dipyridamole (Dipyridamole) tablet
[Barr Laboratories, Inc.]
Dipyridamole is a platelet inhibitor 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:
C24H40N8O4 Molecular Weight: 504.63
Dipyridamole is an intensely yellow, crystalline powder or needles. It is very soluble in methanol, in alcohol, and in chloroform; slightly soluble in water; very slightly soluble in acetone and in ethyl acetate.
Dipyridamole Tablets, USP for oral administration contain:
Active Ingredient: TABLETS 25, 50, and 75 mg; Dipyridamole USP 25, 50 and 75 mg respectively.
Inactive Ingredients: Colloidal silicon dioxide, hypromellose, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, propylene glycol, stearic acid, sodium starch glycolate, and titanium dioxide.
It is believed that platelet reactivity and interaction with prosthetic cardiac valve surfaces, resulting in abnormally shortened platelet survival time, is a significant factor in thromboembolic complications occurring in connection with prosthetic heart valve replacement.
Dipyridamole has been found to lengthen abnormally shortened platelet survival time in a dose-dependent manner.
In three randomized controlled clinical trials involving 854 patients who had undergone surgical placement of a prosthetic heart valve, dipyridamole, in combination with warfarin, decreased the incidence of postoperative thromboembolic events by 62 to 91% compared to warfarin treatment alone. The incidence of thromboembolic events in patients receiving the combination of dipyridamole and warfarin ranged from 1.2 to 1.8%. In three additional studies involving 392 patients taking dipyridamole and coumarin-like anticoagulants, the incidence of thromboembolic events ranged from 2.3 to 6.9%.
In these trials, the coumarin anticoagulant was begun between 24 hours and 4 days postoperatively, and the dipyridamole was begun between 24 hours and 10 days postoperatively. The length of follow-up in these trials varied from 1 to 2 years.
Dipyridamole does not influence prothrombin time or activity measurements when administered with warfarin.
Dipyridamole is a platelet adhesion inhibitor, although the mechanism of action has not been fully elucidated. The mechanism may relate to inhibition of red blood cell uptake of adenosine, itself an inhibitor of platelet reactivity, phosphodiesterase inhibition leading to increased cyclic-3', 5'-adenosine monophosphate within platelets, and inhibition of thromboxane A2 formation which is a potent stimulator of platelet activation.
In dogs intraduodenal doses of dipyridamole of 0.5 to 4.0 mg/kg produced dose-related decreases in systemic and coronary vascular resistance leading to decreases in systemic blood pressure and increases in coronary blood flow. Onset of action was in about 24 minutes and effects persisted for about 3 hours.
Similar effects were observed following IV dipyridamole in doses ranging from 0.025 to 2.0 mg/kg.
In man the same qualitative hemodynamic effects have been observed. However, acute intravenous administration of dipyridamole may worsen regional myocardial perfusion distal to partial occlusion of coronary arteries.
Following an oral dose of dipyridamole, the average time to peak concentration is about 75 minutes. The decline in plasma concentration following a dose of dipyridamole fits a two-compartment model. The alpha half-life (the initial decline following peak concentration) is approximately 40 minutes. The beta half-life (the terminal decline in plasma concentration) is approximately 10 hours. Dipyridamole is highly bound to plasma proteins. It is metabolized in the liver where it is conjugated as a glucuronide and excreted with the bile.
Dipyridamole is indicated as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement.
Dipyridamole should be used with caution in patients with hypotension since it can produce peripheral vasodilation.
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. Mutagenicity tests of dipyridamole with bacterial and mammalian cell systems were negative. 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).
Pregnancy Category B: Reproduction studies have been performed in mice, rabbits and rats at oral dipyridamole doses of up to 125 mg/kg, 40 mg/kg and 1000 mg/kg, respectively (about 1½, 2 and 25 times the maximum recommended daily human oral dose, respectively, on a mg/m2 basis) and have revealed no evidence of harm to the fetus due to dipyridamole. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, dipyridamole should be used during pregnancy only if clearly needed.
As dipyridamole is excreted in human milk, caution should be exercised when dipyridamole is administered to a nursing woman.
Safety and effectiveness in children below the age of 12 years has not been established.
Adverse reactions at therapeutic doses are usually minimal and transient. On long-term use of dipyridamole initial side effects usually disappear. The following reactions were reported in two heart valve replacement trials comparing dipyridamole and warfarin therapy to either warfarin alone or warfarin and placebo:
|Dizziness||13.6 %||8.2 %|
|Abdominal distress||6.1 %||3.5 %|
|Headache||2.3 %||0.0 %|
|Rash||2.3 %||1.1 %|
Other reactions from uncontrolled studies include diarrhea, vomiting, flushing and pruritus. In addition, angina pectoris has been reported rarely, and there have been rare reports of liver dysfunction. On those uncommon occasions when adverse reactions have been persistent or intolerable, they have ceased on withdrawal of the medication.
When dipyridamole was administered concomitantly with warfarin, bleeding was no greater in frequency or severity than that observed when warfarin was administered alone.
Hypotension, if it occurs, is likely to be of short duration, but a vasopressor drug may be used if necessary. The oral LD50 in rats is greater than 6,000 mg/kg while in dogs, the oral LD50 is approximately 40 mg/kg. Since dipyridamole is highly protein bound, dialysis is not likely to be of benefit.
Adjunctive Use in Prophylaxis of Thromboembolism after Cardiac Valve Replacement: The recommended dose is 75-100 mg four times daily as an adjunct to the usual warfarin therapy. Please note that aspirin is not to be administered concomitantly with coumarin anticoagulants.
25 mg: White, round, film-coated, unscored tablets. Debossed with stylized b on one side and 252 on the other side. Available in bottles of:
90 NDC 0555-0252-14
100 NDC 0555-0252-02
500 NDC 0555-0252-04
1000 NDC 0555-0252-05
5000 NDC 0555-0252-06
50 mg: White, round, film-coated, unscored tablets. Debossed with stylized b on one side and 285 on the other side. Available in bottles of:
100 NDC 0555-0285-02
500 NDC 0555-0285-04
1000 NDC 0555-0285-05
75 mg: White, round, film-coated, unscored tablets. Debossed with BARR on one side and 286 on the other side. Available in bottles of:
100 NDC 0555-0286-02
500 NDC 0555-0286-04
1000 NDC 0555-0286-05
Dispense with a child-resistant closure in a tight, light-resistant container as defined in the USP/NF.
Store at 20º to 25ºC (68º to 77ºF) [See USP Controlled Room Temperature].
BARR LABORATORIES, INC.
POMONA, NY 10970
BR-252, 285, 286
Data are from FDA and U.S. National Library of Medicine.