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  • CLASSES

    Direct Thrombin Inhibitors

    BOXED WARNING

    Abrupt discontinuation

    Avoid the abrupt discontinuation of dabigatran in the absence of adequate alternative anticoagulation. Discontinuing dabigatran puts patients at an increased risk of thrombotic events. If dabigatran must be discontinued for reasons other than pathological bleeding or completion of therapy, consider administering another anticoagulant, and reinitiate therapy with dabigatran as soon as medically appropriate.

    Epidural anesthesia, lumbar puncture, spinal anesthesia

    Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated with dabigatran. Epidural or spinal hematomas that may result in long-term or permanent paralysis may occur in patients who are anticoagulated and are receiving neuraxial anesthesia or undergoing spinal puncture. To reduce the potential risk of bleeding, it is best to perform the placement or removal of an epidural catheter or lumbar puncture when the anticoagulant effect of dabigatran is low based on the pharmacokinetic profile of dabigatran. The exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; history of spinal deformity or spinal surgery; and traumatic or repeated epidural or spinal puncture. If epidural anesthesia, lumbar puncture, or spinal anesthesia is employed, monitor patients frequently for signs and symptoms of neurological impairment (e.g., midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction). Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral direct thrombin inhibitor
    For reduction of risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation, for treatment and reduction in risk of recurrence of DVT and PE, and for the prophylaxis of DVT and PE following hip replacement surgery
    No routine monitoring; anticoagulant effect can be reversed with idarucizumab when clinically indicated

    COMMON BRAND NAMES

    Pradaxa

    HOW SUPPLIED

    Pradaxa Oral Cap: 75mg, 110mg, 150mg

    DOSAGE & INDICATIONS

    For stroke prophylaxis and systemic embolism prophylaxis in patients with non-valvular atrial fibrillation.
    Oral dosage
    Adults

    150 mg PO twice daily. Data from the RE-LY trial (n = 18,113) indicate dabigatran 150 mg PO twice daily was associated with lower rates of stroke and systemic embolism (2.2% vs. 3.4%; HR 0.65, CI 0.52-0.81; p < 0.0001) compared to warfarin. Clinical practice guidelines recommend dabigatran 150 mg PO twice daily over adjusted-dose vitamin K antagonist therapy (i.e., warfarin) for most patients with atrial fibrillation, including paroxysmal atrial fibrillation, at intermediate or high risk of stroke (e.g., CHADS2 score 1 or higher). Dabigatran therapy is not recommended for patients with severe renal failure, mitral stenosis, stable coronary artery disease, intracoronary stents, and acute coronary syndrome. For patients with atrial fibrillation for more than 48 hours or unknown duration undergoing elective electrical or pharmacological cardioversion, clinical practice guidelines recommend dabigatran as an option for therapeutic anticoagulation for at least 3 weeks prior to cardioversion or a transesophageal echocardiography (TEE)-guided approach and for at least 4 weeks after successful cardioversion, regardless of the baseline risk of stroke.

    For the treatment of deep venous thrombosis (DVT) and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5—10 days.
    Oral dosage
    Adults

    150 mg PO twice daily.

    For deep venous thrombosis (DVT) prophylaxis and pulmonary embolism prophylaxis.
    For deep venous thrombosis (DVT) prophylaxis and pulmonary embolism prophylaxis in patients undergoing total hip replacement surgery.
    Oral dosage
    Adults

    110 mg PO on first day beginning 1 to 4 hours after surgery and after hemostasis has been achieved, then 220 mg PO once daily for 28 to 35 days. If dabigatran is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg PO once daily. Clinical practice guidelines recommend dabigatran as an alternative to the preferred low molecular weight heparin as antithrombotic prophylaxis for patients undergoing total hip replacement surgery. The concomitant use of an intermittent pneumatic compression device (IPCD) during the hospital stay is also encouraged. For patients who decline or are uncooperative with injections or an IPCD, dabigatran is a preferred alternative for thromboprophylaxis.

    For deep venous thrombosis (DVT) prophylaxis and pulmonary embolism prophylaxis in patients undergoing total knee replacement surgery†.
    Oral dosage
    Adults

    150 mg or 220 mg PO once daily for 6 to 10 days starting with a half-dose 1 to 4 hours after surgery has been studied to reduce the risk of venous thromboembolism in patients undergoing total knee replacement surgery. Data from this study indicate that dabigatran 150 mg or 220 mg once daily was non-inferior to enoxaparin for reducing the risk of total venous thromboembolism and all-cause mortality after total knee replacement surgery. Furthermore, there was no significant difference in the frequency of major bleeding events between both dabigatran doses and enoxaparin. Clinical practice guidelines recommend dabigatran as an alternative to the preferred low molecular weight heparin as antithrombotic prophylaxis for patients undergoing total knee replacement surgery. Per these guidelines, prophylaxis should continue for a minimum of 10 to 14 days; a duration of up to 35 days after surgery is suggested. The concomitant use of an intermittent pneumatic compression device (IPCD) during the hospital stay is also encouraged. For patients who decline or are uncooperative with injections or an IPCD, dabigatran is a preferred alternative for thromboprophylaxis.

    For the reduction in risk of recurrence of deep venous thrombosis (DVT) and pulmonary embolism in patients who have been previously treated.
    Oral dosage
    Adults

    150 mg PO twice daily.

    MAXIMUM DOSAGE

    Adults

    300 mg/day PO.

    Elderly

    300 mg/day PO.

    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

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

    Renal Impairment

    For reduction in risk of stroke and systemic embolism in non-valvular atrial fibrillation:
    CrCl more than 30 mL/min: No dosage adjustment needed.
    CrCl 15 to 30 mL/min: 75 mg PO twice daily.
    CrCl less than 15 mL/min: Dosing recommendations are not provided by the manufacturer.
    With concomitant use of P-glycoprotein (P-gp) inhibitors:
    CrCl 30 to 50 mL/min: Dose reduction to 75 mg PO twice daily should be considered when coadministered with the P-gp inhibitors dronedarone or ketoconazole; dose adjustment is not necessary when coadministered with other P-gp inhibitors.
    CrCl less than 30 mL/min: Avoid coadministration.
     
    For treatment or reduction in risk of recurrence of DVT and PE and prophylaxis of DVT and PE following hip replacement surgery:
    CrCl more than 30 mL/min: No dosage adjustment needed.
    CrCl 30 mL/min or less: Dosing recommendations are not provided by the manufacturer.
    With concomitant use of P-glycoprotein (P-gp) inhibitors:
    CrCl less than 50 mL/min: Avoid coadministration.
     
    Hemodialysis
    Dabigatran is removed by dialysis; dosing recommendations are not provided by the manufacturer.

    ADMINISTRATION

     
    NOTE: A MedGuide is available for dabigatran and is to be dispensed with every prescription and prescription refill.

    Oral Administration
    Oral Solid Formulations

    Administer without regard to food.
    Capsules should be swallowed whole with a full glass of water. Do not open, break, crush, or chew prior to or during administration. Breaking, chewing, or emptying the contents of the capsule could result in increased systemic exposure of dabigatran, which may increase the risk for bleeding.
    If a dose is missed, it should be administered as soon as possible on the same day. However, skip the missed dose if it cannot be taken at least 6 hours before the next scheduled dose.
    Storage: Due to the potential for product breakdown from moisture and loss of potency, capsules must be dispensed and stored in the manufacturer bottle with the original desiccant cap or blister package. Do not repackage or store capsules in any other container. If dispensed in the manufacturer bottle, the product must be used within 4 months of opening.

    STORAGE

    Pradaxa:
    - Product must be used within 4 months after opening
    - Protect from moisture
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    - Store in original package until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Dabigatran is contraindicated in patients with a history of serious dabigatran hypersensitivity, such as an anaphylactic reaction.

    Anticoagulant therapy, bleeding

    Dabigatran is contraindicated in any patient with active pathological bleeding, as dabigatran use increases the risk of bleeding and can cause significant, sometimes fatal bleeding. Risk factors for bleeding include the use of other anticoagulant therapy (i.e., drugs that increase the risk of bleeding such as antiplatelet drugs, heparin, fibrinolytic therapy, selective serotonin re-uptake inhibitors, P-gp inhibitors, and chronic NSAID use) and delivering a baby. Promptly evaluate for any signs or symptoms of blood loss such as a drop in hemoglobin and/or hematocrit or hypotension. Evaluation of renal function should be considered. The half-life and anticoagulant activity of dabigatran are increased in patients with renal dysfunction. If active pathological bleeding occurs, dabigatran should be discontinued. Post-marketing reports of serious, sometimes fatal, bleeding events have been reported. The FDA is analyzing the events to determine whether these reports are occurring more often than would be expected and reviewing the reports for evidence of inappropriate dosing, use of interacting drugs, or other clinical factors that might lead to a bleeding event. In a large (n = 18,000) comparative trial of dabigatran and warfarin, major bleeding events occurred at similar rates with the 2 drugs. The FDA recommends that healthcare professionals who prescribe dabigatran follow the recommendations in the approved drug label. A reversal agent, idarucizumab, is available when the reversal of the anticoagulant effect of dabigatran is needed for emergent or urgent surgeries or procedures or in cases of life-threatening or uncontrolled bleeding. If the reversal agent is not available to the practitioner, alternative treatment can be employed, based on conservative approaches, but should only be pursued in the absence of accessibility to the specific reversal agent. Dabigatran has low protein binding and can be dialyzed with removal of approximately 50% of the drug over 4 hours; however, data are limited regarding this approach. Prothrombin complex concentrates or recombinant factor VIIa may be considered, but the use of these agents has not been evaluated in clinical trials. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of dabigatran. The manufacturer recommends consideration for the use of platelet concentrates in patients with thrombocytopenia or if long-acting antiplatelet drugs have been used.

    Abrupt discontinuation

    Avoid the abrupt discontinuation of dabigatran in the absence of adequate alternative anticoagulation. Discontinuing dabigatran puts patients at an increased risk of thrombotic events. If dabigatran must be discontinued for reasons other than pathological bleeding or completion of therapy, consider administering another anticoagulant, and reinitiate therapy with dabigatran as soon as medically appropriate.

    Surgery

    Dabigatran should be used with extreme caution in patients undergoing surgery and interventions due to the risk of bleeding. If possible, dabigatran should be discontinued 1 to 2 days (CrCl 50 mL/min or more) or 3 to 5 days (CrCl less than 50 mL/min) prior to invasive or surgical procedures. Consider a longer time between dabigatran discontinuation and surgical intervention for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required. If surgery cannot be delayed, there is an increased risk of bleeding, which should be weighed against the urgency of the intervention. Idarucizumab, a specific dabigatran reversal agent, should be considered for emergency surgery or urgent procedures where reversal of the anticoagulant effect of dabigatran is needed. Dabigatran should be restarted as soon as medically appropriate.

    Dialysis, renal failure, renal impairment

    Use dabigatran with caution in patients with renal impairment; the anticoagulant activity and half-life of dabigatran are increased in these patients. Renal impairment and P-glycoprotein (P-gp) inhibition are the major independent risk factors for increased dabigatran exposure and consequent increased risk for bleeding. Assess renal function before initiation of dabigatran therapy and during clinical situations that may be associated with a decline in renal function. A dosage reduction is required when dabigatran is administered to patients with severe renal impairment (CrCl <= 30 mL/min). Dosage recommendations are not available for patients with CrCl < 15 mL/min or for those with renal failure on dialysis. The concomitant use of dabigatran and P-gp inhibitors is not recommended in patients with severe renal impairment (CrCl < 30 mL/min); dabigatran dosage adjustments are recommended for patients with moderate impairment who are also taking certain P-gp inhibitors.

    Geriatric

    Dabigatran has been studied in geriatric patients. In the RE-LY trial, 82% of patients were 65 years of age or older and 40% were at least 75 years of age. The risk of stroke and bleeding increases with age; however, according to the manufacturer, the risk-benefit profile is favorable among all age groups. Impaired renal function is an independent risk factor for an increase in exposure to dabigatran; assess creatinine clearance as clinically indicated since the elderly are more likely to have reduced renal clearance. According to the Beers Criteria, dabigatran is a potentially inappropriate medication (PIM) in patients 75 years of age and older and caution is recommended since there is a greater risk of bleeding than with warfarin and reported rates with other target-specific oral anticoagulants. In addition, there is a lack of evidence of efficacy and safety in patients with a creatinine clearance (CrCl) less than 30 mL/min and the Beers expert panel recommends avoiding dabigatran in this patient population due to an increased risk of bleeding.

    Children, infants, neonates

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

    Labor, obstetric delivery, pregnancy

    Dabigatran is classified as FDA pregnancy category C. Animal reproductive studies have shown adverse effects on reproductive capacity and vaginal/uterine bleeding close to parturition. The safety and efficacy of dabigatran during labor and delivery have not been studied; however, labor and obstetric delivery are considered risk factors for bleeding. Consider the increased risk of bleeding and stroke before using dabigatran in this setting.

    Breast-feeding

    It is not known whether dabigatran is excreted in human milk. If pharmacotherapy is necessary in the nursing mother, the American Academy of Pediatrics (AAP) considers warfarin to be usually compatible with breast-feeding. Low-molecular weight heparins and heparin have relatively high molecular weights ; therefore, these drugs are not expected to be excreted into human milk to a clinically significant degree. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Mechanical heart valves, prosthetic heart valves

    Dabigatran is contraindicated for use in patients with mechanical heart valves. The safety and efficacy of dabigatran in patients with bileaflet mechanical heart valves was evaluated in the RE-ALIGN trial in which patients with recently implanted (within 3 days post-operatively) or implanted more than 3 months prior to enrollment were randomized to dose adjusted warfarin or dabigatran (150, 220, or 300 mg twice daily). The trial was terminated early due to more thromboembolic events (valve thrombosis, stroke, and myocardial infarction) and major bleeding in the dabigatran group compared to the warfarin group. All patients with major bleeding had pericardial bleeding. The thromboembolic events and major bleeding were seen in patients initiated on dabigatran post-operatively as well as those whose valves had been implanted more than 3 months prior to enrollment. The use of dabigatran in patients with bio-prosthetic heart valves has not been studied and is not recommended.

    Epidural anesthesia, lumbar puncture, spinal anesthesia

    Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated with dabigatran. Epidural or spinal hematomas that may result in long-term or permanent paralysis may occur in patients who are anticoagulated and are receiving neuraxial anesthesia or undergoing spinal puncture. To reduce the potential risk of bleeding, it is best to perform the placement or removal of an epidural catheter or lumbar puncture when the anticoagulant effect of dabigatran is low based on the pharmacokinetic profile of dabigatran. The exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include use of indwelling epidural catheters; concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants; history of spinal deformity or spinal surgery; and traumatic or repeated epidural or spinal puncture. If epidural anesthesia, lumbar puncture, or spinal anesthesia is employed, monitor patients frequently for signs and symptoms of neurological impairment (e.g., midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction). Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

    Intramuscular injections

     Intramuscular injections of other medications should not be administered to patients receiving dabigatran. IM injections may cause bleeding, bruising, or hematomas.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 3.1-6.1
    anaphylactic shock / Rapid / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    intracranial bleeding / Delayed / 0.1-0.3
    pericardial effusion / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    esophageal ulceration / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    thrombosis / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    stroke / Early / Incidence not known

    Moderate

    bleeding / Early / 0-19.4
    edema / Delayed / 0-1.0
    esophagitis / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    urticaria / Rapid / 0-1.0
    pruritus / Rapid / 0-1.0
    rash (unspecified) / Early / 0-1.0
    dyspepsia / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    gastroesophageal reflux / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) The use of abciximab within 7 days of use an oral anticoagulant is contraindicated unless the patient's prothrombin time is less than or equal to 1.2 times the control value. Because abciximab inhibits platelet aggregation, additive effects may be seen when abciximab is given in combination with other agents that affect hemostasis such as other platelet inhibitors (e.g. aspirin, ASA, clopidogrel, dipyridamole, ticlopidine), thrombolytic agents (e.g. alteplase, reteplase, streptokinase), and anticoagulants (e.g., heparin, warfarin). However, in clinical trials with abciximab, aspirin and heparin were administered concomitantly. The bleeding risk is significantly increased with concurrent abciximab and thrombolytic therapy; the risks of combination therapy should be weighed against the potential benefits. The GUSTO V study evaluated reduced-dose reteplase in combination with full dose abciximab, in comparison to full dose reteplase alone in patients with acute myocardial infarction (MI); all patients received concurrent aspirin and heparin therapy. The combination regimen was associated with a two-fold increase in moderate to severe non-intracranial bleeding complications, including spontaneous GI bleeding. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Although NSAIDs lacks platelet inhibitory effects, an increased risk for GI bleeding is possible when NSAIDs are administered during abciximab therapy.
    Ado-Trastuzumab emtansine: (Major) Use caution if coadministration of anticoagulants such as antithrombin III, apixaban, argatroban, bivalirudin, dabigatran, dalteparin, danaparoid, desirudin, enoxaparin, fondaparinux, heparin, lepirudin, rivaroxaban, and warfarin with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding with ado-trastuzumab emtansine therapy. According to the manufacturer of ado-trastuzumab emtansine, if anticoagulant therapy cannot be avoided, additional monitoring of platelets and bleeding risk may be necessary. In a randomized, multicenter, open-label clinical trial of patients with HER2-positive metastatic breast cancer, hemorrhage occurred in 32.2% (>= grade 3, 1.8%) of patients treated with ado-trastuzumab emtansine (n = 490) compared with 16.4% (>= grade 3, 0.8%) of those who received lapatinib plus capecitabine (n = 488); some patients who experienced bleeding were also receiving anticoagulation therapy, antiplatelet therapy, or had thrombocytopenia, while others had no known additional risk factors.
    Alteplase, tPA: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Altretamine: (Moderate) Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Amiodarone: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with amiodarone, a 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 amiodarone 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 amiodarone, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. Coadministration of dabigatran and a single oral dose of 600 mg amiodarone resulted in an increase in dabigatran AUC and Cmax by 58% and 50%, respectively. In addition, coadministration resulted in a 65% increase in renal clearance of dabigatran. Due to the long half-life of amiodarone, the increase in renal clearance may persist after discontinuation of amiodarone. Data from the RE-LY trial indicate no significant changes in dabigatran trough concentrations were seen in patients who received concomitant therapy with amiodarone. In clinical studies, dabigatran was found to have no effect on the pharmacokinetics of amiodarone. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Amoxicillin; Clarithromycin; Lansoprazole: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with clarithromycin, a P-gp inhibitor. Although the coadministration of dabigatran and clarithromycin has no effect on the pharmacokinetics of dabigatran or clarithromycin in healthy subjects, 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 clarithromycin 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 clarithromycin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with lansoprazole, a 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 lansoprazole 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 lansoprazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with clarithromycin, a P-gp inhibitor. Although the coadministration of dabigatran and clarithromycin has no effect on the pharmacokinetics of dabigatran or clarithromycin in healthy subjects, 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 clarithromycin 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 clarithromycin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with omeprazole, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran while taking products containing omeprazole including omeprazole; sodium bicarbonate. 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 omeprazole 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 omeprazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    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 other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. In addition, a phase II trial, aspirin (81 mg or 325 mg) was randomly assigned to patients with atrial fibrillation receiving dabigatran (150 mg twice daily). Data obtained from logistic regression analysis suggest that the concomitant administration of aspirin and dabigatran may increase the risk of bleeding from 12% to 18% (81 mg aspirin) or 24% (325 mg aspirin). Monitor patients closely for signs of bleeding if dabigatran or anagrelide is given concomitantly with aspirin.
    Anthracyclines: (Moderate) Due to the thrombocytopenic effects of anthracyclines, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, rivaroxaban is a mild P-glycoprotein (P-gp) inhibitor and doxorubicin is a major substrate of P-gp. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of P-gp, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of rivaroxaban and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Antithrombin III: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Antithymocyte Globulin: (Moderate) Drugs that can cause thrombocytopenia, such as antithymocyte globulin, may lead to an increased risk of bleeding when given concurrently with anticoagulants.
    Apixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Argatroban: (Major) Based on the pharmacology of dabigatran and apixaban, coadminsitration could cause additive risk of bleeding.
    Arsenic Trioxide: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Aspirin, ASA; 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.
    Aspirin, ASA; Omeprazole: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with omeprazole, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran while taking products containing omeprazole including omeprazole; sodium bicarbonate. 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 omeprazole 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 omeprazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Atazanavir; Cobicistat: (Moderate) Avoid the coadministration of dabigatran and cobicistat in patients with severe renal impairment (CrCl less than 30 mL/minute). 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 cobicistat in patients with CrCl less than 50 mL/minute. Coadministration may result in increased dabigatran serum concentrations, increasing the risk of dabigatran adverse effects. Dabigatran is a substrate of p-glycoprotein (P-gp) and cobicistat is a P-gp inhibitor. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) In general, avoid coadministration of dabigatran with P-glycoprotein (P-gp) inducers, such as phenobarbital. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
    Azithromycin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with azithromycin, a 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 azithromycin 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 azithromycin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) In general, avoid coadministration of dabigatran with P-glycoprotein (P-gp) inducers, such as phenobarbital. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
    Betrixaban: (Major) Avoid concurrent use of betrixaban with dabigatran due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and other anticoagulants are used concomitantly. Coadministration of betrixaban and other anticoagulants may increase the risk of bleeding.
    Bevacizumab: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Bivalirudin: (Major) Based on the pharmacology of dabigatran and bivalirudin, coadministration could cause additive risk of bleeding.
    Boceprevir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with boceprevir, 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 boceprevir 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 boceprevir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Bosutinib: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with bosutinib, a 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 bosutinib in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with bosutinib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Bupropion; Naltrexone: (Moderate) Give the extended-release injectable suspension of naltrexone cautiously to patients taking anticoagulants. Steps should be taken to avoid the risk of bleeding and hematoma formation following intramuscular injection.
    Cabozantinib: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with cabozantinib, 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 cabozantinib in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with cabozantinib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Canagliflozin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with canagliflozin, 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 canagliflozin in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with canagliflozin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Canagliflozin; Metformin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with canagliflozin, 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 canagliflozin in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with canagliflozin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Carbamazepine: (Major) In general, avoid coadministration of dabigatran with P-glycoprotein (P-gp) inducers, such as carbamazepine. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
    Carbenicillin: (Moderate) Some penicillins (e.g., carbenicillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Carvedilol: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with carvedilol, a 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 carvedilol 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 carvedilol, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Celecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Chondroitin; Glucosamine: (Moderate) Increased effects from concomitant anticoagulant drugs such as 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 such as warfarin until data confirming the safety of MSM in patients taking these drugs 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 warfarin should be observed for increased bleeding.
    Cilostazol: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Citalopram: (Major) Patients should be instructed to monitor for signs and symptoms of bleeding while taking a selective serotonin reuptake inhibitor (SSRI) concurrently with dabigatran and to promptly report any bleeding events to their prescriber. Although clinical data are limited, SSRIs may potentiate the hypoprothrombinemic effects of anticoagulants, perhaps by inhibiting platelet aggregation.
    Clarithromycin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with clarithromycin, a P-gp inhibitor. Although the coadministration of dabigatran and clarithromycin has no effect on the pharmacokinetics of dabigatran or clarithromycin in healthy subjects, 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 clarithromycin 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 clarithromycin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Clopidogrel: (Moderate) Coadministration of dabigatran and clopidogrel (300 mg or 600 mg loading dose) resulted in an increase in dabigatran AUC and Cmax of 30% and 40%, respectively; however capillary bleeding times were not further prolonged compared to clopidogrel monotherapy. In addition, coagulation measures for dabigatran's effect (aPTT, ECT, and TT) were unchanged, and inhibition of platelet aggregation (IPA), a measure of clopidogrel's effect, was unchanged. However, the manufacturer notes that the concomitant use of dabitatran and platelet inhibiting agents may increase the risk of bleeding. Monitor patients closely for signs of bleeding if dabigatran is given concomitantly with any platelet inhibiting agents.
    Cobicistat: (Moderate) Avoid the coadministration of dabigatran and cobicistat in patients with severe renal impairment (CrCl less than 30 mL/minute). 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 cobicistat in patients with CrCl less than 50 mL/minute. Coadministration may result in increased dabigatran serum concentrations, increasing the risk of dabigatran adverse effects. Dabigatran is a substrate of p-glycoprotein (P-gp) and cobicistat is a P-gp inhibitor. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Avoid the coadministration of dabigatran and cobicistat in patients with severe renal impairment (CrCl less than 30 mL/minute). 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 cobicistat in patients with CrCl less than 50 mL/minute. Coadministration may result in increased dabigatran serum concentrations, increasing the risk of dabigatran adverse effects. Dabigatran is a substrate of p-glycoprotein (P-gp) and cobicistat is a P-gp inhibitor. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Avoid the coadministration of dabigatran and cobicistat in patients with severe renal impairment (CrCl less than 30 mL/minute). 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 cobicistat in patients with CrCl less than 50 mL/minute. Coadministration may result in increased dabigatran serum concentrations, increasing the risk of dabigatran adverse effects. Dabigatran is a substrate of p-glycoprotein (P-gp) and cobicistat is a P-gp inhibitor. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Cod Liver Oil: (Major) Cod liver oil should be used only with caution and with frequent monitoring in patients on concurrent anticoagulants. In a limited number of patients, the hypoprothrombinemic response to warfarin was increased following large doses of vitamin A. Additionally, omega-3 fatty acids contained in cod liver oil may inhibit platelet aggregation. Theoretically, the risk of bleeding may be increased, but some studies that combined omega-3 fatty acids and anticoagulant 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 3 to 6 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 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 cod liver oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly. (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are 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 3-6 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 fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
    Conivaptan: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with conivaptan, a 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 conivaptan 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 conivaptan, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Crizotinib: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with crizotinib is necessary in patients with CrCL greater than 50 mL/minute. Avoid coadministration in patients with CrCL less than 50 mL/minute 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 in patients with CrCL less than 30 mL/minute in patients with non-valvular atrial fibrillation. Dabigatran is a P-glycoprotein (P-gp) substrate. Crizotinib inhibits P-gp at clinically relevant concentrations and has the potential to increase plasma concentrations of drugs that are substrates of P-gp. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function.
    Cyclosporine: (Major) Avoid concomitant use of dabigatran and cyclosporine. Increased serum concentrations of dabigatran and an increased risk of bleeding are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with cyclosporine, a P-gp inhibitor. P-gp inhibition is a major independent factor that results in increased exposure to dabigatran.
    Cytarabine, ARA-C: (Moderate) Due to the thrombocytopenic effects of pyrimidine analogs, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Daclatasvir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with daclatasvir, a 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 daclatasvir 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 daclatasvir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dalteparin: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Danaparoid: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Danazol: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
    Darunavir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with darunavir, a 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 in patients with CrCl < 50 ml/min. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl < 30 ml/min), avoid coadministration with P-gp inhibitors, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Darunavir; Cobicistat: (Moderate) Avoid the coadministration of dabigatran and cobicistat in patients with severe renal impairment (CrCl less than 30 mL/minute). 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 cobicistat in patients with CrCl less than 50 mL/minute. Coadministration may result in increased dabigatran serum concentrations, increasing the risk of dabigatran adverse effects. Dabigatran is a substrate of p-glycoprotein (P-gp) and cobicistat is a P-gp inhibitor. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with darunavir, a 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 in patients with CrCl < 50 ml/min. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl < 30 ml/min), avoid coadministration with P-gp inhibitors, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir as ritonavir and paritaprevir are P-gp inhibitors. 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), avoid coadministration with P-gp inhibitors like ritonavir in patients with CrCl less than 50 mL/min. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/min), avoid coadministration with ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as ritonavir and paritaprevir are P-gp inhibitors. 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 ritonavir in patients with CrCl less than 50 mL/min. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/min), avoid coadministration with ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as ritonavir and paritaprevir are P-gp inhibitors. 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), avoid coadministration with P-gp inhibitors like ritonavir in patients with CrCl less than 50 mL/min. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/min), avoid coadministration with ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ritonavir, a 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 ritonavir 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 ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Dasatinib: (Moderate) Due to the thrombocytopenic and possible platelet inhibiting effects of dasatinib, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. In addition, dasatinib is an inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. Coadministration may result in increases in rivaroxaban exposure and may increase bleeding risk. Caution should be exercised if patients are required to take anticoagulants concomitantly with dasatinib.
    Decitabine: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
    Defibrotide: (Severe) Coadministration of defibrotide with antithrombotic agents like anticoagulants 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 systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
    Denileukin Diftitox: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Desirudin: (Major) Any agent which may enhance the risk of hemorrhage should generally be discontinued before initiating desirudin therapy. These agents include anticoagulants. If coadministration cannot be avoided, close clinical and laboratory monitoring should be conducted. If a patient is switched from oral anticoagulants to desirudin therapy or from desirudin to oral anticoagulants, the anticoagulant activity should continue to be closely monitored with appropriate methods. That activity should be taken into account in the evaluation of the overall coagulation status of the patient during the switch.
    Desvenlafaxine: (Major) Platelet aggregation may be impaired by desvenlafaxine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication in patients receiving anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
    Dextromethorphan; Quinidine: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with quinidine, a 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 quinidine 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 quinidine, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. Coadministration of quinidine 200 mg every 2 hours up to a total dose of 1000 mg and dabigatran administered over 3 consecutive days, the last evening dose on Day 3 with or without quinidine pre-dosing, resulted in an increase in dabigatran AUC and Cmax of 53% and 56%, respectively. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Diclofenac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diclofenac; Misoprostol: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diflunisal: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diltiazem: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with diltiazem, a 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 diltiazem 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 diltiazem, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Diphenhydramine; Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diphenhydramine; Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    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.
    Dronedarone: (Major) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with dronedarone, a 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 dronedarone in patients with CrCl less than 50 mL/minute. When used in patients with non-valvular atrial fibrillation, avoid the coadministration of dabigatran and dronedarone in patients with severe renal impairment (CrCl less than 30 mL/minute), and consider reducing the dabigatran dose to 75 mg twice daily when dronedarone and dabigatran are coadministered in patients with moderate renal impairment (CrCl 30 to 50 mL/min). Simultaneous administration of dabigatran and dronedarone (administered once or twice daily) increases exposure to dabigatran by 70 to 140% compared to dabigatran alone. The increase in exposure is only 30 to 60% higher compared to dabigatran alone when dronedarone is administered 2 hours after dabigatran. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any anticoagulants. There is an additive risk of beeding.
    Duloxetine: (Major) Platelet aggregation may be impaired by duloxetine 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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Edoxaban: (Major) Avoid concurrent use of edoxaban with dabigatran due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if edoxaban and other anticoagulants are used concomitantly. Coadministration of edoxaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with edoxaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from edoxaban.
    Eliglustat: (Major) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with eliglustat, a 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 eliglustat 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 eliglustat, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Eltrombopag: (Moderate) Use caution when discontinuing eltrombopag in patients receiving anticoagulants (e.g., warfarin, enoxaparin, dabigatran, rivaroxaban). The risk of bleeding and recurrent thrombocytopenia is increased in patients receiving these drugs when eltrombopag is discontinued.
    Enoxaparin: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Epoprostenol: (Moderate) When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding.
    Eptifibatide: (Moderate) Concomitant use of eptifibatide and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
    Erythromycin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with erythromycin, a 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 erythromycin 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 erythromycin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Erythromycin; Sulfisoxazole: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with erythromycin, a 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 erythromycin 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 erythromycin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Escitalopram: (Major) Patients should be instructed to monitor for signs and symptoms of bleeding while taking a selective serotonin reuptake inhibitor (SSRI) concurrently with dabigatran and to promptly report any bleeding events to their prescriber. Although clinical data are limited, SSRIs may potentiate the hypoprothrombinemic effects of anticoagulants, perhaps by inhibiting platelet aggregation.
    Esomeprazole; Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Esterified Estrogens; Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Estramustine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Etodolac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Etravirine: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with etravirine, a 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 etravirine in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with etravirine, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Ezetimibe; Simvastatin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with simvastatin, a P-gp inhibitor. An alternative statin agent that does not inhibit P-gp should be considered. Consider patient risks versus benenfits. If use together is medically necessary, then patients should be monitored for increased adverse effects of dabigatran and an increased risk for bleeding. In one clinical trial, patients receiving dabigatran etexilate with simvastatin or lovastatin experienced a higher risk of major hemorrhage relative to the use of other statins that are not P-gp inhibitors. 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 simvastatin 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 simvastatin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Famotidine; Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fenoprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are 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 3-6 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 fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Floxuridine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Fluorouracil, 5-FU: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Fluoxetine: (Major) Patients should be instructed to monitor for signs and symptoms of bleeding while taking a selective serotonin reuptake inhibitor (SSRI) concurrently with dabigatran and to promptly report any bleeding events to their prescriber. Although clinical data are limited, SSRIs may potentiate the hypoprothrombinemic effects of anticoagulants, perhaps by inhibiting platelet aggregation.
    Fluoxetine; Olanzapine: (Major) Patients should be instructed to monitor for signs and symptoms of bleeding while taking a selective serotonin reuptake inhibitor (SSRI) concurrently with dabigatran and to promptly report any bleeding events to their prescriber. Although clinical data are limited, SSRIs may potentiate the hypoprothrombinemic effects of anticoagulants, perhaps by inhibiting platelet aggregation.
    Flurbiprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Fluvoxamine: (Major) Patients should be instructed to monitor for signs and symptoms of bleeding while taking a selective serotonin reuptake inhibitor (SSRI) concurrently with dabigatran and to promptly report any bleeding events to their prescriber. Although clinical data are limited, SSRIs may potentiate the hypoprothrombinemic effects of anticoagulants, perhaps by inhibiting platelet aggregation.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Fondaparinux: (Major) Discontinue dabigatran before starting fondaparinux due to the increased bleeding risk, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.
    Fosamprenavir: (Major) In general, avoid coadministration of dabigatran with P-glycoprotein (P-gp) inducers, such as fosamprenavir. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
    Fosphenytoin: (Moderate) In general, avoid coadministration of dabigatran with P-glycoprotein (P-gp) inducers, such as phenytoin or fosphenytoin. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
    Fulvestrant: (Moderate) Because fulvestrant is given intramuscularly, it should not be used or given with caution in patients receiving anticoagulants. Fulvestrant IM injections may cause bleeding, bruising, or hematomas in these patients.
    Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive bleeding may occur if anticoagulants are given in combination with garlic, allium sativum. In regard to warfarin, no substantial clinical data are available to support or deny a potential for interaction; the data are limited to a random case report. A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    Ginger, Zingiber officinale: (Moderate) Additive bleeding may occur if anticoagulants are given in combination with ginger, zingiber officinale. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Patients taking ginger and an anticoagulant should be monitored closely for bleeding.
    Ginkgo, Ginkgo biloba: (Major) Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants. Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents. A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion.
    Glecaprevir; Pibrentasvir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with glecaprevir, a 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 glecaprevir 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 glecaprevir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. In drug interaction studies, coadministration of dabigatran with glecaprevir; pibrentasvir resulted in over a 2-fold increase in the AUC of dabigatran. (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with pibrentasvir, a 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 pibrentasvir 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 pibrentasvir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. In drug interaction studies, coadministration of dabigatran with glecaprevir; pibrentasvir resulted in over a 2-fold increase in the AUC of dabigatran.
    Grapefruit juice: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with grapefruit juice, a 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), avoid coadministration with P-gp inhibitors like grapefruit juice in patients with CrCl < 50 ml/min. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl < 30 ml/min), avoid coadministration with grapefruit juice, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin, and others) thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, cilostazol and others). Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with any of these agents. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin; stability of the diet can be an important factor in maintaining anticoagulation goals. Occult sources of vitamin K include green tea and green tea dietary supplements. Published data are limited in regard to this interaction. A patient with previous INRs of 3.2. and 3.79 on a dose of 7.5mg daily of warfarin (goal INR 2.5 to 3.5) had an INR of 1.37. One month later, the patient's INR was 1.14. The patient admitted that he had started consuming 0.51 gallon of green tea daily approximately one week prior to the INR of 1.37. The patient denied noncompliance and other changes in diet, medications, or health. The patient discontinued green tea and one week later his INR was 2.55. While the amount of vitamin K in a single cup of brewed green tea may not be high (0.03 mcg/100 g), the actual amount may vary from cup to cup depending on the amount of tea leaves used, the length of time the tea bags are allowed to brew, and the volume of tea consumed. Additionally, if a patient drinks multiple cups of tea per day, the amount of vitamin K could reach significance. It is recommended that patients on warfarin maintain a stable intake of green tea.
    Guarana: (Major) Guarana has been shown to possess minor antiplatelet activity and, therefore, concurrent use of guarana and anticoagulants or platelet inhibitors should be avoided.
    Hemin: (Major) Because hemin has exhibited transient, mild anticoagulant effects during clinical studies, concurrent use of anticoagulants should be avoided. The extent and duration of the hypocoagulable state induced by hemin has not been established.
    Heparin: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Hydrocodone; Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Hydroxyurea: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Ibritumomab Tiuxetan: (Moderate) Due to the thrombocytopenic effects of the ibritumomab tiuxetan therapeutic regimen, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Ibrutinib: (Minor) Use caution with concomitant use of ibrutinib and anticoagulants such as dabigatran. Bleeding or bruising events occurred in 48 to 63% (grade 3 or 4, 5 to 6%) of patients treated with ibrutinib in clinical trials. The mechanism for bleeding is not well understood, and the risk of hemorrhage may be increased in patients receiving anticoagulant therapy.
    Ibuprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Oxycodone: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ibuprofen; Pseudoephedrine: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    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.
    Ifosfamide: (Moderate) Due to the thrombocytopenic effects of ifosfamide, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Iloperidone: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with iloperidone, 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 iloperidone in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with iloperidone, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding.
    Imatinib: (Major) Due to the thrombocytopenic effects of imatinib, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Monitor closely for bleeding.
    Indomethacin: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Interferon Alfa-2a: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b; Ribavirin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfacon-1: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Intravenous Lipid Emulsions: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are 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 3-6 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 fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
    Isavuconazonium: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with isavuconazonium, 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 isavuconazonium 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 isavuconazonium, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) In general, avoid coadministration of dabigatran with P-gp inducers, such as rifampin. Concomitant administration of 600 mg rifampin for 7 days followed by a single dose of dabigatran decreased dabigatran AUC and Cmax by 66% and 67%, respectively. Dabigatran exposure returned to normal 7 days after cessation of rifampin therapy.
    Isoniazid, INH; Rifampin: (Major) In general, avoid coadministration of dabigatran with P-gp inducers, such as rifampin. Concomitant administration of 600 mg rifampin for 7 days followed by a single dose of dabigatran decreased dabigatran AUC and Cmax by 66% and 67%, respectively. Dabigatran exposure returned to normal 7 days after cessation of rifampin therapy.
    Itraconazole: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with itraconazole, a 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 itraconazole 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 itraconazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Ivacaftor: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ivacaftor, 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 ivacaftor in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with ivacaftor, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Kava Kava, Piper methysticum: (Moderate) Kava kava, Piper methysticum does appear to have some anti-thrombotic activity. Persons who are receiving anticoagulants should not take kava kava without first discussing use with their health care professional. Kava kava, Piper methysticum exhibits antithrombotic activity and also inhibits CYP isozymes important in warfarin clearance such as CYP2C9, 2C19, 1A2 and 3A4. Avoid concurrent use of herbs which interact with warfarin when possible. If these herbal products are taken concurrently with warfarin, monitor INR and adjust warfarin dosage to attain clinical and anticoagulant endpoints.
    Ketoconazole: (Major) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ketoconazole, a 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 ketoconazole in patients with CrCl less than 50 mL/minute. When used in patients with non-valvular atrial fibrillation, avoid the coadministration of dabigatran and systemic ketoconazole in patients with severe renal impairment (CrCl less than 30 mL/minute), and consider reducing the dabigatran dose to 75 mg twice daily when ketoconazole and dabigatran are coadministered in patients with moderate renal impairment (CrCl 30 to 50 ml/min). Coadministration of dabigatran and ketoconazole results in increased dabigatran serum concentrations and, therefore, an increased risk of bleeding. Coadministration of a single dose of 400 mg ketoconazole increased the dabigatran AUC and Cmax by 138% and 135%, respectively. Coadministration of multiple daily doses of 400 mg ketoconazole increased dabigatran AUC and Cmax by 153% and 149%, respectively. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Ketoprofen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ketorolac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Lansoprazole: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with lansoprazole, a 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 lansoprazole 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 lansoprazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Lansoprazole; Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use. (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with lansoprazole, a 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 lansoprazole 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 lansoprazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Lapatinib: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with lapatinib, a 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 lapatinib 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 lapatinib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Ledipasvir; Sofosbuvir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ledipasvir; sofosbuvir. Ledipasvir is a 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 ledipasvir; sofosbuvir 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 ledipasvir; sofosbuvir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Lepirudin: (Major) Based on the pharmacology of dabigatran and lepirudin, coadministration could cause an additive risk of bleeding.
    Levomilnacipran: (Major) 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 anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Lomitapide: (Moderate) Concomitant use of lomitapide and dabigatran may result in increased serum concentrations of dabigatran. According to the manufacturer of lomitapide, dose reduction of dabigatran should be considered during concurrent use. Lomitapide is an inhibitor of P-glycoprotein (P-gp) and dabigatran is a P-gp substrate.
    Lomustine, CCNU: (Moderate) Due to the bone marrow suppressive and thrombocytopenic effects of lomustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Lopinavir; Ritonavir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with lopinavir; ritonavir, a 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 lopinavir; ritonavir 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 lopinavir; ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ritonavir, a 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 ritonavir 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 ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Lovastatin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with lovastatin, a P-gp inhibitor. An alternative statin agent that does not inhibit P-gp should be considered. Consider patient risks versus benenfits. If use together is medically necssary, patients should be monitored for increased adverse effects of dabigatran and an increased risk for bleeding. In one clinical trial, patients receiving dabigatran etexilate with lovastatin or simvastatin experienced a higher risk of major hemorrhage relative to the use of other statins that are not P-gp inhibitors. 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 lovastatin 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 lovastatin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Lovastatin; Niacin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with lovastatin, a P-gp inhibitor. An alternative statin agent that does not inhibit P-gp should be considered. Consider patient risks versus benenfits. If use together is medically necssary, patients should be monitored for increased adverse effects of dabigatran and an increased risk for bleeding. In one clinical trial, patients receiving dabigatran etexilate with lovastatin or simvastatin experienced a higher risk of major hemorrhage relative to the use of other statins that are not P-gp inhibitors. 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 lovastatin 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 lovastatin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Lumacaftor; Ivacaftor: (Major) Concomitant use of dabigatran and lumacaftor; ivacaftor may alter dabigatran exposure; avoid coadministration if possible. Dabigatran is a substrate of the drug transporter P-glycoprotein (P-gp). In vitro data suggest that lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect of lumacaftor; ivacaftor on P-gp transport is not clear, but substrate exposure may be affected. FDA-approved labeling for dabigatran recommends, in general, to avoid coadministration with P-gp inducers. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax. Labeling also recommends to avoid coadministration with P-gp inhibitors in patients with a CrCl less than 50 mL/minute when used for treatment or reduction in risk of deep vein thrombosis (DVT) or pulmonary embolism or prophylaxis of DVT or PE following hip replacement surgery and in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function.
    Lumacaftor; Ivacaftor: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ivacaftor, 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 ivacaftor in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with ivacaftor, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Meclofenamate Sodium: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Mefenamic Acid: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Mefloquine: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with mefloquine, a 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 mefloquine 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 mefloquine, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Meloxicam: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
    Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs such as 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 such as warfarin until data confirming the safety of MSM in patients taking these drugs 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 warfarin should be observed for increased bleeding.
    Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
    Mifepristone, RU-486: (Major) When mifepristone, RU-486 is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the increased risk of serious bleeding. Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with mifepristone, RU-486, a 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 mifepristone, RU-486 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 mifepristone, RU-486, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Milnacipran: (Major) 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 anticoagulants. The causality and mechanism of this potential interaction have not been established. Patients should be instructed to monitor for signs and symptoms of bleeding while taking an SNRI with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Miltefosine: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
    Mycophenolate: (Moderate) Mycophenolate may causes thrombocytopenia and increase the risk for bleeding. Agents which may lead to an increased incidence of bleeding in patients with thrombocytopenia include anticoagulants.
    Nabumetone: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naltrexone: (Moderate) Give the extended-release injectable suspension of naltrexone cautiously to patients taking anticoagulants. Steps should be taken to avoid the risk of bleeding and hematoma formation following intramuscular injection.
    Nandrolone Decanoate: (Moderate) Androgens can enhance the effects of anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain prothrombin time at the desired therapeutic level. When anabolic steroid or androgen therapy is started or stopped in patients on anticoagulant therapy, close monitoring is required. Additionally, nandrolone decanoate may generate a pharmacodynamic interaction with warfarin by independently affecting the activity of circulating coagulation proteins. Androgens reduce the amount or activity of circulating coagulant proteins thereby enhancing the anticoagulant effect of warfarin.
    Naproxen: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Pseudoephedrine: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Naproxen; Sumatriptan: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Natural Antineoplastics: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Nelfinavir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with nelfinavir, a 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 nelfinavir 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 nelfinavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Neratinib: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with neratinib is necessary in patients with CrCL greater than 50 mL/minute. Avoid coadministration in patients with CrCL less than 50 mL/minute 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 in patients with CrCL less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function.
    Niacin; Simvastatin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with simvastatin, a P-gp inhibitor. An alternative statin agent that does not inhibit P-gp should be considered. Consider patient risks versus benenfits. If use together is medically necessary, then patients should be monitored for increased adverse effects of dabigatran and an increased risk for bleeding. In one clinical trial, patients receiving dabigatran etexilate with simvastatin or lovastatin experienced a higher risk of major hemorrhage relative to the use of other statins that are not P-gp inhibitors. 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 simvastatin 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 simvastatin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Nicardipine: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with nicardipine, a 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 nicardipine 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 nicardipine, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Nifedipine: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with nifedipine, 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 nifedipine 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 nifedipine, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Nilotinib: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with nilotinib, a 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 nilotinib 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 nilotinib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Nintedanib: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary.
    Nonsteroidal antiinflammatory drugs: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    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.
    Omacetaxine: (Major) Avoid the concomitant use of omacetaxine and anticoagulants when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as ritonavir and paritaprevir are P-gp inhibitors. 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 ritonavir in patients with CrCl less than 50 mL/min. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/min), avoid coadministration with ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as ritonavir and paritaprevir are P-gp inhibitors. 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), avoid coadministration with P-gp inhibitors like ritonavir in patients with CrCl less than 50 mL/min. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/min), avoid coadministration with ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ritonavir, a 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 ritonavir 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 ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Omeprazole: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with omeprazole, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran while taking products containing omeprazole including omeprazole; sodium bicarbonate. 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 omeprazole 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 omeprazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Omeprazole; Sodium Bicarbonate: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with omeprazole, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran while taking products containing omeprazole including omeprazole; sodium bicarbonate. 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 omeprazole 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 omeprazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Orlistat: (Moderate) Patients on chronic stable doses of anticoagulants, like dabigatran, should be monitored closely for changes in coagulation parameters when orlistat is prescribed. Reports of decreased prothrombin, increased INR, and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants.
    Oxandrolone: (Moderate) An increased effect of anticoagulants may occur with oxandrolone; the anticoagulant dosage may need adjustment downward with oxandrolone initiation or adjustment upward with oxandrolone discontinuation to maintain the desired clinical effect. Oxandrolone suppresses clotting factors II, V, VII, and X, which results in an increased prothrombin time. An increase in plasminogen-activator activity, and serum concentrations of plasminogen, protein C, and antithrombin III have occurred with several 17-alpha-alkylated androgens. For example, concurrent use of oxandrolone and warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). A multidose study of oxandrolone (5 or 10 mg PO twice daily) in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80 to 85% dose reduction) was necessary to maintain a target INR of 1.5. According to the manufacturer, if oxandrolone therapy is initiated in a patient already receiving warfarin, the dose of warfarin may need to be decreased significantly to reduce the potential for excessive INR elevations and associated risk of serious bleeding events. The patient should be closely monitored with frequent evaluation of the INR and clinical parameter, and the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen therapy is changed or discontinued.
    Oxaprozin: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Paliperidone: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with paliperidone, 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 paliperidone in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with paliperidone, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Pantoprazole: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with pantoprazole, a 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 pantoprazole 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 pantoprazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Paroxetine: (Major) Patients should be instructed to monitor for signs and symptoms of bleeding while taking a selective serotonin reuptake inhibitor (SSRI) concurrently with dabigatran and to promptly report any bleeding events to their prescriber. Although clinical data are limited, SSRIs may potentiate the hypoprothrombinemic effects of anticoagulants, perhaps by inhibiting platelet aggregation.
    Pentosan: (Major) 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 anticoagulants (e.g., dabigatran) in combination with pentosan.
    Phenobarbital: (Major) In general, avoid coadministration of dabigatran with P-glycoprotein (P-gp) inducers, such as phenobarbital. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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: (Moderate) In general, avoid coadministration of dabigatran with P-glycoprotein (P-gp) inducers, such as phenytoin or fosphenytoin. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
    Photosensitizing agents: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Piperacillin: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Piperacillin; Tazobactam: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Pirfenidone: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with pirfenidone, a weak 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 pirfenidone 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 pirfenidone, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Piroxicam: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Ponatinib: (Major) Concomitant use of ponatinib, a P-gp inhibitor, and dabigatran, a P-gp substrate, may increase the exposure of dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment may result in increased exposure of dabigatran compared to that seen with either factor alone. The use of dabigatran and P-gp inhibitors in patients with severe renal impairment (creatinine clearance of 15-30 ml/min) should be avoided.
    Porfimer: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Posaconazole: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with posaconazole, a 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 posaconazole 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 posaconazole, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone (DHEA) 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): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
    Prasugrel: (Moderate) Concomitant use of prasugrel and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
    Primidone: (Major) In general, avoid coadministration of dabigatran with primidone because of P-gp induction by phenobarbital, an active metabolite of primidone. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
    Propafenone: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with propafenone, a 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 propafenone 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 propafenone, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Quinidine: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with quinidine, a 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 quinidine 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 quinidine, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. Coadministration of quinidine 200 mg every 2 hours up to a total dose of 1000 mg and dabigatran administered over 3 consecutive days, the last evening dose on Day 3 with or without quinidine pre-dosing, resulted in an increase in dabigatran AUC and Cmax of 53% and 56%, respectively. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Rabies Immune Globulin, human RIG: (Minor) The intramuscular rabies immune globulin, human RIG should be administered cautiously to persons receiving anticoagulants. If used concurrently, monitor patients closely for bleeding at the IM injection site. All steps to avoid hematoma formation are recommended.
    Ranolazine: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ranolazine, a 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 ranolazine 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 ranolazine, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Regorafenib: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with regorafenib, 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 regorafenib in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with regorafenib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Reteplase, r-PA: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Rifampin: (Major) In general, avoid coadministration of dabigatran with P-gp inducers, such as rifampin. Concomitant administration of 600 mg rifampin for 7 days followed by a single dose of dabigatran decreased dabigatran AUC and Cmax by 66% and 67%, respectively. Dabigatran exposure returned to normal 7 days after cessation of rifampin therapy.
    Rifaximin: (Moderate) Coadministration of dabigatran and rifaximin may result in increased dabigatran serum concentrations, increasing the risk of dabigatran adverse effects. Coadministration of dabigatran and rifaximin should be avoided in patients with severe renal impairment (CrCl <= 30 ml/min). Dabigatran is a substrate of P-glycoprotein (P-gp); rifaximin is a mild P-gp inhibitor. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Ritonavir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ritonavir, a 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 ritonavir 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 ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Rivaroxaban: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with dabigatran.
    Rofecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Rolapitant: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with rolapitant, a 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 rolapitant 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 rolapitant, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Sapropterin: (Moderate) Caution is advised with the concomitant use of sapropterin and dabigatran as coadministration may result in increased systemic exposure of dabigatran. Dabigatran is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side 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 sapropterin 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 sapropterin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Saquinavir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with saquinavir, a 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 saquinavir 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 saquinavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Selective serotonin reuptake inhibitors: (Major) Patients should be instructed to monitor for signs and symptoms of bleeding while taking a selective serotonin reuptake inhibitor (SSRI) concurrently with dabigatran and to promptly report any bleeding events to their prescriber. Although clinical data are limited, SSRIs may potentiate the hypoprothrombinemic effects of anticoagulants, perhaps by inhibiting platelet aggregation.
    Sertraline: (Major) Patients should be instructed to monitor for signs and symptoms of bleeding while taking a selective serotonin reuptake inhibitor (SSRI) concurrently with dabigatran and to promptly report any bleeding events to their prescriber. Although clinical data are limited, SSRIs may potentiate the hypoprothrombinemic effects of anticoagulants, perhaps by inhibiting platelet aggregation.
    Simeprevir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with simeprevir, 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 simeprevir in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with simeprevir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Simvastatin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with simvastatin, a P-gp inhibitor. An alternative statin agent that does not inhibit P-gp should be considered. Consider patient risks versus benenfits. If use together is medically necessary, then patients should be monitored for increased adverse effects of dabigatran and an increased risk for bleeding. In one clinical trial, patients receiving dabigatran etexilate with simvastatin or lovastatin experienced a higher risk of major hemorrhage relative to the use of other statins that are not P-gp inhibitors. 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 simvastatin 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 simvastatin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Simvastatin; Sitagliptin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with simvastatin, a P-gp inhibitor. An alternative statin agent that does not inhibit P-gp should be considered. Consider patient risks versus benenfits. If use together is medically necessary, then patients should be monitored for increased adverse effects of dabigatran and an increased risk for bleeding. In one clinical trial, patients receiving dabigatran etexilate with simvastatin or lovastatin experienced a higher risk of major hemorrhage relative to the use of other statins that are not P-gp inhibitors. 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 simvastatin 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 simvastatin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) Increased dabigatran serum concentrations may occur when dabigatran is coadministered with voxilaprevir. Monitor dabigatran serum concentrations and adjust dabigatran dose as necessary. Dabigatran is a P-glycoprotein (P-gp) substrate and voxilaprevir inhibits P-gp.
    Sorafenib: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with sorafenib, 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 sorafenib in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with sorafenib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    St. John's Wort, Hypericum perforatum: (Major) In general, avoid coadministration of dabigatran with P-gp inducers, such as St. John's Wort, Hypericum perforatum. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
    Streptokinase: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Sulfinpyrazone: (Major) Sulfinpyrazone should be avoided when possible with concurrent anticoagulants, thrombin inhibitors, and thrombolytic agents due to potential for increased bleeding risk. Alternative uricosuric agents may be considered. Sulfinpyrazone is a platelet inhibitor and exhibits antithrombotic actions in addition to its uricosuric effects. Additive hematological effects are possible as a result of the platelet inhibitory effects of sulfinpyrazone; the sulfide metabolite of sulfinpyrazone appears responsible for this effect. Sulfinpyrazone is also known to markedly potentiate the effect of warfarin. Sulfinpyrazone may inhibit CYP2C9, leading to a decrease in the clearance of S-warfarin. If concurrent therapy is warranted, significant initial dosage reductions (e.g., 50%) of warfarin may be necessary, with further dosage adjusted based on INR values. The INR should be closely monitored during concurrent therapy with warfarin, particularly during the initiation or termination phases of sulfinpyrazone treatment.
    Sulindac: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Suvorexant: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with suvorexant, a 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 suvorexant 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 suvorexant, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Tacrolimus: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with tacrolimus, 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 tacrolimus in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation andsevere renal impairment (CrCl less than 30 mL/minute), avoid coadministration with tacrolimus, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Tamoxifen: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with tamoxifen, a 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 tamoxifen 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 tamoxifen, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Taxanes: (Moderate) Due to the thrombocytopenic effects of taxanes, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Telaprevir: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with telaprevir, 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 telaprevir 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 telaprevir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Telavancin: (Moderate) Telavancin has no effect on coagulation or platelet aggregation; however, caution is advised when administering telavancin concurrently with anticoagulants as telavancin may interfere with laboratory tests used in monitoring these medications. The coagulation tests affected by telavancin include prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), activated clotting time, and coagulation based factor Xa tests. When measured shortly after completion of a telavancin infusion, the results of these tests are increased; however, the effects of telavancin on these tests dissipate over time as plasma concentrations of telavancin decrease. Therefore, when administering telavancin in conjunction with anticoagulants ensure that blood samples for these coagulation tests are collected as close as possible to the patient's next telavancin dose.
    Telithromycin: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with telithromycin, 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 telithromycin 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 telithromycin, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Temsirolimus: (Major) Use caution if coadministration of temsirolimus with dabigatran is necessary in patients with CrCL higher than 50 mL/minute, and monitor for an increase in dabigatran-related adverse reactions. Avoid coadministration in patients with CrCL less than 50 mL/minute 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 in patients with CrCL less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Temsirolimus is a P-glycoprotein (P-gp) inhibitor in vitro, and dabigatran is a P-gp substrate. Pharmacokinetic data are not available for concomitant use of temsirolimus with P-gp substrates, but exposure to dabigatran is likely to increase.
    Tenecteplase, TNK-tPA: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Testosterone: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with testosterone, a 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 testosterone 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 testosterone, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Thrombolytic Agents: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Ticagrelor: (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.
    Ticarcillin: (Moderate) Some penicillins (e.g., ticarcillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Ticarcillin; Clavulanic Acid: (Moderate) Some penicillins (e.g., ticarcillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
    Ticlopidine: (Moderate) Because ticlopidine inhibits platelet aggregation, a potential additive risk for bleeding exists if ticlopidine is given in combination with other agents that affect hemostasis such as anticoagulants. Per the manufacturer of ticlopidine, if a patient is switched from an anticoagulant or a thrombolytic agent to ticlopidine, the former drug should be discontinued prior to the administration of ticlopidine.
    Tinzaparin: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Tipranavir: (Major) In general, avoid coadministration of dabigatran with P-gp inducers, such as tipranavir, a mild inducer. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
    Tirofiban: (Moderate) Concomitant use of tirofiban and other agents that affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding.
    Tolmetin: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Tolvaptan: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with tolvaptan, 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 tolvaptan 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 tolvaptan, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) 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.
    Trandolapril; Verapamil: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with verapamil, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran while taking products containing verapamil including trandolapril; verapamil. 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 verapamil 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 verapamil, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. Concomitant administration of verapamil and dabigatran results in an increased Cmax and AUC of dabigatran; the extent depends on the formulation of verapamil and timing of administration. The greatest increase in exposure of dabigatran occurs when verapamil is present in the gut when dabigatran is taken. In a pharmacokinetic study, immediate-release verapamil given 1 hour prior to dabigatran administration produced the greatest increase in exposure. If verapamil is administered 2 hours after dabigatran administration, the increase in AUC is negligible. Data from the RE-LY trial indicate no significant changes in dabigatran trough concentrations were seen in patients who received concomitant therapy with verapamil. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Trazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on anticoagulant therapy.
    Treprostinil: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Ulipristal: (Moderate) In the absence of clinical data, co-administration of ulipristal and P-gp substrates with narrow therapeutic indexes (e.g., dabigatran) is not recommended, particulary with daily administration regimens of ulipristal. It is not clear if single dose administration of ulipristal for emergency contraception would result in interactions of clinical significance. Dabigatran is a substrate of P-glycoprotein (P-gp), and ulipristal is mild inhibitor of P-gp. If the two drugs must be used together, use caution and monitor closely. Based on clinical data for 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 ulipristal 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 ulipristal, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Urokinase: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Valdecoxib: (Major) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Vandetanib: (Moderate) Use vandetanib and dabigatran together with caution; dabigatran levels may increase resulting in increased toxicity. Monitor patients for signs or symptoms of dabigatran adverse effects. Dabigatran is a P-glycoprotein (P-gp) substrate; vandetanib increased the AUC and Cmax values of a sensitive P-gp substrate by 23% and 29%, respectively, in a cross-over study (n = 14). P-gp inhibition and renal impairment are the major independent factors that result in increased dabigatran exposure. 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 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 P-gp inhibitors, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function.
    Vemurafenib: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with vemurafenib, 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 vemurafenib 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 vemurafenib, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Venlafaxine: (Major) Platelet aggregation may be impaired by venlafaxine 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 anticoagulants. Elevations in prothrombin time, activated partial thromboplastin and INR values have been reported post-marketing when venlafaxine was added to established warfarin therapy. Monitor INR levels when venlafaxine is added to or discontinued from warfarin therapy. Patients should be instructed to monitor for signs and symptoms of bleeding while taking venlafaxine concurrently with an anticoagulant medication and to promptly report any bleeding events to the practitioner.
    Verapamil: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with verapamil, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran while taking products containing verapamil including trandolapril; verapamil. 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 verapamil 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 verapamil, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. Concomitant administration of verapamil and dabigatran results in an increased Cmax and AUC of dabigatran; the extent depends on the formulation of verapamil and timing of administration. The greatest increase in exposure of dabigatran occurs when verapamil is present in the gut when dabigatran is taken. In a pharmacokinetic study, immediate-release verapamil given 1 hour prior to dabigatran administration produced the greatest increase in exposure. If verapamil is administered 2 hours after dabigatran administration, the increase in AUC is negligible. Data from the RE-LY trial indicate no significant changes in dabigatran trough concentrations were seen in patients who received concomitant therapy with verapamil. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
    Verteporfin: (Minor) Drugs that decrease clotting, such as anticoagulants, could decrease the efficacy of photodynamic therapy.
    Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. In addition, both vilazodone and warfarin are highly protein bound, which may result in displacement of warfarin from protein binding sites and an increased anticoagulant effect. It would be prudent for clinicians to monitor the INR and clinical status of the patient closely if vilazodone is added to or removed from the regimen of a patient stabilized on warfarin.
    Vorapaxar: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. 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 anticoagulants. In a phase II trial, aspirin (81 mg or 325 mg) was randomly assigned to patients with atrial fibrillation receiving dabigatran (150 mg twice daily). Data obtained from logistic regression analysis suggest that the concomitant administration of aspirin and dabigatran may increase the risk of bleeding from 12% to 18% (81 mg aspirin) or 24% (325 mg aspirin). Monitor patients closely for signs of bleeding if dabigatran is given concomitantly with other platelet inhibitors.
    Vorinostat: (Moderate) Concomitant use of vorinostat with anticoagulants may result in an additive risk of bleeding due to vorinostat-induced thrombocytopenia; monitor patients closely.
    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 anticoagulants. 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 anticoagulants and to promptly report any bleeding events to the practitioner. Co-administration of vortioxetine and warfarin has not been shown to significantly affect the pharmacokinetics of either agent.
    Warfarin: (Major) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Zonisamide: (Moderate) Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with zonisamide, 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 zonisamide 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 zonisamide, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.

    PREGNANCY AND LACTATION

    Pregnancy

    It is not known whether dabigatran is excreted in human milk. If pharmacotherapy is necessary in the nursing mother, the American Academy of Pediatrics (AAP) considers warfarin to be usually compatible with breast-feeding. Low-molecular weight heparins and heparin have relatively high molecular weights ; therefore, these drugs are not expected to be excreted into human milk to a clinically significant degree. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Dabigatran and its active metabolites are competitive, direct thrombin inhibitors that inhibit both free and clot-bound thrombin. Dabigatran prevents thrombin-induced platelet aggregation and the development of a thrombus by preventing the thrombin-mediated conversion of fibrinogen into fibrin during the coagulation cascade.

    PHARMACOKINETICS

    Dabigatran etexilate mesylate is administered orally. It is absorbed as the dabigatran etexilate ester, which is then hydrolyzed forming dabigatran, the active moiety. Dabigatran is approximately 35% bound to plasma proteins with a volume of distribution of 50 to 70 L. Pharmacokinetics are proportional to dose. After oral absorption, dabigatran is metabolized by esterases to four active acyl glucuronides that have pharmacological activity similar to dabigatran; each acyl glucoronide accounts for < 10% of total dabigatrin in the plasma. 
     
    Affected cytochrome P450 isoenzymes and drug transporter: P-gp
    Dabigatran is a substrate of the efflux transporter P-glycoprotein (P-gp) and plasma concentrations may be affected by P-gp inhibitors and inducers. Dabigatran is not an inhibitor, inducer, or substrate of CYP450 enzymes. It is eliminated primarily in the urine. The half-life is 12—17 hours in healthy subjects.
     
    Dabigatran prolongs the activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and thrombin time (TT) at recommended therapeutic doses. The median peak aPTT is approximately 2x control following an oral dose of 150 mg and is 1.5x control 12 hours after the last dose, with < 10% of patients exceeding 2x control. In patients receiving the 150 mg dose in the RE-LY trial, the median trough aPTT was 52 (40 – 76) seconds and the median trough ECT was 63 (44 – 103) seconds. The INR may or may not be elevated in patients receiving dabigatran and is relatively insensitive to the activity of dabigatran.

    Oral Route

    The absolute bioavailability following oral administration is 3—7%. The maximum plasma concentration (Cmax) occurs 1 hour after administration in the fasted state. Administration of dabigatran after a high-fat meal delays the time to Cmax by 2 hours but has no effect on the bioavailability of dabigatran. Oral bioavailability increases by 75% when the pellets are taken without the capsule shell.

    Intravenous Route

    After intravenous administration, 80% of the dabigatran dose is eliminated renally.