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` VIMOVO (naproxen and esomeprazole magnesium) delayed-release
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` tablets, for oral use
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` Initial US Approval: 2010
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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use
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` VIMOVO safely and effectively. See full prescribing information for
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` VIMOVO.
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`WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
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`GASTROINTESTINAL EVENTS
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` See full prescribing information for complete boxed warning.
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`• Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased
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` risk of serious cardiovascular thrombotic events, including myocardial
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` infarction and stroke, which can be fatal. This risk may occur early in
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` treatment and may increase with duration of use. (5.1)
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`• VIMOVO is contraindicated in the setting of coronary artery bypass
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` graft (CABG) surgery. (4, 5.1)
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`• NSAIDs, including naproxen, a component of VIMOVO, cause an
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` which can be fatal. These events can occur at any time during use and
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` without warning symptoms. Elderly patients and patients with a prior
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` history of peptic ulcer disease and/or GI bleeding are at greater risk
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` for serious GI events. (5.2)
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` ---------------------------RECENT MAJOR CHANGES-------------------------
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` Warnings and Precautions, Drug Reaction with Eosinophilia and Systemic
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` Symptoms (DRESS) (5.10)
` 4/2021, 3/2022
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` Fetal Toxicity (5.11)
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` 4/2021
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` Hypomagnesemia and Mineral Metabolism (5.24)
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` 3/2022
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` ---------------------------INDICATIONS AND USAGE---------------------------
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` VIMOVO is a combination of naproxen, a non-steroidal anti-inflammatory
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` drug (NSAID), and esomeprazole magnesium, a proton pump inhibitor (PPI)
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` indicated in adult and adolescent patients 12 years of age and older weighing
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` at least 38 kg, requiring naproxen for symptomatic relief of arthritis and
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` esomeprazole magnesium to decrease the risk of developing naproxen­
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` The naproxen component of VIMOVO is indicated for relief of signs and
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` • osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults.
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` • juvenile idiopathic arthritis (JIA) in adolescent patients.
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` The esomeprazole magnesium component of VIMOVO is indicated to
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` decrease the risk of developing naproxen-associated gastric ulcers. (1)
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` Limitations of Use:
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`• Do not substitute VIMOVO with the single-ingredient products of
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` naproxen and esomeprazole magnesium. (1)
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`• VIMOVO is not recommended for initial treatment of acute pain because
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` the absorption of naproxen is delayed compared to absorption from other
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`• Controlled studies do not extend beyond 6 months. (1)
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` -----------------------DOSAGE ANDADMINISTRATION----------------------
` Administration
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`• Use the lowest naproxen dose for the shortest duration consistent with
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` individual patient treatment goals. (2.1, 5.1).
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` If a total daily dose of less than 40 mg esomeprazole is more appropriate,
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` a different treatment should be considered. (2.1)
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`• Swallow VIMOVO tablets whole with liquid at least 30 minutes before
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` meals. (2.1)
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` Recommended Dosage (2.2)
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` Adolescents 12 years of age and older weighing 38 kg to less than 50 kg:
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` One VIMOVO tablet twice daily of 375 mg naproxen/20 mg of
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` esomeprazole
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` Adults and adolescents 12 years of age and older greater than 50 kg:
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` One VIMOVO tablet twice daily of either:
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`• 375 mg naproxen/20 mg of esomeprazole; or
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`• 500 mg of naproxen/20 mg of esomeprazole
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` Renal or Hepatic Impairment (2.3)
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`• Avoid in moderate/severe renal impairment or severe hepatic impairment.
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`• Consider dose reduction in mild/moderate hepatic impairment.
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`Reference ID: 4947201
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`•
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` ---------------------DOSAGE FORMS AND STRENGTHS---------------------
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` VIMOVO delayed-release tablets (3):
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`• 375 mg enteric-coated naproxen /20 mg immediate-release esomeprazole
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`• 500 mg enteric-coated naproxen /20 mg immediate-release esomeprazole
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`-----------------------------CONTRAINDICATIONS------------------------------
`• Known hypersensitivity to naproxen, esomeprazole magnesium,
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` substituted benzimidazoles, or to any components of the drug product
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` including omeprazole. (4)
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`• History of asthma, urticaria, or other allergic-type reactions after taking
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` aspirin or other NSAIDs. (4)
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` In the setting of coronary artery bypass graft (CABG) surgery. (4)
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` In patients receiving rilpivirine-containing products. (4, 7)
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` -----------------------WARNINGSAND PRECAUTIONS-----------------------
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`• Hepatotoxicity: Inform patients of warning signs and symptoms of
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` hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if
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` clinical signs and symptoms of liver disease develop. (5.3)
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`• Hypertension: Patients taking some antihypertensive medications may have
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` pressure. (5.4, 7)
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`• Heart Failure and Edema: Avoid use of VIMOVO in patients with severe
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` heart failure unless benefits are expected to outweigh risk of worsening heart
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` failure. (5.5)
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`• Renal Toxicity: Monitor renal function in patients with renal or hepatic
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` impairment, heart failure, dehydration, or hypovolemia. Avoid use of
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` VIMOVO in patients with advanced renal disease unless benefits are
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` expected to outweigh risk of worsening renal function. (5.6)
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`• Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction
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`• Exacerbation of Asthma Related to Aspirin Sensitivity: VIMOVO is
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` contraindicated in patients with aspirin-sensitive asthma. Monitor patients
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` with preexisting asthma (without aspirin sensitivity). (5.8)
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`• Serious Skin Reactions: Discontinue VIMOVO at first appearance of skin
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` rash or other signs of hypersensitivity. (5.9)
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`• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS):
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` Discontinue and evaluate clinically (5.10)
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`• Fetal Toxicity: Limit use of NSAIDs, including VIMOVO, between about
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` 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal
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` dysfunction. Avoid use of NSAIDs in women at about 30 weeks gestation
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` dysfunction and premature closure of the fetal ductus arteriosus (5.11, 8.1)
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`• Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with
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` any signs of symptoms of anemia. (5.12, 7)
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`• Masking of Inflammation and Fever: Potential for diminished utility of
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` diagnostic signs in detecting infections. (5.13)
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`• Laboratory Monitoring: Obtain CBC and chemistry profile periodically during
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` treatment. Monitor hemoglobin periodically in patients on long-
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` treatment who have an initial value of 10 g or less. (5.14)
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`• Active Bleeding: Withdraw treatment in patients who experience active and
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` clinically significant bleeding. (5.15)
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`• Concomitant NSAID Use: Do not use VIMOVO with other naproxen­
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`• Gastric Malignancy: In adults, symptomatic response to esomeprazole does
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` not preclude the presence of gastric malignancy. Consider additional follow-
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` up and diagnostic testing. (5.17)
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`• Acute Tubulointerstitial Nephritis: Discontinue treatment and evaluate
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` patients. (5.18)
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`• Clostridium difficile-Associated Diarrhea: PPI therapy may be associated
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` with increased risk of Clostridium difficile associated diarrhea. (5.19)
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`• Bone Fracture: Long-term and multiple daily dose PPI therapy may be
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` associated with an increased risk for osteoporosis-related fractures of the hip,
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`• Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous, new onset
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` or exacerbation of existing disease; discontinue VIMOVO and refer to
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` specialist for evaluation. (5.21)
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` Interaction with Clopidogrel: Avoid concomitant use. (5.22, 7)
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`• Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g.,
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` longer than 3 years) may lead to malabsorption or a deficiency of
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` cyanocobalamin. (5.23)
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`• Hypomagnesemia and Mineral Metabolism: Reported rarely with prolonged
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` treatment with PPIs. (5.24)
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`Interaction with St. John’s Wort or Rifampin: Avoid concomitant use. (5.25,
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` 7)
` Interactions with Diagnostic Investigations for Neuroendocrine Tumors:
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` Increases in intragastric pH may result in hypergastrinemia,
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`•
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`

`

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`-----------------------------DRUG INTERACTIONS--------------------------------
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` See full prescribing information for a list of clinically important drug interactions.
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` (7)
` -----------------------USE IN SPECIFIC POPULATIONS-----------------------
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`• Females and Males of Reproductive Potential: NSAIDs are associated
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` with reversible infertility. Consider withdrawal of VIMOVO in women
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` who have difficulties conceiving. (8.3)
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` SEE 17 FOR PATIENT COUNSELING INFORMATION and FDA-
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` Approved Medication Guide
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` Revised: 03/2022
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` 5.25 Concomitant Use of St. John's Wort or Rifampin with VIMOVO
`5.26 Interactions with Diagnostic Investigations for Neuroendocrine
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` Tumors
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` 5.27 Concomitant Use of VIMOVO with Methotrexate
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` 5.28 Fundic Gland Polyps
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` ADVERSE REACTIONS
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` 6.1 Clinical Trials Experience
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` 6.2 Postmarketing Experience
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` DRUG INTERACTIONS
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` USE IN SPECIFIC POPULATIONS
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` 8.1 Pregnancy
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` 8.2 Lactation
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` 8.3 Females and Males of Reproductive Potential
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` 8.4 Pediatric Use
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` 8.5 Geriatric Use
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` 8.6 Hepatic Impairment
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` 8.7 Renal Impairment
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` 10 OVERDOSAGE
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` 11 DESCRIPTION
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` 12 CLINICAL PHARMACOLOGY
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` 12.1 Mechanism of Action
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` 12.2 Pharmacodynamics
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` 12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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` 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
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` 13.2 Animal Toxicology and/or Pharmacology
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` 14 CLINICAL STUDIES
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` 16 HOW SUPPLIED/STORAGE AND HANDLING
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` 17 PATIENT COUNSELING INFORMATION
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` *Sections or subsections omitted from the full prescribing information are
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`•
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` enterochromaffin-like cell hyperplasia, and increased Chromogranin A
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` neuroendocrine tumors. (5.26)
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` Interaction with Methotrexate: Concomitant use with PPIs may
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` elevate and/or prolong serum concentrations of methotrexate and/or
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` its metabolite, possibly leading to toxicity. (5.27, 7)
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`• Fundic Gland Polyps: Risk increases with long-term PPI use,
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` especially beyond one year. Use the shortest duration of therapy.
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` (5.28)
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` -----------------------------ADVERSE REACTIONS-------------------------------
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` Most common adverse reactions in clinical trials (>5%) are gastritis and
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` diarrhea. (6.1)
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` To report SUSPECTED ADVERSE REACTIONS, contact Horizon
` at 1-866-479-6742 or FDA at 1-800-FDA-1088 or
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` www.fda.gov/medwatch.
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` FULL PRESCRIBING INFORMATION: CONTENTS*
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`
` WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
`
`
`
` GASTROINTESTINAL EVENTS
`
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`
`
` INDICATIONS AND USAGE
`1
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` DOSAGE AND ADMINISTRATION
`2
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` 2.1 Important Administration Instructions
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` 2.2 Recommended Dosage
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` 2.3 Use in Renal Impairment or Hepatic Impairment
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` DOSAGE FORMS AND STRENGTHS
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`3
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` CONTRAINDICATIONS
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`4
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` 5 WARNINGS AND PRECAUTIONS
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` 5.1 Cardiovascular Thrombotic Events
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` 5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
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` 5.3 Hepatotoxicity
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` 5.4 Hypertension
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` 5.5 Heart Failure and Edema
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` 5.6 Renal Toxicity and Hyperkalemia
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` 5.7 Anaphylactic Reactions
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` 5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
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` 5.9 Serious Skin Reactions
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`5.10 Drug Reaction with Eosinophilia and Systemic Symptoms
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` (DRESS)
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` 5.11 Fetal Toxicity
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` 5.12 Hematologic Toxicity
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` 5.13 Masking of Inflammation and Fever
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` 5.14 Laboratory Monitoring
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` 5.15 Active Bleeding
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` 5.16 Concomitant NSAID Use
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` 5.17 Presence of Gastric Malignancy
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` 5.18 Acute Tubulointerstitial Nephritis
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` 5.19 Clostridium difficile-Associated Diarrhea
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` 5.20 Bone Fracture
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` 5.21 Cutaneous and Systemic Lupus Erythematosus
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` 5.22 Interaction with Clopidogrel
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` 5.23 Cyanocobalamin (Vitamin B-12) Deficiency
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` 5.24 Hypomagnesemia and Mineral Metabolism
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`Reference ID: 4947201
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`

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`FULL PRESCRIBING INFORMATION
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` WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
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` Cardiovascular Thrombotic Events
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` ▪ Non-Steroidal Anti-inflammatory Drugs (NSAIDs), a component of VIMOVO, cause an increased risk
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` of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be
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` fatal. This risk may occur early in treatment and may increase with duration of use [see Warnings and
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` Precautions (5.1)].
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` Contraindications (4), and Warnings and Precautions (5.1)].
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` Gastrointestinal Bleeding, Ulceration, and Perforation
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` ▪ NSAIDs, a component of VIMOVO cause an increased risk of serious gastrointestinal (GI) adverse
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` events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.
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` These events can occur at any time during use and without warning symptoms. Elderly patients and
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` GI events [see Warnings and Precautions (5.2)].
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` 1
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` INDICATIONS AND USAGE
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` VIMOVO, a combination of naproxen and esomeprazole magnesium, is indicated in adult and adolescent
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` patients 12 years of age and older weighing at least 38 kg, requiring naproxen for symptomatic relief of
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` • osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults.
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` juvenile idiopathic arthritis (JIA) in adolescent patients.
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` The esomeprazole magnesium component of VIMOVO is indicated to decrease the risk of developing
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` Limitations of Use:
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`• Do not substitute VIMOVO with the single-ingredient products of naproxen and esomeprazole
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`• VIMOVO is not recommended for initial treatment of acute pain because the absorption of
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` naproxen is delayed compared to absorption from other naproxen-containing products.
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`• Controlled studies do not extend beyond 6 months [see Use in Specific Populations (8.4), Clinical
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` Studies (14)].
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` DOSAGE AND ADMINISTRATION
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` Important Administration Instructions
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`• Use the lowest naproxen dose for the shortest duration consistent with individual patient
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` treatment goals [see Warnings and Precautions (5.1)].
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`• Carefully consider the potential benefits and risks of VIMOVO and other treatment
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` options before deciding to use VIMOVO.
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`• VIMOVO does not allow for administration of a lower daily dose of esomeprazole
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` magnesium. If a total daily dose of less than 40 mg esomeprazole is more appropriate, a
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` different treatment should be considered.
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`2
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`2.1
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`Reference ID: 4947201
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` Swallow VIMOVO tablets whole with liquid. Do not split, chew, crush or dissolve the
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` Patients should be instructed that if a dose is missed, it should be taken as soon as
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` missed dose, and should be instructed to take the next dose on time. Patients should be
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` instructed not to take 2 doses at one time to make up for a missed dose.
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`• Antacids may be used while taking VIMOVO.
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` Recommended Dosage
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` The recommended dosage of VIMOVO by indication is shown in the table:
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` Patient Population
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` Adults
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` Greater than 50 kg
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` Recommended Dosage
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` One VIMOVO tablet twice daily
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` of either:
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` 375 mg naproxen/20 mg of
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` esomeprazole; or
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` 500 mg naproxen/20 mg of
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` esomeprazole
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` One VIMOVO tablet twice daily
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` of: 375 mg naproxen/20 mg of
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` esomeprazole
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` Indication
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` Rheumatoid Arthritis,
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` Osteoarthritis, and
` Ankylosing Spondylitis
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` Juvenile Idiopathic
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` Arthritis in Adolescent
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` Patients 12 Years of Age
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` and Older and Weighing at
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` Least 38 kg
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` 38 kg to less than 50 kg
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` Use in Renal Impairment or Hepatic Impairment
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` Renal Impairment
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` Naproxen-containing products are not recommended for use in patients with moderate to severe
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` Precautions (5.6), Use in Specific Populations (8.7)].
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` Hepatic Impairment
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` Monitor patients with mild to moderate hepatic impairment closely and consider a possible dose
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` reduction based on the naproxen component of VIMOVO.
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` VIMOVO should be avoided in patients with severe hepatic impairment [see Warnings and
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` Precautions (5.3), Use in Specific Populations (8.6)].
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` DOSAGE FORMS AND STRENGTHS
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` VIMOVO is an oval, yellow, delayed-release tablets for oral administration containing either:
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` 375 mg enteric-coated naproxen and 20 mg immediate-release esomeprazole tablets
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` printed with 375/20 in black, or
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` 500 mg enteric-coated naproxen and 20 mg immediate-release esomeprazole tablets
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` printed with 500/20 in black.
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`•
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` CONTRAINDICATIONS
` VIMOVO is contraindicated in the following patients:
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`• Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to naproxen,
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` esomeprazole magnesium, substituted benzimidazoles, or to any components of the drug
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` product, including omeprazole. Hypersensitivity reactions to esomeprazole may include
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` anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis,
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` and urticaria [see Warnings and Precautions (5.7, 5.8, 5.9, 5.18), Adverse Reactions (6.2)].
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`2.2
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`2.3
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`3
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`4
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`Reference ID: 4947201
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`

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`•
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`• History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
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` Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such
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` In the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions
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` (5.1)].
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`• Proton pump inhibitors (PPIs), including esomeprazole magnesium, are
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` contraindicated in patients receiving rilpivirine-containing products [see Drug
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` Interactions (7)].
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`5
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`5.1
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` WARNINGS AND PRECAUTIONS
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` Cardiovascular Thrombotic Events
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` Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration
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` have shown an increased risk of serious cardiovascular (CV) thrombotic events, including
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` myocardial infarction (MI), and stroke, which can be fatal. Based on available data, it is unclear
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` that the risk for CV thrombotic events is similar for all NSAIDS. The relative increase in serious
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` CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with
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` and without known CV disease or risk factors for CV disease. However, patients with known CV
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` disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events,
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` serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV
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` thrombotic risk has been observed most consistently at higher doses.
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` To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest
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` previous CV symptoms. Patients should be informed about the symptoms of serious CV events
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` and the steps to take if they occur.
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` There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of
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` serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an
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` NSAID, such as naproxen, increases the risk of serious gastrointestinal (GI) events [see Warnings
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` and Precautions (5.2)].
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` Status Post Coronary Artery Bypass Graft (CABG) Surgery
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` Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the
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` first 10–14 days following CABG surgery found an increased incidence of myocardial infarction
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` and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4)].
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` Post-MI Patients
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` Observational studies conducted in the Danish National Registry have demonstrated that patients
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` death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the
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` incidence of death in the first year post-MI was 20 per 100-person years in NSAID-treated patients
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` compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute
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` in NSAID users persisted over at least the next four years after follow-up.
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` Avoid the use of VIMOVO in patients with a recent MI unless the benefits are expected to
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` recent MI, monitor patients for signs of cardiac ischemia.
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`5.2
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` Gastrointestinal Bleeding, Ulceration, and Perforation
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` NSAIDs, including naproxen, can cause serious gastrointestinal (GI) adverse events including
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` inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine,
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`Reference ID: 4947201
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`

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` or large intestine, which can be fatal. These serious adverse events can occur at any time, with
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` or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who
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` develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers,
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` gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients
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` treated for 3-6 months, and in about 2% to 4% of patients treated for one year. However, even
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` short-term NSAID therapy is not without risk.
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` Risk Factors for GI Bleeding, Ulceration, and Perforation
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` Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a
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` greater than 10-fold increased risk for developing a GI bleed compared to patients without these
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` risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs
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` include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin,
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` anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older
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` age; and poor general health status. Most postmarketing reports of fatal GI events are in elderly
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` or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are
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` at increased risk for GI bleeding.
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` Strategies to Minimize the GI Risks in NSAID-treated patients:
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`• Use the lowest effective dosage for the shortest possible duration.
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`• Avoid administration of more than one NSAID at a time.
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`• Avoid use in patients at higher risk unless benefits are expected to outweigh the increased
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` risk of bleeding. For such as patients, as well as those with active GI bleeding, consider
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` alternate therapies other than NSAIDs.
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`• Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
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`•
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` If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and
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` discontinue VIMOVO until a serious GI adverse event is ruled out.
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` In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor
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` patients more closely for evidence of GI bleeding [see Drug Interactions (7)].
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`•
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` NSAIDs should be given with care to patients with a history of inflammatory bowel disease
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`(ulcerative colitis, Crohn’s disease) as their condition may be exacerbated.
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`5.3
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` Hepatotoxicity
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` Elevations of ALT or AST (three or more times the upper limit of the normal [ULN]) have been
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` reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, and
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` sometimes fatal, cases of severe hepatic injury, including jaundice and fatal fulminant hepatitis,
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` liver necrosis, and hepatic failure have been reported.
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` Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients
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` Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue,
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`lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms).
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` If clinical signs and symptoms consistent with liver disease develop, or if systemic
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` manifestations occur (e.g., eosinophilia, rash, etc.), discontinue VIMOVO immediately, and
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` perform a clinical evaluation of the patient.
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` VIMOVO should be avoided in patients with severe hepatic impairment [see Dosage and
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` Administration (2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
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`5.4
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` Hypertension
` NSAIDs, including VIMOVO, can lead to new onset of hypertension or worsening of pre­
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` existing hypertension, either of which may contribute to the increased incidence of CV events.
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`Reference ID: 4947201
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`

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` Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazides diuretics, or loop
` diuretics may have impaired response to these therapies when taking NSAIDs [see Drug
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` Interactions (7)].
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` Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the
` course of therapy.
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`5.5
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