Aggrenox precautions

List of precautions
General Coronary Artery Disease Hepatic Insufficiency Hypotension Renal Failure Risk of Bleeding Laboratory Tests Drug Interactions Carcinogenesis, Mutagenesis, Impairment of Fertility Pregnancy Labor and Delivery Nursing Mothers Pediatric Use

General
Aggrenox capsules is not interchangeable with the individual components of aspirin and Persantine® Tablets.

Return to top

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. ' Return to top

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

Return to top

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

Return to top

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

Return to top

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.

Return to top

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.

Return to top

Drug Interactions
No pharmacokinetic drug-drug interaction studies were conducted with the Aggrenox formulation. The following information was obtained from the literature.

Adenosine: Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary.

Angiotensin Converting Enzyme (ACE) Inhibitors: Due to the indirect effect of aspirin on the renin-angiotensin conversion pathway, the hyponatremic and hypotensive effects of ACE inhibitors may be diminished by concomitant administration of aspirin.

Acetazolamide: Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion.

Anticoagulant Therapy (heparin and warfarin): Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and effects on platelets. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk.

Anticonvulsants: Salicylic acid can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels.

Beta Blockers: The hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention.

Cholinesterase Inhibitors: Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis.

Diuretics: The effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased ]]renal blood flow]] and salt and fluid retention.

Methotrexate: Salicylate can inhibit renal clearance of methotrexate, leading to bone marrow toxicity, especially in the elderly or renal impaired.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): The concurrent use of aspirin with other NSAIDs may increase bleeding or lead to decreased renal function.

Oral Hypoglycemics: Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.

Uricosuric Agents (probenecid and sulfinpyrazone): Salicylates antagonize the uricosuric action of uricosuric agents.

Return to top

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.

Return to top

Pregnancy
Teratogenic Effects: Pregnancy Category D.

Return to top

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, Aggrenox® (aspirin / extended-release dipyridamole) capsules should be avoided in the third trimester of pregnancy and during labor and delivery.

Return to top

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

Return to top

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.

Return to top