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` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` 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
`
`
` use
` Initial US Approval: 2016
`
`
` -------------------------RECENT MAJOR CHANGES---------------------------­
`
`
` Warnings and Precautions,
`
` 11/2020
`
`
`
` Acute Tubulointerstitial Nephritis (5.8)
`
`
` 04/2021
`
` Warnings and Precautions: Fetal Toxicity (5.19)
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` Warnings and Precautions: Drug Reaction with Eosinophilia and 04/2021
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` Systemic Symptoms (DRESS) (5.19)
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`•
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`•
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`•
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` -----------------------------INDICATIONS AND USAGE-------------------------­
`
` 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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`•
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`•
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`•
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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,
`
`
`
`
`
`
`
` reducing the combined risk of death and nonfatal MI in patients with a
`
`
`
` 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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`
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` chronic stable angina pectoris,
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` 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
`
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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
`
`
`
` coronary syndrome, acute myocardial infarction or before percutaneous
`
`
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`
`
`
`
` coronary intervention. (1)
`
`
` Has not been shown to reduce the risk of gastrointestinal bleeding due to
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`
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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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`•
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`•
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`•
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`•
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`•
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` Reduction in Antiplatelet Activity with Clopidogrel due to Interference
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` 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
`
` 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
`
`
` patients.(5.8)
`
` Clostridium difficile-Associated Diarrhea: PPI 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.,
`
`
` 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:
`
` 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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` Fetal Toxicity: Limit use of NSAIDs, including YOSPRALA, between
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` about 20 to 30 weeks in pregnancy due to the risk of
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` oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs in
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` women at about 30 weeks gestation and later in pregnancy due to the
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` risks of oligohydramnios/fetal renal dysfunction and premature closure
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` of the fetal ductus arteriosus (5.18, 8.1)
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` Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS):
`
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`
`
` Discontinue and evaluate clinically (5.19)
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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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`
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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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`
`•
`
`
`•
`
`
`
` --------------------------------ADVERSE REACTIONS---------------------------­
` 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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`
` 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.
`
`
`
`
`
`
`
`
`
`
`---------------------------------DRUG INTERACTIONS---------------------------­
`
`
`
`
`
`
`
`
`
`
` See full prescribing information for a list of clinically important drug
` interactions. (7)
`
`
`
`
`
`
`
`
`
`
` ------------------------USE IN SPECIFIC POPULATIONS--------------------­
`•
`
` Lactation: Breastfeeding not recommended. (8.2)
`
`
`
`
`
`•
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Revised: 04/2021
`
`
`
` -------------------------DOSAGE AND ADMINISTRATION--------------------­
`•
`
` Recommended dosage: One tablet daily at least 60 minutes before a
`
`
`
`
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`
`
`
`
`
`
` meal. (2.1, 2.2)
`
`
` Do not split, chew, crush or dissolve the tablet. (2.2)
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`
`•
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`
`
` ----------------------DOSAGE FORMS AND STRENGTHS-------------------­
`
`
`
` Delayed-Release Tablets (3):
`•
`
`
`
`
`
` 81 mg delayed-release aspirin/40 mg immediate-release omeprazole
`
`
`
`•
`
` 325 mg delayed-release aspirin/40 mg immediate-release omeprazole
`
`
`
`
`
`
`
`
`
`
`--------------------------------CONTRAINDICATIONS---------------------------­
`
`•
`
`
`
`
`
`
`
`
`
`
`
` History of asthma, urticaria, or other allergic-type reactions after taking
` aspirin or other NSAIDs. (4)
`
`
`
`
`
`
`
` In pediatric patients with suspected viral infections, with or without
`
`
`
` fever, because of the risk of Reye's Syndrome. (4)
`
`
`
`
`
`
`
`
`
` Known hypersensitivity to aspirin, omeprazole, substituted
`
`
`
`
`
` benzimidazoles or to any of the excipients of YOSPRALA. (4)
`
`
`
`
`
`
`
` Patients receiving rilpivirine-containing products. (4, 7)
`
`
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`
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`
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`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
` ------------------------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)
`
`
`
`
`
`•
`
`
`•
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1
`
`
`
` 2
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` 3
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` 4
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` 5
`
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`
` INDICATIONS AND USAGE
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosage
`
`
`
`2.2 Administration Instructions
`
`
`
`
`
`
`
`
`
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
` WARNINGS AND PRECAUTIONS
`
`
`5.1 Coagulation Abnormalities
`
`
`5.2 GI Adverse Reactions
`
`
`
`
`5.3 Bleeding Risk with Use of Alcohol
`
`
`
`
`
`
`
`5.4
`
` Interaction with Clopidogrel
`
`5.5
`
` Interaction with Ticagrelor
`
`
`5.6 Renal Failure
`
`
`5.7 Presence of Gastric Malignancy
`
`
`
`
`
`5.8 Acute Tubulointerstitial Nephritis
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4786757
`
`5.9 Clostridium difficile-Associated Diarrhea
`
`
`
`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 Fetal Toxicity
`
`
`
`
`
`
`
`
`
`
`
` 5.19 Drug Reaction with Eosinophilia and Systemic
`
`
`
`
`
` Symptoms (DRESS)
`5.20 Abnormal Laboratory Tests
`
`
`
`5.21 Fundic Gland Polyps
`
`
`
`
`
`
` ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`
`
`
`
`
`
`
`
`
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`
`
`
`
` 6
`
`
`
`

`

`
`
` 12
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` 13
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`
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` 14
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` 16
`
`
`
` 17
`
`
`CLINICAL PHARMACOLOGY
`
` 12.1 Mechanism of Action
`
` 12.2 Pharmacodynamics
`
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`
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`
`
`
`
` 12.3 Pharmacokinetics
`
`
`
`
`
`
` 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.
`
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`
`
`
`
`
`
` 6.2 Post-Marketing Experience
`
`DRUG INTERACTIONS
`
` USE IN SPECIFIC POPULATIONS
`
`
`
`
`
`
`
`
`
` 8.1 Pregnancy
`
`
`
`
`
` 8.2
`
`
`
` Lactation
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 8.3 Females and Males of Reproductive Potential
`
` 8.4 Pediatric Use
`
` 8.5 Geriatric Use
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 8.6 Renal Impairment
` 8.7 Hepatic Impairment
`
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`
` 7
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` 8
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` 10
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` 11
`
`
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`
`
`
`
` 8.8 Asian Population
`
`OVERDOSAGE
`
`DESCRIPTION
`
`Reference ID: 4786757
`
`

`

`
`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.
`
`
`
`
`
`
`• The tablets are to be swallowed whole with liquid. Do not split, chew, crush or dissolve the
`
`
`
`
`
`
` tablet.
`
`• Use the lowest effective dose of YOSPRALA based on the individual patient’s treatment
`
`
`
`
`
` goals and to avoid potential dose dependent adverse reactions including bleeding.
`
`
`
` If a dose of YOSPRALA is missed, advise patients to take it as soon as it is remembered. If
`
`
`
`
`
`
` it is almost time for the next dose, skip the missed dose. Take the next dose at the regular
`
`
`
`
` 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
`
`
`
`
`
` stroke.
`
`•
`
`
`
`
` 3
`
` 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
`
`
`
`
` 81/40, or
`• 325 mg delayed-release aspirin and 40 mg immediate-release omeprazole, printed with
`
`
`
`
` 325/40.
`
`
`
` 4
`
`
`
` CONTRAINDICATIONS
`
`
`
` YOSPRALA is contraindicated in:
`
`
`
`
`
`
`
`3
`
`
`
`Reference ID: 4786757
`
`

`

`• 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,
`
` bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and
`
` Precautions (5.8), Adverse Reactions (6.2)].
`• Proton pump inhibitor (PPI)–containing products, including YOSPRALA, are
`
`
` 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
`
`
` 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 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
`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
`
`
`
` YOSPRALA, discontinue treatment.
`
` 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 YOSPRALA.
`
`
` Interaction with Clopidogrel
`
` Avoid concomitant use of YOSPRALA 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 YOSPRALA, consider alternative anti-platelet therapy [see Drug
`
`
`
` Interactions (7), Clinical Pharmacology (12.3)].
`
`
` 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)].
`
`
`
`
` 5
`
`
`
` 5.1
`
`
`
` 5.2
`
`
`
` 5.3
`
`
`
` 5.4
`
`
`
` 5.5
`
`
`
` 5.6
`
`
`
` 5.7
`
` 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
`
`
`
`
`
`4
`
`
`
`Reference ID: 4786757
`
`

`

` adult patients who experience gastric symptoms during treatment with YOSPRALA or have a
`
` 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 occr
`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 diagnosed on
`
`
` biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia).
`Discontinue YOSPRALA and evaluate patients with suspected acute TIN [see
`
`
`
`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)].
`
`
`
`
`
`
`
`
`
`
`
`
` 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
` 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
`
`
`
`
` 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 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
` 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
`
`
`
` 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
`
`
`
`
`
`
`5
`
`
`
`Reference ID: 4786757
`
`

`

` 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
`
` 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
` required magnesium replacement and discontinuation of the PPI. For patients expected to be on
`
`
`
` prolonged treatment or who take YOSPRALA with medications such as digoxin or drugs that
`may cause hypomagnesemia (e.g., diuretics), consider monitoring magnesium levels prior to
`
` initiation of YOSPRALA 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 YOSPRALA
`
` 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 YOSPRALA
`
`
`
` 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
` YOSPRALA may be considered in some patients [see Drug Interactions (7)].
`
`
`5.18 Fetal Toxicity
`
`
`
`
`
` Premature Closure of Fetal Ductus Arteriosus:
`
`
`
`Avoid use of NSAIDs, including YOSPRALA, in pregnant women starting at about 30 weeks
`
`
` of gestation and later. NSAIDs, including YOSPRALA, increase the risk of premature closure
`
` of the fetal ductus arteriosus at approximately this gestational age.
`
`
`
` Oligohydramnios/Neonatal Renal Impairment:
`
`Use of NSAIDs, including YOSPRALA, at about 20 weeks gestation or later in pregnancy may
`cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal
`impairment. These adverse outcomes are seen, on average, after days to weeks of treatment,
`although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID
`initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation.
`Complications of prolonged oligohydramnios may, for example, include limb contractures and
`
` delayed lung maturation. In some postmarketing cases of impaired neonatal renal function,
` invasive procedures such as exchange transfusion or dialysis were required.
`
`
`
` If NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit
`
`
`
` YOSPRALA use to the lowest effective dose and shortest duration possible. Consider
`ultrasound monitoring of amniotic fluid if YOSPRALA treatment is needed for a pregnant
`woman. Discontinue YOSPRALA if oligohydramnios occurs and follow up according to
`
`
` clinical practice [see Use in Specific Populations (8.1)].
`
`
`
`
`
`
`6
`
`
`
`Reference ID: 4786757
`
`

`

`
`
`
`
`
`
` Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
`
`
`
`
`
` 5.19
`
`
`
` 5.20
`
`
`
` 5.21
`
`
`
` 6
`
` Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in
`
`
` patients taking NSAIDs such as YOSPRALA. Some of these events have been fatal or life-
`threatening. DRESS typically, although not exclusively, presents with fever, rash,
`lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis,
`nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of
`DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this
`disorder is variable in its presentation, other organ systems not noted here may be involved. It
`
` is important to note that early manifestations of hypersensitivity, such as fever or
`lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms
`
`
` are present, discontinue YOSPRALA and evaluate the patient immediately.
`
` Abnormal Laboratory Tests
`
` Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum
`
`
` creatinine, hyperkalemia, proteinuria, and prolonged bleeding time.
`
` 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.
`
`
`
`
`
` ADVERSE REACTIONS
`
` The following adverse reactions are discussed in greater detail in other sections of the labeling:
`• Coagulation Abnormalities [see Warnings and Precautions (5.1)]
`
`
`• Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2)]
`
`
`
`
`
`
`
`
`• Bleeding Risk with Use of Alcohol [see Warnings and Precautions (5.3)]
`
`
`
`
`
`
`
`•
`
` Interaction with Clopidogrel [see Warnings and Precautions (5.4)]
`
`
`
`
`
`
`•
`
` Interaction with Ticagrelor [see Warnings and Precautions (5.5)]
`
`
`
`
`
`
`• Renal Failure [see Warnings and Precautions (5.6)]
`
`
`
`
`
`
`
`•
`
`
` Presence of Gastric Malignancy [see Warnings and Precautions (5.7)]
`
`
`
`
`
`• Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.8)]
`
`
`
`
`
`
`
`• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.9)]
`
`
`
`
`
`
`
`• Bone Fracture [see Warnings and Precautions (5.10)]
`
`
`
`
`
`
`
`• Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.11)]
`
`
`
`
`
`
`
`• Hepatic Impairment [see Warnings and Precautions (5.12)]
`
`
`
`
`
`
`
`
`• Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.13)]
`
`
`
`
`
`
`
`• Hypomagnesemia [see Warnings and Precautions (5.14)]
`
`
`
`
`
`
`
`• Reduced Effect of Omeprazole with St. John’s Wort or Rifampin [see Warnings and
`
`
`
`
`
`
`
` Precautions (5.15)]
` Interactions with Diagnostic Investigations for Neuroendocrine Tumors [see Warnings
`
`
` and Precautions (5.16)]
`
`•
`
`
`
`
`
` Interaction with Methotrexate [see Warnings and Precautions (5.17)]
`•
`
` Fetal Toxicity [see Warnings and Precautions (5.18)]
`
`
`
`
`
`
`• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and
`
`
`
`
`
`
` Precautions (5.19)]
`• Abnormal Laboratory Tests [see Warnings and Precautions (5.20)]
`
`
`
`
`
`
`
`•
`
` Fundic Gland Polyps [see Warning and Precautions (5.21)]
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6.1
`
` Clinical Studies Experience
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trials