Symbravo
meloxicam, rizatriptan · Tablet · Oral
Uses
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 ).
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) ] .
Dosage forms and strengths
Tablets: 20 mg meloxicam and 10 mg rizatriptan, white and modified capsule-shaped, debossed with “MXRZ” on one side and “20/10” on the other. Tablets: 20 mg meloxicam and 10 mg rizatriptan ( 3 )
Contraindications
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 )
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 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 meloxicam, increases the risk of serious gastrointestinal (GI) events [see Warnings & 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 MI 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. Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina with Rizatriptan SYMBRAVO should not be given to patients with ischemic or vasospastic coronary artery disease. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of rizatriptan. Some of these reactions occurred in patients without known coronary artery disease (CAD).
Side effects
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) ] Rizatriptan General: Allergic conditions including anaphylaxis/ anaphylactic reaction, angioedema, wheezing, and toxic epidermal necrolysis [see Contraindications (4) ] Neurological/Psychiatric: Seizure Special Senses: Dysgeusia
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 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.
Use in specific populations
Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of SYMBRAVO in women who have difficulties conceiving ( 8.3 ). 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 of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including SYMBRAVO, 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 SYMBRAVO treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue SYMBRAVO and follow up according to clinical practice [see Data] . Labor or Delivery There are no studies on the effects of SYMBRAVO during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data for Meloxicam Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible.
Pregnancy
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 of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including SYMBRAVO, 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 SYMBRAVO treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue SYMBRAVO and follow up according to clinical practice [see Data] . Labor or Delivery There are no studies on the effects of SYMBRAVO during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data for Meloxicam Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.
Pediatric use
8.4 Pediatric Use Safety and effectiveness of SYMBRAVO in pediatric patients have not been established.
Geriatric use
8.5 Geriatric Use Clinical studies of SYMBRAVO did not include subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, hepatic, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, treat for the fewest number of days per month, as needed, and monitor patients for adverse effects [see Warnings and Precautions (5.1 , 5.2 , 5.8 , 5.11 )] . Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving SYMBRAVO [see Warnings and Precautions (5.1 , 5.9 )] .
Overdosage
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 took 6- to 11-times the highest available oral dose of meloxicam tablets (15 mg); all recovered. Cholestyramine is known to accelerate the clearance of meloxicam. Accelerated removal of meloxicam by 4 g doses of cholestyramine given three times a day was demonstrated in a clinical trial. Administration of cholestyramine may be useful following an overdosage. Overdose of Rizatriptan In a clinical pharmacology study in which 12 adult subjects received rizatriptan at total cumulative doses of 80 mg (given within four hours), two of the subjects experienced syncope, dizziness, bradycardia including third degree AV block, vomiting, and/or incontinence. Based on the pharmacology of rizatriptan, hypertension or myocardial ischemia could occur after overdosage. Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with rizatriptan. Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if clinical symptoms are not observed. The effects of hemo- or peritoneal dialysis on serum concentrations of rizatriptan are unknown.
Description
11 DESCRIPTION SYMBRAVO contains meloxicam, a nonsteroidal anti-inflammatory drug (NSAID), and rizatriptan (as rizatriptan benzoate), a selective 5-HT 1B/1D receptor agonist. Meloxicam Meloxicam has the molecular formula C 14 H 13 N 3 O 4 S 2 and is chemically designated as 4-hydroxy-2-methyl-N-(5 methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide. It has a molecular weight of 351.4 g/mole. The structural formula is: Meloxicam is a pastel yellow solid, practically insoluble in water, with higher solubility observed in strong acids and bases. It is very slightly soluble in methanol. Meloxicam has an apparent partition coefficient (log P) = 0.1 in n-octanol/buffer pH 7.4. Meloxicam has pKa values of 1.1 and 4.2. Rizatriptan Rizatriptan benzoate has the molecular formula C 15 H 19 N 5 · C 7 H 6 O 2 and is chemically designated as N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H indole-3 ethanamine monobenzoate. The molecular weight of the free base rizatriptan is 269.4 g/mole. The structural formula is: Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C. Each SYMBRAVO tablet for oral administration contains 20 mg of meloxicam and 10 mg of rizatriptan (equivalent to 14.5 mg of rizatriptan benzoate). Each tablet also contains the excipients colloidal silicon dioxide, crospovidone, magnesium stearate, microcrystalline cellulose, partially hydrolyzed polyvinyl alcohol, polyethylene glycol, povidone, pregelatinized starch, sodium bicarbonate, sulfobutyl-ether-ß-cyclodextrin sodium, talc, and titanium dioxide. Structure Structure
Mechanism of action
12.1 Mechanism of Action SYMBRAVO contains meloxicam and rizatriptan. Meloxicam has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of meloxicam, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Meloxicam is a potent inhibitor of prostaglandin synthesis in vitro. Meloxicam 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 meloxicam is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues. Rizatriptan binds with high affinity to human cloned 5-HT 1B/1D receptors. Rizatriptan presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT 1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.
How supplied
16.1 How Supplied SYMBRAVO tablets are white, modified capsule-shaped, film-coated and debossed with "MXRZ" on one side and "20/10" on the other. SYMBRAVO is supplied in the following package configuration: Package Configuration Strength NDC Code Bottles of 9 tablets meloxicam 20 mg and rizatriptan 10 mg 81968-020-09 16.2 Storage and Handling Store SYMBRAVO in the original bottle at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] .
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Cardiovascular Thrombotic Effects Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their healthcare provider immediately [see Warnings and Precautions (5.1) ] . Risk of Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospasm-Related Events, and Cerebrovascular Events Inform patients that rizatriptan, a component of SYMBRAVO, may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up [see Warnings and Precautions (5.1 , 5.3 , 5.4 , 5.6 , 5.7 )] . Gastrointestinal Bleeding, Ulceration, and Perforation Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their healthcare provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2) ] . Anaphylactic Reactions Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.5 , 5.16) ] . Hepatotoxicity 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 these occur, instruct patients to stop SYMBRAVO and seek immediate medical therapy [see Warnings and Precautions (5.8) ] . Heart Failure and Edema Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.10) ] . Serious Skin Reactions, including DRESS Advise patients to stop SYMBRAVO immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Contraindications (4) , Warnings and Precautions (5.12 , 5.13 )] . Female Fertility Advise females of reproductive potential who desire pregnancy that meloxicam, a component of SYMBRAVO, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3) ] . Lactation Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed [see Use in Specific Populations (8.2 )] . Fetal Toxicity Inform pregnant women to avoid use of SYMBRAVO and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with SYMBRAVO is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.14) , Use in Specific Populations (8.1) ] . Avoid Concomitant Use of NSAIDs Inform patients that the concomitant use of SYMBRAVO with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) , Drug Interactions (7.1) ] . Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia. Use of NSAIDs and Low-Dose Aspirin Inform patients not to use low-dose aspirin concomitantly with SYMBRAVO until they talk to their healthcare provider [see Drug Interactions (7.1) ] . Medication Overuse Headache Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary) [see Warnings and Precautions (5.17) ] . Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the use of SYMBRAVO, particularly during combined use with SSRIs or SNRIs [see Warnings and Precautions (5.18) , Drug Interactions (7.1) , Clinical Pharmacology (12.3)]. Ability to Perform Complex Tasks Since migraines or treatment with SYMBRAVO may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of SYMBRAVO. Distributed by: Axsome Therapeutics, Inc. New York, NY 10007 AXSOME THERAPEUTICS and SYMBRAVO are trademarks or registered trademarks of Axsome Therapeutics, Inc. in the United States and other countries. For patent information: www.axsome.com/IP ©2025 Axsome Therapeutics, Inc. All rights reserved. SYM-USPI-001.001-20250224
Label text from the FDA structured product label by Axsome Therapeutics, Inc. (revised Nov 21, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Meloxicam in 1 product
- Rizatriptan Benzoate in 1 product
Symbravo NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 81968-020 | Meloxicam 20 mg/1; Rizatriptan Benzoate 10 mg/1 Tablet | Axsome Therapeutics, Inc. | NDA |
Frequently asked questions
What is Symbravo used for?
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…
What are the side effects of Symbravo?
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… See the full label for the complete list.
Who makes Symbravo?
Symbravo is listed by 1 labeler in the FDA NDC directory, including Axsome Therapeutics, Inc..