ASPIRIN and Extended-Release DIPYRIDAMOLE

1 INDICATIONS AND USAGE Aspirin and extended-release dipyridamole capsule is 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 capsule is a combination of aspirin and dipyridamole, antiplatelet agents, 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 capsule is 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 (2.1) 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.

3 DOSAGE FORMS AND STRENGTHS Aspirin and extended-release Dipyridamole 25 mg/200 mg capsules are available as a hard gelatin capsule, with red opaque colored cap and ivory opaque colored body, size ‘0 Xel’ hard gelatin capsule imprinted with ‘M’ on cap and ‘25’ on body in black ink, containing yellow colored extended-release pellets of Dipyridamole and a yellow colored immediate release pellets of Aspirin. Capsule: 25 mg aspirin/200 mg extended-release dipyridamole (3)

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 capsule is contraindicated in patients with known hypersensitivity to any of the product components. 4.2 Allergy Aspirin 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 may cause severe urticaria, angioedema or bronchospasm. 4.3 Reye Syndrome Do not use aspirin in children or teenagers with viral infections because of the risk of Reye syndrome.

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 (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Micro Labs USA, Inc. at 1-855-839-8195 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 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 aspirin and extended-release dipyridamole capsules, 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 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 1 presents the annualized event rate for adverse events that occurred in 1%/year or more of patients treated with aspirin and extended-release dipyridamole capsules where the incidence was also at least 1%/year 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 Body System/Preferred Term Aspirin And Extended-Release Dipyridamole n (%/year) b ER-DP Alone n (%/year) b ASA Alone n (%/year) b Placebo n (%/year) b Total Number of Patients 1650 1654 1649 1649 Central and Peripheral Nervous System Disorders Headache 647(28.25) 634 (27.91) 558 (22.10) 543 (22.29) Gastrointestinal System Disorders Dyspepsia 303 (13.23) 288 (12.68) 299 (11.84) 275 (11.29) Abdominal Pain 289 (12.62) 255 (11.22) 262 (10.38) 239 (9.81) Nausea 264 (11.53) 254 (11.18) 210 (8.32) 232 (9.53) Diarrhea 210 (9.17) 257 (11.31) 112 (4.44) 161 (6.61) Vomiting 138 (6.03) 129 (5.68) 101 (4.00) 118 (4.84) Platelet, Bleeding and Clotting Disorders Hemorrhage NOS 52 (2.27) 24 (1.06) 46 (1.82) 24 (0.99) a Reported by ≥1%/year of patients during aspirin and extended-release dipyridamole capsules treatment where the incidence was at least 1%/year greater than in those treated with placebo. b Annual event rate per 100 pt-years = 100* number of subjects with event/subject-years. Subject-years is defined as cumulative number of days on treatment divided by 365.25. 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 a Treatment Groups Aspirin And Extended-Release Dipyridamole n (%/year) b ER-DP n (%/year) b ASA n (%/year) b Placebo n (%/year) b Total Number of Patients 1650 1654 1649 1649 Patients with at least one Adverse Event that led t …

7 DRUG INTERACTIONS Co-administration with anticoagulants, 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 Adenosinergic agents (e.g. adenosine, regadenoson) Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary. Dipyridamole also increases the cardiovascular effects of regadenoson, an adenosine A 2A -receptor agonist. The potential risk of cardiovascular side effects with intravenous adenosinergic agents may be increased during the testing period when dipyridamole is not held 48 hours prior to stress testing. Angiotensin Converting Enzyme (ACE) Inhibitors Because of 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 capsules 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published studies and postmarketing experience with aspirin and extended-release dipyridamole capsules use during pregnancy have not identified a clear association between aspirin and extended-release dipyridamole capsules use and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Aspirin and extended-release dipyridamole capsule contains low-dose aspirin which is an NSAID (see Clinical Considerations). In animal reproduction studies, there were adverse developmental effects with administration of aspirin in rats and rabbits at doses about 66 and 44 times, respectively, the human exposure at the maximum recommended daily dose of aspirin-dipyridamole. Reproduction studies with dipyridamole in mice, rabbits, and rats have revealed no evidence of harm to the fetus up to doses about 25 times the maximum recommended daily human dose of aspirin-dipyridamole. Nonclinical data are suggestive of a possible potentiation of aspirin-related fetal toxicity when combined with dipyridamole (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4 and 15 to 20%, respectively. Clinical Considerations Labor and Delivery Aspirin and extended-release dipyridamole capsules, which contains dipyridamole and low-dose aspirin, increases the risk for bleeding [see Warnings and Precautions (5.1) ]. Maternal use of high-dose aspirin can result in excessive blood loss at delivery, prolonged gestation, prolonged labor, intracranial hemorrhage in premature infants, low birth weight, stillbirth, and neonatal death. Data Human Data Published data from clinical trials, observational studies, case series, and case reports over several decades have not identified a clear association between aspirin­ dipyridamole use in pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, these studies cannot definitively establish the absence of any aspirin-dipyridamole associated risks. Methodological limitations of these studies include variability in the timing and dose of drug exposure (e.g., most exposures occurred beyond the first trimester) and the small sample sizes of individual studies. Animal Data 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 aspirin-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 1000 mg/kg, respectively (about 11⁄2, 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 to the fetus due to dipyridamole. When 330 mg aspirin/kg/day was combined with 75 mg dipyridamole/kg/day in the rat at doses about 66 and 2 times, respectively, the maximum recommended daily human dose, the resorption rate approached 100%. 8.2 Lactation Risk Summary Based on data from a clinical lactation study in breastfeeding women taking low-dose aspirin, the metabolite salicylic acid is present in human milk in low levels (see Data) . Dipyridamole is also present in human milk. There is no information on the effects of aspirin and extended-release dipyridamol …

12.1 Mechanism of Action The antithrombotic action of aspirin and extended-release dipyridamole capsule 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.

11 DESCRIPTION Aspirin and extended-release dipyridamole capsule is a combination antiplatelet agent intended for oral administration. Each hard gelatin capsule contains 200 mg dipyridamole in an extended-release form and 25 mg aspirin, as an immediate-release. In addition, each capsule contains the following inactive ingredients: caprylic/capric mono/diglycerides, D&C yellow #10 Aluminum Lake, FD&C blue #1/brilliant blue FCF Aluminum Lake, glyceryl monostearate, hypromellose, methacrylic acid and methacrylate copolymer, microcrystalline cellulose, povidone K30, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, talc, tartaric acid, titanium dioxide, triacetin and triethyl citrate. Each capsule shell contains gelatin, ferric oxide red, ferric oxide yellow, titanium dioxide and water. Black imprint ink composition contains ferrosoferric oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution. 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 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 (acetylsalicylic acid) is chemically known as benzoic acid, 2-(acetyloxy)-, and has the following structural formula: Aspirin 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. Aspirin Structure

10 OVERDOSAGE Because of the dose ratio of dipyridamole to aspirin, overdosage of aspirin and extended-release dipyridamole capsule 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 vasodilatory 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Aspirin and extended-release Dipyridamole 25 mg/200 mg capsules are available as a hard gelatin capsule, with red opaque colored cap and ivory opaque colored body, size ‘0 Xel’ hard gelatin capsule imprinted with ‘M’ on cap and ‘25’ on body in black ink, containing yellow colored extended-release pellets of Dipyridamole and a yellow colored immediate release pellets of Aspirin. NDC: 63629-5045-1: 90 Capsules in a BOTTLE Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature]. Protect from excessive moisture. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504