Yosprala: Package Insert and Label Information

YOSPRALA- aspirin and omeprazole tablet, film coated
PHARMACEUTIKA LTD

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:

  • 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)].
  • Proton pump inhibitor (PPI)–containing products, including YOSPRALA, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7)].

5 WARNINGS AND PRECAUTIONS

5.1 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.

5.2 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.

5.3 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.

5.4 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)].

5.5 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)].

5.6 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)].

5.7 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 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 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)].

5.9 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 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 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.

5.20 Fundic Gland Polyps

PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

7 DRUG INTERACTIONS

Tables 2 and 3 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with YOSPRALA and instructions for preventing or managing them.

Consult the labeling of concomitantly used drugs to obtain further information about interactions with omeprazole or aspirin.

Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with YOSPRALA and Interaction with Diagnostics
Antiretrovirals
Clinical Impact: The effect of PPIs, such as omeprazole, on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.
  • Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)].
  • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)].
  • There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.
Intervention: Rilpivirine-containing products: Concomitant use with YOSPRALA is contraindicated [see Contraindications (4)]. Atazanavir: Avoid concomitant use with YOSPRALA. See prescribing information for atazanavir for dosing information.Nelfinavir: Avoid concomitant use with YOSPRALA. See prescribing information for nelfinavir.Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.Other antiretrovirals: See prescribing information for specific antiretroviral drugs.
Heparin and Warfarin
Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.Aspirin can increase the anticoagulant activity of heparin and warfarin, increasing bleeding risk.
Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.Monitor and adjust the dose of heparin and warfarin as needed.
Methotrexate
Clinical Impact: Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs, such as omeprazole, have been conducted [see Warnings and Precautions (5.17)].
Intervention: A temporary withdrawal of YOSPRALA may be considered in some patients receiving high-dose methotrexate.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel
Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.
Intervention: Avoid concomitant use with YOSPRALA. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.4)].
Citalopram
Clinical Impact: Concomitant use of omeprazole results in increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].
Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.
Cilostazol
Clinical Impact: Concomitant use of omeprazole results in increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol).
Intervention: Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.
Phenytoin
Clinical Impact: Potential for increased exposure of phenytoin with concomitant omeprazole. Aspirin can displace protein-bound phenytoin leading to a decrease in the total concentration of phenytoin.
Intervention: Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.
Diazepam
Clinical Impact: Increased exposure of diazepam with concomitant omeprazole [see Clinical Pharmacology (12.3)].
Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.
Ticagrelor
Clinical Impact: Maintenance doses of aspirin above 100 mg reduce the effectiveness of ticagrelor.
Intervention: Avoid concomitant use of ticagrelor with the 325 mg/40 mg tablet strength of YOSPRALA [see Warnings and Precautions (5.5)].
Digoxin
Clinical Impact: Potential for increased exposure of digoxin with concomitant omeprazole [see Clinical Pharmacology (12.3)].
Intervention: Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.
Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use Yosprala with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption.
Tacrolimus
Clinical Impact: Potential for increased exposure of tacrolimus with concomitant omeprazole, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
Intervention: Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.
ACE-Inhibitors
Clinical Impact: Aspirin may diminish the antihypertensive effect of ACE-inhibitors.
Intervention: Monitor blood pressure as needed.
Beta Blockers
Clinical Impact: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin.
Intervention: Monitor blood pressure as needed in patients taking YOSPRALA concomitantly with beta blockers for hypertension.
Diuretics
Clinical Impact: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin.
Intervention: Monitor blood pressure as needed.
NSAIDs
Clinical Impact: The concurrent use of NSAIDs and aspirin may increase the risk of serious adverse events, including increased bleeding or decreased renal function.
Intervention: Monitor for signs and symptoms of bleeding or decreased renal function.
Oral Hypoglycemics
Clinical Impact: Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.
Intervention: Monitor blood sugar as needed.
Acetazolamide
Clinical Impact: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity).
Intervention: Adjust the dose of acetazolamide if signs of toxicity occur.
Uricosuric Agents (Probenecid)
Clinical Impact: Aspirin antagonizes the uricosuric action of uricosuric agents.
Intervention: Monitor serum uric acid levels as needed.
Valproic Acid
Clinical Impact: Concomitant use of aspirin can displace protein-bound valproic acid, leading to an increase in serum concentrations of valproic acid.
Intervention: Monitor valproic acid serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for valproic acid.
Interactions with Investigations of Neuroendocrine Tumors
Clinical Impact: 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 investigations for neuroendocrine tumors [see Warnings and Precautions (5.16), Clinical Pharmacology (12.2)].
Intervention: Temporarily stop YOSPRALA treatment 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.
Interaction with Secretin Stimulation Test
Clinical Impact: Omeprazole can cause a hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Intervention: Temporarily stop YOSPRALA treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
False Positive Urine Tests for THC
Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs such as omeprazole.
Intervention: An alternative confirmatory method should be considered to verify positive results.
Other
Clinical Impact: There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram) with omeprazole.
Intervention: Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with YOSPRALA.
Table 3: Clinically Relevant Interactions Affecting YOSPRALA When Co- Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers
Clinical Impact: Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].
Intervention: St. John’s Wort, rifampin: Avoid concomitant use with YOSPRALA [see Warnings and Precautions (5.15)]. Ritonavir-containing products: See prescribing information for specific drugs.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact: Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].
Intervention: Voriconazole: Avoid concomitant use with YOSPRALA.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2021. All Rights Reserved.