Aspirin and Extended-Release Dipyridamole

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%) Platelet, Bleeding and Clotting Disorders Hemorrhage NOS 52 (3%) 24 (1%) 46 (3%) 24 (1%) Epistaxis 39 (2%) 16 (1%) 45 (3%) 25 (2%) Purpura 23 (1%) 8 (0%) 9 (1%) 7 (0%) Neoplasm Neoplasm NOS 28 (2%) 16 (1%) 23 (1%) 20 (1%) Red Blood Cell Disorders Anemia 27 (2%) 16 (1%) 19 (1%) 9 (1%) a Reported by ≥1% of patients during aspirin and extended-release dipyridamole treatment where the incidence was greater than in those treated with placebo. Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID. NOS = not otherwise specified. Discontinuation due to adverse events in ESPS2 was 25% for aspirin and extended-release dipyridamole, 25% for extended-release dipyridamole, 19% for aspirin and 21% for placebo (refer to Table 2). Table 2 Incidence of Adverse Events that Led to the Discontinuation of Treatment: Adverse Events with an Incidence of ≥1% in the Aspirin and Extended-release Dipyridamole Group Treatment Groups Aspirin and Extended-release Dipyridamole ER-DP ASA Placebo Total Number of Patients 1,650 1,654 1,649 1,649 Patients with at least one Adverse Event that led to treatment discontinuation 417 (25%) 419 (25%) 318 (19%) 352 (21%) Headache 165 (10%) 166 (10%) 57 (3%) 69 (4%) Dizziness 85 (5%) 97 (6%) 69 (4%) 68 (4%) Nausea 91 (6%) 95 (6%) 51 (3%) 53 (3%) Abdominal Pain 74 (4%) 64 (4%) 56 (3%) 52 (3%) Dyspepsia 59 (4%) 61 (4%) 49 (3%) 46 (3%) Vomiting 53 (3%) 52 (3%) 28 (2%) 24 (1%) Diarrhea 35 (2%) 41 (2%) 9 (<1%) 16 (<1%) Stroke 39 (2%) 48 (3%) 57 (3%) 73 (4%) Transient Ischemic Attack 35 (2%) 40 (2%) 26 (2%) 48 (3%) Angina Pectoris 23 (1%) 20 (1%) 16 (<1%) 26 (2%) Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID. 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 aspirin and extended-release dipyridamole 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 aspirin and extended-release dipyridamole showed a decline (mean change from baseline) in hemoglobin of 0.25 g/dL, hematocrit of 0.75% and erythrocyte count of 0.13x10 6 /mm 3 . 6.2 Post-Marketing Experience 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 aspirin and extended-release dipyridamole. 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. To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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.

11 DESCRIPTION Aspirin and extended-release dipyridamole is a combination antiplatelet agent intended for oral administration. Each hard gelatin capsule contains 200 mg dipyridamole, USP in an extended-release form and 25 mg aspirin USP, as an immediate-release sugar-coated tablet. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, corn starch, hypromellose, hypromellose phthalate, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, polyethylene glycol, simethicone, stearic acid, sucrose, talc, tartaric acid, triethyl citrate and triacetin. Each capsule shell contains D&C Yellow #10, gelatin, iron oxide red, iron oxide yellow, purified water, sodium lauryl sulfate and titanium dioxide. The imprinting inks contain butyl alcohol, D&C Yellow #10, dehydrated alcohol, FD&C Red #40, isopropyl alcohol, povidone, propylene glycol, shellac, sodium hydroxide and titanium dioxide. Dipyridamole, USP Dipyridamole, USP is an antiplatelet agent chemically described as 2,2',2'',2'''-[(4,8-Dipiperidinopyrimido[5,4- d ]pyrimidine-2,6-diyl)dinitrilo]-tetraethanol. It has the following structural formula: Dipyridamole, USP is an odorless yellow crystalline substance, having a bitter taste. It is soluble in dilute acids, methanol and chloroform, and is practically insoluble in water. Aspirin, USP The antiplatelet agent aspirin, USP (acetylsalicylic acid) is chemically known as benzoic acid, 2- (acetyloxy)-, and has the following structural formula: Aspirin, USP is an odorless white needle-like crystalline or powdery substance. When exposed to moisture, aspirin hydrolyzes into salicylic and acetic acids, and gives off a vinegary odor. It is highly lipid soluble and slightly soluble in water. chem struc DP chem struc ASP

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.

10 OVERDOSAGE Because of the dose ratio of dipyridamole to aspirin, overdosage of aspirin and extended-release dipyridamole is likely to be dominated by signs and symptoms of dipyridamole overdose. In case of real or suspected overdose, seek medical attention or contact a Poison Control Center immediately. Careful medical management is essential. Based upon the known hemodynamic effects of dipyridamole, symptoms such as warm feeling, flushes, sweating, restlessness, feeling of weakness and dizziness may occur. A drop in blood pressure and tachycardia might also be observed. Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. Severity of aspirin intoxication is determined by measuring the blood salicylate level. The early signs of salicylic overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approaching 200 mcg/mL. In severe cases, hyperthermia and hypovolemia are the major immediate threats to life. Plasma concentrations of aspirin above 300 mcg/mL are clearly toxic. Severe toxic effects are associated with levels above 400 mcg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g. Treatment of overdose consists primarily of supporting vital functions, increasing drug elimination, and correcting acid-base disturbances. Consider gastric emptying and/or lavage as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal as a slurry may be beneficial if less than 3 hours have passed since ingestion. Charcoal absorption should not be employed prior to emesis and lavage. Follow acid-base status closely with serial blood gas and serum pH measurements. Maintain fluid and electrolyte balance. Administer replacement fluid intravenously and augment with correction of acidosis. Treatment may require the use of a vasopressor. Infusion of glucose may be required to control hypoglycemia. Administration of xanthine derivatives (e.g., aminophylline) may reverse the hemodynamic effects of dipyridamole overdose. Plasma electrolytes and pH should be monitored serially to promote alkaline diuresis of salicylate if renal function is normal. In patients with renal insufficiency or in cases of life-threatening intoxication, dialysis is usually required to treat salicylic overdose; however, since dipyridamole is highly protein bound, dialysis is not likely to remove dipyridamole. Exchange transfusion may be indicated in infants and young children.

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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The antithrombotic action of aspirin and extended-release dipyridamole is the result of the additive antiplatelet effects of dipyridamole and aspirin. Dipyridamole Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in vivo ; the inhibition occurs in a dose-dependent manner at therapeutic concentrations (0.5 to 1.9 mcg/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A 2 -receptor thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3",5"-adenosine monophosphate (cAMP) levels. Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP). Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic-3",5"guanosine monophosphate-PDE (cGMP-PDE), thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, now identified as nitric oxide). Aspirin Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of thromboxane A 2 , a powerful inducer of platelet aggregation and vasoconstriction. 12.2 Pharmacodynamics The effect of either agent on the other"s inhibition of platelet reactivity has not been evaluated. 12.3 Pharmacokinetics There are no significant interactions between aspirin and dipyridamole. The kinetics of the components are unchanged by their co-administration as aspirin and extended-release dipyridamole. Dipyridamole Absorption Peak plasma levels of dipyridamole are achieved 2 hours (range 1 to 6 hours) after administration of a daily dose of 400 mg aspirin and extended-release dipyridamole (given as 200 mg BID). The peak plasma concentration at steady-state is 1.98 mcg/mL (1.01 to 3.99 mcg/mL) and the steady-state trough concentration is 0.53 mcg/mL (0.18 to 1.01 mcg/mL). Effect of Food When aspirin and extended-release dipyridamole capsules were taken with a high fat meal, dipyridamole peak plasma levels (C max ) and total absorption (AUC) were decreased at steady-state by 20% to 30% compared to fasting. Due to the similar degree of inhibition of adenosine uptake at these plasma concentrations, this food effect is not considered clinically relevant. Distribution Dipyridamole is highly lipophilic (log P=3.71, pH=7); however, it has been shown that the drug does not cross the blood-brain barrier to any significant extent in animals. The steady-state volume of distribution of dipyridamole is about 92 L. Approximately 99% of dipyridamole is bound to plasma proteins, predominantly to alpha 1-acid glycoprotein and albumin. Metabolism and Elimination Dipyridamole is metabolized in the liver, primarily by conjugation with glucuronic acid, of which monoglucuronide which has low pharmacodynamic activity is the primary metabolite. In plasma, about 80% of the total amount is present as parent compound and 20% as monoglucuronide. Most of the glucuronide metabolite (about 95%) is excreted via bile into the feces, with some evidence of enterohepatic circulation. Renal excretion of parent compound is negligible and urinary excretion of the glucuronide metabolite is low (about 5%). With intravenous (i.v.) treatment of dipyridamole, a triphasic profile is obtained: a rapid alpha phase, with a half-life of about 3.4 minutes, a beta phase, with a half-life of about 39 minutes, (which, together with the alpha phase accounts for about 70% of the total area under the curve, AUC) and a prolonged elimination phase λz with a half-life of about 15.5 hours. Due to the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with aspirin and extended-release dipyridamole which, in Trial 9.123 was 13.6 hours. Special Populations Geriatric Patients: In ESPS2 [see Clinical Studies (14) ] , plasma concentrations (determined as AUC) of dipyridamole in healthy elderly subjects (>65 years) were about 40% higher than in subjects younger than 55 years receiving treatment with aspirin and extended-release dipyridamole. Hepatic Dysfunction: No study has been conducted with aspirin and extended-release dipyridamole in patients with hepatic dysfunction. In a study conducted with an intravenous formulation of dipyridamole, patients with mild to severe hepatic insufficiency showed no change in plasma concentrations of dipyridamole but showed an increase in the pharmacologically inactive monoglucuronide metabolite. Dipyridamole can be dosed without restriction as long as there is no evidence of hepatic failure. Renal Dysfunction: No study has been conducted with aspirin and extended-release dipyridamole in patients with renal dysfunction. In ESPS2 patients [see Clinical Studies (14) ] , with creatinine clearances ranging from about 15 mL/min to >100 mL/min, no changes were observed in the pharmacokinetics of dipyridamole or its glucuronide metabolite if data were corrected for differences in age. Aspirin Absorption Peak plasma levels of aspirin are achieved 0.63 hours (0.5 to 1 hour) after administration of a 50 mg aspirin daily dose from aspirin and extended-release dipyridamole (given as 25 mg BID). The peak plasma concentration at steady-state is 319 ng/mL (175 to 463 ng/mL). Aspirin undergoes moderate hydrolysis to salicylic acid in the liver and the gastrointestinal wall, with 50% to 75% of an administered dose reaching the systemic circulation as intact aspirin. Effect of Food When aspirin and extended-release dipyridamole capsules were taken with a high fat meal, there was no difference for aspirin in AUC at steady-state, and the approximately 50% decrease in C max was not considered clinically relevant based on a similar degree of cyclooxygenase inhibition comparing the fed and fasted state. Distribution Aspirin is poorly bound to plasma proteins and its apparent volume of distribution is low (10 L). Its metabolite, salicylic acid, is highly bound to plasma proteins, but its binding is concentration-dependent (nonlinear). At low concentrations (<100 mcg/mL), approximately 90% of salicylic acid is bound to albumin. Salicylic acid is widely distributed to all tissues and fluids in the body, including the central nervous system, breast milk and fetal tissues. Early signs of salicylate overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approximating 200 mcg/mL [see Adverse Reactions (6) and Overdosage (10) ] . Metabolism and Elimination Aspirin is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 20 minutes. Plasma levels of aspirin are essentially undetectable 2 to 2.5 hours after dosing and peak salicylic acid concentrations occur 1 hour (range: 0.5 to 2 hours) after administration of aspirin. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide and a number of minor metabolites. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10 to 20 g), the plasma half-life may be increased to over 20 hours. The elimination of acetylsalicylic acid follows first-order kinetics with aspirin and extended-release dipyridamole and has a half-life of 0.33 hours. The half-life of salicylic acid is 1.71 hours. Both values correspond well with data from the literature at lower doses which state a resultant half-life of approximately 2 to 3 hours. At higher doses, the elimination of salicylic acid follows zero-order kinetics (i.e., the rate of elimination is constant in relation to plasma concentration), with an apparent half-life of 6 hours or higher. Renal excretion of unchanged drug depends upon urinary pH. As urinary pH rises above 6.5, the renal clearance of free salicylate increases from <5% to >80%. Alkalinization of the urine is a key concept in the management of salicylate overdose [see Overdosage (10) ] . Following therapeutic doses, about 10% is excreted as salicylic acid and 75% as salicyluric acid, as the phenolic and acyl glucuronides, in urine. Special Populations Hepatic Dysfunction: Avoid aspirin in patients with severe hepatic insufficiency. Renal Dysfunction: Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/min). Aspirin and Extended-release Dipyridamole Capsules Drug Interaction A dedicated drug interaction study was conducted in 60 healthy volunteers to evaluate the effects of omeprazole 80 mg administered once daily on the pharmacokinetics (PK) of dipyridamole and the pharmacodynamics (PD) of acetylsalicylic acid when co-administered with aspirin and extended-release dipyridamole twice daily. Dipyridamole exposure (C max and AUC) at steady-state were similar with or without omeprazole co-administration. The pharmacokinetics of acetylsalicylic acid was not characterized. However, the antiplatelet activity as measured by arachidonic acid induced platelet aggregation was similar between the treatment arms at steady-state.

12.1 Mechanism of Action The antithrombotic action of aspirin and extended-release dipyridamole is the result of the additive antiplatelet effects of dipyridamole and aspirin. Dipyridamole Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in vivo ; the inhibition occurs in a dose-dependent manner at therapeutic concentrations (0.5 to 1.9 mcg/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A 2 -receptor thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3",5"-adenosine monophosphate (cAMP) levels. Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP). Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic-3",5"guanosine monophosphate-PDE (cGMP-PDE), thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, now identified as nitric oxide). Aspirin Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of thromboxane A 2 , a powerful inducer of platelet aggregation and vasoconstriction.

12.2 Pharmacodynamics The effect of either agent on the other"s inhibition of platelet reactivity has not been evaluated.

12.3 Pharmacokinetics There are no significant interactions between aspirin and dipyridamole. The kinetics of the components are unchanged by their co-administration as aspirin and extended-release dipyridamole. Dipyridamole Absorption Peak plasma levels of dipyridamole are achieved 2 hours (range 1 to 6 hours) after administration of a daily dose of 400 mg aspirin and extended-release dipyridamole (given as 200 mg BID). The peak plasma concentration at steady-state is 1.98 mcg/mL (1.01 to 3.99 mcg/mL) and the steady-state trough concentration is 0.53 mcg/mL (0.18 to 1.01 mcg/mL). Effect of Food When aspirin and extended-release dipyridamole capsules were taken with a high fat meal, dipyridamole peak plasma levels (C max ) and total absorption (AUC) were decreased at steady-state by 20% to 30% compared to fasting. Due to the similar degree of inhibition of adenosine uptake at these plasma concentrations, this food effect is not considered clinically relevant. Distribution Dipyridamole is highly lipophilic (log P=3.71, pH=7); however, it has been shown that the drug does not cross the blood-brain barrier to any significant extent in animals. The steady-state volume of distribution of dipyridamole is about 92 L. Approximately 99% of dipyridamole is bound to plasma proteins, predominantly to alpha 1-acid glycoprotein and albumin. Metabolism and Elimination Dipyridamole is metabolized in the liver, primarily by conjugation with glucuronic acid, of which monoglucuronide which has low pharmacodynamic activity is the primary metabolite. In plasma, about 80% of the total amount is present as parent compound and 20% as monoglucuronide. Most of the glucuronide metabolite (about 95%) is excreted via bile into the feces, with some evidence of enterohepatic circulation. Renal excretion of parent compound is negligible and urinary excretion of the glucuronide metabolite is low (about 5%). With intravenous (i.v.) treatment of dipyridamole, a triphasic profile is obtained: a rapid alpha phase, with a half-life of about 3.4 minutes, a beta phase, with a half-life of about 39 minutes, (which, together with the alpha phase accounts for about 70% of the total area under the curve, AUC) and a prolonged elimination phase λz with a half-life of about 15.5 hours. Due to the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with aspirin and extended-release dipyridamole which, in Trial 9.123 was 13.6 hours. Special Populations Geriatric Patients: In ESPS2 [see Clinical Studies (14) ] , plasma concentrations (determined as AUC) of dipyridamole in healthy elderly subjects (>65 years) were about 40% higher than in subjects younger than 55 years receiving treatment with aspirin and extended-release dipyridamole. Hepatic Dysfunction: No study has been conducted with aspirin and extended-release dipyridamole in patients with hepatic dysfunction. In a study conducted with an intravenous formulation of dipyridamole, patients with mild to severe hepatic insufficiency showed no change in plasma concentrations of dipyridamole but showed an increase in the pharmacologically inactive monoglucuronide metabolite. Dipyridamole can be dosed without restriction as long as there is no evidence of hepatic failure. Renal Dysfunction: No study has been conducted with aspirin and extended-release dipyridamole in patients with renal dysfunction. In ESPS2 patients [see Clinical Studies (14) ] , with creatinine clearances ranging from about 15 mL/min to >100 mL/min, no changes were observed in the pharmacokinetics of dipyridamole or its glucuronide metabolite if data were corrected for differences in age. Aspirin Absorption Peak plasma levels of aspirin are achieved 0.63 hours (0.5 to 1 hour) after administration of a 50 mg aspirin daily dose from aspirin and extended-release dipyridamole (given as 25 mg BID). The peak plasma concentration at steady-state is 319 ng/mL (175 to 463 ng/mL). Aspirin undergoes moderate hydrolysis to salicylic acid in the liver and the gastrointestinal wall, with 50% to 75% of an administered dose reaching the systemic circulation as intact aspirin. Effect of Food When aspirin and extended-release dipyridamole capsules were taken with a high fat meal, there was no difference for aspirin in AUC at steady-state, and the approximately 50% decrease in C max was not considered clinically relevant based on a similar degree of cyclooxygenase inhibition comparing the fed and fasted state. Distribution Aspirin is poorly bound to plasma proteins and its apparent volume of distribution is low (10 L). Its metabolite, salicylic acid, is highly bound to plasma proteins, but its binding is concentration-dependent (nonlinear). At low concentrations (<100 mcg/mL), approximately 90% of salicylic acid is bound to albumin. Salicylic acid is widely distributed to all tissues and fluids in the body, including the central nervous system, breast milk and fetal tissues. Early signs of salicylate overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approximating 200 mcg/mL [see Adverse Reactions (6) and Overdosage (10) ] . Metabolism and Elimination Aspirin is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 20 minutes. Plasma levels of aspirin are essentially undetectable 2 to 2.5 hours after dosing and peak salicylic acid concentrations occur 1 hour (range: 0.5 to 2 hours) after administration of aspirin. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide and a number of minor metabolites. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10 to 20 g), the plasma half-life may be increased to over 20 hours. The elimination of acetylsalicylic acid follows first-order kinetics with aspirin and extended-release dipyridamole and has a half-life of 0.33 hours. The half-life of salicylic acid is 1.71 hours. Both values correspond well with data from the literature at lower doses which state a resultant half-life of approximately 2 to 3 hours. At higher doses, the elimination of salicylic acid follows zero-order kinetics (i.e., the rate of elimination is constant in relation to plasma concentration), with an apparent half-life of 6 hours or higher. Renal excretion of unchanged drug depends upon urinary pH. As urinary pH rises above 6.5, the renal clearance of free salicylate increases from <5% to >80%. Alkalinization of the urine is a key concept in the management of salicylate overdose [see Overdosage (10) ] . Following therapeutic doses, about 10% is excreted as salicylic acid and 75% as salicyluric acid, as the phenolic and acyl glucuronides, in urine. Special Populations Hepatic Dysfunction: Avoid aspirin in patients with severe hepatic insufficiency. Renal Dysfunction: Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/min). Aspirin and Extended-release Dipyridamole Capsules Drug Interaction A dedicated drug interaction study was conducted in 60 healthy volunteers to evaluate the effects of omeprazole 80 mg administered once daily on the pharmacokinetics (PK) of dipyridamole and the pharmacodynamics (PD) of acetylsalicylic acid when co-administered with aspirin and extended-release dipyridamole twice daily. Dipyridamole exposure (C max and AUC) at steady-state were similar with or without omeprazole co-administration. The pharmacokinetics of acetylsalicylic acid was not characterized. However, the antiplatelet activity as measured by arachidonic acid induced platelet aggregation was similar between the treatment arms at steady-state.

20240109

6

3 DOSAGE FORMS AND STRENGTHS 25 mg/200 mg capsules with a red opaque cap and a yellow opaque body, filled with light yellow to yellow extended-release dipyridamole pellets and a white to off-white, round, film-coated, biconvex, unscored, plain aspirin tablet. The capsule is imprinted axially with “AN” in yellow ink on the cap and “596” in red ink on the body. Capsule: 25 mg aspirin/200 mg extended-release dipyridamole (3)

Aspirin and Extended-Release Dipyridamole Aspirin and Extended-Release Dipyridamole METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A CELLULOSE, MICROCRYSTALLINE STEARIC ACID SUCROSE TALC TARTARIC ACID TRIETHYL CITRATE TRIACETIN D&C YELLOW NO. 10 GELATIN FERRIC OXIDE RED FERRIC OXIDE YELLOW WATER SODIUM LAURYL SULFATE TITANIUM DIOXIDE BUTYL ALCOHOL FD&C RED NO. 40 ISOPROPYL ALCOHOL POVIDONE PROPYLENE GLYCOL SHELLAC SODIUM HYDROXIDE DIMETHICONE ASPIRIN ASPIRIN DIPYRIDAMOLE DIPYRIDAMOLE POLYETHYLENE GLYCOL, UNSPECIFIED SILICON DIOXIDE STARCH, CORN HYPROMELLOSES HYPROMELLOSE PHTHALATE (24% PHTHALATE, 55 CST) LACTOSE MONOHYDRATE red-opaque yellow-opaque AN;596

13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility In studies in which dipyridamole was administered in the feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in males and up to 142 weeks in females), there was no evidence of drug-related carcinogenesis. The highest dose administered in these studies (75 mg/kg/day) was, on a mg/m 2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) in mice and about twice the MRHD in rats. Combinations of dipyridamole and aspirin (1:5 ratio) tested negative in the Ames test, in vivo chromosome aberration tests (in mice and hamsters), oral micronucleus tests (in mice and hamsters) and oral dominant lethal test (in mice). Aspirin, alone, induced chromosome aberrations in cultured human fibroblasts. Mutagenicity tests of dipyridamole alone with bacterial and mammalian cell systems were negative. Combinations of dipyridamole and aspirin have not been evaluated for effects on fertility and reproductive performance. There was no evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times the MRHD on a mg/m 2 basis). A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1,250 mg/kg (more than 30 times the MRHD on a mg/m 2 basis). Aspirin inhibits ovulation in rats.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility In studies in which dipyridamole was administered in the feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in males and up to 142 weeks in females), there was no evidence of drug-related carcinogenesis. The highest dose administered in these studies (75 mg/kg/day) was, on a mg/m 2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) in mice and about twice the MRHD in rats. Combinations of dipyridamole and aspirin (1:5 ratio) tested negative in the Ames test, in vivo chromosome aberration tests (in mice and hamsters), oral micronucleus tests (in mice and hamsters) and oral dominant lethal test (in mice). Aspirin, alone, induced chromosome aberrations in cultured human fibroblasts. Mutagenicity tests of dipyridamole alone with bacterial and mammalian cell systems were negative. Combinations of dipyridamole and aspirin have not been evaluated for effects on fertility and reproductive performance. There was no evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times the MRHD on a mg/m 2 basis). A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1,250 mg/kg (more than 30 times the MRHD on a mg/m 2 basis). Aspirin inhibits ovulation in rats.

ANDA206392

Aspirin and Extended-Release Dipyridamole

Aspirin and Extended-Release Dipyridamole

42291-116

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL 25 200

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Risk of Bleeding Inform patients that as with other antiplatelet agents, there is a general risk of bleeding including intracranial and gastrointestinal bleeding. Inform patients about the signs and symptoms of bleeding, including occult bleeding. Tell patients to notify their physician if they are prescribed any drug which may increase risk of bleeding. Counsel patients who consume three or more alcoholic drinks daily about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. Pregnancy Inform patients that aspirin is known to be harmful to fetuses and ask the patient to notify them if they are or become pregnant. Headaches Some patients may experience headaches upon treatment initiation; these are usually transient. In case of intolerable headaches, tell patients to contact their physician. Dosage and Administration Tell patients that aspirin and extended-release dipyridamole capsules should be swallowed whole, and not chewed or crushed. If you miss a dose, continue with your next dose on your regular schedule. Do not take a double dose. Storage Inform patients to protect aspirin and extended-release dipyridamole capsules from moisture. Manufactured for: AvKARE Pulaski, TN 38478 Mfg. Rev. 12-2015-00 AV 04/17 (P)

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%) Platelet, Bleeding and Clotting Disorders Hemorrhage NOS 52 (3%) 24 (1%) 46 (3%) 24 (1%) Epistaxis 39 (2%) 16 (1%) 45 (3%) 25 (2%) Purpura 23 (1%) 8 (0%) 9 (1%) 7 (0%) Neoplasm Neoplasm NOS 28 (2%) 16 (1%) 23 (1%) 20 (1%) Red Blood Cell Disorders Anemia 27 (2%) 16 (1%) 19 (1%) 9 (1%) a Reported by ≥1% of patients during aspirin and extended-release dipyridamole treatment where the incidence was greater than in those treated with placebo. Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID. NOS = not otherwise specified. Discontinuation due to adverse events in ESPS2 was 25% for aspirin and extended-release dipyridamole, 25% for extended-release dipyridamole, 19% for aspirin and 21% for placebo (refer to Table 2). Table 2 Incidence of Adverse Events that Led to the Discontinuation of Treatment: Adverse Events with an Incidence of ≥1% in the Aspirin and Extended-release Dipyridamole Group Treatment Groups Aspirin and Extended-release Dipyridamole ER-DP ASA Placebo Total Number of Patients 1,650 1,654 1,649 1,649 Patients with at least one Adverse Event that led to treatment discontinuation 417 (25%) 419 (25%) 318 (19%) 352 (21%) Headache 165 (10%) 166 (10%) 57 (3%) 69 (4%) Dizziness 85 (5%) 97 (6%) 69 (4%) 68 (4%) Nausea 91 (6%) 95 (6%) 51 (3%) 53 (3%) Abdominal Pain 74 (4%) 64 (4%) 56 (3%) 52 (3%) Dyspepsia 59 (4%) 61 (4%) 49 (3%) 46 (3%) Vomiting 53 (3%) 52 (3%) 28 (2%) 24 (1%) Diarrhea 35 (2%) 41 (2%) 9 (<1%) 16 (<1%) Stroke 39 (2%) 48 (3%) 57 (3%) 73 (4%) Transient Ischemic Attack 35 (2%) 40 (2%) 26 (2%) 48 (3%) Angina Pectoris 23 (1%) 20 (1%) 16 (<1%) 26 (2%) Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID. 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 aspirin and extended-release dipyridamole 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 aspirin and extended-release dipyridamole showed a decline (mean change from baseline) in hemoglobin of 0.25 g/dL, hematocrit of 0.75% and erythrocyte count of 0.13x10 6 /mm 3 .

8.5 Geriatric Use Of the total number of subjects in ESPS2, 61 percent were 65 and over, while 27 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) ] .

8.2 Labor and Delivery Aspirin can result in excessive blood loss at delivery as well as prolonged gestation and prolonged labor. Because of these effects on the mother and because of adverse fetal effects seen with aspirin during the later stages of pregnancy [see Warnings and Precautions (5.4) ] , avoid aspirin and extended-release dipyridamole in the third trimester of pregnancy and during labor and delivery.

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.

8.4 Pediatric Use Safety and effectiveness of aspirin and extended-release dipyridamole in pediatric patients have not been studied. Due to the aspirin component, use of this product in the pediatric population is not recommended [see Contraindications (4.3) ] .

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

8 USE IN SPECIFIC POPULATIONS Pregnancy Category D (8.1) 8.1 Pregnancy Teratogenic Effects, Pregnancy Category D. [see Warnings and Precautions (5.4) ]. 8.2 Labor and Delivery Aspirin can result in excessive blood loss at delivery as well as prolonged gestation and prolonged labor. Because of these effects on the mother and because of adverse fetal effects seen with aspirin during the later stages of pregnancy [see Warnings and Precautions (5.4) ] , avoid aspirin and extended-release dipyridamole in the third trimester of pregnancy and during labor and delivery. 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. 8.4 Pediatric Use Safety and effectiveness of aspirin and extended-release dipyridamole in pediatric patients have not been studied. Due to the aspirin component, use of this product in the pediatric population is not recommended [see Contraindications (4.3) ] . 8.5 Geriatric Use Of the total number of subjects in ESPS2, 61 percent were 65 and over, while 27 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) ] . 8.6 Patients with Severe Hepatic or Severe Renal Dysfunction Aspirin and extended-release dipyridamole has not been studied in patients with hepatic or renal impairment. Avoid using aspirin containing products, such as aspirin and extended-release dipyridamole in patients with severe hepatic or severe renal (glomerular filtration rate < 10 mL/min) dysfunction [see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED Aspirin and extended-release dipyridamole capsules, 25 mg/200 mg, are available as two piece hard gelatin capsules, with a red opaque cap and a yellow opaque body, filled with light yellow to yellow extended-release dipyridamole pellets and a white to off-white, round, film-coated, biconvex, unscored, plain aspirin tablet. The capsule is imprinted axially with “AN” in yellow ink on the cap and “596” in red ink on the body. Aspirin and extended-release dipyridamole capsules are supplied as follows: Bottles of 60: NDC 42291-116-60 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from excessive moisture.