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Dabigatran: Drug information

Dabigatran: Drug information
(For additional information see "Dabigatran: Patient drug information" and see "Dabigatran: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Thrombotic events:

Premature discontinuation of dabigatran increases the risk of thrombotic events. If anticoagulation with dabigatran is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

Spinal/Epidural hematoma:

Epidural or spinal hematomas may occur in patients treated with dabigatran who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. 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, or other anticoagulants; a history of traumatic or repeated epidural or spinal punctures; a history of spinal deformity or spinal surgery; optimal timing between the administration of dabigatran and neuraxial procedures is not known.

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.

Brand Names: US
  • Pradaxa
Brand Names: Canada
  • APO-Dabigatran;
  • Pradaxa
Pharmacologic Category
  • Anticoagulant;
  • Anticoagulant, Direct Thrombin Inhibitor;
  • Direct Oral Anticoagulant (DOAC)
Dosing: Adult

Note: Do not interchange dosage forms on a milligram-to-milligram basis and do not combine more than one dosage form to achieve the total dose; not all dosage forms are approved for the same indications or age groups.

The adult dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editor: Edith A Nutescu, PharmD, MS, FCCP.

Nonvalvular atrial fibrillation

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism):

Oral capsule: 150 mg twice daily. Note: Patients who are particularly concerned about the risk of bleeding or those assessed to be at increased risk of bleeding, may be considered candidates for an alternative lower dose regimen of 110 mg twice daily (off-label dose) (Eikelboom 2013; Manning 2018; Mannucci 2013).

Post-percutaneous coronary intervention with stent placement and nonvalvular atrial fibrillation (off label):

Oral capsule: 110 mg or 150 mg twice daily; administer with an appropriate antithrombotic regimen including clopidogrel (preferred P2Y12 inhibitor in this situation) with or without aspirin, depending on the risks for thrombosis and bleeding, and time since PCI; dabigatran dose depends on patient specific thrombotic and bleeding risk factors (ACC [Kumbhani 2021]; AHA/ACC/HRS [January 2014]; AHA/ACC/HRS [January 2019]; Cannon 2017; Khan 2020).

Venous thromboembolism

Venous thromboembolism:

Deep vein thrombosis and/or pulmonary embolism (treatment): Note: Dabigatran has not been studied in patients with active cancer; another anticoagulant is likely more appropriate (ASCO [Key 2020]; ACCP [Kearon 2016]).

After at least 5 days of initial therapy with a parenteral anticoagulant, transition to dabigatran in hemodynamically stable patients:

Oral capsule: 150 mg twice daily.

Duration of therapeutic anticoagulation (first episode, general recommendations): Optimal duration of therapy is unknown and is dependent on many factors, such as presence of provoking events, patient risk factors for recurrence and bleeding, and individual preferences.

Provoked venous thromboembolism: 3 months (provided provoking risk factor is no longer present) (ACCP [Kearon 2016]).

Unprovoked venous thromboembolism: ≥3 months depending on risk of venous thromboembolism (VTE) recurrence and bleeding (ACCP [Kearon 2012]; ACCP [Kearon 2016]; ISTH [Baglin 2012]).

Note: All patients receiving indefinite therapeutic anticoagulation with no specified stop date should be reassessed at periodic intervals.

Venous thromboembolism prophylaxis in total hip arthroplasty or total knee arthroplasty (alternative agent):

Total hip arthroplasty:

Oral capsule: Initial: 110 mg given 1 to 4 hours after completion of surgery and establishment of hemostasis or when dabigatran is not initiated on day of surgery, give an initial dose of 220 mg after hemostasis has been achieved; then continue maintenance dose of 220 mg once daily for a minimum of 10 to 14 days. Optimal duration of prophylaxis is unknown but it is usually given for a minimum of 10 to 14 days and can be extended for up to 35 days; some experts suggest a duration in the higher end of range (30 days) for total hip arthroplasty (Eikelboom 2001; Falck-Ytter 2012; Pai 2020).

Total knee arthroplasty (off-label use) :

Oral capsule: Initial: 110 mg given 1 to 4 hours after completion of surgery and establishment of hemostasis or when dabigatran is not initiated on day of surgery, give an initial dose of 220 mg after hemostasis has been achieved; then continue maintenance dose of 220 mg once daily (Eriksson 2007a) for a minimum of 10 to 14 days; may be extended up to 35 days. Optimal duration of prophylaxis is unknown. Some experts suggest a duration in the lower end of the range (10 to 14 days) for total knee arthroplasty (Eikelboom 2001; Falck-Ytter 2012; Pai 2020).

Transitioning between anticoagulants: Note: This provides general guidance on transitioning between anticoagulants; also refer to local protocol for additional detail:

Transitioning from another anticoagulant to dabigatran capsules:

Transitioning from low molecular weight heparin or fondaparinux (therapeutic dose) to dabigatran capsules:

General transition recommendation: Initiate dabigatran within 2 hours prior to the time of the next scheduled dose of the parenteral anticoagulant.

Venous thromboembolism initial treatment (alternate recommendation): For acute VTE, some experts start dabigatran within 6 to 12 hours after the last dose of a twice daily low molecular weight heparin regimen and within 12 to 24 hours after a once daily regimen (Hull 2022).

Transitioning from unfractionated heparin continuous infusion to dabigatran capsules: Start dabigatran when unfractionated heparin is stopped (consult local protocol if aPTT is above or below the target range).

Transitioning from warfarin to dabigatran capsules: Discontinue warfarin and initiate dabigatran when the INR is <2.

Transitioning from dabigatran capsules to another anticoagulant:

Transitioning from dabigatran capsules to low molecular weight heparin, fondaparinux, or unfractionated heparin continuous infusion: After the last dose of dabigatran, wait 12 hours (CrCl ≥30 mL/minute) or 24 hours (CrCl <30 mL/minute) before starting a parenteral anticoagulant.

Transitioning from dabigatran capsules to warfarin: One option is to stop dabigatran, start warfarin the same day, and bridge with a parenteral anticoagulant until the desired INR is reached (Leung 2019). An alternative is to overlap the two agents. If this is done, the timing of warfarin initiation is based on CrCl as outlined below:

CrCl >50 mL/minute: Initiate warfarin 3 days before discontinuing dabigatran.

CrCl 30 to 50 mL/minute: Initiate warfarin 2 days before discontinuing dabigatran.

CrCl 15 to 30 mL/minute: Initiate warfarin 1 day before discontinuing dabigatran.

CrCl <15 mL/minute: Dabigatran should not be used.

Note: Dabigatran can elevate the INR, complicating interpretation if overlapped with warfarin. To minimize interference, check INR near the end of dabigatran dosing interval. Warfarin's effect on the INR will be better reflected only after dabigatran has been stopped for ≥2 days.

Transitioning between direct oral anticoagulants: Start the new direct oral anticoagulant (DOAC) when the next dose of the previous DOAC was scheduled to be given (Leung 2019).

Transitioning between anticoagulants in the perioperative setting: See 2017 AHA Scientific Statement, "Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting" and/or 2017 ACC Expert Consensus Decision Pathway, “Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation.”

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: The following recommendations apply to adult dosing of the capsule formulation only; not all dosage forms are approved for the same indications and age groups.

Note: Clinical trials evaluating safety and efficacy utilized the Cockcroft-Gault formula with the use of actual body weight (data on file; Boehringer Ingelheim Pharmaceuticals Inc 2012).

Deep vein thrombosis and/or pulmonary embolism (treatment): Note: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance, specifically when CrCl <50 mL/minute; consult drug interactions database for more information.

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl ≤30 mL/minute: Avoid use (Dager 2018). No clinical data as patients with CrCl ≤30 mL/minute were excluded from clinical trials (Schulman 2009; Schulman 2013; Schulman 2014).

Hemodialysis/peritoneal dialysis: Avoid use (Dager 2015; expert opinion).

Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): Note: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance, specifically when CrCl <50 mL/minute; consult drug interactions database for more information.

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl 15 to ≤30 mL/minute: Oral capsule: 75 mg twice daily. Note: Patients with CrCl <30 mL/minute were excluded from the RE-LY trial (Connolly 2009). Recommended dose is based on pharmacokinetic data suggesting that this dose provides similar exposure to the recommended dose in patients with CrCl >30 mL/minute (Hariharan 2012; Kooiman 2016; Liesenfeld 2011); safety and efficacy have not been established. Some experts consider dabigatran contraindicated in patients with severe kidney impairment (CrCl ≤30 mL/minute) (ACCP [Guyatt 2012]).

CrCl <15 mL/minute: Avoid use (AHA/ACC/HRS [January 2019]).

Hemodialysis, intermittent (thrice weekly): Avoid use (AHA/ACC/HRS [January 2019]). Dialyzable (49% to 59% over 4 hours [Khadzhynov 2013]). Use in hemodialysis patients has been associated with increased risk of major bleeding (Feldberg 2019).

Peritoneal dialysis: Avoid use (AHA/ACC/HRS [January 2019]).

Venous thromboembolism prophylaxis: Note: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance, specifically when CrCl <50 mL/minute; consult drug interactions database for more information.

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl ≤30 mL/minute: Avoid use (expert opinion). Patients with CrCl <30 mL/minute were excluded from clinical trials (Eriksson 2007a; Eriksson 2007b; Eriksson 2011).

Hemodialysis/peritoneal dialysis: Avoid use (Dager 2015; expert opinion).

Additional guideline recommendations: Geriatric patients ≥65 years of age: CrCl <30 mL/minute: Avoid use in older adults with CrCl <30 mL/minute due to lack of efficacy and safety evidence (Beers Criteria [AGS 2019]).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling; consistent changes in exposure or pharmacodynamics were not observed in a study of patients with moderate impairment.

Dosing: Pediatric

(For additional information see "Dabigatran: Pediatric drug information")

Note: Dabigatran is available in different dosage forms (eg, capsules, oral pellets); the approved indications and intended age groups are not the same for each dosage form. The dosage forms are not interchangeable on a mg:mg basis due to pharmacokinetic differences (eg bioavailability). Use caution when selecting the dosage form and dose; combining dosage forms to achieve total dose is not recommended.

Venous thromboembolic event (VTE), treatment and prevention: Note: For treatment, initiate dabigatran after 5 days of treatment with a parenteral anticoagulant; for prevention, initiate dabigatran after treatment is complete. Adjust dose during treatment according to age and actual weight:

Oral pellets:

Note: Dosing is based on weight AND age; use caution when selecting dose. Twice-daily dosing should be as close to a 12-hour dosing interval as is possible.

Infants 3 to <4 months:

Weight 3 to <4 kg: Oral pellets: Oral: 30 mg twice daily.

Weight 4 to <7 kg: Oral pellets: Oral: 40 mg twice daily.

Weight 7 to <9 kg: Oral pellets: Oral: 50 mg twice daily.

Infants 4 to <5 months:

Weight 3 to <4 kg: Oral pellets: Oral: 30 mg twice daily.

Weight 4 to <7 kg: Oral pellets: Oral: 40 mg twice daily.

Weight 7 to <9 kg: Oral pellets: Oral: 60 mg twice daily.

Infants 5 to <6 months:

Weight 3 to <4 kg: Oral pellets: Oral: 30 mg twice daily.

Weight 4 to <5 kg: Oral pellets: Oral: 40 mg twice daily.

Weight 5 to <7 kg: Oral pellets: Oral: 50 mg twice daily.

Weight 7 to <11 kg: Oral pellets: Oral: 60 mg twice daily.

Infants 6 to <7 months:

Weight 4 to <5 kg: Oral pellets: Oral: 40 mg twice daily.

Weight 5 to <7 kg: Oral pellets: Oral: 50 mg twice daily.

Weight 7 to <9 kg: Oral pellets: Oral: 60 mg twice daily.

Weight 9 to <11 kg: Oral pellets: Oral: 80 mg twice daily.

Infants 7 to <8 months:

Weight 4 to <5 kg: Oral pellets: Oral: 40 mg twice daily.

Weight 5 to <7 kg: Oral pellets: Oral: 50 mg twice daily.

Weight 7 to <9 kg: Oral pellets: Oral: 60 mg twice daily.

Weight 9 to <11 kg: Oral pellets: Oral: 80 mg twice daily.

Infants 8 to <9 months:

Weight 4 to <5 kg: Oral pellets: Oral: 40 mg twice daily.

Weight 5 to <7 kg: Oral pellets: Oral: 50 mg twice daily.

Weight 7 to <9 kg: Oral pellets: Oral: 60 mg twice daily.

Weight 9 to <11 kg: Oral pellets: Oral: 80 mg twice daily.

Weight 11 to <13 kg: Oral pellets: Oral: 100 mg twice daily.

Infants 9 to <10 months:

Weight 4 to <5 kg: Oral pellets: Oral: 40 mg twice daily.

Weight 5 to <7 kg: Oral pellets: Oral: 50 mg twice daily.

Weight 7 to <9 kg: Oral pellets: Oral: 70 mg twice daily.

Weight 9 to <11 kg: Oral pellets: Oral: 80 mg twice daily.

Weight 11 to <13 kg: Oral pellets: Oral: 100 mg twice daily.

Infants 10 to <11 months:

Weight 5 to <7 kg: Oral pellets: Oral: 50 mg twice daily.

Weight 7 to <9 kg: Oral pellets: Oral: 70 mg twice daily.

Weight 9 to <11 kg: Oral pellets: Oral: 80 mg twice daily.

Weight 11 to <16 kg: Oral pellets: Oral: 100 mg twice daily.

Infants 11 to <12 months:

Weight 5 to <7 kg: Oral pellets: Oral: 50 mg twice daily.

Weight 7 to <9 kg: Oral pellets: Oral: 70 mg twice daily.

Weight 9 to <11 kg: Oral pellets: Oral: 90 mg twice daily.

Weight 11 to <13 kg: Oral pellets: Oral: 100 mg twice daily.

Weight 13 to <16 kg: Oral pellets: Oral: 140 mg twice daily.

Children <1.5 years:

Weight 5 to <7 kg: Oral pellets: Oral: 50 mg twice daily.

Weight 7 to <9 kg: Oral pellets: Oral: 70 mg twice daily.

Weight 9 to <11 kg: Oral pellets: Oral: 90 mg twice daily.

Weight 11 to <13 kg: Oral pellets: Oral: 100 mg twice daily.

Weight 13 to <21 kg: Oral pellets: Oral: 140 mg twice daily.

Children 1.5 to <2 years:

Weight 5 to <7 kg: Oral pellets: Oral: 50 mg twice daily.

Weight 7 to <9 kg: Oral pellets: Oral: 70 mg twice daily.

Weight 9 to <11 kg: Oral pellets: Oral: 90 mg twice daily.

Weight 11 to <13 kg: Oral pellets: Oral: 110 mg twice daily.

Weight 13 to <21 kg: Oral pellets: Oral: 140 mg twice daily.

Weight 21 to <26 kg: Oral pellets: Oral: 180 mg twice daily.

Children 2 to <12 years:

Weight 7 to <9 kg: Oral pellets: Oral: 70 mg twice daily.

Weight 9 to <11 kg: Oral pellets: Oral: 90 mg twice daily.

Weight 11 to <13 kg: Oral pellets: Oral: 110 mg twice daily.

Weight 13 to <16 kg: Oral pellets: Oral: 140 mg twice daily.

Weight 16 to <21 kg: Oral pellets: Oral: 170 mg twice daily.

Weight 21 to <41 kg: Oral pellets: Oral: 220 mg twice daily.

Weight ≥41 kg: Oral pellets: Oral: 260 mg twice daily.

Capsules:

Children ≥8 years and Adolescents <18 years:

Weight 11 to <16 kg: Capsules: Oral: 75 mg twice daily.

Weight 16 to <26 kg: Capsules: Oral: 110 mg twice daily.

Weight 26 to <41 kg: Capsules: Oral: 150 mg twice daily.

Weight 41 to <61 kg: Capsules: Oral: 185 mg twice daily.

Weight 61 to <81 kg: Capsules: Oral: 220 mg twice daily.

Weight ≥81 kg: Capsules: Oral: 260 mg twice daily.

Transitioning between anticoagulants:

Infants ≥3 months, Children, and Adolescents <18 years:

Note: This provides general guidance on transitioning between anticoagulants; also refer to institutional protocol for additional detail:

Transitioning from parenteral anticoagulant to dabigatran: Capsules and oral pellets:

Transitioning from low molecular weight heparin or fondaparinux (therapeutic dose) to dabigatran: Initiate dabigatran 0 to 2 hours prior to the time of the next scheduled dose of the parenteral anticoagulant.

Transitioning from continuously administered parenteral anticoagulant (eg, IV unfractionated heparin) to dabigatran: Start dabigatran when continuously administered parenteral anticoagulant is discontinued.

Transitioning from warfarin to dabigatran: Discontinue warfarin and initiate dabigatran when the INR is <2.

Transitioning from dabigatran to another anticoagulant: Capsules and oral pellets:

Transitioning from dabigatran to parenteral anticoagulant: After the last dose of dabigatran, wait 12 hours before starting a parenteral anticoagulant.

Transitioning from dabigatran to warfarin: Note: Dabigatran can elevate the INR, complicating interpretation if overlapped with warfarin. To minimize interference, check INR near the end of dabigatran dosing interval. Warfarin's effect on the INR will be better reflected only after dabigatran has been stopped for ≥2 days. Calculate eGFR using the Schwartz formula:

eGFR ≥50 mL/minute/1.73 m2: Initiate warfarin 3 days before discontinuing dabigatran.

eGFR <50 mL/minute/1.73 m2: Dabigatran should not be used (has not been studied).

Transitioning from dabigatran in the perioperative setting: Note: Calculate eGFR using the Schwartz formula: Capsules and oral pellets:

eGFR >80 mL/minute/1.73 m2: Discontinue dabigatran 24 hours before elective surgery.

eGFR 50 to 80 mL/minute/1.73 m2: Discontinue dabigatran 2 days before elective surgery.

eGFR <50 mL/minute/1.73 m2: Dabigatran should not be used (has not been studied).

Note: Longer times may be considered prior to major surgery, spinal puncture, or placement of a spinal or epidural catheter or port where more complete hemostasis may be required.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing adjustment for toxicity:

Infants ≥3 months, Children, and Adolescents <18 years: Oral:

Active pathological bleeding: Capsules, oral pellets: Discontinue dabigatran.

Acute renal failure: Capsules, oral pellets: Discontinue dabigatran and consider alternative anticoagulant therapy.

Dosing: Kidney Impairment: Pediatric

Venous thromboembolic events, prevention and treatment:

Infants ≥3 months, Children, and Adolescents <18 years: Note: Calculate eGFR using the Schwartz formula: Capsules, oral pellets: Oral:

eGFR ≥50 mL/minute/1.73 m2: No adjustment needed.

eGFR <50 mL/minute/1.73 m2: Avoid use (has not been studied); risk for increased exposure exist.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling; consistent changes in exposure or pharmacodynamics were not observed in a study of adult patients with moderate impairment.

Dosing: Older Adult

Deep vein thrombosis and/or pulmonary embolism, nonvalvular atrial fibrillation (to prevent stroke and systemic embolism), venous thromboembolism prophylaxis:

Oral: Numerous reports of excess anticoagulation, including fatalities, have been observed with use in older adults (ISMP [Smetzer 2012]; ISMP [Smetzer 2015]).

Patients >65 years of age: Refer to adult dosing. No dosage adjustment required unless renal impairment exists; however, risk of bleeding increases with age.

Patients ≥75 years of age: Use with extreme caution or consider other treatment options (see Warnings/Precautions) (Beers Criteria [AGS 2019]; ISMP [Smetzer 2012]; ISMP [Smetzer 2015]). No dosage adjustment provided in manufacturer’s labeling based on age alone (unless renal impairment coexists); however, risk of bleeding increases with age.

Dosing: Obesity: Adult

The recommendations for dosing in obese patients are based upon the best available evidence and clinical expertise. Senior Editorial Team: Jeffrey F. Barletta, PharmD, FCCM; Manjunath P. Pai, PharmD, FCP; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC.

Class 1 and 2 obesity (BMI 30 to 39 kg/m2): No dosage adjustment necessary. If patient's actual body weight is >120 kg, use other anticoagulants (eg, other direct oral anticoagulants [DOACs] where data support use or vitamin K antagonists) (ISTH [Martin 2021]; expert opinion). Refer to adult dosing for indication-specific doses.

Class 3 obesity (BMI ≥40 kg/m2): Use other anticoagulants (eg, other DOACs where data support use or vitamin K antagonists) (ISTH [Martin 2021]; expert opinion).

Rationale for recommendations:

There are very limited data in patients with obesity evaluating changes in dabigatran concentrations (Coons 2020; Covert 2020; Kido 2020; ISTH [Martin 2021]; Piran 2018; Rocca 2018; Sebaaly 2020). With increases in body weight, dabigatran concentrations are reduced and apparent Vd is increased; however, the AUC at steady state is not affected and the effect on clinical outcomes related to nonvalvular atrial fibrillation is insignificant (Rocca 2018; Reilly 2014; Liesenfeld 2011).

The International Society on Thrombosis and Haemostasis 2021 guideline suggests avoiding the use of dabigatran etexilate in patients with a BMI >40 kg/m2 or weight >120 kg due to the lack of clinical data in this population (ISTH [Martin 2021]). In addition, there have been several case reports of dabigatran failure in patients with BMI ≥40 kg/m2 (Breuer 2013; Nasir 2017; Rafferty 2013; Safouris 2015). Further prospective studies in patients with class 3 obesity (eg, BMI ≥40 kg/m2) or actual body weight >120 kg are necessary to clearly define impact on dosing for these patients (expert opinion).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Pradaxa: 75 mg [contains carrageenan]

Pradaxa: 110 mg, 150 mg [contains carrageenan, fd&c blue #2 (indigotine)]

Generic Equivalent Available: US

No

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Pradaxa: 75 mg, 110 mg, 150 mg [contains fd&c blue #2 (indigotine), fd&c yellow #6 (sunset yellow)]

Generic: 75 mg, 110 mg, 150 mg

Product Availability

Pradaxa oral pellets: FDA approved June 2021; anticipated availability is currently unknown. Information pertaining to this product within the monograph is pending revision. Consult the prescribing information for additional information.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Pradaxa capsules: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/022512s041lbl.pdf#page=27

Pradaxa oral pellets: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214358s000lbl.pdf#page=14

Administration: Adult

Oral capsule: Administer capsules with a full glass of water without regard to meals; however, if dyspepsia occurs, consider administration with meals. Do not break, chew, or open capsules, as this will lead to 75% increase in absorption and potentially serious adverse reactions.

Administration: Pediatric

Oral: Twice-daily dosing (morning and evening) should be separated by 12 hours when possible. Note: Combining dosage forms to achieve the total dose is not recommended.

Capsules: Administer with a full glass of water without regard to meals; however, if upset stomach occurs, consider administration with meals. Do not break, chew, or open capsules, as this will lead to 75% increase in absorption and potentially serious adverse reactions.

Oral pellets: Do not administer via oral syringes or feeding tubes. Do not mix with milk, milk products, or soft foods containing milk products. May mix with soft foods or apple juice to administer before meals as follows:

Soft foods: Mix dose using oral pellets with 2 teaspoons of room temperature baby rice cereal (prepared with water), mashed carrots, apple sauce, or mashed banana; administer within 30 minutes of mixing, discard if not used within 30 minutes. Do not mix with any other food.

Apple juice: Spoon oral pellets directly into patient's mouth and swallow with apple juice or mix dose using oral pellets with 1 to 2 ounces of apple juice; administer within 30 minutes of mixing, discard if not used within 30 minutes.

Missed dose: Take missed dose as soon as possible on the same day; skip missed dose if <6 hours before the next dose. Do not double a dose to make up for a skipped dose.

Partial dose: Oral pellets: If patient only consumes a partial dose, a second dose is not recommended; the next dose should be given as scheduled 12 hours later.

Use: Labeled Indications

Deep venous thrombosis and pulmonary embolism treatment and prevention: Treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in pediatric patients ≥3 months to <12 years of age (oral pellets), pediatric patients ≥8 to <18 years of age (capsules), and adults (capsules) who have been treated with a parenteral anticoagulant for ≥5 days; to reduce the risk of recurrence of DVT and PE in pediatric patients ≥3 months of age to <12 years of age (oral pellets), pediatric patients ≥8 to <18 years of age (capsules), and adults (capsules) who have been previously treated.

Nonvalvular atrial fibrillation: Prevention of stroke and systemic embolism in adult patients (capsules) with nonvalvular atrial fibrillation.

Venous thromboembolism prophylaxis in total hip arthroplasty: Prophylaxis of DVT and PE in adult patients (capsules) who have undergone total hip arthroplasty.

Use: Off-Label: Adult

Venous thromboembolism prophylaxis in total knee arthroplasty

Medication Safety Issues
Sound-alike/look-alike issues:

Dabigatran may be confused with vigabatrin

Pradaxa may be confused with Plavix

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.

National Patient Safety Goals:

The Joint Commission (TJC) requires healthcare organizations that provide anticoagulant therapy to have approved protocols and evidence-based practice guidelines in place to reduce the risk of anticoagulant-associated patient harm. Patients receiving anticoagulants should receive individualized care through a defined process that includes medication selection, dosing (including adjustments for age, renal function, or liver function), drug-drug interactions, drug-food interactions, other applicable risk factors, monitoring, patient and family education, proper administration, reversal of anticoagulation, management of bleeding events, and perioperative management. This does not apply to routine short-term use of anticoagulants for prevention of venous thromboembolism during procedures or hospitalizations (NPSG.03.05.01).

Geriatric Patients: High-Risk Medication:

Beers Criteria: Dabigatran is identified in the Beers Criteria as a potentially inappropriate medication to be used with caution for the treatment of VTE or atrial fibrillation in patients 75 years and older due to an increased risk of GI bleeding compared to warfarin and to reported rates of other direct oral anticoagulants when used for long-term treatment of VTE or atrial fibrillation (Beers Criteria [AGS 2019]).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.

>10%:

Gastrointestinal: Gastrointestinal signs and symptoms (25% to 40%)

Hematologic & oncologic: Hemorrhage (10% to 19%; major hemorrhage: ≤6%)

1% to 10%: Gastrointestinal: Abdominal discomfort (≤8%), abdominal pain (≤8%), dyspepsia (4% to 8%), epigastric discomfort (≤8%), esophagitis (≤3%), gastritis (≤3%), gastroesophageal reflux disease (≤3%), gastrointestinal hemorrhage (≤7%; major: ≤3%), hemorrhagic gastritis (≤3%), upper abdominal pain (≤8%)

<1%:

Cardiovascular: Acute myocardial infarction, hemorrhagic stroke, subarachnoid hemorrhage, subdural hematoma

Genitourinary: Genitourinary tract hemorrhage (major)

Hematologic & oncologic: Retroperitoneal hemorrhage (major)

Hypersensitivity: Allergic angioedema, anaphylactic shock, anaphylaxis, hypersensitivity reaction

Nervous system: Intracranial hemorrhage

Neuromuscular & skeletal: Hemarthrosis (major), muscle hemorrhage (major)

Frequency not defined:

Gastrointestinal: Gastrointestinal ulcer

Hematologic & oncologic: Spinal hematoma (with spinal puncture or spinal/epidural anesthesia)

Nervous system: Epidural intracranial hemorrhage (with spinal puncture or spinal/epidural anesthesia)

Postmarketing:

Dermatologic: Alopecia

Gastrointestinal: Esophageal ulcer

Hematologic & oncologic: Agranulocytosis, neutropenia, thrombocytopenia

Hypersensitivity: Angioedema

Contraindications

Serious hypersensitivity (eg, anaphylaxis or anaphylactic shock) to dabigatran or any component of the formulation; active pathological bleeding; patients with mechanical prosthetic heart valve(s)

Canadian labeling: Additional contraindications (not in US labeling): Severe renal impairment (CrCl <30 mL/minute); bleeding diathesis, patients with spontaneous or pharmacological hemostatic impairment or clinically significant active bleeding (including GI bleeding); lesions at risk of clinically significant bleeding (eg, hemorrhagic or ischemic cerebral infarction) within previous 6 months; nursing women; concomitant therapy with strong P-glycoprotein inhibitors (eg, oral ketoconazole); concomitant use with other anticoagulants including unfractionated heparin (except when used to maintain central venous or arterial catheter patency or during catheter ablation for atrial fibrillation), low molecular weight heparins, heparin derivatives (eg, fondaparinux), antithrombin agents (eg, bivalirudin), and oral anticoagulants (eg, warfarin, rivaroxaban, apixaban) except during transitioning of therapy from or to dabigatran

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: The most common complication is bleeding, including severe and potentially fatal bleeding. Risk factors for bleeding include concurrent use of drugs that increase the risk of bleeding (eg, antiplatelet agents, heparin), renal impairment, and elderly patients (especially if low body weight). Discontinue in patients with active pathological bleeding. Important: Idarucizumab is the most effective agent for dabigatran reversal; efficacy and safety of idarucizumab have not been established in pediatric patients. Protamine and vitamin K do not reverse or impact anticoagulant effects of dabigatran. Dabigatran is dialyzable (~57% removed over 4 hours); however, supporting data are limited for utilizing this method. Depending on the bleeding severity, activated oral charcoal should be considered if ingestion occurred within 1 to 2 hours of presentation. The following alternative options may also be considered depending on the clinical scenario and availability of idarucizumab: 4-factor unactivated prothrombin concentrate (PCC) (eg, Kcentra) or 4-factor activated prothrombin complex concentrate (aPCC) (eg, FEIBA). Some studies and case reports have shown moderate success in correcting coagulation tests with some of these agents; however, correction of coagulation tests does not imply reversal of the anticoagulation effect of the medication (AHA/ASA [Hemphill 2015; EHRA [Heidbuchel 2015]; NCS/SCCM [Frontera 2016]). Platelet concentrates should be considered when thrombocytopenia is present or long-acting antiplatelet drugs have been used.

• Thromboembolic events: [US Boxed Warning]: Upon premature discontinuation, the risk of thrombotic events is increased. If dabigatran must be discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider the use of another anticoagulant during the time of interruption. In patients with non-valvular atrial fibrillation who had an acute ischemic stroke while receiving a direct oral anticoagulant (DOAC) (eg, dabigatran), guidelines generally support withholding oral anticoagulation until 1 to 2 weeks after the ischemic stroke (time frame may vary with shorter times for transient ischemic attack or small, non-disabling stroke and longer times for moderate to severe stroke) (AHA [Raval 2017]; AHA/ASA [Kernan 2014]; EHRA [Heidbuchel 2015]).

Disease-related concerns:

• Antiphospholipid syndrome: Use is not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome; safety and efficacy have not been established. Patients positive for all three antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-beta-2 glycoprotein I) may have increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

• GI/Bariatric surgery: Altered absorption: Evaluate the risk versus benefit of possible decreased drug absorption. Dabigatran capsules are designed to release in the stomach, which is dependent on an acidic environment. Absorption primarily occurs in the proximal small intestine. Surgeries that increase the pH (more alkaline) of the stomach (eg, Roux-en-Y gastric bypass) or decrease small intestine sites may decrease absorption of dabigatran (Hakeam 2017). The available data are conflicting for absorption alterations, derived from small populations, and underrepresent individual DOACs and distinct surgeries (Kröll 2017; Kröll 2018; Lee 2013; Rottenstreich 2018).

• Hepatic impairment: Use in patients with moderate hepatic impairment (Child-Pugh class B) demonstrated large inter-subject variability; however, no consistent change in exposure or pharmacodynamics was seen. Patients with active liver disease were excluded from the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial (Connolly 2009).

• Renal impairment: Evaluate renal function prior to and during therapy, particularly if used in patients with any degree of preexisting renal impairment or in any condition that may result in a decline in renal function (eg, hypovolemia, dehydration, concomitant use of medications with a potential to affect renal function); dabigatran concentrations may increase in any degree of renal impairment and increase the risk of bleeding. In moderate impairment, serum concentrations may increase 3 times higher than normal compared to concentrations in patients with normal renal function. Discontinue therapy in any patient who develops acute renal failure.

• Valvular heart disease: Use is not recommended in patients with valvular heart disease, including the presence of a bioprosthetic heart valve; use is contraindicated in patients with mechanical prosthetic heart valves. In addition to several case reports, one clinical trial reported significantly more thromboembolic events and an excess of major bleeding in patients with mechanical prosthetic heart valves receiving dabigatran compared to those receiving adjusted-dose warfarin (Chu 2012; Price 2012; Stewart 2012). Avoid use of DOACs in patients with moderate to severe mitral stenosis (AHA/ACC/HRS [January 2019]). However, a DOAC may be used in patients with AF and native aortic valve disease, tricuspid valve disease, or mitral regurgitation when anticoagulation is required (AHA/ACC/HRS [January 2014]; AHA/ACC/HRS [January 2019]; AHA/ACC [Nishimura 2017]).

Concurrent drug therapy issues:

• Antithrombotic agents: Due to an increased risk of bleeding, avoid use, if possible, with other direct thrombin inhibitors (eg, bivalirudin), unfractionated heparin or heparin derivatives, low molecular weight heparins (eg, enoxaparin), fondaparinux, thienopyridines (eg, clopidogrel), GPIIb/IIIa antagonists (eg, eptifibatide), aspirin, coumarin derivatives, sulfinpyrazone, and ticagrelor. NSAIDs should be used cautiously. Appropriate doses of unfractionated heparin may be used to maintain catheter patency.

• Drug/drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult Drug Interactions database for more detailed information.

Special populations:

• Elderly: Use with extreme caution or consider other treatment options. No dosage adjustment is recommended in the manufacturer's labeling based on age alone (unless renal impairment coexists); however, risk of bleeding increases with age. Numerous reports of excess anticoagulation, including fatalities, have been observed with use in older adults (ISMP [Smetzer 2012]; ISMP [Smetzer 2015]). In particular, an increased risk of GI bleeding has been observed in patients ≥75 years of age despite similar efficacy observed with dabigatran in the elderly as compared to warfarin-treated patients (Graham 2015; Sharma 2015). Dabigatran is associated with more than a 5-fold variation in plasma concentrations in patients receiving the same dose, indicating a wide therapeutic range. Significant factors affecting increased dabigatran plasma concentrations have been found to be increasing age, decreased CrCl, lower body weight and female gender. Renal function was the predominant patient characteristic determining plasma concentrations, with age as the most important covariate (Reilly 2014). Depending on individual patient characteristics, particularly advanced age and potential for renal impairment, consider other treatment options (Kalabalik 2015).

Dosage form specific issues:

• Product interchangeability: Do not interchange dosage forms on a milligram-to-milligram basis and do not combine more than 1 dosage form to achieve the total dose; not all dosage forms are approved for the same indications or age groups.

Other warnings/precautions:

• Appropriate use: Surgical patients: When temporary interruption is necessary before surgery, the timing of discontinuation depends on renal function and risk for bleeding complications. In adult patients with CrCl ≥50 mL/minute, discontinue therapy ~24 to 48 hours before surgery depending on risk for bleeding. In adult patients with CrCl <50 mL/minute, discontinue therapy ~72 to 120 hours before surgery depending on risk for bleeding. In pediatric patients with CrCl ≥80 mL/minute, discontinue therapy 24 hours before elective surgery. In pediatric patients with CrCl 50 to 80 mL/minute, discontinue therapy 48 hours before elective surgery. Use in pediatric patients with CrCl <50 mL/minute has not been studied; avoid use. Consider discontinuing for a longer period of time in patients undergoing major surgery, spinal puncture, or insertion of a spinal or epidural catheter or port. There is an increased risk of bleeding if surgery cannot be delayed and this risk should be weighed against the urgency of surgery; idarucizumab is the most effective agent for dabigatran reversal in adult patients (safety and efficacy have not been established in pediatric patients). Resume dabigatran as soon as medically appropriate. When there is adequate hemostasis after surgery, may reinstitute therapy after 24 hours if there is low risk for bleeding or after 48 to 72 hours if there is high risk for bleeding. Other specific considerations can be found in expert scientific statements and consensus pathways (AHA [Raval 2017]; ACC [Doherty 2017]).

• Spinal or epidural hematoma: [US Boxed Warning]: Spinal or epidural hematomas may occur with neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture in patients who are anticoagulated; may result in long-term or permanent paralysis. The risk of spinal/epidural hematoma is increased with the use of indwelling epidural catheters, concomitant administration of other drugs that affect hemostasis (eg, NSAIDs, platelet inhibitors, other anticoagulants), in patients with a history of traumatic or repeated epidural or spinal punctures, or a history of spinal deformity or spinal surgery. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dabigatran is low; however, the optimal timing between the administration of dabigatran and neuraxial procedures is not known. Monitor frequently for signs and symptoms of neurologic impairment (eg, midline back pain, numbness/weakness of legs, bowel/bladder dysfunction); prompt diagnosis and treatment are necessary. In patients who are anticoagulated or pharmacologic thromboprophylaxis is anticipated, assess risks versus benefits prior to neuraxial interventions.

Metabolism/Transport Effects

Substrate of P-glycoprotein/ABCB1 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Acalabrutinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Dabigatran Etexilate. Agents with Antiplatelet Properties may increase the serum concentration of Dabigatran Etexilate. This mechanism applies specifically to clopidogrel. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk C: Monitor therapy

Alemtuzumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

AmLODIPine: May diminish the therapeutic effect of Dabigatran Etexilate. Risk C: Monitor therapy

Antacids: May decrease the serum concentration of Dabigatran Etexilate. Management: Dabigatran etexilate Canadian product labeling recommends avoiding concomitant use with antacids for 24 hours after surgery. In other situations, administer dabigatran etexilate 2 hours prior to antacids. Monitor clinical response to dabigatran therapy. Risk D: Consider therapy modification

Anticoagulants: Dabigatran Etexilate may enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of dabigatran etexilate with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination

Antiplatelet Agents (P2Y12 Inhibitors): May enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Antiplatelet Agents (P2Y12 Inhibitors) may increase the serum concentration of Dabigatran Etexilate. Specifically, clopidogrel may increase dabigatran serum concentrations. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Risk D: Consider therapy modification

Apixaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of apixaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination

Asciminib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Aspirin: May enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling states that low dose aspirin could be considered, but the use of antiplatelets are not recommended for stroke prevention in patients with atrial fibrillation. Risk D: Consider therapy modification

Bisoprolol: May increase the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy

Bromperidol: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Caplacizumab: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Collagenase (Systemic): Anticoagulants may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy

Dasatinib: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Deferasirox: Anticoagulants may enhance the adverse/toxic effect of Deferasirox. Specifically, the risk for GI ulceration/irritation or GI bleeding may be increased. Risk C: Monitor therapy

Deoxycholic Acid: Anticoagulants may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Risk C: Monitor therapy

Dronedarone: May increase the serum concentration of Dabigatran Etexilate. Management: Dose reductions and/or avoidance of this combination may be necessary. Specific recommendations vary by renal function and indication for dabigatran. Refer to full interaction monograph for details. Risk D: Consider therapy modification

Edoxaban: May enhance the anticoagulant effect of Anticoagulants. Refer to separate drug interaction content and to full drug monograph content regarding use of edoxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Management: Some limited combined use may be indicated during periods of transition from one anticoagulant to another. See the full edoxaban drug monograph for specific recommendations on switching anticoagulant treatment. Risk X: Avoid combination

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Fluconazole: May enhance the anticoagulant effect of Dabigatran Etexilate. Risk C: Monitor therapy

Gilteritinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Hemin: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

Herbal Products with Anticoagulant/Antiplatelet Effects (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Anticoagulants. Bleeding may occur. Risk C: Monitor therapy

Ibritumomab Tiuxetan: Anticoagulants may enhance the adverse/toxic effect of Ibritumomab Tiuxetan. Both agents may contribute to an increased risk of bleeding. Risk C: Monitor therapy

Ibrutinib: May enhance the anticoagulant effect of Dabigatran Etexilate. Ibrutinib may increase the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy

Icosapent Ethyl: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Inotersen: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Kanamycin: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Dabigatran Etexilate. Management: Dose reductions and/or avoidance of this combination may be necessary. Specific recommendations vary by renal function and indication for dabigatran. Refer to full interaction monograph for details. Risk D: Consider therapy modification

Lasmiditan: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors). Risk X: Avoid combination

LevETIRAcetam: May diminish the therapeutic effect of Dabigatran Etexilate. Risk C: Monitor therapy

Limaprost: May enhance the adverse/toxic effect of Anticoagulants. The risk for bleeding may be increased. Risk C: Monitor therapy

Lipid Emulsion (Fish Oil Based): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Lonafarnib: May increase the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy

Lovastatin: May enhance the anticoagulant effect of Dabigatran Etexilate. Risk C: Monitor therapy

Lumacaftor and Ivacaftor: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may decrease the serum concentration of P-glycoprotein/ABCB1 Substrates (High risk with Inhibitors or Inducers). Risk C: Monitor therapy

Mesoglycan: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

MiFEPRIStone: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased. Risk X: Avoid combination

Nintedanib: Anticoagulants may enhance the adverse/toxic effect of Nintedanib. Specifically, the risk for bleeding may be increased. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Nonsteroidal Anti-Inflammatory Agents (Nonselective): May enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Management: A comprehensive risk to benefit assessment should be done for all patients before any concurrent use of dabigatran and nonsteroidal anti-inflammatory drugs (NSAIDs). If combined, monitor patients extra closely for signs and symptoms of bleeding. Risk D: Consider therapy modification

Nonsteroidal Anti-Inflammatory Agents (Topical): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Obinutuzumab: Anticoagulants may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Risk C: Monitor therapy

Omacetaxine: Anticoagulants may enhance the adverse/toxic effect of Omacetaxine. Specifically, the risk for bleeding-related events may be increased. Management: Avoid concurrent use of anticoagulants with omacetaxine in patients with a platelet count of less than 50,000/uL. Risk X: Avoid combination

Omega-3 Fatty Acids: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Oritavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, oritavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C: Monitor therapy

Pentosan Polysulfate Sodium: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of Dabigatran Etexilate. Management: Avoid concurrent use of dabigatran with P-glycoprotein inducers whenever possible. Risk X: Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Risk C: Monitor therapy

PHENobarbital: May decrease the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy

Primidone: May decrease the serum concentration of Dabigatran Etexilate. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the adverse/toxic effect of Anticoagulants. Specifically, the antiplatelet effects of these agents may lead to an increased risk of bleeding with the combination. Risk C: Monitor therapy

Red Yeast Rice: May enhance the anticoagulant effect of Dabigatran Etexilate. Risk C: Monitor therapy

Rivaroxaban: Anticoagulants may enhance the anticoagulant effect of Rivaroxaban. Refer to separate drug interaction content and to full drug monograph content regarding use of rivaroxaban with vitamin K antagonists (eg, warfarin, acenocoumarol) during anticoagulant transition and bridging periods. Risk X: Avoid combination

Salicylates: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Simvastatin: May enhance the anticoagulant effect of Dabigatran Etexilate. Risk C: Monitor therapy

Sodium Zirconium Cyclosilicate: May decrease the serum concentration of Dabigatran Etexilate. Management: Separate the administration of sodium zirconium cyclosilicate and dabigatran by at least 2 hours. Risk D: Consider therapy modification

Sugammadex: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Sulodexide: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Telavancin: May diminish the therapeutic effect of Anticoagulants. Specifically, telavancin may artificially increase the results of laboratory tests commonly used to monitor anticoagulant effectiveness, which could lead to incorrect decisions to decrease anticoagulant doses. Risk C: Monitor therapy

Thrombolytic Agents: May enhance the anticoagulant effect of Dabigatran Etexilate. Management: Carefully monitor for bleeding. Dabigatran Canadian labeling recommends avoiding use with thrombolytic agents. Consider avoiding alteplase treatment of acute ischemic stroke in patients receiving dabigatran (see full drug monograph for details). Risk C: Monitor therapy

Tibolone: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Ticagrelor: May enhance the anticoagulant effect of Dabigatran Etexilate. Ticagrelor may increase the serum concentration of Dabigatran Etexilate. Management: Carefully consider the anticipated risks and benefits of this combination. Increase monitoring bleeding if these agents are combined and consider avoiding the use of this combination in the presence of reduced renal function. Risk D: Consider therapy modification

Tipranavir: May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Urokinase: May enhance the anticoagulant effect of Anticoagulants. Risk X: Avoid combination

Valproate Products: May diminish the therapeutic effect of Dabigatran Etexilate. Risk C: Monitor therapy

Vitamin E (Systemic): May enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Anticoagulants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Vorapaxar: May enhance the adverse/toxic effect of Anticoagulants. More specifically, this combination is expected to increase the risk of bleeding. Risk X: Avoid combination

Zanubrutinib: May enhance the adverse/toxic effect of Anticoagulants. Risk C: Monitor therapy

Food Interactions

Food has no effect on the bioavailability of dabigatran, but delays the time to peak plasma concentrations by 2 hours. Management: Administer without regard to meals.

Reproductive Considerations

Information related to the use of direct-acting oral anticoagulants in pregnancy is limited; until safety data are available, adequate contraception is recommended during therapy for patients who may become pregnant. Patients planning to become pregnant should be switched to alternative anticoagulants prior to conception (Cohen 2016). The risk of clinically significant uterine bleeding is increased in patients on oral anticoagulants; surgical interventions may be required.

Pregnancy Considerations

An ex vivo human placenta dual perfusion model illustrated that dabigatran crossed the placenta at term; dabigatran etexilate mesylate (prodrug) had limited placental transfer (Bapat 2014).

Use of direct-acting oral anticoagulants increases the risk of bleeding in all patients. When used in pregnancy, there is also the potential for fetal bleeding or subclinical placental bleeding which may increase the risk of miscarriage, preterm delivery, fetal compromise, or stillbirth (Cohen 2016).

Information related to the use of dabigatran etexilate in pregnancy is limited (Beyer-Westendorf 2016; Beyer-Westendorf 2020; Lameijer 2018; Sessa 2019).

Data are insufficient to evaluate the safety of direct-acting oral anticoagulants during pregnancy and use in pregnant patients is not recommended (ACOG 2018; Regitz-Zagrosek [ESC 2018]). Agents other than dabigatran etexilate are preferred for the treatment of AF or VTE in pregnant patients (Howard 2018; Kearon 2016; Lip 2018; Regitz-Zagrosek [ESC 2018]). Patients should be switched to an alternative anticoagulant if pregnancy occurs during therapy. Fetal monitoring that includes evaluations for fetal bleeding and assessments for risk of preterm delivery are recommended if the direct-acting oral anticoagulant is continued (Cohen 2016).

Breastfeeding Considerations

Dabigatran etexilate is present in breast milk.

Information is available from 2 women given dabigatran etexilate 220 mg orally 2 to 7 days postpartum. Breast milk was sampled up to 10 hours following a single dose. Maximum concentrations occurred ~2 hours (maternal plasma) and ~7 hours (breast milk) after the dose. Dabigatran peak concentrations were 204.6 ng/mL (maternal plasma) and 8 ng/mL (breast milk) in subject 1 and 414.9 ng/mL (maternal plasma) and 53 ng/mL (breast milk) in subject 2. The women in this study had chosen not to breastfeed (Ayuk 2020).

Breastfeeding is not recommended by the manufacturer. Until safety data are available, direct-acting oral anticoagulants are not recommended for use in patients who are breastfeeding; use of an alternative anticoagulant is preferred (ACOG 2018; Beyer-Westendorf 2020; Cohen 2016).

Monitoring Parameters

CBC, aPTT, PT, serum creatinine, and liver function tests prior to initiation, when clinically indicated, and at least annually (AHA/ACC/HRS [January 2014]; AHA/ACC/HRS [January 2019]; Leung 2019); signs of bleeding.

Routine coagulation testing is not required or necessary for direct oral anticoagulants (DOACs). There are currently no FDA-approved assays or calibration reagents available.

In clinical situations when assessment of the anticoagulant effect is useful (eg, acute care, periprocedural settings, absorption), evaluating a recent creatinine clearance and time since the last dose was ingested is usually sufficient for guiding clinical decisions. The following coagulation testing may also be helpful in quantitative assessments to exclude clinically relevant dabigatran levels: Dilute thrombin time, ecarin clotting time, or ecarin chromogenic assays (ACC [Tomaselli 2020]; AHA [Raval 2017]; Leung 2019).

If a sensitive reagent is used, normal partial thromboplastin time usually excludes clinically relevant serum concentrations although a therapeutic range has not been established for quantification. Thrombin time is highly sensitive and a normal value excludes clinically relevant levels (ACC [Tomaselli 2020]; AHA [Raval 2017]).

Reference Range

Adult: The International Council for Standardization in Haematology (ICSH) provides examples of dabigatran drug levels for the 150 mg twice-daily dose, with an expected mean peak of ~175 ng/mL (25th to 75th percentile of 117 to 275 ng/mL) and an expected mean trough of ~60 to 91 ng/mL (25th to 75th percentile, 39 to 143 ng/mL) (Gosselin 2018). These values are intended to be used as guides to provide evidence of drug absorption, not as therapeutic targets (Leung 2019).

Pediatric: At therapeutic dabigatran doses, activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), and thrombin time (TT) are prolonged. A median peak aPTT of ~2 x control and a median trough aPTT of 1.5 x control were observed in subjects taking dabigatran 150 mg twice daily in the RE-LY trial. A therapeutic range has not been established for aPTT or for other tests of anticoagulant activity.

Mechanism of Action

Prodrug lacking anticoagulant activity that is converted in vivo to the active dabigatran, a specific, reversible, direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin. Inhibits coagulation by preventing thrombin-mediated effects, including cleavage of fibrinogen to fibrin monomers, activation of factors V, VIII, XI, and XIII, and inhibition of thrombin-induced platelet aggregation.

Pharmacokinetics

Absorption: Rapid; initially slow postoperatively.

Distribution: Vd: 50 to 70 L.

Protein binding: ~35%.

Metabolism: Hepatic; dabigatran etexilate is rapidly and completely hydrolyzed to dabigatran (active form) by plasma and hepatic esterases; dabigatran undergoes hepatic glucuronidation to active acylglucuronide isomers (similar activity to parent compound; each of four isomers account for <10% of total dabigatran in plasma).

Bioavailability: 3% to 7%; oral pellets showed 37% higher relative bioavailability in adults, however, this cannot be extrapolated to pediatric patients.

Half-life elimination:

Pediatrics:

Capsules: 12 to 14 hours.

Oral pellets: 9 to 11 hours.

Adults: Capsules: 12 to 17 hours; Elderly patients: 14 to 17 hours; Mild to moderate renal impairment: 15 to 18 hours; Severe renal impairment: 28 hours (Stangier 2010).

Time to peak, plasma: Dabigatran: Fasting state: 1 hour; delayed 2 hours by food (no effect on bioavailability).

Excretion: Primarily in urine.

Pharmacokinetics: Additional Considerations

Renal function impairment: Exposure to dabigatran increases with the severity of renal impairment. AUC increases 1.5, 3.2, and 6.3 times in patients with mild (CrCl 50 to 80 mL/minute), moderate (CrCl 30 to 50 mL/minute), and severe (CrCl 15 to 30 mL/minute) renal impairment, respectively.

Pricing: US

Capsules (Pradaxa Oral)

75 mg (per each): $9.92

110 mg (per each): $9.92

150 mg (per each): $9.92

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Averodab (EG);
  • Cogadexa (EG);
  • Dabigat (BD);
  • Dabiran (BD);
  • Oxogartan (EG);
  • Pradaxa (AE, AR, AT, AU, BB, BE, BH, CH, CL, CN, CO, CU, CY, CZ, DE, DK, EC, EE, EG, ES, FI, FR, GB, GR, HK, HR, ID, IE, IL, IN, IS, IT, JO, JP, KR, KW, LB, LT, LU, LV, MT, MY, NL, NO, NZ, PE, PH, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, TH, TR, TW, UA, UY, VE, VN, ZA);
  • Pradaxar (CR, DO, GT, HN, NI, PA, SV)


For country abbreviations used in Lexicomp (show table)

REFERENCES

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