Dipyridamole is a non-nitrate coronary vasodilator that also inhibits platelet aggregation. When used alone, it is ineffective as an antithrombotic for patients with acute MI, DVT, or TIAs and therefore must be combined with other anticoagulant drugs, such as warfarin, to prevent thrombosis in patients with valvular or vascular disorders. In combination with other antiplatelet agents, routine use of dipyridamole is questionable, except perhaps in patients in whom foreign surfaces (i.e., artificial heart valves) may contribute to the thrombotic risk. Intravenously administered dipyridamole is used as an adjunct to thallous chloride TI 201 in myocardial perfusion imaging to assess coronary artery disease in individuals unable to perform an exercise stress test. Dipyridamole was originally approved in 1961 for use in the treatment of angina but has never been found effective for this condition. In 1986, dipyridamole was approved for use as an antiplatelet agent, but much controversy surrounds its place in treatment of this condition. The FDA has classified dipyridamole as lacking evidence of effectiveness for the treatment of chronic angina pectoris; an opinion supported by one review. Clinicians should note, however, that dipyridamole may still be useful for other indications; for example, a dosage form combining aspirin with dipyridamole is approved for stroke prophylaxis.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Dilution
-Dilute in at least a 1:2 ratio with 0.45% Sodium Chloride Injection, 0.9% Sodium Chloride Injection, or 5% Dextrose Injection for a total volume of 20 to 50 mL.
Intravenous infusion
-Do not mix with other drugs in the same syringe or infusion container.
-Infuse IV a maximum rate of 0.142 mg/kg/minute IV.
The adverse effects of dipyridamole therapy usually are dose-related and transient, and resolve with continued therapy.
The adverse effect profile of oral dipyridamole as combination therapy with warfarin has been studied in two heart valve replacement trials. More patients receiving dipyridamole tablets plus warfarin experienced dizziness (13.6% of patients receiving warfarin plus dipyridamole versus 8.2% of patients receiving warfarin only). Dizziness was also reported following the administration of the injectable formulation, at a rate of 11.8%. Headache is another CNS reaction reported with dipyridamole use, occurring more frequently in patients receiving the oral tablets with warfarin compared to warfarin alone (2.3% vs. 0%) and reported in 12.2% of patients receiving the injection. Other CNS adverse effects include paresthesias (post-marketing with the tablets; 1.3% with the injection), fatigue (post-marketing; 1.2%), hypoesthesia (0; 0.5%), nervousness/anxiety (0; 0.2%), drowsiness (0; 0.03%), migraine (0; 0.03%), depersonalization (0; 0.03%), and vertigo (0; 0.03%).
Serious adverse reactions associated with the administration of intravenous dipyridamole injection have included cardiac death, fatal and non-fatal myocardial infarction (0.1%), ventricular fibrillation, symptomatic ventricular tachycardia (0.2%), stroke, transient cerebral ischemia, and seizures. There have been reported cases of asystole, sinus node arrest, sinus node depression, and conduction block. None of these reactions have been reported with the oral tablets. The exacerbation of preexisting angina due to coronary steal is likely due to the vasodilatory effects of dipyridamole; chest pain (unspecified) and angina pectoris have been reported with the intravenous formulation (both at a rate of 19.7%) and the oral formulation (both reported rarely). ECG abnormalities were reported following intravenous administration and included ST-T changes (7.5%), extrasystoles (5.2%), sinus tachycardia (3.2%), and unspecified changes (0.8%). Intravenous administration has also been reported to induce dyspnea (2.6%), blood pressure lability (1.6%), hypertension (1.5%), arrhythmia exacerbation (0.6%), bradycardia (0.2%), AV block (0.1%), syncope (0.1%), orthostatic hypotension (0.1%), atrial fibrillation (0.1%), supraventricular tachycardia (SVT) (0.1%), ventricular arrhythmia (0.03%), heart block (0.03%), cardiomyopathy (0.03%), and edema (0.03%). Adverse events reported with both intravenous and oral tablet use include hypotension (4.6% with the intravenous formulation; post-marketing with the tablets), flushing (3.4%; reported, but rate not given), and palpitations (0.3%; post-marketing).
In rare cases increased bleeding during or after surgery has been observed in patients who received dipyridamole tablets concomitantly with warfarin. However, while dipyridamole decreases platelet aggregation, during normal use the instance of bleeding is no greater in frequency or severity than that observed when warfarin was administered alone. Bleeding has not been reported with intravenous administration. There have been post-marketing reports of thrombocytopenia in patients taking the tablets.
During clinical trials with dipyridamole oral tablets, there were rare reports of liver dysfunction and elevated hepatic enzymes; hepatitis and cholelithiasis were reported during post-marketing surveillance.
Following the intravenous administration of dipyridamole, there have been reports of earache (0.1%), tinnitus (0.1%), unspecified visual impairment or abnormality (0.1%), and ocular pain (0.03%).
Adverse gastrointestinal effects reported with both the tablet and intravenous formulations of dipyridamole (respectively) include abdominal pain or distress (6.1%; 0.7%), nausea (post-marketing; 4.6%), vomiting (reported with high tablet doses, no rate given; 0.4%), and dyspepsia (post-marketing; 1%). Diarrhea was reported with the use of the oral tablets, though no incidence rate was given. In patients who received the intravenous injection, xerostomia (0.8%), flatulence (0.6%), eructation (0.1%), dysphagia (0.03%), tenesmus (0.03%), dysgeusia (0.1%), thirst (0.03%), and appetite stimulation (0.03%) were reported.
Adverse respiratory reactions have been reported with the use of the injectable formulation of dipyridamole, including pharyngitis (0.3%), hyperventilation (0.1%), rhinitis (0.1%), cough (0.03%), and pleural pain (0.03%). No respiratory reactions were reported with the use of the tablets.
Serious adverse reactions associated with the administration of dipyridamole, including anaphylactoid reactions, hypersensitivity reactions, severe bronchospasm (0.2% with the injection; rate not reported with the tablets), angioedema, and laryngeal edema. Rash (unspecified) (rate not reported with the injection; 2.3% with the tablets), urticaria, pruritus, dermatitis, and alopecia have also been reported. With intravenous administration, there is a risk of an injection site reaction (0.4%), injection site pain (0.1%), and diaphoresis (0.4%).
Musculoskeletal adverse effects and pain at different sites has been reported with dipyridamole use. These adverse effects include arthralgia (0.3% with the injection, post-marketing with the tablets), asthenia (0.3%; 0), dysphonia (0.03%; 0), hypertonia (0.3%; 0), intermittent claudication (0.03%; 0), malaise (0.3%; post-marketing), myalgia (0.9%; post-marketing), tremor (0.1%; 0), rigor (0.1%; 0), abnormal coordination (0.03%; 0), and leg muscle cramps (0.03%; 0). Pain was not reported with the use of the oral tablets, but was reported with the injection including unspecified pain (2.6%), back pain (0.6%), renal pain (0.03%), perineal pain (0.03%), and breast pain (0.03%).
Dipyridamole should not be used in patients with hypotension because the drug could exacerbate this condition, especially when administered parenterally or in excessive doses. Use dipyridamole with caution in patients at risk for syncope, since the drug may induce orthostatic hypotension in some patients.
Dipyridamole is not effective in relieving unstable angina pectoris and should not be substituted for appropriate anti-anginal therapy. In addition, it is believed that administration of the drug can increase the incidence of myocardial ischemia in these patients secondary to causing 'coronary steal,' resulting in additional cardiovascular complications such as hypotension, cardiac arrest, or cardiac arrhythmias.
Caution should be used when administering intravenous dipyridamole to patients with asthma. Intravenous dipyridamole, used for diagnostic purposes, may increase the risk of bronchospasm.
Use dipyridamole during pregnancy only if clearly needed. There are no adequate and well-controlled studies of dipyridamole use in pregnant women. No harm to the fetus was observed in animal reproduction studies with mice, rabbits, and rats receiving 1.5 to 25 times the maximum recommended daily oral dose in humans.
Dipyridamole is excreted in human milk; administer with caution to a breast-feeding woman. The effect of this exposure on a nursing infant is not known.
Elevations of hepatic enzymes and hepatic failure have been reported in association with dipyridamole. In patients with mild to severe hepatic insufficiency, no change in plasma concentrations of dipyridamole occurred. Dipyridamole pharmacokinetics have not been studied in patients with severe hepatic disease; initiate dosage with caution since dipyridamole is primarily eliminated hepatically.
Geriatric adults may be more susceptible to orthostatic hypotension from oral use of dipyridamole. The Beers Criteria consider the short-acting oral form of dipyridamole a potentially inappropriate medication in geriatric adults and should be avoided due to the possibility of orthostatic hypotension and the availability of more effective alternatives. Intravenous dipyridamole is acceptable for use in cardiac stress testing.
The safe and effective use of dipyridamole in children less than 12 years of age has not been established.
For arterial thromboembolism prophylaxis:
-in patients with prosthetic heart valves:
Oral dosage:
Adults and Adolescents: 75 to 100 mg PO 4 times daily as an adjunct to the usual warfarin therapy.
-in patients with valvular heart disease* (i.e., mitral valve disease):
Oral dosage:
Adults: 225 to 400 mg/day PO in combination with warfarin.
-in recipients of a coronary artery bypass graft*:
Oral dosage:
Adults: 100 mg PO 4 times daily for 2 days before surgery; 100 mg PO 1 hour after surgery; then 75 mg in combination with aspirin 7 hours after surgery; then 75 mg PO 3 times daily. Dipyridamole may be discontinued 1 week after surgery.
For secondary prophylaxis of transient ischemic attack (TIA)* in combination with aspirin:
Oral dosage:
Adults: Dosages of 225-400 mg/day PO alone or in combination with aspirin have been studied. Use of dipyridamole as a single agent is not warranted for prevention of TIAs or ischemic stroke. In combination with aspirin, dipyridamole has been equally effective in women and men but diabetic patients appear to respond less dramatically to this combination than non-diabetic patients. It is not clear, however, if dipyridamole offers additional benefit over aspirin alone.
For use in coronary artery disease diagnosis (i.e., dipyridamole stress echocardiography) as an adjunct to thallium myocardial perfusion imaging:
Intravenous dosage:
Adults: 0.57 mg/kg/dose IV over 4 minutes. Max: 60 mg. Doses up to 0.84 mg/kg/dose given over 6 to 10 minutes can be safely given.
For the treatment of dilated cardiomyopathy*:
Oral dosage:
Adults: Dosage not established. 75 mg PO once daily, 300 mg PO once daily, or 75 mg PO 3 times daily has been used.
For the treatment of proteinuria* associated with membranous glomerulonephritis:
Oral dosage:
Adults: In a small trial, patients with membranous glomerulonephritis were evaluated during three 30-day study periods, each 45 days apart. Patients received either no treatment, dipyridamole 300 mg/day PO, or the combination of dipyridamole 225 mg/day PO with aspirin. Treatment with dipyridamole alone or in combination reduced 24-hour protein excretion by 54% and 56%, respectively.
Children*: In an uncontrolled study, dipyridamole 4-10 mg/kg/day PO resulted in a significant decrease in urine protein excretion in 53% (32/60) of children with various renal diseases. Effects on protein excretion were observed within a few months of treatment.
For myocardial infarction prophylaxis* in patients who have sustained a prior myocardial infarction (MI):
Oral dosage:
Adults: Dosages of 225 mg/day PO plus aspirin or 400 mg/day PO have been studied. A beneficial antiplatelet effect of dipyridamole in patients who have sustained a MI is questionable. The American College of Chest Physicians (ACCP) does not recommend dipyridamole (alone or with aspirin) for post-MI patients. A dose of 75 mg PO three times daily has been used in combination with aspirin in the PARIS I and II studies. In the PARIS I study, neither aspirin or the combination of aspirin-dipyridamole was found to be superior to placebo. In the PARIS II study, a significant reduction in coronary events was seen relative to the placebo group, however, it could not be determined if dipyridamole offered any improvement over aspirin alone. In the only study of dipyridamole as a single agent (100 mg PO four times daily), no benefit was seen on thrombotic complications or death when used for secondary prophylaxis of myocardial infarction.
Children: Safety and efficacy have not been established.
Maximum Dosage Limits:
-Adults
400 mg/day PO.
-Elderly
400 mg/day PO.
-Adolescents
400 mg/day PO.
-Children
Specific maximum dosage information is not available.
Patients with Hepatic Impairment Dosing
It appears no dosage adjustment of dipyridamole is needed in patients with mild to moderate hepatic insufficiency. Dipyridamole is primarily eliminated via hepatic metabolism. Dipyridamole has not been studied in patients with severe hepatic impairment; initiate dosage with caution.
Patients with Renal Impairment Dosing
No dosage adjustment needed.
*non-FDA-approved indication
Abciximab: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
Abrocitinib: (Contraindicated) Concurrent use with dipyridamole is contraindicated during the first 3 months of abrocitinib therapy due to an increased risk of bleeding with thrombocytopenia.
Acebutolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Acetaminophen; Aspirin, ASA; Caffeine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy. (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Acetaminophen; Aspirin, ASA; Caffeine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy. (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Acetaminophen; Aspirin: (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Acetaminophen; Caffeine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy.
Acetaminophen; Caffeine; Pyrilamine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy.
Acetaminophen; Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Adenosine: (Major) The vasoactive effects of adenosine are potentiated by dipyridamole; smaller doses of adenosine may be effective if used concurrently with dipyridamole. When used for supraventricular tachyarrhythmias in adults, reduce the initial adenosine dose to 3 mg. When possible, withhold dipyridamole for at least 5 half-lives before adenosine use for diagnostic imaging.
Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of platelet inhibitors with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
ADP receptor antagonists: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
Alteplase: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Aminolevulinic Acid: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Amlodipine; Celecoxib: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Anagrelide: (Moderate) Because anagrelide and dipyridamole inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
Antithrombin III: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
Antithymocyte Globulin: (Moderate) An increased risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia, such as antithymocyte globulin. Platelet inhibitors should be used cautiously in patients with thrombocytopenia following the administration of antithymocyte globulin or other drugs that cause significant thrombocytopenia due to the increased risk of bleeding.
Apixaban: (Major) The concomitant use of apixaban and platelet inhibitors (e.g, aspirin) may increase the risk of bleeding. In the ARISTOTLE trial (comparative trial of apixaban and warfarin in patients with nonvalvular atrial fibrillation), concomitant use of aspirin increased the bleeding risk of apixaban from 1.8%/year to 3.4%/year. If given concomitantly, patients should be educated about the signs and symptoms of bleeding and be instructed to report them immediately or go to an emergency room.
Argatroban: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., clopidogrel, platelet glycoprotein IIb/IIIa inhibitors, ticlopidine, etc.) in combination with argatroban.
Arsenic Trioxide: (Moderate) Concurrent use of dipyridamole and antineoplastic agents may lead to an increased risk of bleeding.
Aspirin, ASA: (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Butalbital; Caffeine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy. (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Caffeine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy. (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Caffeine; Orphenadrine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy. (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Dipyridamole: (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Omeprazole: (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Aspirin, ASA; Oxycodone: (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Atenolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Atenolol; Chlorthalidone: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Beta-blockers: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Betaxolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Betrixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and platelet inhibitors are used concomitantly. Coadministration of betrixaban and platelet inhibitors may increase the risk of bleeding.
Bexarotene: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including bexarotene.
Bisoprolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Bivalirudin: (Moderate) When used as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), bivalirudin is intended for use with aspirin (300 to 325 mg/day PO) and has been studied only in patients receiving concomitant aspirin. Generally, an additive risk of bleeding may be seen in patients receiving other platelet inhibitors (other than aspirin). In clinical trials in patients undergoing PTCA, patients receiving bivalirudin with heparin, warfarin, or thrombolytics had increased risks of major bleeding events compared to those receiving bivalirudin alone. According to the manufacturer, the safety and effectiveness of bivalirudin have not been established when used in conjunction with platelet inhibitors other than aspirin. However, bivalirudin has been safely used as an alternative to heparin in combination with provisional use of platelet glycoprotein IIb/IIIa inhibitors during angioplasty (REPLACE-2). In addition, two major clinical trials have evaluated the use of bivalirudin in patients receiving streptokinase following acute myocardial infarction (HERO-1, HERO-2). Based on the these trials, bivalirudin may be considered an alternative to heparin therapy for use in combination with streptokinase for ST-elevation MI. Bivalirudin has not been sufficiently studied in combination with other more specific thrombolytics.
Brimonidine; Timolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Bupivacaine; Meloxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Butalbital; Acetaminophen; Caffeine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy. (Moderate) Although aspirin may be used in combination with dipyridamole, both drugs are associated with bleeding. Monitor for bleeding during concomitant therapy.
Caffeine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that caffeine be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with the chronic dipyridamole therapy. (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy.
Caffeine; Sodium Benzoate: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy.
Caplacizumab: (Major) Avoid concomitant use of caplacizumab and platelet inhibitors when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Carteolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Carvedilol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Celecoxib: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Celecoxib; Tramadol: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Chlorambucil: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Cilostazol: (Moderate) Because cilostazol and dipyridamole inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
Citalopram: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Cladribine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Clofarabine: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Clopidogrel: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking platelet inhibitors is advised. The efficacy and safety of administering injectable collagenase to a patient taking a platelet inhibitor within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
Dabigatran: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
Dalteparin: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
Danazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
Dasatinib: (Moderate) Due to the thrombocytopenic and possible platelet inhibiting effects of dasatinib, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Defibrotide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like platelet inhibitors is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue antithrombotic agents prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Deoxycholic Acid: (Moderate) Use deoxycholic acid with caution in patients receiving platelet inhibitors. Excessive bruising or bleeding may occur in and around the treatment area.
Desvenlafaxine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Diclofenac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Diclofenac; Misoprostol: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Diflunisal: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Diphenhydramine; Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Diphenhydramine; Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Dorzolamide; Timolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Duloxetine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Edoxaban: (Major) Coadministration of edoxaban and platelet inhibitors should be avoided due to an increased risk of bleeding during concurrent use. Occasionally, short-term coadministration may be necessary in patients transitioning to and from edoxaban. Long-term coadminstration is not recommended. Promptly evaluate any signs or symptoms of blood loss in patients on concomitant therapy.
Enoxaparin: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
Eptifibatide: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
Ergotamine; Caffeine: (Major) Methylxanthines, through antagonism of adenosine and thus pharmacologic-induced coronary vasodilation, have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with chronic dipyridamole therapy.
Escitalopram: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Esmolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Etodolac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Fenoprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
Fludarabine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Fluoxetine: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Flurbiprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Fluvoxamine: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Fondaparinux: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
Garlic, Allium sativum: (Moderate) Use together with caution. Garlic produces clinically significant antiplatelet effects, and a risk for bleeding may occur if platelet inhibitors are given in combination with garlic.
Ginger, Zingiber officinale: (Moderate) Ginger inhibits thromboxane synthetase, a platelet aggregation inducer, and is a prostacyclin agonist so additive bleeding may occur if platelet inhibitors are given in combination with ginger, zingiber officinale.
Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and platelet inhibitors as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
Green Tea: (Major) Some green tea products contain caffeine. Methylxanthines have been associated with false-negative results during dipyridamole-thallium 201 stress testing. It is recommended that methylxanthines (caffeine, caffeinated beverages and foods, theophylline, etc.) be discontinued for at least 24 hours prior to stress testing. An interaction is not expected when methylxanthines are used concomitantly with the chronic dipyridamole therapy. However, because dipyridamole is a platelet inhibitor and green tea has demonstrated antiplatelet effects in animals, it may be prudent to avoid the concomitant use of green tea with chronic dipyridamole therapy as the risk of bleeding may be increased.
Heparin: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
Hydrocodone; Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with platelet function such as platelet inhibitors; the risk of bleeding may be increased. If coadministration with platelet inhibitors is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
Ibrutinib: (Moderate) The concomitant use of ibrutinib and antiplatelet agents such as dipyridamole may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Ibuprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Ibuprofen; Famotidine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Ibuprofen; Oxycodone: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Ibuprofen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
Iloprost: (Moderate) When used concurrently with platelet inhibitors, inhaled iloprost may increase the risk of bleeding.
Indomethacin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Inotersen: (Moderate) Use caution with concomitant use of inotersen and dipyridamole due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of dipyridamole in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Intravenous Lipid Emulsions: (Moderate) Because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with other platelet inhibitors. Theoretically, the risk of bleeding may be increased.
Ketoprofen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Ketorolac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Labetalol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Levobunolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Levomilnacipran: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of levomilnacipran and platelet inhibitors. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
Lomustine, CCNU: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as lomustine.
Meclofenamate Sodium: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Mefenamic Acid: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Meloxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Mercaptopurine, 6-MP: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Methoxsalen: (Minor) Agents that affect platelet function, such as platelet inhibitors, could decrease the efficacy of methoxsalen when used during photodynamic therapy.
Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs including increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants or antiplatelets including clopidogrel until data confirming the safety of these drug combinations are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving clopidogrel should be observed for increased bleeding.
Metoprolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Metoprolol; Hydrochlorothiazide, HCTZ: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Milnacipran: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of milnacipran and platelet inhibitors. Serotonin-norepinephrine reuptake inhibitors (SNRIs) affect platelet activation; therefore, concomitant use may increase the risk of bleeding.
Mycophenolate: (Moderate) Platelet Inhibitors inhibit platelet aggregation and should be used cautiously in patients with thrombocytopenia, as mycophenolate can also cause thrombocytopenia.
Nabumetone: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Nadolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Naproxen; Esomeprazole: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Naproxen; Pseudoephedrine: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Nebivolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Nebivolol; Valsartan: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Nonsteroidal antiinflammatory drugs: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
Olanzapine; Fluoxetine: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Oxaprozin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Paroxetine: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Pentosan: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
Pentostatin: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Pentoxifylline: (Moderate) A potential additive risk for bleeding exists if platelet inhibitors are given in combination with other agents that affect hemostasis such as pentoxifylline.
Photosensitizing agents (topical): (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Pindolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Piroxicam: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Platelet Glycoprotein IIb/IIIa Inhibitors: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Prasterone is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
Prasugrel: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
Propranolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Purine analogs: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Regadenoson: (Major) Dipyridamole may change the effects of regadenoson. Although the effects are not specified, this may be due to dipyridamole's coronary vasodilatory action. When possible, withhold dipyridamole for at least two days prior to the administration of regadenoson.
Reteplase, r-PA: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Riociguat: (Contraindicated) Coadministration of riociguat and phosphodiesterase inhibitors, including nonspecific phosphodiesterase inhibitors like dipyridamole ,is contraindicated due to the risk of hypotension. A high rate of discontinuation for hypotension has been reported when riociguat was combined with specific phosphodiesterase-5 inhibitors, for example.
Rivaroxaban: (Major) Avoid concurrent administration of platelet inhibitors such as dipyridamole with rivaroxaban unless the benefit outweighs the risk of increased bleeding. An increase in bleeding time to 45 minutes was observed in 2 drug interaction studies where another platelet inhibitor and rivaroxaban (15 mg single dose) were coadministered in healthy subjects. In the first study, the increase in bleeding time to 45 minutes was observed in approximately 45% of patients. Approximately 30% of patients in the second study had the event. The change in bleeding time was approximately twice the maximum increase seen with either drug alone. No change in the pharmacokinetic parameters of either drug were noted.
Selective serotonin reuptake inhibitors: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Selumetinib: (Moderate) Closely monitor for bleeding if coadministration of selumetinib and platelet inhibitors is necessary as concurrent use may increase the bleeding risk; adjust the platelet inhibitor dose as appropriate. Selumetinib contains vitamin E which can inhibit platelet aggregation.
Sertraline: (Moderate) Platelet aggregation may be impaired by SSRIs due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving platelet inhibitors. Monitor for signs and symptoms of bleeding.
Sotalol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Sulindac: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Sumatriptan; Naproxen: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Tenecteplase: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Theophylline, Aminophylline: (Major) Aminophylline may cause false-negative results during dipyridamole-thallium 201 stress testing. Discontinue aminophylline for at least 24 hours prior to this type of stress testing. Maintenance aminophylline therapy and other xanthine derivatives may abolish the coronary vasodilatation induced by dipyridamole administration via antagonism of adenosine. No interaction of concern is expected when aminophylline is used concomitantly with the chronic dipyridamole therapy. (Major) Theophylline may cause false-negative results during dipyridamole-thallium 201 stress testing. Discontinue theophylline for at least 24 hours prior to this type of stress testing. Maintenance theophylline therapy and other xanthine derivatives may abolish the coronary vasodilatation induced by dipyridamole administration via antagonism of adenosine. No interaction of concern is expected when theophylline is used concomitantly with the chronic dipyridamole therapy.
Thioguanine, 6-TG: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
Thrombolytic Agents: (Major) Concomitant administration of platelet inhibitors and thrombolytic agents could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution.
Ticagrelor: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
Timolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
Tipranavir: (Moderate) Caution should be used when administering tipranavir to patients receiving platelet inhibitors. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including platelet inhibitors, that may have caused or contributed to these events.
Tirofiban: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis such as platelet glycoprotein IIb/IIIa inhibitors including abciximab, eptifibatide, and tirofiban.
Tolmetin: (Moderate) Monitor for signs and symptoms of bleeding during concomitant platelet inhibitor and chronic nonsteroidal antiinflammatory drug (NSAID) use. Concomitant use increases the risk of bleeding.
Trazodone: (Moderate) Platelet aggregation may be impaired by trazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Treprostinil: (Moderate) Monitor patients for signs and symptoms of bleeding if treprostinil is administered with dipyridamole. Treprostinil inhibits platelet aggregation; dipyridamole is a platelet inhibitor. Coadministration increases the risk of bleeding.
Venlafaxine: (Moderate) Platelet aggregation may be impaired by serotonin norepinephrine reuptake inhibitors (SNRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with a platelet inhibitor and to promptly report any bleeding events to the practitioner.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with platelet inhibitors is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease platelet aggregation could decrease the efficacy of verteporfin therapy.
Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with salicylates or other platelet inhibitors and to promptly report any bleeding events to the practitioner. Platelet aggregation may be impaired by vilazodone due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., aspirin, cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors).
Vorapaxar: (Moderate) Because vorapaxar and dipyridamole inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
Vorinostat: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of dipyridamole and vorinostat. Due to the thrombocytopenic effects of vorinostat, an additive risk of bleeding may occur in patients taking platelet inhibitors.
Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving platelet inhibitors (e.g., cilostazol, clopidogrel, dipyridamole, ticlopidine, platelet glycoprotein IIb/IIIa inhibitors). Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
Warfarin: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis. Per the manufacturer, dipyridamole does not influence prothrombin time or activity when administered with warfarin; bleeding frequency and severity are similar when dipyridamole is administered with or without warfarin. In rare cases, however, increased bleeding has been observed during or after surgery. Regardless, caution is advised as both anticoagulants including warfarin and platelet inhibitors such as dipyridamole affect hemostasis and combination therapy could increase the risk of bleeding.
Dipyridamole increases coronary blood flow by selectively dilating the small resistance vessels that supply the heart. This coronary vasodilatory action involves an accumulation of the endogenous compound adenosine, a potent coronary vasodilator and inhibitor of platelet aggregation. Adenosine induces vasodilation directly by stimulating adenosine receptors on the smooth muscle membrane and/or indirectly by increasing the synthesis of cyclic adenosine monophosphate (cAMP), an inhibitor of platelet function. Adenosine also interferes with enzymatic degradation of cAMP by phosphodiesterase. Dipyridamole presumably inhibits adenosine deaminase as well as phosphodiesterase, allowing levels of cAMP to remain increased. Coronary blood vessels in the ischemic area are not affected by dipyridamole, presumably because they are already fully dilated.
Dipyridamole's mechanism of action for inhibiting platelet aggregation has yet to be clearly established, although it is postulated that the same mechanisms that explain its vasodilatory properties may be involved. Dipyridamole-induced elevations in cAMP concentrations block the release of arachidonic acid from membrane phospholipids and reduce thromboxane A2 activity. In addition, dipyridamole directly stimulates the release of prostacyclin, which induces adenylate cyclase activity, thereby raising the intraplatelet concentration of cAMP and further inhibiting platelet aggregation.
Dipyridamole, in conjunction with warfarin therapy, has been shown to prolong the survival of platelets in patients with valvular heart disease and to maintain platelet count in patients undergoing open-heart surgery. Dipyridamole alone will not inhibit platelet aggregation, and the drug should not be used in these patients unless an oral anticoagulant agent is administered concurrently. Dipyridamole does not decrease cardiac work, and myocardial oxygen consumption is unchanged.
Intravenous dipyridamole appears to moderately decrease blood pressure and increase heart rate and cardiac output in response to the vasodilatory action of the drug. Oral administration does not produce these hemodynamic effects, perhaps due to its poor oral bioavailability.
Dipyridamole is administered orally and intravenously. Dipyridamole distributes widely throughout the body tissues, crosses the placenta, and is secreted into breast milk. Dipyridamole is highly protein-bound, averaging 91-99%, mainly to albumin but also to alpha-1-acid glycoprotein. Dipyridamole undergoes hepatic metabolism, primarily glucuronidation, and these glucuronide conjugates are eliminated mainly in the feces, although enterohepatic circulation can occur. A small amount of dipyridamole and its conjugates may be excreted in the urine. The plasma half-life of the drug appears to be biphasic and variable, with an alpha half-life of approximately 1 hour and a terminal or beta half-life of 12 hours.
-Route-Specific Pharmacokinetics
Oral Route
Absorption of dipyridamole following an oral dose is slow, variable, and unpredictable. Bioavailability has been reported to range from 37-66%. Peak plasma concentrations of the drug occur approximately 1-3 hours after oral administration.
-Special Populations
Hepatic Impairment
In patients with mild to severe hepatic insufficiency, no change in plasma concentrations of dipyridamole occurred.
Renal Impairment
After the data from the ESPS2 study was corrected for age, renal impairment (i.e., defined as creatinine clearance (CrCl) ranging from approximately 15 mL/min to greater than 100 mL/min) had no affect on the pharmacokinetics of dipyridamole or its glucuronide metabolite. Dipyridamole is unlikely to be significantly removed by hemodialysis due to its high protein binding.
Geriatric
The AUC of dipyridamole in healthy elderly subjects (> 65 years) was about 40% higher than in subjects younger than 55 years receiving treatment with dipyridamole and aspirin in the ESPS2 study.