Aspirin and Dipyridamole: Package Insert and Label Information (Page 3 of 4)

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 1–6 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 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).

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 (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 (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.

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 Cmax 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 λz 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 2−2.5 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 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.

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 StudiesA 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 (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.

13  NONCLINICAL TOXICOLOGY

13.1  Carcinogenesis, Mutagenesis, Impairment of Fertility

In studies in which dipyridamole was administered in the feed to mice (up to 111 weeks in males and females) and rats (up to 128 weeks in males and up to 142 weeks in females), there was no evidence of drug-related carcinogenesis. The highest dose administered in these studies (75 mg/kg/day) was, on a mg/m2 basis, about equivalent to the maximum recommended daily human oral dose (MRHD) in mice and about twice the MRHD in rats.

Combinations of dipyridamole and aspirin (1:5 ratio) tested negative in the Ames test, in vivo chromosome aberration tests (in mice and hamsters), oral micronucleus tests (in mice and hamsters) and oral dominant lethal test (in mice). Aspirin, alone, induced chromosome aberrations in cultured human fibroblasts. Mutagenicity tests of dipyridamole alone with bacterial and mammalian cell systems were negative.

Combinations of dipyridamole and aspirin have not been evaluated for effects on fertility and reproductive performance. There was no evidence of impaired fertility when dipyridamole was administered to male and female rats at oral doses up to 500 mg/kg/day (about 12 times the MRHD on a mg/m2 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/m2 basis). Aspirin inhibits ovulation in rats.

14 CLINICAL STUDIES

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: aspirin and extended-release dipyridamole capsules 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.

Stroke Endpoint

Aspirin and extended-release dipyridamole 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 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.)
a 0.010 <p‑value ≤0.050; b p‑value ≤0.010.

Individual Treatment Group

Aspirin and Extended-Release Dipyridamole

1650

157 ( 9.5%)

89.9% (88.4%, 91.4%)

ER-DP

1654

211 (12.8%)

86.7% (85.0%, 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        

vs. ER-DP

0.002b

24.4%

0.72 (0.58, 0.90)

Aspirin and Extended-Release Dipyridamole          vs. ASA

0.008b

22.1%

0.74 (0.59, 0.92)

Aspirin and Extended-Release Dipyridamole       

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)

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

aspirin-dipyr-fig1.jpg
(click image for full-size original)

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

Combined Stroke or Death Endpoint

In ESPS2, aspirin and extended-release dipyridamole reduced the risk of stroke or death by 24.2% compared to placebo.

Aspirin and extended-release dipyridamole 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, 11.0% 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, aspirin alone and extended-release dipyridamole alone treatment groups were not statistically significant. These incidence rates for aspirin and extended-release dipyridamole and aspirin alone are consistent with previous aspirin studies in stroke and TIA patients.

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