Label: PERSANTINE- dipyridamole tablet, coated
- NDC Code(s): 0597-0017-01, 0597-0018-01, 0597-0019-01
- Packager: Boehringer Ingelheim Pharmaceuticals, Inc.
- Category: HUMAN PRESCRIPTION DRUG LABEL
- DEA Schedule: None
- Marketing Status: New Drug Application
Updated December 16, 2019
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PERSANTINE® (dipyridamole USP) 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:
Inactive IngredientsTABLETS 25 mg, 50 mg, and 75 mg: acacia, carnauba wax, corn starch, edible white ink, lactose monohydrate, magnesium stearate, D&C yellow #10 aluminum lake, D&C red #30, helendon aluminum pink lake, sodium benzoate, methylparaben, propylparaben, polyethylene glycol, povidone, sucrose, talc, titanium dioxide, and white wax.
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.
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® (dipyridamole USP) tablets were begun between 24 hours and 10 days postoperatively. The length of follow-up in these trials varied from 1 to 2 years.
Mechanism of Action
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 (0.5–1.9 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).
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).
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.
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.
Pharmacokinetics 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.
- INDICATIONS AND USAGE
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.
Stress Testing with Intravenous Dipyridamole and Other Adenosinergic Agents: Clinical experience suggests that patients being treated with PERSANTINE tablets who also require pharmacological stress testing with intravenous dipyridamole or other adenosinergic agents (e.g. adenosine, regadenoson) should interrupt PERSANTINE tablets for 48 hours prior to stress testing.
Intake of PERSANTINE tablets within 48 hours prior to stress testing with intravenous dipyridamole or other adenosinergic agents may increase the risk for cardiovascular side effects of these agents and may impair the sensitivity of the test.
Adenosinergic agents (e.g., adenosine, regadenoson): Dipyridamole has been reported to increase the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage may be necessary. Dipyridamole also increases the cardiovascular effects of regadenoson, an adenosine A2A-receptor agonist. The potential risk of cardiovascular side effects with intravenous adenosinergic agents may be increased during the testing period when dipyridamole is not held 48 hours prior to stress testing.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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).
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 1 ½, 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, PERSANTINE tablets should be used during pregnancy only if clearly needed.
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 in Table 1 were reported in two heart valve replacement trials comparing PERSANTINE tablets and warfarin therapy to either warfarin alone or warfarin and placebo:
Table 1 Adverse Reactions Reported in 2 Heart Valve Replacement Trials Adverse Reaction PERSANTINE
Tablets / Warfarin
Placebo / Warfarin Number of patients 147 170 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 Persantine® (dipyridamole USP) tablets were administered concomitantly with warfarin, bleeding was no greater in frequency or severity than that observed when warfarin was administered alone. In rare cases, increased bleeding during or after surgery has been observed.
In post-marketing reporting experience, there have been rare reports of hypersensitivity reactions (such as rash, urticaria, severe bronchospasm, and angioedema), larynx edema, fatigue, malaise, myalgia, arthritis, nausea, dyspepsia, paresthesia, hepatitis, thrombocytopenia, alopecia, cholelithiasis, hypotension, palpitation, and tachycardia.
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.
Symptomatic treatment is recommended, possibly including a vasopressor drug. Gastric lavage should be considered. Administration of xanthine derivatives (e.g., aminophylline) may reverse the hemodynamic effects of dipyridamole overdose. Since dipyridamole is highly protein bound, dialysis is not likely to be of benefit.
- DOSAGE AND ADMINISTRATION
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INGREDIENTS AND APPEARANCE
dipyridamole tablet, coated
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0597-0017 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DIPYRIDAMOLE (UNII: 64ALC7F90C) (DIPYRIDAMOLE - UNII:64ALC7F90C) DIPYRIDAMOLE 25 mg Product Characteristics Color ORANGE (Orange) Score no score Shape ROUND (shape) Size 5mm Flavor Imprint Code 17 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0597-0017-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 06/01/1999 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA012836 06/01/1999 PERSANTINE
dipyridamole tablet, coated
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0597-0018 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DIPYRIDAMOLE (UNII: 64ALC7F90C) (DIPYRIDAMOLE - UNII:64ALC7F90C) DIPYRIDAMOLE 50 mg Product Characteristics Color ORANGE (Orange) Score no score Shape ROUND (shape) Size 8mm Flavor Imprint Code 18 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0597-0018-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 06/01/1999 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA012836 06/01/1999 PERSANTINE
dipyridamole tablet, coated
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0597-0019 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength DIPYRIDAMOLE (UNII: 64ALC7F90C) (DIPYRIDAMOLE - UNII:64ALC7F90C) DIPYRIDAMOLE 75 mg Product Characteristics Color ORANGE (Orange) Score no score Shape ROUND (shape) Size 9mm Flavor Imprint Code 19 Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0597-0019-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 06/01/1999 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA012836 06/01/1999 Labeler - Boehringer Ingelheim Pharmaceuticals, Inc. (603175944) Registrant - Boehringer Ingelheim Pharmaceuticals Inc. (603175944) Establishment Name Address ID/FEI Business Operations Boehringer Ingelheim Promeco, S.A. de C.V. 812579472 ANALYSIS(0597-0017, 0597-0019, 0597-0018) , MANUFACTURE(0597-0017, 0597-0019, 0597-0018) Establishment Name Address ID/FEI Business Operations Malgrat Pharma Chemicals, S.L.U. 468215759 API MANUFACTURE(0597-0017, 0597-0018, 0597-0019)