Dosing and uses of Yosprala (aspirin/omeprazole)
Adult dosage forms and strengths
Aspirin enteric-coated, delayed-release/omeprazole immediate-release
Tablet consists of an enteric-coated delayed-release aspirin core surrounded by an immediate-release omeprazole layer
tablet
- 81mg/40mg
- 325mg/40mg
Prevention of Cardiovascular and Cerebrovascular Events
Indicated for patients requiring aspirin for secondary prevention of cardiovascular and cerebrovascular events who are at risk of developing aspirin-associated gastric ulcers
1 tablet PO qDay (available in combinations that contain aspirin 81 mg or 325 mg)
Cardiovascular secondary prevention: Generally 81 mg of aspirin has been accepted as an effective dose for secondary cardiovascular prevention
Consider the need for the 325-mg combination as recommended by current clinical practice guidelines
Also see Administration
Dosage modifications
Renal impairment
- Mild-to-moderate: No dose reduction required
- Severe (GFR <10 mL/min): Avoid use owing to the aspirin component (also see Cautions)
Hepatic impairment
- Avoid use with any degree of hepatic impairment
- Hepatic impairment increases omeprazole systemic exposure
Dosing Considerations
Limitations of use
- Aspirin component is delayed release; not for use as the initial dose of aspirin therapy during onset of acute coronary syndrome, during acute myocardial infarction, or before percutaneous coronary intervention (PCI)
- The combination has not been shown to reduce the risk of gastrointestinal bleeding due to aspirin
- Not interchangeable with the individual components of aspirin and omeprazole
Pediatric dosage forms and strengths
Safety and efficacy not established
Yosprala (aspirin/omeprazole) adverse (side) effects
>10%
325 mg/40 mg (325-mg enteric-coated aspirin alone)
Gastritis 18% (16%)
1-10%
Nausea (3%)
Diarrhea (3%)
Gastric polyps (2%)
Noncardiac chest pain (2%)
<1%
Upper or lower GI bleed
Small bowel obstruction
Postmarketing Reports
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 syndrome, 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, interstitial nephritis, urticaria, 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; 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
- 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 frequency, testicular pain
Warnings
Contraindications
Known allergy to aspirin and other NSAIDs
Patients with the syndrome of asthma, rhinitis, and nasal polyps; aspirin may cause severe urticaria, angioedema, or bronchospasm
Known hypersensitivity to aspirin, omeprazole, substituted benzimidazoles, or any of the excipients in the formulation
Proton pump inhibitors (PPIs) are contraindicated with rilpivirine-containing products
Not indicated for pediatric patients (safety and efficacy not established); aspirin is contraindicated in children with suspected viral infections, with or without fever, because of the risk of Reye syndrome with concomitant use of aspirin in certain viral illnesses
Cautions
Aspirin
- Even low doses of aspirin can inhibit platelet function, leading to an increase in bleeding time; monitor for signs of bleeding
- Aspirin is associated with serious 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
- Avoid with severe renal failure (GFR <10 mL/min); regular use of aspirin is associated with a dose-dependent increased risk of chronic renal failure; aspirin decreases GFR and renal blood flow, especially with preexisting renal disease
- Long-term moderate-to high doses of aspirin may result in elevations in serum ALT levels; avoid with any degree of hepatic impairment
- Aspirin may elevate hepatic enzymes, blood urea nitrogen, and serum creatinine; may cause hyperkalemia, proteinuria, and prolonged bleeding time
- NSAIDs, including aspirin, may cause premature closure of the fetal ductus arteriosus; avoid use in pregnant women starting at 30 weeks of gestation (see Pregnancy)
Omeprazole
- Avoid use in Asian patients with unknown CYP2C19 genotype or those who are known to be poor metabolizers (see Drug Interactions and Pharmacogenomics)
- Acute interstitial nephritis has been observed in patients taking PPIs
- PPIs are possibly associated with increased incidence of C difficile-associated diarrhea (CDAD); consider diagnosis of CDAD for patients taking PPIs who have diarrhea that does not improve
- Published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine, particularly with prolonged (>1 yr), high-dose therapy
- Daily long-term use (eg, >3 years) may lead to malabsorption or a deficiency of cyanocobalamin
- Cutaneous lupus erythematosus and systemic lupus erythematosus (SLE) have been reported with PPIs
- Hypomagnesemia may occur with prolonged use (>1 year); adverse effects may result and include tetany, arrhythmias, and seizures; in 25% of cases reviewed, magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued
- Decreased gastric acidity increases serum chromogranin A (CgA) levels and may cause false-positive diagnostic results for neuroendocrine tumors; temporarily discontinue PPIs before assessing CgA levels
Drug interaction overview
- Also see Interactions section and Drug Interaction Checker
- Aspirin
- Because of its ability to inhibit platelet aggregation, low dose aspirin is often used in conjunction with anticoagulants for prevention of thrombotic CV events; closely monitor INR, and for signs and symptoms of bleeding
- Maintenance doses of aspirin >100 mg reduce ticagrelor effect in preventing thrombotic cardiovascular events; avoid coadministration of ticagrelor with the 325-mg/40-mg tablet strength
- Counsel patients who consume ≥3 alcoholic drinks/day about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin
- Aspirin may decrease antihypertensive effect of ACE-inhibitors, beta blockers, or diuretics
- Moderate aspirin doses may increase effect of oral hypoglycemics
- Omeprazole
- PPIs are contraindicated with rilpivirine-containing products
- Omeprazole inhibits hepatic isoenzyme CYP2C19 and may decrease metabolism of drugs that are CYP2C19 substrates (eg, citalopram, cilostazol, phenytoin, diazepam, tacrolimus)
- Coadministration of clopidogrel with 80-mg omeprazole reduces clopidogrel’s pharmacological activity, even when administered 12 hr apart; avoid coadministration; clopidogrel’s antiplatelet effect is entirely due to an active metabolite; the metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications (eg, omeprazole) that interfere with CYP2C19 activity
- CYP2C19 or CYP3A4 inducers (eg, St John’s Wort or rifampin) can substantially decrease omeprazole concentrations; avoid coadministration
- Coadministration of PPIs with methotrexate (primarily at high dose) may elevate and prolong methotrexate serum levels and/or its metabolite, possibly leading to toxicity
- May increase exposure to digoxin; monitor digoxin concentrations and adjust dose as needed to maintain therapeutic serum concentrations
- May reduce absorption of drugs that are dependent on gastric pH for absorption (eg, iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Pregnancy
Pregnancy
Human data
- Aspirin
- Use of NSAIDs, including aspirin, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus and use of high-dose aspirin for long periods in pregnancy may also increase the risk of bleeding in the brain of premature infants; avoid use beyond 30 weeks of gestation
- Data from several controlled and observational studies with aspirin use in the first or second trimester of pregnancy have not reported a clear association with major birth defects or miscarriage risk
- A prospective cohort study of 50,282 mother-child pairs (the Collaborative Perinatal Project) assessing adverse outcomes by level of aspirin exposure did not report aspirin-induced teratogenicity, altered neonatal birth weight, or perinatal deaths at any exposure level
- A multinational study involving more than 9,000 women, CLASP (Collaborative Low-dose Aspirin Study in Pregnancy), found that low-dose aspirin reduced fetal morbidity in a select population of women with early-onset preeclampsia, but did not identify adverse effects in the pregnant woman, fetus, or newborn (followed to age 12 and 18 months) in association with the use of low-dose aspirin during pregnancy
- Omeprazole
- Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women not exposed
- The number of infants exposed in utero to omeprazole who had any malformation, low birth weight, low Apgar score, or hospitalization was similar to women not exposed in each study
- Exceptions were the number of infants born with ventricular septal defects and the number of stillborn infants were both slightly higher in the omeprazole-exposed infants than the expected number in this population in 1 study
Female reproductive potentiaL
- Small studies in women treated with NSAIDs have demonstrated a reversible delay in ovulation
Lactation
Individual components, aspirin and omeprazole, are secreted in human milk
Limited data describe the presence of aspirin in human milk at relative infant doses of 2.5-10.8% of the maternal weight-adjusted dosage
Case reports of breastfeeding infants whose mothers were exposed to aspirin during lactation describe adverse reactions, including metabolic acidosis, thrombocytopenia, and hemolysis
Limited data describe the presence of omeprazole in human milk at a relative infant dose of 0.9% of the maternal weight-adjusted dosage; there are no reports of adverse effects of omeprazole on the breastfed infant
Because of the potential for serious adverse reactions in the infant, including the potential for aspirin to cause metabolic acidosis, thrombocytopenia, hemolysis, or Reye syndrome, breastfeeding is not recommended during treatment
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Yosprala (aspirin/omeprazole)
Mechanism of action
Aspirin: Inhibits synthesis of thromboxane A2 (prostaglandin derivative) by acetylation of platelet cyclooxygenase, thus inhibiting platelet aggregation
Omeprazole: Proton pump inhibitor (PPI); binds to H+/K+-exchanging ATPase (proton pump) at the secretory surface of the gastric parietal cells, which results in suppression of basal and stimulated gastric acid secretion
Absorption
Take at least 1 hr before meal; food (ie, high-fat meal) significantly prolongs salicylic acid Tmax by 10 hr and reduces omeprazole absorption by 67-84%
Salicylic acid
- Intersubject variability range: 17-96%
- Absorption rate from the GI tract is dependent upon the presence or absence of food, gastric pH (the presence or absence of GI antacids or buffering agents), and other physiologic factors
- Enteric coated aspirin products are erratically absorbed from the GI tract
- Peak plasma time: 2.5 hr (81 mg); 4-4.5 hr (325 mg)
- Peak plasma concentration: 2.6 mcg/mL (81 mg); 2.5 mcg/mL (325 mg)
- AUC: 3 mcg·hr/mL (81 mg); 2.9 mcg·hr/mL
Omeprazole
- Intersubject variability range: 33-136%
- Peak plasma time: 0.5 hr
- Peak plasma concentration: 617-856 ng/mL
- AUC: 880-1384 mcg·hr/mL
Distribution
Salicylic acid
- Salicylic acid is widely distributed to all tissues and fluids in the body including the CNS, breast milk, and fetal tissues; highest concentrations are found in the plasma, liver, renal cortex, heart, and lungs
- Protein bound: Concentration dependent; ~90% (concentration >100 mcg/mL); ~75% (concentration >400 mcg/mL)
Omeprazole
- Protein bound: ~95%
Metabolism
Salicylic acid
- Aspirin (acetylsalicylic acid) is rapidly hydrolyzed to salicylic acid
- Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites
- Metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide
Omeprazole
- Extensively metabolized by CYP; of which the major part of its metabolism is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major metabolite in plasma
- The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of omeprazole sulphone
Elimination
Salicylic acid
- Half-life: 2.4 hr
- Renal excretion of unchanged drug depends upon urine pH; as urinary pH rises >6.5, the renal clearance of free salicylate increases from 5% >80%
- Urinary excretion: 10% (salicylic acid); 75% salicyluric acid); 10% (phenolic glucuronide); 5% (acyl glucuronide)
Omeprazole
- Half-life: 1 hr
- Excretion: 77% urine (as metabolites); remainder in feces
Pharmacogenomics
CYP2C19 poor metabolizers
- Asians have ~4-fold higher exposure to omeprazole than whites
- CYP2C19, a polymorphic enzyme, is involved in the metabolism of omeprazole
- ~15-20% of Asians are CYP2C19 poor metabolizers
- Tests are available to identify a patient’s CYP2C19 genotype
- Avoid use in Asian patients with unknown CYP2C19 genotype or those who are known to be poor metabolizers
Administration
Oral Administration
Take at least 1 hr before a meaL
Swallow whole with liquid; do not split, chew, crush or dissolve
Storage
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
Store in the original container with desiccant and keep the bottle tightly closed to protect from moisture
Dispense in a tight container if package is subdivided
