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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) ] .

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…

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 )

No overdoses of SYMBRAVO were reported during clinical trials in adults. Evaluation and treatment of SYMBRAVO overdose is based on experience with the individual components, meloxicam and rizatriptan. In case of an overdosage, discontinue SYMBRAVO and contact a regional poison control center at 1-800-222-1222. Overdose of Meloxicam Symptoms following acute meloxicam overdoses have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare [see Warnings and Precautions (5.2 , 5.9 , 5.11 , 5.15 )] . Manage patients with symptomatic and supportive care following a meloxicam 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). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may be employed but are not likely to be useful due to high protein binding. There is limited experience with meloxicam overdose. In four reported cases of meloxicam overdose, patients…

U.S. Poison Control: call or text 1-800-222-1222 (free, 24/7). In an emergency call 911. From the FDA label; not medical advice.

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 failure. These effects are usually reversible. Propranolol has been shown to increase the plasma AUC of rizatriptan. Intervention During concomitant use of SYMBRAVO and ACE-inhibitors, ARBs, or beta blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of SYMBRAVO and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.11) ] . When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. The concomitant use of SYMBRAVO with propranolol is contraindicated. Diuretics Clinical Impact Clinical studies, as well as postmarketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. However, studies with furosemide agents and meloxicam have not demonstrated a reduction in natriuretic effect. Furosemide single and multiple dose pharmacodynamics and pharmacokinetics are not affected by multiple doses of meloxicam. Intervention During concomitant use of SYMBRAVO with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.11) ] . Lithium Clinical Impact NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention During concomitant use of SYMBRAVO and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention During concomitant use of SYMBRAVO and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact Concomitant use of meloxicam and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention During concomitant use of SYMBRAVO and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact Concomitant use of meloxicam with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2) ] . Intervention The concomitant use of SYMBRAVO with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact Concomitant use of meloxicam and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention During concomitant use of SYMBRAVO and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Patients taking SYMBRAVO should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. In patients with creatinine clearance below 45 mL/min, the concomitant administration of SYMBRAVO with pemetrexed is not recommended. CYP2C9 Inhibitors Clinical Impact In vitro studies indicate that CYP2C9 (cytochrome P450 metabolizing enzyme) plays an important role in the metabolic pathway of meloxicam with a minor contribution of the CYP3A4 isozyme. Thus, concomitant usage of CYP2C9 inhibitors (e.g., amiodarone, fluconazole) may lead to abnormally high plasma levels of meloxicam due to reduced metabolic clearance [see Use in Specific Populations (8.8) , Clinical Pharmacology (12.3, 12.5)] . Intervention Use of SYMBRAVO in patients undergoing treatment with CYP2C9 inhibitors is not recommended. Ergot-Containing Drugs Clinical Impact Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Intervention Because these effects may be additive with rizatriptan, use of ergotamine-containing or ergot-type medications (e.g., dihydroergotamine or methysergide) and SYMBRAVO within 24 hours is contraindicated [see Contraindications (4) ]. 5-HT 1 Agonists Clinical Impact Vasospastic effects may be additive with co-administration within 24 hours of another 5-HT1 agonists. Intervention Use of SYMBRAVO within 24 hours of another 5HT 1 agonist is contraindicated [see Contraindications (4) ] . Monoamine Oxidase Inhibitors Clinical Impact MAO-A inhibitors increase the systemic exposure of rizatriptan and its metabolite. Intervention SYMBRAVO is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors [see Contraindications (4) ] .