Aggrenox®
Dipyridamole--ASA
Antiplatelet Agent
Boehringer Ingelheim
http://www.boehringer-ingelheim.com/corporate/home/home.asp
Aggrenox Monograph PDF download here.
CPS:PIS_m009200
Pharmacology
Blood platelets participate actively in the
pathogenesis of atherosclerotic lesions and thrombosis which is the principle
cause of most strokes and transient ischemic attacks (TIAs). Platelets are
believed to adhere to denuded, dysfunctional endothelium and to release
mitogenic substances, such as platelet-derived growth factor (PDGF), that
foster the lesion's progression to rupture and thrombosis. The antithrombotic
action of Aggrenox is the result of the additive antiplatelet effects of
dipyridamole and ASA.
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 plasma
concentrations (0.5 to 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).
Reduced platelet aggregation reduces platelet consumption towards normal
levels.
Dipyridamole also
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).
ASA: ASA inhibits platelet aggregation by
irreversible inhibition of platelet cyclo-oxygenase and thus inhibits the
generation of thromboxane A2, a powerful inducer of platelet
aggregation and vasoconstriction. In studies of platelet activity inhibition,
25 mg ASA was administered b.i.d. to 5 subjects for 2.5 days.
Complete inhibition of collagen-induced aggregation was achieved by the 5th
dose of ASA, and maximal effect persisted up to 2 to 3 days following
stoppage of drug.
Pharmacokinetics
There are no significant interactions between
ASA and dipyridamole. The kinetics of the components are unchanged by their
coadministration as Aggrenox. Aggrenox is not interchangeable with the
individual components of ASA and dipyridamole.
Dipyridamole: Absorption: The dissolution and
absorption of dipyridamole from Aggrenox is independent of the pH of the
gastrointestinal tract. Peak plasma levels are achieved in 1.5 to 2 h
after administration. The absolute bioavailability of dipyridamole from
Aggrenox is about 70%. With a daily maintenance dose of 400 mg of the
extended release formulation, peak plasma levels at steady state are between
1.5 to 3 µg/mL and trough levels are between 0.4 to 0.8 µg/mL.
Pharmacokinetic studies
to determine the effect of food have not been conducted with Aggrenox.
Distribution: Due to its high lipophilicity,
dipyridamole distributes to many organs; however it has been shown that the
drug does not cross the blood brain barrier to any significant extent.
Metabolism and Elimination: Dipyridamole is
metabolized in the liver. 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%). The
dominant half-life for elimination after oral or i.v. administration is about
40 minutes.
Pharmacokinetics of Dipyridamole in Special
Populations: Geriatrics: Plasma concentrations (determined as area under the
curve, AUC) of dipyridamole in healthy elderly subjects (>65 years) are
about 30 to 50% higher than in subjects younger than 55 years, on
treatment with Aggrenox. The difference is caused mainly by reduced clearance.
Hepatic Dysfunction: Patients with mild to
severe hepatic insufficiency show no change in plasma concentrations of
dipyridamole compared to healthy volunteers, but show an increase in the
pharmacologically inactive monoglucuronide metabolite. Dipyridamole can be
dosed without restriction as long as there is no evidence of liver failure.
Renal Dysfunction: Renal excretion of
dipyridamole is very low (about 5%). In patients 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.
ASA: Absorption: The rate of absorption of ASA
from the gastrointestinal tract is dependent on the dosage form, the presence
or absence of food, gastric pH, and other physiologic factors. Since ASA
produces its pharmacodynamic effect via the irreversible acetylating of
platelets, the time course of its pharmacodynamic activity is not dependent on
the pharmacokinetics of ASA but rather on the lifespan of the platelets
(approximately 8 to 10 days). Therefore, small differences in the
pharmacokinetics of ASA, such as variations in its absorption rate or in
elimination, are largely irrelevant to its pharmacologic activity with chronic
administration. ASA 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 ASA. Peak plasma levels
of ASA are achieved 0.5 to 1 hour after administration of a
50 mg ASA daily dose from Aggrenox (given as 25 mg b.i.d.). Peak mean
plasma concentration at steady state is 319 ng/mL (175 to 463 ng/mL).
Distribution: ASA is poorly bound to plasma
proteins and its apparent volume of distribution is low (10 L). At low
plasma 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 CNS, 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
Effects and Overdose: Symptoms and Treatment).
Metabolism: ASA is rapidly hydrolyzed in plasma
to salicylic acid, with a half-life of 15 to 30 minutes. Plasma
levels of ASA are essentially undetectable 1 to 2 hours after dosing
and peak salicylic acid concentrations occur within 1 to 2 hours of
administration of ASA. 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.
Elimination: The elimination of salicylic acid
follows first order kinetics at lower doses, with a resultant half-life of
approximately 2 to 3 hours. 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 Overdose: Symptoms
and Treatment). Following therapeutic doses, about 10% is excreted as salicylic
acid and 75% as salicyluric acid, in urine.
Pharmacokinetics of ASA in Special Populations:
Hepatic Dysfunction: Due to the ASA component, Aggrenox is to be avoided in
patients with severe hepatic insufficiency.
Renal Dysfunction: Due to the ASA component,
Aggrenox is to be avoided in patients with severe renal failure (glomerular
filtration rate less than 10 mL/min).
Indications
Prevention of stroke in patients who have had a
previous stroke or a transient ischemic attack (TIA).
Contraindications
In patients with hypersensitivity to
dipyridamole, ASA or any of the other product components.
Due to the ASA
component, Aggrenox is also contraindicated in patients with known allergy to
NSAID products and in patients with the syndrome of asthma, rhinitis, and nasal
polyps.
Warnings
Alcohol Warning: Patients who consume three or
more alcoholic drinks every day should be counseled about the bleeding risks
involved with chronic, heavy alcohol use while taking Aggrenox, due to the ASA
component.
Peptic Ulcer Disease: Patients with a history of
active peptic ulcer disease should avoid using Aggrenox, which can cause
gastric mucosal irritation, and bleeding, due to the ASA component.
Children
Safety and effectiveness of Aggrenox in
pediatric patients has not been studied. Therefore, Aggrenox should not be used
in pediatric patients.
Pregnancy
There are no adequate and well-controlled
studies of Aggrenox in pregnant women. Because animal reproduction studies are
not always predictive of human response, Aggrenox should be given during the
first two trimesters of pregnancy only if the potential benefit to the mother
justifies the potential risk to the fetus. Due to the ASA component, Aggrenox
should not be prescribed during the third trimester of pregnancy.
Precautions
General
Aggrenox should be used with caution in patients
with severe coronary artery disease (e.g., unstable angina or recently
sustained myocardial infarction), due to the vasodilatory effect of the
dipyridamole component. Chest pain may be aggravated in patients with
underlying coronary artery disease who are receiving dipyridamole. Patients
being treated with Aggrenox should not receive additional i.v. dipyridamole. If
pharmacological stress testing with i.v. dipyridamole for coronary artery
disease is considered necessary, then Aggrenox should be discontinued 24 hours
prior to testing, otherwise the sensitivity of the i.v. stress test could be
limited.
For stroke or TIA
patients for whom ASA is indicated to prevent recurrent myocardial infarction
(MI) or angina pectoris, the dose of ASA in Aggrenox has not been proven to
provide adequate treatment for these cardiac indications.
ASA should not be used
in children or teenagers for viral infections, with or without fever, because
of the risk of Reye's syndrome with concomitant use of ASA in certain viral
illnesses.
Due to the ASA
component, Aggrenox should be avoided in patients with severe renal failure
(glomerular filtration rate less than 10 mL/min) and in patients with
severe hepatic insufficiency.
Aggrenox should be used
with caution in patients with inherited (hemophilia) or acquired (liver disease
or vitamin K deficiency) bleeding disorders, due to the fact that even low
doses of ASA can inhibit platelet function leading to an increase in bleeding
time.
Gastrointestinal side
effects include stomach pain, heartburn, nausea, vomiting, diarrhea, and gross
gastrointestinal bleeding. Although minor upper gastrointestinal 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 gastrointestinal symptoms. Physicians should inform patients about
the signs and symptoms of gastrointestinal side effects and what steps to take
if they occur.
Carcinogenesis and Impairment of Fertility:
Carcinogenesis: In carcinogenicity studies in rats and mice with the
combination of dipyridamole and ASA at the ratio of 1:6 over a period of 125
and 105 weeks respectively, no significant tumorigenic effect was observed
at maximum doses of 450 mg/kg (corresponding to a share of 75 mg/kg
of dipyridamole, 9 times the maximum recommended daily human dose for a 50
kg person on a mg/kg basis [or 1.5 to 2.1 times on a mg/m2
basis]), and 375 mg/kg ASA, 375 times the maximum recommended daily
human dose for a 50 kg person on a mg/kg basis (or 58 to
83 times on a mg/m2 basis).
Fertility: Fertility studies with dipyridamole
revealed no evidence of impaired fertility in rats at oral dosages of up to
1250 mg/kg, 156 times the maximum recommended human dose on a mg/kg
basis for a 50 kg person (or 35 times on a mg/m2 basis). ASA
inhibits ovulation in rats.
Lactation
Dipyridamole and ASA are excreted in human
breast milk in low concentrations. Therefore, caution should be exercised when
Aggrenox is administered to a nursing woman.
Laboratory Tests: ASA has been associated with
elevated hepatic enzymes, blood urea nitrogen and serum creatinine,
hyperkalemia, proteinuria and prolonged bleeding time. Over the course of the
24-month study (ESPS2), patients treated with Aggrenox showed a decline (mean
change from baseline) in hemoglobin of 0.25 g/dL, hematocrit of 0.75%, and
erythrocyte count of 0.13x106/mm3.
Drug Interactions
Adenosine: Dipyridamole has been reported to
increase the plasma levels and cardiovascular effects of adenosine. Adjustment
of adenosine dosage may be necessary.
Cholinesterase Inhibitors: The dipyridamole
component of Aggrenox may counteract the anticholinesterase effect of
cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis.
The following drug
interactions are associated with the ASA component of Aggrenox:
Angiotensin Converting Enzyme (ACE) Inhibitors:
Due to the indirect effect of the ASA component on the renin-angiotensin
conversion pathway, the hyponatremic and hypotensive effects of ACE inhibitors
may be diminished by concomitant administration of Aggrenox.
Acetazolamide: Due to the ASA component,
concurrent use of Aggrenox and acetazolamide can lead to high serum
concentrations of acetazolamide (and toxicity) due to competition at the renal
tubule for secretion.
Anticoagulant Therapy (heparin and warfarin): Patients
on anticoagulation therapy are at increased risk for bleeding because of
drug-drug interactions and effects on platelets. ASA can displace warfarin from
protein binding sites, leading to prolongation of both the prothrombin time and
the bleeding time. The ASA component of Aggrenox can increase the anticoagulant
activity of heparin, increasing bleeding risk.
Anticonvulsants: The ASA component of Aggrenox
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 Aggrenox
due to inhibition of renal prostaglandins by ASA, leading to decreased renal
blood flow and salt and fluid retention.
Diuretics: The effectiveness of diuretics in
patients with underlying renal or cardiovascular disease may be diminished by
the concomitant administration of Aggrenox due to inhibition of renal
prostaglandins by ASA, leading to decreased renal blood flow and salt and fluid
retention.
Methotrexate: The ASA component of Aggrenox can
inhibit renal clearance of methotrexate, leading to bone marrow toxicity,
especially in the elderly or renally impaired.
NSAIDs: Due to the ASA component, the concurrent
use of Aggrenox with other NSAIDs may increase bleeding or lead to decreased
renal function.
Oral Hypoglycemics: Aggrenox may increase the
effectiveness of oral hypoglycemic drugs, leading to hypoglycemia.
Uricosuric Agents (probenecid and
sulfinpyrazone) and Natriuretic Agents: The ASA component of Aggrenox
antagonizes the uricosuric action of uricosuric agents. ASA decreased the
natriuretic effect of spironolactone in healthy volunteers.
Ibuprofen: The concomitant administration of
ibuprofen in healthy volunteers shortened the platelet aggregation inhibitory
effect of ASA.
Adverse Effects
A 24-month, multicentre, double-blind,
randomized study (ESPS2) was conducted to compare the efficacy and safety of
Aggrenox with placebo, extended release dipyridamole alone and ASA 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 3 months prior to randomization.
Table 1 presents the
incidence of adverse events that occurred in 1% or more of patients treated
with Aggrenox where the incidence was also greater than those patients treated
with placebo.
Discontinuation due to
adverse events in ESPS2 was 27.8% for Aggrenox, 28.2% for extended release
dipyridamole, 23.2% for ASA, and 23.7% for placebo.
Rare Adverse Reactions: Adverse reactions that
occurred in less than 1% of patients treated with Aggrenox in the ESPS2 study
and that were medically judged to be possibly related to either dipyridamole or
ASA are listed below.
CPS:Aggrenox_t1Click here for Table 1
Table 1: Aggrenox
Incidence of Adverse Events in ESPS2a
|
Body System/Preferred Term
|
Individual Treatment
Group
|
|
|
Aggrenox
|
ER-DP Alone
|
ASA Alone
|
Placebo
|
|
|
Total Number of Patients
|
1650
|
1654
|
1649
|
1649
|
|
|
Total Number (%) of Patients With at
Least One On-Treatment Adverse Event
|
1319 (79.9%)
|
1305 (78.9%)
|
1323 (80.2%)
|
1304 (79.1%)
|
|
|
Central and Peripheral Nervous Systems
Disorders
|
|
Headache
|
647 (39.2%)
|
634 (38.3%)
|
558 (33.8%)
|
543 (32.9%)
|
|
|
Convulsions
|
28 (1.7%)
|
15 (0.9%)
|
28 (1.7%)
|
26 (1.6%)
|
|
|
Gastrointestinal
|
|
Dyspepsia
|
303 (18.4%)
|
288 (17.4%)
|
299 (18.1%)
|
275 (16.7%)
|
|
|
Abdominal Pain
|
289 (17.5%)
|
255 (15.4%)
|
262 (15.9%)
|
239 (14.5%)
|
|
|
Nausea
|
264 (16.0%)
|
254 (15.4%)
|
210 (12.7%)
|
232 (14.1%)
|
|
|
Diarrhea
|
210 (12.7%)
|
257 (15.5%)
|
112 (6.8%)
|
161 (9.8%)
|
|
|
Vomiting
|
138 (8.4%)
|
129 (7.8%)
|
101 (6.1%)
|
118 (7.2%)
|
|
|
Hemorrhage Rectum
|
26 (1.6%)
|
22 (1.3%)
|
16 (1.0%)
|
13 (0.8%)
|
|
|
Melena
|
31 (1.9%)
|
10 (0.6%)
|
20 (1.2%)
|
13 (0.8%)
|
|
|
Hemorrhoids
|
16 (1.0%)
|
13 (0.8%)
|
10 (0.6%)
|
10 (0.6%)
|
|
|
Gastrointestinal Hemorrhage
|
20 (1.2%)
|
5 (0.3%)
|
15 (0.9%)
|
7 (0.4%)
|
|
|
Body as a Whole—General
|
|
Pain
|
105 (6.4%)
|
88 (5.3%)
|
103 (6.2%)
|
99 (6.0%)
|
|
|
Fatigue
|
95 (5.8%)
|
93 (5.6%)
|
97 (5.9%)
|
90 (5.5%)
|
|
|
Back Pain
|
76 (4.6%)
|
77 (4.7%)
|
74 (4.5%)
|
65 (3.9%)
|
|
|
Accidental Injury
|
42 (2.5%)
|
24 (1.5%)
|
51 (3.1%)
|
37 (2.2%)
|
|
|
Malaise
|
27 (1.6%)
|
23 (1.4%)
|
26 (1.6%)
|
22 (1.3%)
|
|
|
Asthenia
|
29 (1.8%)
|
19 (1.1%)
|
17 (1.0%)
|
18 (1.1%)
|
|
|
Syncope
|
17 (1.0%)
|
13 (0.8%)
|
16 (1.0%)
|
8 (0.5%)
|
|
|
Psychiatric
|
|
Amnesia
|
39 (2.4%)
|
40 (2.4%)
|
57 (3.5%)
|
34 (2.1%)
|
|
|
Confusion
|
18 (1.1%)
|
9 (0.5%)
|
22 (1.3%)
|
15 (0.9%)
|
|
|
Anorexia
|
19 (1.2%)
|
17 (1.0%)
|
10 (0.6%)
|
15 (0.9%)
|
|
|
Somnolence
|
20 (1.2%)
|
13 (0.8%)
|
18 (1.1%)
|
9 (0.5%)
|
|
|
Musculoskeletal
|
|
Arthralgia
|
91 (5.5%)
|
75 (4.5%)
|
91 (5.5%)
|
76 (4.6%)
|
|
|
Arthritis
|
34 (2.1%)
|
25 (1.5%)
|
17 (1.0%)
|
19 (1.2%)
|
|
|
Arthrosis
|
18 (1.1%)
|
22 (1.3%)
|
13 (0.8%)
|
14 (0.8%)
|
|
|
Myalgia
|
20 (1.2%)
|
16 (1.0%)
|
11 (0.7%)
|
11 (0.7%)
|
|
|
Respiratory
|
|
Coughing
|
25 (1.5%)
|
18 (1.1%)
|
32 (1.9%)
|
21 (1.3%)
|
|
|
Upper Respiratory Tract Infection
|
16 (1.0%)
|
9 (0.5%)
|
16 (1.0%)
|
14 (0.8%)
|
|
|
Cardiovascular, General
|
|
Cardiac Failure
|
26 (1.6%)
|
17 (1.0%)
|
30 (1.8%)
|
25 (1.5%)
|
|
|
Platelet, Bleeding and Clotting
Disorders
|
|
Hemorrhage NOS
|
52 (3.2%)
|
24 (1.5%)
|
46 (2.8%)
|
24 (1.5%)
|
|
|
Epistaxis
|
39 (2.4%)
|
16 (1.0%)
|
45 (2.7%)
|
25 (1.5%)
|
|
|
Purpura
|
23 (1.4%)
|
8 (0.5%)
|
9 (0.5%)
|
7 (0.4%)
|
|
|
Any Bleedingb
|
144 (8.7%)
|
77 (4.7%)
|
135 (8.2%)
|
74 (4.5%)
|
|
|
Severity of Bleeding:c
|
|
Mild
|
84 (5.1%)
|
53 (3.2%)
|
82 (5.0%)
|
52 (3.2%)
|
|
|
Moderate
|
33 (2.0%)
|
