A 24-month, multicenter, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of Aggrenox capsules with placebo, extended-release dipyridamole alone and aspirin alone. The study was conducted in a total of 6602 male and female patients who had experienced a previous ischemic stroke or transient ischemia of the brain within three months prior to randomization.

Table 2 presents the incidence of adverse events that occurred in 1% or more of patients treated with Aggrenox capsules where the incidence was also greater than in those patients treated with placebo. There is no clear benefit of the dipyndamole/aspinn combination over aspirin with respect to safety.

Table 2: Incidence of Adverse Events in ESPS2*

Discontinuation due to adverse events in ESPS2 was 25% for Aggrenox, 25% for extended-release dipyridamole, 19% for aspirin, and 21% for placebo (refer to Table 3)

Table 3: Incidence of Adverse Events that Led to the Discontinuation of Treatment: Adverse Events with an Incidence of ≥ 1% in the Aggrenox group

Headache was most notable in the first month of treatment.

Other Adverse Events

Adverse reactions that occurred in less than 1% of patients treated with Aggrenox (aspirin/extended-release dipyridamole) capsules in the ESPS2 study and that were medically judged to be possibly related to either dipyridamole or aspirin are listed below (see WARNINGS).

Body as a Whole: Allergic reaction, fever

Cardiovascular: Hypotension

Central Nervous System: Coma, dizziness, paresthesia, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage

Gastrointestinal: Gastritis, ulceration and perforation

Hearing and Vestibular Disorders: Tinnitus, and deafness. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as a clinical indicator of salicylism

Heart Rate and Rhythm Disorders: Tachycardia, palpitation, arrhythmia, supraventricular tachycardia

Liver and Biliary System Disorders: Cholelithiasis, jaundice, hepatic function abnormal

Metabolic and Nutritional Disorders: Hyperglycemia, thirst

Platelet, Bleeding and Clotting Disorders: Hematoma, gingival bleeding

Psychiatric Disorders: Agitation

Reproductive: Uterine hemorrhage

Respiratory: Hyperpnea, asthma, bronchospasm, hemoptysis, pulmonary edema

Special Senses Other Disorders: Taste loss

Skin and Appendages Disorders: Pruritus, urticaria

Urogenital:Renal insufficiency and failure, hematuria

Vascular (Extracardiac) Disorders: Flushing

The following is a list of additional adverse reactions that have been reported either in the literature or are from postmarketing spontaneous reports for either dipyridamole or aspirin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure.

Body as a Whole: Hypothermia, chest pain

Cardiovascular: Angina pectoris

Central Nervous System: Cerebral edema

Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia

Gastrointestinal: Pancreatitis, Reye's syndrome, hematemesis

Hearing and Vestibular Disorders: Hearing loss

Hypersensitivity: Acute anaphylaxis, laryngeal edema

Liver and Biliary System Disorders: Hepatitis, hepatic failure

Musculoskeletal: Rhabdomyolysis

Metabolic and Nutritional Disorders: Hypoglycemia, dehydration

Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia

Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding

Respiratory: Tachypnea, dyspnea

Skin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising, ecchymosis, and hematoma

Urogenital: Interstitial nephritis, papillary necrosis, proteinuria

Vascular (Extracardiac Disorders): Allergic vasculitis

Other adverse events: anorexia, aplastic anemia, migraine, pancytopenia, thrombocytosis.

Laboratory Changes

Over the course of the 24-month study (ESPS2), patients treated with Aggrenox showed a decline (mean change from baseline) in hemoglobin of 0.25 g/dL, hematocrit of 0.75%, and erythrocyte count of 0.13x10⁶/mm³.

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.

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