Aggrenox Side Effects

Please note - some side effects for Aggrenox may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA at http://www.fda.gov/medwatch/ or 1-800-FDA-1088 (1-800-332-1088).

Side Effects of Aggrenox - for the Consumer

Aggrenox Extended-Release Capsules

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Aggrenox Extended-Release Capsules:

Constipation; diarrhea; dizziness; headache; heartburn; indigestion; stomach pain.

Severe allergic reactions (rash; hives; itching; difficulty swallowing or breathing; tightness in the chest; swelling of the hands, mouth, face, lips, eyes, throat, or tongue); bloody or black, tarry stools; chest pain; convulsions; dark urine or pale stools; hoarseness; memory loss; nausea; severe stomach pain; stroke; unusual fatigue; vomiting with or without blood; yellowing of the skin or eyes.

Aggrenox Side Effects - for the Professional

Aggrenox

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 dipyridamole/aspirin combination over aspirin with respect to safety.

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).

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.

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.

Side Effects by Body System

General

Generally, aspirin-dipyridamole adverse effects most commonly affected the gastrointestinal (GI) and hematologic systems. Headache has been the single most frequently reported adverse effect. During clinical trials, the percent of patients reporting at least one adverse event was 79.9% in the aspirin-dipyridamole group and 79.1% in the placebo group. Discontinuation occurred in the treatment and placebo groups at a rate of 25% and 21%, respectively.

General adverse events affecting the body as a whole, occurring at a rate equal to or greater than 1% in patients receiving aspirin-dipyridamole, and more frequently than in the placebo group (treatment vs. placebo, respectively) included pain 6.4% vs. 6.0%, fatigue 5.8% vs. 5.5%, accidental injury 2.5% vs. 0.2%, malaise 1.6% vs. 1.3%, asthenia 1.8% vs. 1.1%, and syncope 1.0% vs. 0.5%. Hypothermia has been reported in medical literature or postmarketing reports for either dipyridamole or aspirin.

Adverse events associated with aspirin-dipyridamole and causing discontinuation during clinical trials included headache 10%, dizziness 5%, nausea 6%, abdominal pain 4%, dyspepsia 4%, vomiting 3%, diarrhea 2%, stroke 2%, transient ischemic attack (TIA) 2%, and angina pectoris 1%. Stroke, TIA, and angina pectoris occurred more frequently in the placebo group and at a rate of 4%, 3%, and 2%, respectively. No clear safety benefit was noted for the use of aspirin-dipyridamole over aspirin alone.

Gastrointestinal

Gastrointestinal (GI) symptoms were the most frequently reported side effects noted during clinical trials. The following adverse effects occurred at a rate equal to or greater than 1% in patients receiving aspirin-dipyridamole and more frequently than in the placebo group (treatment vs. placebo, respectively): dyspepsia 18.4% vs. 16.7%, abdominal pain 17.5% vs. 14.5%, nausea 16.0% vs. 14.1%, diarrhea 12.7% vs. 9.8%, vomiting 8.4% vs. 7.2%, rectal bleeding 1.6% vs. 0.8%, melena 1.9% vs. 0.8%, hemorrhoids 1.0% vs. 0.6%, and GI bleeding 1.2% vs. 0.4%.

Adverse events occurring at a rate of less than 1% and considered possibly related to either dipyridamole or aspirin included taste loss, gingival bleeding, gastritis, ulceration, perforation and cholelithiasis. Adverse reactions reported in medical literature or postmarketing reports for either dipyridamole or aspirin have included pancreatitis and hematemesis.

Nervous system

Nervous system side effects occurring at a rate equal to or greater than 1% in patients receiving aspirin-dipyridamole and more frequently than in the placebo group (treatment vs. placebo, respectively) included: headache 39.2% vs. 32.9% and convulsions 1.7% vs. 1.6%. Headache is typically the most frequently occurring adverse effect reported during clinical trials, but it may be more noticeable during the first month of treatment. Adverse events occurring at a rate of less than 1% and considered possibly related to either dipyridamole or aspirin included coma, dizziness, paresthesia, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage. Cerebral edema has been reported in medical literature or postmarketing reports for either dipyridamole or aspirin.

Cardiovascular

Cardiovascular adverse effects presenting as cardiac failure occurred in 1.6% of patients receiving aspirin-dipyridamole compared to 1.5% of patients in the placebo group. Hypotension, flushing, tachycardia, palpitation, and arrhythmia occurred at a rate of less than 1% and were considered possibly related to dipyridamole. Adverse reactions reported in medical literature or postmarketing reports for either dipyridamole or aspirin have included chest pain and angina pectoris.

Hematologic

Hematologic side effects occurring at a rate equal to or greater than 1% in patients receiving aspirin-dipyridamole and more frequently than in the placebo group (treatment vs. placebo, respectively) included hemorrhage 3.2% vs. 1.5%, epistaxis 2.4% vs. 1.5%, purpura 1.4% vs. 0.4%, anemia 1.6% vs. 0.5%. Hematoma occurred at a rate of less than 1% and was considered possibly related to either dipyridamole or aspirin.

Adverse reactions reported in medical literature or postmarketing reports for either dipyridamole or aspirin have included prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, and thrombocytopenia. Although reported for either dipyridamole or aspirin a causal relationship has not been established for aplastic anemia, pancytopenia, and thrombocytosis.

Hepatic

Hepatic adverse events occurring at a rate of less than 1% and considered possibly related to either dipyridamole or aspirin included jaundice and abnormal hepatic function. Hepatitis and hepatic failure associated with either dipyridamole or aspirin have been reported in medical literature or postmarketing reports.

Metabolic

Metabolic adverse events occurring at a rate of less than 1% and considered possibly related to either dipyridamole or aspirin included hyperglycemia and thirst. Adverse reactions reported in medical literature or postmarketing reports for either dipyridamole or aspirin have included hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia, hypoglycemia, and dehydration. Salicylates have been reported to displace triiodothyronine (T3) and thyroxine (T4) from protein binding sites. The initial effect is an increase in serum free T4 concentrations.

Other

Tinnitus cannot be used as a clinical indicator of salicylism in patients with high frequency hearing loss as these patients may have difficulty perceiving tinnitus.

Otic adverse effects of tinnitus and deafness occurred at a rate of less than 1% and were considered possibly related to either dipyridamole or aspirin. Hearing loss has been reported in medical literature or postmarketing reports associated with either dipyridamole or aspirin.

Reye's syndrome associated with aspirin has been reported in medical literature or postmarketing reports.

Musculoskeletal

Musculoskeletal side effects occurring at a rate equal to or greater than 1% in patients receiving aspirin-dipyridamole and more frequently than in the placebo group (treatment vs. placebo, respectively) included: arthralgia 5.5% vs. 4.6%, arthritis 2.1% vs. 1.2%, arthrosis 1.1% vs. 0.8%, back pain 4.6% vs. 3.9%, and myalgia 1.2% vs. 0.7%. Rhabdomyolysis has been reported in medical literature or postmarketing reports for either dipyridamole or aspirin.

Hypersensitivity

Hypersensitivity reactions reported in medical literature or postmarketing reports for either dipyridamole or aspirin have included acute anaphylaxis, allergic vasculitis, and laryngeal edema.

Oncologic

Oncologic adverse events occurring at a rate equal to or greater than 1% in patients receiving aspirin-dipyridamole and more frequently than in the placebo group were reported as unspecified neoplasms, 1.7% vs. 1.2% (treatment vs. placebo, respectively).

Respiratory

Respiratory side effects occurring at a rate equal to or greater than 1% in patients receiving aspirin-dipyridamole and more frequently than in the placebo group (treatment vs. placebo, respectively) included: coughing 1.5% vs. 1.3% and upper respiratory tract infection 1% vs. 0.8%. Hyperpnea, asthma, bronchospasm, hemoptysis, pulmonary edema occurred at a rate of less than 1% and were considered possibly related to either dipyridamole or aspirin. Tachypnea and dyspnea have been reported in medical literature or postmarketing reports for either dipyridamole or aspirin.

Renal

Renal insufficiency and failure occurred at a rate of less than 1% and were considered possibly related to either dipyridamole or aspirin. Adverse reactions reported in medical literature or postmarketing reports for either dipyridamole or aspirin have included interstitial nephritis and papillary necrosis.

Genitourinary

Genitourinary side effects of uterine hemorrhage and hematuria occurred at a rate of less than 1% and were considered possibly related to either dipyridamole or aspirin. Proteinuria associated with either dipyridamole or aspirin has been reported in medical literature or postmarketing reports.

Dermatologic

Dermatologic symptoms of pruritus and urticaria occurred in less than 1% of treatment patients and were considered possibly related to either dipyridamole or aspirin. Adverse reactions reported in medical literature or postmarketing reports for either dipyridamole or aspirin have included rash, alopecia, angioedema, and Stevens-Johnson syndrome.

Psychiatric

Psychiatric side effects occurring at a rate equal to or greater than 1% in patients receiving aspirin-dipyridamole and more frequently than in the placebo group (treatment vs. placebo, respectively) included amnesia 2.4% vs. 2.1%, confusion 1.1% vs. 0.9%, anorexia 1.2% vs. 0.9%, and somnolence 1.2% vs. 0.5%. Agitation has occurred at a rate of less than 1% and was considered possibly related to either dipyridamole or aspirin. Although reported either in medical literature or postmarketing reports for either dipyridamole or aspirin a causal relationship has not been established for anorexia.

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