Treximet

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.

The development of a potentially life-threatening serotonin syndrome may occur with triptans, including treatment with TREXIMET, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). If concomitant treatment with TREXIMET and an SSRI (e.g., fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram) or SNRI (e.g., venlafaxine, duloxetine) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. 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) (see PRECAUTIONS: Drug Interactions).

TREXIMET contains an NSAID. NSAID-containing products can 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. These trends continue with longer duration of use, increasing the likelihood of developing a serious gastrointestinal event at some time during the course of therapy. However, even short-term therapy is not without risk. Among 3,302 patients with migraine who received TREXIMET in premarketing 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.

NSAID-containing products, including 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 to 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, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal gastrointestinal events are 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 patients treated with an NSAID-containing product, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of gastrointestinal 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.

NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated.

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, heart failure, liver dysfunction, 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.

Advanced Renal Disease: Treatment with TREXIMET is not recommended in patients with advanced renal disease. If therapy with TREXIMET must be initiated, close monitoring of the patient’s renal function is advisable (see CLINICAL PHARMACOLOGY: Pharmacokinetics and PRECAUTIONS: Renal Effects). No information is available from controlled clinical studies regarding the use of TREXIMET in patients with advanced renal disease.

As with other NSAID-containing products, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to naproxen. 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, PRECAUTIONS: Preexisting Asthma, and PRECAUTIONS: Drug Interactions).

Anaphylactic/anaphylactoid reactions have occurred in patients receiving sumatriptan. 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 (see CONTRAINDICATIONS). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Anaphylactoid reactions, like anaphylaxis, may have a fatal outcome.

NSAID-containing products, including TREXIMET, 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.

TREXIMET should not be used in late pregnancy because NSAID-containing products have been shown to cause premature closure of the ductus arteriosus. TREXIMET should not be used during early pregnancy unless the potential benefit justifies the potential risk to the fetus (see PRECAUTIONS: Pregnancy).