Aspirin and Extended-Release Dipyridamole

1 INDICATIONS AND USAGE Aspirin and extended-release dipyridamole capsules are indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis. Aspirin and extended-release dipyridamole capsulesis a combination antiplatelet agent indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis (1)

2 DOSAGE AND ADMINISTRATION Aspirin and extended-release dipyridamole capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets. The recommended dose of aspirin and extended-release dipyridamole capsules is one capsule given orally twice daily, one in the morning and one in the evening. Swallow capsules whole without chewing. Aspirin and extended-release dipyridamole capsules can be administered with or without food. One capsule twice daily (morning and evening) with or without food (2) In case of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning; resume BID dosing within one week (2) Do not chew capsule (2) Not interchangeable with the individual components of aspirin and dipyridamole tablets (2) Dispense in this unit-of-use container (16) 2.1 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. 2.1 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.

5 WARNINGS AND PRECAUTIONS Aspirin and extended-release dipyridamole capsulesincreases the risk of bleeding (5.1) Avoid use in patients with severe hepatic or renal insufficiency (5.2, 5.3) Can cause fetal harm when administered to a pregnant woman, especially in the third trimester (5.4) 5.1 Risk of Bleeding Aspirin and extended-release dipyridamole 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, anagrelide, fibrinolytic therapy and chronic use of NSAIDs) [see Drug Interactions (7.1) ] . Intracranial Hemorrhage In European Stroke Prevention Study-2 (ESPS2), the incidence of intracranial hemorrhage was 0.6% in the aspirin and extended-release dipyridamole 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 aspirin and extended-release dipyridamole 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 aspirin and extended-release dipyridamole capsules contain 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) ] . 5.3 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) ] . 5.4 Pregnancy Because aspirin and extended-release dipyridamole capsules contain aspirin, aspirin and 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), avoid aspirin and extended-release dipyridamole 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/m 2 basis, about 66 and 44 times, respectively, the dose of aspirin contained in the maximum recommended daily human dose of aspirin and extended-release dipyridamole. 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 1,000 mg/kg, respectively (about 1½, 2 and 25 times the maximum recommended daily human oral dose, respectively, on a mg/m 2 basis) and have revealed no evidence of harm …

4 CONTRAINDICATIONS Hypersensitivity to any product ingredients (4.1) Patients with known allergy to NSAIDs (4.2) Patients with the syndrome of asthma, rhinitis and nasal polyps (4.2) 4.1 Hypersensitivity Aspirin and extended-release dipyridamole capsules are contraindicated in patients with known hypersensitivity to any of the product components. 4.2 Allergy Aspirin, USP is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug (NSAID) products and in patients with the syndrome of asthma, rhinitis and nasal polyps. Aspirin, USP may cause severe urticaria, angioedema or bronchospasm. 4.3 Reye Syndrome Do not use aspirin, USP in children or teenagers with viral infections because of the risk of Reye syndrome. 4.1 Hypersensitivity Aspirin and extended-release dipyridamole capsules are contraindicated in patients with known hypersensitivity to any of the product components. 4.2 Allergy Aspirin, USP is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug (NSAID) products and in patients with the syndrome of asthma, rhinitis and nasal polyps. Aspirin, USP may cause severe urticaria, angioedema or bronchospasm. 4.3 Reye Syndrome Do not use aspirin, USP in children or teenagers with viral infections because of the risk of Reye syndrome.

7 DRUG INTERACTIONS Co-administration with anti-coagulants, antiplatelets, or NSAIDs can increase risk of bleeding (7.1) Decreased renal function can occur with co-administration with NSAIDs (7.1) 7.1 Drug Interaction Study Information Obtained From 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. Anticoagulants and Antiplatelets Patients taking aspirin and extended-release dipyridamole in combination with anticoagulants, antiplatelets, or any substance impacting coagulation are at increased risk for bleeding. 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. Anagrelide Patients taking aspirin in combination with anagrelide are at an increased risk of bleeding. 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. 7.1 Drug Interaction Study Information Obtained From 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. Anticoagulants and Antiplatelets Patients taking aspirin and extended-release dipyridamole in combination with anticoagulants, antiplatelets, or any substance impacting coagulation are at increased risk for bleeding. 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. Anagrelide Patients taking aspirin in combination with anagrelide are at an increased risk of bleeding…

8.1 Pregnancy Teratogenic Effects, Pregnancy Category D. [see Warnings and Precautions (5.4) ].

8.3 Nursing Mothers Both dipyridamole and aspirin are excreted in human milk. Exercise caution when aspirin and extended-release dipyridamole capsules are administered to a nursing woman.

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: Hypersensitivity [see Contraindications (4.1) ] Allergy [see Contraindications (4.2) ] Risk of Bleeding [see Warnings and Precautions (5.1) ] The most frequently reported adverse reactions (>10% and greater than placebo) were headache, dyspepsia, abdominal pain, nausea and diarrhea (6) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or www.avkare.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 aspirin and extended-release dipyridamole was established in the European Stroke Prevention Study-2 (ESPS2). ESPS2 was a double-blind, placebo-controlled study that evaluated 6,602 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 aspirin and extended-release dipyridamole, 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 aspirin and extended-release dipyridamole with placebo, extended-release dipyridamole alone and aspirin alone. The study was conducted in a total of 6,602 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 aspirin and extended-release dipyridamole 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. Table 1 Incidence of Adverse Events in ESPS2 a Individual Treatment Group Aspirin and Extended-release Dipyridamole ER-DP Alone ASA Alone Placebo Body System/Preferred Term 1,650 1,654 1,649 1,649 Total Number of Patients Total Number (%) of Patients With at Least One On-Treatment Adverse Event 1,319 (80%) 1,305 (79%) 1,323 (80%) 1,304 (79%) Central and Peripheral Nervous System Disorders Headache 647 (39%) 634 (38%) 558 (34%) 543 (33%) Convulsions 28 (2%) 15 (1%) 28 (2%) 26 (2%) Gastrointestinal System Disorders Dyspepsia 303 (18%) 288 (17%) 299 (18%) 275 (17%) Abdominal Pain 289 (18%) 255 (15%) 262 (16%) 239 (14%) Nausea 264 (16%) 254 (15%) 210 (13%) 232 (14%) Diarrhea 210 (13%) 257 (16%) 112 (7%) 161 (10%) Vomiting 138 (8%) 129 (8%) 101 (6%) 118 (7%) Hemorrhage Rectum 26 (2%) 22 (1%) 16 (1%) 13 (1%) Melena 31 (2%) 10 (1%) 20 (1%) 13 (1%) Hemorrhoids 16 (1%) 13 (1%) 10 (1%) 10 (1%) GI Hemorrhage 20 (1%) 5 (0%) 15 (1%) 7 (0%) Body as a Whole - General Disorders Pain 105 (6%) 88 (5%) 103 (6%) 99 (6%) Fatigue 95 (6%) 93 (6%) 97 (6%) 90 (5%) Back Pain 76 (5%) 77 (5%) 74 (4%) 65 (4%) Accidental Injury 42 (3%) 24 (1%) 51 (3%) 37 (2%) Malaise 27 (2%) 23 (1%) 26 (2%) 22 (1%) Asthenia 29 (2%) 19 (1%) 17 (1%) 18 (1%) Syncope 17 (1%) 13 (1%) 16 (1%) 8 (0%) Psychiatric Disorders Amnesia 39 (2%) 40 (2%) 57 (3%) 34 (2%) Confusion 18 (1%) 9 (1%) 22 (1%) 15 (1%) Anorexia 19 (1%) 17 (1%) 10 (1%) 15 (1%) Somnolence 20 (1%) 13 (1%) 18 (1%) 9 (1%) Musculoskeletal System Disorders Arthralgia 91 (6%) 75 (5%) 91 (6%) 76 (5%) Arthritis 34 (2%) 25 (2%) 17 (1%) 19 (1%) Arthrosis 18 (1%) 22 (1%) 13 (1%) 14 (1%) Myalgia 20 (1%) 16 (1%) 11 (1%) 11 (1%) Respiratory System Disorders Coughing 25 (2%) 18 (1%) 32 (2%) 21 (1%) Upper Respiratory Tract Infection 16 (1%) 9 (1%) 16 (1%) 14 (1%) Cardiovascular Disorders, General Cardiac Failure 26 (2%) 17 (1%) 30 (2%) 25 (2%) Pl…