Dabigatran Etexilate Mesylate

Dosage Forms And Strengths

150 mg capsules with a light blue opaque cap imprinted in black with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted in black with “R150”.

110 mg capsules with a light blue opaque cap imprinted in black with the Boehringer Ingelheim company symbol and a light blue opaque body imprinted in black with “R110”.

75 mg capsules with a cream-colored opaque cap imprinted in black with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted in black with “R75”.

Storage And Handling

PRADAXA 75 mg capsules have a cream-colored opaque cap imprinted with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted with “R75”. The color of the imprinting is black. The capsules are supplied in the packages listed:

NDC 0597-0149-54 Unit of use bottle of 60 capsules
NDC 0597-0149-60 Blister package containing 60 capsules (10 x 6 capsule blister cards)

PRADAXA 110 mg capsules have a light blue opaque cap imprinted with the Boehringer Ingelheim company symbol and a light blue opaque body imprinted with “R110”. The color of the imprinting is black. The capsules are supplied in the packages listed:

NDC 0597-0108-54 Unit of use bottle of 60 capsules
NDC 0597-0108-60 Blister package containing 60 capsules (10 x 6 capsule blister cards)

PRADAXA 150 mg capsules have a light blue opaque cap imprinted with the Boehringer Ingelheim company symbol and a cream-colored opaque body imprinted with “R150”. The color of the imprinting is black. The capsules are supplied in the packages listed:

NDC 0597-0135-54 Unit of use bottle of 60 capsules
NDC 0597-0135-60 Blister package containing 60 capsules (10 x 6 capsule blister cards)

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Once opened, the product must be used within 4 months. Keep the bottle tightly closed. Store in the original package to protect from moisture.

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Store in the original package to protect from moisture.

Keep out of the reach of children.

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc.; Ridgefield, CT 06877 USA. Revised: November 2015

Mechanism Of Action

Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Because thrombin (serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.

Pharmacodynamics

At recommended therapeutic doses, dabigatran etexilate prolongs the coagulation markers such as aPTT, ECT, and TT. INR is relatively insensitive to the exposure to dabigatran and cannot be interpreted the same way as used for warfarin monitoring.

The aPTT test provides an approximation of PRADAXA's anticoagulant effect. The average time course for effects on aPTT, following approved dosing regimens in patients with various degrees of renal impairment is shown in Figure 2. The curves represent mean levels without confidence intervals; variations should be expected when measuring aPTT. While advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting, the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of PRADAXA is not precisely known. In the RE-LY trial, the median (10th to 90th percentile) trough aPTT in patients receiving the 150 mg dose was 52 (40 to 76) seconds.

Figure 2 : Average Time Course for Effects of Dabigatran on aPTT, Following Approved PRADAXA Dosing Regimens in Patients with Various Degrees of Renal Impairment*

*Simulations based on PK data from a study in subjects with renal impairment and PK/aPTT relationships derived from the RE-LY study; aPTT prolongation in RE-LY was measured centrally in citrate plasma using PTT Reagent Roche Diagnostics GmbH, Mannheim, Germany. There may be quantitative differences between various established methods for aPTT assessment.

The degree of anticoagulant activity can also be assessed by the ecarin clotting time (ECT). This test is a more specific measure of the effect of dabigatran than activated partial thromboplastin time (aPTT). In the RE-LY trial, the median (10th to 90th percentile) trough ECT in patients receiving the 150 mg dose was 63 (44 to 103) seconds.

In orthopedic hip surgery patients, maximum aPTT response (Emax) to dabigatran and baseline aPTT were higher shortly after surgery than at later time points (e.g. ≥ 3 days after surgery).

No prolongation of the QTc interval was observed with dabigatran etexilate at doses up to 600 mg.

Pharmacokinetics

Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moiety. Dabigatran is metabolized to four different acyl glucuronides and both the glucuronides and dabigatran have similar pharmacological activity. Pharmacokinetics described here refer to the sum of dabigatran and its glucuronides. Dabigatran displays dose-proportional pharmacokinetics in healthy subjects and patients in the range of doses from 10 to 400 mg.

The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3 to 7%. Dabigatran etexilate is a substrate of the efflux transporter P-gp. After oral administration of dabigatran etexilate in healthy volunteers, Cmax occurs at 1 hour post-administration in the fasted state. Coadministration of PRADAXA with a high-fat meal delays the time to Cmax by approximately 2 hours but has no effect on the bioavailability of dabigatran; PRADAXA may be administered with or without food.

The oral bioavailability of dabigatran etexilate increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule formulation. PRADAXA capsules should therefore not be broken, chewed, or opened before administration.

Dabigatran is approximately 35% bound to human plasma proteins. The red blood cell to plasma partitioning of dabigatran measured as total radioactivity is less than 0.3. The volume of distribution of dabigatran is 50 to 70 L. Dabigatran pharmacokinetics are dose proportional after single doses of 10 to 400 mg. Given twice daily, dabigatran's accumulation factor is approximately two.

Dabigatran is eliminated primarily in the urine. Renal clearance of dabigatran is 80% of total clearance after intravenous administration. After oral administration of radiolabeled dabigatran, 7% of radioactivity is recovered in urine and 86% in feces. The half-life of dabigatran in healthy subjects is 12 to 17 hours.

After oral administration, dabigatran etexilate is converted to dabigatran. The cleavage of the dabigatran etexilate by esterase-catalyzed hydrolysis to the active principal dabigatran is the predominant metabolic reaction. Dabigatran is not a substrate, inhibitor, or inducer of CYP450 enzymes. Dabigatran is subject to conjugation forming pharmacologically active acyl glucuronides. Four positional isomers, 1-O, 2-O, 3-O, and 4-O-acylglucuronide exist, and each accounts for less than 10% of total dabigatran in plasma.

An open, parallel-group single-center study compared dabigatran pharmacokinetics in healthy subjects and patients with mild to moderate renal impairment receiving a single dose of PRADAXA 150 mg. Exposure to dabigatran increases with severity of renal function impairment (Table 8). Similar findings were observed in the RELY, RE-COVER and RE-NOVATE II trials.

Table 8 : Impact of Renal Impairment on Dabigatran Pharmacokinetics

Administration of PRADAXA in patients with moderate hepatic impairment (Child-Pugh B) showed a large inter-subject variability, but no evidence of a consistent change in exposure or pharmacodynamics.

Drug Interactions

A summary of the effect of coadministered drugs on dabigatran exposure is shown in Figures 3.1 and 3.2.

In the orthopedic hip surgery patients, limited clinical data with P-gp inhibitors is available.

Figure 3.1:  Effect of P-gp Inhibitor or Inducer (rifampicin) Drugs on Peak and Total Exposure to Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The Perpetrator and Dabigatran Etexilate Dose and Dosing Frequency are given as well as the Time of Perpetrator Dosing in Relation to Dabigatran Etexilate Dose (Time Difference)

Figure 3.2: Effect of Non-P-gp Inhibitor or Inducer, Other Drugs, on Peak and Total Exposure to Dabigatran (Cmax and AUC). Shown are the Geometric Mean Ratios (Ratio) and 90% Confidence Interval (90% CI). The Perpetrator and Dabigatran Etexilate Dose and Dosing Frequency are given as well as the Time of Perpetrator Dosing in Relation to Dabigatran Etexilate Dose (Time Difference)

In RE-LY, dabigatran plasma samples were also collected. The concomitant use of proton pump inhibitors, H2 antagonists, and digoxin did not appreciably change the trough concentration of dabigatran.

In clinical studies exploring CYP3A4, CYP2C9, P-gp and other pathways, dabigatran did not meaningfully alter the pharmacokinetics of amiodarone, atorvastatin, clarithromycin, diclofenac, clopidogrel, digoxin, pantoprazole, or ranitidine.

Clinical Studies

The clinical evidence for the efficacy of PRADAXA was derived from RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy), a multi-center, multinational, randomized parallel group trial comparing two blinded doses of PRADAXA (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3) in patients with non-valvular, persistent, paroxysmal, or permanent atrial fibrillation and one or more of the following additional risk factors:

• Previous stroke, transient ischemic attack (TIA), or systemic embolism
• Left ventricular ejection fraction < 40%
• Symptomatic heart failure, ≥ New York Heart Association Class 2
• Age ≥ 75 years
• Age ≥ 65 years and one of the following: diabetes mellitus, coronary artery disease (CAD), or hypertension

The primary objective of this study was to determine if PRADAXA was non-inferior to warfarin in reducing the occurrence of the composite endpoint, stroke (ischemic and hemorrhagic) and systemic embolism. The study was designed to ensure that PRADAXA preserved more than 50% of warfarin's effect as established by previous randomized, placebo-controlled trials of warfarin in atrial fibrillation. Statistical superiority was also analyzed.

A total of 18,113 patients were randomized and followed for a median of 2 years. The patients' mean age was 71.5 years and the mean CHADS2 score was 2.1. The patient population was 64% male, 70% Caucasian, 16% Asian, and 1% black. Twenty percent of patients had a history of a stroke or TIA and 50% were Vitamin K antagonist (VKA) naïve, defined as less than 2 months total lifetime exposure to a VKA. Thirty-two percent of the population had never been exposed to a VKA. Concomitant diseases of patients in this trial included hypertension 79%, diabetes 23%, and CAD 28%. At baseline, 40% of patients were on aspirin and 6% were on clopidogrel. For patients randomized to warfarin, the mean percentage of time in therapeutic range (INR 2 to 3) was 64%.

Relative to warfarin and to PRADAXA 110 mg twice daily, PRADAXA 150 mg twice daily significantly reduced the primary composite endpoint of stroke and systemic embolism (see Table 9 and Figure 4).

Table 9 : First Occurrence of Stroke or Systemic Embolism in the RE-LY Study*

Figure 4 : Kaplan-Meier Curve Estimate of Time to First Stroke or Systemic Embolism

The contributions of the components of the composite endpoint, including stroke by subtype, are shown in Table 10. The treatment effect was primarily a reduction in stroke. PRADAXA 150 mg twice daily was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.

Table 10 : Strokes and Systemic Embolism in the RE-LY Study

In the RE-LY trial, the rate of all-cause mortality was lower on dabigatran 150 mg than on warfarin (3.6% per year versus 4.1% per year). The rate of vascular death was lower on dabigatran 150 mg compared to warfarin (2.3% per year versus 2.7% per year). Non-vascular death rates were similar in the treatment arms.

The efficacy of PRADAXA 150 mg twice daily was generally consistent across major subgroups (see Figure 5).

Figure 5 : Stroke and Systemic Embolism Hazard Ratios by Baseline Characteristics*

* Randomized ITT

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified. The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

In RE-LY, a higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

In the randomized, parallel group, double-blind trials, RE-COVER and RE-COVER II, patients with deep vein thrombosis and pulmonary embolism received PRADAXA 150 mg twice daily or warfarin (dosed to target INR of 2 to 3) following initial treatment with an approved parenteral anticoagulant for 5-10 days.

In RE-COVER, the median treatment duration during the oral only treatment period was 174 days. A total of 2539 patients (30.9% patients with symptomatic PE with or without DVT and 68.9% with symptomatic DVT only) were treated with a mean age of 54.7 years. The patient population was 58.4% male, 94.8% white, 2.6% Asian, and 2.6% black. The concomitant diseases of patients in this trial included hypertension (35.9%), diabetes mellitus (8.3%), coronary artery disease (6.5%), active cancer (4.8%), and gastric or duodenal ulcer (4.4%). Concomitant medications included agents acting on renin-angiotensin system (25.2%), vasodilators (28.4%), serum lipid-reducing agents (18.2%), NSAIDs (21%), beta-blockers (14.8%), calcium channel blockers (8.5%), ASA (8.6%), and platelet inhibitors excluding ASA (0.6%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 60% in RE-COVER study.

In RE-COVER II, the median treatment duration during the oral only treatment period was 174 days. A total of 2568 patients (31.8% patients with symptomatic PE with or without DVT and 68.1% with symptomatic DVT only) were treated with a mean age of 54.9 years. The patient population was 60.6% male, 77.6% white, 20.9% Asian, and 1.5% black. The concomitant diseases of patients in this trial included hypertension (35.1%), diabetes mellitus (9.8%), coronary artery disease (7.1%), active cancer (3.9%), and gastric or duodenal ulcer (3.8%). Concomitant medications included agents acting on renin-angiotensin system (24.2%), vasodilators (28.6%), serum lipid-reducing agents (20.0%), NSAIDs (22.3%), beta-blockers (14.8%), calcium channel blockers (10.8%), ASA (9.8%), and platelet inhibitors excluding ASA (0.8%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 57% in RE-COVER II study.

In studies RE-COVER and RE-COVER II, the protocol specified non-inferiority margin (2.75) for the hazard ratio was derived based on the upper limit of the 95% confidence interval of the historical warfarin effect. PRADAXA was demonstrated to be non-inferior to warfarin (dosed to target INR of 2 to 3) (Table 11) based on the primary composite endpoint (fatal PE or symptomatic non-fatal PE and/or DVT) and retains at least 66.9% (RE-COVER) and 63.9% (RE-COVER II) of the historical warfarin effect respectively.

Table 11 : Primary Efficacy Endpoint for RE-COVER and RE-COVER II – Modified ITTa Population

In the randomized, parallel group, double-blind, pivotal trial, RE-MEDY, patients received PRADAXA 150 mg twice daily or warfarin (dosed to target INR of 2 to 3) following 3 to 12 months of treatment with anticoagulation therapy for an acute VTE. The median treatment duration during the treatment period was 534 days. A total of 2856 patients were treated with a mean age of 54.6 years. The patient population was 61% male, and 90.1% white, 7.9% Asian and 2.0% black. The concomitant diseases of patients in this trial included hypertension (38.6%), diabetes mellitus (9.0%), coronary artery disease (7.2%), active cancer (4.2%), and gastric or duodenal ulcer (3.8%). Concomitant medications included agents acting on renin-angiotensin system (27.9%), vasodilators (26.7%), serum lipid reducing agents (20.6%), NSAIDs (18.3%), beta-blockers (16.3%), calcium channel blockers (11.1%), aspirin (7.7%), and platelet inhibitors excluding ASA (0.9%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 62% in the study.

In study RE-MEDY, the protocol specified non-inferiority margin (2.85) for the hazard ratio was derived based on the point estimate of the historical warfarin effect. PRADAXA was demonstrated to be non-inferior to warfarin (dosed to target INR of 2 to 3) (Table 12) based on the primary composite endpoint (fatal PE or symptomatic non-fatal PE and/or DVT) and retains at least 63.0% of the historical warfarin effect. If the non-inferiority margin was derived based on the 50% retention of the upper limit of the 95% confidence interval, PRADAXA was demonstrated to retain at least 33.4% of the historical warfarin effect based on the composite primary endpoint.

Table 12 : Primary Efficacy Endpoint for RE-MEDY – Modified ITTa Population

In a randomized, parallel group, double-blind, pivotal trial, RE-SONATE, patients received PRADAXA 150 mg twice daily or placebo following 6 to 18 months of treatment with anticoagulation therapy for an acute VTE. The median treatment duration was 182 days. A total of 1343 patients were treated with a mean age of 55.8 years. The patient population was 55.5% male, 89.0% white, 9.3% Asian, and 1.7% black. The concomitant diseases of patients in this trial included hypertension (38.8%), diabetes mellitus (8.0%), coronary artery disease (6.0%), history of cancer (6.0%), gastric or duodenal ulcer (4.5%), and heart failure (4.6%). Concomitant medications included agents acting on renin-angiotensin system (28.7%), vasodilators (19.4%), beta-blockers (18.5%), serum lipid reducing agents (17.9%), NSAIDs (12.1%), calcium channel blockers (8.9%), aspirin (8.3%), and platelet inhibitors excluding ASA (0.7%). Based on the outcome of the primary composite endpoint (fatal PE, unexplained death, or symptomatic non-fatal PE and/or DVT), PRADAXA was superior to placebo (Table 13).

Table 13 : Primary Efficacy Endpoint for RE-SONATE – Modified ITTa Population

In the randomized, parallel group, double-blind, non-inferiority trials, RE-NOVATE and RE-NOVATE II patients received PRADAXA 75 mg orally 1-4 hours after surgery followed by 150 mg daily (RE-NOVATE), PRADAXA 110 mg orally 1-4 hours after surgery followed by 220 mg daily (RE-NOVATE and RE-NOVATE II) or subcutaneous enoxaparin 40 mg once daily initiated the evening before surgery (RE-NOVATE and RE-NOVATE II) for the prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip replacement surgery.

Overall, in RE-NOVATE and RE-NOVATE II, the median treatment duration was 33 days for PRADAXA and 33 days for enoxaparin. A total of 5428 patients were treated with a mean age of 63.2 years. The patient population was 45.3% male, 96.1% white, 3.6% Asian, and 0.4 % black. The concomitant diseases of patients in these trials included hypertension (46.1%), venous insufficiency (15.4%), coronary artery disease (8.2%), diabetes mellitus (7.9%), reduced renal function (5.3%), heart failure (3.4%), gastric or duodenal ulcer (3.0%), VTE (2.7%), and malignancy (0.1%). Concomitant medications included cardiac therapy (69.7%), NSAIDs (68%), vasoprotectives (29.7%), agents acting on renin-angiotensin system (29.1%), beta-blockers (21.5%), diuretics (20.8%), lipid modifying agents (18.2%), any antithrombin/anticoagulant (16.0%), calcium channel blockers (13.6%), low molecular weight heparin (7.8%), aspirin (7.0%), platelet inhibitors excluding ASA (6.9%), other antihypertensives (6.7%), and peripheral vasodilators (2.6%).

For efficacy evaluation all patients were to have bilateral venography of the lower extremities at 3 days after last dose of study drug unless an endpoint event had occurred earlier in the study. In the primary efficacy analysis, PRADAXA 110 mg orally 1-4 hours after surgery followed by 220 mg daily was non-inferior to enoxaparin 40 mg once daily in a composite endpoint of confirmed VTE (proximal or distal DVT on venogram, confirmed symptomatic DVT, or confirmed PE) and all cause death during the treatment period (Tables 14 and 15). In the studies 2628 (76.5%) patients in RE-NOVATE and 1572 (78.9%) patients in RE-NOVATE II had evaluable venograms at study completion.

Table 14 : Primary Efficacy Endpoint for RE-NOVATE

Table 15 : Primary Efficacy Endpoint for RE-NOVATE II

Your pharmacist can provide more information about dabigatran.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Embolism Associated with Atrial Fibrillation

Reduction in risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.1 2 3 5 18 20 21 30 32

Some evidence suggests that dabigatran 150 mg twice daily may produce similar or superior outcomes in such patients compared with warfarin.18 19 20 41 69 1007

The American College of Chest Physicians (ACCP), American Stroke Association (ASA), ACC, AHA, and other experts currently recommend that antithrombotic therapy be given to all patients with nonvalvular atrial fibrillation (i.e., atrial fibrillation in the absence of rheumatic mitral stenosis, a prosthetic heart valve, or mitral valve repair) who are considered to be at increased risk of stroke, unless contraindicated.19 20 21 39 80 81 82 988 989 990 999 1007

Antithrombotic therapy in patients with atrial flutter generally managed in the same manner as in patients with atrial fibrillation.999 1007

Choice of antithrombotic therapy is based on patient's risk for stroke and bleeding.80 81 82 988 989 990 999 1007 In general, oral anticoagulant therapy (traditionally warfarin) is recommended in patients at moderate to high risk of stroke and acceptably low risk of bleeding, while aspirin or no antithrombotic therapy may be considered in patients at low risk of stroke.80 81 82 988 989 990 999 1007 1017 Patients considered to be at increased risk of stroke generally include those with prior ischemic stroke or TIA, advanced age (e.g., ≥75 years), history of hypertension, diabetes mellitus, or CHF.80 81 82 990 999 1007 In addition, female sex is considered an important risk factor for stroke in patients with atrial fibrillation, particularly in patients ≥75 years of age.1017

ACCP and other experts suggest the use of dabigatran as an alternative to warfarin in selected patients with atrial fibrillation at increased risk of stroke (e.g., warfarin-naive patients, those with difficulty maintaining therapeutic INRs with warfarin, those taking multiple drugs that may interact with warfarin).18 19 20 30 35 39 41 69 70 71 1007 Warfarin may continue to be preferred in certain patients such as those with severe renal insufficiency or liver disease, a history of dyspepsia or GI ulcer, hemodynamically important valvular heart disease or a prosthetic heart valve, and in those already achieving excellent anticoagulation control with warfarin (e.g., INR in therapeutic range >70% of the time).18 20 39 69 70 71 73

Relative efficacy and safety of dabigatran and other non-vitamin K antagonist oral anticoagulants (e.g., apixaban, rivaroxaban) remains to be fully elucidated.66 67 68 70 989

AHA and ASA state that apixaban, dabigatran, or rivaroxaban may be a useful alternative to warfarin for the prevention of stroke and systemic thromboembolism in selected women with paroxysmal or permanent atrial fibrillation and certain risk factors who do not have a prosthetic heart valve or hemodynamically important valve disease, severe renal failure (Clcr <15 mL/minute),1038 lower body weight (<50 kg), or advanced liver disease (impaired baseline clotting function).1017

When selecting an appropriate anticoagulant, consider individual patient's risks of stroke and bleeding; patient compliance, preference, and comorbidities; cost; availability of agents to reverse anticoagulant effects in case of bleeding complications; availability of facilities to monitor INR; and degree of current INR control in patients already taking warfarin.8 18 19 21 22 68 69 70 71 72 988 989 999 1007

Do not use in patients with prosthetic mechanical heart valves; increased risk of serious thromboembolic and bleeding events observed in such patients receiving dabigatran compared with warfarin therapy.1 49 (See Patients with Prosthetic Heart Valves under Cautions.)

Efficacy and safety not evaluated in patients with other forms of valvular heart disease, including those with bioprosthetic heart valves; use not recommended in such patients.1 49

Treatment and Secondary Prevention of DVT and/or PE

Treatment and secondary prevention of acute DVT and/or PE following initial treatment with a parenteral anticoagulant for 5–10 days.1 74 75

Also used as extended therapy to reduce the risk of recurrent DVT and PE in patients treated previously for the acute thromboembolic event.1 74 75 76

Recommended by ACCP as an acceptable option for long-term anticoagulation in patients with proximal DVT and/or PE after initial treatment with a parenteral anticoagulant; however, pending additional data with dabigatran, ACCP suggests use of warfarin or LMWH over dabigatran in such patients.1005

Cardioversion of Atrial Fibrillation/Flutter

Has been used for prevention of stroke and systemic embolism in patients undergoing pharmacologic or electric cardioversion for atrial fibrillation/flutter†.1007

Although warfarin is traditionally used, dabigatran is recommended by ACCP as an acceptable choice of anticoagulant for precardioversion anticoagulation in patients with atrial fibrillation lasting >48 hours or of unknown duration; prolonged precardioversion anticoagulation generally is not required in patients with atrial fibrillation of short duration (e.g., ≤48 hours).1007

Thromboprophylaxis in Major Orthopedic Surgery

Prevention of postoperative DVT and PE in patients undergoing hip-replacement surgery.1 1003

As effective as enoxaparin in reducing the risk of venous thromboembolism in patients undergoing elective total hip-replacement surgery with similar rates of bleeding.1 1041 1042

Has been used for prevention of thromboembolism in patients undergoing total knee-replacement surgery†.1003 1049 1050

ACCP considers dabigatran an acceptable option for pharmacologic thromboprophylaxis in patients undergoing total hip- or knee-replacement surgery; however, a low molecular weight heparin (LMWH) generally is preferred.1003 Dabigatran may be a reasonable choice when an LMWH is not available or cannot be used.1003 For additional details, consult the most recent ACCP Evidence-based Clinical Practice Guidelines on Antithrombotic Therapy and Prevention of Thrombosis available at .

When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy, bleeding risk, logistics, and compliance.1003

Cerebral Embolism

Has been used for secondary prevention of cardioembolic stroke in patients with TIAs† or ischemic stroke† and concurrent atrial fibrillation.1009 ACCP suggests use of dabigatran (150 mg twice daily) over warfarin in such patients.1009

Antiplatelet agents generally preferred over oral anticoagulation for secondary prevention of noncardioembolic stroke in patients with a history of ischemic stroke or TIA.1009

Storage

Oral

25°C (may be exposed to 15–30°C).1 Store in original package (i.e., bottles or blister pack) to protect from moisture.1

Advise patients about special storage and handling requirements.36 Dispense only in original bottle with desiccant cap to minimize product breakdown from moisture.36 (See Advice to Patients.)

Once bottle is opened, manufacturer recommends that drug be used within 4 months.1 Keep bottle tightly closed.1

Keep out of reach of children.1

• Selective, competitive, reversible direct thrombin inhibitor.2 12 Prevents thrombus formation by binding free and clot-bound thrombin, thereby inhibiting the conversion of fibrinogen to fibrin.1 2 12 Also inhibits thrombin-mediated platelet aggregation.1 2 12

• Administered and absorbed as dabigatran etexilate mesylate, an inactive ester prodrug; hydrolyzed by esterases in plasma and liver to dabigatran, the principal active moiety.1 7 11 13 Dabigatran metabolized to several acyl glucuronides with similar activity as dabigatran.1 11

• Prolongs TT and ECT linearly over the range of therapeutic plasma concentrations.1 10 11 Prolongs aPTT in a curvilinear manner.1 10 11 INR may be elevated, but is not a reliable assessment of dabigatran activity.1 10 11 ECT is the preferred method for measuring anticoagulant activity of dabigatran; median trough (12 hours post-dose) value of 63 seconds with dabigatran etexilate 150 mg twice daily.1 10 May also use aPTT qualitatively, with a ratio >1 indicating presence of drug in plasma; average peak or trough values of 2 or 1.5 times control, respectively, with dabigatran etexilate 150 mg twice daily.1 10 12 39

• Risk of bleeding.1 Patients should seek emergency medical care if they experience manifestations of serious bleeding (e.g., unusual bruising, including bruises with unknown cause or that enlarge; pink or brown urine; red or black, tarry stool; coughing up blood; vomiting blood; vomitus with the appearance of coffee grounds).1

• Patients should consult healthcare provider for other manifestations of bleeding (e.g., pain, swelling, or discomfort in a joint, headaches, dizziness, weakness, recurrent nose bleeds, unusual bleeding from the gums, prolonged bleeding from a cut, heavier than normal menstrual or vaginal bleeding).1

• Importance of advising patients who have had neuraxial anesthesia or spinal puncture to monitor for manifestations of spinal or epidural hematoma (e.g., back pain, tingling or numbness in lower limbs, muscle weakness, stool or urine incontinence), particularly if they are receiving concomitant NSAIAs, platelet-aggregation inhibitors, or other anticoagulants; importance of immediately contacting a clinician if any of these symptoms occur.1

• Risk of adverse GI reactions.1 Patients should consult healthcare provider if they experience dyspepsia, burning, nausea, abdominal pain/discomfort, epigastric discomfort, or indigestion.1

• Patients should inform healthcare provider that they are taking dabigatran before scheduling any invasive or dental procedure.1

• Importance of informing healthcare provider if patient has had or plans to have a heart valve replacement.1

• Importance of swallowing capsules whole with a full glass of water, without breaking, chewing, or otherwise emptying the contents of the capsule.1 Do not sprinkle contents of capsules on food or into a beverage.1

• Importance of taking dabigatran exactly as prescribed.1 Do not stop taking dabigatran without discussing with prescriber.1

• Instruct patients to take missed dose as soon as remembered but only if it can be taken at least 6 hours prior to next scheduled dose.1

• Importance of informing patient of special storage and handling requirements for drug.1 36 Store only in original container, not in pill boxes or organizers.1 36 Protect from moisture.1 Remove only one capsule from container right before use, then close bottle tightly.1 36 When more than one bottle is dispensed, only open one bottle at a time.1 Do not open or puncture blister on blister package until time of use.36 Per manufacturer, use capsules within 4 months after the bottle is first opened.1 (See Stability.)

• Importance of providing patient a copy of manufacturer’s patient information.1

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.