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` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
`
`
`
`
`
`
`
` 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, Fundic Gland Polyps (5.19)
`
`
`
`
`
` 06/2018
`
`
`
`
` -----------------------------INDICATIONS AND USAGE--------------------------
`
`
` YOSPRALA is a combination of aspirin, an anti-platelet agent, and
`
`
`
`
`
`
`
`
` omeprazole, a proton pump inhibitor (PPI), 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
`
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`
`
`
`
`
` which aspirin is already indicated.
`
`
`
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`
`
`
`
`
` 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. (1)
`
`
`
`
`
` Limitations of Use:
`
`
`
`
`
`
`
`
`
`
`
`
` Not for use as the initial dose of aspirin therapy during onset of acute
`
`
`
`
` coronary syndrome, acute myocardial infarction or before percutaneous
`
`
`
`
`
`
`
`
` coronary intervention. (1)
`
`
` Has not been shown to reduce the risk of gastrointestinal bleeding due to
`
`
`
`
`
` aspirin. (1)
`
`
`
` Do not substitute YOSPRALA with the single-ingredient products of
`
` aspirin and omeprazole. (1)
`
`
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`
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`
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`
`
`
`
`
`
` -------------------------DOSAGE AND ADMINISTRATION---------------------
`
`
` Recommended dosage: One tablet daily at least 60 minutes before a 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)
`
`
`
`
`
`
`
` substituted
`
`
` Known
` hypersensitivity
`aspirin,
`
`
` to
` omeprazole,
`
`
`
` benzimidazoles or to any of the excipients of YOSPRALA. (4)
`
`
`
`
`
`
` Patients receiving rilpivirine-containing products. (4, 7)
`
`
`
`
`
`
`
`
`
` ------------------------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)
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`
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`
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`
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`
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`
`
`
`
`Reference ID: 4274297
`
`
`
`
`
`
`
`
`
` Reduction in Antiplatelet Activity with Clopidogrel due to Interference
` with CYP2C19 Metabolism: Consider other antiplatelet therapy. (5.4, 7)
`
`
`
`
`
`
`
`
`
` Reduction in Efficacy of Ticagrelor: Avoid use with the 325/40 strength
`
`
`
`
`
`
`
`
`
`
`
` of YOSPRALA. (5.5, 7)
`
`
`
`
` Renal Failure: Avoid YOSPRALA in patients with severe renal failure.
`
`
`
` (5.6, 8.6)
`
`
`
`
`
`
`
`
`
` Gastric Malignancy: In adults, response to gastric symptoms does not
`
`
`
` preclude the presence of gastric malignancy; Consider additional follow-
`
`
`
`
`
` up and diagnostic testing. (5.7)
`
`
`
`
`
`
`
`
`
` Acute Interstitial Nephritis: Observed in patients taking PPIs. (5.8)
`
`
`
` Clostridium difficile-Associated Diarrhea: PPI therapy may be associated
`
`
`
`
`
`
`
`
` with increased risk; use lowest dose and shortest duration of treatment.
`
`
`
`
`
`
`
`
`
`
`
` (5.9)
`
`
`
`
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`
`
`
`
` Bone Fracture: Long-term and multiple daily dose PPI therapy may be
`
`
`
` associated with an increased risk for osteoporosis-related fractures of the
`
`
`
`
`
`
`
` hip, wrist or spine; use lowest dose and shortest duration of treatment.
`
`
`
`
`
`
`
`
`
`
` (5.10)
`
`
`
`
`
`
`
` Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new
`
`
`
` onset or exacerbation of existing disease; discontinue YOSPRALA and
`
`
`
`
`
`
`
` refer to specialist for evaluation. (5.11)
`
`
`
`
`
` Hepatic Impairment: Avoid YOSPRALA in patients with all degrees of
`
`
`
`
` hepatic impairment. (5.12, 8.7)
`
`
`
`
`
`
`
`
` Cyanocobalamin (Vitamin B-12) Deficiency: Daily long-term use (e.g.,
`
`
` longer than 3 years) of PPI may lead to malabsorption or deficiency.
`
`
`
`
`
`
`
`
`
`
`
`
` (5.13)
`
`
`
`
` Hypomagnesemia: Reported rarely with prolonged treatment with PPIs;
` consider monitoring magnesium levels. (5.14)
`
`
`
`
`
` Reduced Effect of Omeprazole with St. John’s Wort or Rifampin: Avoid
`
`
`
`
`
` concomitant use. (5.15, 7)
`
`
`
`
`
`
`
`
` Interactions with Diagnostic Investigations for Neuroendocrine Tumors:
`
`
`
` Increased Chromogranin A (CgA) levels may interfere with diagnostic
`
`
`
`
`
`
` investigations for neuroendocrine tumors; temporarily stop YOSPRALA
`
`
`
`
`
`
` 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
`
`
`
`
`
`
` renally impaired: Use with PPIs may elevate and/or prolong serum levels
`
`
`
`
`
`
`
`
` of methotrexate and/or its metabolite, possibly leading to toxicity. With
`
`
`
`
`
`
`
`
`
` high dose methotrexate, consider a
` temporary withdrawal of
`
`
`
`
`
`
`
` YOSPRALA. (5.17, 7)
`
`
`
`
` Premature closure of the ductus arteriosus: Avoid use in pregnant women
`
`
`
`
` starting at 30 weeks gestation. (5.18, 8.1)
`
`
`
`
`
`
`
`
`
`
` Abnormal Laboratory Tests: Aspirin has been associated with elevated
`
`
`
`
`
`
`
` hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia,
`
`
`
`
`
` proteinuria, and prolonged bleeding time. (5.19)
`
`
`
`
`
`
`
` Fundic Gland Polyps: Risk increases with long-term use, especially
`
`
`
`
`
`
`
` beyond one year. Use the shortest duration of therapy. (5.20)
`
`
`
`
`
`
`
`
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`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` --------------------------------ADVERSE REACTIONS----------------------------
`
` Most common adverse reactions in adults (≥ 2%) are: gastritis, nausea, diarrhea,
`
`
`
`
`
`
`
` gastric polyps, and non-cardiac chest pain. (6.1)
`
`
`
`
`
`
`
`
`
`
`
`
`
` To report SUSPECTED ADVERSE REACTIONS, contact Aralez
`
`
` Pharmaceuticals at 1-866-207-6592 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
`
`
`
`
`
` associated with
` reversible
` infertility. Consider withdrawal of
`
`
`
`
`
`
` YOSPRALA in women who have difficulties conceiving. (8.3)
`
`
`
`
`
`
`
`
`
`
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION and Medication
`
` Guide.
`
`
`
`
`
`
`
`
`
`
`
`
`
` Issued: 06/2018
`
`
`

`

`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`
`
` 6
`
`
`
`
`
`
`
` 7
`
`
`
` 8
`
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` 10
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` 11
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` 12
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` 13
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` 14
`
`
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` 16
`
`
`
` 17
`
`
`
`
`
` ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`
`
`
`
`
`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
`
`
`
`
`8.8 Asian Population
`
`
`
`
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`
`12.2 Pharmacodynamics
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` *Sections or subsections omitted from the full prescribing information are not
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`Interaction with Ticagrelor
`
`5.5
`
`
`
`5.6 Renal Failure
`
`
`
`5.7 Presence of Gastric Malignancy
`
`
`
`
`
`
`5.8 Acute Interstitial Nephritis
`
`
`
`
`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
`
`
`Interactions with Diagnostic Investigations for
`
`
`
`
`
`
`Neuroendocrine Tumors
`
`
`
`Interaction with Methotrexate
`
`5.17
`
`
`
`
`5.18 Premature Closure of the Fetal Ductus Arteriosus
`
`
`
`
`
`
`
`
`5.19 Abnormal Laboratory Tests
`
`
`
`
`
`5.20 Fundic Gland Polyps
`
`
`
`
`
`
`
`
` 5.16
`
`
`
` listed.
`
`
`
`Reference ID: 4274297
`
`

`

`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.
`
`
`
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` 2.2 Administration Instructions
`
` Take YOSPRALA once daily at least 60 minutes before a meal.
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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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` tablet.
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` 3
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`Reference ID: 4274297
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` 3
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` 4
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` 5
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` 5.1
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` 5.2
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`
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`
`
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` Use the lowest effective dose of YOSPRALA based on the individual patient’s treatment
`
`
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`
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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.
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` Do not stop taking YOSPRALA suddenly as this could increase the risk of heart attack or
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` stroke.
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` DOSAGE FORMS AND STRENGTHS
`
` Oval, blue-green, film-coated, delayed-release tablets for oral administration containing either:
`
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` 81 mg delayed-release aspirin and 40 mg immediate-release omeprazole, printed with 81/40,
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` or
` 325 mg delayed-release aspirin and 40 mg immediate-release omeprazole, printed with
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` 325/40.
`
` CONTRAINDICATIONS
`
` YOSPRALA is contraindicated in:
`
`
` Patients with known allergy to aspirin and other nonsteroidal anti-inflammatory drug
`
`
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` products (NSAIDs) and in patients with the syndrome of asthma, rhinitis, and nasal polyps.
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` Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma).
`
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` Pediatric patients with suspected viral infections, with or without fever, because of the risk
`
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`
`
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` 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 [see
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`
`
`
` Warnings and Precautions (5.8), Adverse Reactions (6.2)].
`
` Proton pump
`
`
`
`
` including YOSPRALA, are
`inhibitor
` (PPI)–containing products,
`
` contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions
`
`
`
`
` (7)].
`
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`
` WARNINGS AND PRECAUTIONS
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`
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` Coagulation Abnormalities
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` Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time.
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` 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.
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`
` 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
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`
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` in one of the 524 patients treated with enteric-coated aspirin. In addition, there were two cases
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`4
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`Reference ID: 4274297
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`

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` of intestinal hemorrhage, one in each treatment group, and one patient treated with YOSPRALA
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` experienced obstruction of the small bowel.
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` 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
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` 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
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`
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` YOSPRALA, discontinue treatment.
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` Bleeding Risk with Use of Alcohol
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` Counsel patients who consume three or more alcoholic drinks every day about the bleeding risks
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` involved with chronic, heavy alcohol use while taking YOSPRALA.
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` 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
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`
`
` clopidogrel to its active metabolite can be impaired by use with concomitant medications, such
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`
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` 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
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`
`
`
` hours apart. When using YOSPRALA, consider alternative anti-platelet therapy [see Drug
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`
`
`
`
` Interactions (7), Clinical Pharmacology (12.3)].
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` 5.3
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` 5.4
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` 5.5
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` 5.6
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` 5.7
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`
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` 5.8
`
`
`
` 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),
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`
`
`
`
`
` Clinical Pharmacology (12.3)].
`
`
` 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 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.
`
`
` Acute Interstitial Nephritis
`
`
`
`
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` 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
`
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`
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` idiopathic hypersensitivity reaction. Discontinue YOSPRALA if acute interstitial nephritis
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`
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` develops [see Contraindications (4)].
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`Reference ID: 4274297
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`5
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`5.9 Clostridium difficile-Associated Diarrhea
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` Published observational studies suggest that PPI-containing therapy like YOSPRALA may be
` associated with an increased risk of Clostridium difficile-associated diarrhea (CDAD), especially
`
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` in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve
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`
`
`
`
` [see Adverse Reactions (6.2)].
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` Use the lowest dose and shortest duration of YOSPRALA appropriate to the condition being
` treated.
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`
`5.10 Bone Fracture
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` Several published observational studies suggest that PPI therapy may be associated with an
`
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` increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture
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`
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` was increased in patients who received high-dose, defined as multiple daily doses, and long-term
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` PPI therapy (a year or longer). Use the lowest dose and shortest duration of YOSPRALA therapy
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` appropriate to the condition being treated. Manage patients at risk for osteoporosis-related
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` fractures according to established treatment guidelines [see Adverse Reactions (6.2)].
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`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.
`
` 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
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` involvement.
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` Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients
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` 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
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`
`
` 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.
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`5.12 Hepatic Impairment
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`
` Long-term moderate to high doses of aspirin may result in elevations in serum ALT levels. These
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` abnormalities resolve rapidly with discontinuation of aspirin. The hepatotoxicity of aspirin is
` usually mild and asymptomatic. Bilirubin elevations are usually mild or absent. Systemic
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`6
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`Reference ID: 4274297
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`

`

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` exposure to omeprazole is increased in patients with hepatic impairment [see Clinical
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`
`
` Pharmacology (12.3)]. Avoid YOSPRALA in patients with any degree of hepatic impairment
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` [see Use in Specific Populations (8.7)].
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`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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` 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
`
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` YOSPRALA.
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`5.14 Hypomagnesemia
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` Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated
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` 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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` 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
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` Drugs which induce the CYP2C19 or CYP3A4 (such as St. John’s Wort or rifampin) can
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` substantially decrease concentrations of omeprazole. Avoid concomitant use of YOSPRALA
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` with St. John’s Wort or rifampin [see Drug Interactions (7)].
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` Interactions with Diagnostic Investigations for Neuroendocrine Tumors
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`
`
`
` 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
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`
`
`
`
` 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
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`
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` should be used for testing, as reference ranges between tests may vary [see Drug Interactions (7)
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`
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` and Clinical Pharmacology (12.2)].
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`5.16
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`5.17
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`
` Interaction with Methotrexate
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`
`
` 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
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` methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of
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`
` YOSPRALA may be considered in some patients [see Drug Interactions (7)].
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`
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`5.18 Premature Closure of Fetal Ductus Arteriosus
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`
`
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` NSAIDs including aspirin, may cause premature closure of the fetal ductus arteriosus. Avoid use
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` of NSAIDs, including YOSPRALA, in pregnant women starting at 30 weeks of gestation (third
`
`
` trimester). [see Use in Specific Populations (8.1)].
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`7
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`Reference ID: 4274297
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`

`

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`5.19 Abnormal Laboratory Tests
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`
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` 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
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`
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` 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
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`
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` asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the
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`
`
`
` shortest duration of PPI therapy appropriate to the condition being treated.
`
`
` ADVERSE REACTIONS
`
`
`
`6
`
`
`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
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`
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` of another drug and may not reflect the rates observed in practice.
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`
` YOSPRALA 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%
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`
`
` of patients in the YOSPRALA arm and were more common than in the control arm, consisting
`
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`
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` of 325 mg of enteric coated (EC)-aspirin.
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`
`
` Table 1: Most Common Adverse Reactions in Study 1 and Study 2*
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`Preferred Term
`
` EC-Aspirin
`
` YOSPRALA
`
`325 mg once
`325 mg/40 mg
`
`daily
`once daily
`
`
`(n=524)
`(n=521)
`
`
`%
`%
`
`
`
`16
`18
`Gastritis
`
`
`
`2
`3
`Nausea
`
`
`
`2
`3
`Diarrhea
`
`
`
`1
`2
`Gastric polyps
`
`
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`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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` 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
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`
` discontinuations due to adverse reactions in the YOSPRALA treatment group were upper
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`
`
` 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.
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`8
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`Reference ID: 4274297
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`

`

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` 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
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`
`
`
`
`
`
` uncertain size, it is not always possible to reliably estimate their frequency or establish a causal
`
`
`
`
`
`
`
` relationship to drug exposure.
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`
`
` 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, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry
`
`
`
`
`
`
` mouth, microscopic colitis, fundic gland polyps.
`
`
`
`
`
`
` Gastroduode