Aggrenox side effects and warnings

List of side effects and warnings
Common Side Effects Other adverse reactions Laboratory Changes Warnings Alcohol Warning Coagulation Abnormalities Gastrointestinal (GI) Side Effects Peptic Ulcer Disease Pregnancy

Common Side Effects
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 shown below 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



Headache was most notable in the first month of treatment.

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Other adverse reactions
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 abnormality
 * 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.

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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.

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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.

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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.

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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.

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

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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 is 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.

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