HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`TREXIMET safely and effectively. See full prescribing information for
`TREXIMET.
`
`TREXIMET (sumatriptan and naproxen sodium) tablets, for oral use
`
`Initial U.S. Approval: 2008
`
`
`WARNING: CARDIOVASCULAR AND GASTROINTESTINAL
`
`
`
`RISKS
`
`
`See full prescribing information for complete boxed warning.
`
`
` Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased
`risk of serious cardiovascular thrombotic events, myocardial
`
`infarction, and stroke, which can be fatal. This risk may increase with
`
`
`duration of use. Patients with cardiovascular disease or risk factors for
`cardiovascular disease may be at greater risk. (5.1)
`
` NSAIDs cause an increased risk of serious gastrointestinal 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 are at
`
`
`greater risk for serious gastrointestinal events. (5.2)
`
`
`
`
`
`--------------------------- RECENT MAJOR CHANGES ---------------------------
`
`
`
`Indications and Usage (1)
` 05/2015
`
`
`Dosage and Administration (2.2)
` 05/2015
`
`
`--------------------------- INDICATIONS AND USAGE ----------------------------
`
`TREXIMET is a combination of sumatriptan, a serotonin (5-HT) 1b/1d
`
`receptor agonist (triptan), and naproxen sodium, a non-steroidal anti-
`
`inflammatory drug, indicated for the acute treatment of migraine with or
`
`
`without aura in adults and pediatric patients 12 years of age and older. (1)
`
`Limitations of Use:
`
`
` Use only if a clear diagnosis of migraine headache has been established. (1)
`
`
`
`
` Not indicated for the prophylactic therapy of migraine attacks. (1)
`
`
`
` Not indicated for the treatment of cluster headache. (1)
`
`
` ----------------------- DOSAGE AND ADMINISTRATION -----------------------
`
`Adults
`
` Recommended dosage: 1 tablet of 85/500 mg. (2.1)
`
`
` Maximum dosage in a 24-hour period: 2 tablets of 85/500 mg; separate
`doses by at least 2 hours. (2.1)
`
`Pediatric Patients 12 to 17 years of Age
`
`
` Recommended dosage: 1 tablet of 10/60 mg. (2.2)
`
`
` Maximum dosage in a 24-hour period: 1 tablet of 85/500 mg.
`
`
`Mild to Moderate Hepatic Impairment
`
`
`
` Recommended dosage: 1 tablet of 10/60 mg. (2.3, 8.7)
`
`--------------------- DOSAGE FORMS AND STRENGTHS----------------------
`
`
`
`Tablets: 85 mg sumatriptan / 500 mg naproxen sodium (3)
`
`
`10 mg sumatriptan / 60 mg naproxen sodium (3)
` ------------------------------ CONTRAINDICATIONS ------------------------------
`
`
`
` History of coronary artery disease or coronary vasospasm. (4)
`
`
`
`
` History of coronary artery bypass graft surgery. (4)
`
`
`
`
` Wolff-Parkinson-White syndrome or other cardiac accessory conduction
`
`
`pathway disorders. (4)
`
` History of stroke, transient ischemic attack, or hemiplegic or basilar
`migraine. (4)
`
`
` Peripheral vascular disease. (4)
`
`
` Ischemic bowel disease. (4)
`
`
` Uncontrolled hypertension. (4)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosage in Adults
`2.2 Dosage in Pediatric Patients 12 to 17 years of age
`
`2.3 Dosage in Patients with Hepatic Impairment
`2.4
` Administration Information
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`
`5.1 Myocardial Ischemia, Myocardial Infarction, Stroke,
`Prinzmetal’s Angina
` Gastrointestinal Bleeding, Ulceration, and Perforation
`
`
`
`5.2
`
`Reference ID: 3756007
`
`
` Recent (within 24 hours) use of another 5-HT1 agonist (e.g., another
`
`
`triptan) or of ergotamine-containing medication. (4)
`
` Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor.
`
`
`(4)
`
` Asthma, rhinitis, and nasal polyps syndrome induced by aspirin or other
`NSAID/analgesic drugs. (4)
`
`
`
` Hypersensitivity to sumatriptan, naproxen, or any other component of
`TREXIMET (angioedema and anaphylaxis seen). (4)
`
`
` Third trimester of pregnancy. (4)
`
` Severe hepatic impairment. (4)
`------------------------ WARNINGS and PRECAUTIONS ------------------------
`
`
`
`
` Myocardial ischemia/infarction, stroke, Prinzmetal’s angina: Perform
`
`cardiac evaluation in patients with cardiovascular risk factors. (5.1)
`
` Arrhythmias: Discontinue TREXIMET if occurs. (5.3)
`
`
` Chest/throat/neck/jaw pain, tightness, pressure, or heaviness: Generally not
`associated with myocardial ischemia; evaluate for coronary artery disease
`in patients at high risk. (5.4)
`
`
` Cerebral hemorrhage, subarachnoid hemorrhage, and stroke: Discontinue
`TREXIMET if occurs. (5.5)
`
`
` Gastrointestinal ischemic reactions and peripheral vasospastic reactions:
`Discontinue TREXIMET if occurs. (5.6)
`
` Hypertension: Monitor blood pressure. (5.7)
`
` Heart failure and edema: Use with caution in patients with fluid retention
`or heart failure. (5.8)
`
` Medication overuse headache: Detoxification may be necessary (5.9)
`
` Serotonin syndrome: Discontinue TREXIMET if occurs. (5.10)
`
` Renal papillary necrosis and other renal injury with long-term use:
`
`Discontinue TREXIMET if occurs. (5.11)
`
`
`
` Anaphylactic reactions: TREXIMET should not be given to patients with
`the aspirin triad. (5.12)
`
`
`
` Serious skin reactions: Discontinue TREXIMET at first sign of rash. (5.13)
`
` Elevated liver enzymes and severe hepatic reactions: Discontinue use
`immediately if abnormal liver enzymes persist or worsen. (5.15)
`
`
` ------------------------------ ADVERSE REACTIONS ------------------------------
`
`
`The most common adverse reactions (incidence 2%) were:
`
`
` Adults: Dizziness, somnolence, nausea, chest discomfort/chest pain,
`
`
`neck/throat/jaw pain/tightness/pressure, paresthesia, dyspepsia, dry mouth.
`(6.1)
`
` Pediatrics: Hot flush (i.e., hot flash[es]) and muscle tightness. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Pernix
`
`Therapeutics at 1-800-793-2145 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`
` ------------------------------ DRUG INTERACTIONS-------------------------------
`
`
` Methotrexate: Increases methotrexate plasma levels. (7.4)
`
`
` Aspirin: Use not recommended. (7.5)
`
`
` Angiotensin-converting enzyme inhibitors, diuretics, beta-blockers: May
`reduce antihypertensive effects. (7.7)
`
` Lithium: Increases lithium plasma levels. (7.9)
`
`
` Warfarin: Higher risk of serious gastrointestinal bleeding. (7.12)
`
`
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`
` Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
` Severe Renal impairment: Not recommended in patients with creatinine
`
`clearance <30 mL/min. (8.6)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved Medication Guide.
`
`Revised: 05/2015
`
`
`5.3
` Arrhythmias
`
`5.4 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure
`
`
` Cerebrovascular Events
`5.5
`
`
` Other Vasospasm Reactions
`5.6
` Hypertension
`5.7
`5.8 Congestive Heart Failure and Edema
`
`5.9 Medication Overuse Headache
`
`5.10 Serotonin Syndrome
`5.11 Renal Toxicity
`
`5.12 Anaphylactic Reactions
`5.13 Serious Skin Reactions
`5.14 Pregnancy
`5.15 Hepatotoxicity
`
`
`

`

`5.16 Hematologic Toxicity
`5.17 Exacerbation Asthma Related to Aspirin Sensitivity
`
`5.18 Seizures
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`7 DRUG INTERACTIONS
`
`
` Ergot-Containing Drugs
`7.1
`7.2 Monoamine Oxidase-A Inhibitors
`
`
` Other 5-HT1 Agonists
`
`7.3
`
` Methotrexate
`7.4
`7.5
` Aspirin
`7.6
`Selective Serotonin Reuptake Inhibitors/Serotonin
`
`Norepinephrine Reuptake Inhibitors and Serotonin
`
`Syndrome
`
` Angiotensin-Converting Enzyme Inhibitors
`
`7.7
`
`
` Diuretics
`
`7.8
`
` Lithium
`7.9
`7.10 Probenecid
`7.11 Propranolol and Other Beta-Blockers
`
`
`
`7.12 Warfarin
`
`
`7.13 Drug/Laboratory Test Interactions
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1
` Pregnancy
`
`
`
`8.2 Labor and Delivery
`
`8.3
` Nursing Mothers
`8.4
` Pediatric Use
`8.5
` Geriatric Use
`8.6
` Renal Impairment
`8.7
` Hepatic Impairment
`10 OVERDOSAGE
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Adults
`14.2 Pediatric Patients 12 to 17 Years of Age
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`Reference ID: 3756007
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`WARNING: CARDIOVASCULAR AND GASTROINTESTINAL RISKS
`
`
`
`
`
`
`
`
` Cardiovascular Risk: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular
`
`thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use.
`Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and
`
`
`Precautions (5.1)].
`
` Gastrointestinal Risk: NSAIDs cause an increased risk of serious gastrointestinal 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 are at greater risk for serious gastrointestinal events [see Warnings and
`
`
`
`Precautions (5.2)].
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`TREXIMET is indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years of age and
`
`older.
`
`
`Limitations of Use:
`
`
`
`
`
` Use only if a clear diagnosis of migraine headache has been established. If a patient has no response to the first migraine attack
`
`
`
`treated with TREXIMET, reconsider the diagnosis of migraine before TREXIMET is administered to treat any subsequent attacks.
`
`
`
`
` TREXIMET is not indicated for the prevention of migraine attacks.
`
`
` Safety and effectiveness of TREXIMET have not been established for cluster headache.
`
`
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`Dosage in Adults
`2.1
`
`The recommended dosage for adults is 1 tablet of TREXIMET 85/500 mg. TREXIMET 85/500 mg contains a dose of sumatriptan
`
`higher than the lowest effective dose. The choice of the dose of sumatriptan, and of the use of a fixed combination such as in
`
`
`
`
`
`TREXIMET 85/500 mg should be made on an individual basis, weighing the possible benefit of a higher dose of sumatriptan with the
`
`
`
`potential for a greater risk of adverse reactions.
`
`
`
`
`The maximum recommended dosage in a 24-hour period is 2 tablets, taken at least 2 hours apart.
`
`The safety of treating an average of more than 5 migraine headaches in adults in a 30-day period has not been established.
`
`
`
`Dosage in Pediatric Patients 12 to 17 Years of Age
`2.2
`
`
`
`
`
`
`
`The recommended dosage for pediatric patients 12 to 17 years of age is 1 tablet of TREXIMET 10/60 mg.
`
`
`
`
`
`
`The maximum recommended dosage in a 24-hour period is 1 tablet of TREXIMET 85/500 mg.
`
`
`
`
`
`
`The safety of treating an average of more than 2 migraine headaches in pediatric patients in a 30-day period has not been established.
`
`Dosing in Patients with Hepatic Impairment
`2.3
`
`
`TREXIMET is contraindicated in patients with severe hepatic impairment [see Contraindications (4), Use in Specific Populations
`
`
`(8.7), Clinical Pharmacology (12.3)].
`
`
`In patients with mild to moderate hepatic impairment, the recommended dosage in a 24-hour period is 1 tablet of TREXIMET 10/60
`mg [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].
`
`
`
`Reference ID: 3756007
`
`

`

`Administration Information
`2.4
`
`
`TREXIMET may be administered with or without food. Tablets should not be split, crushed, or chewed.
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`10 mg sumatriptan/60 mg naproxen sodium, light-blue film-coated tablets, debossed on one side with “TREXIMET” and the other
`
`
`
`side with “10-60”.
`
`
`
`85 mg sumatriptan/500 mg naproxen sodium, blue film-coated tablets, debossed on one side with “TREXIMET”.
`
`
`
`4
`CONTRAINDICATIONS
`
`TREXIMET is contraindicated in the following patients:
`
`
`
`Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or
`
`
`coronary artery vasospasm, including Prinzmetal’s angina [see Warnings and Precautions (5.1)].
`
`
` History of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)].
`
`
`
`
` Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders [see
`Warnings and Precautions (5.3)].
`
` History of stroke or transient ischemic attack (TIA) or history of hemiplegic or basilar migraine because these patients are at a
`higher risk of stroke [see Warnings and Precautions (5.5)].
`
`
`
` Peripheral vascular disease [see Warnings and Precautions (5.6)].
`
`
`Ischemic bowel disease [see Warnings and Precautions (5.6)].
`
`
`
` Uncontrolled hypertension [see Warnings and Precautions (5.7)].
`
`
`
`
` Recent use (i.e., within 24 hours) of ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or
`methysergide), or another 5-hydroxytryptamine1 (5-HT1) agonist [see Drug Interactions (7.1, 7.3)].
`
`
` Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor
`
`
`
`[see Drug Interactions (7.2), Clinical Pharmacology (12.3)].
`
`
`
` Asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs [see Warnings and Precautions (5.12, 5.13,
`
`5.17)].
`
`
` Hypersensitivity to sumatriptan, naproxen, or any other component of TREXIMET. Reactions have included angioedema and
`
`anaphylaxis [see Warnings and Precautions (5.12)].
`
`
` Third trimester of pregnancy [see Warnings and Precautions (5.14), Use in Specific Populations (8.1)].
`
`
`
`
`
`
`
` Severe hepatic impairment [see Warnings and Precautions (5.15), Use in Specific Populations (8.7), Clinical Pharmacology
`
`
`
`(12.3)].
`
`
`5
`WARNINGS AND PRECAUTIONS
`
`Myocardial Ischemia, Myocardial Infarction, Stroke, Prinzmetal’s Angina
`5.1
`
`
`
`
`The use of TREXIMET is contraindicated in patients with ischemic or vasospastic coronary artery disease (CAD) or with a history of
`
`
`CABG surgery due to increased risk of serious cardiovascular events with sumatriptan and NSAIDS [see Contraindications (4)].
`
`
`
`
`
`Cardiovascular Events With Sumatriptan
`
`
`There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring 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.
`
`Cardiovascular Events With Nonsteroidal Anti-inflammatory Drugs
`
`
`Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years’ duration have shown an increased risk of
`
`
`serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2
`
`selective and nonselective, may have a similar risk. Patients with known cardiovascular disease or risk factors for cardiovascular
`
`Reference ID: 3756007
`
`

`

`
` disease may be at greater risk. To minimize the potential risk for an adverse cardiovascular event in patients treated with an
` NSAID, the lowest effective dose should be used for the shortest duration possible.
`
`
`
`
`
`
`
` There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious cardiovascular thrombotic
` events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious gastrointestinal
`
`
`
`
`
`
` events [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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) prior to receiving TREXIMET. If there is evidence of CAD or
`
`
`
`
` coronary artery vasospasm, TREXIMET is contraindicated. For patients with multiple cardiovascular risk factors who have a negative
`
`
` cardiovascular evaluation, consider administering the first dose of TREXIMET in a medically supervised setting and performing an
`
` electrocardiogram (ECG) immediately following administration of TREXIMET. For such patients, consider periodic cardiovascular
`
`
`
`evaluation in intermittent long-term users of TREXIMET.
`
` Physicians and patients should remain alert for the development of cardiovascular events, even in the absence of previous
`
`
`
` cardiovascular symptoms. Patients should be informed about the signs and/or symptoms of serious cardiovascular events and the steps
`to take if they occur.
`
` Premarketing Experience with TREXIMET
`
`
`Among 3,302 adult patients with migraine who received TREXIMET in premarketing controlled and uncontrolled clinical trials, a 47­
`
`
`
`
`year-old female with cardiac risk factors in an open-label 12-month safety trial experienced signs and symptoms of acute coronary
`syndrome approximately 2 hours after receiving TREXIMET.
`
`5.2
`Gastrointestinal Bleeding, Ulceration, and Perforation
`
`
`
`NSAIDs, including naproxen, a component of TREXIMET cause serious gastrointestinal adverse events including inflammation,
`
`
`
`bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse
`
`
`
`
`
`events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only 1 in 5 patients who develop a
`
`
`
`serious upper gastrointestinal adverse event on NSAID therapy is symptomatic. Upper gastrointestinal ulcers, gross bleeding, or
`
`
`
`
`perforation caused by NSAIDs appear to occur in approximately 1% of patients treated daily for 3 to 6 months and in about 2% to 4%
`
`of patients treated for 1 year. However, even short-term therapy is not without risk.
`
`
`Among 3,302 adult patients with migraine who received TREXIMET in controlled and uncontrolled clinical trials, 1 patient
`
`experienced a recurrence of gastric ulcer after taking 8 doses over 3 weeks, and 1 patient developed a gastric ulcer after treating an
`
`average of 8 attacks per month over 7 months.
`
`
`
`
`
`
`TREXIMET should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding.
`
`
`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 concomitant use of oral corticosteroids or
`anticoagulants or antiplatelets (including low-dose aspirin), longer duration of NSAID therapy, smoking, use of alcohol, older age, and
`poor general health status. Most postmarketing reports of fatal gastrointestinal events occurred in elderly or debilitated patients, and
`
`therefore special care should be taken in treating this population.
`
`
`To minimize the potential risk for an adverse gastrointestinal event in NSAID-treated patients, the lowest effective dose should be
`
`
`
`used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of gastrointestinal
`
`Reference ID: 3756007
`
`

`

`
`ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious gastrointestinal
`
`adverse event is suspected. This should include discontinuation of the NSAID until a serious gastrointestinal adverse event is ruled
`
`
`out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.
`
`
`5.3
`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.
`
`5.4 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. However, perform a cardiac evaluation if these patients are at high cardiac risk. The
`
`use of TREXIMET is contraindicated in patients with CAD and those with Prinzmetal’s variant angina.
`
`5.5 Cerebrovascular Events
`
`Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have
`resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having
`
`
`
`been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also,
`
`
`patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue
`
`
`
`
`
`
`
`TREXIMET if a cerebrovascular event occurs.
`
`Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical
`
`
`
`symptoms, exclude other potentially serious neurological conditions. TREXIMET is contraindicated in patients with a history of
`stroke or TIA [see Contraindications (4)].
`
`
`5.6 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. In patients who
`
`
`
`experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out a
`
`
`
`vasospastic reaction before receiving additional TREXIMET.
`
`
`
`Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists.
`
`
`
`Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have
`not been clearly established.
`
`
`
`5.7 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 patients without a history of hypertension.
`
`
`
`
`NSAIDs, including naproxen, a component of TREXIMET, can lead to onset of new hypertension or worsening of preexisting
`
`
`
`hypertension, either of which may contribute to the increased incidence of cardiovascular events. Patients taking thiazides or loop
`
`
`
`diuretics may have impaired response to these therapies when taking NSAIDs.
`
`
`
`
`Monitor blood pressure in patients treated with TREXIMET. TREXIMET is contraindicated in patients with uncontrolled
`
`
`
`hypertension [see Contraindications (4)].
`
`
`
`Reference ID: 3756007
`
`

`

`
`
`
`5.8 Heart Failure and Edema
`
`Fluid retention, edema, and peripheral edema have been observed in some patients taking NSAIDs. 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,
`
`
`
`
`
`
`
`
`this should be considered in patients whose overall intake of sodium must be severely restricted. TREXIMET should be used with
`
`caution in patients with fluid retention or heart failure.
`
`
`5.9 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. Detoxification of patients, including withdrawal of the
`
`overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
`
`
`5.10 Serotonin Syndrome
`
`
`Serotonin syndrome may occur with TREXIMET, particularly during coadministration with selective serotonin reuptake inhibitors
`(SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see Drug
`Interactions (7.6)]. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma),
`
`
`
`autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia,
`
`
`incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within
`
`minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue TREXIMET if serotonin syndrome is
`suspected.
`
`
`
`5.11 Renal Toxicity
`
`
`
`Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen
`
`
`
`
`in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients
`
`
`
`
`
`administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow,
`
`which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function,
`
`
`hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and angiotensin-converting enzyme (ACE)
`
`inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
`
`
`TREXIMET should be discontinued if clinical signs and symptoms consistent with renal disease develop or if systemic manifestations
`occur.
`
`TREXIMET is not recommended for use in patients with severe renal impairment (creatinine clearance [CrCl] <30 mL/min) [see Use
`
`in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 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.
`
`
`5.12 Anaphylactic Reactions
`
`
`
`Anaphylactic reactions may occur in patients without known prior exposure to either component of TREXIMET. Such reactions can
`
`
`
`be life-threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of
`
`sensitivity to multiple allergens. TREXIMET is contraindicated in patients with a history of hypersensitivity reaction to sumatriptan,
`naproxen, or any other component of TREXIMET [see Contraindications (4)].
`
`
`
`
`Reference ID: 3756007
`
`

`

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`
`
`TREXIMET should not be given to patients with the aspirin triad. This symptom complex typically occurs in patients with asthma
`
`who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or
`other NSAIDs [see Contraindications (4)].
`
`
`
`5.13 Serious Skin Reactions
`
`NSAID-containing products can cause serious adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic
`
`
`
`
`
`epidermal necrolysis, which can be fatal. These serious events may occur without warning. Patients should be informed about the
`
`
`
`signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or
`
`any other sign of hypersensitivity.
`
`
`5.14 Pregnancy
`
`TREXIMET should not be used during the third trimester of pregnancy because NSAID-containing products have been shown to
`
`cause premature closure of the ductus arteriosus [see Contraindications (4), Use in Specific Populations (8.1)].
`
`
`5.15 Hepatotoxicity
`
`
`
`
`Borderline elevations of 1 or more liver tests may occur in up to 15% of patients who take NSAIDs including naproxen, a component
`
`
`
`of TREXIMET. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These abnormalities may
`
`progress, may remain essentially unchanged, or may be transient with continued therapy. Notable (3 times the upper limit of normal)
`
`
`
`
`
`
`
`elevations of SGPT (ALT) or SGOT (AST) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In
`
`addition, cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure, some of
`
`
`
`them with fatal outcomes, have been reported with NSAIDs.
`
`
`TREXIMET is contraindicated in patients with severe hepatic impairment [see Use in Specific Populations (8.7), Clinical
`
`Pharmacology (12.3)]. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has
`
`
`
`
`
`
`occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with TREXIMET.
`
`TREXIMET should be discontinued 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.
`
`
`
`5.16 Hematologic Toxicity
`
`
`
`Anemia is sometimes seen in patients receiving NSAIDs. This may be due to fluid retention, occult or gross gastrointestinal blood
`
`
`loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including TREXIMET,
`
`
`should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
`
`
`
`
`
`NSAID-containing products inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike
`aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving TREXIMET who
`
`
`may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving
`
`anticoagulants, should be carefully monitored.
`
`
`
`
`5.17
`Exacerbation of Asthma Related to Aspirin Sensitivity
`
`
`Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been
`
`
`associated with severe bronchospasm that can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other
`
`
`
`
`
`
`NSAIDs has been reported in such aspirin-sensitive patients, TREXIMET should not be administered to patients with this form of
`
`aspirin sensitivity and should be used with caution in patients with preexisting asthma [see Contraindications (4), Warnings and
`
`
`
`
`
`
`
`Precautions (5.12)].
`
`
`Reference ID: 3756007
`
`

`

`Seizures
`5.18
`
`
`
` Seizures have been reported following administration of sumatriptan. Some have occurred in patients with either a history of seizures
`
` or concurrent conditions predisposing to seizures. There are also reports in patients where no such predisposing factors are apparent.
`
`
` TREXIMET should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure
`
`
` threshold.
`
`
`
`6
`
` ADVERSE REACTIONS
` The following serious adverse reactions are described below and elsewhere in labeling:
`
`
`
`
`  Myocardial Ischemia/Infarction, Stroke, Prinzmetal’s Angina [see Warnings and Precautions (5.1)]
`
`
`
` Gastrointestinal effects [see Warnings and Precautions (5.2)]
`
`
`
` Arrhythmias [see Warnings and Precautions (5.3)]
`
`
`
`
`  Chest, throat, neck, and/or jaw pain/tightness/pressure [see Warnings