SYMBRAVO

1 INDICATIONS AND USAGE SYMBRAVO is indicated for the acute treatment of migraine with or without aura in adults. Limitations of Use SYMBRAVO should only be used where a clear diagnosis of migraine has been established. If a patient has no response for the first migraine attack treated with SYMBRAVO, the diagnosis of migraine should be reconsidered before SYMBRAVO is administered to treat any subsequent attacks. SYMBRAVO is not indicated for the preventive treatment of migraine attacks. SYMBRAVO is not indicated for the treatment of cluster headache. SYMBRAVO is a combination of meloxicam (an NSAID) and rizatriptan (a serotonin (5-HT) 1B/1D receptor agonist (triptan)), indicated for the acute treatment of migraine with or without aura in adults ( 1 ). Limitations of Use SYMBRAVO should only be used where a clear diagnosis of migraine has been established ( 1 ). SYMBRAVO is not indicated for the preventive treatment of migraine ( 1 ). SYMBRAVO is not indicated for the treatment of cluster headache ( 1 ).

2 DOSAGE AND ADMINISTRATION The recommended dose of SYMBRAVO is one tablet by mouth as needed ( 2.1 ). The maximum daily dose is 20 mg meloxicam and 10 mg rizatriptan (1 tablet) ( 2.1 ). 2.1 Recommended Dose The recommended dose of SYMBRAVO is one tablet (containing 20 mg meloxicam and 10 mg rizatriptan) by mouth, as needed for the acute treatment of migraine. The maximum daily dose should not exceed one tablet. The safety and effectiveness of a second dose for the same migraine attack have not been established. The safety of treating, on average, more than 7 headaches in a 30-day period has not been established. Use for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5) ] . 2.2 Administration Swallow SYMBRAVO tablets whole. Do not crush, divide, or chew the tablets. SYMBRAVO can be taken with or without food. 2.3 Not Substitutable with Other Formulations of Meloxicam and of Rizatriptan SYMBRAVO tablets have not shown equivalent systemic exposures to other formulations of oral meloxicam and of oral rizatriptan. Therefore, SYMBRAVO tablets are not substitutable with other formulations of oral meloxicam or oral rizatriptan products, even if the milligram strengths are the same. Do not substitute SYMBRAVO with similar dose strengths of other meloxicam or rizatriptan products [see Clinical Pharmacology (12.3) ] .

5 WARNINGS AND PRECAUTIONS Cardiovascular Thrombotic Events, Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina: Perform cardiac evaluation in patients with multiple cardiovascular risk factors ( 5.1 ). Arrhythmias: Discontinue dosing if arrhythmia occurs ( 5.3 ). Cerebral Hemorrhage, Subarachnoid Hemorrhage, and Stroke: Discontinue dosing if occurs ( 5.4 ). Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs ( 5.5 ). Chest/Throat/Neck/Jaw Pain, Tightness, Pressure, or Heaviness: Generally not associated with myocardial ischemia; evaluate patients at high risk ( 5.6 ). Gastrointestinal Ischemic Events, Peripheral Vasospastic Reactions: Discontinue dosing if occurs ( 5.7 ). 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 ( 5.8 ). Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.9 , 7.1 ). Heart Failure and Edema: Avoid use of SYMBRAVO in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.10 ). Renal Toxicity and Hyperkalemia: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Use is not recommended in patients with moderate to severe renal insufficiency; avoid the use in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function ( 4 , 5.11 ). Serious Skin Reactions: Discontinue SYMBRAVO at first appearance of skin rash or other signs of hypersensitivity ( 5.12 ). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue SYMBRAVO and evaluate clinically ( 5.13 ). Fetal Toxicity: Limit use of NSAIDs, including SYMBRAVO, 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 ( 5.14 , 8.1 ). Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.15 , 7.1 ). Exacerbation of Asthma Related to Aspirin Sensitivity: SYMBRAVO is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.16 ). Medication Overuse Headache: Detoxification may be necessary ( 5.17 ). Serotonin Syndrome: Discontinue dosing if occurs ( 5.18 ). 5.1 Cardiovascular Thrombotic Events and Myocardial Infarction Cardiovascular Thrombotic Events with NSAIDS 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 treat…

4 CONTRAINDICATIONS SYMBRAVO is contraindicated in patients with: Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease [see Warnings & Precautions (5.1) ] . Coronary artery vasospasm including Prinzmetal’s angina [see Warnings & Precautions (5.1) ] . In the setting of coronary artery bypass graft (CABG) surgery [see Warnings & Precautions (5.1) ] . History of stroke or transient ischemic attack (TIA) [see Warnings & Precautions (5.4) ] . Hemiplegic or basilar migraine. Peripheral vascular disease (PVD) [see Warnings & Precautions (5.7) ] . Ischemic bowel disease [see Warnings & Precautions (5.7) ] . Uncontrolled hypertension [see Warnings & Precautions (5.9) ] . Concomitant use of propranolol [see Drug Interactions (7.1) ] Recent use (i.e., within 24 hours) of an ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), or another 5-HT1 agonist (e.g., another triptan) [see Drug Interactions (7.1) ] . Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Known hypersensitivity (e.g., anaphylactic reactions and angioedema seen) to SYMBRAVO, meloxicam, rizatriptan, NSAIDs or any of the excipients in SYMBRAVO [see Warnings & Precautions (5.5) , Adverse Reactions (6.2) ] . History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings & Precautions (5.16 )] . Moderate to severe renal insufficiency in patients who are at risk for renal failure due to volume depletion or who are on dialysis [see Warnings & Precautions (5.11 )]. Ischemic coronary artery disease or other significant underlying cardiovascular disease ( 4 ) Coronary artery vasospasm ( 4 ) In the setting of CABG surgery ( 4 ) History of stroke or transient ischemic attack ( 4 ) Hemiplegic or basilar migraine ( 4 ) Peripheral vascular disease ( 4 ) Ischemic bowel disease ( 4 ) Uncontrolled hypertension ( 4 ) Concomitant use of propranolol ( 4 ) Recent (within 24 hours) use of an ergotamine-containing medication, ergot-type medication (such as dihydroergotamine or methysergide), another 5-HT 1 agonist (e.g., another triptan) ( 4 ) Concurrent administration or recent discontinuation (i.e., within the past 2 weeks) of a MAO-A inhibitor ( 4 ) Known hypersensitivity to SYMBRAVO, meloxicam, rizatriptan, NSAIDs, triptans, or any of the excipients in SYMBRAVO ( 4 ) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) Moderate to severe renal insufficiency in patients who are at risk for renal failure due to volume depletion or who are on dialysis ( 4 )

7 DRUG INTERACTIONS Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking SYMBRAVO with drugs that interfere with hemostasis. Concomitant use of SYMBRAVO and analgesic doses of aspirin is not generally recommended ( 7.1 ). ACE Inhibitors, ARBs, or Beta-Blockers: Concomitant use with SYMBRAVO may diminish the antihypertensive effect of these drugs. Monitor blood pressure ( 7.1 ). ACE Inhibitors and ARBs: Concomitant use with SYMBRAVO 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 furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects ( 7.1 ). Lithium: Monitor for increases in lithium plasma levels ( 7.1 ) Methotrexate: Monitor for increases methotrexate plasma levels. ( 7.1 ). 7.1 Drugs Having Clinically Important Interactions with SYMBRAVO See Table 2 for clinically significant drug interactions with SYMBRAVO [see Clinical Pharmacology (12.3) ] . Table 2: Clinically Important Drug Interactions with SYMBRAVO Drugs That Interfere with Hemostasis Clinical Impact Meloxicam and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of meloxicam 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 SYMBRAVO 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 (5.15) ] . Caution should be used when administering SYMBRAVO with warfarin since patients on warfarin may experience changes in International Normalized Ratio (INR) and an increased risk of bleeding complications when a new medication is introduced. Aspirin Clinical Impact 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 incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.2 )]. Intervention Concomitant use of SYMBRAVO and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.15) ] . In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Warnings and Precautions (5.2) ] . Meloxicam in SYMBRAVO is not a substitute for low dose aspirin for cardiovascular protection. SSRIs/SNRIs and Serotonin Syndrome Clinical Impact Cases of serotonin syndrome have been reported during co-administration of triptans and SSRIs or SNRIs [see Warnings and Precautions (5.18) ]. Intervention SYMBRAVO treatment should be discontinued if serotonin syndrome is suspected. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta blockers. In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failu…

8.1 Pregnancy SYMBRAVO has not been studied in pregnant women. However, there are data pertaining to the use of the individual components, meloxicam and rizatriptan during pregnancy. These data are described below. Risk Summary 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 infants born to women with migraine range from 2.2% to 2.9% and the reported rate of miscarriage was 17%, which are similar to rates reported in women without migraine. Meloxicam Use of NSAIDs, including SYMBRAVO, 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 SYMBRAVO use between about 20 and 30 weeks of gestation, and avoid SYMBRAVO 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 SYMBRAVO, 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. In animal reproduction studies, embryofetal death was observed in rats and rabbits treated during the period of organogenesis with meloxicam at oral doses equivalent to 0.5 and 4.9 times, respectively, the maximum recommended human dose (MRHD) of 20 mg of meloxicam, based on body surface area (mg/m 2 ). Increased incidence of septal heart defects was observed in rabbits treated throughout embryogenesis with meloxicam at an oral dose equivalent to 59 times the MRHD of 20 mg of meloxicam on a mg/m 2 basis. In pre- and post-natal reproduction studies, there was an increased incidence of dystocia, delayed parturition, and decreased offspring survival at 0.06 times the MRHD of 20 mg of meloxicam on a mg/m 2 basis. No teratogenic effects were observed in rats and rabbits treated with meloxicam during organogenesis at an oral dose equivalent to 2 and 20 times, respectively, the MRHD of 20 mg of meloxicam on a mg/m 2 basis [se e 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 meloxicam, 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. Rizatriptan Available human data on the use of rizatriptan in pregnant women are not sufficient to draw conclusions about drug-associated risk for major birth defects and miscarriage. In animal studies, developmental toxicity was observed following oral administration of rizatriptan during pregnancy (decreased fetal body weight in rats) or throughout pregnancy and lactation (increased mortality, decreased body weight, and neurobehavioral impairment in rat offspring) at doses greater than the MRHD of 10 mg rizatriptan on a mg/m 2 basis [see Animal Data] . Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with migraine, there is an increased risk of adverse perinatal outcomes in the mother, including pre-eclampsia and gestational hypertension. Fetal/Neonatal Adverse Reactions Premature Closure o…

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Cardiovascular Thrombotic Events and Myocardial Infarction [see Warnings and Precautions (5.1) ] GI Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.2) ] Arrhythmias [see Warnings and Precautions (5.3) ] Cerebrovascular Events [see Warnings and Precautions (5.4) ] Anaphylactic Reactions [see Warnings and Precautions (5.5)] Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure [see Warnings and Precautions (5.6) ] Other Vasospasm Reactions [see Warnings and Precautions (5.7) ] Hepatotoxicity [see Warnings and Precautions (5.8) ] Hypertension/Increase in Blood Pressure [see Warnings and Precautions (5.9) ] Heart Failure and Edema [see Warnings and Precautions (5.10) ] Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.11) ] Serious Skin Reactions [see Warnings and Precautions (5.12)] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.13) ] Fetal Toxicity [see Warnings and Precautions (5.14) ] Hematologic Toxicity [see Warnings and Precautions (5.15) ] Exacerbation of Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.16 )] Medication Overuse Headache [see Warnings and Precautions (5.17) ] Serotonin Syndrome [see Warnings and Precautions (5.18) ] Most common adverse reactions (≥1% and greater than placebo) are dizziness and somnolence ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Axsome Therapeutics at 1-800-484-1672 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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In two randomized, double-blind, controlled trials in adults with migraine, a total of 581 patients received a single dose of SYMBRAVO after the onset of a migraine attack (Studies 1 and 2) [see Clinical Studies (14) ] . The most common adverse reactions from these two trials after treatment with SYMBRAVO (incidence ≥1% and greater than placebo) are provided in Table 1. Table 1: Incidence (≥1% and Greater than Placebo) of Adverse Reactions after a Single Dose of SYMBRAVO in Adults (Study 1 and Study 2) SYMBRAVO N=581 a % Rizatriptan 10 mg N=434 b % Meloxicam 20 mg N=433 b % Placebo N=361 a % Somnolence 2 2 2 1 Dizziness 2 2 1 1 a Study 1 and Study 2 pooled b Data from Study 1 only; Study 2 did not include arms with each individual component Long-term safety was assessed in 706 patients dosing intermittently for up to 12 months in an open-label extension trial where patients treated at least 2 migraines per month with SYMBRAVO. Of these 706 patients, 496 patients were exposed to SYMBRAVO for at least 6 months, and 132 were exposed for at least 12 months, all of whom treated at least 2 migraine attacks per month, on average. 6.2 Postmarketing Experience The following adverse reactions have been reported with the individual components of SYMBRAVO, meloxicam and rizatriptan, from postmarketing experience. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Meloxicam Blood and Lymphatic System Disorders: Agranulocytosis Hepatobiliary Disorders: Jaundice; liver failure Psychiatric Disorders: Alterations in mood (such as mood elevation) Renal and Urinary Disorders: Acute urinary retention; interstitial nephritis Reproductive System and Breast Disorders: Infertility female Skin and Subcutaneous Tissue Disorders: Anaphylactic reactions including shock; erythema multiforme; exfoliative dermatitis; Stevens-Johnson syndrome; fixed drug eruption (FDE); toxic epidermal necrolysis [see Warnings and Precautions (5.12)…