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warnings and cautions
5 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 VIMOVO should be used with caution in these patients (5.4, 8.5) • Treatment should be withdrawn when active and clinically significant bleeding from any source occurs (5.5) • Elevated liver enzymes and, rarely, severe hepatic reactions.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) • Should be avoided in patients with severe hepatic impairment (e.g., Childs-Pugh C) • 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) • 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. (5.18) • Hypomagnesemia has been reported rarely with prolonged treatment with PPIs (5.19) • Avoid concomitant use of VIMOVO with St John’s Wort or rifampin due to the potential reduction in esomeprazole levels. (5.20, 7.16) 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 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) ]. 5.2 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. 5.4 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 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. Gastrointestinal symptomatic response to therapy with VIMOVO does not preclude the presence of gastric malignancy. 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. 5.5 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 diuretics and ACE inhibitors, and the elderly. 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 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. 5.10 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 develop, or if systemic manifestations occur (eg, 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 should be avoided in patients with severe hepatic impairment [see Dosage and Administration (2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) ]. 5.12 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 Pre-existing 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 fatal. Since cross reactivity, including bronchospasm, between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, VIMOVO should not be 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. 5.15 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. 5.16 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. 5.17 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. 5.18 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. Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop esomeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Pharmacodynamics (12.2) ]. 5.19 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. [see Adverse Reactions (6.2) ] 5.20 Concomitant use of St John's Wort or Rifampin with VIMOVO Drugs that induce CYP2C19 or CYP3A4 (such as St John’s Wort or rifampin) can substantially decrease esomeprazole concentrations. Avoid concomitant use of VIMOVO with St John’s Wort or rifampin [see Drug Interactions (7.15)].