HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
` VIMOVO safely and effectively. See full prescribing information for
`
`
`
`
` VIMOVO.
`
`
`VIMOVO (naproxen and esomeprazole magnesium) delayed-release
`
`
`
`
`tablets, for oral use
`
`
`Initial US Approval: 2010
`
`
`
` 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)
`
`• 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)
`
`
`
`
`----------------------------RECENT MAJOR CHANGES------------------------­
`• Active Bleeding: Withdraw treatment in patients who experience active
`
`
`
`
`
`
`
`
`
`5/2016
`Boxed Warning
`and clinically significant bleeding. (5.14)
`
`
`
`
`
`
`Dosage and Administration (2)
`5/2016
`• Concomitant NSAID Use: Do not use VIMOVO with other naproxen­
`
`
`
`
`
`
`5/2016
`Contraindications (4)
`containing products or other non-aspirin NSAIDs. (5.15)
`
`
`
`
`
`Warnings and Precautions, Cardiovascular Thrombotic
`• Gastric Malignancy: In adults, symptomatic response to esomeprazole
`
`
`
`
`
`
`Events (5.1)
`5/2016
`does not preclude the presence of gastric malignancy. Consider additional
`
`
`
`
`
`
`Warnings and Precautions, Gastrointestinal Bleeding, Ulceration,
`follow-up and diagnostic testing. (5.16)
`
`
`
`
`
`
`And Perforation (5.2)
`5/2016
`• Acute Interstitial Nephritis: Observed in patients taking PPIs. (5.17)
`
`
`
`
`
`
`
`
`
`Warnings and Precautions, Atrophic Gastritis (5.17), removed 10/2016
`• Clostridium difficile-Associated Diarrhea: PPI therapy may be associated
`
`
`
`
`
`
`Warnings and Precautions, Cutaneous and Systemic Lupus
`with increased risk of Clostridium difficile associated diarrhea. (5.18)
`
`
`
`
`
`
`
`Erythematosus (5.20)
`10/2016
`• Bone Fracture: Long-term and multiple daily dose PPI therapy may be
`
`
`
`associated with an increased risk for osteoporosis-related fractures of the
`
`
`---------------------------INDICATIONS AND USAGE--------------------------­
`hip, wrist or spine. (5.19)
`
`
`
`
`
`VIMOVO is a fixed combination of naproxen, a non-steroidal anti-
`• Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous, new
`
`
`
`
`
`
`
`inflammatory drug, and esomeprazole, a proton pump inhibitor (PPI)
`onset or exacerbation of existing disease; discontinue VIMOVO and refer
`
`
`
`
`
`
`indicated for the relief of signs and symptoms of osteoarthritis, rheumatoid
`to specialist for evaluation. (5.20)
`
`
`
`
`
`
`arthritis, and ankylosing spondylitis and to decrease the risk of developing
`• Interaction with Clopidogrel: Avoid concomitant use. (5.21, 7)
`
`
`
`
`
`
`
`gastric ulcers in patients at risk of developing NSAID associated gastric
`• Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g.,
`
`
`
`
`ulcers. (1)
`longer than 3 years) may lead to malabsorption or a deficiency of
`
`
`
`Limitations of Use:
`cyanocobalamin. (5.22)
`
`
`
`
`
`
`
`VIMOVO is not interchangeable with the individual components of
`
`•
`• Hypomagnesemia: Reported rarely with prolonged treatment with PPIs.
`
`
`
`
`
`naproxen and esomeprazole magnesium. (1)
`(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)
`
`
`
`
`
`
`-----------------------------ADVERSE REACTIONS------------------------------­
`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.
`
`
`
`
`
`----------------------------DRUG INTERACTIONS------------------------------­
`
`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)
`
`
`
`
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION---------------------­
`
`One tablet twice daily. Should be avoided in moderate/severe renal
`
`
`
`insufficiency or in severe hepatic insufficiency. Consider dose reduction in
`
`
`
`mild/moderate hepatic insufficiency. (2)
`
`
`• Use the lowest effective dose for the shortest duration consistent with
`
`
`
`
`individual patient treatment goals. (2).
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS--------------------­
`
`
`VIMOVO delayed-release tablets (3):
`
`
`
`
`375 mg enteric-coated naproxen /20 mg immediate-release
`
`•
`
`
`esomeprazole magnesium
`
`
`
`
`500 mg enteric-coated naproxen /20 mg immediate-release
`
`
`esomeprazole magnesium.
`
`
`•
`
`
`
`-----------------------------CONTRAINDICATIONS-----------------------------­
`
`
`• 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)
`
`-----------------------WARNINGS AND PRECAUTIONS----------------------­
`
`• 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)
`
`
`
`
`
`
`Reference ID: 4010746
`
`

`

` • Females and Males of Reproductive Potential: NSAIDs are associated
`
`
`
`
`with reversible infertility. Consider withdrawal of VIMOVO in women
`
`who have difficulties conceiving. (8.3)
`
`
`
`
`
`SEE 17 FOR PATIENT COUNSELING INFORMATION and FDA-
`
`Approved Medication Guide
`
`
`Revised October 2016
`
`
`
`6
`
`
`7
`
`8
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`
`
`5.24 Concomitant Use of St. John's Wort or Rifampin with VIMOVO
`
`5.25 Interaction with Diagnostic Investigations for Neuroendocrine Tumors
`
`
`
`5.26 Concomitant Use of VIMOVO with Methotrexate
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2 Postmarketing Experience
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Lactation
`
`
`
`8.3 Females and Males of Reproductive Potential
`
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic Insufficiency
`
`8.7 Renal Insufficiency
`
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`CLINICAL STUDIES
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`PATIENT COUNSELING INFORMATION
`
`
`
`14
`
`16
`
`17
`
`*Sections or subsections omitted from the full prescribing information are not
`
`
`listed
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: RISK OF SERIOUS CARDIOVASCULAR AND
`
`
`GASTROINTESTINAL EVENTS
`
`
`INDICATIONS AND USAGE
`1
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`3
`DOSAGE FORMS AND STRENGTHS
`
`
`4
`CONTRAINDICATIONS
`
`
`5
`WARNINGS AND PRECAUTIONS
`
`
`5.1 Cardiovascular Thrombotic Events
`
`
`
`5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
`
`
`
`5.3 Hepatotoxicity
`
`
`5.4 Hypertension
`
`
`5.5 Heart Failure and Edema
`
`
`5.6 Renal Toxicity and Hyperkalemia
`
`
`5.7 Anaplyactic Reactions
`
`
`5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
`
`
`
`
`
`5.9 Serious Skin Reactions
`
`
`5.10 Premature Closure of the Fetal Ductus Arteriosus
`
`
`5.11 Hematologic Toxicity
`
`
`5.12 Masking of Inflammation and Fever
`
`
`
`5.13 Laboratory Monitoring
`
`5.14 Active Bleeding
`
`5.15 Concomitant NSAID Use
`
`
`5.16 Presence of Gastric Malignancy
`
`
`
`5.17 Acute Interstitial Nephritis
`
`
`5.18 Clostridium difficile-Associated Diarrhea
`
`
`
`5.19 Bone Fracture
`
`
`5.20 Cutaneous and Systemic Lupus Erythematosus
`
`
`
`5.21 Interaction with Clopidogrel
`
`
`
`
`5.22 Cyanocobalamin (Vitamin B-12) Deficiency
`
`
`5.23 Hypomagensemia
`
`
`
`
`
`Reference ID: 4010746
`
`

`

`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`
` WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS
`
`
`
`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)].
`
`
`
`
`
` 1
`
`
`
`2
`
`
`
`
`
`
`
`
` INDICATIONS AND USAGE
`
`
`
` VIMOVO is a combination product that contains naproxen and esomeprazole. It is indicated for
` the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis
`
`
` and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID-
`
`
` associated gastric ulcers. 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.
`
`
`
`
`
` Limitations of Use:
`
`
`
`
`VIMOVO is not interchangeable with the individual components of naproxen and esomeprazole
`
`
`magnesium.
`
`
`DOSAGE AND ADMINISTRATION
`
`
`
` Use the lowest dose for the shortest duration consistent with individual patient treatment goals
`
` [see Warnings and Precautions (5.1)]. Carefully consider the potential benefits and risks of
`
`
`
`
`
`
` VIMOVO and other treatment options before deciding to use VIMOVO. VIMOVO does not
`
`
` allow for administration of a lower daily dose of esomeprazole. If a dose of esomeprazole lower
`
`
`
` than a total daily dose of 40 mg is more appropriate, a different treatment should be considered.
`
`
`
`Rheumatoid Arthritis, Osteoarthritis and Ankylosing Spondylitis
`
`The dosage is one tablet twice daily of VIMOVO 375 mg naproxen and 20 mg of esomeprazole
`
`
`
`or 500 mg naproxen and 20 mg of esomeprazole.
`
`
`
`The tablets are to be swallowed whole with liquid. Do not split, chew, crush or dissolve the tablet.
`
`VIMOVO is to be taken at least 30 minutes before meals.
`
`
`
`Geriatric Patients
`
`Studies indicate that although total plasma concentration of naproxen is unchanged, the unbound
`
`plasma fraction of naproxen is increased in the elderly. Use caution when high doses are required
`
`
`and some adjustment of dosage may be required in elderly patients. As with other drugs used in
`
`the elderly use the lowest effective dose [see Use in Specific Populations (8.5) and Clinical
`
`
`
`
`
`Pharmacology (12.3)].
`
`
`
`
`
`
`Reference ID: 4010746
`
`

`

`
`
`
`
`Patients with Moderate to Severe Renal Impairment
`
`Naproxen-containing products are not recommended for use in patients with moderate to severe
`
`or severe renal impairment (creatinine clearance <30 mL/min) [see Warnings and Precautions
`
`
`
`
`
`(5.6) and Use in Specific Populations (8.7)].
`
`
`
`Hepatic Insufficiency
`
`
`
`Monitor patients with mild to moderate hepatic impairment closely and consider a possible dose
`
`
`reduction based on the naproxen component of VIMOVO.
`
`
`VIMOVO should be avoided in patients with severe hepatic impairment [see Warnings and
`
`
`Precautions (5.3), Use in Specific Populations (8.6)].
`
`
`
`Pediatric Patients
`
`
`The safety and efficacy of VIMOVO in children younger than 18 years has not been established.
`
`
`
`VIMOVO is therefore not recommended for use in children.
`
`
` 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 magnesium
`
`
` tablets printed with 375/20 in black, or
`
` • 500 mg enteric-coated naproxen and 20 mg immediate-release esomeprazole magnesium
`
`
` tablets printed with 500/20 in black.
`
`
`
`
`
`
`
`
`
`•
`
`
`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)].
`
`
`
`
` WARNINGS AND PRECAUTIONS
` 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
`
`
`
`
`
`
`
`
`
` 3
`
`4
`
`
` 5
`
`
` 5.1
`
`
`
`
`
`
`Reference ID: 4010746
`
`

`

`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`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.
`
`
`
`
`5.2
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`Reference ID: 4010746
`
`

`

`
`•
`
`
`•
`
`
`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.
`
`
`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)].
`
`
`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.
`
`
`
`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.
`
`
`
`Renal Toxicity and Hyperkalemia
`
`Renal Toxicity
`
`
`
`
`5.3
`
`
`
`
`
`
`
`5.4
`
`
`5.5
`
`
`
`
`5.6
`
`
`
`
`Reference ID: 4010746
`
`

`

`
`
`
`
`
`
` 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.
`
`
`
`
`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.
`
`
`
`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.
`
`
`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)].
`
`
`
`
`
`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)].
`
`
`
`
`
`
`
`
`
`5.7
`
`
`5.8
`
`
`5.9
`
`
`5.10
`
`
`
`
`Reference ID: 4010746
`
`

`

`
`
`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.
`
`
`
`Presence of Gastric Malignancy
`
`
`
`
`
`
`