radiolabeled dose of a 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.  There is no significant metabolism with MAO-B.²

Naproxen is extensively metabolized by CYP 2C9 to 6-0-desmethyl naproxen and the glucoronide conjugate.  Both metabolites are inactive.²

            Elimination:

Sumatriptan is excreted approximately 60% renally, with approximately 40% found in the feces.  Naproxen is largely renally eliminated with approximately 95% of any dose excreted in the urine, primarily as naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%), or their conjugates (66% to 92%).²

Efficacy:

Silberstein SD, Mannix LK, Goldstein J, Couch JR, Byrd SC, Ames MH et al.  Multimechanistic (sumatriptan-naproxen) early intervention for the acute treatment of migraine.  Neurology. 2008;71:114-21.

Study design: two randomized, double-blind, parallel group, placebo-controlled

Description of study: The authors of the study were investigating the efficacy and tolerability of a fixed-dose, single-tablet as early intervention acute therapy for migraine. Patients having migraine with or without aura were enrolled in the study.  Patients treated a single migraine within 1 hour of onset of migraine head pain and while the pain was mild with either sumatriptan/naproxen or placebo.  The primary efficacy measure was the percentage of patients who became pain-free 2 hours postdose.  Intent-to-treat analysis was performed on 576 and 535 migraineurs.  At 2 hours postdose, 52% and 51% of sumatriptan/naproxen-treated patients were pain free, as compared to 17% and 15% of placebo-treated patients (p<0.001).  Significant pain-free response in favor of sumatriptan-naproxen were demonstrated as early as 30 minutes, maintained at 1 hour, and sustained from 2 to 24 hours.  The most commonly reported adverse events were nausea (<4%) and dizziness (<2%). 

Limitations: The results of the study are not able to be generalized to all migraine types since the exclusion criteria limited participants to those who had an identifiable mild pain phase.  In addition, the inclusion of mostly white patients in this study limits the results of this study from being extrapolated to other ethnic populations.

Conclusion: The authors concluded that the fixed-dose single-tablet formulation of sumatriptan/naproxen was effective and well tolerated in an early intervention paradigm for the acute treatment of migraine, including traditional and nontraditional symptoms.  While the study is limited in efficacy to only those who have an identifiable mild pain phase, it should be considered a valid option for treatment in these patients who have failed on prior migraine therapies. 

Landy S, DeRossett SE, Rapoport A, Rothrock J, Ames MH, McDonald SA.  Two Double-Blind, Multicenter, Randomized, Placebo-Controlled, Single-Dose Studies of Sumatriptan/Naproxen Sodium in the Acute Treatment of Migraine: Function, Productivity, and Satisfaction Outcomes. MedGenMed. 2007;9(2):53.

Study design: two double-blind, parallel group, randomized, placebo-controlled

Description of study: The trial examined the efficacy of sumatriptan/naproxen formulated with RT technology in improving the return to normal level of functioning, productivity, and satisfaction in patients treating one migraine of moderate to severe intensity.  In each trial there were four treatment groups: sumatriptan/naproxen, sumatriptan 85mg, naproxen sodium 500 mg, and placebo.  The primary outcome measures were assessed using diary cards every 30 minutes for the first 2 hours, and hourly from 2 to 24 hours while awake, and the Productivity Assessment Questionnaire (PAQ) and the Patient Perception of Migraine Questionnaire (PPMQ) 24 hours after study drug was administered.  Compared with the other groups, the sumatriptan/naproxen group reported significantly higher levels of normal functioning at 4 hours compared with 4,7, and 11 hours for the sumatriptan, naproxen (p <.001) and placebo groups (p<.001) respectively.  Study 2 had results of similar significance.  It was also found that the combination tablet produced greater reductions in workplace productivity loss compared with placebo in both studies (p<.001), and participants taking the combination tablet were consistently more satisfied with their treatment compared with patients in other treatment groups and compared with their usual migraine treatment medications.

Limitations: A major limitation of this study is the fact that the comparator of sumatriptan tablets used were 85 mg tablets, and this strength of tablet is not available in the United States.  As a result, the efficacy differences found may not be similar to those found if a 50 mg tablet or 100 mg tablet was used.  In addition, there did not appear to be significantly different findings in all outcome measures when comparing sumatriptan/naproxen with sumatriptan alone.  This may limit the conclusions that can be ascertained about the added benefit of the combination tablet over sumatriptan alone in differences in ability to function, productivity, and satisfaction.  Lastly, there was no comparison of taking sumatriptan tablets and naproxen tablets together; therefore the efficacy of combing the medications as separate tablets cannot be assessed. 

Conclusion: The authors concluded that treatment with sumatriptan/naproxen sodium allowed significantly more subjects to return to normal or mildly impaired functioning more quickly, and sumatriptan/naproxen sodium patients were significantly more satisfied with their treatment compared with other groups.  The combination tablet showed efficacy; whether this efficacy is truly superior to sumatriptan alone is not entirely clear from this article.  While the combination tablet is an option for the treatment of moderate to severe migraines, it should only be considered after other treatments have failed. 

Brandes JL, Kudrow D, Stark SR, O’Carroll CP. Adelman JU, O’Donnell, et al.  Sumatriptan-Naproxen for Acute Treatment of Migraine.  JAMA. 2007;297(13):1443-54.

Study design:  The study consisted of 2 replicate, parallel, double-blind, controlled clinical trials.

Description of study: The studies each consisted of a screening visit followed by outpatient treatment of a single migraine attack and a follow-up visit occurring 1 to 5 days after treatment.  At the screening visit, patients meeting eligibility criteria were randomized 1:1:1:1 to receive one of the following: a single tablet containing sumatriptan 85 mg and naproxen sodium 500mg; a single tablet of sumatriptan, 85mg; a single tablet of naproxen sodium 500mg; or placebo.  The primary efficacy outcome measures of the studies were: (1) to determine the efficacy and safety of sumatriptan-naproxen sodium vs placebo as assessed by headache relief and the incidences of photophobia, phonophobia, and nausea 2 hours after the dosing and (2) to evaluate the efficacy of sumatriptan-naproxen sodium compared with each monotherapy, using sustained pain-free response as the outcome measure.  Sumatriptan-naproxen sodium was superior to both placebo and monotherapy in the primary efficacy analyses.  In the primary outcome measure of two-hour headache relief, Sumatriptan-naproxen sodium was significantly more effective than placebo for incidences of headache relief, absence of photophobia, and absence of phonophobia in both studies (P<0.001).  After adjusting for baseline imbalances in incidences of nausea, the incidence of absence of nausea 2 hours after dosing was significantly higher in sumatriptan-naproxen compared to placebo in study 1 (P<0.007) but did not differ in study 2 (P=0.71).  Sumatriptan-naproxen sodium also proved to be superior to monotherapy in the primary outcome measure of twenty-four hour sustained pain-free response.  In study 1 the incidence of pain-free response was 25% with sumatriptan-naproxen sodium compared with 16% with sumatriptan monotherapy (P<0.01), 10% with naproxen sodium monotherapy (P<0.001), and 8% with placebo (P<0.001).  Study two showed similar results. 

Limitations:  Most patients in this study had previously treated migraine headaches with NSAIDs and triptans, therefore the degree to which the efficacy data from this study can be extrapolated to NSAID- and triptan-naïve patients and to patients with migraine refractory to NSAIDs and/or triptans is unknown.  In addition, the inclusion of mostly white patients in this study limits the results of this study from being extrapolated to other ethnic populations.  Lastly, there was no comparison of taking sumatriptan tablets and naproxen tablets together; therefore the efficacy of combing the medications as separate tablets cannot be assessed. 

Conclusions: The authors concluded that the combination tablet of sumatriptan/naproxen sodium for acute treatment of migraine resulted in more favorable clinical benefits compared with either monotherapy, with an acceptable and well-tolerated adverse effect profile.  These conclusions are somewhat misleading based results of the raw data.  The combination tablet, while superior in most characteristics was not superior in all across both studies; nor was it superior in the different levels of migraine severity.  Overall, this product was proven to be efficacious; however, it should not be a first line recommendation.   

Contraindications:

• History, signs, or symptoms of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes^2,3
• Significant underlying cardiovascular diseases, coronary artery bypass graft (CABG) surgery^2,3
• Concomitant use in patients with uncontrolled hypertension due to potential increase in blood pressure^2,3
• Concurrent MAO-A inhibitor use or use within 2 weeks of discontinuation of MAO-A inhibitor treatment^2,3
• Ergot-containing or ergot-type medications (i.e. dihydroergotamine or methysergide) should not be used within 24 hours of Treximet administration^2,3
• 5-HT₁ agonist administration within 24 hours of Treximet use
• Hemiplegic or basilar-type migraine, safety and efficacy not established^1,2,3
• Hepatic impairment^2,3
• Susceptibility to aspirin or NSAID-induced asthma, rhinitis, urticaria, or nasal polyps^2,3
• Hypersensitivity to sumatriptan, naproxen, or other components of Treximet^2,3
• Allergic or anaphylactoid reactions, possibly fatal, can occur with naproxen-containing products regardless of prior history of such reaction^2.3

Precautions:

• Known cardiovascular disease or presence of risk factors; increased risk for serious cardiovascular thrombotic events, myocardial infarction, and stroke; risk for these may increase with extended use³
• Gastrointestinal (GI) ulceration, bleeding or perforation, or history of condition; increased risk of serious GI adverse events; these events can occur at any time^2,3
• Anemia can occur with extended duration of use^2,3
• Aspirin-sensitive asthma, including bronchospasm, due to cross-reactivity between aspirin and other NSAIDs should be avoided; severe bronchospasm and fatalities may occur^2,3
• Use with caution in patients with pre-existing asthma^2,3
• Cerebral hemorrhage, subarachnoid hemorrhage, stroke, as well as other cerebrovascular events, some potentially fatal, have been reported^2,3
• Chest, jaw, or neck pain/discomfort have been reported; rarely these symptoms have been reported with ischemic ECG changes^2,3
• Preexisting hematologic disease (coagulopathy or hemophilia) or thrombocytopenia, or history of coagulation defects; may prolong bleeding time^1,2,3
• Concomitant use with anticoagulants or oral corticosteroids; increases risk of GI bleeding^2,3
• Coronary vasospasm and related events; peripheral vascular ischemia and colonic ischemia have been reported, as well as transient and permanent blindness; can occur in without prior history of cardiac disease or coronary artery disease^2,3
• Dietary sodium intake restriction; each tablet of Treximet contains 61.2 mg of sodium (2.7 mEq/500 mg naproxen sodium)³
• Elderly or incapacitated patients; increased risk for renal injury or toxicity, and potentially fatal gastrointestinal bleeding^1,3
• Epilepsy or conditions associated with decreased seizure threshold; use with caution due to reports of seizure³
• Extended duration of use has been associated with increased risk of gastrointestinal or renal injury³
• Heart failure or fluid retention; potential exacerbation of fluid retention, edema, and subsequent renal toxicity or injury³
• Hypertension, controlled; can exacerbate condition, use with caution^2,3
• Late Pregnancy, premature closure of the ductus arteriosus can occur^2,3
• Risk factors associated with coronary artery disease (CAD) such as hypertension, hypercholesterolemia, smoking, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, male over 40 years of age^2,3
• Risk factors for GI bleed, including smoking and alcohol use³
• Renal disease or impairment; risk of renal toxicity and injury increased; not recommended in advanced disease^2,3
• Skin reactions; serious and potentially fatal, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis can occur³
• Serotonin syndrome can occur³

Adverse effects:

            Cardiovascular:

Common: chest pain/chest discomfort (2-3%)³

Rare: acute coronary syndrome, acute myocardial infarction, cardiac dysrhythmia, hypertensive crisis, coronary artery spasm, peripheral ischemia³

            Gastrointestinal:

Common: indigestion (2-3%), nausea (3-4%), xerostomia (2%)^2,3

Rare: ischemic colitis³

            Immunologic:

Rare: anaphylactoid reaction³

            Neurologic:

Common: dizziness (3-5%), paresthesia (2-3%), somnolence (3-4%)³

Rare: cerebral hemorrhage, cerebrovascular accident, seizure, subarachnoid hemorrhage³

            Ophthalmic:

Rare: transient and permanent blindness, abnormal vision³

            Other:

Common: neck/throat/jaw pain/tightness/pressure (>2%)²

Rare: Death due to serious cardiac events³

Drug Interactions:

Ergot alkaloids: prolonged or additive vasospastic effects.¹

5-HT₁ receptor agonists: increased risk for vasospastic reactions.^2,3

Monoamine Oxidase Inhibitors: increased systemic exposure of sumatriptan.¹

Ethanol: increased adverse GI effects.¹

Tricyclic antidepressants: increased risk for development of serotonin syndrome.¹

Serotonin reuptake inhibitors/Serotonin norepinephrine reuptake inhibitors: increased risk for development of serotonin syndrome.¹

Medications that potentiate serotonin transmission: increased risk for development of serotonin syndrome.¹

Naproxen-containing products: additive pharmacodynamic effects, including a potential increase of adverse GI effects.¹

Tobacco: increased risk of GI side-effects.¹

Corticosteroids: increased risk of GI side-effects.¹

Platelet Inhibitors: increased risk of serious GI events.¹

Salicylates: enhanced of effect of naproxen due to drug displacement from binding site.¹

Anticoagulants: additive risk of GI bleeding, platelet aggregation inhibition, and prolonged bleeding time.¹

Thrombolytic agents: additive risk of GI bleeding, platelet aggregation inhibition, and prolonged bleeding time.¹

Lithium: elevated lithium levels and potential lithium toxicity.¹

Methotrexate: elevated and prolonged serum methotrexate concentrations.¹

Cyclosporine: increased risk of cyclosporine toxicity, including potential renal dysfunction.¹

Probenecid: increase in naproxen plasma concentration.¹

Ginkgo, Garlic, Ginger: potential increased risk of bleeding.¹

Bisphosphonates: potential increased GI adverse reactions.¹

Diuretics: increase the risk of renal failure; decreased diuretic and antihypertensive efficacy.^2,3

ACE Inhibitors: possible potentiating of renal disease states; decreased diuretic and antihypertensive efficacy.^2,3

Nephrotoxic Agents: concurrent therapy with naproxen can increase the risk for additive nephrotoxicity.²

Cholinesterase Inhibitors: additive pharmacodynamic GI effects.²

Yasmin: drospirenone may increase serum potassium concentrations, monitoring of serum potassium in the first month is recommended.²

Highly protein-bound medications: naproxen is 99% protein-bound and therefore may displace other highly protein-bound drugs from albumin or vice versa.²

Inhibitors/Inducers of CYP2C9:  increased or decreased plasma naproxen concentrations.²

Quinolones: possible increased risk of CNS stimulation and convulsive seizures.²

Dosing/Administration:

Usual dose: 1 tablet by mouth at onset of moderate to severe headache, may repeat in 2 hours if needed (maximum of 2 tablets per 24 hours).  The safety and efficacy of the second dose has not been established. 

Geriatric dose: The effect of age on the pharmacokinetics of Treximet has not been studied.²

Pediatric dose: Safety and efficacy has not been established in this patient population.³

Renal impairment dose: Not recommended in patients with a creatinine clearance of less that 30 ml/min.²

Hepatic impairment dose: Not recommended in patients with hepatic impairment because Treximet is a fixed-dose combination and cannot be adjusted for this population.²

Use in special circumstances:

Treximet is a category C medication.  It should only be used when the risks outweigh the benefits.  Infant risk during breastfeeding cannot be ruled out; therefore it is not recommended to use Treximet while breastfeeding.³

Conclusion:

Overall Treximet should be considered a reasonable option for treating migraines of mild to moderate severity.  Advantages of therapy with Treximet are increased compliance as a result of having two medications in one tablet, dual action in treating migraine headaches, and proven efficacy over placebo.  Disadvantages of the medication include increased cost of a branded medication, and the medication having only slightly more efficacy than sumatriptan monotherapy.  Before this medication can be recommended as first line agent, efficacy of taking sumatriptan and naproxen together as separate tablets should be ruled out.  If efficacy of each monotherapy taken together is equal to the combination tablet, then this therapy should be used first.  In addition, the efficacy studies assessed only included sumatriptan monotherapy as an 85 mg tablet.  Since this strength is not marketed or available, it seems unreasonable to use this as a comparator.  More studies need to be conducted comparing the combination tablet with the commercially available strengths of sumatriptan. 

Recommended References:

1. Treximet. Clinical Pharmacology. [Internet database]. Gold Standard, Inc. 2007.  Available at http://www.clincalpharmacology.com.  Accessed November 14, 2007. 
2. Treximet [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008.
3. Treximet.  In: DRUGDEX System [Internet databse]. Greenwood Village, Colo: Thomson Micromedex.  Updated periodically.  Accessed November 14, 2007.
4. Silberstein SD, Mannix LK, Goldstein J, Couch JR, Byrd SC, Ames MH et al.  Multimechanistic (sumatriptan-naproxen) early intervention for the acute         treatment of migraine.  Neurology. 2008;71:114-21.
5. Landy S, DeRossett SE, Rapoport A, Rothrock J, Ames MH, McDonald SA.  Two Double-Blind, Multicenter, Randomized, Placebo-Controlled, Single-Dose Studies of Sumatriptan/Naproxen Sodium in the Acute Treatment of Migraine: Function, Productivity, and Satisfaction Outcomes. MedGenMed. 2007;9(2):53.
6. Brandes JL, Kudrow D, Stark SR, O’Carroll CP. Adelman JU, O’Donnell, et al.  Sumatriptan-Naproxen for Acute Treatment of Migraine.  JAMA. 2007;297(13):1443-54.

Prepared by: Jennifer Curtis, Doctor of Pharmacy Candidate