^ Clostridium Difficile-associated Diarrhea
Published observational studies suggest that PPI-containing therapy like ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA 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 TABLETSA appropriate to the condition being treated.
^ Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients, families, or caregivers of the following before initiating therapy with ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA and periodically during the course of ongoing therapy.
^ 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.
ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA 325 mg/40 mg was studied primarily in two randomized, double-blind controlled clinical trials (n=524) of 6 months duration. Table 1 lists adverse reactions that occurred in >2% of patients in the ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA arm and were more common than in the control arm, consisting of 325 mg of enteric coated (EC)-aspirin.
In Study 1 and Study 2 combined, 7% of patients taking ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA discontinued due to adverse reactions compared to 11% of patients taking EC-aspirin alone. The most common reasons for discontinuations due to adverse reactions in the ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA treatment group were upper abdominal pain (<1%, n=2), diarrhea (<1%, n=2) and dyspepsia (<1%, n=2).
^ Description
The active ingredients of ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA are aspirin which is an antiplatelet agent and omeprazole which is a PPI.
ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA (aspirin and omeprazole) is an oval, blue-green, multi-layer film-coated, delayed-release tablet consists of an enteric coated delayed-release aspirin core surrounded by an immediate-release omeprazole layer for oral administration. Each delayed-release tablet contains either 81 mg aspirin and 40 mg omeprazole printed with 81/40, or 325 mg aspirin and 40 mg omeprazole printed with 325/40.
The excipients used in the formulation of ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA are all inactive and United States Pharmacopeia/National Formulary (USP/NF) defined. The inactive ingredients in ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA include: carnauba wax, colloidal silicon dioxide, corn starch, FD&C Blue #2, glyceryl monostearate, hydroxypropyl methycellulose, methacrylic acid copolymer dispersion, microcrystalline cellulose, polydextrose, polyethylene glycol, polysorbate 80, povidone, pre-gelatinized starch, sodium phosphate dibasic anhydrous, stearic acid, talc, titanium dioxide, triacetin, triethyl citrate, yellow iron oxide.
Aspirin is acetylsalicylic acid and is chemically known as benzoic acid, 2-(acetyloxy). Aspirin is an odorless white needle-like crystalline or powdery substance. When exposed to moisture, aspirin hydrolyzes into salicylic and acetic acids and gives off a vinegary odor. It is highly lipid soluble and slightly soluble in water. Aspirin irreversibly inhibits platelet COX-1.
Omeprazole is a white to off-white crystalline powder which melts with decomposition at about 155°C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions.
Omeprazole is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H- benzimidazole, a compound that inhibits gastric acid secretion.
^ 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 TABLETSA were: gastric ulcer hemorrhage in one of the 521 patients treated with ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA 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 TABLETSA 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 TABLETSA, discontinue treatment.
^ Presence Of Gastric Malignancy
In adults, response to gastric symptoms with ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA 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 TABLETSA or have a symptomatic relapse after completing treatment. In older patients, also consider an endoscopy.
^ 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 TABLETSA.
^ 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 TABLETSA [see Drug Interactions (7)].
^ Hepatic Impairment
Long-term moderate to high doses of aspirin may result in elevations in serum ALT levels [see Warnings and Precautions (5.12)]. Systemic exposure to omeprazole is increased in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. Avoid ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA in patients with any degree of hepatic impairment.
^ 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 TABLETSA, in pregnant women starting at 30 weeks of gestation (third trimester). [see Use in Specific Populations (8.1)].
^ Overdosage
There is no clinical data on overdosage with ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA.
^ Renal Failure
Avoid ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA 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)].
^ 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.
^ Renal Impairment
No dose reduction of ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA is necessary in patients with mild to moderate renal impairment. Avoid ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA in patients with severe renal impairment (glomerular filtration rate less than 10 mL/minute) due to the aspirin component [see Warnings and Precautions (5.6), Clinical Pharmacology (12.3)].
^3 Dosage Forms And Strengths
Oval, blue-green, film-coated, delayed-release tablets for oral administration containing either:
^ Pediatric Use
The safety and efficacy of ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA has not been established in pediatric patients. ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA is contraindicated in pediatric patients with suspected viral infections, with or without fever, because of the risk of Reye's syndrome with concomitant use of aspirin in certain viral illnesses [see Contraindications (4)].
^4 Contraindications
ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA is contraindicated in:
^ 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 TABLETSA with St. John's Wort or rifampin [see Drug Interactions (7)].
^ 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 TABLETSA if acute interstitial nephritis develops [see Contraindications (4)].
^ How Supplied/storage And Handling
ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA (aspirin 81 mg/omeprazole 40 mg) and (aspirin 325 mg/omeprazole 40 mg) delayed-release tablets are oval, blue-green, film-coated tablets printed with 81/40 and 325/40 respectively in black ink. ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA tablets are packaged in high density polyethylene (HDPE) bottles with desiccants and are supplied as:
^ Geriatric Use
Of the total number of patients who received ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA (n=900) in clinical trials, 62% were ≥65 years of age and 15% were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience with aspirin and omeprazole has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].
^ Recommended Dosage
^ 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 TABLETSA, 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.
^ Carcinogenesis, Mutagenesis, Impairment Of Fertility
Studies to evaluate the potential effects of ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA on carcinogenicity, mutagenicity, or impairment of fertility have not been conducted.
^ Asian Population
In studies of healthy subjects, Asians had approximately a four-fold higher exposure to omeprazole than Caucasians. CYP2C19, a polymorphic enzyme, is involved in the metabolism of omeprazole. Approximately 15% to 20% of Asians are CYP2C19 poor metabolizers. Tests are available to identify a patient's CYP2C19 genotype. Avoid use in Asian patients with unknown CYP2C19 genotype or those who are known to be poor metabolizers [see Clinical Pharmacology (12.5)].
^ 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 TABLETSA 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 TABLETSA and periodically during treatment [see Adverse Reactions (6.2)].
^ Post-marketing Experience
The following adverse reactions have been identified during post-approval use of aspirin and omeprazole separately. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
^ Cyanocobalamin (vitamin B- ) 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 TABLETSA.
^7 Drug Interactions
Tables 2 and 3 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA and instructions for preventing or managing them.
Consult the labeling of concomitantly used drugs to obtain further information about interactions with omeprazole or aspirin.
^ Administration Instructions
^ 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 TABLETSA 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)].
^ 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 TABLETSA 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)].
^ Abnormal Laboratory Tests
Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time.
^ Pharmacogenomics
CYP2C19, a polymorphic enzyme, is involved in the metabolism of omeprazole. The CYP2C19*1 allele is fully functional while the CYP2C19*2 and *3 alleles are nonfunctional. There are other alleles associated with no or reduced enzymatic function. Patients carrying two fully functional alleles are extensive metabolizers and those carrying two loss-of-function alleles are poor metabolizers. In extensive metabolizers, omeprazole is primarily metabolized by CYP2C19. The systemic exposure to omeprazole varies with a patient's metabolism status: poor metabolizers > intermediate metabolizers > extensive metabolizers. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers.
In a pharmacokinetic study of single 20 mg omeprazole dose, the AUC of omeprazole in Asian subjects was approximately four-fold of that in Caucasians [see Use in Specific Populations (8.8)].
^ Interaction With Clopidogrel
Avoid concomitant use of ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA 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 TABLETSA, consider alternative anti-platelet therapy [see Drug Interactions (7), Clinical Pharmacology (12.3)].
^ 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 TABLETSA may be considered in some patients [see Drug Interactions (7)].
^1 Indications And Usage
ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA, a combination of aspirin and omeprazole, is indicated for patients who require aspirin for secondary prevention of cardiovascular and cerebrovascular events and who are at risk of developing aspirin associated gastric ulcers.
The aspirin component of ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA is indicated for:
The omeprazole component of ASPIRIN AND OMEPRAZOLE DELAYED-RELEASE TABLETSA is indicated for decreasing the risk of developing aspirin-associated gastric ulcers in patients at risk for developing aspirin-associated gastric ulcers due to age (≥ 55) or documented history of gastric ulcers.
^ 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.
^Principal Display Panel - Mg/ Mg Tablet Bottle Label
NDC 73457-415-80
30 tablets
aspirin and omeprazoledelayed-release tablets
81 mg/40 mg tablets
Dispense with accompanying Medication GuideDo not split, chew, crush, or dissolve the tablet.
Innovida Therapeutique Corporation
Rx only
^ Mechanism Of Action
Aspirin (acetylsalicylic acid) is an inhibitor of both prostaglandin synthesis and platelet aggregation. The differences in activity between aspirin and salicylic acid are thought to be due to the acetyl group on the aspirin molecule. This acetyl group is responsible for the inactivation of cyclo-oxygenase via acetylation.
Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the [H+/K+]-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.
^ 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 TABLETSA in patients with any degree of hepatic impairment [see Use in Specific Populations (8.7)].