Treximet

— THERAPEUTIC CATEGORIES —
  • Migraine and headache
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Treximet Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Sumatriptan (as succinate), naproxen sodium; 85/500mg; tabs.

    Pharmacological Class

    Selective 5-HT1B/1D receptor agonist + NSAID.

    How Supplied

    Tabs—9

    How Supplied

    Treximet 85/500 mg contains 119 mg of sumatriptan succinate equivalent to 85 mg of sumatriptan and 500 mg of naproxen sodium and is supplied as blue film-coated tablets debossed on one side with Treximet in bottles of 9 tablets with desiccant.

    Treximet 10/60 mg contains 14 mg of sumatriptan succinate equivalent to 10 mg of sumatriptan and 60 mg of naproxen sodium and is supplied as light-blue film-coated tablets debossed on one side with Treximet and the other side with 10-60 in bottles of 9 tablets with desiccant.

    Storage

    Store at 25°C (77°F); excursions permitted to 15°- 30°C (59°- 86°F) [see USP Controlled Room Temperature]. Do not repackage; dispense and store in original container with desiccant.

    Manufacturer

    Currax Pharmaceuticals LLC

    Generic Availability

    YES

    Treximet Indications

    Indications

    Acute treatment of migraine with or without aura in adults and children ≥12yrs old.

    Limitations of Use

    Use only if clear diagnosis of migraine. Not indicated for prevention of migraine attacks. Safety and effectiveness not established for cluster headache.

    Treximet Dosage and Administration

    Prior to Treatment Evaluations

    Correct volume status in dehydrated or hypovolemic patients prior to initiating Treximet.

    Adult

    Use lowest effective dose for shortest duration. Swallow whole. 1 tab (85/500mg) once; may repeat once after 2 hours; max 2 tabs/day. Mild to moderate hepatic impairment: 1 tab (10/60mg)/day. The safety of treating an average of more than 5 migraines in a 30-day period has not been established.

    Children

    <12yrs: not established. Use lowest effective dose for shortest duration. Swallow whole. 12–17yrs: 1 tab (10/60mg) once; max 1 tab (85/500mg)/day. Mild to moderate hepatic impairment: 1 tab (10/60mg)/day. The safety of treating an average of more than 2 migraines in a 30-day period has not been established.

    Treximet Contraindications

    Contraindications

    Ischemic coronary artery disease (CAD) (eg, angina pectoris, MI, silent ischemia). Coronary artery vasospasm (including Prinzmetal's angina). Coronary artery bypass graft surgery. Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. History of stroke or TIA. History of hemiplegic or basilar migraine. Peripheral vascular disease. Ischemic bowel disease. Uncontrolled hypertension (HTN). Within 24hrs of ergot-type drugs (eg, methysergide, dihydroergotamine) or other 5-HT1 agonists. During or within 2 weeks after discontinuing MAO-type A inhibitors. Aspirin allergy. Severe hepatic impairment.

    Treximet Boxed Warnings

    Boxed Warning

    Risk of serious cardiovascular and gastrointestinal events.

    Boxed Warning

    Cardiovascular Thrombotic Events

    • Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.

    • Treximet is contraindicated in the setting of coronary artery bypass graft (CABG) surgery.

    Gastrointestinal Bleeding, Ulceration, and Perforation

    • NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events.

    Treximet Warnings/Precautions

    Warnings/Precautions

    Increased risk of serious cardiovascular events (including MI, stroke). Exclude cardiovascular disease in patients with multiple risk factors (eg, increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) before initiating; if negative, supervise 1st dose, consider monitoring ECG. Avoid in severe heart failure; if necessary, monitor. Increased risk of serious GI adverse events (including inflammation, bleeding, ulceration, perforation). History of ulcer disease and/or GI bleeding. Discontinue if serious arrhythmias or cerebrovascular events occur or if serotonin syndrome is suspected. Peripheral or GI vascular ischemia and infarction following other 5-HT1 agonists. Hypertension; monitor BP closely. Hepatic impairment. Discontinue if signs/symptoms of liver or renal disease develop, or if abnormal LFTs persist or worsen. Severe renal impairment (CrCl<30mL/min): not recommended; monitor in mild or moderate impairment, pre-existing kidney disease, dehydration. Hypovolemia. Hyperkalemia. Coagulation disorders. Monitor CBCs, blood chemistry, hepatic, and renal function in long-term therapy. Pre-existing asthma. Seizure disorders. May mask signs of infection or fever. Discontinue at 1st sign of rash or any other hypersensitivity. Elderly. Debilitated. Labor & delivery. May be associated with a reversible delay in ovulation in females of reproductive potential. Pregnancy (avoid during ≥30 weeks gestation): increased risk of premature closure of the fetal ductus arteriosus; (20–30 weeks gestation): may cause fetal renal dysfunction/oligohydramnios; if treatment needed, limit dose and duration of use. Nursing mothers: minimize infant exposure by avoiding breastfeeding for 12hrs after dose.

    Warnings/Precautions

    Cardiovascular (CV) Thrombotic Events

    • CV Events with Sumatriptan: Rare reports of serious cardiac adverse reactions, including acute myocardial infarction, have occurred within a few hours following administration of sumatriptan. Some of these reactions occurred in patients without known CAD. Treximet may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD.

    • CV Thrombotic Events with Nonsteroidal Anti-inflammatory Drugs: 

      • Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 years duration have shown an increased risk of serious CV thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. The increase in CV thrombotic risk has been observed most consistently at higher doses. 

      • Use the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse CV event in NSAID-treated patients. Remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. 

      • There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events.

    • Status Post Coronary Artery Bypass Graft (CABG) Surgery: NSAIDs are contraindicated in the setting of CABG.

    • Post-MI Patients: Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. 

    • Prior to receiving Treximet, perform a cardiovascular evaluation in patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD). If there is evidence of CAD or coronary artery vasospasm, Treximet is contraindicated. Consider administering the first dose of Treximet in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of Treximet for patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of Treximet.

    Gastrointestinal Bleeding, Ulceration, and Perforation

    • Serious gastrointestinal adverse events, including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, may occur with the use of NSAIDS, including naproxen, a component of Treximet. These serious adverse events can be fatal and can occur at any time, with or without warning symptoms, in patients treated with NSAIDs.

    • Risk Factors for GI Bleeding, Ulceration, and Perforation: 

      • Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing gastrointestinal bleeding compared with patients with neither of these risk factors.

      • Other factors that increase the risk for gastrointestinal bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. 

      • Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients, and therefore special care should be taken in treating this population. Patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

      • Strategies to Minimize the GI Risks in NSAID-treated patients: Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For high risk patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. •Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue Treximet until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding.

    Arrhythmias

    • Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. 

    • Discontinue Treximet if these disturbances occur.  

    • Treximet is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. 

    Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure

    • Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with sumatriptan and are usually non-cardiac in origin. 

    • Perform a cardiac evaluation if these patients are at high cardiac risk. Treximet is contraindicated in patients with CAD and those with Prinzmetal’s variant angina. 

    Cerebrovascular Events

    • Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities.  Patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). 

    • Discontinue Treximet if a cerebrovascular event occurs.

    • Exclude other potentially serious neurological conditions prior to treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms. Treximet is contraindicated in patients with a history of stroke or TIA.

    Other Vasospasm Reactions 

    • Sumatriptan may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud′s syndrome.

    • Rule out a vasospastic reaction prior to receiving additional Treximet in patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist.

    Hepatotoxicity

    • Treximet is contraindicated in patients with severe hepatic impairment.

    • During treatment, evaluate for evidence of a more severe hepatic reaction  if the patient presents with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred.

    • Discontinue if clinical signs and symptoms consistent with liver disease develop, if systemic manifestations occur (e.g., eosinophilia, rash), or if abnormal liver tests persist or worsen. 

    • Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flulike" symptoms). 

    • Discontinue immediately and perform a clinical evaluation of the patient If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.).

    Hypertension

    • Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including sumatriptan, a component of Treximet. This occurrence has included patients without a history of hypertension.

    • May lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of cardiovascular events. 

    • May cause impaired response to angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, thiazide diuretics, or loop diuretics.

    • Monitor blood pressure. Treximet is contraindicated in patients with uncontrolled hypertension.

    Heart Failure and Edema

    • May blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs])

    • Avoid use in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. 

    • Monitor for signs of worsening heart failure if used in patients with severe heart failure.  

    • Consider overall intake of sodium since each Treximet 85/500 mg tablet contains approximately 60 mg of sodium and each Treximet 10/60 mg tablet contains approximately 20 mg of sodium.

    Medication Overuse Headache

    • Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). 

    • Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. 

    • May be necessary to detoxify patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache). 

    Serotonin Syndrome

    • The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. 

    • Discontinue if serotonin syndrome is suspected.

    Renal Toxicity and Hyperkalemia

    • Long-term administration of NSAIDs has increased risk of renal toxicity in patients with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and angiotensin-converting enzyme (ACE) inhibitors or ARBs, and the elderly.

    • Discontinue if clinical signs and symptoms consistent with renal disease develop or if systemic manifestations occur. 

    • Not recommended for use in patients with severe renal impairment (creatinine clearance [CrCl] <30 mL/min), unless the benefits are expected to outweigh the risk of worsening renal function.

    • If Treximet is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Monitor renal function in patients with mild (CrCl = 60 to 89 mL/min) or moderate (CrCl = 30 to 59 mL/min) renal impairment, preexisting kidney disease, or dehydration.

    • The renal effects of Treximet may hasten the progression of renal dysfunction in patients with pre-existing renal disease.

    • Correct volume status in dehydrated or hypovolemic patients prior to initiating Treximet. 

    • Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during treatment.

    • Avoid use in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Treximet is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

    • Increases in serum potassium concentration, including hyperkalemia, have been reported with the use of NSAIDs, even in some patients without renal impairment.

    Anaphylactic Reactions 

    • Do not administer to patients with the aspirin triad.

    • Treximet is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan, naproxen, or any other component of Treximet. Naproxen has been associated with anaphylactic reactions in patients without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma. Seek emergency help if an anaphylactic reaction occurs. 

    Serious Skin Reactions

    • May cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.

    • Discontinue at the first appearance of skin rash or any other sign of hypersensitivity. Treximet is contraindicated in patients with previous serious skin reactions to NSAIDs.

    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

    • Discontinue and evaluate immediately if signs or symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) are present.

    Fetal Toxicity 

    • Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs, including Treximet, in pregnant women at about 30 weeks gestation and later. NSAIDs, including Treximet, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. 

    • Oligohydramnios/Neonatal Renal Impairment: Use of NSAIDs, including Treximet, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. 

      • If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit Treximet use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if Treximet treatment extends beyond 48 hours. Discontinue Treximet if oligohydramnios occurs and follow up according to clinical practice. 

    Hematologic Toxicity

    • Monitor hemoglobin or hematocrit if signs or symptoms of anemia develop.  

    • May increase risk of bleeding events with comorbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs). Monitor for signs of bleeding.

    Exacerbation of Asthma Related to Aspirin Sensitivity 

    • A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Treximet is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

    • Monitor for changes in the signs and symptoms of asthma when Treximet is used in patients with preexisting asthma (without known aspirin sensitivity).

    Seizures

    • Use caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold. 

    Masking of Inflammation and Fever

    • May diminish the utility of diagnostic signs in detecting infections. 

    Laboratory Monitoring

    • Consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically due to serious GI bleeding, hepatotoxicity, and renal injury which may occur without warning symptoms or signs. 

    Pregnancy Considerations

    Risk Summary  

    • May cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Limit dose and duration of use between about 20 and 30 weeks of gestation, and avoid use at about 30 weeks of gestation and later in pregnancy.

    • Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women at about 30 weeks gestation and later. Increased risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

    • Oligohydramnios/Neonatal Renal Impairment: May cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment if used at about 20 weeks gestation or later in pregnancy. 

      • If treatment is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If treatment extends beyond 48 hours, consider ultrasound monitoring of amniotic fluid.  Discontinue treatment if oligohydramnios occurs.

    • Labor or Delivery: There are no studies on the effects of naproxen tablets during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. 

    Nursing Mother Considerations

    Risk Summary

    • There are no data on the effects of naproxen or sumatriptan on the breastfed infant or the effects of naproxen or sumatriptan on milk production.   

    • The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Treximet and any potential adverse effects on the breastfed infant from Treximet or from the underlying maternal condition.  

    • Clinical Considerations: Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with sumatriptan tablets.

    Pediatric Considerations

    Safety and effectiveness of Treximet in pediatric patients under 12 years of age have not been established.

    Geriatric Considerations

    Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. Treximet is not recommended for use in elderly patients who have decreased renal function, higher risk for unrecognized CAD, and increases in blood pressure that may be more pronounced in the elderly.

    Prior to receiving Treximet, perform a cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of CAD).

    Renal Impairment Considerations

    Treximet is not recommended for use in patients with creatinine clearance less than 30 mL/min. Monitor the serum creatinine or creatinine clearance in patients with mild (CrCl = 60 to 89 mL/min) or moderate (CrCL = 30 to 59 mL/min) renal impairment, preexisting kidney disease, or dehydration.

    Hepatic Impairment Considerations

    Treximet is contraindicated in patients with severe hepatic impairment. For patients with mild or moderate hepatic impairment, the Treximet dose should be reduced.

     

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential

    • Infertility in Females: May delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. 

    • Consider withdrawing treatment in women who have difficulties conceiving or who are undergoing investigation of infertility.

    Treximet Pharmacokinetics

    Absorption

    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.

    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%. 

    Distribution

    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.

    Metabolism

    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.

    Elimination

    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.

    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. 

    Treximet Interactions

    Interactions

    See Contraindications. Concomitant aspirin, salicylates (eg, diflunisal, salsalate) or other NSAIDs: not recommended. Increased risk of GI bleed with anticoagulants, antiplatelets, oral corticosteroids, SSRIs, SNRIs, smoking, alcohol, or prolonged NSAID therapy; monitor. May antagonize, or increase risk of renal failure with diuretics (eg, loop or thiazides), ACE inhibitors, ARBs, or β-blockers; monitor closely. Potentiates digoxin; monitor levels. May potentiate lithium, methotrexate, cyclosporine; monitor for toxicity. Concomitant with pemetrexed may increase risk of pemetrexed-associated myelosuppression, renal, and GI toxicity. Serum levels increased by probenecid. Risk of serotonin syndrome with concomitant SSRIs, SNRIs, TCAs, MAOIs. May interfere with 5HIAA urinary assays or Porter-Silber tests.

    Treximet Adverse Reactions

    Adverse Reactions

    Dizziness, somnolence, nausea, chest or neck/throat/jaw discomfort/pain, paresthesia, dyspepsia, dry mouth; cardiovascular thrombotic events, GI ulcer/bleed, hepatotoxicity, renal toxicity, hypersensitivity reactions, serious skin reactions (eg, exfoliative dermatitis, Stevens-Johnson Syndrome, toxic epidermal necrolysis), Drug Reaction with Eosinophilia and Systemic Symptoms (discontinue if occurs), anemia. Children: hot flush, muscle tightness.

    Treximet Clinical Trials

    Clinical Trials

    Adults

    In 2 randomized, double-blind, multicenter, parallel-group trials (Study 1 and Study 2), the efficacy of Treximet 85/500 mg (sumatriptan and naproxen sodium) was evaluated for the acute treatment of migraine with or without aura in adults. Patients were randomly assigned to receive either placebo or each individual active component of Treximet as comparison treatments (Study 1 and Study 2). Patients were instructed to treat a migraine of moderate to severe pain with 1 tablet. No rescue medication was allowed within 2 hours postdose. 

    Headache relief was defined as a reduction in headache severity from moderate or severe pain to mild or no pain. 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.

    Results from Study 1 and Study 2 showed that 65% and 57% of patients treated with Treximet, respectively, achieved headache pain relief 2 hours postdose compared with 28% and 29% of those treated with placebo (P <.05). Moreover, in Study 1 and 2, a significantly greater proportion of patients treated with Treximet 85/500 mg (25% and 23%) remained pain free without the use of other medications for 24 hours postdose compared with those treated with placebo (8% and 9%) or either sumatriptan (16% and 14%) or naproxen sodium (10%) alone (all P <.01).

    There was a decreased incidence of photophobia, phonophobia, and nausea 2 hours after the administration of Treximet 85/500 mg compared with placebo. Regardless of the presence of aura, Treximet 85/500 mg was more effective than placebo for: 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

    In a randomized, double-blind, multicenter, parallel-group, placebo-controlled, multicenter trial (Study 3), the efficacy of Treximet was evaluated for the acute treatment of migraine with or without aura in pediatric patients 12 to 17 years of age. Eligible patients included thos with 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 randomly assigned 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. 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 showed that a significantly greater proportion of patients who received Treximet 10/60 mg (29%), 30/180 mg (27%), 85/500 mg (24%) were pain free at 2 hours postdose compared with placebo (10%) (all P <.01).

    A significantly greater percentage of pediatric patients remained pain free without use of other medications 2 through 24 hours postdose 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. 

    There was a significant decrease in the incidence of photophobia and phonophobia 2 hours after the administration of a single dose of 85/500 mg compared with placebo, whereas the incidence of nausea was comparable. There was also 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. 

    Treximet Note

    Not Applicable

    Treximet Patient Counseling

    Patient Counseling

    Cardiovascular Thrombotic Events, Prinzmetal's Angina, Other Vasospasm-Related Events, Arrhythmias and Cerebrovascular Events 

    • Be alert for symptoms of cardiovascular thrombotic effects such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for signs and symptoms of chest pain, shortness of breath, weakness, irregular heartbeat, significant rise in blood pressure, weakness and slurring of speech, and should be advised to report any of these symptoms to their health care provider immediately. 

    Gastrointestinal Bleeding, Ulceration, and Perforation 

    • Report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. 

    • Inform patients of the increased risk for and the signs and symptoms of GI bleeding in the setting of concomitant use of low-dose aspirin for cardiac prophylaxis.

    Hepatotoxicity 

    • Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). Discontinue Treximet and seek immediate medical therapy if signs and symptoms of hepatotoxicity occur.

    Anaphylactic Reactions 

    • Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat), which can be life-threatening or fatal. Instruct patients to seek immediate emergency help if these reactions occur.

    Serious Skin Reactions, including DRESS 

    • Inform patients that Treximet may increase the risk of serious skin side effects such as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS, which may result in hospitalizations and even death. 

    • Be alert for the signs and symptoms of skin rash and blisters, fever, or other signs of hypersensitivity such as itching - serious skin reactions may occur without warning. 

    • Discontinue Treximet immediately and contact their healthcare providers immediately if any type of rash or fever develops. 

    Fetal Toxicity 

    • Avoid use of Treximet and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with Treximet is necessary for a pregnant woman between about 20 to 30 weeks gestation, the patient may need to be monitored for oligohydramnios if treatment continues for longer than 48 hours.  

    Lactation 

    • Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed.

    Female Fertility 

    • Treximet may be associated with a reversible delay in ovulation.

    Heart Failure and Edema 

    • Be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur.

    Concomitant Use with Other Triptans or Ergot Medications 

    • Inform patients that use of Treximet within 24 hours of another triptan or an ergot-type medication (including dihydroergotamine or methysergide) is contraindicated.

    Serotonin Syndrome 

    • Caution patients about the risk of serotonin syndrome with the use of Treximet or other triptans, particularly during concomitant use with SSRIs, SNRIs, TCAs, and MAO inhibitors.

    Medication Overuse Headache 

    • Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary).

    Ability to Perform Complex Tasks

    • May cause somnolence and dizziness, and instruct patients to evaluate their ability to perform complex tasks after administration of Treximet.

    Asthma 

    • Patients with preexisting asthma should seek immediate medical attention if their asthma worsens after taking Treximet. Do not administer Treximet in patients with a history of aspirin-sensitive asthma.

    Avoid Concomitant Use of NSAIDs 

    • The concomitant use of Treximet with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy. Alert patients of “over the counter” medications that contain NSAIDs for treatment of colds, fever, or insomnia. 

    Use of NSAIDS and Low-Dose Aspirin

    • Do not use low-dose aspirin concomitantly with Treximet until consulting a healthcare provider.

    Cost Savings Program

    Treximet Savings Card: https://www.treximet.com/

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