warnings and cautions
5 WARNINGS AND PRECAUTIONS Coagulation Abnormalities : Risk of increased bleeding time with aspirin, especially in patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders. Monitor patients for signs of increased bleeding. ( 5.1 ) GI Adverse Reactions (including ulceration and bleeding) : Monitor for signs and symptoms and discontinue treatment if bleeding occurs. ( 5.2 ) Bleeding Risk with Use of Alcohol : Avoid heavy alcohol use (three or more drinks every day). ( 5.3 ) Reduction in Antiplatelet Activity with Clopidogrel due to Interference with CYP2C19 Metabolism : Consider other antiplatelet therapy. ( 5.4 , 7 ) Reduction in Efficacy of Ticagrelor : Avoid use with the 325/40 strength of aspirin and omeprazole delayed-release tablets. ( 5.5 , 7 ) Renal Failure : Avoid aspirin and omeprazole delayed-release tablets in patients with severe renal failure. ( 5.6 , 8.6 ) Gastric Malignancy : In adults, response to gastric symptoms does not preclude the presence of gastric malignancy; Consider additional follow-up and diagnostic testing. ( 5.7 ) Acute Interstitial Nephritis : Observed in patients taking PPIs. ( 5.8 ) Clostridium difficile -Associated Diarrhea : PPI therapy may be associated with increased risk; use lowest dose and shortest duration of treatment. ( 5.9 ) Bone Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine; use lowest dose and shortest duration of treatment. ( 5.10 ) Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue aspirin and omeprazole delayed-release tablets and refer to specialist for evaluation. ( 5.11 ) Hepatic Impairment : Avoid aspirin and omeprazole delayed-release tablets in patients with all degrees of hepatic impairment. ( 5.12 , 8.7 ) Cyanocobalamin (Vitamin B-12) Deficiency : Daily long-term use (e.g., longer than 3 years) of PPI may lead to malabsorption or deficiency. ( 5.13 ) Hypomagnesemia : Reported rarely with prolonged treatment with PPIs; consider monitoring magnesium levels. ( 5.14 ) Reduced Effect of Omeprazole with St. John's Wort or Rifampin : Avoid concomitant use. ( 5.15 , 7 ) Interactions with Diagnostic Investigations for Neuroendocrine Tumors : Increased Chromogranin A (CgA) levels may interfere with diagnostic investigations for neuroendocrine tumors; temporarily stop aspirin and omeprazole delayed-release tablets at least 14 days before assessing CgA levels ( 5.16 , 7 ) Bone Marrow Toxicity with Methotrexate, especially in the elderly or renally impaired : Use with PPIs may elevate and/or prolong serum levels of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate, consider a temporary withdrawal of aspirin and omeprazole delayed-release tablets. ( 5.17 , 7 ) Premature closure of the ductus arteriosus : Avoid use in pregnant women starting at 30 weeks gestation. ( 5.18 , 8.1 ) Abnormal Laboratory Tests : Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. ( 5.19 ) Fundic Gland Polyps : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy. ( 5.20 ) 5.1 Coagulation Abnormalities Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding disorders. Monitor patients for signs of increased bleeding. 5.2 Gastrointestinal Adverse Reactions Aspirin is associated with serious gastrointestinal (GI) adverse reactions, including inflammation, bleeding ulceration and perforation of the upper and lower GI tract. Other adverse reactions with aspirin include stomach pain, heartburn, nausea, and vomiting. Serious GI adverse reactions reported in the clinical trials of aspirin and omeprazole delayed-release tablets were: gastric ulcer hemorrhage in one of the 521 patients treated with aspirin and omeprazole delayed-release tablets and duodenal ulcer hemorrhage in one of the 524 patients treated with enteric-coated aspirin. In addition, there were two cases of intestinal hemorrhage, one in each treatment group, and one patient treated with aspirin and omeprazole delayed-release tablets experienced obstruction of the small bowel. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, monitor patients for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Inform patients about the signs and symptoms of GI adverse reactions. If active and clinically significant bleeding from any source occurs in patients receiving aspirin and omeprazole delayed-release tablets, discontinue treatment. 5.3 Bleeding Risk with Use of Alcohol Counsel patients who consume three or more alcoholic drinks every day about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin and omeprazole delayed-release tablets. 5.4 Interaction with Clopidogrel Avoid concomitant use of aspirin and omeprazole delayed-release tablets with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that interfere with CYP2C19 activity. Co-administration of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using aspirin and omeprazole delayed-release tablets, consider alternative anti-platelet therapy [see Drug Interactions (7) , Clinical Pharmacology (12.3) ]. 5.5 Interaction with Ticagrelor Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor in preventing thrombotic cardiovascular events. Avoid concomitant use of ticagrelor with the 325 mg/40 mg tablet strength of aspirin and omeprazole delayed-release tablets [see Drug Interactions (7) ]. 5.6 Renal Failure Avoid aspirin and omeprazole delayed-release tablets in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute). Regular use of aspirin is associated in a dose-dependent manner with an increased risk of chronic renal failure. Aspirin use decreases glomerular filtration rate and renal blood flow especially with patients with pre-existing renal disease. [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. 5.7 Presence of Gastric Malignancy In adults, response to gastric symptoms with aspirin and omeprazole delayed-release tablets does not preclude the presence of gastric malignancy. Consider additional gastrointestinal follow-up and diagnostic testing in adult patients who experience gastric symptoms during treatment with aspirin and omeprazole delayed-release tablets or have a symptomatic relapse after completing treatment. In older patients, also consider an endoscopy. 5.8 Acute Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including omeprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue aspirin and omeprazole delayed-release tablets if acute interstitial nephritis develops [see Contraindications (4) ]. 5.9 Clostridium difficile -Associated Diarrhea Published observational studies suggest that PPI-containing therapy like aspirin and omeprazole delayed-release tablets may be associated with an increased risk of Clostridium difficile -associated diarrhea (CDAD), especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2) ]. Use the lowest dose and shortest duration of aspirin and omeprazole delayed-release tablets appropriate to the condition being treated. 5.10 Bone Fracture Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Use the lowest dose and shortest duration of aspirin and omeprazole delayed-release tablets therapy appropriate to the condition being treated. Manage patients at risk for osteoporosis-related fractures according to established treatment guidelines [see Adverse Reactions (6.2) ]. 5.11 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematous cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE), and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly.Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI associated SLE is usually milder than non-drug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment, but some cases occurred days or years after initiating treatment. SLE occurred primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving aspirin and omeprazole delayed-release tablets, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serologicial testing (e.g., ANA) may be positive and elevated serologicial test results may take longer to resolve than clinical manifestations. 5.12 Hepatic Impairment Long-term moderate to high doses of aspirin may result in elevations in serum ALT levels. These abnormalities resolve rapidly with discontinuation of aspirin. The hepatotoxicity of aspirin is usually mild and asymptomatic. Bilirubin elevations are usually mild or absent. Systemic exposure to omeprazole is increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) ]. Avoid aspirin and omeprazole delayed-release tablets in patients with any degree of hepatic impairment [see Use in Specific Populations (8.7) ]. 5.13 Cyanocobalamin (Vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with aspirin and omeprazole delayed-release tablets. 5.14 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 aspirin and omeprazole delayed-release tablets with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), consider monitoring magnesium levels prior to initiation of aspirin and omeprazole delayed-release tablets and periodically during treatment [see Adverse Reactions (6.2) ]. 5.15 Reduced Effect of Omeprazole with St. John's Wort or Rifampin Drugs which induce the CYP2C19 or CYP3A4 (such as St. John's Wort or rifampin) can substantially decrease concentrations of omeprazole. Avoid concomitant use of aspirin and omeprazole delayed-release tablets with St. John's Wort or rifampin [see Drug Interactions (7) ] . 5.16 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to omeprazole-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic interventions for neuroendocrine tumors. Temporarily discontinue treatment with aspirin and omeprazole delayed-release tablets at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Drug Interactions (7) and Clinical Pharmacology (12.2) ]. 5.17 Interaction with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of aspirin and omeprazole delayed-release tablets may be considered in some patients [see Drug Interactions (7) ]. 5.18 Premature Closure of Fetal Ductus Arteriosus NSAIDs including aspirin, may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including aspirin and omeprazole delayed-release tablets, in pregnant women starting at 30 weeks of gestation (third trimester). [see Use in Specific Populations (8.1) ] . 5.19 Abnormal Laboratory Tests Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. 5.20 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.