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Mechanism Of Action
The antithrombotic action of AGGRENOX is the result of the additive antiplatelet effects of dipyridamole and aspirin.
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 (0.5-1.9 μg/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A2-receptor thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3',5'-adenosine monophosphate (cAMP) levels. Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP).
Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic-3',5'guanosine monophosphate-PDE (cGMP-PDE), thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, now identified as nitric oxide).
Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of thromboxane A2, 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 AGGRENOX.
Absorption Peak plasma levels of dipyridamole are achieved 2 hours (range 1–6 hours) after administration of a daily dose of 400 mg AGGRENOX (given as 200 mg BID). The peak plasma concentration at steady-state is 1.98 μg/mL (1.01–3.99 μg/mL) and the steady-state trough concentration is 0.53 μg/mL (0.18–1.01 μg/mL).
Effect of Food
When AGGRENOX capsules were taken with a high fat meal, dipyridamole peak plasma levels (Cmax) and total absorption (AUC) were decreased at steady-state by 2030% 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.
Dipyridamole is highly lipophilic (log P=3.71, pH=7); however, it has been shown that the drug does not cross the blood-brain barrier to any significant extent in animals. The steady-state volume of distribution of dipyridamole is about 92 L. Approximately 99% of dipyridamole is bound to plasma proteins, predominantly to alpha 1-acid glycoprotein and albumin.
Metabolism and Elimination
Dipyridamole is metabolized in the liver, primarily by conjugation with glucuronic acid, of which monoglucuronide which has low pharmacodynamic activity is the primary metabolite. In plasma, about 80% of the total amount is present as parent compound and 20% as monoglucuronide. Most of the glucuronide metabolite (about 95%) is excreted via bile into the feces, with some evidence of enterohepatic circulation. Renal excretion of parent compound is negligible and urinary excretion of the glucuronide metabolite is low (about 5%). With intravenous (i.v.) treatment of dipyridamole, 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 λz with a 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.
Geriatric Patients: In ESPS2 [see Clinical Studies], 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 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.
Renal Dysfunction: No study has been conducted with AGGRENOX in patients with renal dysfunction.
In ESPS2 patients [see Clinical Studies], 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.
Peak plasma levels of aspirin are achieved 0.63 hours (0.5–1 hour) after administration of a 50 mg aspirin daily dose from AGGRENOX (given as 25 mg BID). The peak plasma concentration at steady-state is 319 ng/mL (175-463 ng/mL). Aspirin undergoes moderate hydrolysis to salicylic acid in the liver and the gastrointestinal wall, with 50%–75% of an administered dose reaching the systemic circulation as intact aspirin.
Effect of Food
When AGGRENOX capsules were taken with a high fat meal, there was no difference for aspirin in AUC at steady-state, and the approximately 50% decrease in Cmax was not considered clinically relevant based on a similar degree of cyclooxygenase inhibition comparing the fed and fasted state.
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 μg/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 μg/mL [see ADVERSE REACTIONS and OVERDOSAGE].
Metabolism and Elimination
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 AGGRENOX 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]. Following therapeutic doses, about 10% is excreted as salicylic acid and 75% as salicyluric acid, as the phenolic and acyl glucuronides, in urine.
Hepatic Dysfunction: Avoid aspirin in patients with severe hepatic insufficiency.
Renal Dysfunction: Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/min).
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 AGGRENOX twice daily. Dipyridamole exposure (Cmax 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.
ESPS2 (European Stroke Prevention Study-2) was a double-blind, placebo-controlled, 24-month study in which 6602 patients over the age of 18 years had an ischemic stroke (76%) or transient ischemic attack (TIA, 24%) within three months prior to entry. Patients were enrolled in 13 European countries between February 1989 and May 1995 and were randomized to one of four treatment groups: AGGRENOX (aspirin/extended-release dipyridamole) 25 mg/200 mg; extended-release dipyridamole (ER-DP) 200 mg alone; aspirin (ASA) 25 mg alone; or placebo. The mean age in this population was 66.7 years with 58% of them being males. Patients received one capsule twice daily (morning and evening). Efficacy assessments included analyses of stroke (fatal or nonfatal) and death (from all causes) as confirmed by a blinded morbidity and mortality assessment group. There were no differences with regard to efficacy based on age or gender; patients who were older had a trend towards more events.
AGGRENOX reduced the risk of stroke by 22.1% compared to aspirin 50 mg/day alone (p = 0.008) and reduced the risk of stroke by 24.4% compared to extended-release dipyridamole 400 mg/day alone (p = 0.002) (Table 3). AGGRENOX 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
|Gehan-Wilcoxon Test P-value||Risk Reduction at 2 Years||Odds Ratio
|Individual Treatment Group|
|Pairwise Treatment Group Comparisons|
|AGGRENOX vs. ER-DP||-||-||-||0.002b||24.4%||0.72
|AGGRENOX vs. ASA||-||-||-||0.008b||22.1%||0.74
|AGGRENOX vs. Placebo||-||-||-||< 0.001b||36.8%||0.59
|ER-DP vs. Placebo||-||-||-||0.036a||16.5%||0.82
|ASA vs. Placebo||-||-||-||0.009b||18.9%||0.80
|a0.010 < p-value ≤ 0.050;
bp-value ≤ 0.010.
Note: ER-DP = extended-release dipyridamole 200 mg; ASA = aspirin 25 mg. The dosage regimen for all treatment groups is BID.
ESPS2: Cumulative Stroke Rate (Fatal or Nonfatal) Over 24 months of Follow-UP
Combined Stroke or Death Endpoint
In ESPS2, AGGRENOX reduced the risk of stroke or death by 12.1% compared to aspirin alone and by 10.3% compared to extended-release dipyridamole alone. These results were not statistically significant. AGGRENOX reduced the risk of stroke or death by 24.2% compared to placebo.
The incidence rate of all-cause mortality was 11.3% for AGGRENOX, 11.0% for aspirin alone, 11.4% for extended-release dipyridamole alone and 12.3% for placebo alone. The differences between the AGGRENOX, aspirin alone and extended-release dipyridamole alone treatment groups were not statistically significant. These incidence rates for AGGRENOX and aspirin alone are consistent with previous aspirin studies in stroke and TIA patients.
Last reviewed on RxList: 12/7/2015
This monograph has been modified to include the generic and brand name in many instances.
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