Bleeding Risk with Use of Alcohol: Avoid heavy alcohol use (three or
`
`
`
`more drinks every day). (5.3)
`
`
`Reduction in Antiplatelet Activity with Clopidogrel due to Interference
`
`
`
`
`with CYP2C19 Metabolism: Consider other antiplatelet therapy. (5.4, 7)
`
`
`
`
`Reduction in Efficacy of Ticagrelor: Avoid use with the 325/40 strength
`
`
`
`
`of 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)
`
`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)
`
`
`
`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)
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`--------------------------------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
`•
`
`
`
`infertility. Consider withdrawal of
`associated with
`reversible
`
`
`YOSPRALA in women who have difficulties conceiving. (8.3)
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
`
`
`Guide.
`
`
`
`Issued: 09/2016
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
`
` YOSPRALA safely and effectively. See full prescribing information for
`
`
`
` YOSPRALA.
`
` YOSPRALA (aspirin and omeprazole) delayed-release tablets, for oral
`
` use
` Initial US Approval: 2016
`
`
`-----------------------------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 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. (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)
`
`
`YOSPRALA is not interchangeable with the individual components of
`
`
`
`aspirin and omeprazole. (1)
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`-------------------------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)
`
`
`
`
`•
`
`
`----------------------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
`aspirin,
`hypersensitivity
`omeprazole,
`to
`Known
`
`
`
`
`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)
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3985760
`
`

`

`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
` 1
`
` 2
`
`
`
` 3
`
`4
`
`5
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 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
`
`
`
`
`5.16
`
`
`6
`
`
`
`7
`
`8
`
`
`
`
`
`
`
`
`
`10
`
`11
`
`12
`
`
`
`
`
`13
`
`
`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 listed.
`
`
`
`14
`
`16
`
`17
`
`Reference ID: 3985760
`
`

`

`
`
` 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.
`
`• YOSPRALA is not interchangeable with the individual components 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.
`
`
`
`
`
`
`Reference ID: 3985760
`
`
`
` 3
`
`

`

`
`
`
`3
`
`
`4
`
`
`5
`
`
`5.1
`
`
`
`5.2
`
`
`•
`
`
`
`
`• 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.
`
`
`
`
`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.
`
`
`CONTRAINDICATIONS
`
`
`
`YOSPRALA is contraindicated in:
`
`
`
`• 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 [see
`
`
`
`
`Warnings and Precautions (5.8), Adverse Reactions (6.2)].
`
`
`
`
`including YOSPRALA, are
`inhibitor
`• Proton pump
`(PPI)–containing products,
`
`
`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.
`
`
`
`
`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
`
`
`
`
`
`Reference ID: 3985760
`
`
`
` 4
`
`
`

`

`
`
`
`
`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)].
`
`
`
`
`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
`Acute interstitial nephritis has been observed in patients taking PPIs including omeprazole.
`
`
`
`Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed
`
`to an idiopathic hypersensitivity reaction. Discontinue YOSPRALA if acute interstitial
`
`nephritis develops [see Contraindications (4)].
`
`
`
`
`
`
` 5
`
`
`
`5.3
`
`
`5.4
`
`
`
`5.5
`
`
`5.6
`
`
`
`5.7
`
`
`5.8
`
`
`
`
`
`Reference ID: 3985760
`
`

`

`
` 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). Onset of CLE occurred up to 2 years after continuous drug therapy (range from
`
`
`
`
`1 to 104 weeks). CLE occurred primarily in older patients, although cases were reported
`
`
`
`in patients as young as 7 months of age. Generally, positive antinuclear antibodies (ANA)
`
`
`and histological findings were observed, consistent with a diagnosis of CLE. Organ
`
`
`involvement was not typically seen. Complete recovery generally has occurred within 12
`
`weeks after discontinuation of the drug.
`
`
`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 30 days after initiating PPI treatment, but some cases
`
`
`
`
`occurred days or years after initiating treatment. SLE occurred primarily in older patients,
`
`
`although cases also occurred in young adults. The majority of patients presented with
`
`
`
`
`rash; however, arthralgia and cytopenia were also reported. Antibody testing for lupus,
`
`
`including ANA and antihistone antibodies, may be positive. Clinical signs and symptoms
`
`
`
`of SLE associated with PPI use were usually reversible once the PPI was discontinued.
`
`
`Clinical symptoms generally resolved within 8 weeks. Elevated serological test results
`
`may take longer to resolve than clinical manifestations.
`
`
`
`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
`
`
`
`
`
`Reference ID: 3985760
`
`
`
` 6
`
`
`

`

`
`
` improve with discontinuation of the PPI alone in 4 to 12 weeks.
`
` 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
`
`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)].
`
`
`
`
`
`
`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)].
`
`
`
`5.16
`
`
`
`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)].
`
`
`
`
`
`
`
`
`Reference ID: 3985760
`
`
`
` 7
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`

`

`
`
`5.18 Premature Closure of Fetal Ductus Arteriosus
`
`
`
`
`
`NSAIDs including aspirin, may cause premature closure of the fetal ductus arteriosus. Avoid
`
`
`use of NSAIDs, including 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.
`
`
`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
`
`
`
`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
`
`
`
`
`
`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.
`
`
`
`
`
`
`Table 1: Most Common Adverse Reactions in Study 1 and Study 2*
`
`
`
`
`
`
`
`
`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
`
`
`
`1
`2
`Non-cardiac chest pain
` *Adverse reactions occurring in ≥2% of YOSPRALA-treated patients and more common than in the control arm
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3985760
`
`
`
` 8
`
`
`

`

`
`
`
`
` 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, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry
`
`
`mouth, microscopic colitis
`
`Benign gastric fundic gland polyps have been noted rarely and appear to be reversible when
`
`
`
`treatment is discontinued.
`
`
`
`
`
`
`Reference ID: 3985760
`
`
`
` 9
`
`
`

`

`
`
`
`
` Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on
`
`
`
`
` long-term treatment with omeprazole. This finding is believed to be a manifestation of the
`
`
` underlying condition, which is known to be associated with such tumors.
` Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia,
`
`
` anemia, thrombocytopenia, leukopenia, leukocytosis
`
` Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal),
`
`
`
`
`
` hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice,
`
` and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]
`
`
` Infections and Infestations: Clostridium difficile-associated diarrhea [see Warnings and
`
`
`
` Precautions (5.9)]
` Metabolism and Nutritional disorders: Hypoglycemia, hypomagnesemia, with or without
`
` hypocalcemia and/or hypokalemia, hyponatremia, weight gain
` Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture
`
`
`
`Nervous System/Psychiatric: Psychiatric and sleep disturbances including depression, agitation,
`aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and
`
`dream abnormalities; tremors, paresthesia; vertigo
`
`Respiratory: Epistaxis, pharyngeal pain
`
`
`Skin: Severe generalized skin reactions including toxic epidermal necrolysis (some fatal),
`
`
`
`Stevens-Johnson syndrome, cutaneous lupus erythematosus and erythema multiforme;
`
`
`
`photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry
`skin; hyperhidrosis
`
`Special Senses: Tinnitus, taste perversion
`
`
`Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome,
`
`
`
`ocular irritation, blurred vision, double vision
`
`Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic
`
`
`pyuria, urinary tract infection, glycosuria, urinary