ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussedelsewhere 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% andgreater than placebo) were headache, dyspepsia, abdominal pain, nausea,and diarrhea (6) To report SUSPECTED ADVERSE REACTIONS,contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most frequently reported adverse reactions (>10% andgreater than placebo) were headache, dyspepsia, abdominal pain, nausea,and diarrhea (6) 6.1 Clinical TrialsExperience. Because clinicaltrials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of drug cannot be directlycompared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.The efficacy and safety of AGGRENOX was establishedin the European Stroke Prevention Study-2 (ESPS2). ESPS2 was double-blind,placebo-controlled study that evaluated 6602 patients over the ageof 18 years who had previous ischemic stroke or transient ischemicattack within ninety days prior to entry. Patients were randomizedto either AGGRENOX, aspirin, ER-DP, or placebo [see Clinical Studies (14) ]; primary endpoints included stroke (fatal or nonfatal)and death from all causes.This24-month, multicenter, double-blind, randomized study (ESPS2) wasconducted to compare the efficacy and safety of AGGRENOX with placebo,extended-release dipyridamole alone and aspirin alone. The study wasconducted in total of 6602 male and female patients who had experienceda previous ischemic stroke or transient ischemia of the brain withinthree months prior to randomization.Table presents the incidence of adverse events that occurred in1% or more of patients treated with AGGRENOX where the incidence wasalso greater than in those patients treated with placebo. There isno clear benefit of the dipyridamole/aspirin combination over aspirinwith respect to safety.Table Incidence of Adverse Events in ESPS2a Individual Treatment Group AGGRENOXER-DP AloneASA AlonePlaceboBody System/Preferred TermaReportedby >=1% of patients during AGGRENOX treatment where the incidence wasgreater than in those treated with placebo.Note: ER-DP extended-releasedipyridamole 200 mg; ASA aspirin 25 mg. The dosage regimen for alltreatment groups is BID. NOS= not otherwise specified. 1650165416491649Total Number ofPatientsTotal Number (%) of Patients WithatLeast One On-Treatment AdverseEvent1319(80%)1305(79%)1323(80%)1304(79%) Central and Peripheral Nervous SystemDisorders 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 and 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%)Discontinuationdue to adverse events in ESPS2 was 25% for AGGRENOX, 25% for extended-releasedipyridamole, 19% for aspirin, and 21% for placebo (refer to Table2)Table Incidence of Adverse Events that Led to the Discontinuationof Treatment: Adverse Events with an Incidence of >=1% in the AGGRENOXGroup Treatment Groups AGGRENOXER-DPASAPlaceboNote: ER-DP extended-release dipyridamole200 mg; ASA aspirin 25 mg. The dosage regimen for all treatmentgroups is BID. Total Number of Patients1650165416491649 Patients with at least one AdverseEventthat 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 thefirst month of treatment.Other Adverse Events Adversereactions that occurred in less than 1% of patients treated with AGGRENOXin the ESPS2 study and that were medically judged to be possibly relatedto either dipyridamole or aspirin are listed below.Body as Whole: Allergic reaction, feverCardiovascular: HypotensionCentral Nervous System: Coma, dizziness, paresthesia, cerebral hemorrhage, intracranialhemorrhage, subarachnoid hemorrhageGastrointestinal: Gastritis,ulceration and perforationHearing and Vestibular Disorders: Tinnitus,and deafness. Patients with high frequency hearing loss may have difficultyperceiving tinnitus. In these patients, tinnitus cannot be used asa clinical indicator of salicylismHeart Rate and Rhythm Disorders: Tachycardia, palpitation, arrhythmia, supraventricular tachycardiaLiver and Biliary SystemDisorders: Cholelithiasis, jaundice, hepatic functionabnormalMetabolicand Nutritional Disorders: Hyperglycemia, thirstPlatelet, Bleeding andClotting 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 courseof the 24-month study (ESPS2), patients treated with AGGRENOX showeda 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 adversereactions that have been reported either in the literature or arefrom post-marketing spontaneous reports for either dipyridamole oraspirin. Because these reactions are reported voluntarily from populationof uncertain size, it is not always possible to estimate reliablytheir frequency or establish causal relationship to drug exposure.Decisions to include these reactions in labeling are typically basedon one or more of the following factors: (1) seriousness of the reaction,(2) frequency of reporting, or (3) strength of causal connection toAGGRENOX.Bodyas Whole: Hypothermia, chest painCardiovascular: Angina pectorisCentral Nervous System: Cerebral edemaFluid and Electrolyte: Hyperkalemia, metabolic acidosis, respiratory alkalosis,hypokalemiaGastrointestinal: Pancreatitis, Reye syndrome,hematemesisHearing and Vestibular Disorders: Hearing lossImmune System Disorders: Hypersensitivity, acute anaphylaxis, laryngeal edemaLiver and Biliary SystemDisorders: Hepatitis, hepatic failureMusculoskeletal: RhabdomyolysisMetabolic and Nutritional Disorders: Hypoglycemia, dehydrationPlatelet, Bleeding and Clotting Disorders: Prolongation of the prothrombin time, disseminated intravascularcoagulation, coagulopathy, thrombocytopeniaReproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight infants,antepartum and postpartum bleedingRespiratory: Tachypnea, dyspneaSkin and Appendages Disorders: Rash, alopecia, angioedema, Stevens-Johnson syndrome, skinhemorrhages such as bruising, ecchymosis, and hematomaUrogenital: Interstitial nephritis, papillary necrosis, proteinuriaVascular (Extracardiac) Disorders: Allergic vasculitisOther Adverse Events: anorexia, aplasticanemia, migraine, pancytopenia, thrombocytosis.

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.. DipyridamoleDipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in vivo; the inhibition occurs in dose-dependent manner at therapeutic concentrations (0.5-1.9 ug/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet 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).. AspirinAspirin 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.. DipyridamoleAbsorptionPeak 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 FoodWhen 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.DistributionDipyridamole 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 55 years 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.. AspirinAbsorptionPeak plasma levels of aspirin are achieved 0.63 hours(0.5-1 hour) after administration of 50 mg aspirin daily dose fromAGGRENOX (given as 25 mg BID). The peak plasma concentration at steady-stateis 319 ng/mL (175-463 ng/mL). Aspirin undergoes moderate hydrolysisto salicylic acid in the liver and the gastrointestinal wall, with50%-75% of an administered dose reaching the systemic circulationas intact aspirin.Effect of FoodWhen AGGRENOXcapsules were taken with high fat meal, there was no differencefor aspirin in AUC at steady-state, and the approximately 50% decreasein Cmax was not considered clinically relevantbased on similar degree of cyclooxygenase inhibition comparing thefed and fasted state.DistributionAspirinis poorly bound to plasma proteins and its apparent volume of distributionis low (10 L). Its metabolite, salicylic acid, is highly bound toplasma proteins, but its binding is concentration-dependent (nonlinear).At low concentrations (<100 ug/mL), approximately 90% of salicylicacid is bound to albumin. Salicylic acid is widely distributed toall tissues and fluids in the body, including the central nervoussystem, breast milk, and fetal tissues. Early signs of salicylateoverdose (salicylism), including tinnitus (ringing in the ears), occurat plasma concentrations approximating 200 ug/mL [see Adverse Reactions (6) and Overdosage (10) ].Metabolism and EliminationAspirin is rapidly hydrolyzed in plasma tosalicylic acid, with half-life of 20 minutes. Plasma levels of aspirinare essentially undetectable 2-2.5 hours after dosing and peak salicylicacid concentrations occur hour (range: 0.5-2 hours) after administrationof aspirin. Salicylic acid is primarily conjugated in the liver toform salicyluric acid, phenolic glucuronide, an acyl glucuronide,and number of minor metabolites. Salicylate metabolism is saturableand total body clearance decreases at higher serum concentrationsdue to the limited ability of the liver to form both salicyluric acidand phenolic glucuronide. Following toxic doses (10-20 g), the plasmahalf-life may be increased to over 20 hours.The elimination of acetylsalicylic acid follows first-orderkinetics with AGGRENOX and has half-life of 0.33 hours. The half-lifeof salicylic acid is 1.71 hours. Both values correspond well withdata from the literature at lower doses which state resultant half-lifeof approximately 2-3 hours. At higher doses, the elimination of salicylicacid follows zero-order kinetics (i.e., the rate of elimination isconstant in relation to plasma concentration), with an apparent half-lifeof hours or higher. Renal excretion of unchanged drug depends uponurinary pH. As urinary pH rises above 6.5, the renal clearance offree salicylate increases from <5% to >80%. Alkalinization of theurine is key concept in the management of salicylate overdose [see Overdosage (10) ]. Following therapeutic doses, about 10% is excreted assalicylic acid and 75% as salicyluric acid, as the phenolic and acylglucuronides, in urine.Special PopulationsHepatic Dysfunction: Avoid aspirinin patients with severe hepatic insufficiency.Renal Dysfunction: Avoid aspirin in patients with severe renal failure (glomerularfiltration rate less than 10 mL/min).AGGRENOXDrugInteractionA dedicated drug interaction studywas conducted in 60 healthy volunteers to evaluate the effects ofomeprazole 80 mg administered once daily on the pharmacokinetics (PK)of dipyridamole and the pharmacodynamics (PD) of acetylsalicylic acidwhen co-administered with AGGRENOX twice daily. Dipyridamole exposure(Cmax and AUC) at steady-state were similar with or without omeprazoleco-administration. The pharmacokinetics of acetylsalicylic acid wasnot characterized. However, the antiplatelet activity as measuredby arachidonic acid induced platelet aggregation was similar betweenthe treatment arms at steady-state.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. ESPS2 (European Stroke Prevention Study-2) was double-blind, placebo-controlled,24-month study in which 6602 patients over the age of 18 years hadan ischemic stroke (76%) or transient ischemic attack (TIA, 24%) withinthree months prior to entry. Patients were enrolled in 13 Europeancountries between February 1989 and May 1995 and were randomized toone 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 populationwas 66.7 years with 58% of them being males. Patients received onecapsule twice daily (morning and evening). Efficacy assessments includedanalyses 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 orgender; patients who were older had trend towards more events.. Stroke EndpointAGGRENOX reduced the risk of stroke by 22.1%compared to aspirin 50 mg/day alone (p 0.008) and reduced the riskof stroke by 24.4% compared to extended-release dipyridamole 400 mg/dayalone (p 0.002) (Table 3). AGGRENOX reduced the risk of stroke by36.8% compared to placebo (p <0.001).Table Summary of First Stroke (Fatal or Nonfatal): ESPS2:Intent-to-Treat Population TotalNumberof PatientsnNumber of PatientsWithStrokeWithin Yearsn (%)Kaplan-Meier Estimateof Survival at 2Years(95% C.I.)Gehan-WilcoxonTestP-valueRisk Reductionat YearsOdds Ratio(95% C.I.)a0.010 <p-value<=0.050; bp-value <=0.010.Note: ER-DP extended-release dipyridamole200 mg; ASA aspirin 25 mg. The dosage regimen for all treatmentgroups is BID. Individual 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---0.002b 24.4%0.72 (0.58, 0.90) AGGRENOX vs. ASA---0.008b 22.1%0.74 (0.59, 0.92) AGGRENOX vs. Placebo---<0.001b 36.8%0.59 (0.48, 0.73) ER-DP vs. Placebo---0.036a 16.5%0.82 (0.67, 1.00) ASA vs. Placebo---0.009b 18.9%0.80 (0.66, 0.97)ESPS2: CumulativeStroke Rate (Fatal or Nonfatal)Over24 months of Follow-UP. Combined Stroke or Death EndpointIn 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 was11.3% for AGGRENOX, 11.0% for aspirin alone, 11.4% for extended-releasedipyridamole alone and 12.3% for placebo alone. The differences betweenthe AGGRENOX, aspirin alone and extended-release dipyridamole alonetreatment groups were not statistically significant. These incidencerates for AGGRENOX and aspirin alone are consistent with previousaspirin studies in stroke and TIA patients.. Figure 1.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. AGGRENOX increases the risk of bleeding (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) AGGRENOX increases the risk of bleeding (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. AGGRENOX increases the risk of bleeding.Risk factors for bleeding include the use of other drugs that increasethe risk of bleeding (e.g., anticoagulants, antiplatelet agents, heparin,anagrelide, fibrinolytic therapy, and chronic use of NSAIDs) [see Drug Interactions (7.1) ].IntracranialHemorrhageIn European Stroke PreventionStudy-2 (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.Gastrointestinal (GI)Side EffectsGI side effects includestomach pain, heartburn, nausea, vomiting, and gross GI bleeding.Although minor upper GI symptoms, such as dyspepsia, are common andcan occur anytime during therapy, physicians should remain alert forsigns of ulceration and bleeding, even in the absence of previousGI symptoms. Inform patients about the signs and symptoms of GI sideeffects and what steps to take if they occur.In ESPS2, the incidence of gastrointestinal bleedingwas 4.1% in the AGGRENOX group, 2.2% in the extended-release dipyridamolegroup, 3.2% in the aspirin group, and 2.1% in the placebo groups. Peptic Ulcer DiseaseAvoid using aspirin in patients with historyof active peptic ulcer disease, which can cause gastric mucosal irritationand bleeding.Alcohol WarningBecause AGGRENOX containsaspirin, counsel patients who consume three or more alcoholic drinksevery day about the bleeding risks involved with chronic, heavy alcoholuse 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.

DRUG INTERACTIONS SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patientlabeling (Patient Information).Risk of BleedingInform patientsthat as with other antiplatelet agents, there is general risk ofbleeding including intracranial and gastrointestinal bleeding. Informpatients about the signs and symptoms of bleeding, including occultbleeding. Tell patients to notify their physician if they are prescribedany drug which may increase risk of bleeding.Counsel patients who consume three or more alcoholic drinks dailyabout the bleeding risks involved with chronic, heavy alcohol usewhile taking aspirin.PregnancyInform patients that aspirinis known to be harmful to fetuses and ask the patient to notify themif they are or become pregnant.HeadachesSome patients may experienceheadaches upon treatment initiation; these are usually transient. In case of intolerable headaches, tell patients to contact theirphysician.Dosage and AdministrationTell patientsthat AGGRENOX capsules should be swallowed whole, and not chewed orcrushed. If you miss dose, continue with your next dose on yourregular schedule. Do not take double dose.StorageInform patients to protectAGGRENOX from moisture.. Risk of BleedingInform patientsthat as with other antiplatelet agents, there is general risk ofbleeding including intracranial and gastrointestinal bleeding. Informpatients about the signs and symptoms of bleeding, including occultbleeding. Tell patients to notify their physician if they are prescribedany drug which may increase risk of bleeding.Counsel patients who consume three or more alcoholic drinks dailyabout the bleeding risks involved with chronic, heavy alcohol usewhile taking aspirin.. PregnancyInform patients that aspirinis known to be harmful to fetuses and ask the patient to notify themif they are or become pregnant.. HeadachesSome patients may experienceheadaches upon treatment initiation; these are usually transient. In case of intolerable headaches, tell patients to contact theirphysician.. Dosage and AdministrationTell patientsthat AGGRENOX capsules should be swallowed whole, and not chewed orcrushed. If you miss dose, continue with your next dose on yourregular schedule. Do not take double dose.. StorageInform patients to protectAGGRENOX from moisture.

OVERDOSAGE SECTION.

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

SPL PATIENT PACKAGE INSERT SECTION.

PatientInformationAggrenox(R) (AG-reh-nox)(aspirin/extended-release dipyridamole)CapsulesRead this Patient Information before youstart taking AGGRENOX and each time you get refill. There may benew information. This information does not take the place of talkingto your healthcare provider about your medical condition or your treatment.What is AGGRENOXAGGRENOX is prescriptionmedicine that contains aspirin and medicine that is slowly releasedin your body, called dipyridamole. AGGRENOX is used to lower the riskof stroke in people who have had mini-stroke (transient ischemicattack or TIA) or stroke due to blood clot.It is not known if AGGRENOX is safe and effective inchildren. See Who should not take AGGRENOXWho should not take AGGRENOXDo nottake AGGRENOX if you:are allergic to any of the ingredients in AGGRENOX. Seethe end of this leaflet for list of ingredients in AGGRENOX.are allergic to non-steroidal anti-inflammatory drugs (NSAIDs)have asthma in combination with runny nose and nasal polypsDo not give AGGRENOXto child or teenager with viral illness. Reye syndrome, life-threateningcondition, can happen when aspirin (an ingredient in AGGRENOX) isused in children and teenagers who have certain viral illnesses.Whatshould tell my doctor before using AGGRENOXBefore taking AGGRENOX,tell your healthcare provider if you:have stomach ulcershave history of bleeding problemshave heart problemshave kidney or liver problemshave low blood pressurehave myasthenia gravishave any other medical conditionsare pregnant or plan to become pregnant. AGGRENOX can harmyour unborn baby, especially if you take it in the last (third) trimesterof pregnancy. You should not take AGGRENOX during pregnancy withoutfirst talking to your healthcare provider. Tell your healthcare providerright away if you become pregnant while taking AGGRENOX.are breast-feeding or plan to breast-feed. AGGRENOX canpass into your milk and may harm your baby. Talk to your healthcareprovider about the best way to feed your baby if you take AGGRENOX.Tell your doctor about allthe medicines you take, including prescription and non-prescriptionmedicines, vitamins and herbal supplements. AGGRENOX and other medicinesmay affect each other causing side effects. AGGRENOX may affect theway other medicines work, and other medicines may affect how AGGRENOXworks.Especially tell your healthcareprovider if you take:a medicine for high blood pressure, irregularheart beat, or heart failureacetazolamide [Diamox(R)]any blood thinner medicines warfarin sodium [Coumadin(R), Jantoven(R)]a heparin medicineanagrelide [Agrylin(R)]a seizure medicinea medicine for Alzheimers diseasea water pillmethotrexate sodium [Trexall(R)]aspirin or non-steroidal anti-inflammatorydrug (NSAIDs). You should not take NSAIDs during treatment with AGGRENOX. Using these medicines with AGGRENOX can increase your riskof bleeding.a medicine for diabetesprobenecid [Probalan(R), Col-Probenecid(R)]Ask your healthcare provider or pharmacistif you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep listof them and show your healthcare provider and pharmacist when youget new medicine.How should take AGGRENOXTake AGGRENOX exactly as prescribed. Your healthcare providerwill tell you how many AGGRENOX to take and when to take them.Headaches are not uncommon when you first start taking AGGRENOX,but often lessen as treatment continues. Tell your healthcare providerif you have severe headache. Your healthcare provider may changethe instructions for taking AGGRENOX.Swallow AGGRENOX whole. Do not crush or chew the capsules.You can take AGGRENOX with or without food.If you miss dose, takeyour next dose at the usual time. Do not take two doses at one time.If you take more AGGRENOX (overdose) than prescribed, callyour healthcare provider or Poison Control Center, or get emergencyhelp right away.Symptoms of an overdoseof AGGRENOX include:a warm feeling or flushingsweatingrestlessnessweakness or dizzinessa fast heart rateringing in the ears What should avoidwhile using AGGRENOXheavy alcohol use. Peoplewho drink three or more alcoholic drinks every day have higher riskof bleeding during treatment with AGGRENOX, because it contains aspirin.What are the possibleside effects of AGGRENOXAGGRENOX may cause serious side effects,including:increased risk of bleeding. You may bleed more easily during AGGRENOX treatment, and it maytake longer than usual for bleeding to stop. This can include:bleeding into your brain (intracranial hemorrhage). This can be medical emergency. Get medical help right awayif you have any of these symptoms while taking AGGRENOX:severe headache with drowsinessconfusion or memory changepass out (become unconscious) bleeding in your stomach or intestine.stomach painheartburn or nauseavomiting blood or vomit looks like coffee groundsred or bloody stools black stools that look like tar new or worsening chest pain in some peoplewith heart disease. Tell your healthcare providerif you have new chest pain or have any change in your chest pain duringtreatment with AGGRENOX. liver problems, includingincreased liver function tests and liver failure. Tell your healthcareprovider if you have any of these symptoms of liver problem whiletaking AGGRENOX:loss of appetitepale colored stoolstomach area (abdomen) painyellowing of your skin or whites of your eyesdark urineitching Call your healthcare provider rightaway if you have any of the symptoms listed above.The most common side effects of AGGRENOXinclude:headacheupset stomachdiarrheaThese are not all the possible sideeffects of AGGRENOX. Tell your healthcare provider or pharmacist ifyou have any side effect that bothers you or that does not go away.Call your healthcare provider for medicaladvice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store AGGRENOXStore AGGRENOX at 59F to 86F (15C to 30C).Keep AGGRENOX capsules dry.Safely throw away medicine that is out of date or no longerneeded.Keep AGGRENOX andall medicines out of the reach of children.General information aboutAGGRENOXMedicinesare sometimes prescribed for purposes other than those listed in thePatient Information. Do not use AGGRENOX for condition for whichit was not prescribed. Do not give AGGRENOX to other people, evenif they have the same symptoms that you have. It may harm them.This Patient Information summarizes themost important information about AGGRENOX. If you would like moreinformation, talk with your healthcare provider. You can ask yourpharmacist or healthcare provider for information about AGGRENOX thatis written for health professionals.For more information, go to www.Aggrenox.com, scan the code below or call Boehringer Ingelheim Pharmaceuticals,Inc. at 1-800-542-6257 or (TTY) 1-800-459-9906.What are the ingredientsin AGGRENOXActive Ingredients: dipyridamole in an extended-releaseform and aspirin Inactive Ingredients: acacia,aluminum stearate, colloidal silicon dioxide, corn starch, dimethicone,hypromellose, hypromellose phthalate, lactose monohydrate, methacrylicacid copolymer, microcrystalline cellulose, povidone, stearic acid,sucrose, talc, tartaric acid, titanium dioxide and triacetin. Eachcapsule shell contains gelatin, red iron oxide and yellow iron oxide,titanium dioxide, and water.. are allergic to any of the ingredients in AGGRENOX. Seethe end of this leaflet for list of ingredients in AGGRENOX.. are allergic to non-steroidal anti-inflammatory drugs (NSAIDs). have asthma in combination with runny nose and nasal polyps. have stomach ulcers. have history of bleeding problems. have heart problems. have kidney or liver problems. have low blood pressure. have myasthenia gravis. have any other medical conditions. are pregnant or plan to become pregnant. AGGRENOX can harmyour unborn baby, especially if you take it in the last (third) trimesterof pregnancy. You should not take AGGRENOX during pregnancy withoutfirst talking to your healthcare provider. Tell your healthcare providerright away if you become pregnant while taking AGGRENOX.. are breast-feeding or plan to breast-feed. AGGRENOX canpass into your milk and may harm your baby. Talk to your healthcareprovider about the best way to feed your baby if you take AGGRENOX.. medicine for high blood pressure, irregularheart beat, or heart failure. acetazolamide [Diamox(R)]. any blood thinner medicines warfarin sodium [Coumadin(R), Jantoven(R)]. heparin medicine. anagrelide [Agrylin(R)]. seizure medicine. medicine for Alzheimers disease. water pill. methotrexate sodium [Trexall(R)]. aspirin or non-steroidal anti-inflammatorydrug (NSAIDs). You should not take NSAIDs during treatment with AGGRENOX. Using these medicines with AGGRENOX can increase your riskof bleeding.. medicine for diabetes. probenecid [Probalan(R), Col-Probenecid(R)]. Take AGGRENOX exactly as prescribed. Your healthcare providerwill tell you how many AGGRENOX to take and when to take them.. Headaches are not uncommon when you first start taking AGGRENOX,but often lessen as treatment continues. Tell your healthcare providerif you have severe headache. Your healthcare provider may changethe instructions for taking AGGRENOX.. Swallow AGGRENOX whole. Do not crush or chew the capsules.. You can take AGGRENOX with or without food.. If you miss dose, takeyour next dose at the usual time. Do not take two doses at one time.. If you take more AGGRENOX (overdose) than prescribed, callyour healthcare provider or Poison Control Center, or get emergencyhelp right away.. warm feeling or flushing. sweating. restlessness. weakness or dizziness. fast heart rate. ringing in the ears heavy alcohol use. Peoplewho drink three or more alcoholic drinks every day have higher riskof bleeding during treatment with AGGRENOX, because it contains aspirin.. increased risk of bleeding. You may bleed more easily during AGGRENOX treatment, and it maytake longer than usual for bleeding to stop. This can include:bleeding into your brain (intracranial hemorrhage). This can be medical emergency. Get medical help right awayif you have any of these symptoms while taking AGGRENOX:severe headache with drowsinessconfusion or memory changepass out (become unconscious) bleeding in your stomach or intestine.stomach painheartburn or nauseavomiting blood or vomit looks like coffee groundsred or bloody stools black stools that look like tar bleeding into your brain (intracranial hemorrhage). This can be medical emergency. Get medical help right awayif you have any of these symptoms while taking AGGRENOX:severe headache with drowsinessconfusion or memory changepass out (become unconscious) severe headache with drowsiness. confusion or memory change. pass out (become unconscious) bleeding in your stomach or intestine.stomach painheartburn or nauseavomiting blood or vomit looks like coffee groundsred or bloody stools black stools that look like tar stomach pain. heartburn or nausea. vomiting blood or vomit looks like coffee grounds. red or bloody stools black stools that look like tar new or worsening chest pain in some peoplewith heart disease. Tell your healthcare providerif you have new chest pain or have any change in your chest pain duringtreatment with AGGRENOX. liver problems, includingincreased liver function tests and liver failure. Tell your healthcareprovider if you have any of these symptoms of liver problem whiletaking AGGRENOX:loss of appetitepale colored stoolstomach area (abdomen) painyellowing of your skin or whites of your eyesdark urineitching loss of appetite. pale colored stool. stomach area (abdomen) pain. yellowing of your skin or whites of your eyes. dark urine. itching headache. upset stomach. diarrhea. Store AGGRENOX at 59F to 86F (15C to 30C).. Keep AGGRENOX capsules dry.. Safely throw away medicine that is out of date or no longerneeded.. aggrenox-qrcode.