Sumatriptan and Naproxen Sodium

Warnings and Precautions ( 5.14 ) 11/2024

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.

3 DOSAGE FORMS AND STRENGTHS Sumatriptan and Naproxen Sodium Tablets, 85 mg/500 mg are white to off-white, modified capsule shaped, film-coated, matted finish tablets debossed with “J78” on one side and plain on the other side. Tablets: 85 mg sumatriptan/500 mg naproxen sodium (3)

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 [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-hydroxytryptamine 1 (5-HT 1 ) 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 (angioedema and anaphylaxis seen). ( 4 ) Severe hepatic impairment. ( 4 )

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 Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 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 ag …

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 with drugs that interfere with hemostasis. Concomitant use of sumatriptan and naproxen sodium and analgesic doses of aspirin is not generally recommended. ( 7.1 ) ACE Inhibitors and ARBs: Concomitant use with sumatriptan and naproxen sodium 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 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 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 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 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 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 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 (220 mg/day or 220 mg 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 aspirin was associated with a significantly increased inc …

8 USE IN SPECIFIC POPULATIONS Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of sumatriptan and naproxen sodium tablets in women who have difficulties conceiving (8.3) 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 ) …

12.1 Mechanism of Action Sumatriptan and naproxen sodium tablets contain sumatriptan and naproxen. Sumatriptan binds with high affinity to cloned 5-HT 1B/1D receptors. Sumatriptan presumably exerts its therapeutic effects in the treatment of migraine headache through agonist effects at the 5-HT 1B/1D receptors on intracranial blood vessels and sensory nerves of the trigeminal system, which result in cranial vessel constriction and inhibition of neuropeptide release. Sumatriptan and naproxen sodium tablets have analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of sumatriptan and naproxen sodium tablets, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Naproxen is a potent inhibitor of prostaglandin synthesis in vitro . Naproxen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because naproxen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

11 DESCRIPTION Sumatriptan and naproxen sodium tablets contain sumatriptan (as the succinate), a selective 5-hydroxytryptamine 1 (5-HT 1 ) receptor subtype agonist, and naproxen sodium, a member of the arylacetic acid group of NSAIDs. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: The molecular formula is C 14 H 21 N 3 O 2 S.C 4 H 6 O 4 , representing a molecular weight of 413.5. Sumatriptan succinate USP is a white or almost white powder that is freely soluble in water, sparingly soluble in methanol, practically insoluble in methylene chloride. Naproxen sodium is chemically designated as (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid, sodium salt, and it has the following structure: The molecular formula is C 14 H 13 NaO 3 , representing a molecular weight of 252.23. Naproxen sodium USP is a white to creamy crystalline powder, sparingly soluble in water, in methanol and in alcohol, practically insoluble in chloroform, in acetone and in toluene. Each sumatriptan and naproxen sodium 85 mg/500 mg tablet for oral administration contains 119 mg of sumatriptan succinate USP equivalent to 85 mg of sumatriptan and 500 mg of naproxen sodium USP. Each tablet also contains the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, crospovidone, dextrose monohydrate, lecithin (soya), maltodextrin, microcrystalline cellulose, silicified microcrystalline cellulose, povidone, sodium bicarbonate, sodium carboxymethyl cellulose, sodium stearyl fumarate, talc, and titanium dioxide. Chemical Structure Chemical Structure

10 OVERDOSAGE Patients (N = 670) have received single oral doses of 140 to 300 mg of sumatriptan without significant adverse effects. Volunteers (N = 174) have received single oral doses of 140 to 400 mg without serious adverse events. Overdose of sumatriptan in animals has been fatal and has been heralded by convulsions, tremor, paralysis, inactivity, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, and lacrimation. Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting and epigastric pain. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [see Warnings and Precautions (5.1 , 5.2) ] . Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Hemodialysis does not decrease the plasma concentration of naproxen because of the high degree of its protein binding. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan. Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222).

16 HOW SUPPLIED/STORAGE AND HANDLING Sumatriptan and naproxen sodium tablets contain 119 mg of sumatriptan succinate, USP equivalent to 85 mg of sumatriptan and 500 mg of naproxen sodium, USP and are supplied as blue, oval, biconvex, film-coated tablets debossed with “410” on one side and plain on other side. They are supplied as follows: Bottles of 9 with Child Resistant Cap.......................................... NDC 47335-410-22 Bottles of 30 with Child Resistant Cap........................................ NDC 47335-410-83 Bottles of 100 with Child Resistant Cap...................................... NDC 47335-410-88 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure.