Yosprala (Page 7 of 9)

12.5 Pharmacogenomics

CYP2C19, a polymorphic enzyme, is involved in the metabolism of omeprazole. The CYP2C19*1 allele is fully functional while the CYP2C19*2 and *3 alleles are nonfunctional. There are other alleles associated with no or reduced enzymatic function. Patients carrying two fully functional alleles are extensive metabolizers and those carrying two loss-of-function alleles are poor metabolizers. In extensive metabolizers, omeprazole is primarily metabolized by CYP2C19. The systemic exposure to omeprazole varies with a patient’s metabolism status: poor metabolizers > intermediate metabolizers > extensive metabolizers. Approximately 3% of Caucasians and 15 to 20% of Asians are CYP2C19 poor metabolizers.

In a pharmacokinetic study of single 20 mg omeprazole dose, the AUC of omeprazole in Asian subjects was approximately four-fold of that in Caucasians [see Use in Specific Populations (8.8)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies to evaluate the potential effects of YOSPRALA on carcinogenicity, mutagenicity, or impairment of fertility have not been conducted.

Aspirin

Administration of aspirin for 68 weeks at 0.5% in the feed of rats was not carcinogenic.

In the Ames Salmonella assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations in cultured human fibroblasts.

Aspirin inhibits ovulation in rats.

Omeprazole

In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44.0 and 140.8 mg/kg/day (about 0.35 to 34 times the human dose of 40 mg per day, based on body surface area) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 3.4 times the human dose of 40 mg per day, based on body surface area) for one year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to 3.2 times the human dose of 40 mg/day, based on body surface area). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males and females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg per day, based on body surface area). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames Salmonella typhimurium assay, an in vitro mouse lymphoma cell forward mutation assay and an in vivo rat liver DNA damage assay.

Omeprazole at oral doses up to 138 mg/kg/day (about 34 times the human dose of 40 mg per day, based on body surface area) was found to have no effect on fertility and reproductive performance.

In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2 -receptor antagonists.

13.2 Animal Toxicology and/or Pharmacology

Aspirin

The acute oral 50% lethal dose in rats is about 1.5 g/kg and in mice 1.1 g/kg. Renal papillary necrosis and decreased urinary concentrating ability occur in rodents chronically administered high doses. Dose-dependent gastric mucosal injury occurs in rats and humans. Mammals may develop aspirin toxicosis associated with GI symptoms, circulatory effects, and central nervous system depression [see Overdosage (10)].

Omeprazole

Reproductive Toxicology Studies

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times the human dose on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 34 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times the human dose on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 3.4 to 34 times the human doses on a body surface area basis).

Juvenile Animal Study

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at oral doses of 70 to 280 mg/kg/day (about 17 to 67 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.

14 CLINICAL STUDIES

Aspirin Trials

Ischemic Stroke and Transient Ischemic Attack (TIA)

In clinical trials of subjects with TIA due to fibrin platelet emboli or ischemic stroke, aspirin has been shown to significantly reduce the risk of the combined endpoint of stroke or death and the combined endpoint of TIA, stroke, or death by about 13 to18%.

Prevention of Recurrent MI and Unstable Angina Pectoris

These indications are supported by the results of six large, randomized, multi-center, placebo-controlled trials of predominantly male post-MI subjects and one randomized placebo-controlled study of men with unstable angina pectoris. Aspirin therapy in MI subjects was associated with a significant reduction (about 20%) in the risk of the combined endpoint of subsequent death and/or nonfatal reinfarction in these patients. In aspirin-treated unstable angina patients the event rate was reduced to 5% from the 10% rate in the placebo group.

Chronic Stable Angina Pectoris

In a randomized, multi-center, double-blind trial designed to assess the role of aspirin for prevention of MI in patients with chronic stable angina pectoris, aspirin significantly reduced the primary combined endpoint of nonfatal MI, fatal MI, and sudden death by 34%. The secondary endpoint for vascular events (first occurrence of MI, stroke, or vascular death) was also significantly reduced (32%).

Revascularization Procedures

Most patients who undergo coronary artery revascularization procedures have already had symptomatic coronary artery disease for which aspirin is indicated. Similarly, patients with lesions of the carotid bifurcation sufficient to require carotid endarterectomy are likely to have had a precedent event. Aspirin is recommended for patients who undergo revascularization procedures if there is a preexisting condition for which aspirin is already indicated.

YOSPRALA trials

Two randomized, multi-center, double-blind trials (Study 1 and Study 2) evaluated the omeprazole component by comparing the incidence of gastric ulcer formation in 524 patients randomized to YOSPRALA 325 mg/40 mg tablets and 525 patients randomized to EC-aspirin 325 mg. Patients were included with a cerebro- or cardiovascular diagnosis if they had been taking daily aspirin 325 mg for at least 3 months, were expected to require daily aspirin 325 mg therapy for at least 6 months and were over 55 years old. Subjects between 18 and 55 years old were also required to have a documented history of gastric or duodenal ulcer within the past 5 years. The majority of patients were male (71%) and white (90%). The majority (57%) of patients were ≥65 years of age. Approximately 11% were also on chronic NSAID therapy.

Studies 1 and 2 showed that YOSPRALA given as 325 mg/40 mg tablets once daily statistically significantly reduced the 6-month cumulative incidence of gastric ulcers compared to EC-aspirin 325 mg once daily. The results at one month, three months, and six months treatment are presented in Table 4.

Table 4: Cumulative Incidence of Gastric Ulcers at 1, 3, and 6 Months
Study 1 Study 2
YOSPRALAN=265Number(%) EC-AspirinN=265Number(%) YOSPRALAN=259Number(%) EC-AspirinN=260Number(%)
*
Study 1: p=0.020 and Study 2: p=0.005 for treatment comparisons of cumulative GU incidence at 6 months.
0-1 Month 3 (1.1) 10 (3.8) 1 (0.4) 8 (3.1)
0-3 Months 8 (3.0) 18 (6.8) 1 (0.4) 17 (6.5)
0-6 Months * 10 (3.8) 23 (8.7) 7 (2.7) 22 (8.5)

In both trials, patients receiving YOSPRALA 325 mg/40 mg tablets had a statistically significantly lower 6-month cumulative incidence of gastric and/or duodenal ulcers compared to EC-aspirin 325 mg (3% vs. 12%).

Upper GI bleeding was reported as a serious adverse reaction in each treatment arm; 1 gastric ulcer hemorrhage in a subject receiving YOSPRALA and 1 duodenal ulcer hemorrhage in a subject receiving EC-aspirin alone.

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