Clinical Pharmacology of Dabigatran: Difference between revisions
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==Overview== | ==Overview== | ||
Dabigatran (Pradaxa in Australia, Europe, USA and Canada; Prazaxa in Japan) is an [[route of administration|oral]] [[anticoagulant]] from the class of the [[direct thrombin inhibitor]]s. It is used for various clinical indications, and in some cases it offers an alternative to [[warfarin]] as the preferred orally administered anticoagulant ("blood thinner"), since it does not require frequent blood tests for [[prothrombin time|international normalized ratio]] monitoring, while offering similar results in terms of efficacy. | Dabigatran (Pradaxa in Australia, Europe, USA and Canada; Prazaxa in Japan) is an [[route of administration|oral]] [[anticoagulant]] from the class of the [[direct thrombin inhibitor]]s. It is used for various clinical indications, and in some cases it offers an alternative to [[warfarin]] as the preferred orally administered anticoagulant ("blood thinner"), since it does not require frequent blood tests for [[prothrombin time|international normalized ratio]] monitoring, while offering similar results in terms of efficacy. Unlike warfarin, no specific way exists to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event.<ref name='Eerenberg2011'>{{cite journal |doi=10.1161/CIRCULATIONAHA.111.029017 |title=Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects |year=2011 |last1=Eerenberg |first1=E. S. |last2=Kamphuisen |first2=P. W. |last3=Sijpkens |first3=M. K. |last4=Meijers |first4=J. C. |last5=Buller |first5=H. R. |last6=Levi |first6=M. |journal=Circulation |volume=124 |issue=14 |pages=1573–9 |pmid=21900088}}</ref><ref name='vanRyn2010'>{{cite journal |doi=10.1160/TH09-11-0758 |title=Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity |year=2010 |last1=Van Ryn |first1=J. |last2=Stangier |first2=J. |last3=Haertter |first3=S. |last4=Liesenfeld |first4=K.-H. |last5=Wienen |first5=W. |last6=Feuring |first6=M. |last7=Clemens |first7=A. |journal=Thrombosis and Haemostasis |volume=103 |issue=6 |pages=1116–27 |pmid=20352166}}</ref><ref name='Hanley2004'>{{cite journal |doi=10.1136/jcp.2003.008904 |title=Warfarin reversal |year=2004 |last1=Hanley |first1=J P |journal=Journal of Clinical Pathology |volume=57 |issue=11 |pages=1132–9 |pmid=15509671 |pmc=1770479}}</ref> | ||
==Mechanism of Action== | ==Mechanism of Action== | ||
Dabigatran and its acyl glucuronides are competitive, [[direct thrombin inhibitor]]s. 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 | Dabigatran and its acyl glucuronides are competitive, [[direct thrombin inhibitor]]s. 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. | ||
are inhibited by the active moieties. | |||
==Pharmacodynamics== | ==Pharmacodynamics== | ||
At recommended therapeutic doses, dabigatran etexilate prolongs the [[aPTT]], [[ECT]], and [[TT]]. With an oral dose of 150 mg twice daily the median peak aPTT is approximately 2x control. Twelve hours after the last dose the median aPTT is 1.5x control, with less than 10% of patients exceeding 2x control. 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. The median (10th to 90th percentile) trough ECT in patients receiving the 150 mg dose was 63 (44 to 103) seconds. The INR test is relatively insensitive to the activity of dabigatran and may or may not be elevated in patients on PRADAXA. When converting a patient from PRADAXA to warfarin therapy, the INR is unlikely to be useful until at least 2 days after discontinuation of PRADAXA. | At recommended therapeutic doses, dabigatran etexilate prolongs the [[aPTT]], [[ECT]], and [[TT]]. With an oral dose of 150 mg twice daily the median peak aPTT is approximately 2x control. Twelve hours after the last dose the median aPTT is 1.5x control, with less than 10% of patients exceeding 2x control. 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. The median (10th to 90th percentile) trough ECT in patients receiving the 150 mg dose was 63 (44 to 103) seconds. The INR test is relatively insensitive to the activity of dabigatran and may or may not be elevated in patients on PRADAXA. When converting a patient from PRADAXA to warfarin therapy, the INR is unlikely to be useful until at least 2 days after discontinuation of PRADAXA. | ||
==Cardiac Electrophysiology== | ==Cardiac Electrophysiology== | ||
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==Pharmacokinetics== | ==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. | 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. | ||
===Absorption=== | ===Absorption=== | ||
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 | 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. | 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. | ||
===Distribution=== | ===Distribution=== | ||
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 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. | ||
===Elimination=== | ===Elimination=== | ||
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. | 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. | ||
===Metabolism=== | ===Metabolism=== | ||
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. | 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. | ||
===Renal Impairment=== | ===Renal Impairment=== | ||
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. Based on pharmacokinetic modeling, estimated exposure to dabigatran increases with the severity of renal function impairment. Similar findings were observed in the RE-LY trial. | 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. Based on pharmacokinetic modeling, estimated exposure to dabigatran increases with the severity of renal function impairment. Similar findings were observed in the RE-LY trial. | ||
{| class="wikitable" border="1" style="width:600px" | {| class="wikitable" border="1" style="width:600px" | ||
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===Impact of Other Drugs on Dabigatran=== | ===Impact of Other Drugs on Dabigatran=== | ||
====P-gp Inducers==== | ====P-gp Inducers==== | ||
'''Rifampin | '''Rifampin''': Rifampin 600 mg once daily for 7 days followed by a single dose of dabigatran decreased its AUC and Cmax by 66% and 67%, respectively. By Day 7 after cessation of rifampin treatment, dabigatran exposure was close to normal. | ||
====P-gp Inhibitors==== | ====P-gp Inhibitors==== | ||
In studies with the P-gp inhibitors [[ketoconazole]], [[amiodarone]], [[verapamil]], and [[quinidine]], the time to peak, terminal half-life, and mean residence time of dabigatran were not affected. Any observed changes in Cmax and AUC are described below. | In studies with the P-gp inhibitors [[ketoconazole]], [[amiodarone]], [[verapamil]], and [[quinidine]], the time to peak, terminal half-life, and mean residence time of dabigatran were not affected. Any observed changes in Cmax and AUC are described below. | ||
'''Ketoconazole | '''[[Ketoconazole]]''': Ketoconazole increased dabigatran AUC0-∞ and Cmax values by 138% and 135%, respectively, after a single dose of 400 mg, and 153%, and 149%, respectively, after multiple daily doses of 400 mg. | ||
'''[[Verapamil]] | '''[[Verapamil]]''': When dabigatran etexilate was coadministered with oral verapamil, the Cmax and AUC of dabigatran were increased. The extent of increase depends on the formulation of verapamil and timing of administration. If verapamil is present in the gut when dabigatran is taken, it will increase exposure to dabigatran with the greatest increase observed when a single dose of immediate-release verapamil is given one hour prior to dabigatran (AUC increased by a factor of 2.4). If verapamil is given 2 hours after dabigatran, the increase in AUC is negligible. In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received verapamil. | ||
'''[[Amiodarone]] | '''[[Amiodarone]]''': When dabigatran etexilate was coadministered with a single 600 mg oral dose of amiodarone, the dabigatran AUC and Cmax increased by 58% and 50%, respectively. The increase in exposure was mitigated by a 65% increase in the renal clearance of dabigatran in the presence of amiodarone. The increase in renal clearance may persist after amiodarone is discontinued because of amiodarone’s long half-life. In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received amiodarone. | ||
'''[[Quinidine]] | '''[[Quinidine]]''': Quinidine was given as 200 mg dose every 2 hours up to a total dose of 1000 mg. Dabigatran etexilate was given over 3 consecutive days, the last evening dose on Day 3 with or without quinidine pre-dosing. Concomitant quinidine administration increased dabigatran’s AUC and Cmax by 53% and 56%, respectively. | ||
'''[[Clarithromycin]] | '''[[Clarithromycin]]''': Coadministered clarithromycin had no impact on the exposure to dabigatran. | ||
====Other Drugs==== | ====Other Drugs==== | ||
'''[[Clopidogrel]]''': When dabigatran etexilate was given concomitantly with a loading dose of 300 mg or 600 mg clopidogrel, the dabigatran AUC and Cmax increased by approximately 30% and 40%, respectively. The concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. When comparing combined treatment and the respective mono-treatments, the coagulation measures for dabigatran’s effect (aPTT, ECT, and TT) remained unchanged, and inhibition of platelet aggregation (IPA), a measurement of clopidogrel’s effect, remained unchanged. | '''[[Clopidogrel]]''': When dabigatran etexilate was given concomitantly with a loading dose of 300 mg or 600 mg clopidogrel, the dabigatran AUC and Cmax increased by approximately 30% and 40%, respectively. The concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. When comparing combined treatment and the respective mono-treatments, the coagulation measures for dabigatran’s effect (aPTT, ECT, and TT) remained unchanged, and inhibition of platelet aggregation (IPA), a measurement of clopidogrel’s effect, remained unchanged. | ||
'''[[Enoxaparin]] | '''[[Enoxaparin]]''': Enoxaparin 40 mg given subcutaneously for 3 days with the last dose given 24 hours before a single dose of PRADAXA had no impact on the exposure to dabigatran or the coagulation measures aPTT, ECT, or TT. | ||
[[Diclofenac]], [[Ranitidine]], and [[Digoxin]]: None of these drugs alters exposure to dabigatran. | '''[[Diclofenac]]''', '''[[Ranitidine]]''', and '''[[Digoxin]]''': None of these drugs alters exposure to dabigatran. | ||
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 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. | ||
===Impact of Dabigatran on Other Drugs=== | ===Impact of Dabigatran on Other Drugs=== | ||
Latest revision as of 05:32, 2 September 2013
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Dabigatran (Pradaxa in Australia, Europe, USA and Canada; Prazaxa in Japan) is an oral anticoagulant from the class of the direct thrombin inhibitors. It is used for various clinical indications, and in some cases it offers an alternative to warfarin as the preferred orally administered anticoagulant ("blood thinner"), since it does not require frequent blood tests for international normalized ratio monitoring, while offering similar results in terms of efficacy. Unlike warfarin, no specific way exists to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event.[1][2][3]
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 aPTT, ECT, and TT. With an oral dose of 150 mg twice daily the median peak aPTT is approximately 2x control. Twelve hours after the last dose the median aPTT is 1.5x control, with less than 10% of patients exceeding 2x control. 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. The median (10th to 90th percentile) trough ECT in patients receiving the 150 mg dose was 63 (44 to 103) seconds. The INR test is relatively insensitive to the activity of dabigatran and may or may not be elevated in patients on PRADAXA. When converting a patient from PRADAXA to warfarin therapy, the INR is unlikely to be useful until at least 2 days after discontinuation of PRADAXA.
Cardiac Electrophysiology
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.
Absorption
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.
Distribution
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.
Elimination
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.
Metabolism
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.
Renal Impairment
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. Based on pharmacokinetic modeling, estimated exposure to dabigatran increases with the severity of renal function impairment. Similar findings were observed in the RE-LY trial.
| Renal Function | CrCl | Increase in AUC | Increase in Cmax | Half-life |
|---|---|---|---|---|
| Normal | 80 | 1X | 1X | 13 |
| Mild | 50 | 1.5X | 1.1X | 15 |
| Moderate | 30 | 3.2X | 1.7X | 18 |
Hepatic Impairment
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
Impact of Other Drugs on Dabigatran
P-gp Inducers
Rifampin: Rifampin 600 mg once daily for 7 days followed by a single dose of dabigatran decreased its AUC and Cmax by 66% and 67%, respectively. By Day 7 after cessation of rifampin treatment, dabigatran exposure was close to normal.
P-gp Inhibitors
In studies with the P-gp inhibitors ketoconazole, amiodarone, verapamil, and quinidine, the time to peak, terminal half-life, and mean residence time of dabigatran were not affected. Any observed changes in Cmax and AUC are described below.
Ketoconazole: Ketoconazole increased dabigatran AUC0-∞ and Cmax values by 138% and 135%, respectively, after a single dose of 400 mg, and 153%, and 149%, respectively, after multiple daily doses of 400 mg.
Verapamil: When dabigatran etexilate was coadministered with oral verapamil, the Cmax and AUC of dabigatran were increased. The extent of increase depends on the formulation of verapamil and timing of administration. If verapamil is present in the gut when dabigatran is taken, it will increase exposure to dabigatran with the greatest increase observed when a single dose of immediate-release verapamil is given one hour prior to dabigatran (AUC increased by a factor of 2.4). If verapamil is given 2 hours after dabigatran, the increase in AUC is negligible. In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received verapamil.
Amiodarone: When dabigatran etexilate was coadministered with a single 600 mg oral dose of amiodarone, the dabigatran AUC and Cmax increased by 58% and 50%, respectively. The increase in exposure was mitigated by a 65% increase in the renal clearance of dabigatran in the presence of amiodarone. The increase in renal clearance may persist after amiodarone is discontinued because of amiodarone’s long half-life. In the population pharmacokinetics study from RE-LY, no important changes in dabigatran trough levels were observed in patients who received amiodarone.
Quinidine: Quinidine was given as 200 mg dose every 2 hours up to a total dose of 1000 mg. Dabigatran etexilate was given over 3 consecutive days, the last evening dose on Day 3 with or without quinidine pre-dosing. Concomitant quinidine administration increased dabigatran’s AUC and Cmax by 53% and 56%, respectively.
Clarithromycin: Coadministered clarithromycin had no impact on the exposure to dabigatran.
Other Drugs
Clopidogrel: When dabigatran etexilate was given concomitantly with a loading dose of 300 mg or 600 mg clopidogrel, the dabigatran AUC and Cmax increased by approximately 30% and 40%, respectively. The concomitant administration of dabigatran etexilate and clopidogrel resulted in no further prolongation of capillary bleeding times compared to clopidogrel monotherapy. When comparing combined treatment and the respective mono-treatments, the coagulation measures for dabigatran’s effect (aPTT, ECT, and TT) remained unchanged, and inhibition of platelet aggregation (IPA), a measurement of clopidogrel’s effect, remained unchanged.
Enoxaparin: Enoxaparin 40 mg given subcutaneously for 3 days with the last dose given 24 hours before a single dose of PRADAXA had no impact on the exposure to dabigatran or the coagulation measures aPTT, ECT, or TT.
Diclofenac, Ranitidine, and Digoxin: None of these drugs alters exposure to dabigatran.
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.
Impact of Dabigatran on Other Drugs
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.
References
- ↑ Eerenberg, E. S.; Kamphuisen, P. W.; Sijpkens, M. K.; Meijers, J. C.; Buller, H. R.; Levi, M. (2011). "Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects". Circulation. 124 (14): 1573–9. doi:10.1161/CIRCULATIONAHA.111.029017. PMID 21900088.
- ↑ Van Ryn, J.; Stangier, J.; Haertter, S.; Liesenfeld, K.-H.; Wienen, W.; Feuring, M.; Clemens, A. (2010). "Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity". Thrombosis and Haemostasis. 103 (6): 1116–27. doi:10.1160/TH09-11-0758. PMID 20352166.
- ↑ Hanley, J P (2004). "Warfarin reversal". Journal of Clinical Pathology. 57 (11): 1132–9. doi:10.1136/jcp.2003.008904. PMC 1770479. PMID 15509671.