The non-vitamin K antagonist oral anticoagulants (NOACs) differ in their uptake, metabolism and excretion, which may increase the potential for unintended adverse events or drug interactions.1-3

A summary of NOAC hepatic, renal and drug contraindications is provided below. View the TGA-approved Product Information for each NOAC for complete details.

NOAC metabolism and use for patients with hepatic or renal impairment

Apixaban (Eliquis), dabigatran (Pradaxa) and rivaroxaban (Xarelto) vary in their degrees of renal excretion, half-lives, metabolism and bioavailability (see Table 1).

All three NOACs have hepatic and renal contraindications, and as a minimum, patients will require assessment of liver and kidney function prior to their initiation and assessment of kidney function every year (see Tables 2 and 3).1-5

Table 1. NOAC metabolism and elimination

NOAC propertyApixaban1,4Dabigatran2,4Rivaroxaban3-5
Renal excretion27%85%36%
Half-lifea12 hours12–17 hours5–13 hours
Metabolism and bioavailabilityMetabolised by CYP3A4/5 (major)

Metabolised by CYP1A2, 2C8, 2C9, 2C19 and 2J2 (minor)

Substrate of P-gp, BCRP

Bioavailability of 50% (10 mg; no food interaction)
Not metabolised by the CYP system

Substrate of P-gp (dabigatran etexilate)

Prodrug dabigatran etexilate is converted to active dabigatran after oral administration, with bioavailability of 6.5% (no food interaction)
Metabolised by CYP3A4, CYP2J2 and CYP-independent mechanisms

Substrate of P-gp, BCRP

Oral bioavailability of 80–100% (10 mg), but 66% with 20 mg tablet under fasting conditions

15 mg and 20 mg tablets should be taken with food

Table 1 abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome P450; NOAC, non-vitamin K antagonist oral anticoagulant; P-gp, P-glycoprotein.

a Half-life is prolonged if renal function is impaired.


Table 2. NOAC use in hepatic impairment

RecommendationApixaban1,4Dabigatran2,4Rivaroxaban3-5
ContraindicatedHepatic disease associated with coagulopathy and clinically relevant bleeding risk, including severe hepatic impairment (Child-Pugh C)Hepatic impairment or liver disease expected to have any impact on survival

Manufacturer also contraindicates use if liver enzymes > 2 x ULN
Significant hepatic disease (including Child-Pugh B and C), which is associated with coagulopathy leading to a clinically relevant bleeding risk
MonitoringPerform liver function tests before starting a NOAC, and investigate if results are abnormal

Table 2 abbreviations: NOAC, non-vitamin K antagonist oral anticoagulant; ULN, upper limit of normal.


Table 3. NOAC use in renal impairment

RecommendationApixaban1,4Dabigatran2,4Rivaroxaban3-5
ContraindicatedCrCl < 25 mL/minCrCl < 30 mL/minUndergoing dialysis

CrCl < 30 mL/min
(15 mg and 20 mg tablets)

CrCl < 15 mL/min
(10 mg tablets)
MonitoringAssess renal function before starting a NOAC

Check renal function at least every year and whenever a clinical circumstance or medication change

Monitor more frequently in patients with impaired renal function

Table 3 abbreviations: NOAC, non-vitamin K antagonist oral anticoagulant; CrCl, creatinine clearance.

NOAC drug–drug interactions

Apixaban, dabigatran and rivaroxaban drug–drug interactions from the Clinical Excellence Commission’s 2016 NOAC guidelines are summarised below (see Tables 4 to 8).

Table 4. Contraindicated drugs (increased NOAC activity)

Interacting drug
Interacts with apixaban?4Interacts with dabigatran?4Interacts with rivaroxaban?4
Azole antifungals
(eg, itraconazole, voriconazole, posaconazole)
YesYes
Yes
Dronedarone
NoYesNo
HIV protease inhibitors (eg, ritonavir)
YesNoYes
Immunosuppressants: Calcineurin inhibitors (eg, ciclosporin, tacrolimus)
NoYesNo
Verapamil
UncertainYes (relative contraindication)bUncertain

b If verapamil needs to be initiated in patients taking dabigatran etexilate, or dabigatran etexilate and verapamil need to be initiated concurrently, dabigatran etexilate should be given at least 2 hours before verapamil for the first 3 days.2


Table 5. Contraindicated drugs (antithrombotic interactions)

Interacting drug
Interacts with apixaban?4Interacts with dabigatran?4Interacts with rivaroxaban?4
Anticoagulants, unless transitioning (eg, warfarin, heparin, low molecular weight heparin)
YesYes
Yes
Antiplatelets: Dual-antiplatelets, ticagrelor
See Table 7Yes (relative contraindication)See Table 7


Table 6. Cautioned drugs (increased NOAC activity)

Interacting drug
Interacts with apixaban?4Interacts with dabigatran?4Interacts with rivaroxaban?4
Amiodarone
NoYes
No
Fluconazole
NoYesNo
Macrolides (eg, clarithromycin)
YesYes
Yes
Selective serotonin re-uptake inhibitors/serotonin noradrenaline re-uptake inhibitors (eg, escitalopram, sertraline, venlafaxine)
Yes (theoretical)YesYes (theoretical)


Table 7. Cautioned drugs (antithrombotic interactions)

Interacting drug
Interacts with apixaban?4Interacts with dabigatran?4Interacts with rivaroxaban?4
Antiplatelets: Aspirin, clopidogrel, prasugrel, dipyridamole
YesYes
Yes
Antiplatelets: Ticagrelor
YesSee Table 5Yes
Non-steroidal anti-inflammatory drugs
YesYesYes


Table 8. Cautioned drugs (reduced NOAC activity)

Interacting drug
Interacts with apixaban?4Interacts with dabigatran?4Interacts with rivaroxaban?4
Anticonvulsants: Phenytoin, carbamazepine
YesYes
Yes
Anticonvulsants: Phenobarbitone
YesNoYes
Rifampicin
YesYes
Yes
St John’s wort
YesNoYes