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
aspirin.
Coagulation Abnormalities: Even low
doses of aspirin can inhibit platelet function leading
to an increase in bleeding time. This can adversely affect
patients with inherited or acquired (liver disease or
vitamin K deficiency) bleeding disorders.
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. Physicians should inform patients
about the signs and symptoms of GI side effects and what
steps to take if they occur.
Peptic Ulcer Disease: Patients with
a history of active peptic ulcer disease should avoid
using aspirin, which can cause gastric mucosal irritation
and bleeding.
PRECAUTIONS
General
AGGRENOXTM is not interchangeable with the individual
components of aspirin and Persantine® Tablets.
Coronary Artery Disease: Dipyridamole has a vasodilatory
effect and should be used with caution in patients with
severe coronary artery disease (e.g., unstable angina
or recently sustained myocardial infarction). Chest pain
may be 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.
Hepatic Insufficiency: Elevations of
hepatic enzymes and hepatic failure have been reported
in association with dipyridamole administration.
Hypotension: Dipyridamole should be
used with caution in patients with hypotension since it
can produce peripheral vasodilation.
Renal Failure: Avoid aspirin in patients
with severe renal failure (glomerular filtration rate
less than 10 mL/minute).
Risk of Bleeding: In ESPS2 the incidence
of gastrointestinal bleeding was 68 patients (4.1%) in
the AGGRENOXTM group, 36 patients (2.2%) in the dipyridamole
group, 52 patients (3.2%) in the aspirin group, and 34
patients (2.1%) in the placebo groups.
The incidence of intracranial hemorrhage was 9 patients
(0.6%) in the AGGRENOXTM group, 6 patients (0.5%) in the
dipyridamole group, 6 patients (0.4%) in the aspirin group
and 7 patients (0.4%) in the placebo groups.
Laboratory Tests
Aspirin has been associated with elevated hepatic enzymes,
blood urea nitrogen and serum creatinine, hyperkalemia,
proteinuria and prolonged bleeding time.
Dipyridamole has been associated with elevated hepatic
enzymes.
Drug Interactions
No pharmacokinetic drug-drug interaction studies were
conducted with the AGGRENOXTM formulation. The following
information was obtained from the literature.
Adenosine: Dipyridamole has been reported
to increase the plasma levels and cardiovascular effects
of adenosine. Adjustment of adenosine dosage may be necessary.
Angiotensin Converting Enzyme (ACE) Inhibitors:
Due to 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.
Anticoagulant Therapy (heparin and warfarin):
Patients on anticoagulation therapy are at increased risk
for bleeding because of drug-drug interactions and effects
on platelets. 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.
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 wflow 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 wflow 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis: Dipyridamole: In a 111-week
oral study in mice and in a 128-142-week oral study in
rats, Persantine® (dipyridamole USP) produced no significant
carcinogenic effects at doses of 8, 25 and 75 mg/kg. For
a 50-kg person of average height (1.46 m2 body surface
area), the dose of dipyridamole at 75 mg/kg/day (225 mg/m2/day
in mice or 450 mg/m2/day in rats) represents 0.76 or 1.5
times the recommended human dose (8 mg/kg/day or 296 mg/m2/day)
on a body surface area basis.
Mutagenicity: Combination of Dipyridamole
and Aspirin: Mutagenicity testing with combination of
dipyridamole and aspirin in a ratio of 1:5 revealed no
mutagenic potential in the Ames test, in vivo chromosome
aberration tests in mice and hamsters, oral micronucleus
tests in mice and hamsters and dominant lethal test in
mice. Aspirin induced chromosome aberrations in cultured
human fibroblasts.
Fertility: Dipyridamole: Reproduction
studies with Persantine® revealed no evidence of impaired
fertility in rats at oral dosages of up to 500 mg/kg/day
or 3000 mg/m2/day (~10 times the recommended human dose
on a body surface area basis). A significant reduction
in number of corpora lutea with consequent reduction in
implantations and live fetuses was, however, observed
at dose of Persantine® of 1250 mg/kg/day or 7500 mg/m2/day
in rats (~25 times the recommended human dose on a body
surface area basis).
Aspirin: Aspirin inhibits ovulation
in rats.
Combination of Dipyridamole and Aspirin:
Combination of dipyridamole and aspirin was not tested
for effect on fertility and reproductive performance.
Pregnancy
Dipyridamole: Pregnancy Category B:
Reproduction studies with dipyridamole have been performed
in mice at doses up to 125 mg/kg (375 mg/m2 , ~1.3 times
the recommended human dose), in rats at doses up to 1000
mg/kg (6000 mg/m2, 20 times the recommended human dose)
and in rabbits at doses up to 40 mg/kg (480 mg/m2, ~1.6
times the recommended human dose) and have revealed no
evidence of harm to the fetus.
Aspirin: Pregnancy Category D: Aspirin
may produce adverse maternal effects: anemia, ante- or
postpartum hemorrhage, prolonged gestation and labor.
Maternal aspirin use during later stages of pregnancy
may cause adverse fetal effects: low birth weight, increased
incidence of intracranial hemorrhage in premature infants,
stillbirths, neonatal death. Aspirin should be avoided
1 week prior to and during labor and delivery because
it can result in excessive blood loss at delivery.
Reproduction studies have been performed with combination
of dipyridamole and aspirin in a ratio of 1:4.4 in rats
and rabbits and have revealed no teratogenic evidence
at doses of up to 405 mg/kg/day in rats and 135 mg/kg/day
in rabbits. However, treatment with combination of dipyridamole
and aspirin at 405 mg/kg/day induced abortion in rats.
The doses of dipyridamole at 75 mg/kg/day represent 1.5
times the recommended human dose on a body surface area
basis. In these studies, aspirin itself was teratogenic
at doses of 330 mg/kg/day (1980 mg/m2/day) in rats (spina
bifida, exencephaly, microphthalmia, and coelosomia) and
110 mg/kg/day (1320 mg/m2/day) in rabbits (congested fetuses,
agenesis of skull and upper jaw, generalized edema with
malformation of the head, and diaphanous skin). The doses
of aspirin at 330 mg/kg/day in rats and at 110 mg/kg/day
in rabbits were ~54 and 36 times the recommended human
dose, respectively, on a body surface area basis.
There were no adequate and well-controlled studies in
pregnant women. AGGRENOXTM should be used during pregnancy
only if the potential benefit justifies the potential
risk to the fetus. Due to the aspirin component, AGGRENOXTM
should be avoided in the third trimester of pregnancy.
Nursing Mothers
Dipyridamole (n=1) and aspirin are excreted in human
breast milk in low concentrations. Therefore, caution
should be exercised when AGGRENOXTM is administered to
a nursing woman.
Pediatric Use
Safety and effectiveness of AGGRENOXTM in
pediatric patients have not been studied. Due to the aspirin
component, use of this product in the pediatric population
is not recommended (See CONTRAINDICATIONS).
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