Yosprala: Coordinated Delivery of a Proton Pump Inhibitor and Aspirin

Abstract

Objective: Review the pharmacology, pharmacokinetics, efficacy, and safety of Yosprala (aspirin and omeprazole). Data Sources: A literature search was conducted using PubMed with the terms “Yosprala,” “PA8140,” and “PA32540” from the initial year through May, 2019. Additional sources were gathered through bibliographies. Aralez Pharmaceuticals Inc was contacted for manufacturer information. Study Selection and Data Extraction: The sources were narrowed to studies done in English language between 1990 and 2019. All viable clinical trials for the use of Yosprala in the secondary prevention of cardiovascular events were included. Data Synthesis: Yosprala is a coordinated delivery system of immediate-release omeprazole 40 mg and enteric-coated aspirin (325 mg or 81 mg). In 2016, the Food and Drug Administration approved Yosprala for the secondary prevention of cardiovascular or cerebrovascular events (ie, stroke or myocardial infarction). While it is recommended that patients take low-dose aspirin for secondary prevention of these events, many patients cannot tolerate the gastrointestinal (GI) adverse effect profile of the drug. Phase 3 clinical trials have proven that Yosprala significantly lowers the occurrence of GI bleeds and ulcers versus aspirin alone (3.2% and 8.6%, respectively; P ≤ .001). The most common adverse effects include infection, diarrhea, and dyspepsia. Conclusion: Yosprala significantly reduces the occurrence of GI ulcers and seems to be a safe and effective option for the secondary prevention of cardiovascular events.

Introduction

It is estimated that 795 000 Americans have a stroke every year. Of those, 185 000 are recurrent.^1,2 Meanwhile, cardiovascular death is the number 1 cause of death in America, with most of these deaths being from myocardial infarctions.^3,4 A once-daily low-dose of acetylsalicylic acid (aspirin [ASA]) is recommended by the American Heart Association for patients with a history of cardiovascular events, including ischemic stroke and myocardial infarction, or for patients who have undergone bypass (coronary artery bypass grafting) or angioplasty.⁵ ASA has been used in the secondary prevention of cardiovascular events since the 1800s.⁶

In a meta-analysis of 6300 patients, ASA use lowered all-cause mortality by 18%, stroke by 20%, and myocardial infarction by 30% in patients taking the medication for secondary prevention.⁶ Although there is astounding evidence on the use of ASA for the secondary prevention of cardiovascular events, adherence rates to this medication are varied and have been reported to be as low as 47% and as high as 72%.^7-9 The low adherence is often attributed to the gastrointestinal (GI) adverse effects associated with ASA. These effects include upper GI bleed, GI ulcers, gastroesophageal reflux disease (GERD), and dyspepsia.^6,8-10 In fact, patients are at a 2-fold increased risk for GI-related adverse effects when taking ASA versus placebo.^6,8 Discontinuing ASA increases the risk of life-threatening cardiovascular events that may occur without this medication.^5,6

Patients at risk for GI-related adverse events (ie, patients over 55 years old, patients 18 to 55 years old with a history of GI ulcers, patients on dual antiplatelet therapy, or patients with concurrent use of a nonsteroidal anti-inflammatory drug [NSAID], and ASA) are often placed on a proton pump inhibitor (PPI).^11,12 PPIs often help curb the GI adverse effect profile of ASA.^11-13 A meta-analysis showed that patients with high to moderate adherence to PPIs were at a lower risk for GI ulcers and bleeds compared with those with no or intermittent PPI use.¹² Up until now, the addition of a PPI to a patient’s regimen has meant adding a second drug to their daily intake. Co-prescribing of medications generally results in lower adherence rates.⁸ Low adherence to the PPI, when paired with ASA, will result in more GI-related events. This return of GI events could lead to the discontinuation of ASA and, again, increase the risk for life-threatening cardiovascular events.

To prevent this cycle from occurring, Aralez Pharmaceuticals, Inc, has created Yosprala, a coordinated delivery tablet containing immediate-release (IR) omeprazole (40 mg) and enteric-coated (EC) ASA (325 mg or 81 mg).¹⁴ Yosprala aims to help patients who require ASA for secondary prevention, but cannot tolerate it due to its GI adverse effect profile. The tablet is designed so that the ASA cannot be released until the pH of the stomach is high enough for the ASA to cause less harm.^14,15 By coordinating the delivery of these 2 medications into 1 tablet, the adherence rates could increase by as much as 13%.¹⁶ This review will focus on the pharmacotherapy of Yosprala to guide practitioners on its use.

Data Selection

A literature search was conducted using PubMed with the terms “Yosprala” and “PA32540” (PA32540 being the chemical reference for omeprazole 40 mg + aspirin 325 mg). Additional sources were gathered through bibliographies and clinicaltrials.gov. Aralez Pharmaceuticals Inc was contacted for product information. The sources were narrowed to studies done in English between the years of 1990 and 2019. All viable clinical trials for the use of Yosprala in the secondary prevention of cardiovascular and cerebrovascular events were included.

Pharmacology and Toxicology

The acidic environment of the stomach does not play host well to ASA. Being a weak acid, ASA is extensively absorbed in the acidity of the stomach.¹⁷ Once it is absorbed, ASA exerts its effects on the wall of stomach by inhibiting cyclooxygenase.^10,18,19 This inhibition of cyclooxygenase significantly lowers the prostaglandins in the wall of the stomach and small intestine.^18,19 Prostaglandins play a vital role in the protection of the mucosal membranes of the GI tract because of their ability to secrete bicarbonate and mucus, and deplete acid secretion.^18,20 With less prostaglandins, the mucus membranes are more susceptible to the acidic environment of the stomach.^18-20 This can lead to GI ulcer formation and other GI adverse effects.^19,20

Yosprala is a coordinated delivery tablet of both EC-ASA and IR omeprazole.¹⁴ The IR formulation of omeprazole is used to immediately raise the pH of the stomach. Once the pH is above 5.5, the ASA core is slowly degraded. Since the omeprazole immediately raises the pH of the environment, the ASA poses less of a threat to form gastric ulcers or bleeds.

Aspirin

Acetylsalicylic acid, also known as aspirin, has several mechanisms of action. It acts as an anti-inflammatory, analgesic, antipyretic, and antiplatelet drug. ASA has many indications including use in myocardial infarction, analgesia, and atrial fibrillation.¹⁰ It is used in the secondary prevention of cardiovascular events mainly because of its antiplatelet activity. ASA irreversibly inhibits prostaglandin cyclooxygenase, which inhibits the aggregation factor thromboxane A₂.¹⁰

Omeprazole

Omeprazole is a PPI. It works by blocking the H+/K+ ATP pump in parietal cells, which suppresses the final step of acid production in the stomach.²¹ It is indicated for use in the treatment of gastric ulcers, heartburn, Helicobacter pylori eradication, and GERD.²¹ Omeprazole is a base and therefore is rapidly degraded in the acidity of the stomach.

Pharmacokinetics and Pharmacodynamics

The pharmacokinetics and pharmacodynamics of Yosprala are similar to those of the 2 main active ingredients: ASA and omeprazole. The IR omeprazole component of PA32540 has a T_max of 0.5 hours, with detectable amounts in the body for up to 10 hours postdose.¹⁸ ASA is not detectable until 2 to 3 hours after the dose was given, with a T_max of 4 to 4.5 hours (ASA 325 mg) or 2.5 hours (ASA 81 mg) and detectable amounts up to 16 hours postdose.¹⁸ With Yosprala, the pH will rise quickly before the ASA becomes detectable in 2 to 3 hours, to decrease the threat of developing GI complications.¹⁸

Yosprala is renally excreted and metabolized through the liver.^14,18 For this reason, it should be avoided in patients with severe hepatic impairment and severe renal dysfunction (glomerular filtration rate <10 mL/min).¹⁴

Food has been known to affect the effects of both omeprazole and ASA. High-fat meals increase the T_max of salicylic acid and reduces the absorption of omeprazole. For this reason, Yosprala is to be given 60 minutes before a high-fat, high-calorie meal.^10,14,21

Clinical Trials

Phase 1

Once daily PA32540 was compared with its separate components of EC-ASA 325 mg + EC omeprazole 40 mg in a randomized, 2-way crossover study. The primary endpoint of the study was to determine the percentage of time the gastric pH was ≥4 over a 24-hour period on the seventh day of treatment.¹⁸ This endpoint would determine if the IR formulation of omeprazole present in PA32540 would have similar, worse, or better efficacy than the EC formulation of omeprazole. The secondary endpoints involved evaluating the pharmacokinetics of PA32540.¹⁸ The study consisted of 26 patients between the ages of 18 and 55 years, both male and female. The patients had to be Helicobacter pylori negative, have no history of GI-related symptoms or diseases, and could not have taken any GI irritating drugs (NSAIDs, bisphosphonates, steroids, etc) for the past 14 days.¹⁸

The patients were on either PA32540 by mouth once a day for 7 days, followed by a minimum washout period of 7 days, and then a 7-day treatment of EC-ASA 325 mg + EC omeprazole 40 mg or vice versa.¹⁸ The patient’s intragastric pH was measured on day 7 of each treatment, over a 24-hour period. The secondary endpoints were measured on days 1, 5, and 7.¹⁸

Results showed that the percentage of time the pH was ≥4 in patient’s receiving PA32540 was 50.6%, versus 57.6% for patients taking EC-ASA 325 mg + EC omeprazole 40 mg.¹⁸ However, the intragastric pH rose more rapidly with PA32540 (0.29 hours vs 0.60 hours).¹⁸ This is directly related to the different formulations of the omeprazole. The IR formulation is unbuffered, that is, it becomes active quicker than the EC formulation, but also that it cannot maintain detectable levels for as long.

Although the IR formulation of omeprazole does not allow the pH to be ≥4 longer than EC omeprazole, the total to exposure to omeprazole from PA32540 was about 51% to 57% of that of EC omeprazole.¹⁸ Previous studies showed these numbers to be similar to those when testing EC omeprazole 20 mg (48.7%).²² Since omeprazole 20 mg is a recommended dosage for acid suppression, a reasonable assumption can be made that IR omeprazole 40 mg in PA32540 is sufficient for acid suppression.

Phase 3

Two randomized, double-blinded, phase 3 controlled clinical trials compared the incidence of GI ulcers between PA32540 and EC-ASA 325 mg alone when used for the secondary prevention of cardiovascular events. The primary endpoint was the occurrence of endoscopy-discovered GI ulcers over a 6-month period.¹³ The study defined a gastric ulcer as a break in the mucosa of ≥3 mm in diameter.¹³ Secondary endpoints included major adverse cardiovascular events (MACE) or major GI symptoms.¹³ Data were analyzed on an intention-to-treat basis with a statistical level of 5%. Based on a power analysis, the study needed to include at least 250 patients to be able to tell if there was a difference between PA32540 and EC-ASA 325 mg.¹³

A total of 1049 patients were included in the studies. The patients ranged in age from 18 to 88 years and had to have a history of cardiovascular disease as well as had been on ASA 325 mg for at least 3 months.¹³ The patients also had to be at an increased risk for developing a GI ulcer.^11-13 Finally, the patients were randomized to receive either PA32540 or EC-ASA 325 mg once a day in a 1:1 ratio.¹³ An endoscopy was done at screening and at 1, 3, and 6 months; if an ulcer was discovered at any time, the patient was discontinued from the study.¹³ If the ulcer was classified as a gastric ulcer, it was considered a primary endpoint; however, if the ulcer was esophageal or duodenal, it was considered an adverse event.¹³

At the end of the 6-month study, the primary endpoint was observed in 3.2% of patients on PA32540 and 8.6% of patients on EC-ASA 325 mg (P ≤ .001).¹³ The median size of the ulcers experienced by patients was recorded as 3 mm in the PA32540 group and 5 mm in the EC-ASA group.¹³ Patients who were on an NSAID at baseline experienced GI ulcerations at a rate of 4.5% with PA32540 versus 10.2% with EC-ASA.¹³ This could be compared with patients not on an NSAID at baseline who experienced a GI ulceration at a rate of 3.1% on PA32540 versus 8.4% on EC-ASA.¹³ In the PA32540 group 3.4% of patients experienced duodenal or esophageal ulcers versus 11.6% in the EC-ASA group (P ≤ .001).¹³ Overall, patients on PA32540 had less GI-related events (eg, erosive gastritis, esophagitis, duodenal ulcer) compared with EC-ASA alone.

The secondary endpoint of MACE was observed in 1.7% of patients on PA32540 versus 2.5% of patients in EC-ASA.¹³ The difference in these numbers is not significant, which is what was expected. The primary goal of PA32540 is not to decrease the number of MACE, but to decrease the amount of GI-related adverse effects associated with ASA use.

Safety

The safety of Yosprala was evaluated in an open-label phase 3 study consisting of 380 patients.³ The patients were to receive Yosprala once a day for 12 months. Of the 380 patients in the study, 292 completed the study.⁸ Patients completed the study if they received PA32540 for at least 348 days. The 88 patients who did not finish the study reported the top reason for discontinuation to be adverse events (13.4%).⁸

In the study population, 73% of patients experienced a treatment-emergent adverse event.⁸ The most common adverse events included infection (sinusitis, bronchitis, and upper respiratory tract infection) and GI disorders (diarrhea and dyspepsia).⁸ Most of these events were recorded in the first 30 days of treatment. A total of 3.7% of the patients involved in the study also experienced MACE.⁸

It is also to be noted that when comparing PA32540 to EC-ASA 325 mg alone, patients on PA32540 experienced significantly less dyspepsia, GERD, erosive esophagitis, or reflux esophagitis than those in the EC-ASA 325 mg group, due to the presence of the PPI (P = .001).¹³ A summary of all adverse effects reported with PA32540 in clinical trials can be found in Table 1.

Table 1.

Summary of Adverse Effects Reported With PA32540 in Clinical Trials.

Trial	Design	Intervention	n; % of Patients Experiencing AE	Duration	AE	MACE, %
Miner et al18	Phase 1; open-label; R, CO	PA32540 compared with EC-ASA 325 mg and EC omeprazole 40 mg	26; 15	21 days	Frequent bowel movement; constipation	—
Whellan et al13	Phase 3; R, DB, CCT	PA32540 compared with EC-ASA 325 mg	1049; 71	6 months	Gastritis, dyspepsia, hiatus hernia, duodenitis, nausea, GERD, duodenal ulcer, erosive esophagitis	Nonfatal MI, 0.96; TIA, 0.19; CHF, 0.19; Mild CAD, 0.19; Planned CABG, 0.19
Goldstein et al8	Phase 3; open-label	PA32540	380; 73.4	12 months	URTI, back pain, bronchitis, nasopharyngitis, diarrhea, dyspepsia, sinusitis, cough	Nonfatal MI, 1.3; ACS, 0.8; unplanned PCI, 0.5; cardiovascular death, 0.3; unplanned CABG, 0.3; ischemic stroke, 0.3; heart failure, 0.3

Abbreviations: ACS, acute coronary syndrome; AE, adverse event; ASA, aspirin; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CCT, controlled clinical trial; CHF, congestive heart failure; CO, crossover; DB, double blinded; EC, enteric coated; GERD, gastroesophageal reflux disease; MACE, major adverse cardiovascular event; MI, myocardial infarction; PCI, percutaneous coronary intervention; R, randomized; TIA, transient ischemic attack; URTI, upper respiratory tract infection.

Special Populations

Yosprala has only been tested in patients ≥18 years of age; therefore, its efficacy and safety cannot be determined for those <18 years of age.^8,13,14,18 However, geriatric safety and efficacy has been established in patients up to 88 years of age.^8,13

Yosprala contains ASA, which when used during pregnancy can increase the risk of bleeding, premature closure of the fetal ductus arteriosus, and may cause neonatal complications. For this reason, Yosprala is not recommended for use in women who are pregnant or breastfeeding.¹⁴

Dosage and Administration

Yosprala is an oral tablet that has 2 Food and Drug Administration–approved strengths: 81 mg/40 mg and 325 mg/40 mg. These products differ only in the amount of EC-ASA that is present in them. Yosprala is to be taken once a day, 60 minutes before a meal. The tablets are to be taken whole; do not crush or chew.¹⁴

Therapeutic Considerations

Through the studies presented here, no therapeutic issues are apparent with Yosprala. When prescribing Yosprala, full consideration should be given to the potential for drug interactions. Antiretrovirals and clopidogrel should not be used with Yosprala. Use of warfarin, digoxin, diuretics, β-blockers, or angiotensin-converting enzyme inhibitors may require additional monitoring.¹⁴

The current cost per tablet of the medication is approximately $1.32, which equates to a monthly cost of $40 and annual expense of less than $500.²³ Information regarding the financial impact of Yosprala is limited; however, at least one study has estimated the potential cost savings of this product.²⁴ This study utilized a Markov model to estimate projected annual savings to a health care plan. This model estimated that inclusion of Yosprala would net $191 in savings per member per year at 1 year.

Discussion

A once daily low-dose ASA is recommended for patients who have experienced a major cardiovascular event to prevent them from having the event again. While ASA is very important for the prevention of these fatal events, adherence to the medication is low due to its GI adverse effect profile.^7-9 Yosprala is a combination product containing IR omeprazole 40 mg and EC-ASA (325 mg or 81 mg), which aims to decrease the GI-related adverse events associated with ASA. The natural pH of the stomach allows ASA to cause damage to the mucosa. Omeprazole raises the pH in the stomach to protect against these threats.

Although EC omeprazole was proven to have double the concentration of IR omeprazole and was shown to stabilize the pH >4 for a longer period of time, the IR formulation of omeprazole, present in Yosprala, raises the pH of the GI tract much faster. This immediate rise in the pH is needed because ASA becomes active within 2 to 3 hours of ingestion. This will allow the ASA to work without posing a severe threat to the GI tract.

Several phase 3 studies further have proven that Yosprala significantly lowers the rates of GI ulcers when compared with EC-ASA 325 mg alone. The most common adverse events of Yosprala include infection, dyspepsia, and diarrhea. The difference in incidence of major cardiovascular events between Yosprala and EC-ASA 325 mg was not significant.

Conclusion

Yosprala has been evaluated as safe and effective for use in patients in need of secondary prevention of cardiovascular events. It would be most beneficial in the patient who needs a higher preventative ASA dose and is at a higher risk for developing GI complications.