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) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY 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) 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 AGGRENOX 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 AGGRENOX, 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 AGGRENOX 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 incidence of adverse events that occurred in 1% or more of patients treated with AGGRENOX where the incidence was also greater than in those patients treated with placebo. There is no clear benefit of the dipyridamole/aspirin combination over aspirin with respect to safety.Table Incidence of Adverse Events in ESPS2 Individual Treatment GroupBody System/Preferred TermAGGRENOXER-DP AloneASA AlonePlacebo Reported by >=1% of patients during AGGRENOX treatment where the incidence was greater than in those treated with placebo.Note: ER-DP extended-release dipyridamole 200 mg; ASA aspirin 25 mg. The dosage regimen for all treatment groups is BIDNOS not otherwise specified.Total Number of Patients1650165416491649Total Number (%) of Patients With at Least One On-Treatment Adverse Event1319 (80%)1305 (79%)1323 (80%)1304 (79%)Central and Peripheral Nervous System Disorders Headache647 (39%)634 (38%)558 (34%)543 (33%) Convulsions28 (2%)15 (1%)28 (2%)26 (2%)Gastrointestinal System Disorders Dyspepsia303 (18%)288 (17%)299 (18%)275 (17%) Abdominal Pain289 (18%)255 (15%)262 (16%)239 (14%) Nausea264 (16%)254 (15%)210 (13%)232 (14%) Diarrhea210 (13%)257 (16%)112 (7%)161 (10%) Vomiting138 (8%)129 (8%)101 6%)118 (7%) Hemorrhage Rectum26 (2%)22 (1%)16 (1%)13 (1%) Melena31 (2%)10 (1%)20 (1%)13 (1%) Hemorrhoids16 (1%)13 (1%)10 (1%)10 (1%) GI Hemorrhage20 (1%)5 (0%)15 (1%)7 (0%)Body as Whole General Disorders Pain105 (6%)88 (5%)103 (6%)99 (6%) Fatigue95 (6%)93 (6%)97 (6%)90 (5%) Back Pain76 (5%)77 (5%)74 (4%)65 (4%) Accidental Injury42 (3%)24 (1%)51 (3%)37 (2%) Malaise27 (2%)23 (1%)26 (2%)22 (1%) Asthenia29 (2%)19 (1%)17 (1%)18 (1%) Syncope17 (1%)13 (1%)16 (1%)8 (0%)Psychiatric Disorders Amnesia39 (2%)40 (2%)57 (3%)34 (2%) Confusion18 (1%)9 (1%)22 (1%)15 (1%) Anorexia19 (1%)17 (1%)10 (1%)15 (1%) Somnolence20 (1%)13 (1%)18 (1%)9 (1%)Musculoskeletal System Disorders Arthralgia91 (6%)75 (5%)91 (6%)76 (5%) Arthritis34 (2%)25 (2%)17 (1%)19 (1%) Arthrosis18 (1%)22 (1%)13 (1%)14 (1%) Myalgia20 (1%)16 (1%)11 (1%)11 (1%)Respiratory System Disorders Coughing25 (2%)18 (1%)32 (2%)21 (1%) Upper Respiratory Tract Infection16 (1%)9 (1%)16 (1%)14 (1%)Cardiovascular Disorders, General Cardiac Failure26 (2%)17 (1%)30 (2%)25 (2%)Platelet, Bleeding Clotting Disorders Hemorrhage NOS52 (3%)24 (1%)46 (3%)24 (1%) Epistaxis39 (2%)16 (1%)45 (3%)25 (2%) Purpura23 (1%)8 (0%)9 (1%)7 (0%)Neoplasm Neoplasm NOS28 (2%)16 (1%)23 (1%)20 (1%)Red Blood Cell Disorders Anemia27 (2%)16 (1%)19 (1%)9 (1%)Discontinuation due to adverse events in ESPS2 was 25% for AGGRENOX, 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: Adverse Events with an Incidence of>=1% in the AGGRENOX Group Treatment Groups AGGRENOXER-DPASAPlaceboNote: ER-DP extended-release dipyridamole 200 mg; ASA aspirin 25 mg. The dosage regimen for all treatment groups is BID Total Number of Patients1650165416491649Patients with at least one Adverse Eventthat led to treatment discontinuation417 (25%)419 (25%)318 (19%)352 (21%) Headache165 (10%)166 (10%)57 (3%)69 (4%) Dizziness85 (5%)97 (6%)69 (4%)68 (4%) Nausea91 (6%)95 (6%)51 (3%)53 (3%) Abdominal Pain74 (4%)64 (4%)56 (3%)52 (3%) Dyspepsia59 (4%)61 (4%)49 (3%)46 (3%) Vomiting53 (3%)52 (3%)28 (2%)24 (1%) Diarrhea35 (2%)41 (2%)9 (<1%)16 (<1%) Stroke39 (2%)48 (3%)57 (3%)73 (4%) Transient Ischemic Attack35 (2%)40 (2%)26 (2%)48 (3%) Angina Pectoris23 (1%)20 (1%)16 (<1%)26 (2%)Headache was most notable in the first month of treatment.Other Adverse Events Adverse reactions that occurred in less than 1% of patients treated with AGGRENOX in the ESPS2 study and that were medically judged to be possibly related to either dipyridamole or aspirin are listed below.Body as Whole: Allergic reaction, feverCardiovascular: HypotensionCentral Nervous System: Coma, dizziness, paresthesia, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhageGastrointestinal: Gastritis, ulceration and perforationHearing and Vestibular Disorders: Tinnitus, and deafness. Patients with high frequency hearing loss may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used as clinical indicator of salicylismHeart Rate and Rhythm Disorders: Tachycardia, palpitation, arrhythmia, supraventricular tachycardiaLiver and Biliary System Disorders: Cholelithiasis, jaundice, hepatic function abnormalMetabolic and Nutritional Disorders: Hyperglycemia, thirstPlatelet, Bleeding and Clotting Disorders: Hematoma, gingival bleeding Psychiatric Disorders: AgitationReproductive: Uterine hemorrhageRespiratory: Hyperpnea, asthma, bronchospasm, hemoptysis, pulmonary edemaSpecial Senses Other Disorders: Taste loss Skin and Appendages Disorders: Pruritus, urticaria Urogenital: Renal insufficiency and failure, hematuriaVascular (Extracardiac) Disorders: FlushingLaboratory Changes Over the course of the 24-month study (ESPS2), patients treated with AGGRENOX showed decline (mean change from baseline) in hemoglobin of 0.25 g/dL, hematocrit of 0.75%, and erythrocyte count of 0.13x106/mm3.. 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 AGGRENOX.Body as Whole: Hypothermia, chest pain Cardiovascular: Angina pectoris Central Nervous System: Cerebral edema Fluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia Gastrointestinal: Pancreatitis, Reye syndrome, hematemesis Hearing and Vestibular Disorders: Hearing loss Immune System Disorders: Hypersensitivity, acute anaphylaxis, laryngeal edema Liver and Biliary System Disorders: Hepatitis, hepatic failure Musculoskeletal: Rhabdomyolysis Metabolic and Nutritional Disorders: Hypoglycemia, dehydration Platelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants, antepartum and postpartum bleeding Respiratory: Tachypnea, dyspnea Skin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skin hemorrhages such as bruising, ecchymosis, and hematoma Urogenital: Interstitial nephritis, papillary necrosis, proteinuria Vascular (Extracardiac Disorders): Allergic vasculitisOther 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 1250 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 AGGRENOX 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 (0.5-1.9 ug/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 co-administration as AGGRENOX. DipyridamoleAbsorption Peak plasma levels of dipyridamole are achieved hours (range 1-6 hours) after administration of daily dose of 400 mg AGGRENOX (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).Effect of Food When AGGRENOX capsules were taken with high fat meal, dipyridamole peak plasma levels (Cmax) 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.Distribution Dipyridamole is highly lipophilic (log P=3.71, pH=7); however, it has been shown that the drug does not cross the blood-brain barrier to any significant extent in animals. The steady-state volume of distribution of dipyridamole is about 92 L. Approximately 99% of dipyridamole is bound to plasma proteins, predominantly to alpha 1-acid glycoprotein and albumin.Metabolism and Elimination Dipyridamole is metabolized in the liver, primarily by conjugation with glucuronic acid, of which monoglucuronide which has low pharmacodynamic activity is the primary metabolite. In plasma, about 80% of the total amount is present as parent compound and 20% as monoglucuronide. Most of the glucuronide metabolite (about 95%) is excreted via bile into the feces, with some evidence of enterohepatic circulation. Renal excretion of parent compound is negligible and urinary excretion of the glucuronide metabolite is low (about 5%). With intravenous (i.v.) treatment of dipyridamole, 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. Due to the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with AGGRENOX which, in Trial 9.123 was 13.6 hours.Special PopulationsGeriatric Patients: In ESPS2 [see Clinical Studies (14) ], plasma concentrations (determined as AUC) of dipyridamole in healthy elderly subjects (>65 years) were about 40% higher than in subjects younger than 55years receiving treatment with AGGRENOX. Hepatic Dysfunction: No study has been conducted with AGGRENOX in patients with hepatic dysfunction.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.Renal Dysfunction: No study has been conducted with AGGRENOX in patients with renal dysfunction.In ESPS2 patients [see Clinical Studies (14) ], with creatinine clearances ranging from about 15 mL/min to >100 mL/min, no changes were observed in the pharmacokinetics of dipyridamole or its glucuronide metabolite if data were corrected for differences in age.. AspirinAbsorption Peak plasma levels of aspirin are achieved 0.63 hours (0.5-1 hour) after administration of 50 mg aspirin daily dose from AGGRENOX (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 Food When AGGRENOX 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 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 ug/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 ug/mL [see Adverse Reactions (6) and Overdosage (10) ].Metabolism and Elimination 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 AGGRENOX 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.Special PopulationsHepatic Dysfunction: Avoid aspirin in patients with severe hepatic insufficiency.Renal Dysfunction: Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/min).

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: AGGRENOX (aspirin/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 AGGRENOX 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 4). AGGRENOX 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 TotalNumberof PatientsnNumber of PatientsWithStroke Within Yearsn (%)Kaplan-Meier Estimateof Survival at Years(95% C.I.)Gehan-WilcoxonTestP-valueRisk Reductionat YearsOdds Ratio(95% C.I.)0.010 p-value <=0.050; p-value <=0.010.Note: ER-DP extended-release dipyridamole 200 mg; ASA aspirin 25 mg. The dosage regimen for all treatment groups is BIDIndividual TreatmentGroup AGGRENOX1650157 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 AGGRENOX vs. ER-DP---0.00224.4%0.72 (0.58, 0.90) AGGRENOX vs. ASA---0.00822.1%0.74 (0.59, 0.92) AGGRENOX vs. Placebo---<0.00136.8%0.59 (0.48, 0.73) ER-DP vs. Placebo---0.03616.5%0.82 (0.67, 1.00) ASA vs. Placebo---0.00918.9%0.80 (0.66, 0.97)ESPS2: Cumulative Stroke Rate (Fatal or Nonfatal) Over 24 months of Follow-UP Combined Stroke or Death Endpoint In ESPS2, AGGRENOX 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. AGGRENOX reduced the risk of stroke or death by 24.2% compared to placebo. Death Endpoint The incidence rate of all cause mortality was 11.3% for AGGRENOX, 11.0% for aspirin alone, 11.4% for extended-release dipyridamole alone and 12.3% for placebo alone. The differences between the AGGRENOX, aspirin alone and extended-release dipyridamole alone treatment groups were not statistically significant. These incidence rates for AGGRENOX and aspirin alone are consistent with previous aspirin studies in stroke and TIA patients. Figure 1.

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. AGGRENOX 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 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. AGGRENOX is combination antiplatelet agent intended for oral administration. Each hard gelatin capsule contains 200 mg dipyridamole in an extended-release form and 25 mg aspirin, as an immediate-release sugar-coated tablet. In addition, each capsule contains the following inactive ingredients: acacia, aluminum stearate, colloidal silicon dioxide, corn starch, dimethicone, hypromellose, hypromellose phthalate, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, povidone, stearic acid, sucrose, talc, tartaric acid, titanium dioxide and triacetin.Each capsule shell contains gelatin, red iron oxide and yellow iron oxide, titanium dioxide and water.. 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 is an odorless yellow crystalline substance, having bitter taste. It is soluble in dilute acids, methanol and 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.. Structural formula of Dipyridamole.. Structural formula of benzoic acid.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. AGGRENOX is not interchangeable with the individual components of aspirin and dipyridamole tablets. The recommended dose of AGGRENOX is one capsule given orally twice daily, one in the morning and one in the evening. Swallow capsules whole without chewing. AGGRENOX can be administered with or without food.. One capsule twice daily (morning and evening) with or without food (2) In case of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning; resume BID dosing within one week (2) Do not chew capsule (2) Not interchangeable with the individual components of aspirin and dipyridamole tablets (2)Dispense in this unit-of-use container (16) One capsule twice daily (morning and evening) with or without food (2) In case of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning; resume BID dosing within one week (2) Do not chew capsule (2) Not interchangeable with the individual components of aspirin and dipyridamole tablets (2). Dispense in this unit-of-use container (16) 2.1 Alternative Regimen in Case of Intolerable Headaches. In the event of intolerable headaches during initial treatment, switch to one capsule at bedtime and low-dose aspirin in the morning. Because there are no outcome data with this regimen and headaches become less of 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 capsules with red cap and an ivory-colored body, containing yellow extended-release pellets incorporating dipyridamole and round white tablet incorporating immediate-release aspirin. The capsule body is imprinted in red with the Boehringer Ingelheim logo and with 01A.. 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. No pharmacokinetic drug-drug interaction studies were conducted with AGGRENOX capsules. The following information was obtained from the literature.. Co-administration with anti-coagulants or NSAIDS can increase risk of bleeding (7.4, 7.10)Decreased renal function can occur with co-administration with NSAIDS (7.10) Co-administration with anti-coagulants or NSAIDS can increase risk of bleeding (7.4, 7.10). Decreased renal function can occur with co-administration with NSAIDS (7.10) 7.1 Adenosine. Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary.. 7.2 Angiotensin Converting Enzyme (ACE) Inhibitors. Due to the indirect effect of aspirin on the renin-angiotensin conversion pathway, the hyponatremic and hypotensive effects of ACE inhibitors may be diminished by concomitant administration of aspirin.. 7.3 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.. 7.4 Anticoagulant Therapy (heparin and warfarin). Patients on anticoagulation therapy are at increased risk for bleeding because of drug-drug interactions and effects on platelets. 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.. 7.5 Anticonvulsants. Salicylic 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. 7.6 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.. 7.7 Cholinesterase Inhibitors. Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis. 7.8 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.. 7.9 Methotrexate. Salicylate can inhibit renal clearance of methotrexate, leading to bone marrow toxicity, especially in the elderly or renal impaired.. 7.10 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). The concurrent use of aspirin with other NSAIDs may increase bleeding or lead to decreased renal function.. 7.11 Oral Hypoglycemics Moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.. 7.12 Uricosuric Agents (probenecid and sulfinpyrazone). Salicylates antagonize the uricosuric action of uricosuric agents.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. AGGRENOX is indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.. AGGRENOX 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).

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 1250 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 AGGRENOX 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 ug/mL. In severe cases, hyperthermia and hypovolemia are the major immediate threats to life. Plasma concentrations of aspirin above 300 ug/mL are clearly toxic. Severe toxic effects are associated with levels above 400 ug/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 hemodynamic effects of dipyridamole overdose. Plasma electrolytes and pH should be monitored serially to promote alkaline diuresis of salicylate if renal function is normal. In patients with renal insufficiency or in cases of life-threatening intoxication, dialysis is usually required to treat salicylic overdose, however since dipyridamole is highly protein bound, dialysis is not likely to remove dipyridamole. Exchange transfusion may be indicated in infants and young children.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Principal Display Panel. Aggrenox 25mg/200mg Label.

PREGNANCY SECTION.

5.4 Pregnancy. Because AGGRENOX contains aspirin, AGGRENOX can cause fetal harm when administered to pregnant woman. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence for intracranial hemorrhage in premature infants, stillbirths and neonatal death. Because of the above and because of the known effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the fetal cardiovascular system (closure of the ductus arteriosus), avoid AGGRENOX in the third trimester of pregnancy [see Use in Specific Populations (8.1) ].Aspirin has been shown to be teratogenic in rats (spina bifida, exencephaly, microphthalmia and coelosomia) and rabbits (congested fetuses, agenesis of skull and upper jaw, generalized edema with malformation of the head, and diaphanous skin) at oral doses of 330 mg/kg/day and 110 mg/kg/day, respectively. These doses, which also resulted in 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 AGGRENOX. 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, the resorption rate approached 100%, indicating potentiation of aspirin-related fetal toxicity. There are no adequate and well-controlled studies of the use of AGGRENOX in pregnant women. If AGGRENOX is used during pregnancy, or if the patient becomes pregnant while taking AGGRENOX, inform the patient of the potential hazard to the fetus.

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. Pregnancy Category (8.1) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Pregnancy Category (8.1) 8.1 Pregnancy. Teratogenic Effects, Pregnancy Category D. [see Warnings and Precautions (5.4) ].. 8.2 Labor and Delivery. Aspirin can result in excessive blood loss at delivery as well as prolonged gestation and prolonged labor. Because of these effects on the mother and because of adverse fetal effects seen with aspirin during the later stages of pregnancy [see Warnings and Precautions (5.4) ], avoid AGGRENOX in the third trimester of pregnancy and during labor and delivery.. 8.3 Nursing Mothers. Both dipyridamole and aspirin are excreted in human milk. Exercise caution when AGGRENOX capsules are administered to nursing woman.. 8.4 Pediatric Use. Safety and effectiveness of AGGRENOX in pediatric patients have not been studied. Due to the aspirin component, use of this product in the pediatric population is not recommended [see Contraindications (4.3) ].. 8.5 Geriatric Use Of the total number of subjects in ESPS2, 61 percent were 65 and over, while 27 percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) ].. 8.6 Patients with Severe Hepatic or Severe Renal Dysfunction. AGGRENOX has not been studied in patients with hepatic or renal impairment. Avoid using aspirin containing products, such as Aggrenox 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. The risk of GI bleeding is increased, especially in patients who are heavy alcohol users, have history of peptic ulcer, or have coagulation abnormalities due to liver disease or vitamin deficiency (5.1) As with other antiplatelets, there is risk of intracranial hemorrhage (5.1) Avoid use in patients with severe hepatic or renal insufficiency (5.2, 5.3) Can cause fetal harm when administered to pregnant woman, especially in the third trimester (5.4) The risk of GI bleeding is increased, especially in patients who are heavy alcohol users, have history of peptic ulcer, or have coagulation abnormalities due to liver disease or vitamin deficiency (5.1) As with other antiplatelets, there is risk of intracranial hemorrhage (5.1) Avoid use in patients with severe hepatic or renal insufficiency (5.2, 5.3) Can cause fetal harm when administered to pregnant woman, especially in the third trimester (5.4) 5.1 Risk of Bleeding. Intracranial HemorrhageIn ESPS2 the incidence of intracranial hemorrhage was 0.6% in the AGGRENOX group, 0.5% in the extended-release dipyridamole (ER-DP) group, 0.4% in the aspirin (ASA) group and 0.4% in the placebo groups.Coagulation AbnormalitiesEven low doses of aspirin can inhibit platelet function leading to an increase in bleeding time. This can adversely affect patients with inherited or acquired (liver disease or vitamin deficiency) bleeding disorders [see Drug Interactions (7.4) ]. 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 incidence of gastrointestinal bleeding was 4.1% in the AGGRENOX group, 2.2% in the extended-release dipyridamole group, 3.2% in the aspirin group, and 2.1% in the placebo groups. Peptic Ulcer Disease Avoid using aspirin in patients with history of active peptic ulcer disease, which can cause gastric mucosal irritation and bleeding.Alcohol Warning Because AGGRENOX contains aspirin, counsel patients who consume three or more alcoholic drinks every day about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.. 5.2 Renal Failure. Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/minute) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. 5.3 Hepatic Insufficiency. Elevations of hepatic enzymes and hepatic failure have been reported in association with dipyridamole administration [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].. 5.4 Pregnancy. Because AGGRENOX contains aspirin, AGGRENOX can cause fetal harm when administered to pregnant woman. Maternal aspirin use during later stages of pregnancy may cause low birth weight, increased incidence for intracranial hemorrhage in premature infants, stillbirths and neonatal death. Because of the above and because of the known effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the fetal cardiovascular system (closure of the ductus arteriosus), avoid AGGRENOX in the third trimester of pregnancy [see Use in Specific Populations (8.1) ].Aspirin has been shown to be teratogenic in rats (spina bifida, exencephaly, microphthalmia and coelosomia) and rabbits (congested fetuses, agenesis of skull and upper jaw, generalized edema with malformation of the head, and diaphanous skin) at oral doses of 330 mg/kg/day and 110 mg/kg/day, respectively. These doses, which also resulted in 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 AGGRENOX. 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, the resorption rate approached 100%, indicating potentiation of aspirin-related fetal toxicity. There are no adequate and well-controlled studies of the use of AGGRENOX in pregnant women. If AGGRENOX is used during pregnancy, or if the patient becomes pregnant while taking AGGRENOX, inform the patient of the potential hazard to the fetus.. 5.5 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. 5.6 Hypotension. Dipyridamole produces peripheral vasodilation, which can exacerbate pre-existing hypotension.. 5.7 General. AGGRENOX capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.