Aggrenox Side Effects, and Drug Interactions - Aspirin/extended-release dipyridamole

Aggrenox Side Effects, and Drug Interactions - Aspirin/extended-release dipyridamole

SIDE EFFECTS

A 24-month, multicenter, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of AGGRENOX (aspirin/extended-release dipyridamole) 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 where the incidence was also greater than in those patients treated with placebo. There is no clear benefit of the dipyridamole/aspirin combination over aspirin with respect to safety.

Discontinuation due to adverse events in ESPS2 was 25% forAGGRENOX, 25% forextended-release dipyridamole, 19% foraspirin, and 21% forplacebo (referto Table 3).

Adverse reactions that occurred in less than 1% of patients treated with AGGRENOX 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 & 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 & 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. 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 & 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. Urogenital: Interstitial nephritis, papillary necrosis, proteinuria. Vascular (Extracardiac Disorders): Allergic vasculitis.

The following is a list of additional adverse events that have been reported either in the literature or are from postmarketing spontaneous reports for either dipyridamole or aspirin. The causal relationship of these adverse events has not been established: anorexia, aplastic anemia, pancytopenia, thrombocytosis.

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.