ASPIRIN AND EXTENDED-RELEASE DIPYRIDAMOLE (Page 3 of 7)

8.2 Lactation

Risk Summary

Based on data from a clinical lactation study in breastfeeding women taking low-dose aspirin, the metabolite salicylic acid is present in human milk in low levels (see Data). Dipyridamole is also present in human milk. There is no information on the effects of aspirin and extended-release dipyridamole capsules or dipyridamole on the breastfed infant or on milk production. There is insufficient information to determine the effects of aspirin on the breastfed infant and no information on the effects of aspirin on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for aspirin and extended-release dipyridamole capsules and any potential adverse effects on the breastfed child from aspirin and extended-release dipyridamole capsules or from the underlying maternal condition.

Data

A published clinical study involved six exclusively breastfeeding women at 1 to 8 months postpartum who were taking 81 mg aspirin daily. Milk samples were collected at steady state, at 0, 1, 2, 4, 8, 12, and 24 hours after taking a dose of aspirin. Aspirin was undetectable in human milk. Salicylic acid was present in milk at low levels (average concentration of 24 ng/mL). Based on an average milk consumption of 150 mL/kg/day, the calculated relative infant dose was 0.4%. No adverse effects on the breastfed infants were noted.

8.4 Pediatric Use

Safety and effectiveness of aspirin and extended-release dipyridamole in pediatric patients have not been studied. Because of the aspirin component, use of this product in the pediatric population is not recommended [ see Contraindications (4.3) ].

8.5 Geriatric Use

Of the total number of subjects in ESPS2, 61% were 65 and over, while 27% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [ see Clinical Pharmacology (12.3) ].

8.6 Patients with Severe Hepatic or Severe Renal Dysfunction

Aspirin and extended-release dipyridamole has not been studied in patients with hepatic or renal impairment. Avoid using aspirin containing products, such as aspirin and extended-release dipyridamole in patients with severe hepatic or severe renal (glomerular filtration rate <10 mL/min) dysfunction [ see Warnings and Precautions (5.2, 5.3) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Because of the dose ratio of dipyridamole to aspirin, overdosage of aspirin and extended-release dipyridamole capsule is likely to be dominated by signs and symptoms of dipyridamole overdose. In case of real or suspected overdose, seek medical attention or contact a Poison Control Center immediately. Careful medical management is essential.

Based upon the known hemodynamic effects of dipyridamole, symptoms such as warm feeling, flushes, sweating, restlessness, feeling of weakness, and dizziness may occur. A drop in blood pressure and tachycardia might also be observed.

Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. Severity of aspirin intoxication is determined by measuring the blood salicylate level. The early signs of salicylic overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations approaching 200 mcg/mL. In severe cases, hyperthermia and hypovolemia are the major immediate threats to life. Plasma concentrations of aspirin above 300 mcg/mL are clearly toxic. Severe toxic effects are associated with levels above 400 mcg/mL. A single lethal dose of aspirin in adults is not known with certainty but death may be expected at 30 g.

Treatment of overdose consists primarily of supporting vital functions, increasing drug elimination, and correcting acid-base disturbances. Consider gastric emptying and/or lavage as soon as possible after ingestion, even if the patient has vomited spontaneously. After lavage and/or emesis, administration of activated charcoal as a slurry may be beneficial if less than 3 hours have passed since ingestion. Charcoal absorption should not be employed prior to emesis and lavage. Follow acid-base status closely with serial blood gas and serum pH measurements. Maintain fluid and electrolyte balance. Administer replacement fluid intravenously and augment with correction of acidosis. Treatment may require the use of a vasopressor. Infusion of glucose may be required to control hypoglycemia.

Administration of xanthine derivatives (e.g., aminophylline) may reverse the vasodilatory effects of dipyridamole overdose. Plasma electrolytes and pH should be monitored serially to promote alkaline diuresis of salicylate if renal function is normal. In patients with renal insufficiency or in cases of life-threatening intoxication, dialysis is usually required to treat salicylic overdose; however, since dipyridamole is highly protein bound, dialysis is not likely to remove dipyridamole. Exchange transfusion may be indicated in infants and young children.

11 DESCRIPTION

Aspirin and extended-release dipyridamole capsule is a combination antiplatelet agent intended for oral administration. Each hard gelatin capsule contains 200 mg dipyridamole in an extended-release form and 25 mg aspirin, as an immediate-release. In addition, each capsule contains the following inactive ingredients: caprylic/capric mono/diglycerides, D&C yellow #10 Aluminum Lake, FD&C blue #1/brilliant blue FCF Aluminum Lake, glyceryl monostearate, hypromellose, methacrylic acid and methacrylate copolymer, microcrystalline cellulose, povidone K30, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, talc, tartaric acid, titanium dioxide, triacetin and triethyl citrate.

Each capsule shell contains gelatin, ferric oxide red, ferric oxide yellow, titanium dioxide and water.

Black imprint ink composition contains ferrosoferric oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

Dipyridamole USP

Dipyridamole USP is an antiplatelet agent chemically described as 2,2′,2”,2”’-[(4,8-Dipiperidinopyrimido[5,4- d ]pyrimidine-2,6-diyl)dinitrilo]-tetraethanol. It has the following structural formula:

Dipyridamole is an odorless yellow crystalline substance, having a bitter taste. It is soluble in dilute acids, methanol and chloroform, and is practically insoluble in water.

Aspirin USP

The antiplatelet agent aspirin (acetylsalicylic acid) is chemically known as benzoic acid, 2-(acetyloxy)-, and has the following structural formula:

Aspirin Structure
(click image for full-size original)

Aspirin is an odorless white needle-like crystalline or powdery substance. When exposed to moisture, aspirin hydrolyzes into salicylic and acetic acids, and gives off a vinegary odor. It is highly lipid soluble and slightly soluble in water.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The antithrombotic action of aspirin and extended-release dipyridamole capsule 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.

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