Alcohol Warning

Patients who consume three or more alcoholic drinks every day should be counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.

Coagulation Abnormalities

Even low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited or acquired (liver disease or vitamin K deficiency) bleeding disorders.

Gastrointestinal (GI) Side Effects

GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Physicians should inform patients about the signs and symptoms of GI side effects and what steps to take if they occur.

Peptic Ulcer Disease

Patients with a history of active peptic ulcer disease should avoid using aspirin, which can cause gastric mucosal irritation, and bleeding.

Pregnancy

Aggrenox (aspirin/extended-release dipyridamole) capsules can cause fetal harm when administered to a pregnant woman. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence for intracranial hemorrhage in premature infants, stillbirths and neonatal death. Because of the above and because of the known effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the fetal cardiovascular system (closure of the ductus arteriosus), Aggrenox capsules should be avoided in the third trimester of pregnancy.

Aspirin has been shown to be teratogenic in rats (spina bifida, exencephaly, microphthalmia and coelosomia) and rabbits (congested fetuses, agenesis of skull and upper jaw, generalized edema with malformation of the head, and diaphanous skin) at oral doses of 330 mg/kg/day and 110 mg/kg/day, respectively. These doses, which also resulted in a high resorption rate in rats (63% of implantations versus 5% in controls), are, on a mg/m² basis, about 66 and 44 times, respectively, the dose of aspirin contained in the maximum recommended daily human dose of Aggrenox (aspirin/extended-release dipyridamole) capsules. Reproduction studies with dipyridamole have been performed in mice, rabbits and rats at oral doses of up to 125 mg/kg, 40 mg/kg and 1000 mg/kg, respectively (about 1½, 2 and 25 times the maximum recommended daily human oral dose, respectively, on a mg/m² basis) and have revealed no evidence of harm to the fetus due to dipyridamole. When 330 mg aspirin/kg/day was combined with 75 mg dipyridamole/kg/day in the rat, the resorption rate approached 100%, indicating potentiation of aspirin-related fetal toxicity. There are no adequate and well-controlled studies in pregnant women. If Aggrenox capsules are used during pregnancy, or if the patient becomes pregnant while taking Aggrenox capsules, the patient should be apprised of the potential hazard to the fetus.

General

Aggrenox capsules are not interchangeable with the individual components of aspirin and Persantine Tablets.

Coronary Artery Disease

Dipyridamole has a vasodilatory effect and should be used with caution in patients with severe coronary artery disease (e.g., unstable angina or recently sustained myocardial infarction). Chest pain may be aggravated in patients with underlying coronary artery disease who are receiving dipyridamole.

For stroke or TIA patients for whom aspirin is indicated to prevent recurrent myocardial infarction (MI) or angina pectoris, the aspirin in this product may not provide adequate treatment for the cardiac indications.

Hepatic Insufficiency

Elevations of hepatic enzymes and hepatic failure have been reported in association with dipyridamole administration.

Hypotension

Dipyridamole should be used with caution in patients with hypotension since it can produce peripheral vasodilation.

Renal Failure

Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute).

Risk of Bleeding

In ESPS2 the incidence of gastrointestinal bleeding was 68 patients (4.1%) in the Aggrenox group, 36 patients (2.2%) in the extended-release dipyridamole group, 52 patients (3.2%) in the aspirin group, and 34 patients (2.1%) in the placebo groups.

The incidence of intracranial hemorrhage was 9 patients (0.6%) in the Aggrenox group, 6 patients (0.5%) in the extended-release dipyridamole group, 6 patients (0.4%) in the aspirin group and 7 patients (0.4%) in the placebo groups.

Laboratory Tests

Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum creatinine, hyperkalemia, proteinuria and prolonged bleeding time.

Dipyridamole has been associated with elevated hepatic enzymes.

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.

Pregnancy

Teratogenic Effects: Pregnancy Category D. (see WARNINGS).

Labor and Delivery

Aspirin can result in excessive blood loss at delivery as well as prolonged gestation and prolonged labor. Because of these effects on the mother and because of adverse fetal effects seen with aspirin during the later stages of pregnancy (see WARNINGS, Pregnancy), Aggrenox (aspirin/extended-release dipyridamole) capsules should be avoided in the third trimester of pregnancy and during labor and delivery.

Nursing Mothers

Both dipyridamole and aspirin are excreted in human milk. Caution should be exercised when Aggrenox capsules is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Aggrenox capsules in pediatric patients have not been studied. Due to the aspirin component, use of this product in the pediatric population is not recommended (see CONTRAINDICATIONS)

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