stration of aspirin. acetazolamide concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion. anticoagulants and antiplatelets patients taking aspirin and extended-release dipyridamole capsules in combination with anticoagulants, antiplatelets, or any substance impacting coagulation are at increased risk for bleeding. aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk. anagrelide patients taking aspirin in combination with anagrelide are at an increased risk of bleeding. anticonvulsants salicylic acid can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. beta blockers the hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. cholinesterase inhibitors dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis. diuretics the effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. methotrexate salicylate can inhibit renal clearance of methotrexate, leading to bone marrow toxicity, especially in the elderly or renal impaired. nonsteroidal anti-inflammatory drugs (nsaids) the concurrent use of aspirin with other nsaids may increase bleeding or lead to decreased renal function. oral hypoglycemics moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia. uricosuric agents (probenecid and sulfinpyrazone) salicylates antagonize the uricosuric action of uricosuric agents.

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 capsules group, 1.58%/year in the extendedrelease 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 a 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 a vasodilatory effect. chest pain may be precipitated or aggravated in patients with underlying coronary artery disease who are receiving dipyridamole. for stroke or tia patients for whom aspirin is indicated to prevent recurrent myocardial infarction (mi) or angina pectoris, the aspirin in this product may not provide adequate treatment for the cardiac indications. 5.5 hypotension dipyridamole produces peripheral vasodilation, which can exacerbate pre-existing hypotension. 5.6 stress testing with intravenous dipyridamole and other adenosinergic agents clinical experience suggests that patients being treated with aspirin and extended-release dipyridamole capsules who also require pharmacological stress testing with intravenous dipyridamole or other adenosinergic agents (e.g. adenosine, regadenoson) should interrupt aspirin and extended-release dipyridamole capsules for 24 to 48 hours prior to stress testing [ see drug interactions ( 7.1 )] . intake of aspirin and extended-release dipyridamole capsules 24 to 48 hours prior to stress testing with intravenous dipyridamole or other adrenosinergic agents may increase the risk for cardiovascular side effects of these agents and impair the sensitivity of the test. 5.7 general aspirin and extended-release dipyridamole capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.

to one capsule at bedtime and low-dose aspirin in the morning. because there are no outcome data with this regimen and headaches become less of a problem as treatment continues, patients should return to the usual regimen as soon as possible, usually within one week.

uble-blind, placebo -controlled study that evaluated 6602 patients over the age of 18 years who had a previous ischemic stroke or transient ischemic attack within ninety days prior to entry. patients were randomized to either aspirin and extended-release dipyridamole capsules, aspirin, er-dp, or placebo [ see clinical studies ( 14 ) ]; primary endpoints included stroke (fatal or nonfatal) and death from all causes. this 24-month, multicenter, double-blind, randomized study (esps2) was conducted to compare the efficacy and safety of aspirin and extended-release dipyridamole capsules with placebo, extended-release dipyridamole alone and aspirin alone. the study was conducted in a total of 6602 male and female patients who had experienced a previous ischemic stroke or transient ischemia of the brain within three months prior to randomization. table 1 presents the annualized event rate for adverse events that occurred in 1%/year or more of patients treated with aspirin and extended-release dipyridamole capsules where the incidence was also at least 1%/year greater than in those patients treated with placebo. there is no clear benefit of the dipyridamole/aspirin combination over aspirin with respect to safety. table 1 incidence of adverse events in esps2 a a reported by ≥1%/year of patients during aspirin and extended-release dipyridamole capsules treatment where the incidence was at least 1%/year greater than in those treated with placebo. b annual event rate per 100pt-years= 100* number of subjects with event/subject-years. subject-years is defined as cumulative number of days on treatment divided by 365.25. note: er-dp = extended-release dipyridamole 200 mg; asa = aspirin 25 mg. the dosage regimen for all treatment groups is bid. nos = not otherwise specified. individual treatment group body system/preferred term aspirin and extended-release dipyridamole capsules n (%/year) b er-dp alone n (%/year) b asa alone n (%/year) b placebo n (%/year) b total number of patients 1650 1654 1649 1649 central and peripheral nervous system disorders headache 647 (28.25) 634 (27.91) 558 (22.10) 543 (22.29) gastrointestinal system disorders dyspepsia 303 (13.23) 288 (12.68) 299 (11.84) 275 (11.29) abdominal pain 289 (12.62) 255 (11.22) 262 (10.38) 239 (9.81) nausea 264 (11.53) 254 (11.18) 210 (8.32) 232 (9.53) diarrhea 210 (9.17) 257 (11.31) 112 (4.44) 161 (6.61) vomiting 138 (6.03) 129 (5.68) 101 (4.00) 118 (4.84) platelet, bleeding and clotting disorders hemorrhage nos 52 (2.27) 24 (1.06) 46 (1.82) 24 (0.99) discontinuation due to adverse events in esps2 was 25% for aspirin and extended-release dipyridamole capsules, 25% for extended-release dipyridamole, 19% for aspirin, and 21% for placebo (refer to table 2). table 2 incidence of adverse events that led to the discontinuation of treatment a a reported by ≥1%/year of patients during aspirin and extended-release dipyridamole capsules treatment where the incidence was at least 1%/year greater than in those treated with placebo. b annual event rate per 100pt-years= 100* number of subjects with event/subject-years. subject-years is defined as cumulative number of days on treatment divided by 365.25. note: er-dp = extended-release dipyridamole 200 mg; asa = aspirin 25 mg. the dosage regimen for all treatment groups is bid treatment groups aspirin and extended-release dipyridamole capsules n(%/year) b er-dp n(%/year) b asa n(%/year) b placebo n(%/year) b total number of patients 1650 1654 1649 1649 patients with at least one adverse event that led 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) headache was most notable in the first month of treatment. 6.2 post-marketing experience the following is a 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 a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to aspirin and extended-release dipyridamole capsules. body as a whole hypothermia, chest pain, allergic reaction, syncope cardiovascular angina pectoris, hypotension central nervous system cerebral edema, dizziness, cerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage fluid and electrolyte hyperkalemia, metabolic acidosis, respiratory alkalosis, hypokalemia gastrointestinal pancreatitis, reye syndrome, hematemesis, gastritis, ulceration and perforation, hemorrhage rectum, melena, gi hemorrhage hearing and vestibular disorders hearing loss heart rate and rhythm disorders tachycardia, palpitation immune system disorders hypersensitivity, acute anaphylaxis, laryngeal edema liver and biliary system disorders hepatitis, hepatic failure, cholelithiasis, jaundice, hepatic function abnormal musculoskeletal rhabdomyolysis, myalgia metabolic and nutritional disorders hypoglycemia, dehydration platelet, bleeding and clotting disorders prolongation of the prothrombin time, disseminated intravascular coagulation, coagulopathy, thrombocytopenia, hematoma, gingival bleeding, epistaxis, purpura psychiatric disorders confusion, agitation respiratory tachypnea, dyspnea, hemoptysis skin and appendages disorders rash, alopecia, angioedema, stevens-johnson syndrome, skin hemorrhages such as bruising, ecchymosis, and hematoma, pruritus, urticaria urogenital interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, hematuria vascular (extracardiac) disorders allergic vasculitis, flushing other adverse events anorexia, aplastic anemia, migraine, pancytopenia, thrombocytosis.

stration of aspirin. acetazolamide concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion. anticoagulants and antiplatelets patients taking aspirin and extended-release dipyridamole capsules in combination with anticoagulants, antiplatelets, or any substance impacting coagulation are at increased risk for bleeding. aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk. anagrelide patients taking aspirin in combination with anagrelide are at an increased risk of bleeding. anticonvulsants salicylic acid can displace protein-bound phenytoin and valproic acid, leading to a decrease in the total concentration of phenytoin and an increase in serum valproic acid levels. beta blockers the hypotensive effects of beta blockers may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. cholinesterase inhibitors dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis. diuretics the effectiveness of diuretics in patients with underlying renal or cardiovascular disease may be diminished by the concomitant administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood flow and salt and fluid retention. methotrexate salicylate can inhibit renal clearance of methotrexate, leading to bone marrow toxicity, especially in the elderly or renal impaired. nonsteroidal anti-inflammatory drugs (nsaids) the concurrent use of aspirin with other nsaids may increase bleeding or lead to decreased renal function. oral hypoglycemics moderate doses of aspirin may increase the effectiveness of oral hypoglycemic drugs, leading to hypoglycemia. uricosuric agents (probenecid and sulfinpyrazone) salicylates antagonize the uricosuric action of uricosuric agents.

estive of a possible potentiation of aspirin-related fetal toxicity when combined with dipyridamole ( see data ) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 and 15-20%, respectively. clinical considerations labor and delivery aspirin and extended-release dipyridamole capsule, which contains dipyridamole and low-dose aspirin, increases the risk for bleeding [see warnings and precautions ( 5.1 )] . maternal use of high-dose aspirin can result in excessive blood loss at delivery, prolonged gestation, prolonged labor, intracranial hemorrhage in premature infants, low birth weight, stillbirth, and neonatal death. data human data published data from clinical trials, observational studies, case series, and case reports over several decades have not identified a clear association between aspirin-dipyridamole use in pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. however, these studies cannot definitively establish the absence of any aspirin-dipyridamole associated risks. methodological limitations of these studies include variability in the timing and dose of drug exposure (e.g., most exposures occurred beyond the first trimester) and the small sample sizes of individual studies. animal data aspirin has been shown to be teratogenic in rats (spina bifida, exencephaly, microphthalmia and coelosomia) and rabbits (congested fetuses, agenesis of skull and upper jaw, generalized edema with malformation of the head, and diaphanous skin) at oral doses of 330 mg/kg/day and 110 mg/kg/day, respectively. these doses, which also resulted in a high resorption rate in rats (63% of implantations versus 5% in controls), are, on a mg/m2 basis, about 66 and 44 times, respectively, the dose of aspirin contained in the maximum recommended daily human dose of aspirin-dipyridamole. reproduction studies with dipyridamole have been performed in mice, rabbits and rats at oral doses of up to 125 mg/kg, 40 mg/kg, and 1000 mg/kg, respectively (about 1½, 2, and 25 times the maximum recommended daily human oral dose, respectively, on a mg/m 2 basis) and have revealed no evidence of harm to the fetus due to dipyridamole. when 330 mg aspirin/kg/day was combined with 75 mg dipyridamole/kg/day in the rat at doses about 66 and 2 times, respectively, the maximum recommended daily human dose, the resorption rate approached 100%. 8.2 lactation risk summary based on data from a clinical lactation study in breastfeeding women taking low-dose aspirin, the metabolite salicylic acid is present in human milk in low levels (see data). dipyridamole is also present in human milk. there is no information on the effects of aspirin and extended-release dipyridamole capsule or dipyridamole on the breastfed infant or on milk production. 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 mother's clinical need for aspirin and extended-release dipyridamole capsule and any potential adverse effects on the breastfed child from aspirin and extended-release dipyridamole capsule or from the underlying maternal condition. data a published clinical study involved six exclusively breastfeeding women at 1 to 8 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 a 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 ) ]. 8.6 patients with severe hepatic or severe renal dysfunction aspirin and extended-release dipyridamole capsules have not been studied in patients with hepatic or renal impairment. avoid using aspirin containing products, such as aspirin and extended-release dipyridamole capsules 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 ) ].

ion of aspirin-related fetal toxicity when combined with dipyridamole ( see data ) . the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 and 15-20%, respectively. clinical considerations labor and delivery aspirin and extended-release dipyridamole capsule, which contains dipyridamole and low-dose aspirin, increases the risk for bleeding [see warnings and precautions ( 5.1 )] . maternal use of high-dose aspirin can result in excessive blood loss at delivery, prolonged gestation, prolonged labor, intracranial hemorrhage in premature infants, low birth weight, stillbirth, and neonatal death. data human data published data from clinical trials, observational studies, case series, and case reports over several decades have not identified a clear association between aspirin-dipyridamole use in pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. however, these studies cannot definitively establish the absence of any aspirin-dipyridamole associated risks. methodological limitations of these studies include variability in the timing and dose of drug exposure (e.g., most exposures occurred beyond the first trimester) and the small sample sizes of individual studies. animal data aspirin has been shown to be teratogenic in rats (spina bifida, exencephaly, microphthalmia and coelosomia) and rabbits (congested fetuses, agenesis of skull and upper jaw, generalized edema with malformation of the head, and diaphanous skin) at oral doses of 330 mg/kg/day and 110 mg/kg/day, respectively. these doses, which also resulted in a high resorption rate in rats (63% of implantations versus 5% in controls), are, on a mg/m2 basis, about 66 and 44 times, respectively, the dose of aspirin contained in the maximum recommended daily human dose of aspirin-dipyridamole. reproduction studies with dipyridamole have been performed in mice, rabbits and rats at oral doses of up to 125 mg/kg, 40 mg/kg, and 1000 mg/kg, respectively (about 1½, 2, and 25 times the maximum recommended daily human oral dose, respectively, on a mg/m 2 basis) and have revealed no evidence of harm to the fetus due to dipyridamole. when 330 mg aspirin/kg/day was combined with 75 mg dipyridamole/kg/day in the rat at doses about 66 and 2 times, respectively, the maximum recommended daily human dose, the resorption rate approached 100%.

it cyclic-3',5'-guanosine monophosphate-pde (cgmp-pde), thereby augmenting the increase in cgmp produced by edrf (endothelium-derived relaxing factor, now identified as nitric oxide). aspirin aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of thromboxane a 2 , a powerful inducer of platelet aggregation and vasoconstriction. 12.2 pharmacodynamics the effect of either agent on the other's inhibition of platelet reactivity has not been evaluated. 12.3 pharmacokinetics there are no significant interactions between aspirin and dipyridamole. the kinetics of the components are unchanged by their co-administration as aspirin and extended-release dipyridamole capsules. absorption dipyridamole peak plasma levels of dipyridamole are achieved 2 hours (range 1 to 6 hours) after administration of a daily dose of 400 mg aspirin and extended-release dipyridamole capsules (given as 200 mg bid). the peak plasma concentration at steady-state is 1.98 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 (0.5–1 hour) after administration of a 50 mg aspirin daily dose from aspirin and extended-release dipyridamole capsules (given as 25 mg bid). the peak plasma concentration at steady-state is 319 ng/ml (175−463 ng/ml). aspirin undergoes moderate hydrolysis to salicylic acid in the liver and the gastrointestinal wall, with 50%–75% of an administered dose reaching the systemic circulation as intact aspirin. effect of food dipyridamole when aspirin and extended-release dipyridamole capsules were taken with a high fat meal, dipyridamole peak plasma levels (c max ) 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 capsules were taken with a high fat meal, there was no difference for aspirin in auc at steady-state, and the approximately 50% decrease in c max was not considered clinically relevant based on a 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, a triphasic profile is obtained: a rapid alpha phase, with a half-life of about 3.4 minutes, a beta phase, with a 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 a prolonged elimination phase λ z with a half-life of about 15.5 hours. because of the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with aspirin and extended-release dipyridamole capsules which was 13.6 hours. aspirin aspirin is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 20 minutes. plasma levels of aspirin are essentially undetectable 2−2.5 hours after dosing and peak salicylic acid concentrations occur 1 hour (range: 0.5−2 hours) after administration of aspirin. salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. following toxic doses (10−20 g), the plasma half-life may be increased to over 20 hours. the elimination of acetylsalicylic acid follows first-order kinetics with aspirin and extended-release dipyridamole capsules and has a 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 a 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 6 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 a 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 populations geriatric patients dipyridamole in esps2 [ see clinical studies ( 14 ) ], plasma concentrations (determined as auc) of dipyridamole in healthy elderly subjects (>65 years) were about 40% higher than in subjects younger than 55 years receiving treatment with aspirin and extended-release dipyridamole capsules. hepatic dysfunction no study has been conducted with aspirin and extended-release dipyridamole capsules in patients with hepatic dysfunction. dipyridamole in a 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 a dedicated drug interaction study was conducted in 60 healthy volunteers to evaluate the effects of omeprazole 80 mg administered once daily on the pharmacokinetics (pk) of dipyridamole and the pharmacodynamics (pd) of acetylsalicylic acid when co-administered with aspirin and extended-release dipyridamole capsules twice daily. dipyridamole exposure (c max and auc) at steady-state were similar with or without omeprazole co-administration. the pharmacokinetics of acetylsalicylic acid was not characterized. however, the antiplatelet activity as measured by arachidonic acid induced platelet aggregation was similar between the treatment arms at steady-state.

50%–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 a high fat meal, dipyridamole peak plasma levels (c max ) 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 capsules were taken with a high fat meal, there was no difference for aspirin in auc at steady-state, and the approximately 50% decrease in c max was not considered clinically relevant based on a 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, a triphasic profile is obtained: a rapid alpha phase, with a half-life of about 3.4 minutes, a beta phase, with a 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 a prolonged elimination phase λ z with a half-life of about 15.5 hours. because of the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with aspirin and extended-release dipyridamole capsules which was 13.6 hours. aspirin aspirin is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 20 minutes. plasma levels of aspirin are essentially undetectable 2−2.5 hours after dosing and peak salicylic acid concentrations occur 1 hour (range: 0.5−2 hours) after administration of aspirin. salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. following toxic doses (10−20 g), the plasma half-life may be increased to over 20 hours. the elimination of acetylsalicylic acid follows first-order kinetics with aspirin and extended-release dipyridamole capsules and has a 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 a 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 6 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 a 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 populations geriatric patients dipyridamole in esps2 [ see clinical studies ( 14 ) ], plasma concentrations (determined as auc) of dipyridamole in healthy elderly subjects (>65 years) were about 40% higher than in subjects younger than 55 years receiving treatment with aspirin and extended-release dipyridamole capsules. hepatic dysfunction no study has been conducted with aspirin and extended-release dipyridamole capsules in patients with hepatic dysfunction. dipyridamole in a 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 a dedicated drug interaction study was conducted in 60 healthy volunteers to evaluate the effects of omeprazole 80 mg administered once daily on the pharmacokinetics (pk) of dipyridamole and the pharmacodynamics (pd) of acetylsalicylic acid when co-administered with aspirin and extended-release dipyridamole capsules twice daily. dipyridamole exposure (c max and auc) at steady-state were similar with or without omeprazole co-administration. the pharmacokinetics of acetylsalicylic acid was not characterized. however, the antiplatelet activity as measured by arachidonic acid induced platelet aggregation was similar between the treatment arms at steady-state.

cts 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 a mg/m 2 basis). a 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 a mg/m 2 basis). aspirin inhibits ovulation in rats.

re older had a trend towards more events. stroke endpoint aspirin and extended-release dipyridamole capsules reduced the risk of stroke by 22.1% compared to aspirin 50 mg/day alone (p = 0.008) and reduced the risk of stroke by 24.4% compared to extended-release dipyridamole 400 mg/day alone (p = 0.002) (table 3). aspirin and extended-release dipyridamole capsules reduced the risk of stroke by 36.8% compared to placebo (p <0.001). table 3 summary of first stroke (fatal or nonfatal): esps2: intent-to-treat population total number of patients n number of patients with stroke within 2 years n (%) kaplan-meier estimate of survival at 2 years (95% c.i.) gehan-wilcoxon test p-value risk reduction at 2 years odds ratio (95% c.i.) individual treatment group aspirin and extended-release dipyridamole capsules 1650 157 ( 9.5%) 89.9% (88.4%, 91.4%) - - - er-dp 1654 211 (12.8%) 86.7% (85%, 88.4%) - - - asa 1649 206 (12.5%) 87.1% (85.4%, 88.7%) - - - placebo 1649 250 (15.2%) 84.1% (82.2%, 85.9%) - - - pairwise treatment group comparisons aspirin and extended-release dipyridamole capsules vs. er-dp - - - 0.002 b 24.4% 0.72 (0.58, 0.9) aspirin and extended-release dipyridamole capsules vs. asa - - - 0.008 b 22.1% 0.74 (0.59,0.92) aspirin and extended-release dipyridamole capsules vs. placebo - - - <0.001 b 36.8% 0.59 (0.48,0.73) er-dp vs. placebo - - - 0.036 a 16.5% 0.82 (0.67, 1) asa vs. placebo - - - 0.009 b 18.9% 0.80 (0.66,0.97) a 0.010 < p-value ≤0.050; b p-value ≤ 0.010. note: er-dp = extended-release dipyridamole 200 mg; asa = aspirin 25 mg. the dosage regimen for all treatment groups is bid. figure 1 esps2: cumulative stroke rate (fatal or nonfatal) over 24 months of follow-up combined stroke or death endpoint in esps2, aspirin and extended-release dipyridamole capsules reduced the risk of stroke or death by 24.2% compared to placebo. aspirin and extended-release dipyridamole capsules reduced the risk of stroke or death by 12.1% compared to aspirin alone and by 10.3% compared to extended-release dipyridamole alone. these results were not statistically significant. death endpoint the incidence rate of all-cause mortality was 11.3% for aspirin and extended-release dipyridamole capsules, 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 capsules, aspirin alone and extended-release dipyridamole alone treatment groups were not statistically significant. these incidence rates for aspirin and extended-release dipyridamole capsules and aspirin alone are consistent with previous aspirin studies in stroke and tia patients. aspirin and extended-release dipyridamole capsules

tell patients to contact their physician. stress test instruct patients who are scheduled to undergo a pharmacologic stress test to tell their healthcare provider that they are taking aspirin and extended-release dipyridamole capsules. dosage and administration tell patients that aspirin and extended-release dipyridamole capsules should be swallowed whole, and not chewed or crushed. if you miss a dose, continue with your next dose on your regular schedule. do not take a double dose. storage inform patients to protect aspirin and extended-release dipyridamole capsules from moisture.