Treximet

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL 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. (

  5.1 Cardiovascular Thrombotic Events

  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 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.

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

  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
    [s
    ee
    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, 5.18)]
    .
  • 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)].
  • Severe hepatic impairment
    [see Warnings and Precautions (5.7), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

  • History of coronary artery disease or coronary vasospasm.
  • In the setting of CABG surgery.
  • Wolff-Parkinson-White syndrome or other cardiac accessory conduction pathway disorders.
  • History of stroke, transient ischemic attack, or hemiplegic or basilar migraine.
  • Peripheral vascular disease.
  • Ischemic bowel disease.
  • Uncontrolled hypertension.
  • Recent (within 24 hours) use of another 5-HT₁agonist (e.g., another triptan) or of ergotamine-containing medication.
  • Concurrent or recent (past 2 weeks) use of monoamine oxidase-A inhibitor.
  • History of asthma, urticaria, other allergic type reactions, rhinitis, or nasal polyps syndrome after taking aspirin or other NSAID/analgesic drugs.
  • Known hypersensitivity to sumatriptan, naproxen, or any components of TREXIMET (angioedema and anaphylaxis seen).
  • Severe hepatic impairment.

  ,

  5.1 Cardiovascular Thrombotic Events

  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 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.

  )
• 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 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.

  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 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.

  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
    [see Drug Interactions (7)]
    .

  )

TREXIMET is indicated for the acute treatment of migraine with or without aura in adults and pediatric patients 12 years of age and older.

• Recommended dosage: 1 tablet of 85/500 mg. (
  2.1 Dosage in Adults

  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)]

  .
  )
• Maximum dosage in a 24-hour period: 2 tablets of 85/500 mg; separate doses by at least 2 hours. (
  2.1 Dosage in Adults

  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)]

  .
  )

• Recommended dosage: 1 tablet of 10/60 mg. (
  2.2 Dosage in Pediatric Patients 12 to 17 Years of Age

  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)]

  .
  )
• Maximum dosage in a 24-hour period: 1 tablet of 85/500 mg.

• Recommended dosage: 1 tablet of 10/60 mg. (
  2.3 Dosing in Patients with Hepatic Impairment

  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)]

  .
  ,
  8.7 Hepatic Impairment

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

  [see Contraindications (4), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)]

  .
  )

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"

• Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of TREXIMET in women who have difficulties conceiving (
  8.3 Females and Males of Reproductive Potential

  Infertility

  Females

  Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including naproxen tablets, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including naproxen tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility.
  )