Dipyridamole USP is a platelet inhibitor chemically described as 2,6-bis-(diethanolamino)-4,8-dipiperidino-pyrimido-(5,4-d) pyrimidine. It has the following structural formula:
C 24 H 40 N 8 O 4 Mol.Wt. 504.63
Dipyridamole is an odorless yellow crystalline powder, having a bitter taste. It is soluble in dilute acids, methanol and chloroform, and practically insoluble in water.
PERSANTINE tablets for oral administration contain:
Active Ingredient TABLETS 25, 50, and 75 mg: dipyridamole USP 25, 50, and 75 mg respectively.
Inactive Ingredients TABLETS 25, 50, and 75 mg: acacia, carnauba wax, corn starch, FD&C blue No. 1 aluminum lake, D&C yellow No. 10 aluminum lake, D&C red No. 30 aluminum lake, lactose, magnesium stearate, polyethylene glycol, povidone, shellac, sodium benzoate, sucrose, talc, titanium dioxide, white wax.
CLINICAL PHARMACOLOGY 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.
PERSANTINE tablets have 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, PERSANTINE tablets, 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 PERSANTINE tablets and warfarin ranged from 1.2 to 1.8%. In three additional studies involving 392 patients taking PERSANTINE tablets 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 PERSANTINE tablets were begun between 24 hours and 10 days postoperatively. The length of follow-up in these trials varied from 1 to 2 years.
PERSANTINE tablets do not influence prothrombin time or activity measurements when administered with warfarin.
Mechanism of Action 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 A 2 formation which is a potent stimulator of platelet activation.
Hemodynamics 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 PERSANTINE 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 PERSANTINE may worsen regional myocardial perfusion distal to partial occlusion of coronary arteries.
and Metabolism Following an oral dose of PERSANTINE tablets, the average time to peak concentration is about 75 minutes. The decline in plasma concentration following a dose of PERSANTINE tablets 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.
PERSANTINE tablets are indicated as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement.
CONTRAINDICATIONS None known.
PRECAUTIONS General PERSANTINE tables should be used with caution in patients with hypotension since it can produce peripheral vasodilation.
Carcinogenesis, Mutagenesis, Impairment of Fertility In a 111 week oral study in mice and in a 128-142 week oral study in rats, dipyridamole USP produced no significant carcinogenic effects at doses of 8, 25 and 75 mg/kg (1, 3.1 and 9.4 times the maximum recommended daily human dose). Mutagenicity testing with dipyridamole was negative. Reproduction studies with dipyridamole revealed no evidence of impaired fertility in rats at dosages up to 60 times the maximum recommended human dose. A significant reduction in number of corpora lutea with consequent reduction in implantations and live fetuses was, however, observed at 155 times the maximum recommended human dose.
Teratogenic Effects PREGNANCY CATEGORY B Reproduction studies have been performed in mice at doses up to 125 mg/kg (15.6 times the maximum recommended daily human dose), rats at doses up to 1000 mg/kg (125 times the maximum recommended daily human dose) and rabbits at doses up to 40 mg/kg (5 times the maximum recommended daily human dose) 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, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers As dipyridamole is excreted in human milk, caution should be exercised when PERSANTINE® (dipyridamole USP) tablets are administered to a nursing woman.
Pediatric Use Safety and effectiveness in the pediatric population below the age of 12 years has not been established.
ADVERSE REACTIONS Adverse reactions at therapeutic doses are usually minimal and transient. On long-term use of PERSANTINE tablets initial side effects usually disappear. The following reactions were reported in two heart valve replacement trials comparing PERSANTINE tablets and warfarin therapy to either warfarin alone or warfarin and placebo:
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 PERSANTINE tablets were administered concomitantly with warfarin, bleeding was no greater in frequency or severity than that observed when warfarin was administered alone.
In postmarketing reporting experience, there have been rare reports of larynx edema, fatigue, malaise, myalgia, arthritis, nausea, dyspepsia, paresthesia, hepatitis, alopecia, cholelithiasis, palpitation, and tachycardia.
Hypotension, if it occurs, is likely to be of short duration, but a vasopressor drug may be used if necessary. The oral LD 50 in mice is 2,150 mg/kg. Single oral doses of 6,000 mg/kg in rats and 350 mg/kg in dogs were lethal. Symptoms of acute toxicity included ataxia, decreased locomotion and diarrhea in rodents and emesis, ataxia and depression in dogs. Since PERSANTINE tablets are highly protein bound, dialysis is not likely to be of benefit.
DOSAGE AND ADMINISTRATION 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.
HOW SUPPLIED PERSANTINE tablets are available as round, orange, sugar-coated tablets of 25 mg, 50 mg and 75 mg coded BI/17, BI/18 and BI/19 respectively.
They are available in the following package sizes:
25 mg Tablets
Bottles of 100 (NDC 0597-0017-01)
Bottles of 1000 (NDC 0597-0017-10)
Unit Dose Packages of 100 (NDC 0597-0017-61)
50 mg Tablets
Bottles of 100 (NDC 0597-0018-01)
Bottles of 1000 (NDC 0597-0018-10)
Unit Dose Packages of 100 (NDC 0597-0018-61)
75 mg Tablets
Bottles of 100 (NDC 0597-0019-01)
Bottles of 500 (NDC 0597-0019-05)
Unit Dose Packages of 100 (NDC 0597-0019-61)
Store below 86°F (30°C).
Caution: Federal law prohibits dispensing without prescription.
Ridgefield, CT 06877