Get your patient on Aspirin And Extended - Release Dipyridamole Capsules, 25 Mg / 200 Mg - Aspirin And Extended - Release Dipyridamole capsule (Aspirin And Extended - Release Dipyridamole)

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

Aspirin and extended-release dipyridamole is contraindicated in patients with known hypersensitivity to any of the product components.

Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug (NSAID) products and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema or bronchospasm.

Do not use aspirin in children or teenagers with viral infections because of the risk of Reye syndrome.

Aspirin and extended-release dipyridamole increases the risk of bleeding. Risk factors for bleeding include the use of other drugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, heparin, anagrelide, fibrinolytic therapy, and chronic use of NSAIDs) [see Drug Interactions (7.1 )].

Intracranial Hemorrhage

In European Stroke Prevention Study-2 (ESPS2), the annualized event rate for intracranial hemorrhage was 0.39%/year in the aspirin and extended-release dipyridamole group, 0.26%/year in the extended-release dipyridamole (ER-DP) group, 0.24%/year in the aspirin (ASA) group, and 0.29%/year in the placebo groups.

Gastrointestinal (GI) Side Effects

GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur anytime during therapy, physicians should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms. Inform patients about the signs and symptoms of GI side effects and what steps to take if they occur .

In ESPS2, the annualized event rate for gastrointestinal bleeding was 2.97%/year in the aspirin and extended-release dipyridamole group, 1.58%/year in the extended-release dipyridamole group, 2.06%/year in the aspirin group, and 1.40%/year in the placebo groups.

Peptic Ulcer Disease

Avoid using aspirin in patients with a history of active peptic ulcer disease, which can cause gastric mucosal irritation and bleeding.

Alcohol Warning

Because aspirin and extended-release dipyridamole 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.

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 )].

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 )].

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.

Dipyridamole produces peripheral vasodilation, which can exacerbate pre-existing hypotension.

Clinical experience suggests that patients being treated with aspirin and extended-release dipyridamole capsules who also require pharmacological stress testing with intravenous dipyridamole or other adenosinergic agents (e.g., adenosine, regadenoson) should interrupt aspirin and extended-release dipyridamole capsules for 48 hours prior to stress testing [see Drug Interactions (7.1 )] .

Intake of aspirin and extended-release dipyridamole capsules within 48 hours prior to stress testing with intravenous dipyridamole or other adenosinergic agents may increase the risk for cardiovascular side effects of these agents and may impair the sensitivity of the test.

Aspirin and extended-release dipyridamole capsules are not interchangeable with the individual components of aspirin and dipyridamole tablets.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The efficacy and safety of aspirin and extended-release dipyridamole was established in the European Stroke Prevention Study-2 (ESPS2). ESPS2 was a double-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, aspirin, ER-DP, or placebo [see Clinical Studies (14 )] ; primary endpoints included stroke (fatal or nonfatal) and death from all causes.

This 24-month, multicenter, double-blind, randomized study (ESPS2) was conducted to compare the efficacy and safety of aspirin and extended-release dipyridamole with placebo, extended-release dipyridamole alone and aspirin alone. The study was conducted in 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 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 treatment where the incidence was at least 1%/year greater than in those treated with placebo.

^b Annual event rate per 100 pt-years = 100• number of subjects with event/subject-years. Subject-years is defined as cumulative number of days on treatment divided by 365.25.

Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID.

NOS = not otherwise specified.

Discontinuation due to adverse events in ESPS2 was 25% for aspirin and extended-release dipyridamole, 25% for extended-release dipyridamole, 19% for aspirin, and 21% for placebo (refer to Table 2).

Table 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 treatment where the incidence was at least 1%/year greater than in those treated with placebo.

^b Annual event rate per 100 pt-years = 100• number of subjects with event/subject-years. Subject-years is defined as cumulative number of days on treatment divided by 365.25.

Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID.

Headache was most notable in the first month of treatment.

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.

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, and drug reaction with eosinophilia and systemic symptoms (DRESS)

Urogenital: Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure, hematuria

Vascular (Extracardiac) Disorders: Allergic vasculitis, flushing

Other Adverse Events: Anorexia, aplastic anemia, migraine, pancytopenia, thrombocytosis.

Adenosinergic agents (e.g., adenosine, regadenoson)

Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary. Dipyridamole also increases the cardiovascular effects of regadenoson, an adenosine A _2A -receptor agonist. The potential risk of cardiovascular side effects with intravenous adenosinergic agents may be increased during the testing period when dipyridamole is not held 48 hours prior to stress testing.

Angiotensin Converting Enzyme (ACE) Inhibitors

Because of the indirect effect of aspirin on the renin-angiotensin conversion pathway, the hyponatremic and hypotensive effects of ACE inhibitors may be diminished by concomitant administration of aspirin.

Acetazolamide

Concurrent use of aspirin and acetazolamide can lead to high serum concentrations of acetazolamide (and toxicity) due to competition at the renal tubule for secretion.

Anticoagulants and Antiplatelets

Patients taking aspirin and extended-release dipyridamole in combination with anticoagulants, antiplatelets, or any substance impacting coagulation are at increased risk for bleeding. Aspirin can displace warfarin from protein binding sites, leading to prolongation of both the prothrombin time and the bleeding time. Aspirin can increase the anticoagulant activity of heparin, increasing bleeding risk.

A nagrelide

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 antithrombotic action of aspirin and extended-release dipyridamole is the result of the additive antiplatelet effects of dipyridamole and aspirin.

Dipyridamole

Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in vivo ; the inhibition occurs in a dose-dependent manner at therapeutic concentrations (0.5 to 1.9 mcg/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A ₂ -receptor thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3',5'-adenosine monophosphate (cAMP) levels. Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP).

Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic-3',5'­-guanosine monophosphate-PDE (cGMP-PDE), thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, now identified as nitric oxide).

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.

The effect of either agent on the other's inhibition of platelet reactivity has not been evaluated.

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.

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 (given as 200 mg BID). The peak plasma concentration at steady-state is 1.98 mcg/mL (1.01 to 3.99 mcg/mL) and the steady-state trough concentration is 0.53 mcg/mL (0.18 to 1.01 mcg/mL).

Aspirin:

Peak plasma levels of aspirin are achieved 0.63 hours (0.5 to 1 hour) after administration of a 50 mg aspirin daily dose from aspirin and extended-release dipyridamole (given as 25 mg BID). The peak plasma concentration at steady-state is 319 ng/mL (175 to 463 ng/mL). Aspirin undergoes moderate hydrolysis to salicylic acid in the liver and the gastrointestinal wall, with 50% to 75% of an administered dose reaching the systemic circulation as intact aspirin.

Effect of Food

Dipyridamole:

When aspirin and extended-release dipyridamole capsules were taken with 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 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 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 to 2.5 hours after dosing and peak salicylic acid concentrations occur 1 hour (range: 0.5 to 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 to 20 g), the plasma half-life may be increased to over 20 hours.

The elimination of acetylsalicylic acid follows first-order kinetics with aspirin and extended-release dipyridamole and has 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 to 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.

Hepatic Dysfunction:

No study has been conducted with aspirin and extended-release dipyridamole 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 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.

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 a mg/m ² 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 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.