This information is not for clinical use. These highlights do not include all the information needed to use Vimovo safely and effectively. Before taking Vimovo please consult with your doctor. See full prescribing information for Vimovo.

Warning

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS See full prescribing information for complete boxed warning. Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use. (5.1) VIMOVO is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1) NSAIDs, including naproxen, a component of VIMOVO, cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. (5.2) Cardiovascular Thrombotic Events Non-Steroidal Anti-inflammatory Drugs (NSAIDs), a component of VIMOVO, cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and Precautions (5.1)]. VIMOVO is contraindicated in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4), and Warnings and Precautions (5.1)]. Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, a component of VIMOVO cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events [see Warnings and Precautions (5.2)].

Recent Changes

Warnings and Precautions, Fundic Gland Polyps (5.27) 06/2018

Indications And Usage

VIMOVO, a combination of naproxen and esomeprazole magnesium, is indicated in adult and adolescent patients 12 years of age and older weighing at least 38 kg, requiring naproxen for symptomatic relief of arthritis and esomeprazole magnesium to decrease the risk for developing naproxen-associated gastric ulcers. The naproxen component of VIMOVO is indicated for relief of signs and symptoms of: osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. juvenile idiopathic arthritis (JIA) in adolescent patients. The esomeprazole magnesium component of VIMOVO is indicated to decrease the risk of developing naproxen-associated gastric ulcers. VIMOVO is a combination of naproxen, a non-steroidal anti-inflammatory drug (NSAID), and esomeprazole magnesium, a proton pump inhibitor (PPI) indicated in adult and adolescent patients 12 years of age and older weighing at least 38 kg, requiring naproxen for symptomatic relief of arthritis and esomeprazole magnesium to decrease the risk of developing naproxen-associated gastric ulcers. The naproxen component of VIMOVO is indicated for relief of signs and symptoms of: osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. juvenile idiopathic arthritis (JIA) in adolescent patients. The esomeprazole magnesium component of VIMOVO is indicated to decrease the risk of developing naproxen-associated gastric ulcers. (1) Limitations of Use: Do not substitute VIMOVO with the single-ingredient products of naproxen and esomeprazole magnesium. (1) VIMOVO is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. (1) Controlled studies do not extend beyond 6 months. (1) Limitations of Use: Do not substitute VIMOVO with the single-ingredient products of naproxen and esomeprazole magnesium. VIMOVO is not recommended for initial treatment of acute pain because the absorption of naproxen is delayed compared to absorption from other naproxen-containing products. Controlled studies do not extend beyond 6 months [see Use in Specific Populations (8.4), Clinical Studies (14)].

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Dosage And Administration

Indication Patient Population Recommended Dosage
Rheumatoid Arthritis, Osteoarthritis, and Ankylosing Spondylitis Adults One VIMOVO tablet twice daily of either: 375 mg naproxen/20 mg of esomeprazole; or 500 mg naproxen/20 mg of esomeprazole
Juvenile Idiopathic Arthritis in Adolescent Patients 12 Years of Age and Older and Weighing at Least 38 kg Greater than 50 kg
38 kg to less than 50 kg One VIMOVO tablet twice daily of: 375 mg naproxen/20 mg of esomeprazole

Dosage Forms And Strengths

VIMOVO is an oval, yellow, delayed-release tablets for oral administration containing either: 375 mg enteric-coated naproxen and 20 mg immediate-release esomeprazole tablets printed with 375/20 in black, or 500 mg enteric-coated naproxen and 20 mg immediate-release esomeprazole tablets printed with 500/20 in black. VIMOVO delayed-release tablets (3): 375 mg enteric-coated naproxen /20 mg immediate-release esomeprazole 500 mg enteric-coated naproxen /20 mg immediate-release esomeprazole.

Contraindications

VIMOVO is contraindicated in the following patients: Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen, esomeprazole magnesium, substituted benzimidazoles, or to any components of the drug product, including omeprazole. Hypersensitivity reactions to esomeprazole may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria [see Warnings and Precautions (5.7, 5.8, 5.9, 5.17) and Postmarketing Experience (6.2)]. History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.8)]. In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]. Proton pump inhibitors (PPIs), including esomeprazole magnesium, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7)]. Known hypersensitivity to naproxen, esomeprazole magnesium, substituted benzimidazoles, or to any components of the drug product including omeprazole. (4) History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. (4) In the setting of coronary artery bypass graft (CABG) surgery. (4) In patients receiving rilpivirine-containing products. (4, 7)

Warning and Cautions

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. (5.3) Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. (5.4, 7) Heart Failure and Edema: Avoid use of VIMOVO in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. (5.5) Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of VIMOVO in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function. (5.6) Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs. (5.7) Exacerbation of Asthma Related to Aspirin Sensitivity: VIMOVO is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). (5.8) Serious Skin Reactions: Discontinue VIMOVO at first appearance of skin rash or other signs of hypersensitivity. (5.9) Premature Closure of Fetal Ductus Arteriosus: Avoid use in pregnant women starting at 30 weeks gestation. (5.10, 8.1) Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs of symptoms of anemia. (5.11, 7) Masking of Inflammation and Fever: Potential for diminished utility of diagnostic signs in detecting infections. (5.12) Laboratory Monitoring: Obtain CBC and chemistry profile periodically during treatment. Monitor hemoglobin periodically in patients on long-term treatment who have an initial value of 10 g or less. (5.13) Active Bleeding: Withdraw treatment in patients who experience active and clinically significant bleeding. (5.14) Concomitant NSAID Use: Do not use VIMOVO with other naproxen-containing products or other non-aspirin NSAIDs. (5.15) Gastric Malignancy: In adults, symptomatic response to esomeprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. (5.16) Acute Interstitial Nephritis: Observed in patients taking PPIs. (5.17) Clostridium difficile-Associated Diarrhea: PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (5.18) Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. (5.19) Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous, new onset or exacerbation of existing disease; discontinue VIMOVO and refer to specialist for evaluation. (5.20) Interaction with Clopidogrel: Avoid concomitant use. (5.21, 7) Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. (5.22) Hypomagnesemia: Reported rarely with prolonged treatment with PPIs. (5.23) Interaction with St. John's Wort or Rifampin: Avoid concomitant use. (5.24, 7) Interactions with Diagnostic Investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia, enterochromaffin-like cell hyperplasia, and increased Chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. (5.25) Interaction with Methotrexate: Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. (5.26, 7) Fundic Gland Polyps: Risk increases with long-term PPI use, especially beyond one year. Use the shortest duration of therapy. (5.27) 5.1 Cardiovascular Thrombotic Events 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 naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings and 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 myocardial infarction 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 after follow-up. Avoid the use of VIMOVO in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If VIMOVO is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including naproxen, can cause serious gastrointestinal (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 NSAIDs. Only one in five 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% to 4% of patients treated for one year. However, even short-term NSAID therapy is not without risk. Risk Factors for GI Bleeding, Ulceration, and Perforation 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 for GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most postmarketing reports of fatal GI events are 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: 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 as 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 VIMOVO 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 [see Drug Interactions (7)]. NSAIDs should be given with care to patients with a history of inflammatory bowel disease (ulcerative colitis, Crohn's disease) as their condition may be exacerbated. 5.3 Hepatotoxicity Elevations of ALT or AST (three or more times the upper limit of the normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, and sometimes fatal, cases of severe hepatic injury, including jaundice and fatal fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including naproxen. 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 VIMOVO immediately, and perform a clinical evaluation of the patient. VIMOVO should be avoided in patients with severe hepatic impairment [see Dosage and Administration (2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)]. 5.4 Hypertension NSAIDs, including VIMOVO, 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 diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7)]. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.5 Heart Failure and Edema The Coxib and traditional NSAID Trialists' Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-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 naproxen 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]) [see Drug Interactions (7)]. Avoid the use of VIMOVO in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If VIMOVO is used in patients with severe heart failure, monitor patients for signs and symptoms of worsening heart failure. 5.6 Renal Toxicity and Hyperkalemia Renal Toxicity Long-term administration of NSAIDs has resulted in renal papillary necrosis 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 was usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of VIMOVO in patients with advanced renal disease. The renal effects of VIMOVO 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 VIMOVO. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of VIMOVO [see Drug Interactions (7)]. Avoid the use of VIMOVO in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal failure. If VIMOVO is used in patients with advanced renal disease, monitor patients for signs of worsening renal function. Hyperkalemia 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. 5.7 Anaphylactic Reactions Naproxen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to naproxen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.8)]. Seek emergency help if an anaphylactic reaction occurs. 5.8 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, VIMOVO is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4)]. When VIMOVO is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.9 Serious Skin Reactions NSAIDs, including naproxen, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of VIMOVO at the first appearance of skin rash or any other sign of hypersensitivity. VIMOVO is contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4)]. 5.10 Premature Closure of Fetal Ductus Arteriosus Naproxen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including VIMOVO, in pregnant women starting at 30 weeks of gestation (third trimester) [see Use in Specific Populations (8.1)]. 5.11 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 VIMOVO has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including VIMOVO, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin and other anticoagulants, antiplatelet agents (e.g., aspirin), and serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase the risk. Monitor these patients for signs of bleeding [see Drug Interactions (7)]. 5.12 Masking of Inflammation and Fever The pharmacological activity of VIMOVO in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.13 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 CBC and chemistry profile periodically [see Warnings and Precautions (5.2, 5.3, 5.6)]. Patients with initial hemoglobin values of 10 g or less who are to receive long-term therapy should have hemoglobin values determined periodically. 5.14 Active Bleeding When active and clinically significant bleeding from any source occurs in patients receiving VIMOVO, the treatment should be withdrawn. 5.15 Concomitant NSAID Use VIMOVO contains naproxen as one of its active ingredients. It should not be used with other naproxen-containing products since they all circulate in the plasma as the naproxen anion. The concomitant use of VIMOVO with any dose of a non-aspirin NSAID should be avoided due to the potential for increased risk of adverse reactions. 5.16 Presence of Gastric Malignancy In adults, response to gastric symptoms with VIMOVO does not preclude the presence of gastric malignancy. Consider additional gastrointestinal follow-up and diagnostic testing in adult patients who experience gastric symptoms during treatment with VIMOVO or have a symptomatic relapse after completing treatment. In older patients, also consider an endoscopy. 5.17 Acute Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including VIMOVO. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue VIMOVO if acute interstitial nephritis develops [see Contraindications (4)]. 5.18 Clostridium difficile-Associated Diarrhea Published observational studies suggest that proton pump inhibitor (PPI) therapy like VIMOVO may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2)]. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated [see Dosage and Administration (2)]. 5.19 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines [see Dosage and Administration (2) and Adverse Reactions (6.2)]. VIMOVO (a combination PPI/NSAID) is approved for use twice a day and does not allow for administration of a lower daily dose of the PPI [see Dosage and Administration (2)]. 5.20 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including esomeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematous cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy inpatients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. SLE is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving VIMOVO, discontinue drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations. 5.21 Interaction with Clopidogrel Avoid concomitant use of esomeprazole with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as esomeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 40 mg esomeprazole reduces the pharmacological activity of clopidogrel. When using esomeprazole, a component of VIMOVO, consider alternative anti-platelet therapy [see Drug Interactions (7) and Clinical Pharmacology (12.3)]. 5.22 Cyanocobalamin (Vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo-or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed. 5.23 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)]. 5.24 Concomitant use of St. John's Wort or Rifampin with VIMOVO Drugs that induce CYP2C19 or CYP3A4 (such as St. John's Wort or rifampin) can substantially decrease esomeprazole concentrations. Avoid concomitant use of VIMOVO with St. John's Wort or rifampin [see Drug Interactions (7)]. 5.25 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop esomeprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Drug Interactions (7), Clinical Pharmacology (12.2)]. 5.26 Concomitant Use of VIMOVO with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7)]. 5.27 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long–term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [see Warnings and Precautions (5.1)] GI Bleeding, Ulceration and Perforations [see Warnings and Precautions (5.2)] Hepatotoxicity [see Warnings and Precautions (5.3)] Hypertension [see Warnings and Precautions (5.4)] Heart Failure and Edema [see Warnings and Precautions (5.5)] Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6)] Anaphylactic Reactions [see Warnings and Precautions (5.7)] Serious Skin Reactions [see Warnings and Precautions (5.9)] Hematologic Toxicity [see Warnings and Precautions (5.11)] Active Bleeding [see Warnings and Precautions (5.14)] Acute Interstitial Nephritis [see Warnings and Precautions (5.17)] Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.18)] Bone Fracture [see Warnings and Precautions (5.19)] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.20)] Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.22)] Hypomagnesemia [see Warnings and Precautions (5.23)] Fundic Gland Polyps [see Warnings and Precautions (5.27)] Most common adverse reactions in clinical trials (>5%) are gastritis and diarrhea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Horizon Pharma USA, Inc. at 1-866-479-6742 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Clinical Trials Experience with VIMOVO 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 practice. The adverse reactions reported below are specific to the clinical trials with VIMOVO. The safety of VIMOVO was evaluated in clinical studies involving 2317 patients (aged 27 to 90 years) and ranging from 3 to 12 months. Patients received either 500 mg/20 mg of VIMOVO twice daily (n=1157), 500 mg of enteric-coated naproxen twice daily (n=426), or placebo (n=246). The average number of VIMOVO doses taken over 12 months was 696±44. The table below lists all adverse reactions, regardless of causality, occurring in >2% of patients receiving VIMOVO and higher in the VIMOVO group than control from two clinical studies (Study 1 and Study 2). Both of these studies were randomized, multi-center, double-blind, parallel studies. The majority of patients were female (67%), white (86%). The majority of patients were 50-69 years of age (83%). Approximately one quarter were on low-dose aspirin. Table 1: Adverse Reactionsreported in >2% of patients and higher in the VIMOVO group than control in Study 1 and Study 2 (endoscopic studies) Preferred term VIMOVO 500 mg/20 mg twice daily (n=428) % EC-Naproxen 500 mg twice daily (n=426) % Gastritis 17 14 Diarrhea 6 5 Upper respiratory tract infection 5 4 Flatulence 4 3 Headache 3 1 Urinary tract infection 2 1 Dysgeusia 2 1 In Study 1 and Study 2, patients taking VIMOVO had fewer premature discontinuations due to adverse reactions compared to patients taking enteric-coated naproxen alone (7.9% vs. 12.5% respectively). The most common reasons for discontinuations due to adverse events in the VIMOVO treatment group were upper abdominal pain (1.2%, n=5), duodenal ulcer (0.7%, n=3) and erosive gastritis (0.7%, n=3). Among patients receiving enteric-coated naproxen, the most common reasons for discontinuations due to adverse events were duodenal ulcer 5.4% (n=23), dyspepsia 2.8% (n=12) and upper abdominal pain 1.2% (n=5). The proportion of patients discontinuing treatment due to any upper gastrointestinal adverse events (including duodenal ulcers) in patients treated with VIMOVO was 4% compared to 12% for patients taking enteric-coated naproxen. The table below lists all adverse reactions, regardless of causality, occurring in >2% of patients and higher in the VIMOVO group than placebo from 2 clinical studies conducted in patients with osteoarthritis of the knee (Study 3 and Study 4). Table 2: Adverse Reactionsreported in >2% of patients and higher in the VIMOVO group than placebo in Study 3 and Study 4 Preferred term VIMOVO 500 mg/20 mg twice daily (n=490) % Placebo (n=246) % Diarrhea 6 4 Abdominal Pain Upper 4 3 Constipation 4 1 Dizziness 3 2 Peripheral edema 3 1 The percentage of subjects who withdrew from the VIMOVO treatment group in these studies due to treatment-emergent adverse events was 7%. There were no preferred terms in which more than 1% of subjects withdrew from any treatment group. The long-term safety of VIMOVO was evaluated in an open-label clinical trial of 239 patients, of which 135 patients received 500 mg/20 mg of VIMOVO for 12 months. There were no differences in frequency or types of adverse reactions seen in the long-term safety study compared to shorter-term treatment in the randomized controlled studies. Clinical Trials Experience with Naproxen and Other NSAIDs In patients taking naproxen in clinical trials, the most frequent reported adverse experiences in approximately 1% to 10% of patients are: Gastrointestinal: heartburn, nausea, dyspepsia, stomatitis Central Nervous System: drowsiness, lightheadedness, vertigo Dermatologic: pruritus, skin eruptions, ecchymoses, sweating, purpura Special Senses: tinnitus, visual disturbances, hearing disturbances Cardiovascular: palpitations General: dyspnea, thirst In patients taking NSAIDs, the following adverse experiences have also been reported in approximately 1% to 10% of patients. Gastrointestinal: gross bleeding/perforation, GI ulcers (gastric/duodenal), vomiting General: abnormal renal function, anemia, elevated liver enzymes, increased bleeding time, rashes The following are additional adverse experiences reported in <1% of patients taking naproxen during clinical trials. Gastrointestinal: pancreatitis Hepatobiliary: jaundice Hemic and Lymphatic: melena, thrombocytopenia, agranulocytosis Nervous System: inability to concentrate Dermatologic: skin rashes In patients taking NSAIDs, the following adverse experiences have also been reported in <1% of patients. Body as a Whole: fever, infection, sepsis, anaphylactic reactions, appetite changes, death Cardiovascular: hypertension, tachycardia, syncope, arrhythmia, hypotension, myocardial infarction Gastrointestinal: dry mouth, glossitis, eructation Hepatobiliary: hepatitis, liver failure Hemic and Lymphatic: rectal bleeding, lymphadenopathy, pancytopenia Metabolic and Nutritional: weight changes Nervous System: anxiety, asthenia, confusion, nervousness, paresthesia, somnolence, tremor, coma, hallucinations Respiratory: asthma, respiratory depression, pneumonia Dermatologic: exfoliative dermatitis Special Senses: blurred vision, conjunctivitis Urogenital: cystitis, dysuria, oliguria/polyuria, proteinuria Clinical Trials Experience with Esomeprazole Magnesium Additional adverse reactions that were reported as possibly or probably related to esomeprazole magnesium with an incidence of <1% are listed below by body system: Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, malaise, pain, rigors Cardiovascular: flushing, hypertension, tachycardia Endocrine: goiter Gastrointestinal: dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting Hearing: earache, tinnitus Hematologic: anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia Hepatic: bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect Reproductive: dysmenorrhea, menstrual disorder, vaginitis Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria Special Senses: otitis media, parosmia, taste loss Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria Visual: conjunctivitis, vision abnormal The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to esomeprazole magnesium, were reported in ≤ 1% of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone. Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine. Endoscopic findings that were reported as adverse reactions include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, hernia, benign polyps or nodules, Barrett's esophagus, and mucosal discoloration. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of VIMOVO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. VIMOVO Body as a Whole: gait disturbance Gastrointestinal: abdominal distension, abdominal pain, gastroesophageal reflux, hematochezia Injury, Poisoning and Procedural Complications: contusion, fall Musculoskeletal and Connective Tissue: joint swelling, muscle spasms Urogenital: renal tubular necrosis Naproxen Body as a Whole: angioneurotic edema, menstrual disorders Cardiovascular: congestive heart failure, vasculitis, pulmonary edema Gastrointestinal: inflammation, bleeding (sometimes fatal, particularly in the elderly), ulceration, and obstruction of the upper or lower gastrointestinal tract, esophagitis, stomatitis, hematemesis, colitis, exacerbation of inflammatory bowel disease (ulcerative colitis, Crohn's disease) Hepatobiliary: hepatitis (some cases have been fatal) Hemic and Lymphatic: eosinophilia, hemolytic anemia, aplastic anemia Metabolic and Nutritional: hyperglycemia, hypoglycemia Nervous System: depression, dream abnormalities, insomnia, malaise, myalgia, muscle weakness, aseptic meningitis, cognitive dysfunction, convulsions Respiratory: eosinophilic pneumonitis Dermatologic: alopecia, urticaria, toxic epidermal necrolysis, erythema multiforme, erythema nodosum, fixed drug eruption, lichen planus, pustular reaction, systemic lupus erythematoses, bullous reactions, including Stevens-Johnson syndrome, photosensitive dermatitis, photosensitivity reactions, including rare cases resembling porphyria cutanea tarda (pseudoporphyria) or epidermolysis bullosa. If skin fragility, blistering or other symptoms suggestive of pseudoporphyria occur, treatment should be discontinued and the patient monitored. Special Senses: hearing impairment, corneal opacity, papillitis, retrobulbar optic neuritis, papilledema Urogenital: glomerular nephritis, hematuria, hyperkalemia, interstitial nephritis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis, raised serum creatinine Reproduction (female): infertility Esomeprazole Magnesium Blood and Lymphatic: agranulocytosis Eye: blurred vision Gastrointestinal: pancreatitis, microscopic colitis, fundic gland polyps Hepatobiliary: hepatic failure, hepatitis with or without jaundice Immune System: anaphylactic reaction/shock, systemic lupus erythematosus Infections and Infestations: GI candidiasis, Clostridium difficile associated diarrhea Metabolism and Nutritional Disorders: hypomagnesemia, with or without hypocalcemia and/or hypokalemia Musculoskeletal and Connective Tissue: muscular weakness, myalgia, bone fracture Nervous System: hepatic encephalopathy Psychiatric: aggression, agitation, hallucination Renal and Urinary: interstitial nephritis Reproductive System and Breast: gynecomastia Respiratory, Thoracic, and Mediastinal: bronchospasm Skin and Subcutaneous Tissue: alopecia, erythema multiforme, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), cutaneous lupus erythematosus

Drug Interactions

See Table 3 and Table 4 for clinically significant drug interactions and interactions with diagnostics with naproxen and esomeprazole magnesium. Table 3: Clinically Significant Drug Interactions with Naproxen and Esomeprazole Magnesium – Affecting Drugs Co-Administered with VIMOVO and Interactions with Diagnostics Drugs That Interfere with Hemostasis Clinical Impact: Naproxen Naproxen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of naproxen and anticoagulants have increased the 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. Esomeprazole Magnesium Increased INR and prothrombin time in patients treated with PPIs, including esomeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant use of esomeprazole 40 mg resulted in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of esomeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. Intervention: Monitor patients with concomitant use of VIMOVO 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 (5.13)]. Clopidogrel: Avoid concomitant use of clopidogrel with VIMOVO. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.21)]. 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 VIMOVO and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.15)]. VIMOVO is not a substitute for low dose aspirin for cardiovascular protection. 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 (including propranolol). 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. Intervention: During concomitant use of VIMOVO and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of VIMOVO 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 (5.6)]. Diuretics Clinical Impact: Clinical studies, as well as post-marketing 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. Intervention: During concomitant use of VIMOVO with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6)]. Antiretrovirals Clinical Impact: The effect of esomeprazole magnesium on antiretroviral drugs is variable. The clinical importance and mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with esomeprazole magnesium may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole magnesium may increase toxicity [see Clinical Pharmacology (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole magnesium. Intervention: Rilpivirine-containing products: Concomitant use with VIMOVO is contraindicated [see Contraindications (4)]. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with VIMOVO. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information of specific drugs. Cilostazol Clinical Impact: Increased exposure of cilostazol and one of its active metabolites (3,4-dihydro-cilostazol) when coadministered with omeprazole magnesium, the racemate of esomeprazole [see Clinical Pharmacology (12.3)]. Intervention: Consider reducing the dose of cilostazol to 50 mg twice daily. Digoxin Clinical Impact: Naproxen The concomitant use of naproxen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Esomeprazole Magnesium Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)]. Intervention: Monitor digoxin concentrations during concomitant use of VIMOVO. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. Lithium Clinical Impact: NSAIDs have produced elevations of plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of VIMOVO and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Naproxen Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Esomeprazole Magnesium Concomitant use of esomeprazole magnesium with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities [see Warnings and Precautions (5.26)]. Intervention: During concomitant use of VIMOVO and methotrexate, monitor patients for methotrexate toxicity. A temporary withdrawal of VIMOVO may be considered in some patients receiving high-dose methotrexate. Cyclosporine Clinical Impact: Concomitant use of naproxen and cyclosporine may increase cyclosporine's nephrotoxicity. Intervention: During concomitant use of VIMOVO and cyclosporine, monitor patients for signs of worsening renal function. Tacrolimus Clinical Impact: Concomitant use of esomeprazole magnesium and tacrolimus may increase exposure of tacrolimus Intervention: During concomitant use of VIMOVO and tacrolimus, monitor tacrolimus whole blood concentrations. NSAIDs and Salicylates Clinical Impact: Concomitant use of naproxen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.2)]. Intervention: The concomitant use of VIMOVO with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of VIMOVO and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of VIMOVO and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, mycophenoloate mofetil, ketoconazole) Clinical Impact: Esomeprazole magnesium can reduce the absorption of other drugs due to its effect on reducing intragastric acidity Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole magnesium is an enantiomer, in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving esomeprazole and MMF. Use VIMOVO with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.25) and Clinical Pharmacology (12.2)]. Intervention: Temporarily stop VIMOVO treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Diazepam Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology (12.3)]. Intervention: Monitor patients for increased sedation and adjust the dose of diazepam as needed. Table 4: Clinically Significant Interactions with Esomeprazole Magnesium -- Affecting Co-Administered Drugs CYP2C19 or CYP3A4 Inducers Clinical Impact: Decreased exposure of esomeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)]. Intervention: St. John's Wort, rifampin: Avoid concomitant use with VIMOVO [see Warnings and Precautions (5.24)]. CYP2C19 or CYP3A4 Inhibitors Clinical Impact: Increased exposure of esomeprazole [see Clinical Pharmacology (12.3)]. Intervention: Voriconazole: Avoid concomitant use with VIMOVO. See full prescribing information for a list of clinically important drug interactions. (7)

Use In Specific Populations

Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation. (5.10, 8.1) Females and Males of Reproductive Potential: NSAIDs are associated with reversible infertility. Consider withdrawal of VIMOVO in women who have difficulties conceiving. (8.3) 8.1 Pregnancy Risk Summary Use of NSAIDs, including VIMOVO, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including VIMOVO, in pregnant women starting at 30 weeks of gestation (third trimester). There are no adequate and well-controlled studies of VIMOVO in pregnant women. VIMOVO contains naproxen and esomeprazole magnesium. Esomeprazole is the S- isomer of omeprazole. Naproxen Data from observational studies regarding potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In animal reproduction studies, naproxen administered during organogenesis to rats and rabbits at doses less than the maximum recommended human daily dose of 1500 mg/day showed no evidence of harm to the fetus [see 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 naproxen resulted in increased pre- and post-implantation loss. Esomeprazole There are no human data for esomeprazole. However, available epidemiologic data for omeprazole (esomeprazole is the S-isomer of omeprazole) fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use [see Data]. In animal studies with administration of oral esomeprazole magnesium in rats changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data]. The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. 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. Clinical Considerations Labor or Delivery There are no studies on the effects of VIMOVO during labor or delivery. In animal studies, NSAIDs, including naproxen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Naproxen When used to delay preterm labor, inhibitors of prostaglandin synthesis, including NSAIDs such naproxen, may increase the risk of neonatal complications such as necrotizing enterocolitis, patent ductus arteriosus and intracranial hemorrhage. Naproxen treatment given in late pregnancy to delay parturition has been associated with persistent pulmonary hypertension, renal dysfunction and abnormal prostaglandin E levels in preterm infants. Esomeprazole Esomeprazole is the S-isomer of omeprazole. Four epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996-2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837, 317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5%, and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rate of major congenital malformations was 4% in the omeprazole group, 2% in controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data There are no reproduction studies in animals with VIMOVO, a combination of naproxen and esomeprazole. Naproxen Reproduction studies with naproxen administered during the period of organogenesis have been performed in rats at 20 mg/kg/day (0.13 times the maximum recommended human daily dose of 1500 mg/day based on body surface area comparison) rabbits at 20 mg/kg/day (0.26 times the maximum recommended human daily dose, based on body surface area comparison), and mice at 170 mg/kg/day (0.56 times the maximum recommended human daily dose based on body surface area comparison) with no evidence of harm to the fetus due to the drug. Esomeprazole No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis) administered during organogenesis and have revealed no evidence of harm to the fetus due to esomeprazole magnesium. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development were performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times a daily human dose of 40 mg on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate post-weaning timeframe were evident at doses equal to or greater than 69 mg /kg/day (about 17 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times a daily human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times the daily human dose of 40 mg on a body surface area basis). Effects on maternal bone were observed in pregnant and lactating rats in the pre- and postnatal toxicity study when esomeprazole magnesium was administered at oral doses of 14 to 280 mg /kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age. 8.2 Lactation Risk Summary Limited data from published literature report that naproxen anion has been found in the milk of lactating women at a concentration equivalent to approximately 1% of maximum naproxen concentration in plasma. Esomeprazole is the S-isomer of omeprazole and limited data from published literature suggest omeprazole may be present in human milk. There is no information on the effects of naproxen or omeprazole on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VIMOVO and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition. 8.3 Females and Males of Reproductive Potential Infertility Females Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including VIMOVO, may delay or prevent rupture of ovarian follicles that may lead to reversible infertility in some women. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Published animal studies have shown that administration of prostaglandin synthesis inhibitors have the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Consider withdrawal of NSAIDs, including VIMOVO, in women who have difficulties conceiving or who are undergoing investigation of infertility. 8.4 Pediatric Use The safety and effectiveness of VIMOVO have been established in adolescent patients 12 years of age and older weighing at least 38 kg for the symptomatic relief of JIA and to decrease the risk of developing naproxen-associated gastric ulcers. Use of VIMOVO in this age group is based on extrapolation of adequate and well-controlled studies in adults and supported by a 6 month safety study including pharmacokinetic assessment of naproxen and esomeprazole magnesium in 36 adolescent patients with JIA. Based on the limited data, the plasma naproxen and plasma esomeprazole concentrations were found to be within the range to that observed to those found in healthy adults. The safety profile of VIMOVO in adolescent patients with JIA was similar to adults with RA. The safety and effectiveness of VIMOVO in pediatric patients less than 12 years of age or less than 38 kg with JIA have not been established. Juvenile Animal Data In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 68 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology (13.2)]. 8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13)]. Of the total number of patients who received VIMOVO (n=1157) in clinical trials, 387 were ≥65 years of age, of which 85 patients were 75 years and over. No meaningful differences in efficacy or safety were observed between these subjects and younger subjects [see Adverse Reactions (6)]. Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound plasma fraction of naproxen is increased in the elderly. Caution is advised when high doses are required and some adjustment of dosage may be required in elderly patients. As with other drugs used in the elderly, it is prudent to use the lowest effective dose [see Dosage and Administration (2) and Clinical Pharmacology (12.3)]. Experience indicates that geriatric patients may be particularly sensitive to certain adverse effects of NSAIDs. Elderly or debilitated patients seem to tolerate peptic ulceration or bleeding less well when these events do occur. Most spontaneous reports of fatal GI events are in the geriatric population [see Warnings and Precautions (5.2)]. Naproxen and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Geriatric patients may be at a greater risk for the development of a form of renal toxicity precipitated by reduced prostaglandin formation during administration of NSAIDs [see Warnings and Precautions (5.6)]. 8.6 Hepatic Impairment VIMOVO should be avoided in patients with severe hepatic impairment because naproxen may increase the risk of renal failure or bleeding and esomeprazole doses should not exceed 20 mg daily in these patients [see Dosage and Administration (2), Warnings and Precautions (5.3) , Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Naproxen-containing products, including VIMOVO, are not recommended for use in patients with advanced renal disease [see Dosage and Administration (2), Warnings and Precautions (5.6)].