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` HIGHLIGHTS OF PRESCRIBING INFORMATION
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` These highlights do not include all the information needed to use
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` YOSPRALA® safely and effectively. See full prescribing information for
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` YOSPRALA.
` YOSPRALA (aspirin and omeprazole) delayed-release tablets, for oral
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` use
` Initial US Approval: 2016
`
`
` -------------------------RECENT MAJOR CHANGES---------------------------­
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`
` Warnings and Precautions,
` Acute Tubulointerstitial Nephritis (5.8)
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` 11/2020
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`
` -----------------------------INDICATIONS AND USAGE-------------------------­
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`
` YOSPRALA is a combination of aspirin, an anti-platelet agent, and
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` omeprazole, a proton pump inhibitor (PPI), indicated for patients who require
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` aspirin for secondary prevention of cardiovascular and cerebrovascular events
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` and who are at risk of developing aspirin associated gastric ulcers.
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` Reduction in Antiplatelet Activity with Clopidogrel due to Interference
` with CYP2C19 Metabolism: Consider other antiplatelet therapy. (5.4, 7)
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` Reduction in Efficacy of Ticagrelor: Avoid use with the 325/40 strength
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` of YOSPRALA. (5.5, 7)
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` Renal Failure: Avoid YOSPRALA in patients with severe renal failure.
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` (5.6, 8.6)
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` Gastric Malignancy: In adults, response to gastric symptoms does not
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` preclude the presence of gastric malignancy; Consider additional follow-
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` up and diagnostic testing. (5.7)
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` Acute Tubulointerstitial Nephritis: Discontinue treatment and evaluate
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` patients. (5.8)
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` Clostridium difficile-Associated Diarrhea: PPI
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` therapy may be
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` associated with increased risk; use lowest dose and shortest duration of
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` treatment. (5.9)
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` Bone Fracture: Long-term and multiple daily dose PPI therapy may be
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` associated with an increased risk for osteoporosis-related fractures of the
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` hip, wrist or spine; use lowest dose and shortest duration of treatment.
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` (5.10)
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` Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new
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` onset or exacerbation of existing disease; discontinue YOSPRALA and
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` refer to specialist for evaluation. (5.11)
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` Hepatic Impairment: Avoid YOSPRALA in patients with all degrees of
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` hepatic impairment. (5.12, 8.7)
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` Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g.,
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` longer than 3 years) of PPI may lead to malabsorption or deficiency.
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` (5.13)
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` Hypomagnesemia: Reported rarely with prolonged treatment with PPIs;
` consider monitoring magnesium levels. (5.14)
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` Reduced Effect of Omeprazole with St. John’s Wort or Rifampin: Avoid
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` concomitant use. (5.15, 7)
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` Interactions with Diagnostic Investigations for Neuroendocrine Tumors:
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` Increased Chromogranin A (CgA) levels may interfere with diagnostic
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` investigations for neuroendocrine tumors; temporarily stop YOSPRALA
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` at least 14 days before assessing CgA levels (5.16, 7)
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` Bone Marrow Toxicity with Methotrexate, especially in the elderly or
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` renally impaired: Use with PPIs may elevate and/or prolong serum
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` levels of methotrexate and/or its metabolite, possibly leading to toxicity.
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` With high dose methotrexate, consider a temporary withdrawal of
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` YOSPRALA. (5.17, 7)
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` Premature closure of the ductus arteriosus: Avoid use in pregnant
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` women starting at 30 weeks gestation. (5.18, 8.1)
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` Abnormal Laboratory Tests: Aspirin has been associated with elevated
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` hepatic enzymes, blood urea nitrogen and serum creatinine,
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` hyperkalemia, proteinuria, and prolonged bleeding time. (5.19)
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` Fundic Gland Polyps: Risk increases with long-term use, especially
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` beyond one year. Use the shortest duration of therapy. (5.20)
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`•
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` To report SUSPECTED ADVERSE REACTIONS, contact Pharm-Olam
` at 1-866-511-6754 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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`---------------------------------DRUG INTERACTIONS---------------------------­
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` See full prescribing information for a list of clinically important drug
` interactions. (7)
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`
` ------------------------USE IN SPECIFIC POPULATIONS--------------------­
`•
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` Lactation: Breastfeeding not recommended. (8.2)
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`•
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` Females and Males of Reproductive Potential Infertility: NSAIDs are
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` associated with
` reversible
` infertility. Consider withdrawal of
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` YOSPRALA in women who have difficulties conceiving. (8.3)
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` See 17 for PATIENT COUNSELING INFORMATION and Medication
`
` Guide.
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`
` Revised: 11/2020
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`
`
` --------------------------------ADVERSE REACTIONS---------------------------­
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` Most common adverse reactions in adults (≥ 2%) are: gastritis, nausea,
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` diarrhea, gastric polyps, and non-cardiac chest pain. (6.1)
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` The aspirin component of YOSPRALA is indicated for:
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`•
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` reducing the combined risk of death and nonfatal stroke in patients who
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` have had ischemic stroke or transient ischemia of the brain due to fibrin
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` platelet emboli,
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` reducing the combined risk of death and nonfatal MI in patients with a
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` previous MI or unstable angina pectoris,
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` reducing the combined risk of MI and sudden death in patients with
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` chronic stable angina pectoris,
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` use in patients who have undergone revascularization procedures
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` (Coronary Artery Bypass Graft [CABG] or Percutaneous Transluminal
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`
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` Coronary Angioplasty [PTCA]) when there is a pre-existing condition
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` for which aspirin is already indicated.
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` The omeprazole component of YOSPRALA is indicated for decreasing the
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` risk of developing aspirin associated gastric ulcers in patients at risk for
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` developing aspirin-associated gastric ulcers due to age (≥ 55) or documented
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` history of gastric ulcers. (1)
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` Limitations of Use:
`•
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` Not for use as the initial dose of aspirin therapy during onset of acute
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` coronary syndrome, acute myocardial infarction or before percutaneous
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` coronary intervention. (1)
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` Has not been shown to reduce the risk of gastrointestinal bleeding due to
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` aspirin. (1)
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` Do not substitute YOSPRALA with the single-ingredient products of
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` aspirin and omeprazole. (1)
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`•
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`•
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` -------------------------DOSAGE AND ADMINISTRATION--------------------­
`•
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` Recommended dosage: One tablet daily at least 60 minutes before a
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` meal. (2.1, 2.2)
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` Do not split, chew, crush or dissolve the tablet. (2.2)
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`•
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` ----------------------DOSAGE FORMS AND STRENGTHS-------------------­
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` Delayed-Release Tablets (3):
`•
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` 81 mg delayed-release aspirin/40 mg immediate-release omeprazole
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`•
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` 325 mg delayed-release aspirin/40 mg immediate-release omeprazole
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`
`
`--------------------------------CONTRAINDICATIONS---------------------------­
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`•
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` History of asthma, urticaria, or other allergic-type reactions after taking
` aspirin or other NSAIDs. (4)
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` In pediatric patients with suspected viral infections, with or without
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` fever, because of the risk of Reye's Syndrome. (4)
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` Known hypersensitivity to aspirin, omeprazole, substituted
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` benzimidazoles or to any of the excipients of YOSPRALA. (4)
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` Patients receiving rilpivirine-containing products. (4, 7)
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`•
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`•
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`•
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` ------------------------WARNINGS AND PRECAUTIONS----------------------­
`•
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` Coagulation Abnormalities: Risk of increased bleeding time with
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` aspirin, especially in patients with inherited (hemophilia) or acquired
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` (liver disease or vitamin K deficiency) bleeding disorders. Monitor
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` patients for signs of increased bleeding. (5.1)
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` GI Adverse Reactions (including ulceration and bleeding): Monitor for
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` signs and symptoms and discontinue treatment if bleeding occurs. (5.2)
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` Bleeding Risk with Use of Alcohol: Avoid heavy alcohol use (three or
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` more drinks every day). (5.3)
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`•
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`•
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` FULL PRESCRIBING INFORMATION: CONTENTS*
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` 1
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` 2
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` 3
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` 4
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` 5
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` INDICATIONS AND USAGE
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` DOSAGE AND ADMINISTRATION
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` 2.1 Recommended Dosage
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` 2.2 Administration Instructions
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` 6
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` 7
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` 8
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` ADVERSE REACTIONS
`
` 6.1 Clinical Studies Experience
`
` 6.2 Post-Marketing Experience
`
`DRUG INTERACTIONS
`
` USE IN SPECIFIC POPULATIONS
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` 8.1 Pregnancy
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` 8.2
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` Lactation
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` 8.3 Females and Males of Reproductive Potential
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` DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
` WARNINGS AND PRECAUTIONS
`
` 5.1 Coagulation Abnormalities
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` 8.4 Pediatric Use
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` 5.2 GI Adverse Reactions
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` 5.3 Bleeding Risk with Use of Alcohol
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` 5.4
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` 5.5
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` Interaction with Clopidogrel
`
` Interaction with Ticagrelor
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` 5.6 Renal Failure
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` 5.7 Presence of Gastric Malignancy
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` 5.8 Acute Tubulointerstitial Nephritis
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` 5.9 Clostridium difficile-Associated Diarrhea
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`
`Reference ID: 4707980
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` 8.5 Geriatric Use
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` 8.6 Renal Impairment
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` 8.7 Hepatic Impairment
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` 8.8 Asian Population
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`

`

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` 10
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` 12
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` 14
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` 16
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` 17
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`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
` 12.1 Mechanism of Action
`
` 12.2 Pharmacodynamics
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` 12.3 Pharmacokinetics
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` 12.5 Pharmacogenomics
`
`NONCLINICAL TOXICOLOGY
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
` 13.2 Animal Toxicology and/or Pharmacology
`
`CLINICAL STUDIES
`
` HOW SUPPLIED/STORAGE AND HANDLING
`
` PATIENT COUNSELING INFORMATION
`
`
`
`
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` *Sections or subsections omitted from the full prescribing information are
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`
`
` not listed.
`
`
`
`5.10 Bone Fracture
`
`
`
`5.11 Cutaneous and Systemic Lupus Erythematosus
`
`
`
`
`
`
`5.12 Hepatic Impairment
`
`
`
`5.13 Cyanocobalamin (Vitamin B-12) Deficiency
`
`
`
`
`
`5.14 Hypomagnesemia
`
`
`5.15 Reduced Effect of Omeprazole with St. John's Wort or
`
`
`
`
`
`
`
`
`
`
`
` Rifampin
`
`
`
` 5.16
`
`
`
` Interactions with Diagnostic Investigations for
`
`
` Neuroendocrine Tumors
`
`
`
`
`
`
`5.17
`
` Interaction with Methotrexate
`
`
`
`5.18 Premature Closure of the Fetal Ductus Arteriosus
`
`
`
`
`
`
`
`5.19 Abnormal Laboratory Tests
`
`
`
`
`5.20 Fundic Glad Polyps
`
`
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`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4707980
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
`
`
`
`
`
` YOSPRALA, 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 YOSPRALA is indicated for:
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
` reducing the combined risk of death and nonfatal stroke in patients who have had
`ischemic stroke or transient ischemia of the brain due to fibrin platelet emboli,
`
`
`
`
`
` reducing the combined risk of death and nonfatal MI in patients with a previous MI or
`unstable angina pectoris,
`
`
` reducing the combined risk of MI and sudden death in patients with chronic stable
`angina pectoris,
`
`• use in patients who have undergone revascularization procedures (Coronary Artery
`
`
`
`
`
` Bypass Graft [CABG] or Percutaneous Transluminal Coronary Angioplasty [PTCA])
`
`
`
` when there is a pre-existing condition for which aspirin is already indicated.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` The omeprazole component of YOSPRALA 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.
`
`
`
`
`
` Limitations of Use:
`• YOSPRALA contains a delayed-release formulation of aspirin and it is not for use as
`
`
`
`
`
`
`
`
` the initial dose of aspirin therapy during onset of acute coronary syndrome, acute
`
`
`
`
`
`
` myocardial infarction or before percutaneous coronary intervention (PCI), for which
`
`
`
` immediate-release aspirin therapy is appropriate.
`
`• YOSPRALA has not been shown to reduce the risk of gastrointestinal bleeding due to
`
`
`
`
`
` aspirin.
`• Do not substitute YOSPRALA with the single-ingredient products of aspirin and
`
`
`
`
`omeprazole.
`
`
`
` 2
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
` 2.1 Recommended Dosage
`• Take one tablet daily.
`
`
`• YOSPRALA is available in combinations that contain 81 mg or 325 mg of aspirin.
`
`
`
` Generally 81 mg of aspirin has been accepted as an effective dose for secondary
`
`
`
`
`
` cardiovascular prevention. Providers should consider the need for 325 mg and refer to
`
`
` current clinical practice guidelines.
`
`
`
` 2.2 Administration Instructions
`
`• Take YOSPRALA once daily at least 60 minutes before a meal.
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`
`
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`
`
`• The tablets are to be swallowed whole with liquid. Do not split, chew, crush or dissolve the
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`
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`
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` tablet.
`
`• Use the lowest effective dose of YOSPRALA based on the individual patient’s treatment
`
`
`
`
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` goals and to avoid potential dose dependent adverse reactions including bleeding.
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`
`
` If a dose of YOSPRALA is missed, advise patients to take it as soon as it is remembered. If
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` it is almost time for the next dose, skip the missed dose. Take the next dose at the regular
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` time. Patients should not take 2 doses at the same time unless advised by their doctor.
`
`• Do not stop taking YOSPRALA suddenly as this could increase the risk of heart attack or
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`
`
`
` stroke.
`
`•
`
`
`
`
` 3
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` DOSAGE FORMS AND STRENGTHS
`
` Oval, blue-green, film-coated, delayed-release tablets for oral administration containing either:
`
`• 81 mg delayed-release aspirin and 40 mg immediate-release omeprazole, printed with
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`
`
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` 81/40, or
`• 325 mg delayed-release aspirin and 40 mg immediate-release omeprazole, printed with
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` 325/40.
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`
` 4
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`
`
` CONTRAINDICATIONS
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`
`
` YOSPRALA is contraindicated in:
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`3
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`Reference ID: 4707980
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`

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`• Patients with known allergy to aspirin and other nonsteroidal anti-inflammatory drug
`
`
`products (NSAIDs) and in patients with the syndrome of asthma, rhinitis, and nasal polyps.
` Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma).
`
`• 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.
`
`• YOSPRALA is contraindicated in patients with known hypersensitivity to aspirin,
`
`
`
` omeprazole, substituted benzimidazoles, or to any of the excipients in the formulation.
`
`
`
`
` Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema,
`
`
` tubulointerstitial nephritis, and urticaria [see Warnings and
`
`
`bronchospasm, acute
`
` Precautions (5.8), Adverse Reactions (6.2)].
`• Proton pump
`
` including YOSPRALA, are
`(PPI)–containing products,
`inhibitor
`
`
`
` contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions
`
` (7)].
`
`
`
` WARNINGS AND PRECAUTIONS
`
` 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.
`
`
`
` Gastrointestinal Adverse Reactions
`including
`
`
` is associated with serious gastrointestinal (GI) adverse reactions,
`
`Aspirin
`
` inflammation, bleeding ulceration and perforation of the upper and lower GI tract. Other
`
`
`
` adverse reactions with aspirin include stomach pain, heartburn, nausea, and vomiting.
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`
`
` Serious GI adverse reactions reported in the clinical trials of YOSPRALA were: gastric ulcer
`
` hemorrhage in one of the 521 patients treated with YOSPRALA 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 YOSPRALA experienced obstruction of the small bowel.
`
`
` Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime
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`
`
`
`
`
` 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.
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`
`
`
` If active and clinically significant bleeding from any source occurs in patients receiving
`
`
`
` YOSPRALA, discontinue treatment.
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`
` Bleeding Risk with Use of Alcohol
`
`
`
` Counsel patients who consume three or more alcoholic drinks every day about the bleeding
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`
`
` risks involved with chronic, heavy alcohol use while taking YOSPRALA.
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`
` 5
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`
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` 5.1
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` 5.2
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` 5.3
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` 5.4
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` 5.5
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` 5.6
`
`
` Interaction with Clopidogrel
` Avoid concomitant use of YOSPRALA with clopidogrel. Clopidogrel is a prodrug. Inhibition
`
`
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`
`
`
`
`
`
`
`
` 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 YOSPRALA, consider alternative anti-platelet
`
`
`
`
` therapy [see Drug Interactions (7), Clinical Pharmacology (12.3)].
`
`
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`
`
`
` 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 YOSPRALA [see Drug Interactions (7)].
`
`
`
` Renal Failure
`
`
`
`
` Avoid YOSPRALA 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)].
`
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` 5.7
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`
`
`
` Presence of Gastric Malignancy
`
`
`
`
`
` In adults, response to gastric symptoms with YOSPRALA does not preclude the presence of
`
`
` gastric malignancy. Consider additional gastrointestinal follow-up and diagnostic testing in
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`4
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`Reference ID: 4707980
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`

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` adult patients who experience gastric symptoms during treatment with YOSPRALA or have a
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`
`
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` symptomatic relapse after completing treatment. In older patients, also consider an endoscopy.
`
`
` 5.8 Acute Tubulointerstitial Nephritis
`
`
` Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may
` occur at any point during PPI therapy. Patients may present with varying signs and symptoms
`
`
`
`
`
` from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal
`
`
` function (e.g., malaise, nausea, anorexia).
` In reported case series, some patients were
`
`
`
`
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` diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or
`
`
`
`
` arthralgia).
`
` Discontinue YOSPRALA and evaluate patients with
` Contraindications (4)].
`
`5.9 Clostridium difficile-Associated Diarrhea
`
`
`
`
`
` Published observational studies suggest that PPI-containing therapy like YOSPRALA 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)].
`
`
`
`
`
`
`
`
` suspected acute TIN
`
`
`
`
`
` [see
`
`
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`
`
` Use the lowest dose and shortest duration of YOSPRALA 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
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`
`
`
`
` term PPI therapy (a year or longer). Use the lowest dose and shortest duration of YOSPRALA
` 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
`
`
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`
` PPI-induced lupus erythematous cases were CLE.
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`
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` 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
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`
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` 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
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` occurred days or years after initiating treatment. SLE occurred primarily in patients ranging
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` from young adults to the elderly. The majority of patients presented with rash; however,
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` arthralgia and cytopenia were also reported.
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`
`
` Avoid administration of PPIs for longer than medically indicated. If signs or symptoms
`
`
` consistent with CLE or SLE are noted in patients receiving YOSPRALA, 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
`
`
`
`
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` 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 YOSPRALA in patients with any degree of hepatic impairment
`
`
`
`
`
`
` [see Use in Specific Populations (8.7)].
`
`
`5.13 Cyanocobalamin (Vitamin B-12) Deficiency
`
`
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` Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer
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` than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or
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`
`
` achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing
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`5
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`Reference ID: 4707980
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` therapy have been reported in the literature. This diagnosis should be considered if clinical
`
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`
`
`
`
` symptoms consistent with cyanocobalamin deficiency are observed in patients treated with
`
` YOSPRALA.
`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
`
`
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` required magnesium replacement and discontinuation of the PPI. For patients expected to be on
`
`
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`
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` prolonged treatment or who take YOSPRALA with medications such as digoxin or drugs that
`
`
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` may cause hypomagnesemia (e.g., diuretics), consider monitoring magnesium levels prior to
`
`
`
`
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` initiation of YOSPRALA and periodically during treatment [see Adverse Reactions (6.2)].
`
`
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`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 YOSPRALA
`
`
`
` with St. John’s Wort or rifampin [see Drug Interactions (7)].
`
`
`
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`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 YOSPRALA
`
`
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` at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels
`
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` 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)
`
`
`
`
`
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` 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
`
`
`
`
`
` YOSPRALA 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
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`
`
` use of NSAIDs, including YOSPRALA, 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.
`
`
`
`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.
`
`
`
` YOSPRALA 325 mg/40 mg was studied primarily in two randomized, double-blind controlled
`
`
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`
`
`
`
`
`
` clinical trials (n=524) of 6 months duration. Table 1 lists adverse reactions that occurred in
` >2% of patients in the YOSPRALA arm and were more common than in the control arm,
`
`
`
`
`
`
`
` consisting of 325 mg of enteric coated (EC)-aspirin.
`
`
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`
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`
`
`
`
` Table 1: Most Common Adverse Reactions in Study 1 and Study 2*
`
`
`
`
`
`
`
`Preferred Term
`
`
`Gastritis
`
`Nausea
`
` YOSPRALA
`
`325 mg/40 mg
`
`once daily
`
`(n=521)
`
`%
`
`18
`
`3
`
` EC-Aspirin
`
`325 mg once
`daily
`
`(n=524)
`
`%
`
`16
`
`2
`
`
`
`
`
`
`
` 6
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`Reference ID: 4707980
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`

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`
`
`2
`3
`Diarrhea
`
`
`
`1
`2
`Gastric polyps
`
`
`
`1
`2
`Non-cardiac chest pain
` *Adverse reactions occurring in ≥2% of YOSPRALA-treated patients and more common than in the control arm
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
` In Study 1 and Study 2 combined, 7% of patients taking YOSPRALA 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 YOSPRALA treatment group were
`
`
`
`
`
`
`upper abdominal pain (<1%, n=2), diarrhea (<1%, n=2) and dyspepsia (<1%, n=2).
`
`
` Less Common Adverse Reactions
`
` In YOSPRALA-treated patients in the clinical trials there were 2 patients with upper GI
`
`
` bleeding (gastric or duodenal) and 2 patients with lower GI bleeding (hematochezia and large
`
`intestinal hemorrhage) and one additional patient experienced obstruction in the small bowel.
`
` See also the full prescribing information of aspirin and omeprazole products for additional
`
`
`
` 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.
`
`Aspirin
`
`
`Body as a Whole: Fever, hypothermia, thirst
`
`
`
`
` Cardiovascular: Dysrhythmias, hypotension, tachycardia
`
`
`
` Central Nervous System: Agitation, cerebral edema, coma, confusion, dizziness, headache,
`
`
`
`
` subdural or intracranial hemorrhage, lethargy, seizures
`
`
`
` Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis
`
`
`
`
` Gastrointestinal: Dyspepsia, GI bleeding, ulceration and perforation, nausea, vomiting,
`
`
` transient elevations of hepatic enzymes, hepatitis, Reye's Syndrome [see Contraindications
`
`
`
`
` (4)], pancreatitis
`
`
`
` Hematologic: Prolongation of the prothrombin time, disseminated intravascular coagulation,
`
` coagulopathy, thrombocytopenia
`
`
`
`
`
` Hypersensitivity: Acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema,
`
` urticaria
`
`
`
` Musculoskeletal: Rhabdomyolysis
`
`
`
` Metabolism: Hypoglycemia (in pediatrics), hyperglycemia
`
`
`
` Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants,
`
` antepartum and postpartum bleeding
`
`
`
`
`
` Respiratory: Hyperpnea, pulmonary edema, tachypnea
`
`
` Special Senses: Hearing loss, tinnitus. Patients with high frequency hearing loss may have
`
`
`
`
` difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of
`
`
`
`
`
` salicylism.
`
`
`
` Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal impairment and failure
`
`
`
`
`
`
`
`
` Omeprazole
`
` Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock,
`
`
` angioedema, bronchospasm [see Contraindications (4)], interstitial nephritis, urticaria (see also
`
`
`
`
`
` Skin below), systemic lupus erythematosus, fever, pain, fatigue, malaise
`
`
`
`
`
`Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood
`
` pressure, peripheral edema
`
` Endocrine: Gynecomastia
`
`
`
` Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration,
`
` esophageal candidiasis, mucos