ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere in the labeling:o 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% andgreater than placebo) were headache, dyspepsia, abdominal pain, nausea,and diarrhea 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 1-844-834-0530 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The most frequently reported adverse reactions (>10% andgreater than placebo) were headache, dyspepsia, abdominal pain, nausea,and diarrhea 6.1) 6.1 Clinical Trials Experience. Because clinicaltrials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of drug cannot be directlycompared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.The efficacy and safety of Aspirin and Extended-Release Dipyridamole Capsules was established in the European Stroke Prevention Study-2 (ESPS2). ESPS2 was double-blind, placebo-controlled study that evaluated 6602 patients over the age of 18 years who had 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 total of 6602 male and female patients who had experienced previous ischemic stroke or transient ischemia of the brain within three months prior to randomization.Table 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 Incidence of Adverse Events in ESPS2 Nausea264 (11.53)254 (11.18)210 (8.32)232 (9.53)Diarrhea210 (9.17)257 (11.31)112 (4.44)161 (6.61)Vomiting138 (6.03)129 (5.68) 101 (4.00) 118 (4.84) Platelet, Bleeding and Clotting DisordersHemorrhage NOS52 (2.27)24 (1.06)46 (1.82)24 (0.99)aReported 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. bAnnual 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. Individual Treatment GroupBody System/Preferred TermAspirin and Extended-Release Dipyridamole Capsules (%/year) ER-DP Alone (%/year) ASA Alonen (%/year) Placebo (%/year) Total Number of Patients1650165416491649Central and Peripheral Nervous System DisordersHeadache 647 (28.25)634 (27.91)558 (22.10)543 (22.29) Gastrointestinal SystemDisordersDyspepsia303 (13.23)288 (12.68)299 (11.84)275 (11.29)Abdominal Pain289 (12.62)255 (11.22)262 (10.38)239 (9.81)Discontinuationdue to adverse events in ESPS2 was 25% for Aspirin and Extended-Release Dipyridamole Capsules, 25% for extended-releasedipyridamole, 19% for aspirin, and 21% for placebo (refer to Table2). Table Incidence of Adverse Events that Led to the Discontinuation of Treatment Treatment Groups Aspirin and Extended-Release Dipyridamole Capsules (%/year) ER-DPn (%/year) ASAn (%/year) Placebon (%/year) bTotal Number of Patients 1650 1654 1649 1649Patients with at least one AdverseEvent that led to treatment discontinuation 417 (18.21) 419 (18.44) 318 (12.59) 352 (14.45) Headache165 (7.20) 166 (7.31) 57 (2.26) 69 (2.83)Nausea 91 (3.97) 95 (4.18) 51 (2.02)53 (2.18)Abdominal Pain 74 (3.23) 64 (2.82) 56 (2.22)52 (2.13)Vomiting 53 (2.31) 52 (2.29) 28 (1.11)24 (0.99)aReported 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. bAnnual 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. Headache was most notable in thefirst month of treatment.. 6.2 Post-Marketing Experience. The following is 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 population of uncertain size, it is not always possible to estimate reliably their frequency or establish 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 Capsules.Body as Whole: Hypothermia, chest pain, allergic reaction, syncope Cardiovascular: Angina pectoris, hypotension Central Nervous System: Cerebral edema, dizziness, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia Gastrointestinal: Pancreatitis, Reye syndrome, hematemesis, gastritis, ulceration and perforation, hemorrhage rectum, melena, GI hemorrhage Hearing and Vestibular Disorders: Hearing loss Heart Rate and Rhythm Disorders: Tachycardia, palpitation Immune System Disorders: Hypersensitivity, acute anaphylaxis, laryngeal edema Liver and Biliary System Disorders: Hepatitis, hepatic failure, cholelithiasis, jaundice, hepatic function abnormal Musculoskeletal: Rhabdomyolysis, myalgia Metabolic and Nutritional Disorders: Hypoglycemia, dehydration Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia, hematoma, gingival bleeding, epistaxis, purpuraPsychiatric Disorders: Confusion, agitation Respiratory: Tachypnea, dyspnea, hemoptysis Skin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising, ecchymosis, and hematoma, pruritus, urticaria, and drug reaction with eosinophilia and systemic symptoms (DRESS)Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, hematuria Vascular (Extracardiac) Disorders: Allergic vasculitis, flushing Other Adverse Events: Anorexia, aplastic anemia, migraine, pancytopenia, thrombocytosis.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, 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 mg/m 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 mg/m basis). significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1250 mg/kg (more than 30 times the MRHD on mg/m basis). Aspirin inhibits ovulation in rats.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The antithrombotic action of Aspirin and Extended-Release Dipyridamole Capsules is the result of the additive antiplatelet effects of dipyridamole and aspirin.. DipyridamoleDipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in vivo; the inhibition occurs in dose-dependent manner at therapeutic concentrations (0.5-1.9 ug/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet 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).. AspirinAspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of thromboxane 2, powerful inducer of platelet aggregation and vasoconstriction. 12.2 Pharmacodynamics. The effect of either agent on the others 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 Capsules.AbsorptionDipyridamole:Peak plasma levels of dipyridamole are achieved hours (range 1-6 hours) after administration of daily dose of 400 mg Aspirin and Extended-Release Dipyridamole Capsules (given as 200 mg BID). The peak plasma concentration at steady-state is 1.98 ug/mL (1.01-3.99 ug/mL) and the steady-state trough concentration is 0.53 ug/mL (0.18-1.01 ug/mL).Aspirin:Peak plasma levels of aspirin are achieved 0.63 hours (0.5-1 hour) after administration of 50 mg aspirin daily dose from Aspirin and Extended-Release Dipyridamole Capsules (given as 25 mg BID). The peak plasma concentration at steady-state is 319 ng/mL (175-463 ng/mL). Aspirin undergoes moderate hydrolysis to salicylic acid in the liver and the gastrointestinal wall, with 50%-75% of an administered dose reaching the systemic circulation as intact aspirin.Effect of FoodDipyridamole:When Aspirin and Extended-Release Dipyridamole Capsules were taken with high fat meal, dipyridamole peak plasma levels (C max) and total absorption (AUC) were decreased at steady-state by 20-30% 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. Aspirin:When Aspirin and Extended-Release Dipyridamole Capsules were taken with high fat meal, there was no difference for aspirin in AUC at steady-state, and the approximately 50% decrease in max was not considered clinically relevant based on similar degree of cyclooxygenase inhibition comparing the fed and fasted state. DistributionDipyridamole: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.Aspirin: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 Overdosage 10)] Metabolism and EliminationDipyridamole: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, triphasic profile is obtained: rapid alpha phase, with half-life of about 3.4 minutes, beta phase, with 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 prolonged elimination phase with half-life of about 15.5 hours. Because of the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with Aspirin and Extended-Release Dipyridamole Capsules which was 13.6 hours. Aspirin:Aspirin is rapidly hydrolyzed in plasma to salicylic acid, with half-life of 20 minutes. Plasma levels of aspirin are essentially undetectable 2-2.5 hours after dosing and peak salicylic acid concentrations occur hour (range: 0.5-2 hours) after administration of aspirin. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, phenolic glucuronide, an acyl glucuronide, and 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 (10-20 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 Capsules and has 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 resultant half-life of approximately 2-3 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 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 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. Specific PopulationsGeriatric Patients:Dipyridamole: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 Capsules. Hepatic Dysfunction:No study has been conducted with Aspirin and Extended-Release Dipyridamole Capsules in patients with hepatic dysfunction.Dipyridamole:In 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.Aspirin:Avoid aspirin in patients with severe hepatic insufficiency.Renal Dysfunction: Dipyridamole: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:Avoid aspirin in patients with severe renal failure (glomerular filtration rate <10 mL/min).Drug Interaction StudiesA 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 Capsules 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. ESPS2 (European Stroke Prevention Study-2) was double-blind, placebo-controlled, 24-month study in which 6602 patients over the age of 18 years had an ischemic stroke (76%) or transient ischemic attack (TIA, 24%) within three months prior to entry. Patients were enrolled in 13 European countries between February 1989 and May 1995 and were randomized to one of four treatment groups: Aspirin and Extended-Release Dipyridamole Capsules -25 mg/200 mg; extended-release dipyridamole (ER-DP) 200 mg alone; aspirin (ASA) 25 mg alone; or placebo. The mean age in this population was 66.7 years with 58% of them being males. Patients received one capsule twice daily (morning and evening). Efficacy assessments included analyses of stroke (fatal or nonfatal) and death (from all causes) as confirmed by blinded morbidity and mortality assessment group. There were no differences with regard to efficacy based on age or gender; patients who were older had trend towards more events.Stroke EndpointAspirin and Extended-Release Dipyridamole Capsules reduced the risk of stroke by 22.1% compared to aspirin 50 mg/day alone (p 0.008) and reduced the risk of stroke by 24.4% compared to extended-release dipyridamole 400 mg/day alone (p 0.002) (Table 3). Aspirin and Extended-Release Dipyridamole Capsules reduced the risk of stroke by 36.8% compared to placebo (p <0.001).. Table Summary of First Stroke (Fatal or Nonfatal): ESPS2: Intent-to-Treat Population Total Number of Patients Number of Patients With Stroke Within Years (%) Kaplan-Meier Estimate of Survival at Years (95% C.I.) Gehan-Wilcoxon Test P-value Risk Reduction at Years Odds Ratio (95% C.I.) a0.010 <p-value <=0.050; bp-value <=0.010. Note: ER-DP extended-release dipyridamole 200 mg; ASA aspirin 25 mg. The dosage regimen for all treatment groups is BID.Individual Treatment Group Aspirin and Extended-Release Dipyridamole Capsules1650157 9.5%)89.9% (88.4%, 91.4%)--- ER-DP1654211 (12.8%)86.7% (85.0%, 88.4%)--- ASA1649206 (12.5%)87.1% (85.4%, 88.7%)--- Placebo1649250 (15.2%)84.1% (82.2%, 85.9%)---Pairwise Treatment Group Comparisons Aspirin and Extended-Release Dipyridamole Capsules vs. ER-DP ---0.002 24.4%0.72 (0.58, 0.90) Aspirin and Extended-Release Dipyridamole Capsules vs. ASA ---0.008 22.1%0.74 (0.59, 0.92) Aspirin and Extended-Release Dipyridamole Capsules vs. Placebo ---<0.001 36.8%0.59 (0.48, 0.73) ER-DP vs. Placebo---0.036 16.5%0.82 (0.67, 1.00) ASA vs. Placebo---0.009 18.9%0.80 (0.66, 0.97)Figure ESPS2: Cumulative Stroke Rate (Fatal or Nonfatal) Over 24 months of Follow-Up Combined Stroke or Death EndpointIn ESPS2, Aspirin and Extended-Release Dipyridamole Capsules reduced the risk of stroke or death by 24.2% compared to placebo.Aspirin and Extended-Release Dipyridamole Capsules reduced the risk of stroke or death by 12.1% compared to aspirin alone and by 10.3% compared to extended-release dipyridamole alone. These results were not statistically significant. Death EndpointThe incidence rate of all-cause mortality was 11.3% for Aspirin and Extended-Release Dipyridamole Capsules, 11.0% for aspirin alone, 11.4% for extended-release dipyridamole alone and 12.3% for placebo alone. The differences between the Aspirin and Extended-Release Dipyridamole Capsules, aspirin alone and extended-release dipyridamole alone treatment groups were not statistically significant. These incidence rates for Aspirin and Extended-Release Dipyridamole Capsules and aspirin alone are consistent with previous aspirin studies in stroke and TIA patients.. Follow-up.

CONTRAINDICATIONS SECTION.

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 nasalpolyps 4.2) Hypersensitivity to any product ingredients 4.1) Patients with known allergy to NSAIDs 4.2) Patients with the syndrome of asthma, rhinitis, and nasalpolyps 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 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.

DESCRIPTION SECTION.

11 DESCRIPTION. Aspirin and Extended-Release Dipyridamole Capsules are combination of aspirin and dipyridamole, antiplatelet agents, intended for oral administration. Each hard gelatin capsule contains 200 mg dipyridamole in an extended-release pellet form and 25 mg aspirin, as in an immediate-release powder form. In addition, each capsule contains the following inactive ingredients: hydrogenated castor oil, hypromellose 2910, hypromellose phthalate, methacrylic acid copolymer, microcrystalline cellulose, povidone, simethicone emulsion, starch, talc, tartaric acid and triacetin. The imprinting ink also contains ammonium hydroxide, n-butyl alcohol, black iron oxide, isopropyl alcohol, propylene glycol and shellac glaze.Each capsule shell contains gelatin, red iron oxide and yellow iron oxide and titanium dioxide.. DipyridamoleDipyridamole is an antiplatelet agent chemicallydescribed 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 yellowcrystalline substance, having bitter taste. It is soluble in diluteacids, methanol and chloroform, and is practically insoluble in water.. aggrenox-structure-1. AspirinThe antiplatelet agent aspirin (acetylsalicylic acid)is chemically known as benzoic acid, 2- (acetyloxy)-, and has thefollowing structural formula: Aspirin is an odorless white needle-likecrystalline or powdery substance. When exposed to moisture, aspirinhydrolyzes into salicylic and acetic acids, and gives off vinegaryodor. It is highly lipid soluble and slightly soluble in water.. aggrenox-structure-2.

DOSAGE & ADMINISTRATION SECTION.

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 2.1) 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) 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 problem as treatment continues, patients should return to the usual regimen as soon as possible, usually within one week.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. No. 00 capsule with Pink Opaque cap and Yellow Opaque body imprinted in black with Lannett and 330, and filled with pellets and powder blend. Capsule: 25 mg aspirin/200 mg extended-release dipyridamole 3) Capsule: 25 mg aspirin/200 mg extended-release dipyridamole 3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Co-administration with anticoagulants, antiplatelets, orNSAIDs can increase risk of bleeding 7.1) Decreased renal function can occur with co-administrationwith NSAIDs 7.1) Co-administration with anticoagulants, antiplatelets, orNSAIDs can increase risk of bleeding 7.1) Decreased renal function can occur with co-administrationwith NSAIDs 7.1) 7.1 Drug Interaction Study Information Obtained From Literature. Adenosinergic agents (e.g. adenosine, regadenoson)Dipyridamole hasbeen reported to increase the plasma levels and cardiovascular effectsof adenosine. Adjustment of adenosine dosage may be necessary. Dipyridamole also increases the cardiovascular effects of regadenoson, an adenosine 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) InhibitorsBecause of the indirect effect ofaspirin on the renin-angiotensin conversion pathway, the hyponatremicand hypotensive effects of ACE inhibitors may be diminished by concomitantadministration of aspirin. AcetazolamideConcurrent use of aspirin and acetazolamidecan lead to high serum concentrations of acetazolamide (and toxicity)due to competition at the renal tubule for secretion. Anticoagulants and AntiplateletsPatients 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, leadingto prolongation of both the prothrombin time and the bleeding time.Aspirin can increase the anticoagulant activity of heparin, increasingbleeding risk. AnagrelidePatients taking aspirin in combinationwith anagrelide are at an increased risk of bleeding. AnticonvulsantsSalicylicacid can displace protein-bound phenytoin and valproic acid, leadingto decrease in the total concentration of phenytoin and an increasein serum valproic acid levels. Beta BlockersThe hypotensive effectsof beta blockers may be diminished by the concomitant administrationof aspirin due to inhibition of renal prostaglandins, leading to decreasedrenal blood flow and salt and fluid retention. Cholinesterase InhibitorsDipyridamole may counteract the anticholinesterase effect of cholinesteraseinhibitors, thereby potentially aggravating myasthenia gravis. DiureticsTheeffectiveness of diuretics in patients with underlying renal or cardiovasculardisease may be diminished by the concomitant administration of aspirindue to inhibition of renal prostaglandins, leading to decreased renalblood flow and salt and fluid retention. MethotrexateSalicylatecan inhibit renal clearance of methotrexate, leading to bone marrowtoxicity, especially in the elderly or renal impaired. Nonsteroidal Anti-InflammatoryDrugs (NSAIDs)The concurrent use of aspirin withother NSAIDs may increase bleeding or lead to decreased renal function. Oral HypoglycemicsModerate doses of aspirin may increase the effectiveness of oralhypoglycemic drugs, leading to hypoglycemia. Uricosuric Agents (probenecid and sulfinpyrazone)Salicylates antagonize the uricosuric action of uricosuricagents.

INDICATIONS & USAGE SECTION.

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 Capsules are 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) Aspirin and Extended-Release Dipyridamole Capsules are 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling Patient Information). Risk of BleedingInform patients that as with other antiplatelet agents, there is 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.PregnancyAdvise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Aspirin and Extended-Release Dipyridamole Capsules [see Use in Specific Populations 8.1)] HeadachesSome patients may experience headaches upon treatment initiation; these are usually transient. In case of intolerable headaches, tell patients to contact their physician.Stress TestInstruct patients who are scheduled to undergo pharmacologic stress test to tell their healthcare provider that they are taking Aspirin and Extended-Release Dipyridamole Capsules.Dosage and AdministrationTell patients that Aspirin and Extended-Release Dipyridamole Capsules should be swallowed whole, and not chewed or crushed. If you miss dose, continue with your next dose on your regular schedule. Do not take double dose.StorageInform patients to protect Aspirin and Extended-Release Dipyridamole Capsules from moisture.. Risk of Bleeding. Pregnancy. Headaches. Stress Test. Dosage and Administration. Storage.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, 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 mg/m 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 mg/m basis). significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 1250 mg/kg (more than 30 times the MRHD on mg/m basis). Aspirin inhibits ovulation in rats.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Becauseof the dose ratio of dipyridamole to aspirin, overdosage of Aspirin and Extended-Release Dipyridamole Capsules is likely to be dominated by signs and symptoms of dipyridamole overdose.In case of real or suspected overdose, seek medical attention or contacta Poison Control Center immediately. Careful medical management isessential.Based upon the knownhemodynamic effects of dipyridamole, symptoms such as warm feeling,flushes, sweating, restlessness, feeling of weakness, and dizzinessmay occur. drop in blood pressure and tachycardia might also beobserved.Salicylate toxicitymay result from acute ingestion (overdose) or chronic intoxication.Severity of aspirin intoxication is determined by measuring the bloodsalicylate level. The early signs of salicylic overdose (salicylism),including tinnitus (ringing in the ears), occur at plasma concentrationsapproaching 200 ug/mL. In severe cases, hyperthermia and hypovolemiaare the major immediate threats to life. Plasma concentrations ofaspirin above 300 ug/mL are clearly toxic. Severe toxic effects areassociated with levels above 400 ug/mL. single lethal dose of aspirinin adults is not known with certainty but death may be expected at30 g.Treatment of overdose consistsprimarily of supporting vital functions, increasing drug elimination,and correcting acid-base disturbances. Consider gastric emptying and/orlavage as soon as possible after ingestion, even if the patient hasvomited spontaneously. After lavage and/or emesis, administrationof activated charcoal as slurry may be beneficial if less than 3hours have passed since ingestion. Charcoal absorption should notbe employed prior to emesis and lavage. Follow acid-base status closelywith serial blood gas and serum pH measurements. Maintain fluid andelectrolyte balance. Administer replacement fluid intravenously andaugment with correction of acidosis. Treatment may require the useof vasopressor. Infusion of glucose may be required to control hypoglycemia.Administration of xanthine derivatives(e.g., aminophylline) may reverse the vasodilatory effects of dipyridamoleoverdose. Plasma electrolytes and pH should be monitored seriallyto promote alkaline diuresis of salicylate if renal function is normal. In patients with renal insufficiency or in cases of life-threateningintoxication, dialysis is usually required to treat salicylic overdose;however, since dipyridamole is highly protein bound, dialysis is notlikely to remove dipyridamole. Exchange transfusion may be indicatedin infants and young children.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

NDC 51407-271-60. 51407-271-60LB ASPIRIN AND DIPYRIDAMOLE 25MG-200 MG ER CAPS.jpg.

PREGNANCY SECTION.

5.4 Coronary Artery Disease. Dipyridamole has 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.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Stress testing with intravenous dipyridamole and other adenosinergic agents 5.6) 12/2019.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information. Aspirin (as pir in) and Extended-Release Dipyridamole dye pir id mole) Capsules Read this Patient Information before youstart taking Aspirin and Extended-Release Dipyridamole Capsules and each time you get refill. There may benew information. This information does not take the place of talkingto your healthcare provider about your medical condition or your treatment.What is Aspirin and Extended-Release Dipyridamole CapsulesAspirin and Extended-Release Dipyridamole Capsules are prescriptionmedicine that contains aspirin and medicine that is slowly releasedin your body, called dipyridamole. Aspirin and Extended-Release Dipyridamole Capsules are used to lower the riskof stroke in people who have had mini-stroke (transient ischemicattack or TIA) or stroke due to blood clot.It is not known if Aspirin and Extended-Release Dipyridamole Capsules are safe and effective inchildren. See Who should not take Aspirin and Extended-Release Dipyridamole Capsules Who should not take Aspirin and Extended-Release Dipyridamole CapsulesDo nottake Aspirin and Extended-Release Dipyridamole Capsules if you: are allergic to any of the ingredients in Aspirin and Extended-Release Dipyridamole Capsules. Seethe end of this leaflet for list of ingredients in Aspirin and Extended-Release Dipyridamole Capsules.are allergic to non-steroidal anti-inflammatory drugs (NSAIDs)have asthma in combination with runny nose and nasal polypsDo not give Aspirin and Extended-Release Dipyridamole Capsules to child or teenager with viral illness. Reye syndrome, life-threateningcondition, can happen when aspirin (an ingredient in Aspirin and Extended-Release Dipyridamole Capsules) isused in children and teenagers who have certain viral illnesses.Whatshould tell my doctor before using Aspirin and Extended-Release Dipyridamole CapsulesBefore taking Aspirin and Extended-Release Dipyridamole Capsules,tell your healthcare provider if you:have stomach ulcershave history of bleeding problemshave heart problemshave kidney or liver problemshave low blood pressurehave myasthenia gravishave any other medical conditionsare pregnant or plan to become pregnant. You should not take Aspirin and Extended-Release Dipyridamole Capsules during pregnancy without first talking to your healthcare provider. Tell your healthcare provider right away if you become pregnant while taking Aspirin and Extended-Release Dipyridamole Capsules.are breast-feeding or plan to breast-feed. Aspirin and Extended-Release Dipyridamole Capsules can pass into your milk. Talk to your healthcare provider about the best way to feed your baby if you take Aspirin and Extended-Release Dipyridamole Capsules.Tell your doctor you are taking Aspirin and Extended-Release Dipyridamole Capsules if you are scheduled to have stress test for your heart.Tell your doctor about allthe medicines you take, including prescription and non-prescriptionmedicines, vitamins and herbal supplements. Aspirin and Extended-Release Dipyridamole Capsules and other medicinesmay affect each other causing side effects. Aspirin and Extended-Release Dipyridamole Capsules may affect theway other medicines work, and other medicines may affect how Aspirin and Extended-Release Dipyridamole Capsules works. Especially tell your healthcareprovider if you take:a medicine for high blood pressure, irregularheart beat, or heart failureacetazolamide [Diamox (R)] any blood thinner medicines warfarin sodium [Coumadin (R), Jantoven (R)] heparin medicineanagrelide [Agrylin (R)] seizure medicinea medicine for Alzheimers diseasea water pillmethotrexate sodium [Trexall (R)] aspirin or non-steroidal anti-inflammatorydrug (NSAIDs). You should not take NSAIDs during treatment with Aspirin and Extended-Release Dipyridamole Capsules. Using these medicines with Aspirin and Extended-Release Dipyridamole Capsules can increase your riskof bleeding. medicine for diabetesprobenecid [Probalan (R), Col-Probenecid (R)] Ask your healthcare provider or pharmacistif you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep listof them and show your healthcare provider and pharmacist when youget new medicine.How should take Aspirin and Extended-Release Dipyridamole CapsulesTake Aspirin and Extended-Release Dipyridamole Capsules exactly as prescribed. Your healthcare providerwill tell you how many Aspirin and Extended-Release Dipyridamole Capsules to take and when to take them.Headaches are not uncommon when you first start taking Aspirin and Extended-Release Dipyridamole Capsules,but often lessen as treatment continues. Tell your healthcare providerif you have severe headache. Your healthcare provider may changethe instructions for taking Aspirin and Extended-Release Dipyridamole Capsules.Swallow Aspirin and Extended-Release Dipyridamole Capsules whole. Do not crush or chew the capsules.You can take Aspirin and Extended-Release Dipyridamole Capsules with or without food.If you miss dose, takeyour next dose at the usual time. Do not take two doses at one time.If you take more Aspirin and Extended-Release Dipyridamole Capsules (overdose) than prescribed, callyour healthcare provider or Poison Control Center, or get emergencyhelp right away.Symptoms of an overdoseof Aspirin and Extended-Release Dipyridamole Capsules include:a warm feeling or flushingsweatingrestlessnessweakness or dizzinessa fast heart rateringing in the ears What should avoidwhile using Aspirin and Extended-Release Dipyridamole Capsulesheavy alcohol use. Peoplewho drink three or more alcoholic drinks every day have higher riskof bleeding during treatment with Aspirin and Extended-Release Dipyridamole Capsules, because it contains aspirin. What are the possibleside effects of Aspirin and Extended-Release Dipyridamole CapsulesAspirin and Extended-Release Dipyridamole Capsules may cause serious side effects,including:increased risk of bleeding. You may bleed more easily during Aspirin and Extended-Release Dipyridamole Capsules treatment, and it maytake longer than usual for bleeding to stop. This can include: bleeding into your brain (intracranial hemorrhage). This can be medical emergency. Get medical help right awayif you have any of these symptoms while taking Aspirin and Extended-Release Dipyridamole Capsules: severe headache with drowsinessconfusion or memory changepass out (become unconscious) bleeding in your stomach or intestine.stomach painheartburn or nauseavomiting blood or vomit looks like coffee groundsred or bloody stools black stools that look like tar new or worsening chest pain in some peoplewith heart disease. Tell your healthcare providerif you have new chest pain or have any change in your chest pain duringtreatment with Aspirin and Extended-Release Dipyridamole Capsules. liver problems, includingincreased liver function tests and liver failure. Tell your healthcareprovider if you have any of these symptoms of liver problem whiletaking Aspirin and Extended-Release Dipyridamole Capsules: loss of appetitepale colored stoolstomach area (abdomen) painyellowing of your skin or whites of your eyesdark urineitching Call your healthcare provider rightaway if you have any of the symptoms listed above.The most common side effects of Aspirin and Extended-Release Dipyridamole Capsules include:headacheupset stomachdiarrheaThese are not all the possible sideeffects of Aspirin and Extended-Release Dipyridamole Capsules. Tell your healthcare provider or pharmacist ifyou have any side effect that bothers you or that does not go away.Call your healthcare provider for medicaladvice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store Aspirin and Extended-Release Dipyridamole CapsulesStore Aspirin and Extended-Release Dipyridamole Capsules at room temperature 68F to 77F (20C to 25C).Keep Aspirin and Extended-Release Dipyridamole Capsules dry.Keep Aspirin and Extended-Release Dipyridamole Capsules andall medicines out of the reach of children.General information aboutAspirin and Extended-Release Dipyridamole Capsules Medicinesare sometimes prescribed for purposes other than those listed in thePatient Information. Do not use Aspirin and Extended-Release Dipyridamole Capsules for condition for whichit was not prescribed. Do not give Aspirin and Extended-Release Dipyridamole Capsules to other people, evenif they have the same symptoms that you have. It may harm them.This Patient Information summarizes themost important information about Aspirin and Extended-Release Dipyridamole Capsules. If you would like moreinformation, talk with your healthcare provider. You can ask yourpharmacist or healthcare provider for information about Aspirin and Extended-Release Dipyridamole Capsules thatis written for health professionals.For more information about Aspirin and Extended-Release Dipyridamole Capsules, call Lannett Company, Inc. at 1-844-834-0530. What are the ingredients in Aspirin and Extended-Release Dipyridamole CapsulesActive Ingredients: dipyridamole in an extended-release form and aspirin Inactive Ingredients: hydrogenated castor oil, hypromellose 2910, hypromellose phthalate, methacrylic acid copolymer, microcrystalline cellulose, povidone, simethicone emulsion, starch, talc, tartaric acid and triacetin. The imprinting ink also contains ammonium hydroxide, n-butyl alcohol, black iron oxide, isopropyl alcohol, propylene glycol and shellac glaze. Each capsule shell contains gelatin, red iron oxide and yellow iron oxide and titanium dioxide. are allergic to any of the ingredients in Aspirin and Extended-Release Dipyridamole Capsules. Seethe end of this leaflet for list of ingredients in Aspirin and Extended-Release Dipyridamole Capsules.. are allergic to non-steroidal anti-inflammatory drugs (NSAIDs). have asthma in combination with runny nose and nasal polyps. have stomach ulcers. have history of bleeding problems. have heart problems. have kidney or liver problems. have low blood pressure. have myasthenia gravis. have any other medical conditions. are pregnant or plan to become pregnant. You should not take Aspirin and Extended-Release Dipyridamole Capsules during pregnancy without first talking to your healthcare provider. Tell your healthcare provider right away if you become pregnant while taking Aspirin and Extended-Release Dipyridamole Capsules.. are breast-feeding or plan to breast-feed. Aspirin and Extended-Release Dipyridamole Capsules can pass into your milk. Talk to your healthcare provider about the best way to feed your baby if you take Aspirin and Extended-Release Dipyridamole Capsules.. medicine for high blood pressure, irregularheart beat, or heart failure. acetazolamide [Diamox (R)] any blood thinner medicines warfarin sodium [Coumadin (R), Jantoven (R)] a heparin medicine. anagrelide [Agrylin (R)] a seizure medicine. medicine for Alzheimers disease. water pill. methotrexate sodium [Trexall (R)] aspirin or non-steroidal anti-inflammatorydrug (NSAIDs). You should not take NSAIDs during treatment with Aspirin and Extended-Release Dipyridamole Capsules. Using these medicines with Aspirin and Extended-Release Dipyridamole Capsules can increase your riskof bleeding. a medicine for diabetes. probenecid [Probalan (R), Col-Probenecid (R)] Take Aspirin and Extended-Release Dipyridamole Capsules exactly as prescribed. Your healthcare providerwill tell you how many Aspirin and Extended-Release Dipyridamole Capsules to take and when to take them.. Headaches are not uncommon when you first start taking Aspirin and Extended-Release Dipyridamole Capsules,but often lessen as treatment continues. Tell your healthcare providerif you have severe headache. Your healthcare provider may changethe instructions for taking Aspirin and Extended-Release Dipyridamole Capsules.. Swallow Aspirin and Extended-Release Dipyridamole Capsules whole. Do not crush or chew the capsules.. You can take Aspirin and Extended-Release Dipyridamole Capsules with or without food.. If you miss dose, takeyour next dose at the usual time. Do not take two doses at one time.. If you take more Aspirin and Extended-Release Dipyridamole Capsules (overdose) than prescribed, callyour healthcare provider or Poison Control Center, or get emergencyhelp right away.. warm feeling or flushing. sweating. restlessness. weakness or dizziness. fast heart rate. ringing in the ears heavy alcohol use. Peoplewho drink three or more alcoholic drinks every day have higher riskof bleeding during treatment with Aspirin and Extended-Release Dipyridamole Capsules, because it contains aspirin. increased risk of bleeding. You may bleed more easily during Aspirin and Extended-Release Dipyridamole Capsules treatment, and it maytake longer than usual for bleeding to stop. This can include: bleeding into your brain (intracranial hemorrhage). This can be medical emergency. Get medical help right awayif you have any of these symptoms while taking Aspirin and Extended-Release Dipyridamole Capsules: severe headache with drowsinessconfusion or memory changepass out (become unconscious) bleeding in your stomach or intestine.stomach painheartburn or nauseavomiting blood or vomit looks like coffee groundsred or bloody stools black stools that look like tar bleeding into your brain (intracranial hemorrhage). This can be medical emergency. Get medical help right awayif you have any of these symptoms while taking Aspirin and Extended-Release Dipyridamole Capsules: severe headache with drowsinessconfusion or memory changepass out (become unconscious) severe headache with drowsiness. confusion or memory change. pass out (become unconscious) bleeding in your stomach or intestine.stomach painheartburn or nauseavomiting blood or vomit looks like coffee groundsred or bloody stools black stools that look like tar stomach pain. heartburn or nausea. vomiting blood or vomit looks like coffee grounds. red or bloody stools black stools that look like tar new or worsening chest pain in some peoplewith heart disease. Tell your healthcare providerif you have new chest pain or have any change in your chest pain duringtreatment with Aspirin and Extended-Release Dipyridamole Capsules. liver problems, includingincreased liver function tests and liver failure. Tell your healthcareprovider if you have any of these symptoms of liver problem whiletaking Aspirin and Extended-Release Dipyridamole Capsules: loss of appetitepale colored stoolstomach area (abdomen) painyellowing of your skin or whites of your eyesdark urineitching loss of appetite. pale colored stool. stomach area (abdomen) pain. yellowing of your skin or whites of your eyes. dark urine. itching headache. upset stomach. diarrhea. Store Aspirin and Extended-Release Dipyridamole Capsules at room temperature 68F to 77F (20C to 25C).. Keep Aspirin and Extended-Release Dipyridamole Capsules dry.

SPL UNCLASSIFIED SECTION.

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 problem as treatment continues, patients should return to the usual regimen as soon as possible, usually within one week.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Aspirin and Extended-Release Dipyridamole Capsules increase the risk of bleeding 5.1) Avoid use in patients with severe hepatic or renal insufficiency 5.2, 5.3) Interrupt Aspirin and Extended-Release Dipyridamole Capsules 48 hours before using intravenous dipyridamole or other adenosinergic agents for stress testing 5.6, 7.1) Aspirin and Extended-Release Dipyridamole Capsules increase the risk of bleeding 5.1) Avoid use in patients with severe hepatic or renal insufficiency 5.2, 5.3) Interrupt Aspirin and Extended-Release Dipyridamole Capsules 48 hours before using intravenous dipyridamole or other adenosinergic agents for stress testing 5.6, 7.1) 5.1 Risk of Bleeding. Aspirin and Extended-Release Dipyridamole Capsules increase 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 HemorrhageIn European Stroke Prevention Study-2 (ESPS2), the annualized event rate for intracranial hemorrhage was 0.39%/year in the Aspirin and Extended-Release Dipyridamole Capsules group, 0.26%/year in the extended-release dipyridamole (ER-DP) group, 0.24%/year in the aspirin (ASA) group, and 0.29%/year in the placebo groups.Gastrointestinal (GI) Side EffectsGI 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 annualized event rate for gastrointestinal bleeding was 2.97%/year in the Aspirin and Extended-Release Dipyridamole Capsules group, 1.58%/year in the extended-release dipyridamole group, 2.06%/year in the aspirin group, and 1.40%/year in the placebo groups.Peptic Ulcer DiseaseAvoid using aspirin in patients with history of active peptic ulcer disease, which can cause gastric mucosal irritation and bleeding.Alcohol WarningBecause 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 Coronary Artery Disease. Dipyridamole has 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.. 5.5 Hypotension. Dipyridamole produces peripheral vasodilation, which can exacerbate pre-existing hypotension.. 5.6 Stress Testing with Intravenous Dipyridamole and OtherAdenosinergic Agents. Clinical experience suggests that patients being treated with Aspirin and Extended-Release Dipyridamole Capsules who also require pharmacological stress testing with intravenous dipyridamole or other adenosinergic agents (e.g. adenosine, regadenoson) should interrupt Aspirin and Extended-Release Dipyridamole Capsules for 48 hours prior to stress testing [see Drug Interactions 7.1)] Intake of Aspirin and Extended-Release Dipyridamole Capsules within 48 hours prior to stress testing with intravenous dipyridamole or other adenosinergic agents may increase the risk for cardiovascular side effects of these agents and may impair the sensitivity of the test.. 5.7 General. Aspirin and Extended-Release Dipyridamole Capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.