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:

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 mg, 50 mg, and 75 mg: dipyridamole USP 25 mg, 50 mg and 75 mg, respectively.

Inactive Ingredients TABLETS 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.

Persantine (dipyridamole USP) tablets are indicated as an adjunct to coumarin anticoagulants in the prevention of postoperative thromboembolic complications of cardiac valve replacement.

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.

PERSANTINE (dipyridamole USP) 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 bottles of 100 tablets as indicated below:

25 mg Tablets...........................(NDC 0597-0017-01)
50 mg Tablets...........................(NDC 0597-0018-01)
75 mg Tablets...........................(NDC 0597-0019-01)

STORE AT 25°C (77°F); EXCURSIONS PERMITTED TO 15-30°C (59°-86°F) [SEE USP CONTROLLED ROOM TEMPERATURE]. KEEP OUT OF REACH OF CHILDREN.

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877, USA. Licensed from: Boehringer Ingelheim International GmbH, Manufactured by: Boehringer Ingelheim Promeco, S.A. de C.V. Mexico City, Mexico. Revised 01/21/05. FDA Rev date: 8/1/2005

Adverse reactions at therapeutic doses are usually minimal and transient. On long-term use of Persantine (dipyridamole USP) tablets initial side effects usually disappear. The following reactions in Table 1 were reported in two heart valve replacement trials comparing Persantine E tablets and warfarin therapy to either warfarin alone or warfarin and placebo:

Table 1: Adverse Reactions Reported in 2 Heart Valve Replacement Trials

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 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.

No pharmacokinetic drug-drug interaction studies were conducted with Persantine (dipyridamole USP) Tablets. 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.

Cholinesterase Inhibitors: Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors, thereby potentially aggravating myasthenia gravis.

No information provided.

General

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.

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.

Laboratory Tests

Dipyridamole has been associated with elevated hepatic enzymes.

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).

Pregnancy

Teratogenic Effects: 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 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 should be used during pregnancy only if clearly needed.

Nursing Mothers

As dipyridamole is excreted in human milk, caution should be exercised when Persantine tablets are administered to a nursing woman.

Pediatric Use

Safety and effectiveness in the pediatric population below the age of 12 years have not been established.

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.

Hypersensitivity to dipyridamole and any of the other components.

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 (dipyridamole USP) 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 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).

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.

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.

No information provided. Please refer to the PRECAUTIONS section.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DIPYRIDAMOLE - ORAL

(dye-peer-ID-ah-mole)

COMMON BRAND NAME(S): Persantine

USES: This medication is used in combination with "blood thinners" such as warfarin to keep clots from forming after heart valve replacements. Clots are a serious complication that can cause strokes, heart attacks, or blocked blood vessels in the lungs (pulmonary embolisms). Dipyridamole belongs to a class of drugs known as platelet inhibitors. It helps to keep blood flowing by stopping platelets from clumping together and by keeping heart blood vessels open.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This drug may also be used to reduce the risk of stroke in patients who are at higher risk of clots, such as those who have had "mini-strokes" (transient ischemia attacks), stroke, heart attack, surgery, or heart valve disease.

HOW TO USE: Take this medication by mouth, usually 4 times daily or as directed by your doctor. This medication is best taken on an empty stomach, but it may be taken with meals if stomach upset occurs.

Dosage is based on your medical condition and response to therapy.

Use this medication regularly in order to get the most benefit from it. To help you remember, use it at the same times each day.

Do not stop taking this medication without consulting your doctor.

SIDE EFFECTS: Dizziness, stomach upset, diarrhea, vomiting, headache, and flushing may occur, particularly at first as your body adjusts to the medication. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these rare but very serious side effects occur: weakness, fainting, stomach pain, pounding/rapid heartbeat, yellowing of eyes/skin, dark urine, unusual bleeding/bruising.

Seek immediate medical attention if any of these rare but very serious side effects occur: chest pain, confusion, severe headache, slurred speech, vision changes, weakness on one side of the body.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling (especially of the face, lips, tongue, or throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking dipyridamole, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: other heart problems (e.g., severe coronary artery disease, recent heart attack, low blood pressure), liver disease.

This drug may make you dizzy. Use caution while driving, using machinery, or doing any activity that requires alertness. Limit alcoholic beverages.

Before having surgery, tell your doctor or dentist that you are using this medication.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

This medication passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

If you are currently taking aspirin, consult your doctor promptly and ask whether to continue or stop taking it with this medication for your specific condition (e.g., stroke prevention). If you are not currently taking aspirin, consult your doctor before starting it for any medical condition.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: adenosine, "blood thinners" (e.g., heparin, enoxaparin, dalteparin, ardeparin, fondaparinux, tinzaparin), other medicines that affect platelets (e.g., ticlopidine, abciximab, eptifibatide, lepirudin), neostigmine, pyridostigmine, valproic acid.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents should call the US National Poison Hotline at 1-800-222-1222. Canada residents should call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., liver function tests) may be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.