Aggrenox (Page 4 of 6)

13  NONCLINICAL TOXICOLOGY

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

In studies in which dipyridamole was administered in the feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in males and up to 142 weeks in females), there was no evidence of drug-related carcinogenesis. The highest dose administered in these studies (75 mg/kg/day) was, on a mg/m2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) in mice and about twice the MRHD in rats.

Combinations of dipyridamole and aspirin (1:5 ratio) tested negative in the Ames test, in vivo chromosome aberration tests (in mice and hamsters), oral micronucleus tests (in mice and hamsters) and oral dominant lethal test (in mice). Aspirin, alone, induced chromosome aberrations in cultured human fibroblasts. Mutagenicity tests of dipyridamole alone with bacterial and mammalian cell systems were negative.

Combinations of dipyridamole and aspirin have not been evaluated for effects on fertility and reproductive performance. There was no evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times the MRHD on a mg/m2 basis). A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1250 mg/kg (more than 30 times the MRHD on a mg/m2 basis). Aspirin inhibits ovulation in rats.

14  CLINICAL STUDIES

ESPS2 (European Stroke Prevention Study-2) was a double-blind, placebo-controlled, 24-month study in which 6602 patients over the age of 18 years had an ischemic stroke (76%) or transient ischemic attack (TIA, 24%) within three months prior to entry. Patients were enrolled in 13 European countries between February 1989 and May 1995 and were randomized to one of four treatment groups: AGGRENOX (aspirin/extended-release dipyridamole) 25 mg/200 mg; extended-release dipyridamole (ER-DP) 200 mg alone; aspirin (ASA) 25 mg alone; or placebo. The mean age in this population was 66.7 years with 58% of them being males. Patients received one capsule twice daily (morning and evening). Efficacy assessments included analyses of stroke (fatal or nonfatal) and death (from all causes) as confirmed by a blinded morbidity and mortality assessment group. There were no differences with regard to efficacy based on age or gender; patients who were older had a trend towards more events.

Stroke EndpointAGGRENOX reduced the risk of stroke by 22.1% compared to aspirin 50 mg/day alone (p = 0.008) and reduced the risk of stroke by 24.4% compared to extended-release dipyridamole 400 mg/day alone (p = 0.002) (Table 3). AGGRENOX reduced the risk of stroke by 36.8% compared to placebo (p <0.001).

Table 3 Summary of First Stroke (Fatal or Nonfatal): ESPS2: Intent-to-Treat Population
TotalNumberof PatientsnNumber of PatientsWithStroke Within 2 Yearsn (%)Kaplan-Meier Estimateof Survival at 2 Years(95% C.I.)Gehan-WilcoxonTestP-valueRisk Reductionat 2 YearsOdds Ratio(95% C.I.)
a 0.010 <p‑value ≤0.050; b p‑value ≤0.010.
Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID.
Individual TreatmentGroup
        AGGRENOX1650157 ( 9.5%)89.9% (88.4%, 91.4%)
        ER-DP1654211 (12.8%)86.7% (85.0%, 88.4%)
        ASA1649206 (12.5%)87.1% (85.4%, 88.7%)
        Placebo1649250 (15.2%)84.1% (82.2%, 85.9%)
Pairwise Treatment Group Comparisons
        AGGRENOX        vs.                ER-DP0.002b 24.4%0.72 (0.58, 0.90)
        AGGRENOX        vs.                ASA0.008b 22.1%0.74 (0.59, 0.92)
        AGGRENOX        vs.                Placebo<0.001b 36.8%0.59 (0.48, 0.73)
        ER-DP vs. Placebo0.036a 16.5%0.82 (0.67, 1.00)
        ASA vs. Placebo0.009b 18.9%0.80 (0.66, 0.97)

ESPS2: Cumulative Stroke Rate (Fatal or Nonfatal)Over 24 months of Follow-UP

Figure 1.
(click image for full-size original)

Combined Stroke or Death Endpoint
In ESPS2, AGGRENOX reduced the risk of stroke or death by 12.1% compared to aspirin alone and by 10.3% compared to extended-release dipyridamole alone. These results were not statistically significant. AGGRENOX reduced the risk of stroke or death by 24.2% compared to placebo.

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