Accepted Manuscript

Title: Pharmacokinetic drug interactions of the non-vitamin K

antagonist oral anticoagulants (NOACs)

Authors: Paolo Gelosa, Laura Castiglioni, Marco Tenconi,

Ludovico Baldessin, Giorgio Racagni, Alberto Corsini,
Stefano Bellosta

PII: S1043-6618(18)30627-3
DOI: https://doi.org/10.1016/j.phrs.2018.07.016
Reference: YPHRS 3953

To appear in: Pharmacological Research

Received date: 29-4-2018

Revised date: 10-7-2018
Accepted date: 16-7-2018

Please cite this article as: Gelosa P, Castiglioni L, Tenconi M, Baldessin L,

Racagni G, Corsini A, Bellosta S, Pharmacokinetic drug interactions of the non-
vitamin K antagonist oral anticoagulants (NOACs), Pharmacological Research (2018),
https://doi.org/10.1016/j.phrs.2018.07.016

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Title
Pharmacokinetic drug interactions of the non-vitamin K antagonist oral
anticoagulants (NOACs)

Paolo Gelosaa, Laura Castiglionib, Marco Tenconic, Ludovico Baldessinc, Giorgio

Racagnib, Alberto Corsinib,d, Stefano Bellostab,d*

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a. Centro Cardiologico Monzino IRCCS, Via C. Parea, 4, 20138 Milan
b. Department of Pharmacological and Biomolecular Sciences, Università degli

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Studi di Milano, Via G. Balzaretti 9, 20133 Milan
c.
EDRA S.p.A., Via G. Spadolini, 7, 20141 Milan

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d.
IRCCS MultiMedica, via G. Fantoli 16, 20138 Milan

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Authors’ emails:
Paolo Gelosa, paolo.gelosa@guest.unimi.it U
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Laura Castiglioni, laura.castiglioni@unimi.it
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Marco Tenconi, m.tenconi@lswr.it
Ludovico Baldessin, l.baldessin@lswr.it
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Giorgio Racagni, giorgio.racagni@unimi.it

Alberto Corsini, alberto.corsini@unimi.it
Stefano Bellosta, stefano.bellosta@unimi.it
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*Corresponding author’s contact information:

Dr. Stefano Bellosta
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Department of Pharmacological and Biomolecular Sciences

University of Milan,
Via G. Balzaretti 9, 20133 Milan, Italy
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Tel. +39 0250318392; Fax +39 0250318284

E-mail: stefano.bellosta@unimi.it
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Graphical abstract

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Abstract
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The use of warfarin, the most commonly prescribed oral anticoagulant, is being
questioned by clinicians worldwide due to warfarin several limitations (a limited
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therapeutic window and significant variability in dose-response among individuals,

in addition to a potential for drug-drug interactions). Therefore, the need for non-
vitamin K antagonist oral anticoagulants (NOACs) with a rapid onset of
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antithrombotic effects and a predictable pharmacokinetic (PK) and

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pharmacodynamic (PD) profile led to the approval of five new drugs: the direct
factor Xa (F-Xa) inhibitors rivaroxaban, apixaban, edoxaban and betrixaban (newly
approved by FDA) and the direct thrombin (factor-IIa) inhibitor dabigatran
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etexilate. The advantages of NOACs over warfarin are a fixed-dosage, the absence
of the need for drug monitoring for changes in anti-coagulation and fewer clinically
significant PK and PD drug–drug interactions. NOACs exposure will likely be
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increased by the administration of strong P-glycoprotein (P-gp) and cytochrome

P450 (CYP) 3A4-inhibitors and may increase the risk of bleeds. On the contrary, P-
gp inducers could significantly decrease the NOACs plasma concentration with an
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associated reduction in their anticoagulant effects.

This manuscript gives an overview of NOACs PK profiles and their drug-drug
interactions potential. This is meant to be of help to physicians in choosing the best
therapeutic approach for their patients.

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Keywords:
Apixaban; betrixaban; dabigatran etexilate; edoxaban; rivaroxaban; warfarin.

Chemical compounds studied in this article: apixaban (PubChem CID: 10182969),

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betrixaban (PubChem CID: 10275777) dabigatran etexilate (PubChem CID:
216210), edoxaban (PubChem CID: 10280735), rivaroxaban (PubChem CID:

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9875401), warfarin (PubChem CID: 54678486).

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1. Introduction
Vitamin K antagonists (VKAs), such as warfarin, are currently the only treatment
with established safety in patients with atrial fibrillation (AF) associated with
rheumatic mitral valve disease and/or a mechanical heart valve prosthesis for
stroke prevention [1] and are widely used for long-term prevention of
thromboembolic complication and oral anticoagulant treatment of venous
thromboembolism (VTE) in AF patients [2,3]. However, the clinical approach to

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anticoagulant therapy has changed recently due to warfarin several limitations
including slow onset and offset of effect, a narrow therapeutic window, and

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variable dose-response relations, which necessitate frequent monitoring using
International Normalized Ratio (INR) and dose adjustments. Polymorphisms in

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genes affecting warfarin pharmacokinetics (PK) and pharmacodynamics (PD) have

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been also described. Moreover, warfarin shows a great number and high incidence
of interactions with drugs, foods and herbal medicines [4], resulting in both
increased or decreased anticoagulant effects and in increased risk of thrombotic or

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major hemorrhagic events [5]. Thus, an adjustment of warfarin dosage is often
necessary to achieve a safe and effective administration avoiding harmful
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interactions.
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Therefore, the need for non-vitamin K antagonist oral anticoagulants (NOACs) with
a rapid onset of the antithrombotic effect and a predictable PK and PD profile, with
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less interactions with drugs, foods and herbal medicines, has been strongly
highlighted by clinicians worldwide. A significant effort has been made to develop
drugs with a wider therapeutic window to allow a fixed-dosage without the need,
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except in emergency situations, for routine laboratory monitoring. Currently, five

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NOACs have gained regulatory approval as alternative therapies to warfarin [6], but
are not licensed in patients with mechanical heart valves [7]. These new drugs
comprise the direct thrombin (factor-IIa) inhibitor dabigatran etexilate [8] and the
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direct factor Xa (F-Xa) inhibitors rivaroxaban [9], apixaban [10], edoxaban [11], all
approved by both EMA and FDA, and betrixaban recently approved by FDA [12].
The direct inhibition of thrombin and F-Xa with small and specific molecules is
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becoming an increasingly attractive antithrombotic strategy [13] thanks to their

rapid onset and offset of action. Indeed, F-Xa plays a key role in blood coagulation
cascade since it is generated via both the intrinsic and extrinsic pathways, and it is
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the rate-limiting step for the generation of thrombin. NOACs are rapidly being
adopted as first-line anticoagulants, and just after few years from their
commercialization they are prescribed in 60% of patients with new diagnosis of
non-valvular AF [14].

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Several meta-analyses suggest that NOACs offer a therapeutic advantage over
standard VKAs treatment since their use is associated with significant reductions in
the risk of major, fatal, intracranial and total bleeding compared with VKAs [15,16].
Moreover, the advantages of NOACs over VKAs are a fixed-dose regimen, no need
for drug monitoring to prevent fluctuations in anti-coagulation levels and fewer
clinically significant PK and PD interactions with drugs, foods and herbal medicines
[17].

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However, despite better PK and PD properties, there is a growing amount of
evidence that plasma level fluctuations of NOACs due to renal function [17],

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pathological conditions (such as chronic kidney diseases or hepatic insufficiency) or
drug interactions [18–21] may have significant repercussions on their safety and

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clinical benefit. In addition, only small differences in NOACs efficacy and safety

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were observed between male and female patients [22].
In the present review, we give an overview on PK profiles and potential for drug-
drug interactions (DDIs) of NOACs, as compared to warfarin PK and known DDIs.

2. Warfarin and other VKAs U

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Coumarin derivatives were discovered more than 70 years ago and include
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warfarin, the most frequently prescribed VKAs worldwide, phenprocoumon and
acenocoumarol [23].
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These drugs are oral anticoagulants that reduce the synthesis of vitamin K-
dependent clotting factors by inhibiting the vitamin K epoxide reductase (VKORC1)
enzyme complex, including factors II, VII, IX, and X, and the anticoagulant proteins
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C and S [24,25]. Although rarely, warfarin is also available for intravenous

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administration [26].
VKAs have been approved for prophylaxis and treatment of deep vein thrombosis
(DVT), thromboembolic complications associated with AF and/or cardiac valve
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replacement and pulmonary embolism (PE) [1,25].

Warfarin is commercialized as a racemic mixture of the R- and S-enantiomer, of
which S-enantiomer has 2-5 times more anticoagulant activity than the R-
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enantiomer [27]. In healthy subjects, warfarin is rapidly absorbed after oral

administration and shows a bioavailability > 95% [28], with the maximum serum
concentration (Cmax) achieved in 90 min (0.3-4 h) [25,29].
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Despite rapid adsorption, the PD effect occurs very slowly within 24 h and its peak
may be delayed 72 to 96 h after warfarin administration. This is consistent with
factor II’s long t1/2 (3 days). Thus, an initial bridging therapy with unfractionated or
low-molecular-weights heparin is need. Warfarin also has a slow offset of action,

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which requires its withdrawal approximately 5 days before any surgery to achieve
a normal INR [25]. Although its absorption is generally not affected by food, the
concomitant and large intake of specific nutrients with high fiber content and/or
which have a laxative effect may decrease its absorption [4]. Moreover, changes in
gastric pH due to treatment with H2-antagonist anti-ulcer drugs have no clinically
significant impact on the absorption of warfarin [30] (Table 1). Warfarin has a weak
inhibitory effect on P-glycoprotein (P-gp) in hepatocytes [31,32] (Figure 1).

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Warfarin has a small volume of distribution (8-10 L) and a high plasma protein

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binding (approximately 99%) [25]. Its enantiomers are largely metabolized in the
liver by different cytochrome P450 (CYP) pathways (Figure 1). In particular, R-

R
warfarin is metabolized by CYP1A1, 1A2, and 3A4, whereas S-warfarin is

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predominantly metabolized by CYP2C9 [33] (Table 1). Changes in CYP2C9
expression may significantly alter warfarin PK and PD parameters [23]. Indeed, a
20% lower warfarin dose is required in patients with the CYP2C9*1/*2 genotype

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[34] and a reduced clearance of S-warfarin is reported in patients with the
CYP2C9*3 genotype [35]. The metabolites of warfarin may be further glucuronated
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before being excreted into bile and urine. The UDP glucuronosyltransferase family
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1 (UGT1) member A1 (UGT1A1) (Figure 1), and likely UGT1A10, may be involved in
the production of warfarin glucuronides.
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Genetic polymorphisms in VKORC1 are also associated with lower dose

requirements and a higher risk of bleeding [36]. However, the increase in bleeding
risk is limited to the first month of treatment. An increased risk of over-
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anticoagulation in VKORC1 variant carriers was also observed in patients treated

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with phenprocoumon or acenocoumarol [37].

Since warfarin is primarily eliminated as inactive metabolite and a small percentage
is excreted unchanged, renal impairment does not change the overall exposure to
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warfarin and no dosage adjustment is necessary [25]. A single, oral dose of warfarin
is eliminated with first-order kinetics and the metabolites are recovered in urine
(about 80%) and feces (about 20%) [23,28]. The mean plasma half-life (t1/2) ranges
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from 20 to 60 h (35-58 h for R-warfarin and 24-33 h for S-warfarin) [28] (Table 1).

The main DDIs affecting warfarin’s PK could be ascribed to a competition for plasma
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protein-binding sites and to inhibition/induction of the expression and/or activity

of CYP enzymes involved in warfarin metabolism. Thus, drugs acting as inhibitors of
CYP2C9, 1A2, and/or 3A4 could increase warfarin exposure leading to a
strengthening of its anticoagulant effect and risk of bleeding (Table 2). On the

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contrary, the concomitant use of inducers of CYP2C9, 1A2, and/or 3A4 may
decrease warfarin pharmacological effects by increasing its metabolism and
clearance (Table 2).
The prescription of VKAs is complicated by the existence of a large inter-individual
variability in treatment response, a narrow therapeutic index, and overdosing often
leads to bleeding [38]. The time patients spend in the therapeutic range is far from
optimal; many patients are under- or over-treated and thus exposed to a high risk

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for stroke or bleeds. The anticoagulant effect could also be affected by dietary
intake of vitamin K [17]. Certain foods and beverages contain large amounts of

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vitamin K thus lowering the effect of warfarin [25]. In theory, vitamin K could be
used as a theoretical antidote, but it might take too long to become effective in

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emergency situations.

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3. Non-vitamin K antagonist oral anticoagulants (NOACs)
3.1 Apixaban

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Apixaban is an oral, selective, direct-acting and reversible F-Xa inhibitor [39] which
is approved in European Union and United States for thromboprophylaxis following
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elective knee or hip replacement surgery [40–42], for reduction of the risk of stroke
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or systemic embolism in patients with non-valvular AF [43–45]. Recently, it has
been approved for the treatment of pulmonary embolism (PE) and DVT and for the
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reduction of the risk of recurrent VTE, DVT and PE [46,47].

Apixaban presents a predictable PK [48] (Table 1), and its exposure is dose-
proportional at the approved daily dosage (2.5-10 mg) [10], with Cmax and area
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under the curve (AUC)0-∞ increasing proportionally to dose. Apixaban has a relative
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oral bioavailability (F) of about 50% [10] and it is absorbed primarily in distal small
intestine and ascending colon [49]. In healthy adults, apixaban Tmax occurs slightly
earlier for oral solution (between 1.5 and 1.8 h) than for tablet (between 2.5 and
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3.3) and t1/2 ranges from 3.6 to 6.8 h after administration of the oral solution while
the overall mean t1/2 of the tablet is approximately 11 h [10]. Overall, apixaban can
be taken with or without food [46]. Crushed or suspended in water is a useful
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method of administration in patients who have difficulty in swallowing whole

tablets [50].
In healthy subjects, the plasma binding protein is about 87% and its volume of
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distribution is approximately 21 L [46].

Apixaban has multiple routes of elimination, including metabolism, biliary and
intestinal excretion, but renal clearance accounts for 27% of total clearance [10,51–
53] (Table 1). Apixaban has a multiphasic elimination profile, characterized by an

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initial rapid decline followed by a more gradual phase. Renal impairment does not
influence apixaban Cmax, while an inverse relationship is observed between
apixaban exposure, as AUC, and parameters of renal function, as creatinine
clearance (CLCR). AUC is 44% greater in subjects with severe renal impairment (CLCR
= 15-29 mL/min) compared to healthy subjects [48]. Two single oral 5 mg doses
were studied in ESRD subjects (2 h before and immediately after hemodialysis
session) [54]. Tmax is reached in 2 h, but t1/2 is higher in healthy subjects. AUC0-∞ is

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36% higher in ESRD subjects when apixaban is administered immediately after
hemodialysis reflecting the reduced apixaban clearance. Cmax is not influenced.

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Thus, apixaban cannot be removed by hemodialysis in case of overdose [46]. Based
on these studies, the use of apixaban is not recommend in patients with CLCR <15

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mL/min or undergoing hemodialysis [46] (Table 3).

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In elderly (aged ≥65 years) subjects, apixaban AUC0-∞ is 32% greater compared with
younger (aged 18-40 years), while Cmax and Tmax are not influenced [55] (Table 3).
Sex has a slight effect on apixaban geometric mean Cmax and AUC0-∞, which are 18%

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and 15% higher in female compared to male subjects, respectively; thus, no dose
adjustment is required [46]. The t1/2 is higher in young female and elderly subjects
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(14-16 h) compared to young male subjects (10 h) likely due to small differences in
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drug renal clearance [55] (Table 3).
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3.1.1 Pharmacokinetic interactions of apixaban with P-gp substrates

Apixaban is a substrate of P-gp and breast cancer resistance protein (BCRP [ABCG2,
also known as CDw338 (cluster of differentiation w338)]) (Table 1; Figure 1), which
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are efflux transporters located in the intestine and whose inhibition would increase
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drug bioavailability [56]. Apixaban is eliminated via multiple pathways, including

metabolism by CYP enzymes, primarily CYP3A4 [52] (but also CYP2J2, 1A2, 2C8,
2C9, and 2C19; Figure 1) [57], renal elimination of unchanged drug, and excretion
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into the intestinal tract [51,58] (Table 1). Although apixaban may interact with P-
gp substrates (atenolol and digoxin) and/or modulators of CYP450 and/or P-gp,
only few apixaban DDIs have been described (Table 4). Ongoing studies are
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investigating the potential PK interactions between oral tacrolimus (weak inhibitor

of P-gp) or cyclosporine (P-gp and CYP3A4 inhibitor) and apixaban in healthy
volunteers, and between dexamethasone (P-gp and CYP3A4 inducer) and apixaban
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in patients with multiple myeloma [59].

Atenolol. Co-administration of apixaban does not modify PK profile of atenolol (100
mg), whereas apixaban Cmax, AUC0-t and AUC0-∞ decrease by 18%, 15%, and 15%,

8
respectively. Tmax and t1/2 values of apixaban are similar following its administration
alone or with atenolol [46,60].
Digoxin. Apixaban does not meaningfully alter the PK of digoxin and no major
bleeding-related adverse events have been reported. Thus, there is no reason to
exclude digoxin as concomitant medication for patients who are treated with
apixaban [46,60].

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3.1.2 Pharmacokinetic interactions of apixaban with CYP and/or P-gp inhibitors
Co-administration of apixaban with inhibitors of CYP3A4 and P-gp activity affects

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apixaban PK profile in a modulator strength-dependent manner (Table 4).
Antiretroviral drugs. Apixaban PK and PD are modulated after co-administration

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with antiretroviral drugs. In particular, the co-administration with ritonavir, the

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most potent HIV protease inhibitor, is expected to increase apixaban AUC due to
the inhibition of CYP3A4 metabolism and P-gp activity [61]. A possible increase in
risk of bleeding, through the inhibition of apixaban metabolism by CYP3A4, is

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observed also in co-administration with cobicistat (a strong inhibitor of CYP3A4 and
of P-gp developed as a PK booster for antiretroviral drugs) [61].
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Diltiazem. Diltiazem (360 mg once a day), which is a weak P-gp and moderate
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CYP3A4 inhibitor, has a moderate effect on apixaban exposure causing a 1.4-fold
increase of apixaban AUC, 1.3-fold of Cmax but with no effect on its Tmax or t1/2
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[46,62].
Azole-antimycotics. Co-administration of apixaban with ketoconazole, a strong
inhibitor of both CYP3A4 and P-gp, induces a doubling of apixaban AUC, 1.6-fold
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increase of Cmax and 2.5 h increase of t1/2 without any change in Tmax [46,62]. Due
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to this strong increase in exposure, apixaban is not recommended in patients

receiving concomitant treatment with strong inhibitors of P-gp and CYP3A4 such as
azole-antimycotics (itraconazole, ketoconazole, posaconazole and voriconazole)
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[46] (Table 4). Concurrent use of fluconazole (a strong inhibitor of CYP2C19 but a
moderate inhibitor of CYP3A4 and CYP2C9) with apixaban was reported to cause
more significant increase in adjusted rate for major bleeding than apixaban alone
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[63].
Macrolides. An increase by 60% and 30% of AUC and Cmax of apixaban, respectively,
is induced by co-administration of clarithromycin or erythromycin [21].
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3.1.3 Pharmacokinetic interactions of apixaban with CYP and/or P-gp inducers

The concomitant use of strong inducers of both P-gp and CYP3A4 may reduce
apixaban plasma concentration [46] (Table 4). No dose adjustment for apixaban is

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necessary during concomitant therapy with those drugs, however its efficacy may
be compromised. Therefore, apixaban is not recommended for the treatment of PE
and DTV in patients treated with strong inducers of CYP3A4 and P-gp [46].
Antiepileptic drugs. The concomitant use of other strong inducers of both CYP3A4
and P-gp, such as antiepileptic drugs, may reduce apixaban plasma concentration
[46]. Carbamazepine, levetiracetam, phenobarbital and phenytoin may induce P-
gp activity thus decreasing the effects of NOACs. In addition, carbamazepine,

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phenobarbital, phenytoin, oxcarbazepine and topiramate may induce the activity
of CYP3A4 activity again decreasing the effect of NOACs [64] (Table 4).

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Antiretroviral drugs. The co-administration with efavirenz or nevirapine, non-
nucleoside reverse transcriptase inhibitors and inducers of CYP3A4, is expected to

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decrease apixaban AUC, possibly by reducing its clinical effect as a result of the

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induction of CYP3A4 activity [61].
Rifampicin. Apixaban co-administration with 600 mg of rifampicin [46,65], a strong
inducer of both CYP3A4 and P-gp, was evaluated in an open-label, randomized,

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sequential crossover study. Rifampicin reduces apixaban AUC0-∞ by 39% and 54%
after intravenous and oral administration, respectively. Consistently with the
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decrease of AUC, apixaban CL is increased by 1.6- fold and CL/F by 2.1-fold after
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intravenous or after oral administration, respectively.
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3.1.4 Pharmacokinetic interactions of apixaban with gastric pH modifiers, food and

activated charcoal
Co-administration of famotidine does not affect apixaban PK parameters (Cmax,
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AUC0-t and AUC0-∞), suggesting that apixaban can be administered regardless of the
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co-administration of gastric pH modifiers [66] (Table 4).

Food has a slight effect on apixaban exposure and t1/2. In an open label study,
subjects were randomized to receive one oral dose of apixaban (2 x 5 mg tablets)
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administered after a fasting period of 10 h or 5 min after consuming a standard

high fat, high calories breakfast. The alternate treatment was administered after a
5 days washout period. Cmax, AUC and t1/2 are similar between fasted and fed
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conditions and median Tmax in the fasting state is similar to that seen in the single
dose study, but is increased by 1 h following administration of apixaban in fed
condition (4 h vs 3 h fasted) [10]. In contrast, a more recent open-label,
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randomized, crossover study [50], performed in the same conditions, shows that
apixaban (1 x 5mg) exposure is decreased (Cmax and AUC0-∞ are 15% and 20% lower,
respectively) and Tmax is achieved earlier (2 h when administered in a fed state
versus 3 h when administered after an overnight fast). The t1/2 values are similar

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for both treatments (11 and 10 h after fed and fasted apixaban administration,
respectively).
In case of an apixaban overdose or accidental ingestion, activated charcoal may be
useful [67]. When activated charcoal is given at 2 or 6 h post-dose, apixaban plasma
concentrations are quantifiable only up to 2 days compared to 3 days without
activated charcoal. Activated charcoal has no effect on the Cmax and Tmax of
apixaban, whereas the AUC decreases by 50 and 28% and t1/2 from 13.4 to 5.3 and

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4.9 h when charcoal is administered post-dose at 2 h and 6 h, respectively.

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3.2 Betrixaban
Betrixaban is the most recently approved oral direct inhibitor of F-Xa by FDA, but

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not by EMA that rejected its approval. Based on data from the APEX trial [68,69],

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FDA approved betrixaban for the prophylaxis of VTE in adult hospitalized patients
for critical acute medical illness who are at risk for thromboembolic complications
due to moderate or severely restricted mobility and other risk factors for VTE [70].

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However, betrixaban is not approved for reduction of the risk of stroke or systemic
embolism in patients with non-valvular AF.
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Betrixaban inhibits free and prothrombinase-bound F-Xa in a concentration-
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dependent manner [71]. A clinically effective antithrombotic effect in humans may
be achieved at concentrations ranging from 5 to 25 ng/mL [72]. Betrixaban, at
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therapeutic and supratherapeutic doses, does not cause clinically relevant changes
in heart rate-corrected QT (QTcI) intervals or other electrocardiographic
parameters [73].
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Betrixaban is rapidly absorbed and after oral administration reaches its Cmax within
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3–4 h in healthy subjects [68,72] (Table 1). It has an oral bioavailability of 34% which
is affected by fatty food, that halves Cmax and AUC. For consistency, betrixaban
should be always taken with food [74]. Plasma protein binding is about 60% and it
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is still uncertain if betrixaban can be removed by hemodialysis [75]. Betrixaban is

principally eliminated unmodified via the hepatobiliary route (82%–89%), likely via
P-gp efflux pump. Unchanged betrixaban is also the predominant form found in
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human plasma and excreta, accounting for 85% of dose excreted in feces [76]. A
small amount of inactive metabolites is excreted in the urine (11%) [74]. Betrixaban
is not metabolized (<1%) by cytochromes (Table 1) and, at a therapeutic
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concentration, does not induce the activities of CYP1A2, 2C9 and 3A4 [12,76]. Thus,
betrixaban is unlikely to have DDIs with CYP substrates, inducers or inhibitors.
However, since betrixaban is a substrate for P-gp (Table 1), DDIs are expected to
occur when administered with potent P-gp inhibitors. Therefore, concomitant

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administration with strong P-gp inhibitors (such as amiodarone, azithromycin,
diltiazem, ketoconazole, verapamil) might increase betrixaban concentration
[74,77] (Table 5). In the case of a co-administration with a P-gp inhibitor, betrixaban
dose should be decreased to one starting oral dose of 80 mg and then 40 mg daily.
However, since betrixaban has been approved only recently, the data on DDIs are
still limited.
Betrixaban has the least renal clearance of all approved NOACs so far (5-13% of

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administered dose) [12,68,72,76] (Table 1). It has a terminal t1/2 of 37 h and a low
peak-to-trough drug concentration ratio [12]. Betrixaban takes a long time to reach

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the steady state (about 6 days) [74], and thus, to speed up the exposure, the
manufacture recommends a 160 mg initial loading dose, followed by 80 mg once

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daily.

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Its unique pharmacological characteristics may allow a broader use of betrixaban
in patients with renal impairment (CLCR <30 mL/min), that were previously excluded
from trials with NOACs and with few anticoagulant options [68,69,72]. In addition,

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since it has a minimal liver metabolism, the accumulation in patients with hepatic
impairment is less likely. However, the lack of a specific and effective reversal agent
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and of data on hemodialyzed patients [74] may be a more significant issue for
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betrixaban compared with the other approved NOACs due to its longer terminal
t1/2 [78] (Table 1).
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Selective serotonin reuptake inhibitors (SSRIs) may inhibit platelet aggregation;

thus, they may also increase bleeding risk if co-administered with anticoagulants
[70].
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3.3 Dabigatran etexilate

Dabigatran and its acyl glucuronides are reversible, low molecular weight, oral
direct thrombin inhibitors with potent antithrombotic effects [79].
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Dabigatran binds competitively and reversibly to the active site (exosite 1) of free
and clot-bound human thrombin, inhibiting the conversion of fibrinogen into fibrin
in a dose- and concentration-dependent fashion [80]. It is currently approved in the
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United States, European Union, Canada and Japan for the prevention of systemic
emboli and stroke in patients with non-valvular AF [81–84], and in addition in
European Union and Canada for the primary prevention of VTE in adult patients
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undergoing elective total knee or hip replacement surgery [82,83].

Dabigatran etexilate shows a predictable and dose-proportional PK in the range of
10-400 mg [8] and its PK profile is characterized by low or moderate variations in
plasma concentration and PK parameters. Dabigatran etexilate is a substrate for P-

12
gp in the intestinal wall [85], thus genetic polymorphisms in the ABCB1 gene, which
encodes for P-gp, are associated with an altered oral availability [86] (Table 1).
However, no association has been reported so far between P-gp polymorphism and
bleeding or ischemic events. Dabigatran pro-drug and its intermediates are poorly
adsorbed and are hardly detectable in the plasma. Indeed, the absolute oral
bioavailability is 6.0% and 1.2% for dabigatran and its active glucuronides,
respectively [8].

T
No time-dependent changes are observed in the PK profile of dabigatran after
multiple dosing [8]. The Cmax occurs within 75–90 min, indicating rapid oral

IP
absorption (Table 1), then dabigatran plasma concentration declines to <30% of the
Cmax 4–6 h post dosing [87]. Food does not affect the bioavailability of dabigatran

R
etexilate but delays the Tmax by 2 hours [82].

SC
In patients undergoing elective hip arthroplasty [87], median Tmax and Cmax are
lower than in healthy subjects, probably due to changes in gastrointestinal motility
[88]. However, the mean AUC is comparable to what observed in healthy
volunteers.
U
At steady state over the 12 hours dosing interval τ, the PK parameters, AUCτ,ss and
N
Cmax,ss, are approximately 20% higher in female than in male subjects, possibly due
A
to sex-related differences in CLCR [76] (Table 3).
Body weight may influence dabigatran PK. Indeed, AUC is decreased by 20% in
M

patients weighing more than 120 Kg and increased by 25% in patients weighing less
than 48 Kg. However, no dosage adjustment is recommended [83].
Dabigatran is moderately distributed (apparent volume of distribution (Vd) range
D

50-70 L) [82] and its binding to plasma proteins is less than 40% (Table 1). Thus, in
TE

case of accidental overdose leading to hemorrhagic complications, it is the only

NOACs that can be removed by hemodialysis [82]. A specific reversal agent
idarucizumab antagonizing the PD effect of dabigatran is available [82].
EP

Dabigatran etexilate is a pro-drug hydrolyzed to its active form by an esterase, with

around 20% of dabigatran conjugated by glucuronosyltransferases to active acyl-
glucuronides [90]. However, moderate hepatic impairment (Child Pugh B) only
CC

slightly slows the bioconversion of dabigatran etexilate into its active form. Thus, a
delayed onset of the PD effect in these patients is unlikely [91]. Conversely,
dabigatran is not a substrate, inhibitor, or inducer of CYP enzymes (Table 1).
A

Dabigatran is eliminated principally via the kidneys [90] and shows a biexponential
decline of its plasma concentrations with a mean terminal t1/2 of 11 h (12-14 h after
multiple doses) [82](Table 1).

13
After twice-daily dosing in elderly subjects aged ≥65 years, the AUC is 1.7- to 2-fold
higher than in young subjects, presumably due to the 20–30% lower CLCR [92] (Table
3). Furthermore, in elderly subjects, AUC and Cmax are about 20–30% higher in
females than in males [92] (Table 3). In patients with mild, moderate, and severe
renal impairment, dabigatran total AUC is increased by 1.5-, 3.1- and 6.3-fold,
respectively, compared with healthy controls. Simultaneously, terminal t1/2 is
increased to 15, 18 and 27 h [18]. For these reasons, dabigatran should be used

T
cautiously in patients with moderate renal impairment (CLCR =30–50 mL/min) and
in those with high risk of bleeding a reduction of dose to 110 mg bid should be

IP
considered [82]. Its use is contraindicated in patients with severe renal insufficiency
(CLCR <30 mL/min) [82] (Table 3).

R
Phase II clinical studies show a clear correlation between plasma dabigatran

SC
concentration and degree of anticoagulant effect [82]. Thus, the overlapping
between PK and PD profiles should be considered in the determination of
dabigatran treatment by clinicians, since certain drug interactions and reduced

U
renal function could enhance the risk of bleeding by increasing dabigatran
exposure.
N
A
3.3.1 Pharmacokinetic interactions of dabigatran with P-gp and/or MATE-1
substrates or inhibitors
M

Dabigatran etexilate and betrixaban are the only NOACs that are not metabolized
by CYP isoenzymes (Table 1) [93]. Combination of dabigatran etexilate with
substrates of CYP isoenzymes, such as atorvastatin (CYP3A4) [94] and diclofenac
D

(CYP2C9) [91], do not show any significant PK changes of dabigatran or of co-

TE

administered drugs. However, dabigatran etexilate is a substrate of the efflux

transporter P-gp which plays a key role in drug absorption and excretion. The
hydrolyzed form of dabigatran is not a P-gp substrate, and therefore the potential
EP

PK DDIs involving P-gp are restricted to its absorption across the intestinal wall.
Digoxin. No significant PK changes of dabigatran are observed with digoxin, a P-gp
substrate, whic also had a negligible impact on dabigatran blood coagulation time,
CC

activated partial thromboplastin time (aPTT) and ecarin clotting times (ECT) [89].

Contrary to P-gp substrates, the PK of dabigatran is significantly influenced by the

A

co-administration with P-gp inhibitors (Table 6). For this reason, dabigatran
etexilate should be administered at least 2 h apart from doses of moderate P-gp
inhibitors [95]. A close clinical surveillance (signs of bleeding or anemia) is required
in the case of co-administration of dabigatran with strong P-gp inhibitors. Systemic

14
ketoconazole, cyclosporine, itraconazole and dronedarone are contraindicated
[82]. Caution must be exercised with mild-moderate P-gp inhibitors (e.g.
amiodarone, posaconazole, quinidine, ticagrelor and verapamil) [82] (Table 6).
Amiodarone. In healthy subjects, the co-administration of amiodarone increases
dabigatran bioavailability by about 50–60% and appropriate dose reduction is
recommended. Since amiodarone has a long t1/2, the potential for DDIs may persist
for weeks after amiodarone discontinuation. Amiodarone increases dabigatran

T
AUCss by 12% in patients with non-valvular AF [96]. In a recent cohort study, co-
administration of amiodarone with dabigatran caused a more significant increase

IP
in adjusted rate for major bleeding than with dabigatran alone [63].
Clarithromycin. A slight increase of dabigatran AUC and Cmax by about 19% and 15%,

R
respectively, is induced by clarithromycin 500 mg bid [82].

SC
Diltiazem. The PK of dabigatran is not affected by diltiazem in patients with non-
valvular AF [96].
Dronedarone. Multiple doses of dronedarone increase Cmax and AUC0-24 of

U
dabigatran etexilate 150 mg bid by 1.73-fold and 2-fold, respectively, increasing
Emax of ECT% and of aPTT% by 1.72- and 1.32-fold compared to dabigatran etexilate
N
alone, respectively [97]. A single 400 mg dose of dronedarone doubles dabigatran
A
AUC0-∞ and Cmax, making the co-administration contraindicated. There is no effect
of dronedarone on dabigatran CLR 0-24 [82].
M

Ketoconazole. The AUC of dabigatran is also increased by 138% and 153% after
single and multiple daily doses of 400 mg of systemic ketoconazole, respectively. A
single oral dose of ketoconazole (400 mg) increased dabigatran Cmax by 135%, while
D

multiple oral dosing (400 mg ketoconazole once daily) by 149 %. On the contrary,
TE

Tmax, t1/2 and the mean residence time of dabigatran are not affected [82].
Quinidine. An increased dabigatran bioavailability is also observed with the co-
administration of quinidine (1 g in 5 doses of 200 mg every 2nd hour) and of
EP

dabigatran etexilate bid over 3 consecutive days. Similar to amiodarone, quinidine

increases dabigatran AUCτ,ss and Cmax,ss by more than 50% [82].
Statins. Simvastatin and lovastatin are associated with a higher risk of major
CC

hemorrhage (compared to other statins) in patients with non-valvular AF and

receiving dabigatran [98]. In vitro studies suggest that statins administered in their
lactone forms (such as simvastatin and lovastatin) are potent inhibitors of intestinal
A

P-gp, thereby increasing systemic dabigatran exposure, whereas other statins are
not [99,100]. Thus, preferential use of statins other than simvastatin and lovastatin
should be considered in these patients. Relevantly, the adjusted incidence rate for

15
major bleeding was significantly lower for concurrent use of atorvastatin with
dabigatran than dabigatran alone [63].
Tacrolimus. Studies in vitro and limited clinical data with everolimus (another P-gp
substrate) suggest that tacrolimus is a weak inhibitor of P-gp and thus it could affect
the PK of dabigatran. Based on these data co-administration of dabigatran with
tacrolimus is not recommended [82].
Verapamil. The exposure to dabigatran, when co-administered with verapamil,

T
depends on the formulation of verapamil and timing of administration [95]. Indeed,
exposure to dabigatran is increased when it is administered within 2 h from

IP
verapamil, with the greatest increase observed when a single dose of immediate-
release verapamil is given 1 h before dabigatran (AUC and Cmax increase by 143%

R
and 179%, respectively, compared to dabigatran alone). When dabigatran is given

SC
2 h before a double dose of extended-release verapamil, only a slight increase in
dabigatran AUC and Cmax (<20% increase) is observed. These changes are not
modified by increasing verapamil dose. The percentage of dose of dabigatran

U
excreted into urine over 24 h increases proportionally to the increased
bioavailability [95]. As t1/2 is not changed, the interaction is most likely related to
N
the absorption of dabigatran, further supporting the notion that DDIs involving P-
A
gp are limited to the gut [101]. Dabigatran does not significantly alter the PK of
verapamil or the PK of the metabolite [95]. In patients with non-valvular AF,
M

administration of verapamil increases the AUCss by 23% [96].

Dabigatran is not only a substrate of P-gp but also of renal multidrug and toxin
extrusion-1 transporters (MATE-1). In healthy HIV-negative volunteers, the co-
D

administration of dabigatran and cobicistat, an inhibitor of both P-gp and MATE-1

TE

[102], results in a significant increase in oral bioavailability of dabigatran (Table 6).

The geometric mean AUC0-∞ and Cmax are both increased by about 127%. The
authors suggest that an administration separated by ≥4 h might avoid the
EP

interaction [103].

3.3.2 Pharmacokinetic interactions of dabigatran etexilate with P-gp inducers

CC

Dabigatran plasma concentration is decreased after the co-administration of

dabigatran etexilate with P-gp inducers (e.g., rifampicin, carbamazepine, and
phenytoin) [82,104] (Table 6).
A

Seven days of pretreatment with rifampicin 600 mg/day reduces dabigatran AUC
by about 66%. Seven days after cessation of rifampicin, dabigatran AUC returns to
a level equivalent to that seen when dabigatran is administered alone [82].

16
Although studies have not been conducted with other P-gp inducers, the
prescribing information recommends avoiding the co-administration with these
agents, since a loss of pharmacological effect may occur [82] (Table 6).

3.3.3 Pharmacokinetic interactions of dabigatran etexilate with gastric pH

modifiers and food
Food and gastric pH have only a slight effect on the exposure to dabigatran (Table

T
1). In healthy volunteers, food has a negligible impact on dabigatran PK. A high-fat
breakfast moderately prolongs its absorption, delaying the time to peak plasma

IP
concentrations by 2 hours without altering AUC and Cmax [82,105]. Instead, the
administration of pantoprazole 40 mg bid decreases by 20–30% and by 45%

R
dabigatran AUC and Cmax, respectively, suggesting that an elevated gastric pH may

SC
influence dabigatran oral absorption [87,92]. Due to dabigatran flat dose-response
curve, this reduction in the dabigatran plasma concentration was not considered
clinically relevant [105]. In non-valvular AF patients, proton-pump inhibitors (PPIs)

U
decrease dabigatran AUCss by 12.5% [96]. Ranitidine treatment showed no clinical
relevant effects on dabigatran absorption [82].
N
A
3.4 Edoxaban
Edoxaban is a once-daily, oral, selective and direct inhibitor of F-Xa. It has recently
M

been approved in Japan for prevention of DVT in patients following orthopedic

surgery, for the treatment and prevention of recurrences of VTE and for the
prevention of stroke and systemic embolism in patients with AF [106].
D

Furthermore, edoxaban is approved in the United States [107] and European Union
TE

[108] for the treatment of DVT and PE and for reduction of the risks of stroke and
systemic embolism in patients with non-valvular AF.
Edoxaban has a dose-proportional multiphasic PK profile at the dose range of 10-
EP

150 mg. Its absolute bioavailability is approximately 62% [108] and remains
constant at the dose range of 10–30 mg (Table 1). [109]. After single oral
administration, edoxaban is rapidly absorbed, with a Tmax of 1-2 h. The t1/2 ranges
CC

from 6 to 11 h. The degree of plasma protein binding of edoxaban ranges from 40%
to 59%, and therefore hemodialysis does not significantly contribute to edoxaban
clearance [107]. The tissues distribution results in a Vd of 300 L [11] (Table 1).
A

After multiple oral edoxaban administrations, the AUC0-τ increases by about 9% and
13% for 90 and 120 mg/daily, respectively, compared to single edoxaban dose.
Conversely, AUC0-τ increases by 46% with multiple 60 mg bid dose. In both
administration strategies, no differences are observed in t1/2 and Cmax, which is

17
reached within 3.5 h from administration. The intersubject variability, expressed as
percentage coefficient of variation, is very low [11].
Edoxaban undergoes limited metabolism through phase 1 and phase 2 enzymes.
Phase 1 metabolism is predominantly mediated by carboxylesterase-1 (CES1) and
less by CYP3A4/5, which form the active metabolites M4, and M6 and M8,
respectively [110,111]. Indeed, M4 reaches less than 10% of the exposure of the
parent compound in healthy subjects, whereas that of the other metabolites is less

T
than 5% [107]. Edoxaban is also a substrate for P-gp, whereas its metabolite M4 is
a substrate for the uptake transporter organic anion–transporting polypeptide 1B1

IP
(OATP1B1) [112] (Table 1).
Thus, genetic polymorphisms in metabolic enzymes and transporters could

R
influence the PK of edoxaban and of its metabolites, although reports are

SC
conflicting [113,114].
Edoxaban in urine, 48 h post dose, ranges from 35% to 39% for all dose levels (Table
1), the majority of which (18%-28%) is excreted within 8 h after administration. Less

U
than 1% of the dose is excreted in the urine as edoxaban after 48 h [11], indicating
that elimination occurs through multiple pathways: renal excretion, biliary
N
excretion, and metabolism (minimally) through conjugation and oxidation by CYP
A
isoenzymes and hydrolysis [110]. Female subjects show 13.1 % lower CL than male
subjects [109] (Table 3), however it doesn't seem to be clinically relevant and no
M

dose adjustment is required [108].

Edoxaban PK profile is markedly influenced by renal function. The AUC of edoxaban
increases by 32, 74 and 72% in patients with mild (CLCR =50 –80 mL/min), moderate
D

(CLCR =30–50 mL/min) and severe (CLCR <30 mL/min) renal impairment, respectively
TE

[115] (Table 3). Similar results are observed in patients with non-valvular AF, in
which the predicted AUC0-24,ss is comparable in 15 mg dose treated patients with
severe renal impairment and in 30 mg dose treated patients with normal or mild
EP

renal impairment [116] (Table 3). Instead, as expected by the low degree of
metabolism, hepatic impairment (Child Pugh A and B) does not significantly change
the peak or total edoxaban exposure or its active metabolite M4 [117] (Table 3).
CC

3.4.1 Pharmacokinetic interactions of edoxaban with P-gp substrates or inhibitors

Several edoxaban DDI studies assessed the potential effects on edoxaban PK by
A

drugs that are known P-gp substrates (atorvastatin and digoxin) and/or P-gp
inhibitors (amiodarone, cyclosporine, dronedarone erythromycin, ketoconazole,
quinidine and verapamil), with varying degrees of CYP inhibition. Indeed, these
drugs theoretically increase the exposure to edoxaban (Table 7).

18
Atorvastatin. The PK of a single oral 60 mg dose of edoxaban is not affected by
atorvastatin (weak inhibitor of CYP3A4) [118]. Indeed, atorvastatin induces an
increase by only 1.7% and 7.9% in edoxaban AUC0-∞ and C24, respectively, and a
decrease by 14.2 % in Cmax.
Digoxin. In a dual-treatment sequence, parallel study, digoxin slightly increases
edoxaban AUC0-τ and Cmax by 9.5% and 15.6%, respectively, whereas it decreases
edoxaban C24 by 9.4% [118,119]. The rate of absorption and t1/2 are not influenced

T
by digoxin.
The limited effects of atorvastatin and digoxin on edoxaban PK may be due to their

IP
weaker affinity for the P-gp transporter.
Amiodarone. The PK of a single oral 60 mg dose of edoxaban is modestly affected

R
by amiodarone (a moderate CYP2C9 inhibitor and weak CYP2D6 inhibitor) [118].

SC
Amiodarone increases edoxaban AUC0-τ and Cmax by 39.8% and 66.0%, respectively,
whereas it reduces the C24 by 25.7% and t1/2 by 11.7%.
Cyclosporine. A single oral dose of cyclosporine (weak CYP3A4 and OATP1B1

U
inhibitor) significantly affects the PK of a single oral 60 mg dose of edoxaban, with
an increase in Cmax and AUC0-∞ of approximately 1.7-fold for edoxaban and of 8.7-
N
and 6.9-fold, for the M4 metabolite, respectively [120].
A
Dronedarone. The PK of edoxaban 60 mg is significantly influenced by dronedarone
[118]. Indeed, dronedarone increases edoxaban AUC0-∞, Cmax and C24 by 84.5%,
M

45.8% and 157.6%, respectively. The median Tmax value also changes from 1.98 h
for edoxaban alone to 2.03 h for edoxaban plus dronedarone.
Erythromycin. Oral erythromycin (a moderate CYP3A4 inhibitor) significantly
D

affects the PK of a single oral 60 mg dose of edoxaban [120]. Erythromycin increases

TE

both edoxaban Cmax and AUC0-∞ by approximately 68% and 85%, respectively,
without affecting median Tmax. An increase in M4 metabolite Cmax by 75% and in
AUC0-∞ of 78% is likely due to a 47% decrease of CL/F.
EP

Ketoconazole. Oral doses of ketoconazole (strong CYP3A4 inhibitor) significantly

affect the PK of a single oral 60 mg dose of edoxaban [120]. Ketoconazole increases
both edoxaban Cmax and AUC0-∞ by approximately 90%. Furthermore, it increases
CC

the median Tmax of edoxaban by about 30 min and decreases the mean CL/F from
38.9 L/h to 20.8 L/h without affecting t1/2. Similarly, Cmax and AUC0-∞ of the M4
metabolite of edoxaban are increased by about 56% and 46%, respectively. The
A

higher exposure for M4 could be the result of an increased bioavailability of

edoxaban in the presence of ketoconazole. There are no changes in mean t1/2.
Quinidine. In a 2-period, 2-treatment crossover study, quinidine (strong inhibitor of
CYP2D6) increases Cmax and AUC0-∞ of edoxaban 60 mg by approximately 85% and

19
77%, respectively [118]. It also increases the C24 of edoxaban by 11.8%, whereas
the rate of edoxaban absorption is not affected. The mean t1/2 value of edoxaban is
instead decreased by approximately 22%.
Verapamil. In a 2-period, 2-treatment crossover study, verapamil (moderate
inhibitor of CYP3A4) increases edoxaban Cmax, AUC0-∞ and C24 by of 53.3%, 52.7%
and 29.1%, respectively [118]. The median Tmax values are slightly reduced when
verapamil is co-administered, from 1.5 h for edoxaban alone to 1.0 h.

T
Taken together these data indicate that concomitant administration of P-gp

IP
inhibitors could highly increase the exposure to edoxaban and therefore potentially
cause clinically meaningful effects (Table 7). The European manufacturer of

R
edoxaban recommends a dose reduction to 30 mg once daily in concomitant use

SC
with cyclosporine, dronedarone, erythromycin, or ketoconazole [108]. However,
the co-administration of edoxaban with quinidine, verapamil, amiodarone or
digoxin does not require dose reduction [108].

U
3.4.2 Pharmacokinetic interactions of edoxaban with CYP and/or P-gp inducers
N
Although edoxaban is poorly metabolized by phase 1 and phase 2 enzymes, co-
A
administered drugs could influence PK profile of edoxaban interfering with P-gp
(Table 7).
M

In healthy subjects, there is only one drug interaction study of edoxaban in

combination with inducers of CYP isoenzymes and/or P-gp.
Rifampicin. In a phase I open-label study, seven days of 600 mg bid of rifampicin
D

(strong inducer of CYP3A4; moderate inducer of CYP2B6, 2C8, 2C9 and 2C19)
TE

significantly affects the PK of a single oral 60 mg dose of edoxaban administered

concomitantly on day 7, resulting in minimal changes (<10%) from the baseline PT
and aPTT values, compared with the administration of edoxaban alone [121].
EP

Although the Cmax, Tmax and the mean plasma edoxaban concentrations are not
affected, rifampicin decreases its AUC0-∞ by 34% compared with the administration
of edoxaban alone.
CC

Rifampicin increases edoxaban apparent oral clearance (CL/F) by 33% and

decreases its t1/2 by 50%. On the contrary, the co-administration of edoxaban and
rifampicin increases M4 metabolite exposure (Cmax and AUC0-∞ are increased by 4.7-
A

and 2.8-fold, respectively, whereas the t1/2 is decreased by approximately 70 %).

The authors of the study suggest that rifampicin reduces edoxaban oral
bioavailability by increasing its P-gp-mediated excretion and its metabolism

20
through CYP3A4/5. The increase of the M4 metabolite is likely due to the inhibitory
effect of rifampicin on OATP1B1, as well as to a potential induction of CES-1.
P-gp inducers (such as phenytoin, carbamazepine, phenobarbital or St. John's
Wort) may reduce edoxaban plasma concentrations. For this reason, the European
manufacturer of edoxaban recommends caution when it is co-administered with P-
gp inducers [108].

T
3.4.3 Pharmacokinetic interactions of edoxaban with gastric pH modifiers and food
Food intake and gastric pH have a modest but negligible clinical impact on

IP
edoxaban PK (Table 1). A crossover study in healthy subjects show that food
increases mean AUC0-t, AUC0-∞ and Cmax by approximately 1.15, 1.12, and 1.06-fold

R
in Japanese subjects, and by approximately 1.15, 1.15, and 1.22-fold in Caucasian

SC
subjects, respectively [122]. A delay in edoxaban absorption (measured as increase
of median Tmax value) of approximately 1 h and 0.5 h is also found in fed Japanese
and Caucasian subjects, respectively. There is no effect on edoxaban renal CL.

U
Similar results were obtained by other studies [11,109]. Edoxaban can be
administered regardless of food [122].
N
In healthy subjects, administration of edoxaban 2 h after esomeprazole at steady
A
state has no significant effect on AUC [123], whereas conflicting data were reported
for Cmax that was unaffected in one study [123] and increased in another one [111].
M

3.5 Rivaroxaban
Rivaroxaban is a potent and highly selective oral direct inhibitor of F-Xa [124,125]
D

which plays a key role in the conversion of prothrombin to thrombin. Rivaroxaban

TE

inhibits Factor Xa without affecting platelet aggregation [126] nor the hemostatic
function of pre-formed thrombin [127].
Rivaroxaban is approved by FDA and EMA for the prevention of venous VTE after
EP

elective hip or knee replacement surgery [128], for the treatment and prevention
of recurrent DVT and PE in adult patients, and for the prevention of stroke and
systemic embolism in adult with non-valvular AF [124,128]. EMA has approved
CC

rivaroxaban also for the secondary prevention of acute coronary syndrome (ACS).
To prevent atherothrombotic events, patients with elevated cardiac biomarkers
following ACS may be treated with the combination of rivaroxaban with aspirin
A

alone or with aspirin plus clopidogrel or ticlopidine [128,129].

Rivaroxaban exhibits a predictable clinical pharmacological effect that allows for
fixed oral doses, does not require routine monitoring of the coagulation [130] and
is not affected in a significant manner by either age [131], gender [132], body

21
weight [133], mild hepatic [132] or renal impairment [134]. The molecule has a
rapid onset of action with a Tmax of 2-4 h [9,135] and 80-100% bioavailability after
a single 10 mg oral dose (Table 1) whether administered as tablet or solution,
regardless of the presence of food [128,136]. However, a 20 mg oral dose has a
bioavailability of 66% under fasting conditions, which increases by 39% with food.
Therefore, the 15 and 20 mg oral doses should be taken with food [128,136]. The
mean t1/2 of rivaroxaban varies among 5-9 h in young individuals and 11-13 h in

T
elderly or ESRD patients [128,131,135,137] (Table 3). A single 5 mg dose of
rivaroxaban inhibits by 28% F-Xa activity after 2 h from administration, but dose-

IP
effect analysis revealed no difference between rivaroxaban and placebo group
[138].

R
Rivaroxaban is eliminated via a dual mode: about 60% undergo metabolic

SC
degradation to inactive metabolites, 50% of which is eliminated by the kidney and
the remaining through the liver and bile routes [137,139]. About 30% of the dose
is eliminated unmodified via renal excretion. Rivaroxaban has an high plasma

U
protein binding [approximately 92–95% (Table 1)], and thus, rivaroxaban is not
expected to be dialyzable [140]. It has a normal glomerular filtration rate, an active
N
renal secretion and its renal clearance is approximately 30–40% of its total
A
clearance [9,134]. This provides the basis for the dose adjustment in moderate to
severe renal impairment (i.e. CLCR <50 mL/min) due to increased drug levels [128].
M

In patients with an estimated CLCR >50 mL/min the drug should be given as a 20 mg
dose once a day, and as a 15 mg once a day dose in patients with an estimated CLCR
of 15-50 mL/min. The current labeling recommendations state that the use of
D

rivaroxaban should be avoided in patients with ESRD (CLCR <15 mL/min) [128] (Table
TE

3).
Rivaroxaban has a systemic clearance of 10 L/h and is classified as a low clearance
drug, lacking relevant pre-systemic first pass extraction [141,142]. Rivaroxaban is
EP

metabolized via CYP3A4, 3A5 and 2J2, and CYP-independent mechanisms

[143,144]. Unchanged rivaroxaban is the main compound, with no major or active
circulating metabolites present [128]. Rivaroxaban does not induce or inhibit major
CC

CYP enzymes, including CYP3A4 or P-gp/Bcrp-mediated transport [128,145].

Clinically relevant DDIs through induction of CYP1A2, 3A4, 2B6 or 2C19 are
considered to be very unlikely [128,143]. P-gp and ABCG2 are the responsible active
A

renal transporters of rivaroxaban [145] (Table 1).

In vitro studies show that the active transport of rivaroxaban is unaffected by
substrates of P-gp and ABCG2 (Table 1).

22
3.5.1 Pharmacokinetic interactions of rivaroxaban with CYP and/or P-gp substrate
Digoxin (P-gp substrate with a narrow therapeutic window), midazolam (a CYP3A4
substrate) and atorvastatin (a P-gp substrate and CYP3A4 inhibitor) co-
administration in healthy controls do not affect rivaroxaban PK and PD [146] (Table
8). Rivaroxaban does not modify digoxin or atorvastatin PK or PD profile. This
suggests that rivaroxaban can be co-administered with either drugs [146].
Rivaroxaban does not induce or inhibit any major CYP isoforms, including CYP3A4,

T
or P-gp/Bcrp transporters [128,145]. The concomitant use of rivaroxaban and these
drugs is quite likely in clinical practice. Rivaroxaban is now in use for the prevention

IP
of stroke in patients with AF [124], and studies on the secondary prevention in
patients with ACS are under way [147].

R
Midazolam. Co-administration of rivaroxaban 20 mg and midazolam 7.5 mg leads

SC
to an increase in rivaroxaban median Tmax from 1.5 h to 4.0 h and slightly decreases
rivaroxaban mean Cmax, a change that is not statistically significant [143].
Rivaroxaban mean AUC remains almost unchanged while midazolam mean AUC

U
decreases by 11% compared with midazolam alone. The mean Cmax is virtually
unaffected. Rivaroxaban does not alter midazolam Tmax and t1/2 and its metabolite
N
[143].
A

3.5.2 Pharmacokinetic interactions of rivaroxaban with strong CYP3A4, P-gp and/or

M

ABCG2 inhibitors
The interaction of rivaroxaban with strong inhibitors of both CYP3A4 and the
transport proteins P-gp and ABCG2 might have a clinically relevant potential (Table
D

8). The biotransformation of rivaroxaban is affected by therapeutically relevant

TE

concentrations of ketoconazole and ritonavir [143]. Therefore, rivaroxaban is

contraindicated in association with azole antimycotics (ketoconazole, itraconazole,
posaconazole and voriconazole), HIV protease inhibitors (i.e., ritonavir) and
EP

conivaptan that could increase rivaroxaban plasma concentrations in a clinically

significant manner, thus increasing the risk of hemorrhages [128,140] (Table 8).
Ketoconazole. The co-administration of rivaroxaban 10 mg in combination with
CC

ketoconazole 200 mg once daily significantly increases rivaroxaban AUC and mean
Cmax by 82% and 53%, respectively [143]. Rivaroxaban total (apparent) body
clearance is also significantly reduced by a mean of 45% with the combination.
A

Ritonavir. The administration of rivaroxaban 10 mg with ritonavir 600 mg bid

significantly increases rivaroxaban AUC and Cmax by 153% and 55%, respectively.
Ritonavir significantly increases rivaroxaban mean plasma concentrations but
decreases its body clearance by 60%.

23
3.5.3 Pharmacokinetic interactions of rivaroxaban with moderate CYP3A4 and P-gp
inhibitors
Moderate to strong inhibitors of CYP3A4 only (erythromycin and clarithromycin) do
not have any significant interactions with rivaroxaban (Table 8).
Clarithromycin. Clarithromycin (a strong inhibitor of CYP3A4 only, but also a weak
to moderate P-gp inhibitor) has a moderate interaction with rivaroxaban

T
(rivaroxaban AUC and Cmax increase by 54% and 40%). After clarithromycin 500 mg
twice daily for 4 days, the co-administration of rivaroxaban 10 mg with

IP
clarithromycin 500 mg increases rivaroxaban mean AUC and Cmax by 54% and 40%,
respectively [143].

R
Erythromycin. The addition of rivaroxaban 10 mg to erythromycin (500 mg three

SC
times daily given for 4 days) significantly increases rivaroxaban AUC and Cmax (34%
and 38%, respectively) and decreases rivaroxaban CL/F by 25% compared with
rivaroxaban alone [143]. However, these changes are similar to the inter-individual

U
variability observed in patients treated with rivaroxaban and are not considered to
be clinically relevant [142].
N
Fluconazole. The administration of rivaroxaban 20 mg to fluconazole 400 mg (given
A
for 4 days) significantly increases rivaroxaban AUC and mean Cmax by 42% and 28%,
respectively [143]. Concurrent use of fluconazole with rivaroxaban was associated
M

with increased risk of major bleeding [63].

Everything considered, the available data suggest that the coadministration of

D

rivaroxaban is acceptable with CYP3A4 and/or P-gp substrates/moderate

TE

inhibitors, but not with strong combined CYP3A4, P-gp and ABCG2 inhibitors (azole-
antimycotics, apart from fluconazole, and HIV protease inhibitors), which inhibit
different pathways involved in rivaroxaban clearance and elimination [143] (Table
EP

8).

3.5.4 Pharmacokinetic interactions of rivaroxaban with inducers of CYP3A4 and P-

CC

gp
The administration of rivaroxaban and of drugs able to induce CYP3A4 such as
rifampicin, a CYP3A4 and P-gp inducer, may decrease the AUC of rivaroxaban by
A

about 50% (Table 8). Rifampicin 600 mg daily decreases rivaroxaban AUC and Cmax
by about 50% and 22%, respectively, with an associated reduction in its
anticoagulant effects [128]. The co-administration should be avoided, or doses of
rivaroxaban will likely require an increase during concurrent rifampicin

24
administration. A close patient control for signs and symptoms of thrombosis must
be enabled. Rifabutin, phenytoin, phenobarbital, rifapentine, St. John’s wort, and
carbamazepine may also reduce rivaroxaban concentrations.

3.5.5 Pharmacokinetic interactions of rivaroxaban with gastric pH modifiers and

food
Rivaroxaban PK or PD are not affected by alteration of the gastric pH by antacids,

T
ranitidine, and omeprazole. Other H2-receptor antagonists or PPIs are also not
expected to interact [148,149].

IP
4. Anticoagulants and antiplatelets interactions with NOACs

R
Although several data on NOAC efficacy, safety and DDIs are available, there is a

SC
widespread lack of knowledge on the application of these findings into clinical
practice. To overcame this gap, a growing amount of studies investigating NOACs
in combination with antiplatelet drugs in patients with or without AF has been

U
recently performed or is currently ongoing [150]. In general, the co-administration
of NOACs with any other anticoagulants is contraindicated due to an increased
N
bleeding risk [46,82,108,128,151], and they must not be used in patients with
A
mechanical heart valves, moderate-to-severe mitral stenosis or valvular AF [152].
To simplify the initial decision of clinicians for oral anticoagulants (OACs) therapy in
M

AF patients, the European Society of Cardiology (ESC) has introduced the CHA2DS2-
VASc score, that is used to assess the risk for stroke, recommending to treat AF
patients with a CHA2DS2-VASc score of 1 for men and 2 for women [1].
D

However, together with the stroke risk score, assessing the risk of bleeding (ATRIA,
TE

HAS-BLED or ORBIT scores) remains a key step in the selection of the appropriate
therapy for stroke prevention in AF patients.
Oral anticoagulation therapy is recommended in preference to a VKA in a patient
EP

with AF who is eligible for a NOAC. The consensus suggests using the lowest dose
effective of the NOAC for stroke prevention, and a dose reduction beyond the
approved dosing tested is not currently recommended [1].
CC

In AF patients with stable coronary artery disease (e.g. with no acute ischemic
events or percutaneous coronary intervention (PCI) in the preceding 1 year), OAC
monotherapy is recommended and not combination therapy with antiplatelets [1].
A

Instead, short-term triple combination therapy of OAC, clopidogrel, and aspirin is

recommended to prevent recurrent coronary and cerebral ischemic events in
patients with ACS, including unstable angina and non-ST segment elevation
myocardial infarction (NSTE-ACS), and ST-segment elevation myocardial infarction

25
(STEMI), receiving PCI [1]. Afterwards, co-administration of NOAC with mono or
dual antiplatelet therapy is the mainstay to reduce the risk of recurrent ischemic
events during the first year after ACS [152].
Finally, NOACs are arousing interest for their use in special patient populations with
arterial and venous thromboembolic risk (e.g., patients with VTE and comorbidities
such as cancer, renal impairment and cirrhosis). However, data on possible
emerging use in these hypercoagulable states are mainly based on case series, thus

T
making the potential benefit still under scrutiny [153].

IP
Among patients eligible for NOAC therapy, the selection of a drug can be
challenging and factors that could decrease the effectiveness and increase the risk

R
of bleeding, including the potential for significant DDIs, should be considered.

SC
Indeed, in case of an increased risk of bleeding, there is no established way to
reverse the anticoagulant effect of NOACs. Due to the high plasma protein binding,
NOACs is not expected to be dialyzable, with the exception of dabigatran [81],

U
which is also the only NOAC with an approved, targeted reversal agent,
idarucizumab [154]. In May 2018, FDA approved ANDEXXA (coagulation factor Xa,
N
inactivated-zhzo) to reverse anticoagulation in case of life-threatening or
A
uncontrolled bleeding in patients treated with rivaroxaban and apixaban [155].
M

In this paragraph we report the PK interactions of NOACs with antiplatelet drugs,

anticoagulants and NSAIDs that should be taken into consideration during the
clinical management of AF patients.
D

In general, despite an increased bleeding risk, the concomitant use of NOACs with
TE

antiplatelet agents is accepted, whereas the concomitant treatment of NOACs with

any other anticoagulants [unfractionated heparin (UFH), low molecular weight
heparins heparin derivatives and VKAs] is contraindicated unless in specific
EP

circumstances, like that of switching OAC therapy [46,82,108,128]. Despite no PK

and PD interactions are reported, the European manufacturer of apixaban
contraindicates the co-administration with medicinal products associated with
CC

serious bleeding, such as thrombolytic agents, GPIIb/IIIa receptor antagonists,

dipyridamole, dextran and sulfinpyrazone [46].
A careful assessment of the potential benefits and risks must be performed before
A

combining this therapy with NOACs in patients with AF and conditions that warrant
mono or dual antiplatelet therapy [46]. Indeed, some of these drugs are substrates
(clopidogrel, enoxaparin), inducers (aspirin) or inhibitors (ticagrelor, naproxen) of
P-gp [46,156,157], suggesting a possible PK interaction with NOACs.

26
Aspirin. Although the PK interactions are not significantly relevant, NOACs should
be used cautiously when co-administered with aspirin or NSAIDs, except for
edoxaban, which is not recommended with the concomitant chronic use of NSAIDs
or high dose aspirin [100].
In detail, no PK or PD interactions were observed when apixaban was co-
administered with high dose aspirin (325 mg once a day) [46]. Similarly, low dose

T
aspirin (100 mg once a day) for 5 days does not influence the PK of edoxaban (60
mg once a day) administered concomitantly. On the contrary, the steady-state

IP
exposure to edoxaban is increased by approximately 30% (AUC0-τ) and 34% (Cmax)
when edoxaban is given with aspirin high dose (325 mg) compared to edoxaban

R
alone, but the reason for the increased exposure with high dose aspirin is unknown

SC
[108,158]. Rivaroxaban does not alter the effect of aspirin on platelet aggregation
and aspirin does not alter the effects of rivaroxaban on clotting parameters
(inhibition of F-Xa activity, prolongation of prothrombin time, aPTT, and HepTest)

U
[159]. However, in patients treated with rivaroxaban for acute VTE, the risk of
clinically relevant bleeding (such as that requiring medical intervention) is
N
increased in those also taking aspirin, compared with those not taking aspirin
A
(hazard ratio 1.8) [160].
Clopidogrel. Apixaban co-administered with clopidogrel (75 mg once a day) alone
M

or with aspirin (162 mg once daily) does not significantly increase bleeding time or
further inhibit platelet aggregation compared to the administration of only the two
antiplatelet agents [46].
D

The concomitant administration of dabigatran etexilate (150 mg twice daily) and

TE

clopidogrel (75 mg once daily) in healthy controls did not influence PK and PD
profiles of either agent. On the contrary, a single loading dose (300 mg or 600 mg)
of clopidogrel administered concomitantly with dabigatran etexilate (150 mg twice
EP

daily) increased dabigatran AUCτ,ss and Cmax,ss by 30-40 % [82,161].

The UK manufacturer of rivaroxaban reports that no PK interaction occurs in
patients given rivaroxaban with clopidogrel 300 mg as a single dose followed by 75
CC

mg daily. Nevertheless, rivaroxaban alone does not increase the bleeding time, but
it appears to increase this effect when given with clopidogrel [128].
Enoxaparin. Co-administration of enoxaparin and NOACs shows an additive effect
A

on anti F-Xa concentrations, despite no PK interactions observed.

In detail, 40 mg single dose of enoxaparin does not affect the PK of 5 mg single dose
of apixaban [162], whereas induces an additive effect on anti-Xa activity [46].
Enoxaparin (40 mg once daily for 3 days) followed by dabigatran etexilate (220 mg

27
single dose) decreases dabigatran etexilate AUC0–∞ and Cmax by 14 % and 16%,
respectively, without affecting its PD properties [82,163]. This study supports the
safety of switching patients from enoxaparin to dabigatran etexilate.
The PK of rivaroxaban is not affected by enoxaparin, but previous reports have
shown that concurrent use of single doses of rivaroxaban 10 mg and 5 mg with
enoxaparin 40 mg have an additive effect on anti-factor Xa concentrations, with no
additional effects on either prothrombin time or aPTT [128].

T
Naproxen. Several studies have been conducted to assess the potential for PK
interactions after the co-administration of NOACs and naproxen (inhibitor of P-gp).

IP
Apixaban does not affect naproxen concentration–time profiles. On the other
hand, the co-administration increases apixaban Cmax, AUC0-∞ and AUC0-t by 61%,

R
54% and 55%, respectively, without any changes in apixaban Tmax and t1/2 [164]. No

SC
prolongation of bleeding time is observed after co-administration, so no dose
adjustment is required [46].
Naproxen (500 mg once daily) for 2 days does not affect Cmax, AUC0-∞ and AUC0-t

U
(the last measurable plasma drug concentration) of a single oral edoxaban dose (60
mg) administered concomitantly on day 2 [108].
N
In a randomized, two-way crossover study, with 500 mg of naproxen for 2 days, a
A
single dose of rivaroxaban 15 mg in healthy subjects increases bleeding time by a
mean of 3.43 min compared with naproxen alone, and one subject had a greater
M

increase [165]. Naproxen increases rivaroxaban AUC by 10%, but this is not
statistically significant. Naproxen does not have any clinically relevant effect on the
PD of rivaroxaban (prolongation of aPTT, prothrombin time, and HepTest, and
D

inhibition of F-Xa activity) [165].

TE

Prasugrel. Apixaban co-administered with prasugrel (60 mg followed by 10 mg once

daily) does not increase bleeding time or further inhibit platelet aggregation [46].
Ticagrelor. Timing of administration influences the PK interaction between
EP

dabigatran and ticagrelor. A 180 mg loading dose of ticagrelor, administered on day

1 together with dabigatran etexilate 110 mg bid, increases dabigatran etexilate
AUCτ,ss and Cmax,ss by 48.3% and 62.7%, respectively. These effects are similar with
CC

multiple doses of ticagrelor. However, when a single loading dose of ticagrelor 180
mg is administered 2 h after morning dose of dabigatran etexilate, taken for 3 days
110 mg bid, the increase of AUCss and Cmax,ss is reduced to 28.8% and 24.1%,
A

respectively. [82]. The manufacturer of dabigatran etexilate recommends to follow

this staggered intake for starting a loading dose of ticagrelor [82].

5. Herbal medicines interactions with warfarin and NOACs

28
Herbal medicines are commonly perceived to be helpful for cardiac condition, and
some of them have showed antiplatelet and anticoagulant activity [166]. Herbs are
often used by patients receiving anticoagulants. Indeed, about 40% of patients with
CVD have used complementary and alternative medicine, including herbal
medicine, in parallel with conventional treatments [167]. It is of note that most
patients are not aware of the potential for herb-drug interactions and rarely inform
their clinicians about their concomitant use. Therefore, patients taking herbal

T
medicine with anticoagulants are more likely to be potentially exposed to herb-
drug interactions [168].

IP
Components of food and herbal supplements may inhibit CYP2C9 but they rarely
achieve appreciable intrahepatic concentrations and the interaction with warfarin

R
usually has no clinical significance [169]. A recent systematic review of the

SC
interactions of herbal medicine with warfarin does not clarify whether herbal
medicines significantly affect warfarin PK-PD parameters [166]. Grapefruit
components inhibit CYP3A4 activity, but only few cases of interactions have been

U
reported [6]. Green tea may reduce INR value, but a significant interaction is
possible only when green tea is consumed in high doses [170]. Other herbal
N
medicines that may affect the activity of CYP enzymes involved in warfarin
A
metabolism (CYP2C9 and CYP3A4) are chamomile, soybean, mango, gingko biloba,
and cranberry, but serious interactions are quite rare and always involve the
M

consumption of very large amounts of herbal medicines [6]. A clinically significant

reduction of the pharmacological effect of warfarin has been observed after a
concomitant long-term consumption of St. John’s wort, that increases the
D

clearance of both the S and the R enantiomers of warfarin [171,172].

TE

It is advisable to check the possible PD interaction of warfarin with herbal

supplement containing vitamin K. Green vegetables, leaves and oil may contain
significant amounts of vitamin K, and their consumption in high quantities may
EP

decrease the INR. On the contrary, a reduced vitamin K consumption or absorption

(following antibiotics use) may result in a drastically increased INR and
anticoagulation. However, warfarin does not show clinically relevant interactions
CC

with food if patients follow a stable diet [173]. Therefore, patients should be
advised to maintain their usual diet and inform the clinicians of any change in diet
or supplements.
A

Regarding NOACs, there is no direct evidence of PK interactions with herbal

inhibitors/inducers of CYP3A4 or modulators of P-gp. Nevertheless, the co-
administration of St. John's wort, a potent inducer of P-gp and CYP3A4, with

29
dabigatran and edoxaban should be made with caution and avoided with apixaban
and rivaroxaban [46,108,174].
Some herbal medicines and component of the diet modulate P-gp (such as gingko
biloba, berberine, black pepper, grape juice, capsaicin, apigenin, lemonin, soybean,
curcumin, green tea) [175]. So far, no clinically important interactions among
herbal medicines and NOACs have been described.

T
6. Conclusions
The main clinically relevant PK interactions of warfarin with drugs are due to

IP
competition for plasma protein-binding sites and to inhibition/induction of the
expression and/or activity of CYP2C9, 1A2, 2C19 and 3A4 isoenzymes. Instead, the

R
data collected so far indicate that herbal medicine, except for St John’s wort, do

SC
not lead to a clinically significant change in the PK profile of warfarin.
NOACs are established alternatives to warfarin, showing several PD and PK
advantages, such as the simplification of anticoagulant treatment, the reduced

U
dependence on regular monitoring of clotting times and the lower reported
incidence of drug-drug interactions.
N
However, NOACs are not devoid of clinical criticalities. Indeed, NOACs exposure will
A
likely be increased by the administration of strong P-gp- and CYP3A4-inhibitor,
resulting in major bleeding. On the contrary, P-gp inducers could significantly
M

decrease the NOACs plasma concentration with an associated reduction in their

anticoagulant effects. In particular, caution is required when dabigatran is
combined with strong inhibitors or inducers of P-gp [82]. Co-administration of
D

rivaroxaban [128], and possibly apixaban [46], with agents that strongly inhibit P-
TE

gp or CYP3A4 is cautioned, whereas is contraindicated when they are co-

administered with drugs that strongly inhibit both P-gp and CYP3A4. Finally, a
reduced dose of betrixaban [74] and edoxaban [108] for patients receiving or
EP

starting concomitant P-gp inhibitors is recommended, whereas edoxaban should

be used with caution when co-administered with P-gp inducers. Currently, new
NOACs are in the pipeline: darexaban, does not appear to be affected by major
CC

inducers of CYP3A4, while nokxaban shows some CYP2D6 and 3A4 activity [57].
However, further studies are still needed to fully define the clinical significance of
these observations.
A

Although co-administration of several drugs with NOACs are not recommended by

the manufactures and the updated guidelines [176], in a recent retrospective
cohort study among 91330 patients taking NOACs for non-valvular AF, the authors
reported that they are often co-administered [63]. In particular, digoxin, diltiazem,

30
amiodarone, and atorvastatin were used in more than 20% of NOAC-exposed
person-quarters. As expected, inhibitors or inducers of P-gp and CYP3A4 (as
amiodarone, rifampicin or phenytoin) were associated with a significantly
increased risk of major bleeding, but some combinations (verapamil, diltiazem,
cyclosporine, ketoconazole, itraconazole, voriconazole, posaconazole or
dronedarone) were not associated with major bleeding. In addition, several of
them (as atorvastatin, digoxin, clarithromycin or erythromycin) were paradoxically

T
associated with a lower bleeding risk. The most plausible reason suggested for this
discrepancy between the observed PK interactions and the expected PD effects

IP
may be that major bleeding is related not only to plasma levels of NOACs, but also
to the comorbidity and the main drug benefits of the concurrent medications.

R
Another reason might be that the limited PK data of NOACs use was mostly

SC
collected from healthy volunteers who have different PK profiles from patients.
Compared with warfarin, NOACs have favorable clinical outcomes but the decision
to anticoagulate and the choice of the appropriate agent are a complex issue in

U
patients with AF and co-morbidities, such as renal or hepatic impairments. All the
NOACs undergo various levels of renal clearance. Therefore, chronic kidney disease
N
and ESRD increase the risk of both stroke and bleeding in these patients [177]. In
A
patients eligible for a NOAC, renal function should be estimated by calculating CLCR
and then monitored at least yearly to adapt the dose accordingly [21]. Indeed,
M

patients with mild to moderate/severe renal failure (CLCR < 50 mL/min) could suffer
an increased NOACs exposure. In details, in patients with moderate renal
impairment (CLCR > 30 mL/min) a dose adjustment is requested for NOACs except
D

for apixaban and betrixaban [46,74], while in patients with severe renal impairment
TE

(CLCR < 30 mL/min), dabigatran is contraindicated [82] and cautious use with
reduced dose of apixaban, betrixaban and edoxaban are recommended
[46,74,108]. In patients with renal impairment, no dose adjustment for rivaroxaban
EP

is recommended [128].
Moreover, hepatic impairment can also considerably change the safety and efficacy
of NOACs not only due to an altered hepatic metabolism but also because
CC

coagulation could be affected by a moderate to severely impaired hepatic function.

In general, NOACs can be used in mild hepatic impairment (Child Pugh A) in absence
of bleeding risk. In the case of moderate hepatic impairment (Child Pugh B),
A

apixaban, betrixaban, dabigatran and edoxaban can be administered, but these

drugs should be avoided in severe hepatic impairment (Child Pugh C). In any case,
no dose adjustment is recommended. Instead, rivaroxaban is not recommended in
patients with moderate to severe hepatic impairment (Child Pugh B or C) [21].

31
However, compared to VKAs, NOACs display better or similar rates of bleeding in
cirrhosis patients [178,179].
Thus, based on differences in NOACs PK and clinical recommendations (Table 9)
and on clinical history of patients, the clinicians should select the most appropriate
anticoagulant agents and eventually withdraw/replace P-gp- and CYP3A4-
modulators from drug regimen to offer their patients the best therapeutic
combinations.

T
Conflict of interest: None

IP
Acknowledgement

R
Alberto Corsini received grants as lecturers from Pfizer, BMS, Sankyo.

SC
This work was supported by EDRA S.p.A.; European Union’s Horizon 2020 research
and innovation programme under the Marie Skłodowska-Curie grant agreement
[No 675527], and by grants from MIUR Progetto Eccellenza.

U
N
A
M
D
TE
EP
CC
A

32
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October 2017).

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Thromb J. 12 (2014) 22. doi:10.1186/1477-9560-12-22.

[184] J. Graff, S. Harder, Anticoagulant therapy with the oral direct factor Xa
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Pharmacokinet. 52 (2013) 243–54. doi:10.1007/s40262-013-0034-0.

[185] J. Stangier, H. Stähle, K. Rathgen, W. Roth, K. Shakeri-Nejad,
Pharmacokinetics and Pharmacodynamics of Dabigatran Etexilate, an Oral
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Safety of the Factor Xa Inhibitor Edoxaban and the Effects of Quinidine in
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A

doi:10.1002/cpdd.53.

53
Figure captions

T
RIP
SC
U
N
A
M

Fig 1.
D
TE
EP
CC
A

54
 R I
SC
Table

Table 1

U
Comparative pharmacology of warfarin [23,25,28,29,180–182] and new oral anticoagulants
[8,10,76,105,108,109,111,122,124,128,183] in healthy subjects

N
Parameters Warfarin Apixaban Betrixaban Dabigatran Edoxaban Rivaroxaban

A
Absorption

M
Tmax (h) 2-4 1-4 3-4 1-3 1-2 2-4
Cmax (ng/mL) 140-220 460 110 256 141
Bioavailability (%) > 95 50-66 34 6-7 50-62 80-100
Binding to transporter
pumps
ED none P-gp and
BCRP
P-gp substrate P-gp and
MATE1
P-gp and
OATP1B1
P-gp and BCRP
substrate
substrate substrateA substrate
PT

Effect of food noneB -15% Cmax, -50% Cmax delayed Tmax slight increase increase of Cmax
shorter Tmax and AUCC by about 2 hC of AUC and and AUCD
Cmax
E

Distribution
Protein bound (%) 99 87 60 35 40-59 92-95
CC

Volume of distribution 8-10 21 32 (L/kg) 50-70 107E 50

(L) 300F
Metabolism
A

Via CYP450 (%) 2C9, 3A4, 2C19, 1A2, 2C8, <1 <2 3A4 (<25) 3A4,2J2 (57)
1A1, 1A2 2J2, 2C9, >CES1
2C19,
3A4 (<32)

Clearance (L/h) 0.14-0.23 3 41 105-170 22 8-10

Excretion

55
 R I
SC
t1/2 (h) 20–60G 5E 20-27 11-14 6-11 5-13H
12F

U
Urinary (%) 80I 27 5-13 85 35-39 35

N
Fecal (%) 20I 47-56 82-89 6 62 26

A
Hemodialyzable no no no yes no no
Prodrug no no no Dabigatran no no

M
etexilate

Active metabolite(s) ED yes no no yes yes no

Pharmacological VKOR Xa Xa IIa Xa Xa
target
PT
ABC = ATP binding cassette; BCRP = breast cancer resistance protein; CES1 = carboxylesterase-1; VKOR = vitamin K epoxide
reductase enzyme; Cmax = peak plasma concentration; CYP450 = cytochrome P450; MATE1 = toxin extrusion-1 transporters; P-gp
= P-glycoprotein; t1/2 = terminal half-life; Tmax = time to reach peak plasma concentration after an oral dose;
E

A
Dabigatran etexilate (prodrug)
B
Dietary Vitamin K influences PD
CC

C
Fatty food
D
Effect of food depends on drug dosage
E
intravenous
F
per os
A

G
t1/2 is 50 h for R-enantiomer and 32 h for S-enantiomer
H
Rivaroxaban half-life = 5-9 h in healthy subjects, 11-13 h in elderly [128]
I
metabolites

56
Table 2

Pharmacokinetic drug-interactions of warfarin

Cytochrome Inhibitors Inducers

P450
CYP2C9 amiodarone, capecitabine, cotrimoxazole, aprepitant, bosentan,
etravirine, fluconazole, fluvastatin, carbamazepine,
fluvoxamine, isoniazid, metronidazole, phenobarbital,
miconazole, oxandrolone, sulfinpyrazone, rifampicin

T
tigecycline, voriconazole, zafirlukast

IP
CYP1A2 acyclovir, allopurinol, amiodarone, caffeine, montelukast, moricizine,
cimetidine, ciprofloxacin, disulfiram, omeprazole,
enoxacin, famotidine, fluvoxamine, phenobarbital, phenytoin

R
methoxsalen, mexiletine, miconazole,
norfloxacin, oral contraceptives,

SC
phenylpropanolamine, propafenone,
propranolol, terbinafine, thiabendazole,
ticlopidine, verapamil, voriconazole,
zileuton
CYP3A4 alprazolam, amiodarone, amlodipine,
amprenavir, aprepitant, atorvastatin, U armodafinil, amprenavir,
aprepitant, bosentan,
N
atazanavir, bicalutamide, cilostazol, carbamazepine,
cimetidine, ciprofloxacin, clarithromycin, efavirenz, etravirine,
A
clofibrate, conivaptan, cyclosporine, modafinil, nafcillin,
darunavir/ritonavir, diltiazem, dronedarone, phenytoin, pioglitazone,
erythromycin, fenofibrate, fluconazole, prednisone, rifampicin,
M

fluoxetine, fluvoxamine, fosamprenavir, rifampicin, rufinamide

imatinib, indinavir, isoniazid, itraconazole,
ketoconazole, lopinavir/ritonavir, nefazodone,
D

nelfinavir, nilotinib, oral contraceptives,

posaconazole, propafenone, ranitidine,
TE

ranolazine, ritonavir, saquinavir,

telithromycin, tipranavir, voriconazole,
zileuton
EP

In bold, clinically relevant interactions with warfarin. Table modified from [6,25].
CC
A

57
Table 3
Pharmacokinetic of NOACs in special populations

special drug PK effects notes references

population
renal apixaban increase of dose reduction is [46]
impairment AUC recommended if at
least two out of the
three following

T
criteria are fulfilled:
age >_80 years,

IP
body weight <_60 kg,
creatinine
>_1.5mg/dL and in

R
patients with CLR 15-
29 mL/min;

SC
administration is not
recommended in
patients with CLR <
15 mL/min or

U
undergoing
hemodialysis
N
betrixaban dose reduction and [74]
close clinical
A
monitoring is
recommended only in
patients with severe
M

renal impairment
dabigatran increase of dose reduction is [21,82]
etexilate AUC and t1/2 recommended in
D

patients at high risk

of bleeding with CLR
TE

< 50 mL/min; caution

is recommended in
patients with CLR 30-
50 mL/min; avoid
EP

administration in
patients with CLR <
30 mL/min
edoxaban increase of dose reduction is [108,115,116]
CC

AUC recommended in
patients with CLR <
50 mL/min;
administration is not
A

recommended in
patients with CLR <
15 mL/min or on
hemodialysis
rivaroxaban increase of dose reduction is [128,137]
t1/2 recommended in

58
 patients with CLR <
50 mL/min; caution is
recommended in
patients with CLR 15-
29 mL/min; avoid
administration in
patients with CLR <
15 mL/min
hepatic apixaban no effect on caution is [21,46,184]
impairment AUC recommended in

T
patients with

IP
elevated liver
enzymes or with
hepatic impairment

R
(Child Pugh A and
B); avoid

SC
administration in
patients with severe
hepatic impairment
(Child Pugh C)
betrixaban
U
administration is not
recommended in
[74]
N
patients with hepatic
impairment
A
dabigatran no effect on caution is [21,82,185]
etexilate AUC recommended in
patients with hepatic
M

impairment (Child
Pugh B);
administration is not
D

recommended in
patients with severe
TE

hepatic impairment
(Child Pugh C)
edoxaban no effect on caution is [21,108,117]
Cmax and AUC recommended in
EP

patients with
elevated liver
enzymes or with
hepatic impairment
CC

(Child Pugh A and

B); avoid
administration in
patients with severe
A

hepatic impairment
(Child Pugh C)
rivaroxaban increase of avoid administration [19,128]
AUC in patients with
hepatic disease
(Child Pugh B and C)

59
 associated with
coagulopathy
elderly apixaban no effect on caution is [46,55]
Tmax and Cmax; recommended for
increase of increased risk of
AUC and t1/2; hemorrhages
decrease of
CLR
betrixaban no clinical relevance [74]

T
dabigatran increase of caution is [82,92]
etexilate AUC recommended, and

IP
renal function should
be assessed in
elderly

R
edoxaban caution is [108]
recommended for

SC
increased risk of
hemorrhages
rivaroxaban increase of no clinical relevance [128,131]
t1/2
gender apixaban decrease of
CLR and U
no dose adjustment
required
[46,55]
N
increase of
t1/2, Cmax and
A
AUC in
female
M

betrixaban no PK no clinical relevance [74]

interaction
dabigatran increase of no clinical relevance [82,88]
etexilate Cmax and AUC
D

in female
TE

edoxaban decrease of no clinical relevance [108,109]

CLR in female
rivaroxaban no clinical relevance [128]
severe obesity all NOACs reduced Data are limited; [21]
EP

(BMI>40 kg/m2 exposure specific

or weight >120 measurements of
kg) drug trough levels
CC

should be considered

low body apixaban increased data are limited; no [21]

weight (<50 edoxaban exposure evidence-based
A

kg) recommendations
can be
given regarding
(further) dose
reduction

60
Table 4

Pharmacokinetic drug-interactions of apixaban

Co- mechanism PK effects notes references

administered
drug
atenolol P-gp substrate slight decrease no clinical [46,60]
of AUC and Cmax relevance;

T
co-administration
is well tolerated

IP
clopidogrel P-gp substrate no PK co-administration [46]
interactions is not
recommended;

R
risk of bleeding
digoxin P-gp substrate no effect on AUC no clinical [46,60]

SC
and Cmax relevance;
co-administration
is well tolerated
enoxaparin P-gp substrate no PK avoid co- [46,162]

amiodarone P-gp and

interactions
expected U
administration
no dose [46]
N
and verapamil CYP3A4 moderate adjustment
inhibitors increase of required
A
apixaban
concentration
azole- P-gp and expected avoid co- [46,61]
M

antimycotics CYP3A4 increase of AUC administration

(itraconazole, inhibitors
posaconazole
D

and
voriconazole),
TE

ritonavir and
cobicistat
diltiazem P-gp and moderate no dose [46,62]
CYP3A4 inhibitor increase of AUC adjustment
EP

and Cmax required

ketoconazole P-gp and increase of AUC, avoid co- [46,62]
CYP3A4 inhibitor Cmax and t1/2 administration
CC

macrolides P-gp and increase of AUC dose adjustment [21]

(clarithromycin, CYP3A4 and Cmax should be
erythromycin) inhibitors considered
A

dronedarone P-gp inhibitor possible limited clinical [21]

increased data; dose
exposure reduction is
recommended
naproxen P-gp inhibitor increase of AUC caution is [46,164]
and Cmax by 61% recommended;
no dose

61
 and 54%, adjustment
respectively. required

quinidine P-gp inhibitor expected no dose [46]

moderate adjustment
increase in required
plasma
concentration
aspirin P-gp inducer no PK caution is [46,156]
interactions recommended;

T
increased risk of

IP
hemorrhages
carbamazepine, P-gp and expected no dose [46]
phenobarbital, CYP3A4 strong reduction of adjustment

R
phenytoin and inducers plasma required but use
St. John’s Wort concentration with caution

SC
levetiracetam P-gp inducer no data are avoid co- [64]
available administration;
reduction of
clinical effects

oxcarbazepine CYP3A4 no data are U

could occur
avoid co- [21,64]
N
and topiramate inducers available administration;
reduction of
A
clinical effects
could occur
rifampicin P-gp and reduction of caution is [46,65]
M

CYP3A4 inducer AUC, increase of recommended;

CL and CL/F no dose
adjustment
D

required
famotidine gastric pH no effect on AUC no clinical [46,66]
TE

modulator and Cmax relevance

prasugrel unknown no PK co-administration [46]
interactions is not
recommended;
EP

increased risk of
hemorrhages
CC
A

62
Table 5

Pharmacokinetic drug-interactions of betrixaban

Co- mechanism PK effects notes references

administered
drug
amiodarone P-gp increase of AUC dose adjustment required [74,77]
inhibitor

T
azithromycin P-gp increase of AUC dose adjustment required [74]
inhibitor

IP
diltiazem P-gp increase of AUC dose adjustment required [77]
inhibitor
ketoconazole P-gp increase of AUC dose adjustment required [74,77]

R
inhibitor and Cmax
verapamil P-gp increase of AUC dose adjustment required [74]

SC
inhibitor and Cmax

U
N
A
M
D
TE
EP
CC
A

63
Table 6

Pharmacokinetic drug-interactions of dabigatran etexilate

Co-administered mechanism PK effects notes references

drug
atorvastatin P-gp substrate no PK no clinical [94]
interaction relevance

T
clopidogrel P-gp substrate high dose caution is [82]
clopidogrel recommended;

IP
increase of AUC increased risk of
and Cmax hemorrhages
diclofenac P-gp substrate no PK no clinical [91]

R
interaction relevance
digoxin P-gp substrate no PK no clinical [89,91]

SC
interaction relevance
enoxaparin P-gp substrate decrease of avoid co- [82]
AUC and Cmax administration
amiodarone P-gp inhibitor increase of AUC close clinical [82,96]
and Cmax
U
monitoring is
recommended
N
clarithromycin P-gp inhibitor increase of AUC close clinical [82]
and Cmax monitoring is
A
recommended
cobicistat P-gp and increase of AUC increase of [103]
M

MATE-1 and Cmax thrombin time

inhibitor
diltiazem P-gp inhibitor no PK no clinical [96]
interaction relevance
D

dronedarone P-gp inhibitor increase of AUC increased ECT% [82,97]

and Cmax and aPTT%;
TE

co-administration
is contraindicated
ketoconazole P-gp inhibitor increase of AUC co-administration [82]
and Cmax is contraindicated
EP

quinidine P-gp inhibitor increase of AUC close clinical [82]

and Cmax monitoring is
recommended
CC

statins P-gp inhibitor possible use of statins [98]

(simvastatin and increased other than
lovastatin) exposure simvastatin or
lovastatin should
be considered
A

ticagrelor P-gp inhibitor increase of AUC a loading dose of [21]

and Cmax 180mg ticagrelor
given 2 h after
110mg dabigatran
etexilate is
recommended

64
Verapamil P-gp inhibitor Dabigatran clinical monitoring [21,95,96]
plasma levels is recommended;
increased advised to use the
by180% with lowest dose
verapamil IR, by dabigatran
60% with
verapamil SR
carbamazepine P-gp inducer decrease of avoid co- [82,104]
phenytoin trough plasma administration
concentration

T
phenobarbital P-gp inducer decrease of avoid co- [104]

IP
trough plasma administration
concentration
rifampicin P-gp inducer decrease of avoid co- [82]

R
AUC administration
St. John’s Wort P-gp inducer expected avoid co- [82]

SC
decrease of administration
AUC
pantoprazole gastric pH decrease of no clinical [87,92,105]
modulator AUC and Cmax relevance
PPIs gastric pH
modulator
slight decrease
AUC U
no clinical
relevance
[82,96]
N
ranitidine gastric pH no PK no clinical [82]
modulator interaction relevance
A
M
D
TE
EP
CC
A

65
Table 7

Pharmacokinetic drug-interactions of edoxaban

Co-administered mechanism PK effects notes references

drug
atorvastatin P-gp substrate no PK no clinical relevance [118]
and CYP3A4 interaction
inhibitor

T
digoxin P-gp substrate no PK no clinical relevance [108,118,119]
interaction

IP
amiodarone P-gp, CYP2C9 increase of no clinical relevance [108,118]
and CYP2D6 AUC0-τ and Cmax,
inhibitor decrease of C24

R
cyclosporine P-gp, CYP3A4 increase of dose reduction is [108,120]
and OATP1B1 AUC and Cmax required

SC
inhibitor of edoxaban
and its
metabolite, M4
dronedarone P-gp inhibitor increase of dose reduction is [108,118]
AUC, Cmax and
C24 of edoxaban U
required
N
erythromycin P-gp and increase of dose reduction is [108,120]
CYP3A4 AUC and Cmax required
A
inhibitor of edoxaban
and its
metabolite, M4
M

ketoconazole P-gp and increase of dose reduction is [108,120]

CYP3A4 AUC and Cmax required
inhibitor of edoxaban
D

and its
metabolites, M1
TE

and M4;
decrease of
AUC and Cmax
of M6
EP

naproxen P-gp inhibitor no PK chronic use is not [108,158]

interaction recommended
quinidine P-gp and moderate no clinical relevance [108,118,186]
CYP2D6 increase of
CC

inhibitor AUC, Cmax and

C24 of edoxaban
and its
metabolite, M4
A

verapamil P-gp and moderate no clinical relevance [108,118]

CYP3A4 increase of
inhibitor AUC, Cmax and
C24 of edoxaban
aspirin P-gp inducer no PK and PD high dose aspirin is [108,156,158]
interactions not recommended;

66
 increased risk of
hemorrhages
rifampicin P-gp, CYP3A4 decrease of caution is [108,121]
and CES-1 AUC; recommended
inducer; increase of
OATP1B1 AUC and Cmax
inhibitor of M4 and M6
carbamazepine P-gp and reduction of caution is [21,108]
CYP3A4 AUC recommended
inducer

T
esomeprazole gastric pH no PK no clinical relevance [123]

IP
modulator interaction

R
SC
U
N
A
M
D
TE
EP
CC
A

67
Table 8

Pharmacokinetic drug-interactions of rivaroxaban

Co- mechanism PK effects notes references

administered
drug
atorvastatin P-gp substrate no PK interaction no clinical [146]
and CYP3A4 relevance

T
inhibitor
clopidogrel P-gp substrate no PK interaction caution is [128]

IP
recommended;
increased risk of
hemorrhages

R
enoxaparin P-gp substrate no PK interaction avoid co- [128]
administration

SC
digoxin P-gp substrate no PK interaction no clinical [146]
relevance
midazolam CYP3A4 increase of Tmax no clinical [128,143]
substrate relevance
warfarin P-gp substrate no PK
interactions U
avoid co-
administration
[128,156]
N
azole- P-gp and increase of AUC avoid co- [128,140,143]
antimycotics CYP3A4 and Cmax administration;
A
(ketoconazole, inhibitors increased risk of
itraconazole, hemorrhages
voriconazole
M

and
posaconazole),
conivaptan and
D

ritonavir
fluconazole CYP3A4 inhibitor increase of AUC no clinical [128,143]
TE

and Cmax relevance

macrolides: P-gp and increase of AUC no clinical [128,143]
clarithromycin, CYP3A4 and Cmax relevance
erythromycin inhibitors
EP

dronedarone P-gp inhibitor expected limited clinical [128]

increased data; avoid co-
plasma administration
CC

concentration
naproxen P-gp inhibitor slight increase of no clinical [165]
AUC relevance

aspirin
A

P-gp inducer no PK interaction caution is [159,160]

recommended;
increased risk of
hemorrhages
carbamazepine, P-gp and reduction of AUC avoid co- [128]
phenytoin, CYP3A4 administration
phenobarbital, inducers

68
rifampicin,
rifabutin,
rifapentine, St.
John’s wort
ranitidine gastric pH no PK interaction no clinical [148]
modulator relevance
omeprazole gastric pH no PK interaction no clinical [149]
modulator relevance

T
R IP
SC
U
N
A
M
D
TE
EP
CC
A

69
 Table 9

Effect of DDIs on NOAC plasma levels and its clinical relevance

betrixaban dabigatran
apixaban edoxaban rivaroxaban
* etexilate
Antiarrhythmic drugs
10
amiodarone  6 1 9

diltiazem 10  8 5 9

T
2
dronedarone 7  5 9
10
quinidine  6 1 9

IP
10
verapamil   6 1 9

Antibiotics
10 8 5 9
azithromycin   

R
clarithromycin 1 6 5
3
erythromycin 2 8
5 9

SC
rifampicin 1  1
3 1
Antiepileptic Drugs
1 2
carbamazepine 10 1
10 10 10 10
levetiracetam
oxcarbazepine
phenobarbital
10
2 U
10
2
10
10
2

2
N
1
phenytoin 2 10
1
10 10 10 10
topiramate
A
Antimycotics
10 10 10
fluconazole 10
M

ketoconazole 1   7
 5
1
1 8 5
itraconazole 1
10 10 10
posaconazole 1
D

10 10 10
voriconazole 1
Antiplatelet, anticoagulant and NSAIDs
4
aspirin 4 4 4
TE

4 4
clopidogrel 4  4
4 4 4
diclofenac 4
enoxaparin 4 4 2 4
EP

naproxen 4 2
 4
4
4 4 4
prasugrel 4
4
ticagrelor 6 4 4
CC

4 4 2
warfarin   4
Anti-ulcer drugs
10 10 10
famotidine 10
10 10 10 10
esomeprazole  
A

10 10 10
omeprazole   10
10 10 10 10
pantoprazole  
10 10 10
PPIs  10
10 10
ranitidine  10 10
Antiviral Drugs
10
cobicistat 10 10 10

70
 1 8 5
ritonavir 1
2 8 5 10
telaprevir 
Cardiovascular Drugs
atenolol 10 10 10 10
10 10 10
atorvastatin     10
10
digoxin   10  10 10
10 10 10 10
lovastatin  
10 10 10 10
simvastatin  
Others

T
10 8
cyclosporine   5 9

IP
midazolam 2
 10
 10
10
1 2 10
St. John’s Wort   1
9 10 10 10
 

R
tacrolimus
10 10 10
SSRIs or SNRIs  

SC
The color-coding indicates the most restrictive clinical recommendations based on the respective
NOAC summary of product characteristic (EMA) [46,82,108,128] and 2018 EHRA practical guide on
NOACs in AF [21]; * for betrixaban based on FDA full prescribing information.

White: No data available.

Gray: No relevant DDI or no dose adjustment required. U
N
Yellow: Caution is recommended.
Orange: Consider dose and posology adjustment or close clinical monitoring.
A
Red: Contraindicated/not recommended.
M

Notes: based on FDA full prescribing information [45,74,81,107,140].

1
In accordance with FDA full prescribing information
2
In accordance with FDA full prescribing information, but the drug is not specifically named
3
Contraindicated/not recommended by FDA full prescribing information
D

4
Consider dose and posology adjustment and close monitoring by FDA full prescribing information
5
No dose adjustment
TE

6
No dose adjustment but avoid in DVT and PE with CLCR <50 ml/min or patients with CLCR <30 ml/min
7
Consider dose adjustment in patients with CLCR 30-50 ml/min and avoid with CLCR <30 ml/min
8
Avoid in DVT and PE with CLCR <50 ml/min or patients with CLCR <30 ml/min
9
Avoid in patients with CLCR <80 ml/min or use should be considered only if potential benefit justifies
EP

the potential risk

10
No indication in FDA full prescribing information
CC

No PK data or expected effect based only on analogue drugs.

 Increase of NOACs exposure has been reported.
 Decrease of NOACs exposure has been reported.
A

 No PK interaction.

SSRIs: selective serotonin reuptake inhibitors

SNRIs: serotonin norepinephrine reuptake inhibitors

71