Sumatriptan and Naproxen Sodium

1 INDICATIONS AND USAGE Sumatriptan and naproxen sodium tablets are 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 sumatriptan and naproxen sodium tablets, reconsider the diagnosis of migraine before sumatriptan and naproxen sodium tablets are administered to treat any subsequent attacks. Sumatriptan and naproxen sodium tablets are not indicated for the prevention of migraine attacks. Safety and effectiveness of sumatriptan and naproxen sodium tablets have not been established for cluster headache. Sumatriptan and naproxen sodium tablets are 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)

2 DOSAGE AND ADMINISTRATION Adults Recommended dosage: 1 tablet of 85 mg/500 mg. (2.1) Maximum dosage in a 24-hour period: 2 tablets of 85 mg/500 mg; separate doses by at least 2 hours. (2.1) Pediatric Patients 12 to 17 years of Age Maximum dosage in a 24-hour period: 1 tablet of 85/500 mg. 2.1 Dosage in Adults The recommended dosage for adults is 1 tablet of sumatriptan and naproxen sodium tablets 85 mg/500 mg. Sumatriptan and naproxen sodium tablets 85 mg/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 sumatriptan and naproxen sodium tablets 85 mg/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)] . 2.2 Dosage in Pediatric Patients 12 to 17 Years of Age The maximum recommended dosage in a 24-hour period is 1 tablet of sumatriptan and naproxen sodium tablets 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)] . 2.3 Dosing in Patients with Hepatic Impairment Sumatriptan and naproxen sodium tablets are contraindicated in patients with severe hepatic impairment [see Contraindications (4), 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)] . 2.4 Administration Information Sumatriptan and naproxen sodium tablets may be administered with or without food. Tablets should not be split, crushed, or chewed.

5 WARNINGS AND PRECAUTIONS Cardiovascular Thrombotic Events: Perform cardiac evaluation in patients with cardiovascular risk factors. (5.1) Arrhythmias: Discontinue sumatriptan and naproxen sodium tablets 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 sumatriptan and naproxen sodium tablets if occurs. (5.5) Other Vasospasm Reactions: Discontinue sumatriptan and naproxen sodium tablets 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 sumatriptan and naproxen sodium tablets 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 sumatriptan and naproxen sodium tablets 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 sumatriptan and naproxen sodium tablets in patients with advanced renal disease. (5.12) Anaphylactic Reactions: Sumatriptan and naproxen sodium tablets should not be given to patients with the aspirin triad. Seek emergency help if an anaphylactic reaction occurs.(5.13) Serious Skin Reactions: Discontinue sumatriptan and naproxen sodium tablets at first sign of rash or other signs of hypersensitivity. (5.14) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. (5.15) Fetal Toxicity: Limit use of NSAIDs, including sumatriptan and naproxen sodium tablets, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. (5.16, 8.1) Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia. (5.17) Exacerbation of Asthma Related to Aspirin Sensitivity: Sumatriptan and naproxen sodium tablets are contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.18) 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 t…

4 CONTRAINDICATIONS Sumatriptan and naproxen sodium tablets are 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, 5.18)]. Known hypersensitivity (e.g., anaphylactic reactions, angioedema, and serious skin reactions) to sumatriptan, naproxen, or any components of sumatriptan and naproxen sodium tablets [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. (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-HT 1 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 sumatriptan and naproxen sodium tablets (angioedema and anaphylaxis seen). (4) Severe hepatic impairment. (4)

7 DRUG INTERACTIONS Drugs that Interfere with Hemostasis (e.g. warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking sumatriptan and naproxen sodium tablets with drugs that interfere with hemostasis. Concomitant use of sumatriptan and naproxen sodium tablets and analgesic doses of aspirin is not generally recommended. (7.1) ACE Inhibitors and ARBs: Concomitant use with sumatriptan and naproxen sodium tablets 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 sumatriptan and naproxen sodium tablets 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) 7.1 Clinically Significant Drug Interactions with Sumatriptan and Naproxen Sodium Tablets See Table 3 for clinically significant drug interactions with NSAIDs or Sumatriptan. Table 3. Clinically Significant Drug Interactions with Naproxen or Sumatriptan Ergot-Containing Drugs Clinical Impact: Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Intervention: Because these effects may be additive, coadministration of sumatriptan and naproxen sodium tablets and ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) within 24 hours of each other is contraindicated. Monoamine Oxidase-A Inhibitors Clinical Impact: MAO-A inhibitors increase systemic exposure of orally administered sumatriptan by 7-fold. Intervention: The use of sumatriptan and naproxen sodium tablets in patients receiving MAO-A inhibitors is contraindicated. Other 5-HT 1 Agonists Clinical Impact: 5-HT 1 agonist drugs can cause vasospastic effects. Intervention: Because these effects may be additive, coadministration of sumatriptan and naproxen sodium tablets and other 5 HT 1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. Drugs That Interfere with Hemostasis Clinical Impact: Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone. Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of sumatriptan and naproxen sodium tablets with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.17)] . Aspirin Clinical Impact: A pharmacodynamic (PD) study has demonstrated an interaction in which lower dose naproxen (220mg/day or 220mg twice daily) interfered with the antiplatelet effect of low-dose immediate-release aspirin, with the interaction most marked during the washout period of naproxen [see Clinical Pharmacology (12.2)] . There is reason to expect that the interaction would be present with prescription doses of naproxen or with enteric-coated low-dose aspirin; however, the peak interference with aspirin function may be later than observed in the PD study due to the longer washout period. Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and …

8.1 Pregnancy Risk Summary Use of NSAIDs, including sumatriptan and naproxen sodium tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of sumatriptan and naproxen sodium tablets use between about 20 and 30 weeks of gestation, and avoid sumatriptan and naproxen sodium tablets use at about 30 weeks of gestation and later in pregnancy ( see Clinical Considerations, Data ). Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including sumatriptan and naproxen sodium tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Data from a prospective pregnancy exposure registry and epidemiological studies of pregnant women have not detected an increased frequency of birth defects or a consistent pattern of birth defects among women exposed to sumatriptan compared with the general population ( see Human Data ). In animal studies, administration of sumatriptan and naproxen, alone or in combination, during pregnancy resulted in developmental toxicity (increased incidences of fetal malformations, embryofetal and pup mortality, decreased embryofetal growth) at clinically relevant doses ( see Animal Data ). Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as naproxen sodium resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The reported rate of major birth defects among deliveries to women with migraine ranged from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which were similar to rates reported in women without migraine. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Several studies have suggested that women with migraine may be at increased risk of preeclampsia and gestational hypertension during pregnancy. Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including sumatriptan and naproxen sodium tablets, can cause premature closure of the fetal ductus arteriosus ( see Data ). Oligohydramnios/Neonatal Renal Impairment: If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If sumatriptan and naproxen sodium tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue sumatriptan and naproxen sodium tablets and follow up according to clinical practice ( see Data ). Labor or Delivery There are no studies on the effects of naproxen tablets during labor or delivery. In animal studies, NSAIDS, including naproxen, inhibit prostaglandin synthesis, cause delayed parturiti…

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] GI Bleeding, Ulceration and Perforation [see Warnings and Precautions (5.2)] Arrhythmias [see Warnings and Precautions (5.3)] Chest, Throat, Neck, and/or Jaw Pain/Tightness/Pressure [see Warnings and Precautions (5.4)] Cerebrovascular Events [see Warnings and Precautions (5.5)] Other Vasospasm Reactions [see Warnings and Precautions (5.6)] Hepatotoxicity [see Warnings and Precautions (5.7)] Hypertension [see Warnings and Precautions (5.8)] Heart Failure and Edema [see Warnings and Precautions (5.9)] Medication Overuse Headache [see Warnings and Precautions (5.10)] Serotonin Syndrome [see Warnings and Precautions (5.11)] Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.12)] Anaphylactic Reactions [see Warnings and Precautions (5.13)] Serious Skin Reactions [see Warnings and Precautions (5.14)] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.15)] Hematological Toxicity [see Warnings and Precautions (5.17)] Exacerbation Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.18)] Seizures [see Warnings and Precautions (5.19)] 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 NorthStar RxLLC at 1-800-206-7821 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults The adverse reactions reported below are specific to the clinical trials with sumatriptan and naproxen sodium tablets 85 mg/500 mg. See also the full prescribing information for naproxen and sumatriptan products. Table 1 lists adverse reactions that occurred in 2 placebo-controlled clinical trials (Study 1 and 2) in adult patients who received 1 dose of study drug. Only adverse reactions that occurred at a frequency of 2% or more in any group treated with sumatriptan and naproxen sodium tablets 85 mg/500 mg and that occurred at a frequency greater than the placebo group are included in Table 1. Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials in Adult Patients with Migraine Adverse Reactions Sumatriptan and Naproxen Sodium Tablets 85 mg/500 mg % (n = 737) Placebo % (n = 752) Sumatriptan 85 mg % (n = 735) Naproxen Sodium 500 mg % (n = 732) Nervous system disorders Dizziness 4 2 2 2 Somnolence 3 2 2 2 Paresthesia 2 <1 2 <1 Gastrointestinal disorders Nausea 3 1 3 <1 Dyspepsia 2 1 2 1 Dry mouth 2 1 2 <1 Pain and other pressure sensations Chest discomfort/chest pain 3 <1 2 1 Neck/throat/jaw pain/tightness /pressure 3 1 3 1 The incidence of adverse reactions in controlled clinical trials was not affected by gender or age of the patients. There were insufficient data to assess the impact of race on the incidence of adverse reactions. Pediatric Patients 12 to 17 Years of Age In a placebo-controlled clinical trial that evaluated pediatric patients 12 to 17 years of age who received 1 dose of sumatriptan and naproxen sodium tablets 10/60 mg, 30/180 mg, or 85/500 mg, adverse reactions occurred in 13% of patients who received 10/60 mg, 9% of patients who received 30/180 mg, 13% who received 85/500 mg, and 8% who received placebo. No patients who received sumatriptan and naproxen sodium tablets experienced adverse reactions leading to withdrawal from the trial. The incidence of adverse reactions in pediatric patients 12 to 17 years of age was comparable ac…