Aggrenox (Page 5 of 7)
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 Endpoint AGGRENOX 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 4). AGGRENOX reduced the risk of stroke by 36.8% compared to placebo (p <0.001).
| TotalNumberof Patientsn | Number of PatientsWithStroke Within 2 Yearsn (%) | Kaplan-Meier Estimateof Survival at 2 Years(95% C.I.) | Gehan-WilcoxonTestP-value | Risk Reductionat 2 Years | Odds Ratio(95% C.I.) | |
| *0.010 < p-value ≤0.050; **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 | ||||||
| AGGRENOX | 1650 | 157 ( 9.5%) | 89.9% (88.4%, 91.4%) | – | – | – |
| ER-DP | 1654 | 211 (12.8%) | 86.7% (85.0%, 88.4%) | – | – | – |
| ASA | 1649 | 206 (12.5%) | 87.1% (85.4%, 88.7%) | – | – | – |
| Placebo | 1649 | 250 (15.2%) | 84.1% (82.2%, 85.9%) | – | – | – |
| Pairwise Treatment Group Comparisons | ||||||
| AGGRENOX vs. ER-DP | – | – | – | 0.002** | 24.4% | 0.72 (0.58, 0.90) |
| AGGRENOX vs. ASA | – | – | – | 0.008** | 22.1% | 0.74 (0.59, 0.92) |
| AGGRENOX vs. Placebo | – | – | – | <0.001** | 36.8% | 0.59 (0.48, 0.73) |
| ER-DP vs. Placebo | – | – | – | 0.036* | 16.5% | 0.82 (0.67, 1.00) |
| ASA vs. Placebo | – | – | – | 0.009** | 18.9% | 0.80 (0.66, 0.97) |
ESPS2: Cumulative Stroke Rate (Fatal or Nonfatal) Over 24 months of Follow-UP
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.
Death Endpoint
The incidence rate of all cause mortality was 11.3% for AGGRENOX, 11.0% for aspirin alone, 11.4% for extended-release dipyridamole alone and 12.3% for placebo alone. The differences between the AGGRENOX, aspirin alone and extended-release dipyridamole alone treatment groups were not statistically significant. These incidence rates for AGGRENOX and aspirin alone are consistent with previous aspirin studies in stroke and TIA patients.
16 HOW SUPPLIED/STORAGE AND HANDLING
AGGRENOX capsules are available as a hard gelatin capsule, with a red cap and an ivory-colored body, 24.0 mm in length, containing yellow extended-release pellets incorporating dipyridamole and a round white tablet incorporating immediate-release aspirin. The capsule body is imprinted in red with the Boehringer Ingelheim logo and with “01A”.
AGGRENOX capsules are supplied in unit-of-use bottles of 60 capsules (NDC 21695-656-60).
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Protect from excessive moisture.
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