Aspirin/Dipyridamole

{{DrugProjectFormSinglePage |authorTag=Sheng Shi, M.D. [1] |genericName=Aspirin/Dipyridamole |aOrAn=a |drugClass=NSAID |indicationType=prophylaxis |indication=stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis |adverseReactions=Abdominal pain, Diarrhea, Indigestion, Bleeding, Blood coagulation disorder with prolonged bleeding time, Arthralgia, Headache |blackBoxWarningTitle=TITLE |blackBoxWarningBody=Condition Name: (Content)

|fdaLIADAdult=

Reduce the risk of stroke

• Dosing information

• AGGRENOX is not interchangeable with the individual components of aspirin and dipyridamole tablets.
• Recommended dose: one capsule PO bid, one in the morning and one in the evening.
• Swallow capsules whole without chewing. AGGRENOX can be administered with or without food.

• Alternative Regimen in Case of Intolerable Headaches

• In the event of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning. Because there are no outcome data with this regimen and headaches become less of a problem as treatment continues, patients should return to the usual regimen as soon as possible, usually within one week.

|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Aspirin/Dipyridamole in adult patients.

|offLabelAdultNoGuideSupport=

Hemodialysis]

• Dosing information

• aspirin 25 milligrams PO bid(mg)/extended-release dipyridamole 200 mg PO bid

|fdaLIADPed=Safety and effectiveness of AGGRENOX in pediatric patients have not been studied. |offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Aspirin/Dipyridamole in pediatric patients. |offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Aspirin/Dipyridamole in pediatric patients. |contraindications====Hypersensitivity===

AGGRENOX is contraindicated in patients with known hypersensitivity to any of the product components.

Allergy

Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with the syndrome of [[asthma‘‘, rhinitis, and [[nasal polyps. Aspirin may causesevere urticaria, angioedema or bronchospasm.

Reye Syndrome

Do not use aspirin in children or teenagers with viral infections because of the risk of Reye syndrome. |warnings=====isk of Bleeding====

AGGRENOX increases the risk of bleeding. Risk factors for bleeding include the use of other drugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs) [see Drug Interactions (7.1)]. Intracranial Hemorrhage In ESPS2 the incidence of intracranial hemorrhage was 0.6% in the AGGRENOX group, 0.5% in the extended-release dipyridamole (ER-DP) group, 0.4% in the aspirin (ASA) group and 0.4% in the placebo groups. 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. Inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. In ESPS2 the incidence of gastrointestinal bleeding was 4.1% in the AGGRENOX group, 2.2% in the extended-release dipyridamole group, 3.2% in the aspirin group, and 2.1% in the placebo groups. Peptic Ulcer Disease Avoid using aspirin in patients with a history of active peptic ulcer disease, which can cause gastric mucosal irritation and bleeding. Alcohol Warning Because AGGRENOX contains aspirin, counsel patients who consume three or more alcoholic drinks every day about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.

5.2  Renal Failure

Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

=Hepatic Insufficiency

Elevations of hepatic enzymes and hepatic failure have been reported in association with dipyridamole administration [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Pregnancy

Because AGGRENOX contains aspirin, AGGRENOX 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), avoid AGGRENOX in the third trimester of pregnancy [see Use in Specific Populations (8.1)]. 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. 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 of the use of AGGRENOX in pregnant women. If AGGRENOX is used during pregnancy, or if the patient becomes pregnant while taking AGGRENOX, inform the patient of the potential hazard to the fetus.

Coronary Artery Disease

Dipyridamole has a vasodilatory effect. Chest pain may be precipitated or 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.

Hypotension

Dipyridamole produces peripheral vasodilation, which can exacerbate pre-existing hypotension.

General

AGGRENOX capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets. |clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The efficacy and safety of AGGRENOX was established in the European Stroke Prevention Study-2 (ESPS2). ESPS2 was a double-blind, placebo controlled study that evaluated 6602 patients over the age of 18 years who had a previous ischemic stroke or transient ischemic attack within ninety days prior to entry. Patients were randomized to either AGGRENOX, aspirin, ER-DP, or placebo [see Clinical Studies (14)]; primary endpoints included stroke (fatal or nonfatal) and death from all causes. This 24-month, multicenter, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of AGGRENOX 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 1 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.

[[File:Aspirin/Dipyridamole_adverse_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

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 2)

[[File:Aspirin/Dipyridamole_adverse_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

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 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

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. |postmarketing=The following is a list of additional adverse reactions that have been reported either in the literature or are from post-marketing 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to AGGRENOX.

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 syndrome, hematemesis Hearing and Vestibular Disorders: Hearing loss Immune System Disorders: 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. |alcohol=Alcohol-Aspirin/Dipyridamole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. }}