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  • CLASSES

    Platelet Camp Enhancing Platelet Aggregation Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    A non-nitrate coronary vasodilator that inhibits platelet aggregation; must be combined with other anticoagulants to prevent thrombosis; useful when combined with ASA for stroke prophylaxis; intravenous dipyridamole is an adjunct to myocardial perfusion imaging in patients unable to perform an exercise stress test.

    COMMON BRAND NAMES

    Persantine

    HOW SUPPLIED

    Dipyridamole Intravenous Inj Sol: 1mL, 5mg
    Dipyridamole/Persantine Oral Tab: 25mg, 50mg, 75mg

    DOSAGE & INDICATIONS

    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 use in coronary artery disease diagnosis (i.e., dipyridamole-stress echocardiography).
    Intravenous dosage
    Adults

    0.57 mg/kg IV administered at a rate of 0.142 mg/kg/minute for 4 minutes. Maximum dose is 60 mg. The radiopharmaceutical is injected within 3—4 minutes after the dipyridamole infusion. In 88 patients with hypertrophic myocardiopathy, a dose of up to 0.84 mg/kg IV over 10 minutes was employed. Testing was completed in all patients with no limiting side effects or adverse reactions. Based on transient regional dyssynergy, the dipyridamole-echocardiography test showed 71% sensitivity, 100% specificity, 100% positive predictive value, and 93% diagnostic accuracy.

    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 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    400 mg/day PO.

    Elderly

    400 mg/day PO.

    Adolescents

    400 mg/day PO.

    Children

    Specific maximum dosage information is not available.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    No dosage adjustment needed.

    ADMINISTRATION

    Injectable Administration
    Intravenous Administration

    Diagnostic aid adjunct: Dilute dose in sufficient amount of 0.45% Sodium Chloride, 0.9% Sodium Chloride (NS), or 5% Dextrose injection to give a total volume of 20—50 ml. Infuse at a rate of 0.142 mg/kg/min for 4 minutes (0.57 mg/kg total).
    Platelet aggregation inhibitor: NOTE: Dipyridamole is not approved by the FDA to be used as a platelet aggregation inhibitor. Add 250 mg to 250 mL of 5% Dextrose injection to give an IV solution containing 1 mg/mL. Infuse IV at a rate of 10 mg/hour.

    STORAGE

    Generic:
    - Protect from freezing
    - Protect from light
    - Store between 59 to 77 degrees F
    - Store in carton until time of use
    Persantine:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Hypotension, orthostatic hypotension, syncope

    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.

    Angina

    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.

    Asthma

    Caution should be used when administering intravenous dipyridamole to patients with asthma. Intravenous dipyridamole, used for diagnostic purposes, may increase the risk of bronchospasm.

    Labor, obstetric delivery, pregnancy

    Dipyridamole is classified as FDA pregnancy risk category B. Reproduction studies have been performed in animals receiving doses of 2—25 times the maximum recommended daily oral dose in humans. No evidence of harm to the fetus due to dipyridamole was seen. However, there are no well-controlled or adequate clinical studies in pregnant women. Administer to pregnant women only if clearly needed. Because dipyridamole decreases platelet aggregation, there may be an increased risk of bleeding during labor and obstetric delivery.

    Breast-feeding

    According to the manufacturer, dipyridamole is excreted in human milk and should be administered with caution to a nursing woman. The effect of this exposure on a nursing infant is not known. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Hepatic disease

    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

    In the ESPS2 study, the AUC (exposure) of dipyridamole in healthy geriatric adults over 65 years of age was about 40% higher than in subjects younger than 55 years of age receiving treatment with a combined oral product of aspirin with dipyridamole. However, no change in dipyridamole dosage is specifically suggested in older adults. Geriatric patients may be more susceptible to orthostatic hypotension from oral use of dipyridamole. According to the Beers Criteria, the short-acting oral form of dipyridamole is considered a potentially inappropriate medication (PIM) for use in geriatric patients and should be avoided in this population due to the possibility of orthostatic hypotension and the availability of more effective alternatives; however, the intravenous form is acceptable for use in cardiac stress testing. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to the OBRA guidelines, platelet inhibitors may cause thrombocytopenia and increase the risk of bleeding. Common side effects of platelet inhibitors include headache, dizziness, and vomiting. Concurrent use with warfarin or NSAIDs may increase the risk of bleeding.

    Children

    The safe and effective use of dipyridamole in children less than 12 years of age has not been established.

    ADVERSE REACTIONS

    Severe

    arrhythmia exacerbation / Early / 0.6-0.6
    bradycardia / Rapid / 0.2-0.2
    ventricular tachycardia / Early / 0.2-0.2
    bronchospasm / Rapid / 0.2-0.2
    AV block / Early / 0.1-0.1
    cardiomyopathy / Delayed / 0-0.1
    atrial fibrillation / Early / 0.1-0.1
    myocardial infarction / Delayed / 0.1-0.1
    visual impairment / Early / 0.1-0.1
    stroke / Early / Incidence not known
    seizures / Delayed / Incidence not known
    ventricular fibrillation / Early / Incidence not known
    asystole / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    laryngeal edema / Rapid / Incidence not known

    Moderate

    angina / Early / 19.7-19.7
    chest pain (unspecified) / Early / 19.7-19.7
    hypotension / Rapid / 4.6-4.6
    sinus tachycardia / Rapid / 3.2-3.2
    dyspnea / Early / 2.6-2.6
    hypertension / Early / 1.5-1.5
    palpitations / Early / 0.3-0.3
    migraine / Early / 0-0.1
    supraventricular tachycardia (SVT) / Early / 0.1-0.1
    orthostatic hypotension / Delayed / 0.1-0.1
    edema / Delayed / 0-0.1
    dysphagia / Delayed / 0-0.1
    dysphonia / Delayed / 0-0.1
    hypertonia / Delayed / 0-0.1
    bleeding / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    cholelithiasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known

    Mild

    dizziness / Early / 11.8-13.6
    headache / Early / 0-12.2
    abdominal pain / Early / 0.7-6.1
    nausea / Early / 4.6-4.6
    flushing / Rapid / 3.4-3.4
    rash / Early / 2.3-2.3
    paresthesias / Delayed / 1.3-1.3
    fatigue / Early / 1.2-1.2
    dyspepsia / Early / 1.0-1.0
    myalgia / Early / 0.9-0.9
    xerostomia / Early / 0.8-0.8
    flatulence / Early / 0.6-0.6
    back pain / Delayed / 0.6-0.6
    hypoesthesia / Delayed / 0.5-0.5
    vomiting / Early / 0.4-0.4
    injection site reaction / Rapid / 0.4-0.4
    diaphoresis / Early / 0.4-0.4
    pharyngitis / Delayed / 0.3-0.3
    malaise / Early / 0.3-0.3
    asthenia / Delayed / 0.3-0.3
    arthralgia / Delayed / 0.3-0.3
    anxiety / Delayed / 0.2-0.2
    drowsiness / Early / 0-0.1
    vertigo / Early / 0-0.1
    syncope / Early / 0.1-0.1
    ocular pain / Early / 0-0.1
    tinnitus / Delayed / 0.1-0.1
    dysgeusia / Early / 0.1-0.1
    appetite stimulation / Delayed / 0-0.1
    eructation / Early / 0.1-0.1
    tenesmus / Delayed / 0-0.1
    hyperventilation / Early / 0.1-0.1
    rhinitis / Early / 0.1-0.1
    cough / Delayed / 0-0.1
    muscle cramps / Delayed / 0-0.1
    tremor / Early / 0.1-0.1
    diarrhea / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    urticaria / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known

    DRUG INTERACTIONS

    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.
    Acebutolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
    Acetaminophen: (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; 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; 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.
    Acetaminophen; Butalbital; 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.
    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; Magnesium Salicylate; Phenyltoloxamine: (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; Phenyltoloxamine; Salicylamide: (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.
    Adenosine: (Major) Adenosine effects are potentiated by dipyridamole; consider reducing the dose of adenosine in patients taking dipyridamole. When adenosine is used in adult patients for supraventricular tachycardia, reduce the initial dose to 3 mg (50% dosage reduction). Dipyridamole inhibits the metabolism of adenosine and blocks its uptake by erythrocytes, thereby enhancing the actions of adenosine when administered concomitantly. Although adenosine's duration of action is short and therefore not likely to cause a considerable interaction, serious adverse events have been reported.
    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.
    Altretamine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors is used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as altretamine.
    Anagrelide: (Moderate) Because anagrelide and dipyridamole inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    Antimetabolites: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antimetabolites.
    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; Butalbital; 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.
    Aspirin, ASA; 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. (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: (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; 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.
    Aspirin, ASA; Pravastatin: (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.
    Bendroflumethiazide; Nadolol: (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.
    Bevacizumab: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    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.
    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; Ergotamine: (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.
    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.
    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.
    Chondroitin; Glucosamine: (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.
    Cilostazol: (Moderate) Because cilostazol and dipyridamole inhibit platelet aggregation, a potential additive risk for bleeding exists if they are coadminsitered.
    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.
    Cod Liver Oil: (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. (Moderate) Cod liver oil contains vitamin A and may increase the risk of bleeding if coadministered with platelet inhibitors.
    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.
    Danaparoid: (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: (Severe) 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.
    Denileukin Diftitox: (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 denileukin difitox.
    Desirudin: (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.
    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.
    Dorzolamide; Timolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any platelet inhibitors within 7 days. These patients are at increased risk of bleeding during drotrecogin alfa therapy.
    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.
    Esmolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
    Estramustine: (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 estramustine.
    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.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    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: (Major) Use Ginkgo biloba with caution in patients taking platelet inhibitors, as it can produce clinically-significant antiplatelet effects. A compound found in Ginkgo biloba, ginkgolide-B, may act as a selective antagonist of platelet activating factor (PAF). Although a review of Ginkgo biloba in 1992 stated that no known drug interactions exist, spontaneous hyphema has been reported in an elderly male who began taking Ginkgo while stabilized on daily aspirin. After ginkgo was stopped, no further bleeding was noted despite continuing the aspirin therapy. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic Ginkgo biloba ingestion.
    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.
    Guarana: (Major) Caffeine is an active component of guarana. 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, foods, and dietary supplements such as guarana, 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.
    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.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
    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.
    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.
    Imatinib: (Moderate) Due to the thrombocytopenic effects of antineoplastics an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    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.
    Labetalol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
    Lepirudin: (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 lepirudin.
    Levobetaxolol: (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) 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 closely monitored for signs and symptoms of bleeding when a platelet inhibitor is administered with an SNRI.
    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.
    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.
    Milnacipran: (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.
    Mycophenolate: (Moderate) Platelet Inhibitors inhibit platelet aggregation and should be used cautiously in patients with thrombocytopenia, as mycophenolate can also cause thrombocytopenia.
    Nadolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
    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) NSAIDs can cause GI bleeding, inhibit platelet aggregation, and prolong bleeding time. If NSAIDs are administered with platelet inhibitors, these pharmacodynamic effects may be increased. The manufacturer of clopidogrel advises that caution be used when used in combination with NSAIDs as an increase in occult GI blood loss occurred when clopidogrel was used concomitantly with naproxen
    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.
    Pegaspargase: (Moderate) Due to the risk of bleeding and coagulopathy during pegaspargase therapy, patients should receive other agents that may increase the risk of bleeding (e.g., anticoagulants, NSAIDs, platelet inhibitors, or thrombolytic agents) with caution.
    Penbutolol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
    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.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Photosensitizing agents: (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.
    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.
    Porfimer: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    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.
    Riociguat: (Severe) 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.
    Sodium Hyaluronate, Hyaluronic Acid: (Moderate) Increased bruising or bleeding at the injection site may occur when using hyaluronate sodium with platelet inhibitors especially if used within the 3 weeks prior to the procedure.
    Sotalol: (Major) Beta-blockers should generally be withheld before dipyridamole-stress testing. Monitor the heart rate carefully following the dipyridamole injection.
    Sulfinpyrazone: (Major) Sulfinpyrazone, when used as a uricosuric agent should be avoided when possible with concurrent platelet inhibitors due to potential for additive antiplatelet effects and increased bleeding risk.
    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.
    Ticlopidine: (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.
    Tinzaparin: (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.
    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.
    Topiramate: (Moderate) Concurrent use of topiramate and drugs that affect platelet function such as aspirin, ASA and other salicylates or platelet inhibitors may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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.
    Tretinoin, ATRA: (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 tretinoin.
    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: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic 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: (Major) Due to the thrombocytopenic effects of vorinostat, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors. Also, torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include vorinostat.
    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.

    PREGNANCY AND LACTATION

    Pregnancy

    Dipyridamole is classified as FDA pregnancy risk category B. Reproduction studies have been performed in animals receiving doses of 2—25 times the maximum recommended daily oral dose in humans. No evidence of harm to the fetus due to dipyridamole was seen. However, there are no well-controlled or adequate clinical studies in pregnant women. Administer to pregnant women only if clearly needed. Because dipyridamole decreases platelet aggregation, there may be an increased risk of bleeding during labor and obstetric delivery.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    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.