`• New onset or worsening of pre-existing hypertension. Blood pressure
`
`
`should be monitored closely during treatment with VIMOVO (5.2, 7.1, 7.4)
`
`
`
`
`• Congestive heart failure and edema. VIMOVO should be used with caution
`
`in patients with fluid retention or heart failure (5.3)
`
`
`• Renal papillary necrosis and other renal injury with long term use. Use
`
`VIMOVO with caution in the elderly, those with impaired renal function,
`
`hypovolemia, salt depletion, heart failure, liver dysfunction, and those taking
`
`diuretics, or ACE-inhibitors. Not recommended for patients with moderate or
`
`severe renal impairment (2, 5.6, 5.7, 7.1, 7.4, 8.7)
`
`• Anaphylactoid reactions. Do not use VIMOVO in patients with the aspirin
`
`triad (5.8)
`
`• Serious skin adverse reactions such as exfoliative dermatitis, Stevens-
`Johnson syndrome, and toxic epidermal necrolysis, which can be fatal and can
`occur without warning. Discontinue VIMOVO at first appearance of skin rash
`
`
`or any other sign of hypersensitivity (5.9)
`
`• Long-term PPI therapy is associated with an increased risk for
`
`
`
`osteoporosis-related fractures of the hip, wrist or spine (5.16)
`
`• Symptomatic response to esomeprazole does not preclude the presence of
`
`gastric malignancy (5.4)
`
`• Atrophic gastritis has been noted on biopsy with long-term omeprazole
`
`therapy (5.4)
`---------------------------------ADVERSE REACTIONS--------------
`Most common adverse reactions in clinical trials (>5%): erosive gastritis,
`
`dyspepsia, gastritis, diarrhea, gastric ulcer, upper abdominal pain, nausea
`
`(6.1).
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca
`at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`----------------------------DRUG INTERACTIONS-----------
`
`• Concomitant use of NSAIDs may reduce the antihypertensive effect of
`
`
`ACE Inhibitors, diuretics, and beta-blockers (7.1, 7.4, 7.9)
`
`
`• Concomitant use of NSAIDs increases lithium plasma levels (7.5)
`
`• Concomitant use of VIMOVO with methotrexate may increase the toxicity
`
`
`of methotrexate (7.6)
`
`
`• Concomitant use of VIMOVO and warfarin may result in increased risk of
`
`
`bleeding complications. Monitor for increases in INR and prothrombin time
`
`(7.7)
`
`• Esomeprazole inhibits gastric acid secretion and may interfere with the
`
`
`absorption of drugs where gastric pH is an important determinant of
`bioavailability (eg, ketoconazole, iron salts and digoxin) (7.11)
`---------------------------USE IN SPECIFIC POPULATIONS-------
`
`• Pregnancy Category C: VIMOVO should not be used in late pregnancy (4,
`5.10, 8.1)
`
`
`• Hepatic Insufficiency: VIMOVO is not recommended in patients with
`
`severe hepatic insufficiency (2, 4, 5.11, 8.6, 12.3)
`
`
`• Renal Insufficiency: VIMOVO is not recommended in patients with
`moderate or severe renal insufficiency (2, 5.6, 5.7, 8.7, 12.3)
`
`
`SEE 17 FOR PATIENT COUNSELING INFORMATION AND FDA
`
`APPROVED PATIENT LABELING OR MEDICATION GUIDE
`
`
`
`REVISED MM/YYYY
`
`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
`
`Initial US Approval:
`
`
`WARNING: CARDIOVASCULAR AND GASTROINTESTINAL
`
`RISKS
`See full prescribing information for complete boxed warning
`Cardiovascular Risk
`
`
`• Naproxen, a component of VIMOVO, may cause an increased risk of
`
`
`
`serious cardiovascular thrombotic events, myocardial infarction, and
`
`stroke, which can be fatal. This risk may increase with duration of use.
`
`
`Patients with cardiovascular disease or risk factors for cardiovascular
`
`disease may be at greater risk. (5.1)
`
`
`
`• VIMOVO is contraindicated for the treatment of peri-operative pain in
`
`the setting of coronary artery bypass graft (CABG) surgery. (4, 5.1)
`
`Gastrointestinal Risk
`
`
`• NSAIDs, including naproxen, a component of VIMOVO, cause an
`
`increased risk of serious gastrointestinal 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 are at greater risk for serious
`
`gastrointestinal (GI) events. (5.4).
`
`-------------------------INDICATIONS AND USAGE-------------------------
`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 (1)
`
`------------------------DOSAGE AND ADMINISTRATION----------------­
`One tablet twice daily. Use the lowest effective dose. Not recommended in
`
`moderate/severe renal insufficiency or in severe hepatic insufficiency.
`
`
`Consider dose reduction in mild/moderate hepatic insufficiency (2)
`
`----------------------DOSAGE FORMS AND STRENGTHS----------------­
`Delayed release tablets: 375 mg/20 mg or 500 mg/20 mg of naproxen and
`
`esomeprazole magnesium (3)
`----------------------------CONTRAINDICATIONS-------------------------
`
`• Known hypersensitivity to any component of VIMOVO or substituted
`benzimidazoles (4)
`
`
`
`• History of asthma, urticaria, or other allergic-type reactions after taking
`
`aspirin or other NSAIDs (4, 5.8, 5.9, 5.13)
`
`• Use during the peri-operative period in the setting of coronary artery
`
`
` bypass graft (CABG) surgery (4, 5.1)
`
`
`
`• Late pregnancy (4, 5.10, 8.1)
`--------------------WARNINGS AND PRECAUTIONS----------------------
`
`
`• Serious and potentially fatal cardiovascular (CV) thrombotic events,
`myocardial infarction, and stroke. Patients with known CV disease/risk factors
`
`may be at greater risk (5.1)
`
`
`• Serious gastrointestinal (GI) adverse events, which can be fatal. The risk is
`greater in patients with a prior history of ulcer disease or GI bleeding, and in
`patients at high risk for GI events, especially the elderly. VIMOVO should be
`
`used with caution in these patients (5.4, 8.5)
`
`
`• Treatment should be withdrawn when active and clinically significant
`bleeding from any source occurs (5.5)
`
`• Elevated liver enzymes and, rarely, severe hepatic reactions. Discontinue
`use immediately if abnormal liver enzymes persist or worsen (5.11, 8.6, 12.3)
`
`_______________________________________________________________________________
`
`
`5.7
`Advanced Renal Disease ....................................................9
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`5.8
`Anaphylactoid Reactions....................................................9
`
`
`
`5.9
`Skin Reactions .....................................................................9
`
`
`
`5.10
`Pregnancy ..........................................................................10
`
`
`
`5.11
`Hepatic Effects...................................................................10
`
`
`
`5.12
`Hematological Effects .......................................................11
`
`
`
`5.13
`Preexisting Asthma ...........................................................11
`
`
`
`5.14
`Concomitant NSAID Use...................................................11
`
`
`
`5.15
`Corticosteroid Treatment..................................................11
`
`
`
`5.16
`Bone Fracture ....................................................................12
`
`
`
`5.17
`Masking of Inflammation and Fever.................................12
`
`
`
`5.18
`Laboratory Tests................................................................12
`
`
`
`ADVERSE REACTIONS .....................................................12
`
`6
`
`
`6.1
`Clinical Studies Experience..............................................12
`
`
`
`
`
`Cardiovascular Risk............................................................................. 4
`
`
`
`INDICATIONS AND USAGE................................................ 4
`
`1
`
`
`2
`DOSAGE AND ADMINISTRATION ..................................... 5
`
`
`
`
`3
`DOSAGE FORMS AND STRENGTHS ................................ 6
`
`
`
`4
`CONTRAINDICATIONS ....................................................... 6
`
`
`
`5
`WARNINGS AND PRECAUTIONS...................................... 6
`
`
`
`5.1
`Cardiovascular Thrombotic Events .................................. 6
`
`
`
`5.2
`Hypertension....................................................................... 7
`
`
`
`5.3
`Congestive Heart Failure and Edema ............................... 7
`
`
`5.4
`Gastrointestinal Effects — Risk of Ulceration, Bleeding,
`
`and Perforation.................................................................................. 7
`
`
`Active Bleeding................................................................... 9
`
`5.5
`
`
`5.6
`Renal Effects ....................................................................... 9
`
`
`

`

`
`
`Postmarketing experience ............................................... 16
`
`6.2
`
`
`DRUG INTERACTIONS ..................................................... 17
`
`7
`
`
`ACE-inhibitors................................................................... 17
`
`7.1
`
`
`Aspirin ............................................................................... 17
`
`7.2
`
`
`Cholestyramine................................................................. 18
`
`7.3
`
`
`Diuretics ............................................................................ 18
`
`7.4
`
`
`Lithium............................................................................... 18
`
`7.5
`
`
`Methotrexate ..................................................................... 18
`
`7.6
`
`
`Anticoagulants.................................................................. 18
`
`7.7
`
`
`Selective Serotonin Reuptake Inhibitors (SSRIs).......... 19
`
`7.8
`
`
`Other Information Concerning Drug Interactions.......... 19
`
`7.9
`
`
`
`Drug/Laboratory Test Interaction.................................... 19
`
`7.10
`
`
`Interactions related to absorption................................... 20
`
`7.11
`
`
`Antiretroviral agents......................................................... 20
`
`7.12
`
`7.13
`Effects on hepatic metabolism/cytochrome P-450
`
`
`pathways.......................................................................................... 21
`
`
`
`Other pharmacokinetic-based interactions.................... 21
`
`7.14
`
`
`USE IN SPECIFIC POPULATIONS ................................... 22
`
`8
`
`
`8.1
`Pregnancy ......................................................................... 22
`
`
`
`8.2
`Labor and Delivery ........................................................... 23
`
`
`
`8.3
`Nursing Mothers ............................................................... 23
`
`
`
`8.4
`Pediatric Use ..................................................................... 23
`
`
`
`8.5
`Geriatric Use ..................................................................... 23
`
`
`
`8.6
`Hepatic Insufficiency........................................................ 24
`
`
`
`8.7
`Renal Insufficiency ........................................................... 24
`
`
`
`OVERDOSAGE .................................................................. 24
`
`10
`
`
`11
`DESCRIPTION ................................................................... 26
`
`
`
`12
`CLINICAL PHARMACOLOGY........................................... 27
`
`
`
`12.1
`Mechanism of Action........................................................ 27
`
`
`
`12.2
`Pharmacodynamics.......................................................... 27
`
`
`
`12.3
`Pharmacokinetics ............................................................. 28
`
`
`
`NONCLINICAL TOXICOLOGY .......................................... 34
`
`13
`
`
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility . 34
`
`
`
`13.2
`Animal Toxicology and/or Pharmacology ...................... 35
`
`
`
`14
`CLINICAL STUDIES .......................................................... 36
`
`
`
`HOW SUPPLIED/STORAGE AND HANDLING ................ 38
`
`16
`
`
`17
`PATIENT COUNSELING INFORMATION ......................... 38
`
`*Sections or subsections omitted from the full prescribing information are
`
`
`not listed
`
`

`

`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`FULL PRESCRIBING INFORMATION
`
`3
`
`
`

`

`
`
`
`
`Cardiovascular Risk
`
`
`ƒ Non-Steroidal Anti-inflammatory Drugs (NSAIDs), a
`component of VIMOVO, may cause an increased risk
`of
`serious
`cardiovascular
`thrombotic
`events,
`
`myocardial infarction, and stroke, which can be fatal.
`
`This risk may increase with duration of use. Patients
`for
`with cardiovascular disease or
`risk
`factors
`
`cardiovascular disease may be at greater risk [see
`
`Warnings and Precautions (5.1)].
`
`ƒ VIMOVO is contraindicated for the treatment of peri­
`operative pain in the setting of coronary artery bypass
`
`graft (CABG) surgery [see Contraindications (4), and
`
`Warnings and Precautions (5.1)].
`
`
`
`
`Gastrointestinal Risk
`
`including naproxen, a component of
`ƒ NSAIDs,
`VIMOVO, cause an
`increased
`risk of serious
`gastrointestinal 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 are at greater risk for serious gastrointestinal
`events [see Warnings and Precautions (5.4)].
`
`
`
`1
`
`INDICATIONS AND USAGE
`VIMOVO is a combination product that contains naproxen
`
`and esomeprazole. It is indicated for the relief of signs and
`rheumatoid arthritis and
`symptoms of osteoarthritis,
`
`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.
`
`
`4
`
`
`

`

`
`
`2
`
`DOSAGE AND ADMINISTRATION
` Carefully consider the potential benefits and risks of
`
`VIMOVO and other treatment options before deciding to use
`VIMOVO. Use the lowest effective dose for the shortest
`duration consistent with individual patient treatment goals.
`
`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)].
`
`Patients With Moderate to Severe Renal Impairment
`Naproxen-containing products are not recommended for use
`in patients with moderate
`to severe or severe renal
`
`(creatinine clearance <30 mL/min).
`[see
`impairment
`
`
`Warnings and Precautions (5.6, 5.7) 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 is not recommended in patients with severe
`hepatic impairment because esomeprazole doses should not
`exceed 20 mg daily in these patients [see Warnings and
`
`
`Precautions (5.11), Use in Specific Populations (8.6) and
`Clinical Pharmacology (12.3)].
`
`
`Pediatric Patients
`
`5
`
`
`

`

`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
`Oval, yellow delayed release tablets for oral administration
`containing either:
`
` • 375 mg enteric coated naproxen and 20 mg
`
`esomeprazole (as magnesium
`trihydrate),
`tablets
`printed with 375/20 in black, or
`
` • 500 mg enteric coated naproxen and 20 mg
`
`esomeprazole (as magnesium
`trihydrate)
`tablets
`printed with 500/20 in black.
`
`
`
`3
`
`4
`
`
` CONTRAINDICATIONS
`in patients with known
`VIMOVO
`is contraindicated
`hypersensitivity
`to naproxen, esomeprazole magnesium,
`substituted benzimidazoles, or to any of the excipients.
`
`in patients who have
`is contraindicated
`VIMOVO
`experienced asthma, urticaria, or allergic-type reactions after
`
`taking aspirin or other NSAIDs. Severe, rarely fatal,
`anaphylactic-like reactions to NSAIDs have been reported in
`such patients [see Warnings and Precautions (5.8, 5.13)].
`
`Hypersensitivity reactions, eg, angioedema and anaphylactic
`reaction/shock, have been reported with esomeprazole use.
`
`VIMOVO is contraindicated for the treatment of peri­
`operative pain in the setting of coronary artery bypass graft
`(CABG) surgery [see Warnings and Precautions (5.1)].
`
`VIMOVO is contraindicated in patients in the late stages of
`pregnancy [see Warnings and Precautions (5.10) and Use in
`Specific Populations (8.1)].
`
`
`WARNINGS AND PRECAUTIONS
`5
`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, myocardial infarction, and stroke, which can be fatal.
`All NSAIDS, both COX-2 selective and nonselective, may
`have a similar risk. Patients with known CV disease or risk
`factors for CV disease may be at greater risk. To minimize
`the potential risk for an adverse CV event in patients treated
`with an NSAID, the lowest effective dose should be used for
`the shortest duration possible. Physicians and patients should
`remain alert for the development of such events, even in the
`6
`
`
`

`

`
`
`5.2
`
`absence of previous CV symptoms. Patients should be
`informed about the signs and/or 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.
`
`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 [see Contraindications (4)].
`
`
` Hypertension
`NSAIDs, including naproxen, a component of VIMOVO, can
`lead to onset of new hypertension or worsening of pre­
`existing hypertension, either of which may contribute to the
`increased incidence of CV events. Patients taking thiazides
`or loop diuretics may have impaired response to these
`therapies when taking NSAIDs. NSAIDs should be used
`with caution in patients with hypertension. Blood pressure
`(BP) should be monitored closely during the initiation of
`
`NSAID treatment and throughout the course of therapy [see
`Drug Interactions (7.1, 7.4)].
`
`5.3 Congestive Heart Failure and Edema
`Fluid retention, edema, and peripheral edema have been
`observed in some patients taking NSAIDs and should be used
`
`with caution in patients with fluid retention, or heart failure.
`
` Gastrointestinal Effects — Risk of Ulceration, Bleeding,
`and Perforation
`NSAIDs, including naproxen, a component of VIMOVO, can
`cause serious gastrointestinal (GI) adverse events including
`
`inflammation, bleeding, ulceration, and perforation of the
`stomach, small intestine, or large intestine, which can be
`
`fatal. While VIMOVO has been shown to significantly
`decrease the occurrence of gastric ulcers compared to
`
`naproxen alone, ulceration and associated complications can
`
`still occur.
`
`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
`
`occur in approximately 1% of patients treated for 3–6
`months, and in about 2–4% of patients treated for one year.
`
`These trends continue with longer duration of use, increasing
`the likelihood of developing a serious GI event at some time
`7
`
`
`5.4
`
`

`

`
`
`during the course of therapy. However, even short-term
`therapy is not without risk. The utility of periodic laboratory
`monitoring has not been demonstrated, nor has it been
`
`adequately assessed.
`
`VIMOVO should be prescribed with caution in those with a
`prior history of ulcer disease or gastrointestinal bleeding.
`
`Patients with a prior history of peptic ulcer disease and/or
`
`gastrointestinal bleeding who use NSAIDs have a greater
`than 10-fold increased risk of developing a GI bleed
`compared to patients with neither of these risk factors. Other
`factors that increase the risk for GI bleeding in patients
`treated with NSAIDs include concomitant use of oral
`corticosteroids or anticoagulants or antiplatelets (including
`low-dose aspirin), longer duration of NSAID therapy,
`
`smoking, use of alcohol, older age, and poor general health
`status. Most spontaneous reports of fatal GI events are in
`elderly or debilitated patients, and therefore special care
`should be taken in treating this population.
`
`To minimize the potential risk for an adverse GI event in
`
`patients treated with an NSAID or NSAID-containing
`product, the lowest effective dose should be used for the
`shortest possible duration. Patients and physicians should
`remain alert for signs and symptoms of GI ulceration and
`bleeding during NSAID therapy and promptly initiate
`additional evaluation and treatment if a serious GI adverse
`event is suspected. This should include discontinuation of
`the NSAID until a serious GI adverse event is ruled out. For
`high risk patients, alternate therapies that do not involve
`NSAIDs should be considered.
`
`Epidemiological studies of the case-control and cohort design
`have demonstrated an association between use of
`psychotropic drugs that interfere with serotonin reuptake and
`the occurrence of upper gastrointestinal bleeding. In two
`studies, concurrent use of an NSAID, COX-2 inhibitor, or
`aspirin potentiated the risk of bleeding [see Drug Interactions
`
`(7.2, 7.8)]. Although these studies focused on upper
`gastrointestinal bleeding, bleeding at other sites cannot be
`ruled out.
`
`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.
`
`therapy with
`to
`Gastrointestinal symptomatic response
`VIMOVO does not preclude
`the presence of gastric
`malignancy.
`
`
`8
`
`
`

`

`
`
`5.5
`
`Atrophic gastritis has been noted occasionally in gastric
`corpus biopsies from patients
`treated
`long-term with
`omeprazole, of which esomeprazole is an enantiomer and a
`component of VIMOVO.
`
`
` Active Bleeding
`When active and clinically significant bleeding from any
`source occurs in patients receiving VIMOVO, the treatment
`should be withdrawn.
`
`5.6 Renal Effects
`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, hypovolemia,
`heart failure, liver dysfunction, salt depletion, those taking
`elderly.
`diuretics
`and ACE
`inhibitors,
`and
`the
`
`Discontinuation of NSAID therapy is usually followed by
`recovery to the pretreatment state.
`
`5.7 Advanced Renal Disease
`No information is available from controlled clinical studies
`regarding the use of VIMOVO in patients with advanced
`
`renal disease. Therefore, treatment with VIMOVO is not
`recommended in these patients with advanced renal disease.
`
`If VIMOVO therapy must be initiated, close monitoring of
`the patient’s renal function is advisable [see Dosage and
`Administration (2), Use in Specific Populations (8.7) and
`Clinical Pharmacology (12.3)].
`
`5.8 Anaphylactoid Reactions
`Anaphylactoid reactions may occur in patients without
`known prior exposure to either component of VIMOVO.
`
`NSAIDs should not be given to patients with the aspirin triad.
`
`This symptom complex typically occurs in asthmatic patients
`
`who experience rhinitis with or without nasal polyps, or who
`exhibit severe, potentially fatal bronchospasm after taking
`aspirin or other NSAIDs [see Contraindications (4)].
`
`Emergency help should be sought in cases where an
`anaphylactoid reaction occurs. Anaphylactoid reactions, like
`
`anaphylaxis, may have a fatal outcome.
`
`5.9 Skin Reactions
`NSAIDs can cause serious skin adverse events such as
`
`exfoliative dermatitis, Stevens-Johnson Syndrome, and toxic
`9
`
`
`

`

`
`
`5.10
`
` epidermal necrolysis, which can be fatal. These serious
`
`events may occur without warning. Patients should be
`informed about the signs and symptoms of serious skin
`manifestations and use of the drug should be discontinued at
`
`the first appearance of skin rash or any other sign of
`
`hypersensitivity.
`
` Pregnancy
`
`Pregnancy Category C
`In late pregnancy, as with other NSAIDs, naproxen, a
`component of VIMOVO should be avoided because it may
`
`cause premature closure of the ductus arteriosus [see
`Contraindications (4), and Use in Specific Populations (8.1)].
`
`5.11 Hepatic Effects
`Borderline elevations of one or more liver tests may occur in
`
`up to 15% of patients taking NSAIDs including naproxen, a
`component of VIMOVO. Hepatic abnormalities may be the
`result of hypersensitivity rather than direct toxicity. These
`laboratory abnormalities may progress, may
`remain
`essentially unchanged, or may be transient with continued
`therapy. The SGPT (ALT) test is probably the most sensitive
`indicator of liver dysfunction. Notable elevations of ALT or
`AST (approximately three or more times the upper limit of
`
`normal) have been reported in approximately 1% of patients
`
`in clinical trials with NSAIDs. In addition, rare cases of
`severe hepatic reactions,
`including
`jaundice and fatal
`fulminant hepatitis, liver necrosis and hepatic failure, some
`
`of them with fatal outcomes, have been reported.
`
`A patient with symptoms and/or signs suggesting liver
`dysfunction, or in whom an abnormal liver test has occurred,
`should be evaluated for evidence of the development of more
`severe hepatic reaction while on therapy with VIMOVO.
`
`If clinical signs and symptoms consistent with liver disease
`
`(eg,
`develop, or
`if
`systemic manifestations occur
`
`eosinophilia, rash, etc.), VIMOVO should be discontinued.
`
`Chronic alcoholic liver disease and probably other diseases
`with decreased or abnormal plasma proteins (albumin) reduce
`the total plasma concentration of naproxen, but the plasma
`
`concentration of unbound naproxen is increased. Caution is
`advised when high doses are required and some adjustment
`of dosage may be required in these patients. It is prudent to
`use the lowest effective dose for the shortest possible
`duration of adequate treatment.
`
`Vimovo is not recommended in patients with severe hepatic
`impairment because esomeprazole doses should not exceed
`
`10
`
`
`

`

`
`
`5.12
`
`20 mg daily in these patients [see Dosage and Administration
`(2), and Use in Specific Populations (8.6)].
`
` Hematological Effects
`
` Anemia is sometimes seen in patients receiving NSAIDs.
`
`This may be due to fluid retention, occult or gross GI blood
`loss, or an incompletely described effect upon erythropoiesis.
`Patients on long-term treatment with NSAIDs, should have
`their hemoglobin or hematocrit checked if they exhibit any
`signs or symptoms of anemia.
`
`NSAIDs inhibit platelet aggregation and have been shown to
`prolong bleeding time in some patients. Unlike aspirin, their
`
`effect on platelet function is quantitatively less, of shorter
`duration, and reversible. Patients receiving VIMOVO who
`may be adversely affected by alterations in platelet function,
`such as those with coagulation disorders or patients receiving
`anticoagulants or antiplatelets, should be carefully monitored.
`
`5.13 Preexisting Asthma
`Patients with asthma may have aspirin-sensitive asthma. The
`use of aspirin in patients with aspirin-sensitive asthma has
`been associated with severe bronchospasm, which can be
`Since cross reactivity, including bronchospasm,
`fatal.
`
`between aspirin and other NSAIDs has been reported in such
`
`should not be
`aspirin-sensitive patients, VIMOVO
`administered to patients with this form of aspirin sensitivity
`and should be used with caution in patients with pre-existing
`asthma.
`
`5.14 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.
`
` Corticosteroid Treatment
`VIMOVO cannot be expected to substitute for corticosteroids
`or
`to
`treat
`corticosteroid
`insufficiency.
`Abrupt
`
`discontinuation of corticosteroids may lead to disease
`exacerbation. Patients on prolonged corticosteroid therapy
`
`should have their therapy tapered slowly if a decision is made
`to discontinue corticosteroids and the patient should be
`observed closely for any evidence of adverse effects,
`including adrenal
`insufficiency and exacerbation of
`symptoms of arthritis.
`
`
`
`5.15
`
`11
`
`

`

`
`
`5.16
`
`
`
` Bone Fracture
`Several studies and literature reports indicate that proton
`pump inhibitor (PPI) therapy is associated with an
`increased risk for osteoporosis-related fractures of the
`hip, wrist, or spine. Those patients with the highest risk
`received high-dose or long-term PPI therapy (a year or
`longer). Patients should use the lowest effective 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. Adequate vitamin D
`and calcium intake is recommended.
`
`
`5.177 Masking of Inflammation and Fever
`The pharmacological activity of VIMOVO in reducing fever
`and inflammation may diminish the utility of these diagnostic
`signs in detecting complications of presumed noninfectious,
`noninflammatory painful conditions.
`
`5.188 Laboratory Tests
`Because serious GI tract ulcerations and bleeding can occur
`without warning symptoms, physicians should monitor for
`signs or symptoms of GI bleeding. Patients on long-term
`
`treatment with NSAIDs should have their CBC and a
`
`chemistry profile checked periodically. If clinical signs and
`symptoms consistent with liver or renal disease develop,
`systemic manifestations occur (eg, eosinophilia, rash, etc.) or
`if abnormal liver tests persist or worsen, VIMOVO should be
`discontinued.
`
`Patients with initial hemoglobin values of 10 g or less who
`are to receive long-term therapy should have hemoglobin
`values determined periodically.
`
`6
` ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`Because clinical trials are conducted under widely varying
`
`conditions, adverse reaction rates observed in the clinical
`trials of a drug cannot be directly compared to rates in the
`clinical trials of another drug and may not reflect the rates
`observed in practice.
`
`The adverse reactions reported below are specific to the
`clinical trials with VIMOVO. See also the full prescribing
`
`information for naproxen and esomeprazole magnesium
`
`products.
`
`The safety of VIMOVO was evaluated in clinical studies
`involving 2317 patients (aged 27 to 90 years) and ranging
`12
`
`
`

`

`from 3-12 months. Patients received either 500 mg/20 mg of
`VIMOVO twice daily (n=1157), 500 mg of en