INFORMATION FOR PATIENTS SECTION.

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 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 Advise 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)]. 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 dose, continue with your next dose on your regular schedule. Do not take double dose. Storage Inform patients to protect aspirin and extended-release dipyridamole capsules from moisture.

ADVERSE REACTIONS SECTION.

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)]. 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 Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch The most frequently reported adverse reactions (>10% and greater than placebo) were headache, dyspepsia, abdominal pain, nausea, and diarrhea (6.1) 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 double-blind, placebo-controlled study that evaluated 6,602 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, 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 total of 6,602 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 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 ESPS2Reported by >=1%/year of patients during aspirin and extended-release dipyridamole treatment where the incidence was at least 1%/year greater than in those treated with placebo. Individual Treatment GroupBody System/Preferred TermAspirin and Extended-Release Dipyridamole (%/year)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.ER-DP Alonen (%/year)ASA Alonen (%/year)Placebon (%/year)Total Number of Patients1,650 1,654 1,649 1,649 Central and Peripheral Nervous System Disorders Headache 647 (28.25) 634 (27.91) 558 (22.10) 543 (22.29) Gastrointestinal System DisordersDyspepsia 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 DisordersHemorrhage NOS 52 (2.27) 24 (1.06) 46 (1.82) 24 (0.99) 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 Incidence of Adverse Events that Led to the Discontinuation of Treatment Treatment Groups Aspirin and Extended-Release Dipyridamole (%/year) ER-DPn (%/year)ASAn (%/year)Placebon (%/year)Total Number of Patients1,650 1,654 1,649 1,649 Patients with at least one Adverse Event that led to treatment discontinuation 417 (18.21) 419 (18.44) 318 (12.59) 352 (14.45) Headache 165 (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) 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.. 6.2 Post Marketing Experience. The following is list of additional adverse reactions that have been reported either in the literature or are from postmarketing 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. 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, palpitationImmune 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, purpura Psychiatric Disorders: Confusion, agitationRespiratory: Tachypnea, dyspnea, hemoptysisSkin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising, ecchymosis, and hematoma, pruritus, urticariaUrogenital: 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/m2 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/m2 basis). 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 mg/m2 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 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 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 A2-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 A2, 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 coadministration as aspirin and extended-release dipyridamole. Absorption Dipyridamole: Peak plasma levels of dipyridamole are achieved hours (range to hours) after administration of 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). Aspirin:Peak plasma levels of aspirin are achieved 0.63 hours (0.5 to hour) after administration of 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 Dipyridamole: When aspirin and extended-release dipyridamole capsules were taken with high fat meal, dipyridamole peak plasma levels (Cmax) 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. 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 Cmax was not considered clinically relevant based on similar degree of cyclooxygenase inhibition comparing the fed and fasted state. Distribution Dipyridamole: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 Elimination Dipyridamole: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 whichwas 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 to 2.5 hours after dosing and peak salicylic acid concentrations occur hour (range: 0.5 to 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 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 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 to 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.Hepatic Dysfunction:No study has been conducted with aspirin and extended-release dipyridamole 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 Studies 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 coadministered with aspirin and extended-release dipyridamole twice daily. Dipyridamole exposure (Cmax and AUC) at steady-state were similar with or without omeprazole coadministration. 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 6,602 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 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 Endpoint Aspirin and extended-release dipyridamole 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 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.) Individual Treatment Group Aspirin and Extended-Release Dipyridamole 1,650 157 (9.5%) 89.9% (88.4%, 91.4%) ---ER-DP 1,654 211 (12.8%) 86.7% (85%, 88.4%) ---ASA 1,649 206 (12.5%) 87.1% (85.4%, 88.7%) ---Placebo 1,649 250 (15.2%) 84.1% (82.2%, 85.9%) ---Pairwise Treatment Group ComparisonsAspirin and Extended-Release Dipyridamole vs. ER-DP - 0.002 24.4% 0.72 (0.58, 0.9) Aspirin and Extended-Release Dipyridamole vs. ASA - 0.008 22.1% 0.74 (0.59, 0.92) Aspirin and Extended-Release Dipyridamole vs. Placebo - <0.001 36.8% 0.59 (0.48, 0.73) ER-DP vs. Placebo - 0.0360.01 p-value <=0.05 16.5% 0.82 (0.67, 1) ASA vs. Placebo - 0.009p-value <=0.01 18.9% 0.8 (0.66, 0.97) Note: ER-DP extended-release dipyridamole 200 mg; ASA aspirin 25 mg. The dosage regimen for all treatment groups is twice daily (BID) Figure ESPS2: Cumulative Stroke Rate (Fatal or Nonfatal)Over 24 months of Follow-UpCombined Stroke or Death Endpoint In ESPS2, aspirin and extended-release dipyridamole reduced the risk of stroke or death by 24.2% compared to placebo.Aspirin and extended-release dipyridamole 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 Endpoint The incidence rate of all cause mortality was 11.3% for aspirin and extended-release dipyridamole, 11% 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, aspirin alone and extended-release dipyridamole alone treatment groups were not statistically significant. These incidence rates for aspirin and extended-release dipyridamole and aspirin alone are consistent with previous aspirin studies in stroke and TIA patients.. spl-aspirin-and-dipyridamole-figure.

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 nasal polyps (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 nasal polyps (4.2). 4.1 Hypersensitivity. Aspirin and extended-release dipyridamole 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.

DESCRIPTION SECTION.

11 DESCRIPTION. Aspirin and dipyridamole are 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, as an immediate-release film-coated tablet. In addition, each capsule contains the following inactive ingredients: tartaric acid, hypromellose, acacia, talc, methacrylic acid copolymer, hypromellose phthalate, triethyl citrate, corn starch, microcrystalline cellulose, colloidal silicon dioxide, stearic acid, titanium dioxide,triacetin, and ethylcellulose. Each capsule shell contains iron oxide red, iron oxide yellow, titanium dioxide, gelatin, water, and sodium lauryl sulfate. Imprinting black ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, and potassium hydroxide. Dipyridamole Dipyridamole 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 yellow crystalline substance. It is soluble in methanol, sparingly soluble in dilute acids, freely soluble in chloroform, and is practically insoluble in water. Aspirin 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 vinegary odor. It is highly lipid soluble and slightly soluble in water.. spl-aspirin-and-dipyridamole-dipyridamole-structure. spl-aspirin-and-dipyridamole-aspirin-structure.

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 twice daily (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 twice daily (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. 25 mg/200 mg hard gelatin capsules, size 00, with red cap and an ivory-colored body, containing yellow extended-release pellets incorporating dipyridamole and round white to off white tablet incorporating immediate-release aspirin. The capsule is imprinted in black ink with the 927 on cap and body.. 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. Coadministration with anti-coagulants, antiplatelets, or NSAIDS can increase risk of bleeding (7.1)Decreased renal function can occur with coadministration with NSAIDS (7.1) Coadministration with anti-coagulants, antiplatelets, or NSAIDS can increase risk of bleeding (7.1). Decreased renal function can occur with coadministration 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) InhibitorsBecause 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 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. AnticonvulsantsSalicylic acid can displace protein-bound phenytoin and valproic acid, leading to 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.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of subjects in ESPS2, 61% were 65 and over, while 27% 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)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Aspirin and extended-release dipyridamole capsules are available as hard gelatin capsule, size 00, with red cap and an ivory-colored body, containing yellow extended-release pellets incorporating dipyridamole and round white to off white tablet incorporating immediate-release aspirin. The capsule is imprinted in black ink with the 927on cap and body. Aspirin and extended-release dipyridamole capsules 25 mg/250 mg are supplied as below: NDC 47335-927-83 Unit of use bottle of 30 capsulesNDC 47335-927-86 Unit of use bottle of 60 capsules Store at 20 to 25C (68 to 77F); excursions permitted between 15 and 30C (59 and 86F) [see USP Controlled Room Temperature]. Protect from excessive moisture.. NDC 47335-927-83 Unit of use bottle of 30 capsules. NDC 47335-927-86 Unit of use bottle of 60 capsules.

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 dipyridamole is combination antiplatelet agent indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis (1). Aspirin and dipyridamole is combination antiplatelet agent indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis (1).

LABOR & DELIVERY SECTION.

8.2 Lactation. Risk SummaryBased on data from 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 dipyridamole or dipyridamole on the breastfed infant or on milkproduction. There is insufficient information to determine the effects of aspirin on the breastfed infant and no information on the effects of aspirin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for aspirin and extended-release dipyridamole and any potential adverse effects on the breastfed child from aspirin and extended-release dipyridamole or from the underlying maternal condition. DataA published clinical study involved six exclusively breastfeeding women at to months postpartum who were taking 81 mg aspirin daily. Milk samples were collected at steady state, at 0, 1, 2, 4, 8, 12, and 24 hours after taking dose of aspirin. Aspirin was undetectable in human milk. Salicylic acid was present in milk at low levels (average concentration of 24 ng/mL). Based on an average milk consumption of 150 mL/kg/day, the calculated relative infant dose was 0.4%. No adverse effects on the breastfed infants were noted.

MECHANISM OF ACTION SECTION.

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 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 A2-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 A2, powerful inducer of platelet aggregation and vasoconstriction.

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/m2 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/m2 basis). 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 mg/m2 basis). Aspirin inhibits ovulation in rats.

OVERDOSAGE SECTION.

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 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. 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. 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 slurry may be beneficial if less than 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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. NDC 47335-927-86 Aspirin and Extended-Release Dipyridamole Capsules 25 mg/200 mg Rx only 60 Capsules Unit-of-use container SUN PHARMA spl-aspirin-and-dipyridamole-label.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. There are no significant interactions between aspirin and dipyridamole. The kinetics of the components are unchanged by their coadministration as aspirin and extended-release dipyridamole. Absorption Dipyridamole: Peak plasma levels of dipyridamole are achieved hours (range to hours) after administration of 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). Aspirin:Peak plasma levels of aspirin are achieved 0.63 hours (0.5 to hour) after administration of 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 Dipyridamole: When aspirin and extended-release dipyridamole capsules were taken with high fat meal, dipyridamole peak plasma levels (Cmax) 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. 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 Cmax was not considered clinically relevant based on similar degree of cyclooxygenase inhibition comparing the fed and fasted state. Distribution Dipyridamole: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 Elimination Dipyridamole: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 whichwas 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 to 2.5 hours after dosing and peak salicylic acid concentrations occur hour (range: 0.5 to 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 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 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 to 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.Hepatic Dysfunction:No study has been conducted with aspirin and extended-release dipyridamole 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 Studies 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 coadministered with aspirin and extended-release dipyridamole twice daily. Dipyridamole exposure (Cmax and AUC) at steady-state were similar with or without omeprazole coadministration. 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from published studies and postmarketing experience with aspirin and extended-release dipyridamole use during pregnancy have not identified clear association between aspirin and extended-release dipyridamole use and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Aspirin and extended-release dipyridamole 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 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 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 recognizedpregnancies is to and 15 to 20%, respectively.Clinical ConsiderationsLabor and DeliveryAspirin and extended-release dipyridamole, 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.DataHuman DataPublished data from clinical trials, observational studies, case series, and case reports over several decades have not identified 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 DataAspirin 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 high resorption rate in rats (63% of implantations versus 5% in controls), are, on 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 1/2 2, and 25 times the maximum recommended daily human oral dose, respectively, on mg/m2 basis) and have revealed no evidence of harm to the fetus due to dipyridamole. When 330 mg aspirin/kg/day was combined with 75 mg dipyridamole/kg/day in the rat at doses about 66 and times, respectively, the maximum recommended daily human dose, the resorption rate approached 100%.

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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from published studies and postmarketing experience with aspirin and extended-release dipyridamole use during pregnancy have not identified clear association between aspirin and extended-release dipyridamole use and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Aspirin and extended-release dipyridamole 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 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 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 recognizedpregnancies is to and 15 to 20%, respectively.Clinical ConsiderationsLabor and DeliveryAspirin and extended-release dipyridamole, 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.DataHuman DataPublished data from clinical trials, observational studies, case series, and case reports over several decades have not identified 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 DataAspirin 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 high resorption rate in rats (63% of implantations versus 5% in controls), are, on 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 1/2 2, and 25 times the maximum recommended daily human oral dose, respectively, on mg/m2 basis) and have revealed no evidence of harm to the fetus due to dipyridamole. When 330 mg aspirin/kg/day was combined with 75 mg dipyridamole/kg/day in the rat at doses about 66 and times, respectively, the maximum recommended daily human dose, the resorption rate approached 100%.. 8.2 Lactation. Risk SummaryBased on data from 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 dipyridamole or dipyridamole on the breastfed infant or on milkproduction. There is insufficient information to determine the effects of aspirin on the breastfed infant and no information on the effects of aspirin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for aspirin and extended-release dipyridamole and any potential adverse effects on the breastfed child from aspirin and extended-release dipyridamole or from the underlying maternal condition. DataA published clinical study involved six exclusively breastfeeding women at to months postpartum who were taking 81 mg aspirin daily. Milk samples were collected at steady state, at 0, 1, 2, 4, 8, 12, and 24 hours after taking dose of aspirin. Aspirin was undetectable in human milk. Salicylic acid was present in milk at low levels (average concentration of 24 ng/mL). Based on an average milk consumption of 150 mL/kg/day, the calculated relative infant dose was 0.4%. No adverse effects on the breastfed infants were noted.. 8.4 Pediatric Use. Safety and effectiveness of aspirin and extended-release dipyridamole capsules in pediatric patients have not been studied. Because of 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% were 65 and over, while 27% 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)]. 8.6Patients 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)].

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). 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). 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 Hemorrhage In European Stroke Prevention Study-2 (ESPS2), the annualized event rate for intracranial hemorrhage was 0.39%/year in the aspirin and extended-release dipyridamole 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 Effects GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Inform patients about the signs and symptoms of GI side effects and what steps to take if they occur. In ESPS2, the annualized event rate for gastrointestinal bleeding was 2.97%/year in the aspirin and extended-release dipyridamole 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 Disease Avoid using aspirin in patients with history of active peptic ulcer disease, which can cause gastric mucosal irritation and bleeding. Alcohol Warning Because aspirin and extended-release dipyridamole capsules contain aspirin, counsel patients who consume three or more alcoholic drinks every day about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin. 5.2 Renal Failure. Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 5.3 Hepatic Insufficiency. Elevations of hepatic enzymes and hepatic failure have been reported in association with dipyridamole administration [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].. 5.4 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 preexisting hypotension.. 5.6 General. Aspirin and extended-release dipyridamole capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.