SUMATRIPTAN AND NAPROXEN SODIUM tablet, film coated [Mylan Pharmaceuticals Inc.]

5.1 Cardiovascular Thrombotic Events

The use of sumatriptan and naproxen sodium tablets 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. Sumatriptan and naproxen sodium tablets 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 sumatriptan and naproxen sodium tablets. If there is evidence of CAD or coronary artery vasospasm, sumatriptan and naproxen sodium tablets are contraindicated. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first dose of sumatriptan and naproxen sodium tablets in a medically supervised setting and performing an electrocardiogram (ECG) immediately following administration of sumatriptan and naproxen sodium tablets. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of sumatriptan and naproxen sodium tablets.

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.

5.2 Gastrointestinal Bleeding, Ulceration, and Perforation

NSAIDs, including naproxen, a component of sumatriptan and naproxen sodium tablets, 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 sumatriptan and naproxen sodium tablets 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 sumatriptan and naproxen sodium tablets 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)].

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 sumatriptan and naproxen sodium tablets if these disturbances occur. Sumatriptan and naproxen sodium tablets are 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 sumatriptan and naproxen sodium tablets 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 sumatriptan and naproxen sodium tablets 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. Sumatriptan and naproxen sodium tablets are 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 sumatriptan and naproxen sodium tablets.

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 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 sumatriptan and naproxen sodium tablets. 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, rare, sometimes fatal cases of severe hepatic injury, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure have been reported with NSAIDs.

Sumatriptan and naproxen sodium tablets 85 mg/500 mg are 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 sumatriptan and naproxen sodium tablets. Sumatriptan and naproxen sodium tablets 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.

Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue sumatriptan and naproxen sodium tablets 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 rare occasions in patients treated with 5-HT1 agonists, including sumatriptan, a component of sumatriptan and naproxen sodium tablets. This occurrence has included patients without a history of hypertension.

NSAIDs, including naproxen, a component of sumatriptan and naproxen sodium tablets, can also 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 angiotensin 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 sumatriptan and naproxen sodium tablets. Sumatriptan and naproxen sodium tablets are 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.

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 sumatriptan and naproxen sodium tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If sumatriptan and naproxen sodium tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Since each sumatriptan and naproxen sodium 85/500 mg tablet contains approximately 46 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 sumatriptan and naproxen sodium tablets, particularly during coadministration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors [see 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 usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue sumatriptan and naproxen sodium tablets if serotonin syndrome is suspected.

5.12 Renal Toxicity and Hyperkalemia

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, dehydration, hypovolemia, heart failure, liver dysfunction, salt depletion, those taking diuretics and angiotensin-converting enzyme (ACE) inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Sumatriptan and naproxen sodium tablets should be discontinued if clinical signs and symptoms consistent with renal disease develop or if systemic manifestations occur.

Sumatriptan and naproxen sodium tablets are not recommended for use in patients with severe renal impairment (creatinine clearance [CrCl] < 30 mL/min) unless the benefits are expected to outweigh the risk of worsening renal function [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. If sumatriptan and naproxen sodium tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function. 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.

The renal effects of sumatriptan and naproxen sodium tablets may hasten the progression of renal dysfunction in patients with preexisting renal disease.

Correct volume status in dehydrated or hypovolemic patients prior to initiating sumatriptan and naproxen sodium tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of sumatriptan and naproxen sodium tablets [see Drug Interactions (7)]. Avoid the use of sumatriptan and naproxen sodium tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If sumatriptan and naproxen sodium tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Hyperkalemia

Increases in serum potassium concentration, including hyperkalemia, have been reported with the use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

5.13 Anaphylactic Reactions

Anaphylactic reactions may occur in patients without known prior exposure to either component of sumatriptan and naproxen sodium tablets. 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 although anaphylactic reactions with naproxen have occurred in patients without known hypersensitivity to naproxen or to patients with aspirin sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.17)]. Sumatriptan and naproxen sodium tablets 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)].

Sumatriptan and naproxen sodium tablets are contraindicated in patients with a history of hypersensitivity reaction to sumatriptan, naproxen, or any other component of sumatriptan and naproxen sodium tablets. Naproxen has been associated with anaphylactic reactions in patients without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.17)]. Seek emergency help if an anaphylactic reaction occurs.

5.14 Serious Skin Reactions

NSAID-containing products can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of sumatriptan and naproxen sodium tablets at the first appearance of skin rash or any other sign of hypersensitivity. Sumatriptan and naproxen sodium tablets are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)].

5.15 Premature Closure of the Ductus Arteriosus

Sumatriptan and naproxen sodium tablets may cause premature closure of the ductus arteriosus. Avoid use of NSAIDs, including sumatriptan and naproxen sodium tablets, in pregnant women starting at 30 weeks of gestation (third trimester) [see Contraindications (4), Use in Specific Populations (8.1)].

5.16 Hematologic Toxicity

Anemia has occurred in patients receiving NSAIDs. This may be due to fluid retention, occult or gross gastrointestinal blood loss, or an incompletely described effect upon erythropoiesis. If a patient treated with sumatriptan and naproxen sodium tablets has signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including sumatriptan and naproxen sodium tablets, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)].

5.17 Exacerbation of Asthma Related to Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, sumatriptan and naproxen sodium tablets are contraindicated in patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma [see Contraindications (4)].

When sumatriptan and naproxen sodium tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

5.18 Seizures

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. Sumatriptan and naproxen sodium tablets should be used with caution in patients with a history of epilepsy or conditions associated with a lowered seizure threshold.

5.19 Masking of Inflammation and Fever

The pharmacological activity of sumatriptan and naproxen sodium tablets in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

5.20 Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.2, 5.7, 5.12)].

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