Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events: TREXIMET should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) or to patients with a history of CABG surgery (see CONTRAINDICATIONS). It is strongly recommended that sumatriptan-containing products not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of CAD and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, TREXIMET should not be administered (see CONTRAINDICATIONS).

For patients with risk factors predictive of CAD who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of TREXIMET take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received sumatriptan. Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining an electrocardiogram (ECG) immediately following first-time use of TREXIMET in patients with risk factors.

It is recommended that patients who are intermittent long-term users of TREXIMET and who have or acquire risk factors predictive of CAD as described above undergo periodic cardiovascular evaluation as they continue to use TREXIMET.

The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to sumatriptan-containing products.

Cardiac Events and Fatalities Associated With 5-HT1 Agonists: Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of sumatriptan. Considering the extent of use of 5-HT1 agonists in patients with migraine, the incidence of these events is extremely low.

The fact that sumatriptan can cause coronary vasospasm, that some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD, and the close proximity of the events to sumatriptan use support the conclusion that some of these cases were caused by the drug. In cases, however, where there has been known underlying coronary artery disease, the relationship is uncertain.

Cardiovascular Thrombotic Events and Fatalities Associated 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 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 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. Physicians and patients should remain alert for the development of such 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.

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: Risk of Gastrointestinal Ulceration, Bleeding, and Perforation With Nonsteroidal Anti-inflammatory Drug Therapy).

Premarketing Experience With TREXIMET: Among 3,302 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 study experienced signs and symptoms of acute coronary syndrome approximately 2 hours after receiving TREXIMET.

Drug-Associated Cerebrovascular Events and Fatalities: Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with oral or subcutaneous sumatriptan, and some have resulted in fatalities. The relationship of sumatriptan to these events is uncertain. In a number of cases, it appears possible that the cerebrovascular events were primary, sumatriptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should also be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., cerebrovascular accident, transient ischemic attack).

Other Vasospasm-Related Events: Sumatriptan may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported. Transient and permanent blindness and significant partial vision loss have been reported with the use of sumatriptan. Visual disorders may also be part of a migraine attack.

Increase in Blood Pressure: TREXIMET is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS). TREXIMET should be used with caution in patients with controlled hypertension.

Significant elevation in blood pressure, including hypertensive crisis, has been reported in patients with and without a history of hypertension receiving sumatriptan. Sumatriptan-containing products should be administered with caution to patients with controlled hypertension as transient increases in blood pressure and peripheral vascular resistance have been observed.

NSAID-containing products 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. The potential effect on blood pressure associated with long-term use of TREXIMET has not been studied. Blood pressure should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema: TREXIMET should be used with caution in patients with fluid retention or heart failure. Fluid retention and edema have been observed in some patients taking NSAIDs. Since each TREXIMET tablet contains 61.2 mg of sodium (about 2.7 mEq/500 mg of naproxen sodium), this should be considered in patients whose overall intake of sodium must be severely restricted.