Meloxicam and Rizatriptan Benzoate (Monograph)

Brand name: Symbravo
Drug class: Selective Serotonin Agonists

Introduction

Meloxicam and rizatriptan benzoate (meloxicam/rizatriptan) is a fixed combination of meloxicam (an NSAID) and rizatriptan (a serotonin [5-HT] 1B/1D receptor agonist [triptan]).

Uses for Meloxicam and Rizatriptan Benzoate

Meloxicam and Rizatriptan has the following uses:

Meloxicam/rizatriptan is indicated for the acute treatment of migraine with or without aura in adults.

Meloxicam/rizatriptan 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 the combination drug, the diagnosis of migraine should be reconsidered before treating any subsequent attacks.

Meloxicam/rizatriptan is not indicated for the preventive treatment of migraine attacks or for the treatment of cluster headache.

Meloxicam and Rizatriptan Benzoate Dosage and Administration

General

Meloxicam and rizatriptan benzoate is available in the following dosage form(s) and strength(s):

Tablets: 20 mg of meloxicam and 10 mg of rizatriptan

Dosage

Adults

Dosage and Administration

• The recommended dose of meloxicam/rizatriptan is one tablet (containing 20 mg meloxicam and 10 mg rizatriptan) orally as needed.

• The maximum daily dose is 1 tablet (20 mg meloxicam and 10 mg rizatriptan). Swallow tablets whole. Do not crush, divide, or chew the tablets.

• Meloxicam/rizatriptan can be taken with or without food.

• The fixed-combination tablets have not shown equivalent systemic exposures to other formulations of oral meloxicam and of oral rizatriptan. Therefore, meloxicam/rizatriptan tablets are not substitutable with other formulations of oral meloxicam or oral rizatriptan products, even if the milligram strengths are the same.

Cautions for Meloxicam and Rizatriptan Benzoate

Contraindications

• 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 the fixed-combination of meloxicam/rizatriptan, meloxicam, rizatriptan, NSAIDs, triptans, or any of the excipients in the fixed-combination preparation.

• 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.

Warnings/Precautions

Warnings

Cardiovascular Thrombotic Events and Myocardial Infarction

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to 3 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.

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.

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 4 years of follow-up.

Meloxicam/rizatriptan 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 MI, occurring within a few hours following administration of rizatriptan. Some of these reactions occurred in patients without known coronary artery disease (CAD). 5-HT1 agonists, including meloxicam/rizatriptan may cause coronary artery vasospasm (Prinzmetal’s Angina), even in patients without a history of CAD.

Triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) should have a cardiovascular evaluation prior to receiving meloxicam/rizatriptan. If there is evidence of CAD or coronary artery vasospasm, meloxicam/rizatriptan should not be administered. For patients who have a negative cardiovascular evaluation, consideration should be given to administration of the first dose of meloxicam/rizatriptan in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following meloxicam/rizatriptan administration. Periodic cardiovascular evaluation should be considered in intermittent long-term users of meloxicam/rizatriptan who have cardiovascular risk factors.

Avoid the use of meloxicam/rizatriptan in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If meloxicam/rizatriptan is used in patients with a recent MI, monitor patients for signs of cardiac ischemia.

GI Bleeding, Ulceration, and Perforation

NSAIDs, including meloxicam, a component of meloxicam/rizatriptan, can cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with meloxicam. Only 1 in 5 patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for 1 year. However, even short-term NSAID therapy is not without risk.

Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective SSRIs; smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.

Strategies to minimize the GI risks in NSAID-treated patients include the following:

• Use the lowest effective dosage for the shortest possible duration.

• Avoid administration of more than one NSAID at a time.

• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs.

• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.

• If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue meloxicam and rizatriptan until a serious GI adverse event is ruled out.

• In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding.

Arrhythmias

Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue meloxicam/rizatriptan if these disturbances occur.

Cerebrovascular Events

Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Discontinue meloxicam/rizatriptan if a cerebrovascular event occurs. Before treating headaches in patients not previously diagnosed with migraine, and in patients with migraine who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. Meloxicam/rizatriptan is contraindicated in patients with a history of stroke or transient ischemic attack.

Anaphylactic Reactions

Meloxicam/rizatriptan can cause anaphylactic reactions. Meloxicam has been associated with anaphylactic reactions in patients with and without known hypersensitivity to the drug and in patients with aspirin-sensitive asthma. Hypersensitivity reactions, including angioedema and anaphylaxis, have also occurred in patients receiving rizatriptan. Seek emergency help if an anaphylactic reaction occurs.

Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure

Sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with meloxicam/rizatriptan and are usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Meloxicam/rizatriptan is contraindicated in patients with ischemic coronary artery disease and those with Prinzmetal’s variant angina.

Other Vasospasm Reactions

5-HT1 agonists, including meloxicam/rizatriptan, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional meloxicam/rizatriptan doses. Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists has not been clearly established.

Hepatotoxicity

Elevations of ALT or AST (3- or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than 3-times ULN) may occur in up to 15% of patients treated with NSAIDs including meloxicam, a component of meloxicam/rizatriptan. 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 clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue meloxicam/rizatriptan immediately, and perform a clinical evaluation of the patient.

Hypertension/Increase in Blood Pressure

NSAIDs, including meloxicam, a component of meloxicam/rizatriptan, can lead to new onset of hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. Significant elevation in blood pressure (BP), including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without a history of hypertension receiving 5-HT1 agonists, including rizatriptan, a component of meloxicam/rizatriptan. In healthy young adult male and female patients who received maximal doses of rizatriptan (10 mg every 2 hours for 3 doses), slight increases in BP (approximately 2-3 mmHg) were observed. Meloxicam/rizatriptan is contraindicated in patients with uncontrolled hypertension. Monitor BP during the initiation of meloxicam/rizatriptan treatment and throughout the course of therapy.

Heart Failure and Edema

The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately 2-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of meloxicam/rizatriptan may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]). Avoid the use of meloxicam/rizatriptan in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If meloxicam/rizatriptan is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

Renal Toxicity and Hyperkalemia

Long-term administration of NSAIDs has resulted in renal papillary necrosis, renal insufficiency, acute renal failure, and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Meloxicam/rizatriptan is not recommended in patients with moderate to severe renal insufficiency and is contraindicated in patients with moderate to severe renal insufficiency who are at risk for renal failure due to volume depletion. No information is available from controlled clinical studies regarding the use of meloxicam in patients with advanced renal disease. The renal effects of meloxicam/rizatriptan may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating the combination drug. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of meloxicam/rizatriptan. Avoid the use of meloxicam/rizatriptan in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If meloxicam/rizatriptan is used in patients with advanced renal disease, monitor patients for signs of worsening renal function.

Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.

Serious Skin Reactions

NSAIDs, including meloxicam/rizatriptan, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of meloxicam/rizatriptan at the first appearance of skin rash or any other sign of hypersensitivity. Meloxicam/rizatriptan is contraindicated in patients with previous serious skin reactions to NSAIDs.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as meloxicam/rizatriptan. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue meloxicam/rizatriptan and evaluate the patient immediately.

Fetal Toxicity

Avoid use of NSAIDs, including meloxicam/rizatriptan, in pregnant women at about 30 weeks gestation and later. NSAIDs, including meloxicam/rizatriptann, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.

Use of NSAIDs, including meloxicam/rizatriptan, at about 20 weeks gestation or later in pregnancy may cause 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. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some postmarketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit meloxicam/rizatriptan use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if meloxicam/rizatriptan treatment extends beyond 48 hours. Discontinue meloxicam/rizatriptan if oligohydramnios occurs and follow up according to clinical practice.

Hematologic Toxicity

Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with meloxicam/rizatriptan has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including meloxicam/rizatriptan, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), SSRIs and SNRIs may increase this risk. Monitor these patients for signs of bleeding.

Exacerbation of Asthma Related to Aspirin Sensitivity

A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, meloxicam/rizatriptan is contraindicated in patients with this form of aspirin sensitivity. When meloxicam/rizatriptan is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

Medication Overuse Headache

Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

Serotonin Syndrome

Serotonin syndrome may occur with triptans, including meloxicam/rizatriptan particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors (MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or GI symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Meloxicam/rizatriptan treatment should be discontinued if serotonin syndrome is suspected.

Masking of Inflammation and Fever

The pharmacological activity of meloxicam/rizatriptan in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

Laboratory Monitoring

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a complete blood count (CBC) and a chemistry profile periodically. Discontinue meloxicam/rizatriptan if GI bleeding occurs or if abnormal liver or renal tests persist or worsen.

Specific Populations

Pregnancy

Meloxicam/rizatriptan has not been studied in pregnant women. However, there are data pertaining to the use of the individual components during pregnancy.

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.

Use of NSAIDs, including meloxicam/rizatriptan, 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 meloxicam/rizatriptan use between about 20 and 30 weeks of gestation, and avoid meloxicam/rizatriptan use at about 30 weeks of gestation and later in pregnancy. Use of NSAIDs, including meloxicam/rizatriptan, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. 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/m² ). 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/m² 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/m² 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/m² 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.

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/m² basis.

In women with migraine, there is an increased risk of adverse perinatal outcomes in the mother, including pre-eclampsia and gestational hypertension.

Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including meloxicam/rizatriptan, can cause premature closure of the fetal ductus arteriosus.

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 meloxicam/rizatriptan treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue meloxicam/rizatriptan and follow up according to clinical practice.

There are no studies on the effects of meloxicam/rizatriptan during labor or delivery. In animal studies, NSAIDs, including meloxicam, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.

Lactation

There are no human data available on whether meloxicam is present in human milk, or on the effects on breastfed infants, or on milk production.

There are no adequate data on the presence of rizatriptan or any active metabolites in human milk, or on the effects of rizatriptan on the breastfed infant, or on milk production. Rizatriptan was excreted in rat milk with levels in milk approximately 6 times those in maternal plasma.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for meloxicam/rizatriptan and any potential adverse effects on the breastfed infant from the meloxicam/rizatriptan or from the underlying maternal condition.

Females and Males of Reproductive Potential

Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including meloxicam/rizatriptan, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of meloxicam/rizatriptan in women who have difficulties conceiving or who are undergoing investigation of infertility.

Pediatric Use

Safety and effectiveness of meloxicam/rizatriptan in pediatric patients have not been established.

Geriatric Use

Clinical studies of meloxicam/rizatriptan did not include subjects 65 years of age and older to determine whether they respond differently from younger subjects.

Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, GI, 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 effect.

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 meloxicam/rizatriptan.

Renal Impairment

The use of meloxicam/rizatriptan, because of the meloxicam component, is contraindicated for patients with moderate to severe renal impairment who are at risk for renal failure due to volume depletion or for patients on hemodialysis, and is not recommended in patients with moderate to severe renal impairment.

Meloxicam/rizatriptan has not been studied in patients with renal impairment. The individual components, meloxicam and rizatriptan, have been studied and the results are described below.

Pharmacokinetics of meloxicam in elderly subjects with mild renal impairment is similar to healthy young subjects. Patients with moderate or severe renal impairment have not been studied. Meloxicam is not dialyzable.

In patients with renal impairment (creatinine clearance 10-60 mL/min/1.73 m²), the AUC0-inf of rizatriptan was not significantly different from that in subjects with normal renal function. In hemodialysis patients, (creatinine clearance <2 mL/min/1.73 m²), however, the AUC for rizatriptan was greater than that in patients with normal renal function. Patients with severe renal impairment have not been studied.

Hepatic Impairment

The use meloxicam/rizatriptan, because of the meloxicam component, with caution in patients with hepatic impairment, and monitor for adverse reactions when used in patients with severe hepatic impairment.

Meloxicam/rizatriptan has not been studied in patients with hepatic impairment. The individual components, meloxicam and rizatriptan, have been studied and the results are described below.

Following oral administration of meloxicam, patients with mild to moderate hepatic impairment had no marked differences in plasma concentrations. Patients with severe hepatic impairment have not been adequately studied. Meloxicam is significantly metabolized in the liver and hepatotoxicity may occur.

Following oral administration of rizatriptan in patients with hepatic impairment caused by mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were similar in patients with mild hepatic impairment and greater in patients with moderate hepatic impairment, compared to a control group of subjects with normal hepatic function.

Poor Metabolizers of CYP2C9 Substrates

In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (e.g., warfarin and phenytoin), the use of meloxicam/rizatriptan is not recommended as they may have abnormally high plasma levels due to reduced metabolic clearance of meloxicam. If meloxicam/rizatriptan is used in patients who are poor CYP2C9 metabolizers, monitor for adverse reactions.

Common Adverse Effects

The most common adverse reactions (≥1% and greater than placebo) are dizziness and somnolence.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Drugs that Interfere with Hemostasis (e.g., warfarin, aspirin, SSRIs/SNRIs): Monitor patients for bleeding who are concomitantly taking meloxicam/rizatriptan with drugs that interfere with hemostasis. Concomitant use of meloxicam/rizatriptan and analgesic doses of aspirin is not generally recommended.

• ACE Inhibitors, ARBs, or Beta-Blockers: Concomitant use with meloxicam/rizatriptan may diminish the antihypertensive effect of these drugs. Monitor blood pressure.

• ACE Inhibitors and ARBs: Concomitant use with meloxicam/rizatriptan 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.

• Diuretics: NSAIDs can reduce natriuretic effect of furosemide and thiazide diuretics. Monitor patients to assure diuretic efficacy including antihypertensive effects.

• Lithium: Monitor for increases in lithium plasma levels.

• Methotrexate: Monitor for increases methotrexate plasma levels.

Actions

Mechanism of Action

Meloxicam and rizatriptan benzoate (meloxicam/rizatriptan) is a fixed combination of meloxicam (an NSAID) and rizatriptan (a serotonin [5-HT] 1B/1D receptor agonist [triptan]). 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.

Advice to Patients

• 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.

• 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.

• 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.

• 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.

• 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 meloxicam and rizatriptan and seek immediate medical therapy.

• 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.

• Advise patients to stop meloxicam/rizatriptan immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible.

• Advise females of reproductive potential who desire pregnancy that meloxicam, a component of meloxicam/rizatriptan, may be associated with a reversible delay in ovulation.

• Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed.

• Inform pregnant women to avoid use of meloxicam/rizatriptan and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with meloxicam/rizatriptan 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.

• Inform patients that the concomitant use of meloxicam/rizatriptan with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of GI toxicity, and little or no increase in efficacy. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.

• Inform patients not to use low-dose aspirin concomitantly with meloxicam/rizatriptan until they talk to their healthcare provider.

• 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).

• Patients should be cautioned about the risk of serotonin syndrome with the use of meloxicam/rizatriptan, particularly during combined use with SSRIs or SNRIs.

• Since migraines or treatment with meloxicam/rizatriptan may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of the combination drug.

Additional Information

AHFSfirstRelease™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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