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aspirin-dipyridam er 25-200 mg generic aggrenox

In stock Manufacturer AMNEAL PHARMACE 65162059606
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Uses

Prosthetic Heart Valves

Dipyridamole is used orally as an adjunct to coumarin anticoagulants (e.g., warfarin) in the prevention of postoperative thromboembolic complications of heart valve replacement. Because warfarin therapy alone may not completely prevent thrombosis in patients with mechanical prosthetic heart valves, dipyridamole has been used in conjunction with warfarin in an effort to reduce the risk of thrombosis in these patients. While some evidence suggests that dipyridamole used in conjunction with warfarin may be more effective in reducing postoperative thromboembolic events in patients with mechanical prosthetic heart valves than use of warfarin alone, the American College of Chest Physicians (ACCP) and other experts generally recommend the addition of low-dose aspirin (rather than dipyridamole) to warfarin therapy in such patients. Dipyridamole should not be used alone, without warfarin, for the prevention of postoperative thromboembolic complications in patients undergoing placement of mechanical prosthetic heart valves since there is no evidence to date that dipyridamole (or other platelet-aggregation inhibitors) would be effective when used alone.

Transient Ischemic Attacks and Completed Thrombotic Stroke

Extended-release dipyridamole in fixed combination with aspirin is used to reduce the risk of stroke in patients who have had transient ischemic attacks (TIAs) or completed thrombotic stroke (secondary prevention).

In a randomized, comparative, placebo-controlled study, patients who had experienced either an ischemic stroke or TIAs were assigned to receive treatment with aspirin (25 mg twice daily), extended-release dipyridamole (200 mg twice daily), aspirin plus extended-release dipyridamole (25 and 200 mg twice daily, respectively), or placebo. All active treatments reduced the risk of the primary end points of stroke (nonfatal or fatal) or stroke and/or death compared with placebo. Aspirin plus dipyridamole reduced the risk of stroke by about 23% compared with aspirin alone and by about 25% compared with dipyridamole alone at 2 years of follow-up; the effects of combined therapy on risk reductions with aspirin and dipyridamole were additive but not synergistic. Aspirin, dipyridamole, and the combination also reduced the incidence of TIAs and other vascular events in a manner consistent with these treatments' effects on the risk of stroke. None of the treatments had a statistically significant effect on the end point of death (i.e., no effect on survival). Headache and GI events were the most common adverse effects in this study, occurring more frequently in the dipyridamole-treated groups, while bleeding from the GI tract or from any site was more common in the aspirin-treated groups.

ACCP, the American Stroke Association (ASA), and the American Heart Association (AHA) recommend antiplatelet therapy for secondary prevention of ischemic atherothrombotic (noncardioembolic) stroke or TIAs in patients with prior TIAs or stroke. These experts consider the combination of aspirin and dipyridamole (25 mg aspirin/200 mg extended-release dipyridamole twice daily) an acceptable antiplatelet option for the prevention of recurrent stroke or other cardiovascular events in such patients; other options include aspirin monotherapy, cilostazol, or clopidogrel. When selecting an appropriate antiplatelet regimen for the secondary prevention of noncardioembolic stroke, factors such as the patient's individual risk for recurrent stroke, tolerance, and cost of the different agents should be considered.

Adjunct to Thallium Myocardial Perfusion Imaging

Dipyridamole is used IV as an adjunct to thallous (thallium) chloride Tl 201 myocardial stress perfusion imaging in patients unable to exercise adequately.

The sensitivity and specificity of dipyridamole-assisted thallium imaging versus coronary arteriography in the detection of coronary artery disease were determined by comparing the results of thallium imaging with those of coronary arteriography under blinded conditions. The sensitivity of dipyridamole-assisted thallium imaging (true positive thallium imaging divided by the number of patients with positive angiograms) was 85% and the specificity (true negative thallium imaging divided by the number of patients with negative angiograms) was about 50%. In a subset of patients who had exercise thallium imaging or dipyridamole-assisted thallium imaging, the sensitivity and specificity of the 2 tests were almost identical.

Other Uses

Dipyridamole also has been used orally to decrease platelet aggregation in a number of other thromboembolic disorders. ACCP suggests postoperative anticoagulant therapy with unfractionated heparin and antiplatelet therapy with aspirin and/or dipyridamole to reduce thromboembolic events in children with heart failure who require implantation of ventricular assist devices. However, for most thromboembolic disorders, it has not been established whether the inclusion of dipyridamole in an antithrombotic regimen substantially enhances the potential benefit compared with that of the other antithrombotic agents (e.g., aspirin) alone, and some evidence suggests that in certain disorders, it may not (e.g., for prevention of thromboembolic complications in patients surviving a myocardial infarction (MI) or following PCI, coronary artery bypass graft [CABG] surgery, lower extremity vascular reconstruction).

ACCP recommends the use of dipyridamole in combination with aspirin as an option for long-term antiplatelet therapy in patients with symptomatic carotid stenosis, including those who have undergone recent carotid endarterectomy.

There currently is no evidence that antiplatelet agents such as dipyridamole or ticlopidine have any advantage over aspirin for mortality reduction following an acute MI.

Dipyridamole has been used in the long-term therapy of chronic angina pectoris based on the premise that prolonged therapy with the drug may reduce the frequency of or eliminate anginal episodes, improve exercise tolerance, and reduce requirements for nitroglycerin. However, well-controlled clinical studies showed that long-term oral administration of dipyridamole does not prevent ECG signs of myocardial ischemia in patients with angina pectoris following exercise or decrease the frequency or severity of anginal attacks, and experts state that there is evidence and/or general agreement that dipyridamole is not useful or effective for the management of chronic angina pectoris. The drug also is not effective for the treatment of acute episodes of angina and is not a substitute for appropriate medical programs for the treatment of angina pectoris.

Dosage and Administration

Administration

Dipyridamole is administered orally or IV. Capsules containing the fixed-combination of extended-release dipyridamole and aspirin should be swallowed whole and should not be chewed. The fixed-combination capsules containing extended-release dipyridamole and aspirin may be administered without regard to food.

Prior to IV administration, dipyridamole injection should be diluted in at least twice the injection volume with 0.45% sodium chloride injection, 0.9% sodium chloride injection, or 5% dextrose injection to a final volume of approximately 20-50 mL. Infusion of undiluted dipyridamole may cause local irritation.

Dosage

The usual adult oral dosage of dipyridamole for adjunctive use with coumarin anticoagulant (e.g., warfarin) therapy in the prevention of postoperative thromboembolic complications of cardiac valve replacement is 75-100 mg 4 times daily.

For the prevention of thromboembolic complications in patients with various other thromboembolic disorders, oral dosage of dipyridamole generally has ranged from 150-400 mg daily, in combination with another platelet-aggregation inhibitor (e.g., aspirin) or warfarin.

For reducing the risk of stroke in patients who have had transient ischemic attacks (TIAs) or completed stroke caused by thrombosis, the usual dosage of oral extended-release dipyridamole is 200 mg in fixed combination with aspirin 25 mg (1 capsule) twice daily in the morning and evening. If headaches become intolerable during initial treatment, the dosage of the dipyridamole/aspirin fixed combination should be reduced to 200 mg of dipyridamole and 25 mg of aspirin (1 capsule) once daily at bedtime and low-dose aspirin should be administered in the morning. Because no outcome data are available with this regimen and headaches diminish during continued treatment, patients should resume the usual regimen (200 mg of extended-release dipyridamole and 25 mg of aspirin twice daily) as soon as possible (usually within 1 week). The amount of aspirin in the fixed-combination preparation may not be adequate to prevent recurrent myocardial infarction (MI) or angina pectoris in patients with stroke or TIA.

When used as an adjunct to thallium myocardial imaging, dipyridamole usually is administered as a single IV dose of 0.57 mg/kg, infused at a rate of 0.142 mg/kg per minute for 4 minutes. Although the maximum tolerated IV dose of dipyridamole has not been determined, clinical experience suggests that a total dose exceeding 60 mg is not needed for any patient. Thallium-201 should be injected within 5 minutes following completion of the dipyridamole infusion.

Cautions

Adverse Effects

Adverse effects associated with oral dipyridamole therapy are generally dose related and reversible and may include headache, dizziness, GI intolerance (e.g., abdominal distress), nausea, vomiting, diarrhea, peripheral vasodilation, flushing, weakness, syncope, rash, and pruritus. Headache is the most common adverse effect of dipyridamole and is most notable during the first month of treatment.(See Dosage and Administration: Dosage, for details on dosage adjustment for headache.) Rarely, angina pectoris or aggravation of angina pectoris has been reported, usually at the beginning of therapy. During postmarketing experience, hypersensitivity reactions (e.g., rash, urticaria, severe bronchospasm, angioedema), laryngeal edema, fatigue, myalgia, arthritis, nausea, dyspepsia, paresthesia, hepatitis, thrombocytopenia, alopecia, cholelithiasis, hypotension, palpitation, and tachycardia have been reported rarely. Most adverse effects of oral dipyridamole are transient and resolve during long-term therapy with the drug; rarely, adverse effects are persistent or intolerable but are reversible when the drug is discontinued. In a large randomized, comparative, placebo-controlled trial, there was no clear safety benefit of treatment with extended-release dipyridamole in fixed combination with aspirin compared with aspirin alone.

Liver dysfunction (e.g., elevations of hepatic enzymes, hepatic failure) have been reported rarely in association with oral dipyridamole.

IV dipyridamole has been associated with serious adverse effects, including acute myocardial ischemia or infarction, cardiac death, ventricular fibrillation, symptomatic ventricular tachycardia, stroke, transient cerebral ischemia, and seizures. Asystole, sinus node arrest, sinus node depression, and conduction block also have been reported with IV dipyridamole therapy. Patients with abnormalities of cardiac impulse formation and conduction or severe coronary artery disease (e.g., unstable angina) may be at increased risk for these events. Anaphylactoid reactions and bronchospasm also have been reported in patients with coronary artery disease undergoing IV dipyridamole-assisted thallium imaging. Patients with a history of asthma may be at greater risk for bronchospasm during IV dipyridamole use.

The most common adverse effects reported in a large clinical trial in which IV dipyridamole was used as an adjunct to thallium myocardial perfusion imaging were chest pain/angina pectoris, electrocardiographic changes (most commonly ST-T changes), headache, and dizziness. Other adverse effects occurring in greater than 1% of patients receiving IV dipyridamole were hypotension, nausea, flushing, dyspnea, unspecified pain, blood pressure lability, hypertension, paresthesia, and fatigue. Cardiovascular adverse effects occurring in 1% or less of patients receiving IV dipyridamole included unspecified ECG abnormalities, unspecified arrhythmia, palpitation, ventricular tachycardia, bradycardia, myocardial infarction (MI), atrioventricular block, syncope, orthostatic hypotension, atrial fibrillation, supraventricular tachycardia, ventricular arrhythmia unspecified, heart block unspecified, cardiomyopathy, intermittent claudication, and edema. Nervous system adverse effects occurring in 1% or less of patients receiving IV dipyridamole included hypoesthesia, hypertonia, nervousness/anxiety, tremor, abnormal coordination, somnolence, dysphonia, migraine, malaise, asthenia, depersonalization, and vertigo. GI system adverse effects occurring in 1% or less of patients receiving IV dipyridamole included dyspepsia, dry mouth, abdominal pain, flatulence, vomiting, eructation, dysphagia, tenesmus, dysgeusia, thirst, and increased appetite. Respiratory system adverse effects occurring in 1% or less of patients receiving IV dipyridamole included pharyngitis, bronchospasm, hyperventilation, rhinitis, coughing, and pleural pain. Musculoskeletal system adverse effects occurring in 1% or less of patients receiving IV dipyridamole included myalgia, back pain, arthralgia, rigor, and leg cramping. Other adverse effects occurring in 1% or less of patients receiving IV dipyridamole include unspecified injection site reaction, diaphoresis, injection site pain, earache, tinnitus, unspecified vision abnormalities, eye pain, renal pain, perineal pain, and breast pain. Allergic reactions including urticaria, pruritus, dermatitis, and rash have been reported rarely during postmarketing experience.

Precautions and Contraindications

When dipyridamole is used orally in fixed combination with aspirin, the cautions, precautions, and contraindications associated with aspirin therapy must be considered in addition to those associated with dipyridamole.

Dipyridamole is contraindicated in patients with hypersensitivity to dipyridamole or any ingredient in the formulation.

Dipyridamole should be used cautiously in patients with hypotension or severe coronary artery disease (e.g., unstable angina or recently sustained MI) since it can cause peripheral vasodilation.

In considering the use of IV dipyridamole-assisted thallium imaging in patients with coronary artery disease, the important clinical information to be gained by the procedure should be weighed against the risk to the patient. The rate of false positive and false negative results of IV dipyridamole-assisted thallium imaging as compared with coronary arteriography should also be considered when choosing to use dipyridamole-assisted thallium imaging.

When thallium myocardial perfusion imaging is performed with IV dipyridamole, parenteral aminophylline (an adenosine receptor antagonist) should be readily available for relieving adverse effects such as bronchospasm or chest pain. Vital signs should be monitored during and for 10-15 minutes after IV infusion of dipyridamole, and an ECG should be obtained using at least 1 chest lead. Should severe chest pain or bronchospasm occur, parenteral aminophylline should be administered by slow IV injection (e.g., 50-100 mg over 30-60 seconds) in doses of 50-250 mg. Patients with severe hypotension should be placed in a supine position with the head tilted down, if necessary, before administration of parenteral aminophylline. If the highest recommended dosage of aminophylline (250 mg) does not relieve chest pain within a few minutes, sublingual nitroglycerin may be administered. If chest pain continues despite such combination therapy, the possibility of MI should be considered. If the clinical condition of the patient with an adverse event permits a 1-minute delay, thallium imaging may be performed during such a time period before reversal of the pharmacologic effects of dipyridamole.

Commercially available extended-release dipyridamole in fixed combination with aspirin is not interchangeable with the individual components of aspirin and conventional dipyridamole tablets (e.g., Persantine).

For patients with stroke or TIA for whom aspirin is indicated to prevent recurrent MI or angina pectoris, the amount of aspirin in the commercially available fixed-combination product may not provide adequate treatment for these cardiac indications.

Pediatric Precautions

Safety and efficacy of oral dipyridamole in pediatric patients younger than 12 years of age have not been established. Safety and efficacy of IV dipyridamole in children have not been established. The safety and efficacy of extended-release dipyridamole in fixed combination with aspirin in children have not been established. The manufacturer of Aggrenox states that because of the aspirin component, this preparation should not be used in pediatric patients..

Mutagenicity and Carcinogenicity

Studies using dipyridamole have not revealed evidence of mutagenicity. No evidence of significant carcinogenic effects was seen in mice or rats receiving 111 or 128-142 weeks, respectively, of oral dipyridamole in dosages not exceeding 75 mg/kg (1 or 2 times the maximum recommended daily human oral dosage in mice or rats, respectively, on a mg/m basis). In vitro mutagenicity tests using dipyridamole in bacterial and mammalian cell systems also did not reveal evidence of mutagenicity.

Pregnancy, Fertility, and Lactation

Pregnancy

Safe use of dipyridamole during pregnancy has not been established. Reproduction studies in mice receiving dipyridamole dosages up to 125 mg/kg daily (1.5 times the maximum recommended daily human oral dosage on a mg/m basis), rats receiving dosages not exceeding 1000 mg/kg daily (25 times the maximum recommended daily human oral dosage on a mg/m basis), and rabbits receiving dosages not exceeding 40 mg/kg daily (2 times the maximum recommended daily human oral dosage on a mg/m basis) have not revealed evidence of harm to the fetus. There are no adequate and controlled studies to date using dipyridamole in pregnant women, and the drug should be used during pregnancy only when clearly needed. Extended-release dipyridamole in fixed combination with aspirin should be avoided in the third trimester of pregnancy and during labor and delivery because of the aspirin component of this preparation; aspirin has been shown to be teratogenic in animals and to cause fetal harm when administered to a pregnant woman. If dipyridamole in fixed combination with aspirin is used during pregnancy or the patient becomes pregnant while taking the fixed combination, the patient should be apprised of the potential hazard to the fetus.

Fertility

Reproduction studies in rats receiving dipyridamole dosages up to 12 times the maximum recommended daily human oral dosage on a mg/m basis have not revealed evidence of impaired fertility. However, a substantial reduction in the number of corpora lutea with a subsequent reduction in the number of implantations and live fetuses was observed in rats receiving 30 times the maximum recommended daily human oral dosage of the drug on a mg/m basis.

Lactation

Because dipyridamole is distributed into milk, the drug should be used with caution in nursing women.

Drug Interactions

Since dipyridamole may inhibit platelet aggregation, heparin and dipyridamole should be used concomitantly with caution and patients should be monitored closely to prevent bleeding; however, the actual incidence of this reaction has not been established.

In a dosage of 400 mg daily, dipyridamole does not affect prothrombin time and can be administered with warfarin. Concomitant use of dipyridamole and warfarin does not appear to increase the frequency or severity of bleeding compared with use of warfarin alone. However, in rare instances, increased bleeding during or after surgery has been observed during such concurrent therapy. Some clinicians recommend maintenance of prothrombin time in the lower end of the therapeutic range during concomitant administration of these drugs to avoid possible bleeding.

Dipyridamole may increase the plasma concentrations and the cardiovascular effects of adenosine; adjustment of adenosine dosage may be necessary. Methylxanthines are competitive adenosine receptor antagonists, and aminophylline has been used effectively to terminate persistent adverse effects of dipyridamole. Use of other xanthine derivatives (e.g., caffeine) or maintenance dosages of oral theophylline may abolish the coronary vasodilation of dipyridamole and lead to false negative thallium imaging results.(See Pharmacology.)

In patients receiving an anticholinesterase agent for the treatment of myasthenia gravis, concomitant use of dipyridamole may counteract the anticholinesterase effects of such inhibitors and potentially aggravate myasthenia gravis.

Pharmacokinetics

Oral dipyridamole is incompletely absorbed from the GI tract; the extent of absorption exhibits interindividual variation. According to the manufacturer, the pharmacokinetics of dipyridamole and aspirin are not altered by concomitant administration in fixed combination. Following oral administration of a dose of dipyridamole as conventional tablets, peak plasma concentrations of the drug are attained in about 45-150 minutes (mean: 75 minutes). The mean serum concentration of dipyridamole 2 minutes following administration of an IV dose of dipyridamole (0.568 mg/kg infused over 4 minutes) was 4.6 mcg/mL. Following oral administration of 200 mg of extended-release dipyridamole in fixed combination with aspirin, oral bioavailability of dipyridamole averages 37-66% and peak plasma dipyridamole concentrations are achieved in about 2 hours (range: 1-6 hours) with twice-daily dosing. Steady-state peak and trough plasma concentrations of dipyridamole average 1.98 and 0.53 mcg/mL, respectively, following administration as the fixed-combination extended-release capsules. When dipyridamole in fixed combination with aspirin was administered with a high-fat meal, dipyridamole peak plasma concentrations and total absorption (area under the concentration-time curve [AUC]) decreased at steady state by 20-30% compared with administration in the fasted state; this effect does not appear to be clinically important.

Animal studies indicate that dipyridamole is widely distributed into body tissues and that small amounts of the drug cross the placenta. Dipyridamole does not cross the blood-brain barrier in animals. Dipyridamole is distributed into human milk. The apparent volume of distribution of IV dipyridamole at steady state is 1-2.5 L/kg, with an apparent central volume of 3-5 liters. The drug is highly bound to plasma proteins, principally to α1-acid glycoprotein (α1-AGP) but also to albumin; 91-99% of the drug reportedly is bound to protein.

Following oral administration, plasma concentrations of dipyridamole decline in a biphasic manner. Half-life of the drug in the initial phase (t½α) is approximately 40-80 minutes and half-life in the terminal elimination phase (t½β) is approximately 10-12 hours.

Following IV administration, plasma concentrations of dipyridamole decline in a triphasic manner, with mean half-lives of 3-12 minutes, 33-62 minutes, and 11.6-15 hours.

Dipyridamole is metabolized in the liver and excreted in the bile, chiefly as the monoglucuronide and a small amount as the diglucuronide. Dipyridamole and its glucuronides may undergo enterohepatic circulation and are excreted mainly in feces. Small amounts are excreted in urine. The mean total body clearance is 2.3-3.5 mL/minute per kg.

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