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    ADP (adenosine Diphosphate) Receptor Antagonist Platelet Aggregation Inhibitors

    BOXED WARNING

    Aspirin coadministration

    Ticagrelor is indicated for use with aspirin at doses of 75 to 100 mg per day. Avoid higher aspirin maintenance doses, as ticagrelor efficacy is decreased when aspirin coadministration exceeds 100 mg per day.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral platelet P2Y12 ADP receptor antagonist
    Used to reduce thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) and patients with coronary artery disease without history of stroke or myocardial infarction; to reduce the risk of stroke in patients with acute ischemic stroke (NIH stroke scale score 5 or lower) or transient ischemic attack
    Boxed warning for bleeding and to not use with maintenance doses of aspirin greater than 100 mg/day

    COMMON BRAND NAMES

    BRILINTA

    HOW SUPPLIED

    BRILINTA Oral Tab: 60mg, 90mg

    DOSAGE & INDICATIONS

    For arterial thromboembolism prophylaxis in patients with acute coronary syndrome (ACS) (unstable angina, acute myocardial infarction), including in patients undergoing percutaneous coronary intervention (PCI).
    Oral dosage
    Adults

    180 mg PO loading dose plus aspirin (usually 325 mg PO) then, beginning 12 hours after loading dose, 90 mg PO twice daily plus aspirin 75 to 100 mg (i.e., 81 mg) PO once daily for 1 year. After 1 year, 60 mg PO twice daily and continue aspirin maintenance dose. Avoid maintenance doses of aspirin above 100 mg/day due to reduced efficacy of ticagrelor.

    For the reduction in risk of first myocardial infarction (myocardial infarction prophylaxis) or stroke in patients with coronary artery disease (CAD) at high risk for these events..
    Oral dosage
    Adults

    60 mg PO twice daily plus aspirin 75 mg to 100 mg PO once daily. Avoid maintenance doses of aspirin above 100 mg/day due to reduced efficacy of ticagrelor.

    For stroke prophylaxis in patients with acute ischemic stroke (NIH stroke scale score 5 or less) or high risk transient ischemic attack (TIA).
    Oral dosage
    Adults

    180 mg PO loading dose plus aspirin (300 mg to 325 mg PO) then 90 mg PO twice daily plus aspirin 75 to 100 mg (i.e., 81 mg) PO once daily for up to 30 days. Avoid maintenance doses of aspirin above 100 mg/day due to reduced efficacy of ticagrelor.

    MAXIMUM DOSAGE

    Adults

    180 mg/day PO after an initial 180 mg load for acute coronary syndrome; 120 mg/day PO for coronary artery disease.

    Geriatric

    180 mg/day PO after an initial 180 mg load for acute coronary syndrome; 120 mg/day PO for coronary artery disease.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild hepatic impairment: No dose adjustment needed.
    Moderate hepatic impairment: Use with caution; carefully weigh the risks versus the benefits of treatment, considering the probable increase in exposure to ticagrelor.
    Severe hepatic impairment: Use is contraindicated.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    May be administered with or without food.
    If a patient misses a dose, they should take their next dose at its scheduled time.
    For patients unable to swallow whole tablets, crush the tablets, mix with water and drink immediately. Refill the glass with water, stir, and drink contents immediately. Alternatively, the mixture may be administered via nasogastric tube (CH8 or greater). The nasogastric tube must be flushed with water after administration of the mixture.

    STORAGE

    BRILINTA:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Ticagrelor is contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product. Hypersensitivity reactions including angioedema have been reported.

    Bleeding, coronary artery bypass graft surgery (CABG), GI bleeding, intracranial bleeding, stroke, surgery

    Ticagrelor is contraindicated in any patient with active pathological bleeding including peptic ulcer (GI bleeding) or intracranial bleeding. Patients with acute ischemic stroke or transient ischemic attacks (TIAs) and an NIH stroke scale score greater than 5, as well as, patients receiving thrombolysis were excluded from the THALES study; thus, ticagrelor is not recommended in these patients. Like other antiplatelet agents, ticagrelor can cause significant, sometimes fatal, bleeding. The risk of bleeding may be increased in older patients, patients with a history of bleeding disorders, performance of percutaneous invasive procedures, and concomitant use of medications that increase the risk of bleeding (e.g., anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs [NSAIDS]). In order to decrease the risk of bleeding, discontinue ticagrelor at least 5 days prior to any surgery, particularly in those with a high risk of bleeding, when possible; ticagrelor may be resumed once hemostasis achieved. Do not start ticagrelor in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). Bleeding should be suspected in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of ticagrelor. Since there is an increased risk of subsequent cardiovascular events associated with discontinuation of ticagrelor, if possible, manage bleeding without stopping ticagrelor. Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers and is not likely to be of benefit in patients with bleeding.

    Hepatic disease

    Avoid the use of ticagrelor in patients with severe hepatic impairment because it is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events. In addition, severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins. Ticagrelor has not been studied in patients with moderate or severe hepatic disease or impairment. In patients with moderate hepatic impairment, consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor.

    Labor, obstetric delivery, pregnancy

    Available data from case-reports of ticagrelor use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. No adequate or well-controlled studies of ticagrelor in pregnant women exist. In animal reproduction studies, ticagrelor caused structural abnormalities at maternal doses about 5 to 7 times the maximum recommended human dose (MRHD) based on body surface area. Pup death and effects on pup growth were seen when ticagrelor was given at doses 10 times the MRHD to rats during late gestation and lactation. Ticagrelor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[44951] Furthermore, ticagrelor should be used with extreme caution near term and during labor and obstetric delivery because of the possibility of maternal postpartum hemorrhage.

    Breast-feeding

    According to the manufacturer, it is unknown if ticagrelor or its metabolites are excreted into human breast milk. Since many drugs are excreted into human milk and due to the potentially serious adverse effects to the infant, the manufacturer states that breastfeeding is not recommended during ticagrelor therapy; thus, either ticagrelor therapy or breast-feeding should be discontinued.[44951] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

    Abrupt discontinuation

    Avoid interruption or the abrupt discontinuation of ticagrelor therapy in patients being treated for coronary artery disease (CAD). Discontinuation of ticagrelor increases the risk of myocardial infarction, stent thrombosis, and death. If it is absolutely necessary to temporarily discontinue treatment (e.g., to treat bleeding or for elective surgery), restart therapy as soon as possible.

    Children, infants, neonates

    The safety and efficacy of ticagrelor in neonates, infants, children, or adolescents have not been established.

    AV block, bradycardia, sick sinus syndrome, syncope

    Use ticagrelor with caution in patients with a history of sick sinus syndrome, second or third degree AV block, or syncope related to bradycardia and not protected by a pacemaker. Ticagrelor can cause ventricular pauses. Bradyarrhythmias, including AV block, have been reported with the postmarketing use of ticagrelor. Patients with sick sinus syndrome, AV block, or bradycardia-related syncope were excluded from ticagrelor clinical trials and may be at increased risk of developing bradyarrhythmias with ticagrelor.

    Aspirin coadministration

    Ticagrelor is indicated for use with aspirin at doses of 75 to 100 mg per day. Avoid higher aspirin maintenance doses, as ticagrelor efficacy is decreased when aspirin coadministration exceeds 100 mg per day.

    Geriatric

    No difference in safety or efficacy is seen between geriatric and younger patients. Approximately half of the patients in the PLATO, PEGASUS, THEMIS, and THALES trials were 65 years of age and older and at least 15% were 75 years of age and older. The relative risk of bleeding was similar in both age and treatment groups. Although no differences were seen in clinical trials, some older patients may be more sensitive to the effects of ticagrelor. 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.

    Heparin-induced thrombocytopenia (HIT)

    Ticagrelor has been reported to cause false negative results in platelet function tests, including the heparin-induced platelet aggregation (HIPA) assay, in patients with heparin-induced thrombocytopenia (HIT). Platelet function test interference is related to P2Y12-receptor inhibition on healthy donor platelets by ticagrelor in the affected patient. Ticagrelor is not expected to have an impact on PF4 antibody testing for HIT. Knowledge of current treatment with ticagrelor is needed with interpretation of HIT functional tests.

    Sleep apnea

    Central sleep apnea, including Cheyne-Stokes respiration, has been reported with postmarketing use of ticagrelor. Patients with central sleep apnea may experience a worsening of their symptoms with ticagrelor therapy. Recurrence or worsening of central sleep apnea or Cheyne-Stokes respiration has been reported in patients following ticagrelor rechallenge. If central sleep apnea is suspected, consider further clinical assessment.

    ADVERSE REACTIONS

    Severe

    bradycardia / Rapid / 2.2-6.6
    atrial fibrillation / Early / 4.6-4.6
    intracranial bleeding / Delayed / 0.3-0.3
    apnea / Delayed / Incidence not known
    Cheyne-Stokes respiration / Early / Incidence not known
    AV block / Early / Incidence not known
    angioedema / Rapid / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known

    Moderate

    dyspnea / Early / 13.8-21.0
    bleeding / Early / 7.7-7.7
    hypertension / Early / 3.8-3.8
    hypotension / Rapid / 3.2-3.2
    chest pain (unspecified) / Early / 3.1-3.1
    hyperuricemia / Delayed / 0.6-0.6

    Mild

    headache / Early / 6.5-6.5
    cough / Delayed / 4.9-4.9
    dizziness / Early / 4.5-4.5
    nausea / Early / 4.3-4.3
    diarrhea / Early / 3.7-3.7
    back pain / Delayed / 3.6-3.6
    fatigue / Early / 3.2-3.2
    syncope / Early / 1.7-1.7
    gynecomastia / Delayed / 0.2-0.2
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Coadministration of opioid agonists, such as dihydrocodeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Acetaminophen; Codeine: (Moderate) Coadministration of opioid agonists, such as codeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Acetaminophen; Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Acetaminophen; Oxycodone: (Moderate) Coadministration of opioid agonists may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Acetaminophen; Propoxyphene: (Major) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant propoxyphene. Coadministration of opioid agonists with ticagrelor delays and reduces the absorption of ticagrelor and its active metabolite due to slowed gastric emptying.
    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.
    Alfentanil: (Moderate) Coadministration of opioid agonists, such as alfentanil, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Alprazolam: (Major) Avoid coadministration of alprazolam and ticagrelor due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ticagrelor, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and ticagrelor is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
    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.
    Aminolevulinic Acid: (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Amiodarone: (Moderate) Coadministration of ticagrelor and amiodarone may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and amiodarone is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as clarithromycin. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with clarithromycin substantially increases ticagrelor exposure which may increase the bleeding risk.
    Anagrelide: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Antithrombin III: (Moderate) Theoretically, as a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving platelet inhibitors (e.g. aspirin, ASA, clopidogrel) concomitantly. Patients should be monitored for appropriate anticoagulation during coadministration of AT III and platelet inhibitors.
    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.
    Apalutamide: (Major) Avoid coadministration of ticagrelor with apalutamide due to decreased plasma concentrations of ticagrelor. Ticagrelor is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ticagrelor exposure by 86%.
    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.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if ticagrelor and aprepitant, fosaprepitant are used concurrently and monitor for an increase in ticagrelor-related adverse effects for several days after administration of a multi-day aprepitant regimen. Ticagrelor is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of ticagrelor. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Ticagrelor is also a weak CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
    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.
    Aspirin, ASA: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding. (Moderate) Coadministration of opioid agonists, such as codeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Aspirin, ASA; Caffeine: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding. (Moderate) Coadministration of opioid agonists, such as dihydrocodeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding.
    Aspirin, ASA; Carisoprodol: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding. (Moderate) Coadministration of opioid agonists, such as codeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding.
    Aspirin, ASA; Dipyridamole: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding. (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.
    Aspirin, ASA; Omeprazole: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding.
    Aspirin, ASA; Oxycodone: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding. (Moderate) Coadministration of opioid agonists may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Aspirin, ASA; Pravastatin: (Moderate) Avoid aspirin maintenance doses of more than 100 mg with concomitant ticagrelor. Maintenance doses of aspirin above 100 mg decreased ticagrelor effectiveness in a clinical trial. After the typical aspirin loading dose of 325 mg, use ticagrelor with an aspirin maintenance dose of 75 to 100 mg. Additionally, both drugs are associated with bleeding. Monitor for bleeding.
    Atazanavir: (Moderate) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as atazanavir. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with atazanavir substantially increases ticagrelor exposure which may increase the bleeding risk.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of ticagrelor with cobicistat due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold. (Moderate) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as atazanavir. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with atazanavir substantially increases ticagrelor exposure which may increase the bleeding risk.
    Avanafil: (Contraindicated) Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors including ticagrelor, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as phenobarbital. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with phenobarbital substantially decreases ticagrelor exposure which may decrease the efficacy of ticagrelor.
    Belladonna; Opium: (Moderate) Coadministration of opioid agonists, such as opium, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Benzhydrocodone; Acetaminophen: (Moderate) Coadministration of opioid agonists, such as benzhydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking ticagrelor. Also monitor for increased bleeding. Concurrent use may increase the exposure of both drugs and the risk of adverse effects. Berotralstat is a P-gp substrate/inhibitor and a moderate CYP3A4 inhibitor; ticagrelor is a sensitive CYP3A4 substrate and P-gp substrate/inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%.
    Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving ticagrelor. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving ticagrelor. Coadministration of betrixaban and platelet inhibitors like ticagrelor increases the risk of bleeding; additionally, betrixaban exposure may increase further increasing bleeding risk. Monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; ticagrelor inhibits P-gp.
    Bexarotene: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including bexarotene.
    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.
    Boceprevir: (Minor) Coadministration of ticagrelor and boceprevir may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate. In vitro data suggests boceprevir is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Brigatinib: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with brigatinib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and brigatinib is a P-gp inhibitor.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and ticagrelor may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; ticagrelor inhibits CYP3A4.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Coadministration of opioid agonists, such as codeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring for adverse events is advised when administering rilpivirine with ticagrelor. Use of these drugs together may result in elevated rilpivirine plasma concentrations. Ticagrelor is a weak inhibitor of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Rilpivirine is primarily metabolized by CYP3A4.
    Cabozantinib: (Minor) Monitor for an increase in ticagrelor-related adverse reactions if coadministration with cabozantinib is necessary. Ticagrelor is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
    Cannabidiol: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with cannabidiol as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and cannabidiol is a P-gp inhibitor.
    Capmatinib: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with capmatinib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and capmatinib is a P-gp inhibitor.
    Carbamazepine: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as carbamazepine. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with carbamazepine substantially decreases ticagrelor exposure which may decrease the efficacy of ticagrelor.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Carvedilol: (Moderate) Altered concentrations of ticagrelor and/or carvedilol may occur during coadministration. Carvedilol and ticagrelor are both substrates and inhibitors of P-glycoprotein (P-gp). Use caution if concomitant use is necessary and monitor for increased side effects.
    Ceritinib: (Major) Avoid coadministration of ticagrelor with ceritinib due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    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; Codeine: (Moderate) Coadministration of opioid agonists, such as codeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Coadministration of opioid agonists, such as dihydrocodeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as dihydrocodeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Chlorpheniramine; Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Cilostazol: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of cilostazol and ticagrelor. Both agents are platelet inhibitors; therefore, concomitant use may increase the risk of bleeding. Platelet aggregation returns to normal within 96 hours of discontinuing cilostazol.
    Citalopram: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Cladribine: (Moderate) Due to the thrombocytopenic effects of purine analogs, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Clarithromycin: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as clarithromycin. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with clarithromycin substantially increases ticagrelor exposure which may increase the bleeding risk.
    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 clopidogrel and ticagrelor inhibit platelet aggregation, a potential additive risk for bleeding exists if the drugs are given in combination. Patients should be instructed to monitor for signs and symptoms of bleeding and to promptly report any bleeding events.
    Cobicistat: (Major) Avoid coadministration of ticagrelor with cobicistat due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and ticagrelor is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro as well as a P-glycoprotein (P-gp) inhibitor; ticagrelor is a weak inhibitor of both CYP3A and P-gp. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
    Codeine: (Moderate) Coadministration of opioid agonists, such as codeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Codeine; Guaifenesin: (Moderate) Coadministration of opioid agonists, such as codeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as codeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Codeine; Phenylephrine; Promethazine: (Moderate) Coadministration of opioid agonists, such as codeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Codeine; Promethazine: (Moderate) Coadministration of opioid agonists, such as codeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    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.
    Conivaptan: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with conivaptan. Coadministration may increase the exposure of ticagrelor. Ticagrelor is a sensitive substrate of CYP3A and P-gp; conivaptan is a moderate CYP3A and P-gp inhibitor.
    Crizotinib: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with crizotinib. Coadministration may increase the exposure of ticagrelor. Ticagrelor is a sensitive substrate of CYP3A; crizotinib is a moderate inhibitor of CYP3A.
    Cyclosporine: (Moderate) Coadministration of ticagrelor and cyclosporine results in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and cyclosporine is a P-gp inhibitor. No dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Dabigatran: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ticagrelor, a mild P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like ticagrelor in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with ticagrelor, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. Coadministration of ticagrelor modestly increases plasma concentrations of dabigatran; the magnitude of increase dependent on the dose and timing of ticagrelor administration. Concurrent use of dabigatran 110 mg PO twice daily and ticagrelor 90 mg PO twice daily increased the dabigatran AUC and Cmax by 26% and 29%, respectively. When coadministered with a loading dose of ticagrelor 180 mg PO, the AUC and Cmax of dabigatran increased by 49% and 65%, respectively; but when ticagrelor 180 mg was given 2 hours after dabigatran, the AUC and Cmax of dabigatran increased by only 27% and 24%, respectively. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dabrafenib: (Major) The concomitant use of dabrafenib and ticagrelor may lead to decreased ticagrelor concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of ticagrelor efficacy. Dabrafenib is a moderate CYP3A4 inducer and ticagrelor is a sensitive CYP3A4 substrate. Concomitant use of dabrafenib with a single dose of another sensitive CYP3A4 substrate decreased the AUC value of the sensitive CYP3A4 substrate by 65%.
    Daclatasvir: (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with ticagrelor, a moderate CYP3A4 inhibitor, increases daclatasvir serum concentrations. In addition, the therapeutic effects of ticagrelor, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor. If these drugs are administered together, monitor patients for adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions.
    Dalteparin: (Moderate) Because ticagrelor inhibits platelet aggregation, a potential additive pharmacodynamic effect for bleeding exists if ticagrelor is given in combination with other agents that affect hemostasis such as warfarin, heparin, or low-molecular weight heparins (LMWHs). No significant pharmacokinetic changes were seen with ticagrelor was coadministered with heparin 100 international units and enoxaparin 1 mg/kg, and the manufacturer states ticagrelor may be administered with unfractionated heparin and low molecular weight heparins.
    Danaparoid: (Moderate) An additive risk of bleeding may be seen in patients receiving other platelet inhibitors in combination with danaparoid. Monitoring of anticoagulant therapy by prothrombin time and Thrombotest is unreliable within 5 hours after danaparoid administration.
    Danazol: (Moderate) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with platelet inhibitors.
    Darunavir: (Major) Avoid coadministration of ticagrelor with darunavir due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Darunavir; Cobicistat: (Major) Avoid coadministration of ticagrelor with cobicistat due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold. (Major) Avoid coadministration of ticagrelor with darunavir due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of ticagrelor with cobicistat due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold. (Major) Avoid coadministration of ticagrelor with darunavir due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of ticagrelor and dasabuvir; ombitasvir; paritaprevir; ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Concomitant use is expected to increase ticagrelor exposure, which may increase bleeding risk. Ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates, and dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. (Major) Avoid the concomitant use of ticagrelor and ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Paritaprevir also inhibits P-gp. Concomitant use is expected to increase ticagrelor exposure, which may increase bleeding risk. Ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir and paritaprevir are CYP3A4 substrates, and ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. (Major) Avoid the concomitant use of ticagrelor and ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Concomitant use with ritonavir substantially increases ticagrelor exposure which may increase the bleeding risk. In addition, ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir is a substrate of both CYP3A4 and P-gp.
    Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and ticagrelor is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant platelet inhibitors may increase the risk of hemorrhage.
    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.
    Delavirdine: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as delavirdine. Although not studied, ticagrelor is a substrate of CYP3A4/5 and concomitant use with delavirdine may increase ticagrelor exposure which may increase the bleeding risk.
    Desirudin: (Moderate) Desirudin should be used with caution in conjunction with drugs which affect platelet function, due to the potential for an additive risk of bleeding.
    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.
    Dexamethasone: (Moderate) Coadministration of ticagrelor with dexamethasone may result in decreased concentrations of ticagrelor. Use combination with caution and monitor for decreased efficacy of ticagrelor. Ticagrelor is a substrate of CYP3A4/5 and dexamethasone is a moderate CYP3A4 inducer.
    Dextromethorphan; Quinidine: (Moderate) Coadministration of ticagrelor and quinidine may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Digoxin: (Moderate) Monitor digoxin concentrations when used concomitantly with ticagrelor. Ticagrelor is a P-gp inhibitor and digoxin is metabolized by P-gp.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as dihydrocodeine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Dipyridamole: (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.
    Dolutegravir; Rilpivirine: (Moderate) Close clinical monitoring for adverse events is advised when administering rilpivirine with ticagrelor. Use of these drugs together may result in elevated rilpivirine plasma concentrations. Ticagrelor is a weak inhibitor of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Rilpivirine is primarily metabolized by CYP3A4.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ticagrelor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with ticagrelor is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; ticagrelor is a weak inhibitor of CYP2C9 and 3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Minor) Coadministration of ticagrelor and dronedarone may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and dronedarone is a P-gp inhibitor (potency unknown). Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    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 (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.
    Duvelisib: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with duvelisib. Coadministration may increase the exposure of ticagrelor. Ticagrelor is a sensitive substrate of CYP3A; duvelisib is a moderate inhibitor of CYP3A.
    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.
    Efavirenz: (Moderate) If possible, avoid use of ticagrelor with efavirenz or efavirenz-containing products (i.e., efavirenz; emtricitabine; tenofovir); coadministration may result in decreased efficacy of ticagrelor, and potentially increased adverse events of efavirenz. Ticagrelor is a substrate and weak inhibitor of CYP3A4/5. Efavirenz has been shown to induce CYP3A in vivo and is partially metabolized by CYP3A4.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ticagrelor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Moderate) If possible, avoid use of ticagrelor with efavirenz or efavirenz-containing products (i.e., efavirenz; emtricitabine; tenofovir); coadministration may result in decreased efficacy of ticagrelor, and potentially increased adverse events of efavirenz. Ticagrelor is a substrate and weak inhibitor of CYP3A4/5. Efavirenz has been shown to induce CYP3A in vivo and is partially metabolized by CYP3A4.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ticagrelor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Moderate) If possible, avoid use of ticagrelor with efavirenz or efavirenz-containing products (i.e., efavirenz; emtricitabine; tenofovir); coadministration may result in decreased efficacy of ticagrelor, and potentially increased adverse events of efavirenz. Ticagrelor is a substrate and weak inhibitor of CYP3A4/5. Efavirenz has been shown to induce CYP3A in vivo and is partially metabolized by CYP3A4.
    Elbasvir; Grazoprevir: (Moderate) Administering elbasvir; grazoprevir with ticagrelor may cause the plasma concentrations of all three drugs to increase; thereby increasing the potential for adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ticagrelor is a substrate and mild inhibitor of CYP3A. Both elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of hepatotoxicity.
    Elexacaftor; tezacaftor; ivacaftor: (Minor) Coadministration of ticagrelor and ivacaftor may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and ivacaftor is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of ticagrelor and eliglustat is not recommended. Ticagrelor is a weak CYP3A inhibitor and P-glycoprotein (P-gp) substrate; eliglustat is a CYP3A and CYP2D6 substrate and P-gp inhibitor. Reduce eliglustat dose to 84 mg PO once daily in extensive CYP2D6 metabolizers with hepatic impairment. Eliglustat exposure and the risk of serious adverse events may be increased. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias) in these patients. In addition, coadministration of eliglustat with ticagrelor, a P-gp substrate may result in increased concentrations of ticagrelor; monitor patients closely for adverse events, including signs and symptoms of bleeding.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of ticagrelor with cobicistat due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ticagrelor with cobicistat due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold. (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ticagrelor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring for adverse events is advised when administering rilpivirine with ticagrelor. Use of these drugs together may result in elevated rilpivirine plasma concentrations. Ticagrelor is a weak inhibitor of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Rilpivirine is primarily metabolized by CYP3A4.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ticagrelor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. (Moderate) Close clinical monitoring for adverse events is advised when administering rilpivirine with ticagrelor. Use of these drugs together may result in elevated rilpivirine plasma concentrations. Ticagrelor is a weak inhibitor of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Rilpivirine is primarily metabolized by CYP3A4.
    Emtricitabine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ticagrelor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Enasidenib: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with enasidenib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and enasidenib is a P-gp inhibitor.
    Encorafenib: (Moderate) Coadministration of encorafenib with ticagrelor may result in increased toxicity or decreased efficacy of ticagrelor. Ticagrelor is a sensitive CYP3A4 substrate. In vitro studies with encorafenib showed time-dependent inhibition of CYP3A4 and induction of CYP3A4. The clinical relevance of the in vivo effect of encorafenib on CYP3A4 is not established.
    Enoxaparin: (Moderate) Because ticagrelor inhibits platelet aggregation, a potential additive pharmacodynamic effect for bleeding exists if ticagrelor is given in combination with other agents that affect hemostasis such low-molecular weight heparins (LMWHs). No significant pharmacokinetic changes were seen with ticagrelor was coadministered with heparin 100 international units and enoxaparin 1 mg/kg, and the manufacturer states ticagrelor may be administered with unfractionated heparin and low molecular weight heparins.
    Enzalutamide: (Major) Avoid coadministration of ticagrelor with enzalutamide due to decreased plasma concentrations of ticagrelor. Ticagrelor is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ticagrelor exposure by 86%.
    Eptifibatide: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
    Erythromycin: (Moderate) Coadministration of ticagrelor and erythromycin may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and erythromycin is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Erythromycin; Sulfisoxazole: (Moderate) Coadministration of ticagrelor and erythromycin may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and erythromycin is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Escitalopram: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Etravirine: (Moderate) Coadministration of ticagrelor and etravirine may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and etravirine is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Everolimus: (Moderate) Monitor everolimus whole blood trough concentrations as appropriate and watch for everolimus-related adverse reactions if coadministration with ticagrelor is necessary. The dose of everolimus may need to be reduced. Everolimus is a P-glycoprotein (P-gp) substrate and ticagrelor is a weak P-gp inhibitor. Coadministration with P-gp inhibitors may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations.
    Ezetimibe; Simvastatin: (Moderate) Avoid simvastatin doses above 40 mg/day PO when used concomitantly with ticagrelor as concomitant use will result in higher serum concentrations of simvastatin. Simvastatin is metabolized by CYP3A4 and ticagrelor is an inhibitor of CYP3A4.
    Fedratinib: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with fedratinib. Coadministration may increase the exposure of ticagrelor. Ticagrelor is a sensitive substrate of CYP3A; fedratinib is a moderate inhibitor of CYP3A.
    Fentanyl: (Moderate) Coadministration of opioid agonists, such as fentanyl, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or ticagrelor; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and ticagrelor is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
    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.
    Flibanserin: (Major) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including ticagrelor, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    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 selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Fluvoxamine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Fondaparinux: (Moderate) There have been no documented pharmacokinetic interactions of fondaparinux with other drugs. However, an additive risk of bleeding may be seen in patients receiving platelet inhibitors.
    Fosamprenavir: (Moderate) Concomitant use of ticagrelor and fosamprenavir may result in elevated fosamprenavir and altered ticagrelor plasma concentrations. Ticagrelor is a substrate and inhibitor of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Amprenavir, the active metabolite of fosamprenavir, is substrate/inducer of P-gp and a substrate/potent inhibitor/moderate inducer of CYP3A4.
    Fosphenytoin: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as phenytoin or fosphenytoin. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with phenytoin substantially decreases ticagrelor exposure which may decrease the efficacy of ticagrelor.
    Fostamatinib: (Moderate) Monitor for ticagrelor toxicities that may require ticagrelor dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a P-gp substrate may increase the concentration of the P-gp substrate. Fostamatinib is a P-gp inhibitor; ticagrelor is a substrate for P-gp. Coadministration of fostamatinib with another P-gp substrate increased the P-gp substrate AUC by 37% and Cmax by 70%.
    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.
    Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with the coadministration of glecaprevir and ticagrelor as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and ticagrelor are both substrates and inhibitors of P-glycoprotein (P-gp). (Moderate) Caution is advised with the coadministration of pibrentasvir and ticagrelor as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Both pibrentasvir and ticagrelor are substrates and inhibitors of P-glycoprotein (P-gp).
    Grapefruit juice: (Moderate) Concomitant use of ticagrelor and grapefruit juice may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and grapefruit is a P-gp inhibitor. Use combination with caution and monitor patients for evidence of bleeding.
    Guaifenesin; Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Heparin: (Moderate) Because ticagrelor inhibits platelet aggregation, a potential additive pharmacodynamic effect for bleeding exists if ticagrelor is given in combination with other agents that affect hemostasis such as heparin. No significant pharmacokinetic changes were seen with ticagrelor was coadministered with heparin 100 international units and enoxaparin 1 mg/kg, and the manufacturer states ticagrelor may be administered with unfractionated heparin and low molecular weight heparins.
    Homatropine; Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Hydrocodone: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Hydrocodone; Ibuprofen: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Hydrocodone; Phenylephrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Hydrocodone; Pseudoephedrine: (Moderate) Coadministration of opioid agonists, such as hydrocodone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Hydromorphone: (Moderate) Coadministration of opioid agonists, such as hydromorphone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    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 ticagrelor 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; Oxycodone: (Moderate) Coadministration of opioid agonists may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    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.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with ticagrelor, a CYP3A substrate, as ticagrelor toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloprost: (Moderate) When used concurrently with platelet inhibitors, inhaled iloprost may increase the risk of bleeding.
    Indinavir: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as indinavir. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with indinavir substantially increases ticagrelor exposure which may increase the bleeding risk.
    Inotersen: (Moderate) Use caution with concomitant use of inotersen and ADP receptor antagonists due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of ADP receptor antagonists 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.
    Isavuconazonium: (Moderate) Coadministration of ticagrelor and isavuconazonium may result in increased exposure to ticagrelor which may increase the bleeding risk. In addition, the exposure to isavuconazonium may be increased resulting in potential adverse effects. Ticagrelor is a substrate and inhibitor of the hepatic isoenzyme CYP3A4 and substrate of the drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of CYP3A4 and an inhibitor of P-gp. Caution and close monitoring are advised if these drugs are used together.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as rifampin. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with rifampin substantially decreases ticagrelor exposure which may decrease the efficacy of ticagrelor.
    Isoniazid, INH; Rifampin: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as rifampin. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with rifampin substantially decreases ticagrelor exposure which may decrease the efficacy of ticagrelor.
    Istradefylline: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with istradefylline as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and istradefylline is a P-gp inhibitor.
    Itraconazole: (Contraindicated) Ticagrelor is contraindicated for use during and for up to 2 weeks after discontinuation of itraconazole treatment. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with itraconazole substantially increases ticagrelor exposure which may increase the bleeding risk.
    Ivabradine: (Moderate) Use caution during coadministration of ivabradine and ticagrelor as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; ticagrelor is a weak inhibitor of CYP3A. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    Ivacaftor: (Minor) Coadministration of ticagrelor and ivacaftor may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and ivacaftor is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Ivosidenib: (Moderate) Monitor for loss of efficacy of ticagrelor during coadministration of ivosidenib; a ticagrelor dose adjustment may be necessary. Ticagrelor is a sensitive substrate of CYP3A4; ivosidenib induces CYP3A4 and may lead to decreased ticagrelor concentrations.
    Ketoconazole: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as ketoconazole. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with ketoconazole substantially increases ticagrelor exposure which may increase the bleeding risk.
    Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ticagrelor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as clarithromycin. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with clarithromycin substantially increases ticagrelor exposure which may increase the bleeding risk.
    Lapatinib: (Moderate) Monitor for an increased risk of treatment-related adverse reactions including bleeding if coadministration of ticagrelor and lapatinib are necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Increased plasma concentrations of lapatinib are likely. Exposure to ticagrelor may also increase. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor.
    Ledipasvir; Sofosbuvir: (Moderate) Coadministration of ticagrelor and ledipasvir; sofosbuvir may result in increased exposure to all three drugs, which may increase the bleeding risk. Both ledipasvir and ticagrelor are P-glycoprotein (P-gp) substrates and inhibitors; sofosbuvir is a P-gp substrate. No dose adjustment is recommended by the manufacturer. Use combination with caution and monitor for evidence of bleeding.
    Lefamulin: (Moderate) Monitor for increased bleeding and lefamulin-related adverse effects if oral lefamulin is administered with ticagrelor as concurrent use may increase exposure from both drugs; an interaction is not expected with intravenous lefamulin. Ticagrelor is a sensitive substrate of CYP3A and a P-gp inhibitor; lefamulin is a CYP3A4 and P-gp substrate and CYP3A4 moderate inhibitor.
    Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with ticagrelor as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; ticagrelor is a weak CYP3A4 inhibitor. Coadministration with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
    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.
    Letermovir: (Moderate) Administering letermovir with ticagrelor may increase ticagrelor concentration and risk for adverse events (e.g. dyspnea, bleeding). Avoid coadministration in patients also receiving cyclosporine, because the magnitude of this interaction may be increased. Ticagrelor is primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
    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.
    Levorphanol: (Moderate) Coadministration of opioid agonists, such as levorphanol, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and ticagrelor may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; ticagrelor inhibits CYP3A4.
    Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and ticagrelor may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; ticagrelor inhibits CYP3A4.
    Lomitapide: (Major) Concomitant use of lomitapide and ticagrelor may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Ticagrelor is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    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.
    Lonafarnib: (Major) Avoid coadministration of ticagrelor with lonafarnib due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions; lonafarnib exposure may also be increased. Ticagrelor is a sensitive CYP3A4 and P-gp substrate and weak CYP3A4 inhibitor; lonafarnib is a sensitive CYP3A4 substrate and P-gp and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by approximately 7-fold.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with ticagrelor, a mild CYP3A4 and P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with ticagrelor, a mild CYP3A4 and P-gp inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Major) Avoid the concomitant use of ticagrelor and ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Concomitant use with ritonavir substantially increases ticagrelor exposure which may increase the bleeding risk. In addition, ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir is a substrate of both CYP3A4 and P-gp.
    Lovastatin: (Major) Avoid lovastatin doses higher than 40 mg/day when used concomitantly with ticagrelor as concomitant use will result in higher serum concentrations of lovastatin. Lovastatin is metabolized by CYP3A4 and ticagrelor is an inhibitor of CYP3A4.
    Lovastatin; Niacin: (Major) Avoid lovastatin doses higher than 40 mg/day when used concomitantly with ticagrelor as concomitant use will result in higher serum concentrations of lovastatin. Lovastatin is metabolized by CYP3A4 and ticagrelor is an inhibitor of CYP3A4.
    Lumacaftor; Ivacaftor: (Major) Avoid concurrent use of lumacaftor; ivacaftor and ticagrelor; coadministration may result in significantly reduced ticagrelor exposure and efficacy. Ticagrelor is primarily metabolized by CYP3A; ticagrelor and its active metabolite are also P-glycoprotein (P-gp) substrates. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp. Although induction of ticagrelor metabolism through the CYP3A pathway may lead to decreased drug efficacy, the net effect of lumacaftor; ivacaftor on P-gp transport is not clear. Additionally, ivacaftor is a CYP3A substrate and in vitro metabolism studies suggest ticagrelor and its active metabolite are weak CYP3A4 inhibitors. Although ivacaftor exposure could theoretically be increased when given with a CYP3A inhibitor, ivacaftor; lumacaftor dosage adjustments are not recommended with concomitant use of a mild CYP3A inhibitor such as ticagrelor due to the induction effects of lumacaftor.
    Lumacaftor; Ivacaftor: (Minor) Coadministration of ticagrelor and ivacaftor may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and ivacaftor is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Maraviroc: (Minor) Use caution if coadministration of maraviroc with ticagrelor is necessary due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A4 and P-glycoprotein substrate (P-gp) and ticagrelor is a weak CYP3A4 and P-gp inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Mefloquine: (Moderate) Coadministration of ticagrelor and mefloquine may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and mefloquine is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Meperidine: (Moderate) Coadministration of opioid agonists, such as meperidine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Meperidine; Promethazine: (Moderate) Coadministration of opioid agonists, such as meperidine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    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.
    Methadone: (Moderate) Coadministration of opioid agonists, such as methadone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    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.
    Mifepristone: (Moderate) Use together with caution and monitor for evidence of increased antiplatelet effect, as well as side effects such as bleeding and dyspnea. CYP3A inhibitors may increase ticagrelor exposure and so increase the risk of dyspnea, bleeding, and other adverse events. No dose adjustment has been recommended. Ticagrelor is a CYP3A4 and P-glycoprotein (P-gp) substrate. Mifepristone inhibits CYP3A4 and may be a P-gp inhibitor. Due to the slow elimination of mifepristone from the body, any interactions that occur may be prolonged.
    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.
    Mitotane: (Major) Avoid the concomitant use of mitotane with ticagrelor due to decreased ticagrelor exposure and efficacy. Mitotane is a strong CYP3A4 inducer and ticagrelor is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of ticagrelor.
    Morphine: (Moderate) Coadministration of opioid agonists, such as morphine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Morphine; Naltrexone: (Moderate) Coadministration of opioid agonists, such as morphine, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Mycophenolate: (Moderate) Platelet Inhibitors inhibit platelet aggregation and should be used cautiously in patients with thrombocytopenia, as mycophenolate can also cause thrombocytopenia.
    Nefazodone: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as nefazodone. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with nefazodone substantially increases ticagrelor exposure which may increase the bleeding risk.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant platelet inhibitors.
    Nelfinavir: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as nelfinavir. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with nelfinavir substantially increases ticagrelor exposure which may increase the risk of bleeding.
    Neratinib: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with neratinib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as ticagrelor. The plasma concentrations of ticagrelor can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days.
    Niacin; Simvastatin: (Moderate) Avoid simvastatin doses above 40 mg/day PO when used concomitantly with ticagrelor as concomitant use will result in higher serum concentrations of simvastatin. Simvastatin is metabolized by CYP3A4 and ticagrelor is an inhibitor of CYP3A4.
    Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ticagrelor, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ticagrelor is a mild inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
    Nisoldipine: (Major) Avoid coadministration of nisoldipine with ticagrelor due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and ticagrelor is a weak CYP3A4 inhibitor.
    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.
    Olanzapine; Fluoxetine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid the concomitant use of ticagrelor and dasabuvir; ombitasvir; paritaprevir; ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Concomitant use is expected to increase ticagrelor exposure, which may increase bleeding risk. Ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates, and dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. (Major) Avoid the concomitant use of ticagrelor and ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Paritaprevir also inhibits P-gp. Concomitant use is expected to increase ticagrelor exposure, which may increase bleeding risk. Ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir and paritaprevir are CYP3A4 substrates, and ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. (Major) Avoid the concomitant use of ticagrelor and ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Concomitant use with ritonavir substantially increases ticagrelor exposure which may increase the bleeding risk. In addition, ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir is a substrate of both CYP3A4 and P-gp.
    Osimertinib: (Moderate) Monitor for an increase in ticagrelor-related adverse reactions, including bleeding, if coadministration with osimertinib is necessary. Ticagrelor is a P-glycoprotein (P-gp) substrate and osimertinib is a P-gp inhibitor.
    Oxycodone: (Moderate) Coadministration of opioid agonists may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Oxymorphone: (Moderate) Coadministration of opioid agonists, such as oxymorphone, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Paroxetine: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    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.
    Pentosan: (Moderate) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving other platelet inhibitors in combination with pentosan.
    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.
    Phenobarbital: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as phenobarbital. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with phenobarbital substantially decreases ticagrelor exposure which may decrease the efficacy of ticagrelor.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as phenobarbital. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with phenobarbital substantially decreases ticagrelor exposure which may decrease the efficacy of ticagrelor.
    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.
    Phenytoin: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as phenytoin. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with phenytoin substantially decreases ticagrelor exposure which may decrease the efficacy of ticagrelor.
    Photosensitizing agents (topical): (Minor) Agents, such as platelet inhibitors, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Platelet Glycoprotein IIb/IIIa Inhibitors: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
    Posaconazole: (Moderate) Coadministration of ticagrelor and posaconazole may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and posaconazole is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    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.
    Primidone: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as primidone. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with primidone may substantially decrease ticagrelor exposure which may decrease the efficacy of ticagrelor.
    Propafenone: (Moderate) Coadministration of ticagrelor and propafenone may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and propafenone is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Propoxyphene: (Major) Consider the use of a parenteral anti-platelet agent for patients with acute coronary syndrome who require concomitant propoxyphene. Coadministration of opioid agonists with ticagrelor delays and reduces the absorption of ticagrelor and its active metabolite due to slowed gastric emptying.
    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.
    Quinidine: (Moderate) Coadministration of ticagrelor and quinidine may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and quinidine is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Ranolazine: (Moderate) Coadministration of ticagrelor and ranolazine may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and ranolazine is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Relugolix: (Major) Avoid concomitant use of relugolix and oral ticagrelor. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ticagrelor at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and ticagrelor is a P-gp inhibitor.
    Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral ticagrelor. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer ticagrelor at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and ticagrelor is a P-gp inhibitor.
    Remifentanil: (Moderate) Coadministration of opioid agonists, such as remifentanil, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Ribociclib: (Major) Avoid coadministration of ticagrelor with ribociclib due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ticagrelor with ribociclib due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Rifampin: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as rifampin. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with rifampin substantially decreases ticagrelor exposure which may decrease the efficacy of ticagrelor.
    Rifapentine: (Major) Avoid coadministration of ticagrelor with rifapentine due to decreased plasma concentrations of ticagrelor. Ticagrelor is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ticagrelor exposure by 86%.
    Rifaximin: (Moderate) Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ticagrelor, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin.
    Rilpivirine: (Moderate) Close clinical monitoring for adverse events is advised when administering rilpivirine with ticagrelor. Use of these drugs together may result in elevated rilpivirine plasma concentrations. Ticagrelor is a weak inhibitor of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Rilpivirine is primarily metabolized by CYP3A4.
    Rimegepant: (Major) Avoid coadministration of rimegepant with ticagrelor; concurrent use may increase rimegepant exposure. Rimegepant is a substrate of P-gp and ticagrelor is a P-gp inhibitor.
    Ritonavir: (Major) Avoid the concomitant use of ticagrelor and ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Concomitant use with ritonavir substantially increases ticagrelor exposure which may increase the bleeding risk. In addition, ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir is a substrate of both CYP3A4 and P-gp.
    Rivaroxaban: (Major) Avoid concurrent administration of platelet inhibitors 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. The coadministration of rivaroxaban and ticagrelor should be undertaken with caution in patients with renal impairment; it is unclear whether a clinically significant interaction occurs when these 2 drugs are coadministered to patients with normal renal function. Ticagrelor is a combined mild CYP3A4 inhibitor and mild P-glycoprotein (P-gp) inhibitor. Rivaroxaban is a substrate of CYP3A4/5 and the P-gp transporter. Coadministration in patients with renal impairment may result in increased exposure to rivaroxaban compared with patients with normal renal function and no inhibitor use since both pathways of elimination are affected. While an increase in exposure to rivaroxaban may be expected, results from an analysis of the ROCKET-AF trial which allowed concomitant administration of rivaroxaban and a combined P-gp inhibitor and weak or moderate CYP3A4 inhibitor did not show an increased risk of bleeding in patients with CrCl 30 to less than 50 mL/minute.
    Saquinavir: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as saquinavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) and concomitant use with saquinavir substantially increases ticagrelor exposure which may increase the bleeding risk.
    Selective serotonin reuptake inhibitors: (Moderate) Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    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 selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving prasugrel. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SSRI concurrently with an antiplatelet medication and to promptly report any bleeding events to the practitioner.
    Simeprevir: (Minor) Coadministration of ticagrelor and simeprevir may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and simeprevir is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Simvastatin: (Moderate) Avoid simvastatin doses above 40 mg/day PO when used concomitantly with ticagrelor as concomitant use will result in higher serum concentrations of simvastatin. Simvastatin is metabolized by CYP3A4 and ticagrelor is an inhibitor of CYP3A4.
    Simvastatin; Sitagliptin: (Moderate) Avoid simvastatin doses above 40 mg/day PO when used concomitantly with ticagrelor as concomitant use will result in higher serum concentrations of simvastatin. Simvastatin is metabolized by CYP3A4 and ticagrelor is an inhibitor of CYP3A4.
    Sofosbuvir; Velpatasvir: (Moderate) Use caution when administering velpatasvir with ticagrelor. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, ticagrelor is a weak inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Plasma concentrations of ticagrelor, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with voxilaprevir, a P-gp inhibitor. Monitor patients for increased side effects if these drugs are administered concurrently. (Moderate) Use caution when administering velpatasvir with ticagrelor. Taking these medications together may increase the plasma concentrations of both drugs, potentially resulting in adverse events. Both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). In addition, ticagrelor is a weak inhibitor of the hepatic enzyme CYP3A4. Velpatasvir is a CYP3A4 substrate.
    Sorafenib: (Moderate) Monitor for an increase in ticagrelor-related adverse reactions, including bleeding, if coadministration with sorafenib is necessary. Ticagrelor is a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
    Sotorasib: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with sotorasib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and sotorasib is a P-gp inhibitor.
    St. John's Wort, Hypericum perforatum: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as St. John's Wort, Hypericum perforatum. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with St. John's Wort may substantially decrease ticagrelor exposure which may decrease the efficacy of ticagrelor.
    Sufentanil: (Moderate) Coadministration of opioid agonists, such as sufentanil, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    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.
    Tacrolimus: (Minor) Coadministration of ticagrelor and tacrolimus may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate. Tacrolimus may be a P-gp inhibitor; however, data are conflicting. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with ticagrelor is necessary. Talazoparib is a P-glycoprotein (P-gp) substrate and ticagrelor is a P-gp inhibitor. Coadministration with other P-gp inhibitors increased talazoparib exposure by 8% to 45%.
    Tapentadol: (Moderate) Coadministration of opioid agonists, such as tapentadol, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Telaprevir: (Minor) Coadministration of ticagrelor and telaprevir may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and telaprevir is a P-gp inhibitor (potency unknown). Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Telithromycin: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as telithromycin. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp) substrate and concomitant use with telithromycin substantially increases ticagrelor exposure which may increase the bleeding risk.
    Temsirolimus: (Moderate) Monitor for an increase in temsirolimus- and ticagrelor-related adverse reactions if coadministration is necessary. Both drugs are P-glycoprotein (P-gp) substrates and inhibitors. Concomitant use is likely to lead to increased concentrations of temsirolimus and ticagrelor.
    Tenofovir Alafenamide: (Minor) Close clinical monitoring for adverse events is advised when administering tenofovir alafenamide with ticagrelor. Use of these drugs together may result in elevated tenofovir plasma concentrations. Ticagrelor is an inhibitor of the drug transporter P-glycoprotein (P-gp).Tenofovir alafenamide is a substrate for P-gp. Of note, when tenofovir alafenamide is administered as part of a cobicistat-containing product, its availability is increased by cobicistat and a further increase of tenofovir alafenamide concentrations is not expected upon coadministration of an additional P-gp inhibitor.
    Tenofovir, PMPA: (Moderate) Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) substrate, concurrently with inhibitors of P-gp, such as ticagrelor. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions.
    Tepotinib: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with tepotinib as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and tepotinib is a P-gp inhibitor.
    Terbinafine: (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering ticagrelor. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; ticagrelor is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
    Tezacaftor; Ivacaftor: (Minor) Coadministration of ticagrelor and ivacaftor may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and ivacaftor is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    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.
    Tinzaparin: (Moderate) Because ticagrelor inhibits platelet aggregation, a potential additive pharmacodynamic effect for bleeding exists if ticagrelor is given in combination with other agents that affect hemostasis such as heparin or low-molecular weight heparins (LMWHs). No significant pharmacokinetic changes were seen with ticagrelor was coadministered with heparin 100 international units and enoxaparin 1 mg/kg, and the manufacturer states ticagrelor may be administered with unfractionated heparin and low molecular weight heparins.
    Tipranavir: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inhibitors, such as tipranavir. Although not studied, ticagrelor is a substrate of CYP3A4/5 and concomitant use with tipranavir may increase ticagrelor exposure which may increase the bleeding risk.
    Tirofiban: (Moderate) Concomitant use of platelet glycoprotein IIb/IIIa inhibitors (i.e., abciximab, eptifibatide, or tirofiban) with an ADP receptor antagonist (i.e., clopidogrel, prasugrel, ticagrelor, or ticlopidine) may be associated with an increased risk of bleeding.
    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.
    Topotecan: (Major) Avoid coadministration of ticagrelor with oral topotecan due to increased topotecan exposure; ticagrelor may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and ticagrelor is a weak P-gp inhibitor. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
    Tramadol: (Moderate) Coadministration of opioid agonists, such as tramadol, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Tramadol; Acetaminophen: (Moderate) Coadministration of opioid agonists, such as tramadol, may delay and reduce the absorption of ticagrelor resulting in reduced exposure and diminished inhibition of platelet aggregation. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring an opioid agonist. Mean ticagrelor exposure decreased up to 36% in ACS patients undergoing PCI when intravenous morphine was administered with a loading dose of ticagrelor; mean platelet aggregation was higher up to 3 hours post loading dose. Similar effects on ticagrelor exposure and platelet inhibition were observed when fentanyl was administered with a ticagrelor loading dose in ACS patients undergoing PCI. Although exposure to ticagrelor was decreased up to 25% in healthy adults administered intravenous morphine with a loading dose of ticagrelor, platelet inhibition was not delayed or decreased in this population.
    Trandolapril; Verapamil: (Moderate) Coadministration of ticagrelor and verapamil may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and verapamil is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence 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 ticagrelor. Treprostinil inhibits platelet aggregation; ticagrelor 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.
    Tucatinib: (Major) Avoid coadministration of ticagrelor with tucatinib due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 and P-glycoprotein (P-gp) substrate; tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with ticagrelor. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and P-gp substrate; ticagrelor is a weak CYP3A4 inhibitor and a P-gp inhibitor.
    Vemurafenib: (Minor) Coadministration of ticagrelor and vemurafenib may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and vemurafenib is a mild P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    Venetoclax: (Major) Reduce the dose of venetoclax by at least 50% and monitor for venetoclax toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) if coadministered with ticagrelor due to the potential for increased venetoclax exposure. Additionally, ticagrelor exposure may be increased. Resume the original venetoclax dose 2 to 3 days after discontinuation of ticagrelor. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate and P-gp inhibitor; ticagrelor is a CYP3A4 (weak) and P-gp inhibitor and P-gp substrate. Coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study.
    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.
    Verapamil: (Moderate) Coadministration of ticagrelor and verapamil may result in increased exposure to ticagrelor which may increase the bleeding risk. Ticagrelor is a P-glycoprotein (P-gp) substrate and verapamil is a P-gp inhibitor. Based on drug information data with cyclosporine, no dose adjustment is recommended by the manufacturer of ticagrelor. Use combination with caution and monitor for evidence of bleeding.
    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).
    Vincristine Liposomal: (Moderate) Ticagrelor is a mild CYP3A4 and P-glycoprotein (P-gp) inhibitor, and vincristine is a CYP3A and P-gp substrate. Coadministration may increase vincristine concentrations; monitor patients for vincristine toxicity if these drugs are used together.
    Vincristine: (Moderate) Ticagrelor is a mild CYP3A4 and P-glycoprotein (P-gp) inhibitor, and vincristine is a CYP3A and P-gp substrate. Coadministration may increase vincristine concentrations; monitor patients for vincristine toxicity if these drugs are used together.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with ticagrelor is necessary. Vinorelbine is a CYP3A4 substrate and ticagrelor is a weak CYP3A4 inhibitor.
    Voclosporin: (Moderate) Monitor for increased bleeding if ticagrelor is coadministered with voclosporin as concurrent use may increase the exposure of ticagrelor. Ticagrelor is a P-gp substrate and voclosporin is a P-gp inhibitor.
    Vorapaxar: (Moderate) Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as ADP receptor antagonists including clopidogrel, prasugrel, ticagrelor, or ticlopidine.
    Voriconazole: (Major) Avoid coadministration of ticagrelor with voriconazole due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
    Vorinostat: (Moderate) Carefully monitor patients for signs and symptoms of bleeding during coadministration of ticagrelor 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) Closely monitor the INR if coadministration of warfarin with ticagrelor is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Ticagrelor is a weak CYP3A4 inhibitor and warfarin is a CYP3A4 substrate. Also, because ticagrelor inhibits platelet aggregation, additive risk for bleeding is possible when given in combination with anticoagulants such as warfarin.
    Zonisamide: (Minor) Zonisamide is a weak inhibitor of P-glycoprotein (P-gp), and ticagrelor is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, it is unknown if ticagrelor or its metabolites are excreted into human breast milk. Since many drugs are excreted into human milk and due to the potentially serious adverse effects to the infant, the manufacturer states that breastfeeding is not recommended during ticagrelor therapy; thus, either ticagrelor therapy or breast-feeding should be discontinued.[44951] Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.

    MECHANISM OF ACTION

    Ticagrelor and its major metabolite reversibly bind to the platelet P2Y12 ADP receptor thereby antagonizing ADP and preventing platelet activation. The maximum inhibition of platelet aggregation (IPA) effect of ticagrelor is reached in approximately 2 hours and maintained for at least 8 hours.

    PHARMACOKINETICS

    Ticagrelor is administered orally. Extensive plasma protein binding (>99%) occurs with ticagrelor and the active metabolite. The volume of distribution at steady state is 88 L. Systemic exposure of the active metabolite is approximately 30—40% of ticagrelor. The main hepatic isoenzyme responsible for the metabolism of ticagrelor is CYP3A4, with CYP3A5 playing a minor role. Ticagrelor is metabolized to an active metabolite and the primary routes of elimination for ticagrelor and its metabolite are hepatic and biliary, respectively. After oral administration of radiolabeled ticagrelor, approximately 84% recovery of radioactivity was seen (58% in the feces, 26% in the urine). Recovery of ticagrelor and the active metabolite in the urine were < 1%. The mean half-life is approximately 7 hours for ticagrelor and 9 hours for the active metabolite.
     
    The maximum inhibition of platelet aggregation (IPA) effect of ticagrelor is reached in approximately 2 hours and maintained for at least 8 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP3A4, CYP3A5, P-gp
    Both ticagrelor and its metabolite are weak inhibitors of CYP3A4/5 and inhibit the P-glycoprotein (P-gp) transporter. Ticagrelor is also a P-gp substrate. Ticagrelor and its metabolite were shown to have no inhibitory effect on CYP1A2, CYP2C19, and CYP2E1. No significant pharmacokinetic interactions were seen in studies comparing ticagrelor 90 mg twice daily to desmopressin 0.3 mcg/hr for 2 hours, atorvastatin 80 mg (CYP3A4 and P-gp substrate), levonorgestrel 0.15 mg once daily (CYP3A4 substrate), ethinyl estradiol 0.03 mg once daily (CYP3A4 substrate and inhibitor and P-gp substrate), or tolbutamide 500 mg.

    Oral Route

    The mean absolute bioavailability of ticagrelor is 36% (range 30—42%). The maximum concentrations for ticagrelor are seen within 1.5 hours (range 1—4 h) and 2.5 hours (range 1.5—5 h) for the active metabolite. When administered as crushed tablets mixed in water either orally or via nasogastric tube, the mixture is bioequivalent to whole tablets with a median tmax of 1 hour for ticagrelor and 2 hours for the active metabolite. Ingestion of a high-fat meal has no effect on ticagrelor Cmax but does increase AUC by 21%. In contrast, a high-fat meal results in an increase in the active metabolite Cmax by 22% with no change in AUC. The drug may be taken with or without food.