Symbravo Drug Information

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 .

Administration Swallow

SYMBRAVO tablets whole. Do not crush, divide, or chew the tablets. SYMBRAVO can be taken with or without food.

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 .

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) . 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.

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 Rizatriptan General: Allergic conditions including anaphylaxis/ anaphylactic reaction, angioedema, wheezing, and toxic epidermal necrolysis Neurological/Psychiatric: Seizure Special Senses: Dysgeusia

Drugs Having Clinically Important Interactions with

SYMBRAVO See Table 2 for clinically significant drug interactions with SYMBRAVO . 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 . 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. Intervention Concomitant use of SYMBRAVO and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding . In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding . 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.

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 . 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 . 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 . 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 . 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. 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 . 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 .

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 . 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 . 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 . 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 . 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 . 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.

Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use. Because the published safety data on neonatal outcomes involved mostly preterm infants, the generalizability of certain reported risks to the full-term infant exposed to NSAIDs through maternal use is uncertain.

Human Data for Rizatriptan In a pregnancy registry for rizatriptan users, no pattern of congenital anomalies or other adverse birth outcomes was identified over the period of 1998 to 2018. However, the lack of identification of any pattern should be viewed with caution, as the number of prospective reports with outcome information was low and did not provide sufficient power to detect an increased risk of individual birth defects associated with the use of rizatriptan. Additionally, there was significant loss to follow-up in the prospective pregnancy reports, further complicating this assessment of an association between rizatriptan and any pattern of congenital anomalies or other adverse birth outcomes. In a study using data from the Swedish Medical Birth Register, live births to women who reported using triptans or ergots during pregnancy were compared with those of women who did not.

Of the 157 births with first-trimester exposure to rizatriptan, 7 infants were born with malformations (relative risk 1.01 ). A study using linked data from the Medical Birth Registry of Norway to the Norwegian Prescription Database compared pregnancy outcomes in women who redeemed prescriptions for triptans during pregnancy, as well as a migraine disease comparison group who redeemed prescriptions for triptans before pregnancy only, compared with a population control group. Of the 310 women who redeemed prescriptions for rizatriptan during the first trimester, 10 had infants with major congenital malformations (OR 1.03 ), while for the 271 women who redeemed prescriptions for rizatriptan before, but not during, pregnancy, 12 had infants with major congenital malformations (OR 1.48 ), each compared with the population comparison group. Animal Data Animal reproduction studies have not been conducted for SYMBRAVO. Meloxicam Meloxicam was not teratogenic when administered to pregnant rats during fetal organogenesis at oral doses up to 4 mg/kg/day (2-fold greater than the MRHD of 20 mg of meloxicam on a mg/m 2 basis). Administration of meloxicam to pregnant rabbits throughout embryogenesis produced an increased incidence of septal defects of the heart at an oral dose of 60 mg/kg/day (59-fold greater than the MRHD of 20 mg of meloxicam on a mg/m 2 basis). The no effect level was 20 mg/kg/day (20-fold greater than the MRHD of 20 mg of meloxicam based on BSA conversion). In rats and rabbits, embryolethality occurred at oral meloxicam doses of 1 mg/kg/day and 5 mg/kg/day, respectively (0.5 and 4.9-fold greater, respectively, than the MRHD of 20 mg of meloxicam on a mg/m 2 basis) when administered throughout organogenesis.

Oral administration of meloxicam to pregnant rats during late gestation through lactation increased the incidence of dystocia, delayed parturition, and decreased offspring survival at meloxicam doses of 0.125 mg/kg/day or greater (0.06 times the MRHD of 20 mg of meloxicam based on BSA comparison). Rizatriptan When rizatriptan (0, 2, 10, or 100 mg/kg/day) was administered orally to pregnant rats throughout organogenesis, a decrease in fetal body weight was observed at the highest doses tested. The no-effect dose for adverse effects on embryofetal development was 10 mg/kg/day (10 times the MRHD of 10 mg of rizatriptan on a mg/m 2 basis). When rizatriptan (0, 5, 10, or 50 mg/kg/day) was administered orally to pregnant rabbits throughout organogenesis, no adverse fetal effects were observed. The highest dose tested of 50 mg/kg/day was 97 times the MRHD of 10 mg of rizatriptan on a mg/m 2 basis.

Placental transfer of drug to the fetus was demonstrated in both species. Oral administration of rizatriptan (0, 2, 10, or 100 mg/kg/day) to female rats prior to and during mating and continuing throughout gestation and lactation resulted in reduced body weight in offspring from birth and throughout lactation at all but the lowest dose tested (2 mg/kg/day). The no-effect dose (2 mg/kg/day) for adverse effects on postnatal development was 2 times the MRHD of 10 mg rizatriptan on a mg/m 2 basis. Oral administration of rizatriptan (0, 5, 100, or 250 mg/kg/day) throughout organogenesis and lactation resulted in neonatal mortality, reduced body weight (which persisted into adulthood), and impaired neurobehavioral function in offspring at all but the lowest dose tested.

The no-effect dose for adverse effects on postnatal development (5 mg/kg/day) was 5 times the MRHD of 10 mg rizatriptan on a mg/m 2 basis.

Pediatric Use Safety and effectiveness of SYMBRAVO in pediatric patients have not been established.

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 . Coronary artery vasospasm including Prinzmetal’s angina . In the setting of coronary artery bypass graft (CABG) surgery . History of stroke or transient ischemic attack (TIA) . Hemiplegic or basilar migraine. Peripheral vascular disease (PVD) . Ischemic bowel disease . Uncontrolled hypertension . Concomitant use of propranolol 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) . Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor . Known hypersensitivity (e.g., anaphylactic reactions and angioedema seen) to SYMBRAVO, meloxicam, rizatriptan, NSAIDs or any of the excipients in SYMBRAVO . 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 . Moderate to severe renal insufficiency in patients who are at risk for renal failure due to volume depletion or who are on dialysis.

Ischemic coronary artery disease or other significant underlying cardiovascular disease Coronary artery vasospasm In the setting of CABG surgery History of stroke or transient ischemic attack Hemiplegic or basilar migraine Peripheral vascular disease Ischemic bowel disease Uncontrolled hypertension Concomitant use of propranolol 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) Concurrent administration or recent discontinuation (i.e., within the past 2 weeks) of a MAO-A inhibitor Known hypersensitivity to SYMBRAVO, meloxicam, rizatriptan, NSAIDs, triptans, or any of the excipients in SYMBRAVO History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs Moderate to severe renal insufficiency in patients who are at risk for renal failure due to volume depletion or who are on dialysis

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 . 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.