Adverse Effects

• Bleeding, dyspepsia, increased risk of MI (0.2% pts treated), elevated ALT; possible increased incidence of CAD than with VKA

to Warfarin

• CrCl>50 mL/min: Start Warfarin 3 days before stopping Dabigatran
• CrCl 30-50: 2 days
• CrCl<15-30: 1 day

to Heparin (CI)

• Stop Dabigatran
• CrCl>30: Start CI Heparin without a bolus in 12 hours
• CrCl< 30: Start CI Heparin without a bolus in 24 hours

to LMWH

• Stop Dabigatran
• CrCl>30: Start LMWH in 12 hours
• CrCl< 30: Start LMWH in 24 hours

to Dabigatran

• N/A

to Apixaban

• Stop Dabigatran
• Start Apixaban at time of next scheduled dose

to Rivaroxaban

• Stop Dabigatran
• Start Rivaroxaban <2 hours before next scheduled dose

to Edoxoban

• Stop Dabigatran
• Start Edoxaban at time of next scheduled dose

*Note: Dabigatran, Rivaroxaban, Edoxaban, and Apixaban affect the INR; measuring the INR during coadministration with warfarin therapy may not be useful for determining an appropriate dose of warfarin. To minimize this effect, check INR at trough level of respective medication

Purpose
To provide details about dabigatran use, the only orally available direct thrombin inhibitor, at IHTC during hospital admission or as outpatient

Indication
VTE treatment and thromboprophylaxis for pediatric patients at least 3 months of age and 3 kg or greater after at least 5 days of initial parenteral anticoagulant treatment, as well as nonvalvular atrial fibrillation prophylaxis for patients at least 8 years of age and 50 kg or greater. Do NOT use in patients with mechanical prosthetic heart valves (contraindicated due to increased risk of thromboembolic events). Dabigatran isn’t recommended in patients with antiphospholipid syndrome. Dabigatran is indicated for pediatric VTE treatment after 5-10 days of parenteral anticoagulation

USE

Dosage Forms

• Dabigatran is available as capsules or oral pellets. The dosage forms are NOT interchangeable on a mg:mg basis due to PK differences (e.g., bioavailability). Combining dosage forms to achieve total dose is NOT recommended. 
• Pellet dosage forms – 20 mg (60 each); 30 mg (60 each); 40 mg (60 each); 50 mg (60 each); 110 mg (60 each); 150 mg (60 each)
• Capsule dosage forms – 75 mg, 150 mg, 110 mg
  

  Oral Pellets	≥3 months to <12 years of age
  Capsules	≥8 years of age

• Patient assistance program for drug: Boehringer-Ingelheim

Initiating Therapy
Minimum Monitoring Requirements: Prior to initiation of therapy or continuation of home therapy, but no longer than 48 hours before, the following labs should be checked: CBC, coagulation profile (PT, PTT, fibrinogen activity), hepatic function panel, creatinine, urine pregnancy if applicable

Administration
Oral Pellets	Administer if able to swallow soft, solid foods by mixing with only the following: apple juice, applesauce, baby rice cereal (prepared with water), mashed carrots, or mashed bananas. The pellets should NOT be administered with any milk products, should NOT be administered via a syringe or feeding tube, and should be administered within 30 min. of mixing with juice or food Soft food amount (applesauce, baby rice cereal, mashed carrots/bananas): ~2 teaspoons Apple juice amount: 1-2 oz.
Capsule	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.

Pharmacokinetics

Half-life	12-14 h
Time to peak	2 to 3 h
Absorption	Lower gastric region and duodenum
Oral availability	~3-7%
Excretion	85% primarily Renal elimination of unchanged drug
Protein binding	~35%

Safety Precautions

Renal impairment: Consider on individual basis in consultation with IHTC, nephrology, and pharmacy for patients with CrCl <50 mL/minute. In general, for eGFR <50 mL/minute/1.73m2, avoid use.

Hepatic impairment: There are no dosage adjustments provided in prescriber information. A small fraction of absorbed dabigatran is metabolized to glucuronides in the liver; however, this conjugation doesn’t change the activity of dabigatran. Therefore, a decrease in liver function isn’t expected to affect the activity of dabigatran significantly. Dabigatran undergoes elimination predominantly (~80%) through the kidney.

Drug-Drug interactions: 

• Substrate of p-glycoprotein
  • P-glycoprotein/ABCB1 Inducers may decrease the serum concentration of dabigatran. Avoid concurrent use of dabigatran with P-glycoprotein inducers whenever possible.
  • Drug interactions that increase drug levels: amiodarone, quinidine, azole antifungals (e.g., ketoconazole), ritonavir
  • Drug interactions that decrease drug levels: rifampin, phenytoin, carbamazepine, St. John’s wort
  • P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolites of dabigatran.
  • Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.) may enhance the anticoagulant effect of Anticoagulants. 
  • Drug-Food Interactions – Food delays the time to peak plasma concentration by 2 hours, administer without regard to meals for capsules.

Pediatric Dosing for VTE treatment and prevention
**Initiate after ≥5 days of parenteral anticoagulation for treatment. For prevention, initiate after treatment complete. Dosing is based on patient WEIGHT and AGE.

Oral Pellets

Infants 3 to <4 months
3 to <4 kg	30 mg q12h
4 to <7 kg	40 mg q12h
7 to <9 kg	50 mg q12h
Infants 4 to <5 months
3 to <4 kg	30 mg q12h
4 to <7 kg	40 mg q12h
7 to <9 kg	60 mg q12h
Infants 5 to <6 months
3 to <4 kg	30 mg q12h
4 to <5 kg	40 mg q12h
5 to <7 kg	50 mg q12h
7 to <11 kg	60 mg q12h
Infants 6 to <8 months
4 to <5 kg	40 mg q12h
5 to <7 kg	50 mg q12h
7 to <9 kg	60 mg q12h
9 to <11k g	80 mg 12h
Infants 8 to <9 months
4 to <5 kg	40 mg q12h
5 to <7 kg	50 mg q12h
7 to <9 kg	60 mg q12h
9 to <11 kg	80 mg 12h
11 to <13 kg	100 mg q12h
Infants 9 to <10 months
4 to <5 kg	40 mg q12h
5 to <7 kg	50 mg q12h
7 to <9 kg	70 mg q12h
9 to <11 kg	80 mg 12h
11 to <13 kg	100 mg q12h
Infants 10 to <11 months
5 to <7 kg	50 mg q12h
7 to <9 kg	70 mg q12h
9 to <11 kg	80 mg 12h
11 to <16 kg	100 mg q12h
Infants 11 to <12 months
5 to <7 kg	50 mg q12h
7 to <9 kg	70 mg q12h
9 to <11 kg	90 mg q12h
11 to <13 kg	100 mg q12h
13 to <16kg	140 mg q12h
Children <1.5 years
5 to <7 kg	50 mg q12h
7 to <9 kg	70 mg q12h
9 to <11 kg	90 mg q12h
11 to <13 kg	100 mg q12h
13 to <21kg	140 mg q12h
Children 1.5 to <2 years
5 to <7 kg	50 mg q12h
7 to <9 kg	70 mg q12h
9 to <11 kg	90 mg q12h
11 to <13 kg	110 mg q12h
13 to <21 kg	140 mg q12h
21 to <26 kg	180 mg q12h
Children 2 to <12 years
7 to <9 kg	70 mg q12h
9 to <11 kg	90 mg q12h
11 to <13 kg	110 mg q12h
13 to <16 kg	140 mg q12h
16 to <21 kg	170 mg q12h
21 to <41 kg	220 mg q12h
≥41 kg	260 mg q12h

Oral Capsules

Children ≥8 years and adolescents
11 to <16 kg	75 mg q12h
16 to <26 kg	110 mg q12h
26 to <41 kg	150 mg q12h
41 to <61 kg	185 mg q12h
61 to <81 kg	220 mg q12h
≥81 kg	260 mg q12h

**It is important to note that in the pediatric clinical trials for dabigatran that continued treatment dosing for secondary prevention of VTE in children beyond the 3-month acute treatment phase, the dosing regimen was NOT changed.

Adult Dosing

• Nonvalvular atrial fibrillation:
  • 150 mg PO BID
  • For CrCl 15-30 mL/min, 75 mg PO BID
  • For CrCl < 15 mL/min, avoid use
• DVT and PE treatment (initiate 5 days after parenteral anticoagulation):
  • 150 mg PO BID
  • Duration: 3 months for provoked VTE (as long as provoking risk factor no longer present) OR ≥3 months for unprovoked VTE
  • For CrCl < 30 mL/min, avoid use
• VTE prophylaxis in total hip or total knee arthroplasty: 
  • 110 mg PO given 1 to 4 hours after completion of surgery and establishment of homeostasis then 220 mg orally once daily for a minimum of 10 to 14 days (optimal duration unknown) OR
  • When dabigatran not initiated on day of surgery, give initial dose of 220 mg after homeostasis, then maintenance of 220 mg by mouth once daily for a minimum of 10 to 14 days (optimal duration unknown)
• Hepatic impairment: there are no dosage adjustments provided in the manufacturer’s labeling; consistent exposure or pharmacodynamics were not observed in a study of patients with moderate impairment

Anticoagulation Monitoring Parameter and Reference Range
Routine coagulation testing is not required for monitoring of dabigatran. There is currently no FDA-approved assay or calibration reagent available. Observed peak and trough concentrations of dabigatran in patients exposed to therapeutic dosing have been reported. If monitoring is indicated, ecarin clotting time (ECT) and diluted thrombin time (dTT) are the preferred tests, but these assays aren’t available at PMCH/Special Coag Lab; additionally, therapeutic ranges haven’t been established

Perioperative Management

• Decision making regarding whether dabigatran needs to be held depends on type of surgery, renal function, and balance of bleeding versus thrombosis risk. The duration for withholding is based upon the estimated dabigatran half-life times 2 to 3 half-lives for low procedural bleeding risk and 4 to 5 drug half-lives for high procedural bleeding risk. If it is indicated, dabigatran should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding, and should be discontinued for at least 24 hours prior to elective surgery or invasive procedures with low bleeding risk or where the bleeding would be non-critical in location easily controlled. 
• In adult patients with CrCl >50mL/minute, discontinue therapy prior to surgery as above. In adult patients with CrCl < 50mL/minute, discontinue dabigatran therapy ~72-120 hours prior to surgery, or longer, depending on risk of bleeding.
• In pediatric patients with CrCl >80 mL/minute, discontinue therapy 24 hours prior to elective surgery with low bleeding risk, or 48 hours prior to elective surgery with moderate or high bleeding risk.
• In pediatric patients with CrCl 50-80 mL/minute, discontinue therapy 48 hours prior to elective surgery with low bleeding risk, and >72 hours prior to elective surgery with moderate or high bleeding risk. 
• Epidural or spinal hematomas have occurred in patients treated with DOACs who are receiving neuraxial anesthesia or undergoing spinal puncture. Optimal timing between the administration of dabigatran and neuraxial procedures is not known. Consider holding for 24-72 hours prior to lumbar punctures for these reasons above.
• In rare cases, in patients with very high risk of thrombosis, bridging with unfractionated heparin may be required to limit the time off anticoagulation.
• Restart dabigatran after the procedure as soon as adequate hemostasis has been established and once cleared by the surgeon or interventionalist. If oral medication cannot be taken after the procedure, consider switching to a parenteral anticoagulant.

Bleeding Precautions & Warnings

• While on anticoagulation avoid aspirin, ibuprofen, or other anti-platelet drugs unless specifically indicated as anti-platelet therapy.
• Try to avoid IM injections and arterial punctures. Apply pressure after venipuncture until bleeding has ceased.

Reversal Information

• Idarucizumab is FDA indicated for reversal of dabigatran. It is recommended for life-threatening bleeding, bleeding into a critical organ, or prior to an emergency procedure.
  • The recommended Adult dose is:  Idarucizumab 5 g IV per dose administered as 2 separate 2.5 g doses no more than 15 minutes apart. Pediatric dosing of Idarucizumab is NOT available. Idarucizumab is on formulary at St. Vincent.
  • Critical site bleeds: Intracranial hemorrhage, including intraparenchymal, subdural, epidural, and subarachnoid hemorrhages; Other CNS hemorrhage, including intraocular, intra- or extra-axial spinal hemorrhages; Pericardial tamponade; Airway, including posterior epistaxis; Hemothorax, intraabdominal bleeding, and retroperitoneal hemorrhage; Extremity bleeds, including intramuscular and intraarticular bleeding concerning for compartment syndrome, bleeding associated with hemodynamic instability, bleeding in a noncompressible vessel (e.g., subclavian)
• If idracuzumab isn’t available, then consider Kcentra (prothrombin complex concentrate) 25-50 units/kg for severe bleeding or NovoSeven (rFVIIa) 90 mcg/kg. FEIBA (activated PCC) 50 units/kg would be a last resort due to higher thrombosis risk. They are on formulary at PMCH but are not labeled by the manufacturer for reversal of rivaroxaban.
• In the setting of overdose, also consider administration of activated charcoal (50 g) if within 2 hours of dose.
• Dabigatran is dialyzable.
• Repeat monitoring tests for anticoagulant and platelets, PT, PTT, and fibrinogen after infusing a reversal agent and q 4-6 hours until severe bleeding risk has passed. Determine if and when anticoagulation should be reinitiated and what agent. Monitor patient for thrombosis and bleeding.

Transition Information

• A bridge anticoagulant is not necessary when transitioning from another anticoagulant to dabigatran therapy. See separate anticoagulant-specific Clinical Case Manual for transitioning from another specific anticoagulant to dabigatran. 
• See table for switching from dabigatran to another anticoagulant

From	To	Action
Dabigatran	Argatroban/Bivalirudin/Enoxaparin/Dalteparin/Fondaparinux/Heparin	Initiate parenteral anticoagulant when next dose of dabigatran would be due. If patient’s CrCl has reduced while on dabigatran, a longer wash out period may be needed before starting new anticoagulant. In cases of increased bleeding risk, consider a risk benefit analysis before omitting initial bolus when transitioning to heparin infusion.
	Apixaban, Betrixaban Edoxaban, or Rivaroxaban	Initiate when the next dose of dabigatran would have been taken. If patient’s CrCl has reduced while on dabigatran, longer wash out period may be needed before starting new anticoagulant.
	Warfarin	Limited data available on switching DOACs to warfarin. Consider coadministering DOAC and warfarin therapy until INR is therapeutic, or stopping DOAC and bridging warfarin with LMWH or UFH if bridging patient is clinically indicated (e.g., start UFH or therapeutic LMWH and warfarin when next dose of rivaroxaban would have been taken).. For normal CrCl, start warfarin 3 days before discontinuing dabigatran. For reduced CrCl 30-50 mL/min, consider starting warfarin 1-2 days before discontinuing dabigatran. All DOACs affect INR so that initial INR during the transition may not be useful for determining the appropriate dose of warfarin.

Pregnancy
Currently, only Lovenox (enoxaparin) and unfractionated heparin are advised for use in pregnant women. Females of childbearing age must be counseled that DOACs are not approved for use during pregnancy and referred for appropriate contraception if needed.

Patient Education and Ongoing Management
Discharging IHTC physician/APP is responsible for ensuring adequate follow-up for anticoagulation management has been scheduled prior to patient leaving the hospital.

References

1.     Pradaxa® (dabigatran etexilate mesylate) oral capsule [Prescribing Information]. Burlington, Ontario, Canada: Boehringer Ingelheim Canada Ltd; June 2021.

2.     Pradaxa® (dabigatran etexilate mesylate) oral pellet [Prescribing Information]. Burlington, Ontario, Canada: Boehringer Ingelheim Canada Ltd; June 2021.

3.     Halton J, Brandão LR, Luciani M, Bomgaars L, Chalmers E, Mitchell LG, Nurmeev I, Sharathkumar A, Svirin P, Gorbatikov K, Tartakovsky I, Simetzberger M, Huang F, Sun Z, Kreuzer J, Gropper S, Reilly P, Brueckmann M, Albisetti M; DIVERSITY Trial Investigators. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol. 2021 Jan;8(1):e22-e33. doi: 10.1016/S2352-3026(20)30368-9. Epub 2020 Dec 5. PMID: 33290737.

4.     Brandão LR, Albisetti M, Halton J, Bomgaars L, Chalmers E, Mitchell LG, Nurmeev I, Svirin P, Kuhn T, Zapletal O, Tartakovsky I, Simetzberger M, Huang F, Sun Z, Kreuzer J, Gropper S, Brueckmann M, Luciani M; DIVERSITY Study Investigators. Safety of dabigatran etexilate for the secondary prevention of venous thromboembolism in children. Blood. 2020 Feb 13;135(7):491-504. doi: 10.1182/blood.2019000998. Erratum in: Blood. 2020 May 7;135(19):1720. PMID: 31805182; PMCID: PMC7019192.

5.     Monagle P, Cuello CA, Augustine C, Bonduel M, Brandão LR, Capman T, Chan AKC, Hanson S, Male C, Meerpohl J, Newall F, O’Brien SH, Raffini L, van Ommen H, Wiernikowski J, Williams S, Bhatt M, Riva JJ, Roldan Y, Schwab N, Mustafa RA, Vesely SK. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. Blood Adv. 2018 Nov 27;2(22):3292-3316. doi: 10.1182/bloodadvances.2018024786. PMID: 30482766; PMCID: PMC6258911.

6.     Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal—full cohort analysis. N Engl J Med. 2017;377(5):431-441

7.     Bower MM, Sweidan AJ, Shafie M, et al. Contemporary reversal of oral anticoagulation in intracerebral hemorrhage. Stroke. 2019;50:529-536

8.     Praxbind (idarucizumab) [product monograph]. Burlington, Ontario, Canada: Boehringer Ingelheim (Canada) Ltd; October 2021

9.     Burnett AE, Mahan CE, Vanquez SR, et al. Guidance of the practical management of direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis. 2016;41:206-232.

10.  Antovic JP, Skeppholm M, Eintrei J, et al. Evaluation of coagulation assays versus LC-MS/MS for determination of dabigatran concentrations in plasma. Eur J Clin Pharmacol. 2013;69:1875-1881.

11.  Christos S, Naples R. Anticoagulation reversal and treatment strategies in major bleeding: update 2016. West J Emerg Med. 2016;17(3):264-270

12.  Shapiro S, Bhatnagar N, Khan A, Beavis J, Keeling D. Idarucizumab for dabigatran overdose in a child. Br J Haematol. (2018) 180:457–9. doi: 10.1111/bjh.14371