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: RISK OF SERIOUS CARDIOVASCULAR AND
`
`
`
`GASTROINTESTINAL EVENTS
`
`
`See full prescribing information for complete boxed warning.
`
`
`
` 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. (5.1)
`
` TREXIMET is contraindicated in the setting of coronary artery bypass
`graft (CABG) surgery (4, 5.1)
`
`
` 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. (5.2)
`
`
`
`
`--------------------------- RECENT MAJOR CHANGES ---------------------------
`
`
`
`Boxed Warning
`05/2016
`
`
`Contraindications (4)
` 05/2016
`
`
`Warnings and Precautions (5.1, 5.2, 5.8, 5.9, 5.12, 5.13,
`
` 05/2016
`5.14, 5.16, 5.17, 5.19, 5.20)
`
`
`--------------------------- 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)
`
`
`
`
` In the setting of CABG 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)
`
` 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)
`
` History of asthma, urticaria, other allergic type reactions, rhinitis, or nasal
`polyps syndrome after taking aspirin or other NSAID/analgesic drugs. (4)
`
`
` Known hypersensitivity to sumatriptan, naproxen, or any components of
`TREXIMET (angioedema and anaphylaxis seen). (4)
`
`
`
` Third trimester of pregnancy. (4)
`
` Severe hepatic impairment. (4)
`------------------------ WARNINGS and PRECAUTIONS ------------------------
`
`
`
`
` Cardiovascular Thrombotic Events: Perform cardiac evaluation in patients
`
`with cardiovascular risk factors. (5.1)
`
`
` Arrhythmias: Discontinue TREXIMET if occurs. (5.3)
`
` Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure: Generally not
`associated with myocardial ischemia; evaluate for coronary artery disease
`in patients at high risk. (5.4)
`
` Cerebrovascular Events: Discontinue TREXIMET if occurs. (5.5)
`
`
`
` Other Vasospasm Reactions: Discontinue TREXIMET if non-coronary
`
`vasospastic reaction occurs. (5.6)
`
` Hepatotoxicity: Inform patients of warning signs and symptoms of
`hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if
`
`clinical signs and symptoms of liver disease develop. (5.7)
`
`
` Hypertension: Patients taking some antihypertensive medications may have
`impaired response to these therapies when taking NSAIDs. Monitor blood
`
`pressure. (5.8)
`
`
` Heart Failure and Edema: Avoid use of TREXIMET in patients with severe
`heart failure unless benefits are expected to outweigh risk of worsening
`heart failure. (5.9)
`
` Medication Overuse Headache: Detoxification may be necessary. (5.10)
`
`
` Serotonin Syndrome: Discontinue TREXIMET if occurs. (5.11)
`
`
` Renal Toxicity and Hyperkalemia: Monitor renal function in patients with
`renal or hepatic impairment, heart failure, dehydration, or hypovolemia.
`
`
`Avoid use of TREXIMET in patients with advanced renal disease. (5.12)
`
` Anaphylactic Reactions: TREXIMET should not be given to patients with
`the aspirin triad. Seep emergency help if an anaphylactic reaction
`
`occurs.(5.13)
`
` Serious Skin Reactions: Discontinue TREXIMET at first sign of rash or
`other signs of hypersensitivity. (5.14)
`
` Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with
`
`any signs or symptoms of anemia. (5.16)
`
` Exacerbation of Asthma Related to Aspirin Sensitivity: TREXIMET is
`contraindicated in patients with aspirin-sensitive asthma. Monitor patients
`with preexisting asthma (without aspirin sensitivity). (5.17)
`
`
` ------------------------------ 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-------------------------------
`
`
` Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs):
`
`
`Monitor patients for bleeding who are concomitantly taking TREXIMET
`
`with drugs that interfere with hemostasis. Concomitant use of TREXIMET
`
`and analgesic doses of aspirin is not generally recommended. (7.1)
`
`
` ACE Inhibitors and ARBs: Concomitant use with TREXIMET in elderly,
`
`volume depleted, or those with renal impairment may result in deterioration
`of renal function. In such high risk patients, monitor for signs of worsening
`
`
`
`renal function. (7.1)
`
`
` Diuretics: NSAIDs can reduce natriuretic effect of loop and thiazide
`diuretics. Monitor patients to assure diuretic efficacy including
`antihypertensive effects. (7.1)
`
`
` Digoxin: Concomitant use with TREXIMET can increase serum
`
`
`concentration and prolong half-life of digoxin. Monitor serum digoxin
`levels. (7.1)
`
` Lithium: Increases lithium plasma levels. (7.1)
`
` Methotrexate: Increases methotrexate plasma levels. (7.1)
`
`
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`
`
`
` Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved Medication Guide.
`
`
`Revised: 05/2016
`
`
`
`Reference ID: 3928586
`
`

`

`
`
`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 Cardiovascular Thrombotic Events
`
`
`5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
`
`5.3 Arrhythmias
`
`
`5.4 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure
`
`
`5.5 Cerebrovascular Events
`
`
`
`5.6 Other Vasospasm Reactions
`
`
`5.7 Hepatotoxicity
`
`
`5.8 Hypertension
`5.9 Heart Failure and Edema
`
`5.10 Medication Overuse Headache
`
`
`5.11 Serotonin Syndrome
`
`
`5.12 Renal Toxicity and Hyperkalemia
`
`
`
`5.13 Anaphylactic Reactions
`
`
`5.14 Serious Skin Reactions
`
`5.15 Premature Closure of the Ductus Arteriosus
`
`
`5.16 Hematologic Toxicity
`5.17 Exacerbation of Asthma Related to Aspirin Sensitivity
`
`5.18 Seizures
`
`
`5.19 Masking of Inflamation and Fever
`
`
`
`
`5.20 Laboratory Monitoring
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`7 DRUG INTERACTIONS
`
`
`7.1 Clinically Significant Drug Interactions with TREXIMET
`
`
`7.2 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: 3928586
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`FULL PRESCRIBING INFORMATION
`
`
`
`WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
`
`
`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 [see Warnings and Precautions (5.1)].
` TREXIMET is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4)
`
`
`
`Warnings and Precautions (5.1)].
`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 [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.
`
`Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and
`
`Precautions (5)].
`
`
`
`
`
`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.
`
`Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and
`
`Precautions (5)].
`
`Reference ID: 3928586
`
`

`

`
`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)].
`
`
`Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and
`
`Precautions (5)].
`
`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)].
`
`
`In the setting 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 (5.8)].
`
`
`
`
` 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)].
`
` Concurrent administration of a monoamine oxidase (MAO)-A inhibitor or recent (within 2 weeks) use of an MAO-A inhibitor
`
`
`
`[see Drug Interactions (7), Clinical Pharmacology (12.3)].
`
`
`
` History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic
`
`
`
`reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.13, 5.14, 5.17)].
`
`
`
`
`
` Known hypersensitivity (e.g., anaphylactic reactions, angioedema, and serious skin reactions) to sumatriptan, naproxen, or any
`components of TREXIMET [see Warnings and Precautions (5.14)].
`
`
`
`
`
`
` Third trimester of pregnancy [see Warnings and Precautions (5.15), Use in Specific Populations (8.1)].
`
`
`
`
`
`
` Severe hepatic impairment [see Warnings and Precautions (5.7), Use in Specific Populations (8.7), Clinical Pharmacology
`
`
`(12.3)].
`
`5
`
`5.1
`
`
`WARNINGS AND PRECAUTIONS
`
`Cardiovascular Thrombotic Events
`
`Reference ID: 3928586
`
`

`

`
` The use of TREXIMET is contraindicated in patients with ischemic or vasospastic coronary artery disease (CAD) and in the setting of
` coronary artery bypass graft (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 Thrombotic 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 (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on
`
`available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV
`
`
`
`thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or
`
`
`
`
`
`risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess
`
`
`serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of
`
`
`serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been
`
`observed most consistently at higher doses.
`
`
`
`
`To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest
`
`duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment
`
`
`
`course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and
`the steps to take if they occur.
`
`
`
`
`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 [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`
`
`Status Post Coronary Artery Bypass Graft (CABG) Surgery
`
`
`Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10–14 days following
`CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of
`
`CABG [see Contraindications (4)].
`
`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. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated
`
`
`
`
`
`
`patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined
`
`
`
`
`somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four
`
`years of follow-up.
`
`
`
`
`
`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
`
`Reference ID: 3928586
`
`

`

`
`
`
`
` 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.
`
`
`Gastrointestinal Bleeding, Ulceration, and Perforation
`5.2
`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.
`
`
`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 gastrointestinal events occurred in elderly or debilitated
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`patients, and therefore special care should be taken in treating this population. Additionally, patients with advanced liver disease
`and/or coagulopathy are at increased risk for GI bleeding.
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`Strategies to Minimize the GI Risks in NSAID-treated patients:
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` Use the lowest effective dosage for the shortest possible duration.
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` Avoid administration of more than one NSAID at a time.
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` Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For high risk patients,
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`as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.
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` Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
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`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.
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`In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI
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`bleeding [see Drug Interactions (7)].
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`
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`5.3
`Arrhythmias
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`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.
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`Reference ID: 3928586
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`

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`TREXIMET is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac
`accessory conduction pathway disorders.
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`5.4 Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure
`
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`Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck, and jaw commonly occur after treatment with
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`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.
`
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`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
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`been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. Also,
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`patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, TIA). Discontinue
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`TREXIMET if a cerebrovascular event occurs.
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`Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical
`
`
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`symptoms, exclude other potentially serious neurological conditions. TREXIMET is contraindicated in patients with a history of
`stroke or TIA [see Contraindications (4)].
`
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`5.6 Other Vasospasm Reactions
`
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`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
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`experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, rule out a
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`vasospastic reaction before receiving additional TREXIMET.
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`Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists.
`
`
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`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.
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`
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`5.7 Hepatotoxicity
`Borderline elevations of 1 or more liver tests may occur in up to 15% of patients who take NSAIDs including naproxen, a component
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`of TREXIMET. Hepatic abnormalities may be the result of hypersensitivity rather than direct toxicity. These abnormalities may
`
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`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
`
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`addition, rare, sometimes fatal cases of severe hepatic injury, including jaundice and fatal fulminant hepatitis, liver necrosis, and
`
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`hepatic failure have been reported with NSAIDs.
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`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
`
`
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`occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with TREXIMET.
`
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`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.
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`Reference ID: 3928586
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`

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`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). If clinical signs and symptoms consistent with liver disease develop, or if
`
`
`
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`systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue TREXIMET immediately, and perform a clinical evaluation
`
`of the patient.
`
`
`5.8 Hypertension
`
`Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on
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`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.
`
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`NSAIDs, including naproxen, a component of TREXIMET, can also lead to onset of new hypertension or worsening of preexisting
`
`
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`hypertension, either of which may contribute to the increased incidence of cardiovascular events. Patients taking angiotensin
`
`
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`converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, thiazide diuretics, or loop diuretics may
`have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)].
`
`
`
`
`
`Monitor blood pressure in patients treated with TREXIMET. TREXIMET is contraindicated in patients with uncontrolled
`hypertension [see Contraindications (4)].
`
`
`
`
`5.9 Heart Failure and Edema
`
`
`
`The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an
`
`
`
`
`approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-
`treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use
`
`
`
`increased the risk of MI, hospitalization for heart failure, and death.
`
`
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`
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`Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of naproxen 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]) [see Drug Interactions (7)].
`
`
`
`
`
`Avoid the use of TREXIMET in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening
`
`
`heart failure. If TREXIMET is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
`
`
`
`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.
`
`
`
`5.10 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.
`
`
`5.11 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
`
`Reference ID: 3928586
`
`

`

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`
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`
`
` Contraindications (4) and Drug Interactions (7.1)]. 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 usuall