Study Points - Course #95010: Managing Drug Interactions with Direct Oral Anticoagulants

1 . Which is important to keep in mind regarding drug transporter systems (e.g., P-glycoprotein [P-gp])?

	A)		These proteins can affect pharmacokinetics.
	B)		Breast cancer resistance protein moves drugs into the liver.
	C)		Most available data are related to organic anion transporting polypeptides.
	D)		It is rare for medications to impact P-gp and CYP450.

REVIEW OF CYP450 AND TRANSPORTER INTERACTIONS

We are still learning about the significance of these transporters on pharmacokinetics. Most of the available data are related to P-glycoprotein (P-gp, multidrug resistance protein 1 [MDR1]). P-gp is a drug efflux pump found in the gut, liver, kidney, blood-brain barrier, and cancer cells. It pumps drugs out of cells and into the gut, bile, and/or urine for excretion [6]. Other examples include BCRP, which pumps drugs out of cells in the gut, liver, and kidney, and OATPs (e.g., OATP1B1, OATP1B3), which move drugs into the liver [5].

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2 . Which drug transport system has the most available data related to its effects on drug pharmacokinetics?

	A)		BCRP
	B)		MATEs
	C)		OATPs
	D)		P-gp

REVIEW OF CYP450 AND TRANSPORTER INTERACTIONS

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3 . Which pair of direct oral anticoagulants are significantly metabolized by CYP3A4?

	A)		Apixaban and dabigatran
	B)		Edoxaban and rivaroxaban
	C)		Apixaban and rivaroxaban
	D)		Edoxaban and dabigatran

REVIEW OF CYP450 AND TRANSPORTER INTERACTIONS

Generally, CYP450 interactions and drug transporter interactions involve substrates, inhibitors, and inducers. Inhibitors may increase levels of CYP450 or P-gp substrates, and inducers may decrease levels of CYP450 or P-gp substrates. For many interactions, CYP450 enzyme inhibition or induction is also involved, and P-glycoprotein substrates are often also CYP3A4 substrates, so the contribution of P-gp inhibition/induction versus CYP450 inhibition/induction can be difficult to discern [7,8,9]. For example, apixaban and rivaroxaban are metabolized by CYP3A4 (Table 1), and absorption of all DOACs is affected by P-glycoprotein (Table 2) [2,10].

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4 . Which of the following medications is a strong inhibitor of CYP3A4?

	A)		Nafcillin
	B)		Oxcarbazepine
	C)		Rifabutin
	D)		Voriconazole

REVIEW OF CYP450 AND TRANSPORTER INTERACTIONS

SELECT CYP450-3A4 PATHWAY DRUG INTERACTIONS

DOAC Substrates^c

Select Inhibitors

Select Inducers

Apixaban

Rivaroxaban

Amiodarone

Amlodipine

Atazanavir^a

Cimetidine

Ciprofloxacin^a

Clarithromycin^b

Cobicistat^b

Conivaptan^a

Cyclosporine^a

Diltiazem^a

Dronedarone^a

Erythromycin^a

Ethinyl estradiol

Fluconazole^a

Fluoxetine

Fluvoxamine^a

Fosamprenavir^a

Grapefruit^b

Indinavir^b

Isoniazid

Itraconazole^b

Ketoconazole^b

Lansoprazole

Lopinavir/ritonavir^b

Mifepristone

Nefazodone^b

Nelfinavir^b

Nicardipine

Posaconazole^b

Ritonavir^b

Saquinavir/ritonavir^b

Ticagrelor

Tipranavir/ritonavir^b

Verapamil^a

Voriconazole^b

Voxelotor

Carbamazepine

Modafinil

Nafcillin

Nevirapine

Oxcarbazepine

Phenobarbital

Phenytoin

Rifabutin

Rifampin

Rifapentine

St. John's wort

Topiramate

^aModerate inhibitors (≥2 to <5-fold increase in exposure, or 50% to 80% decrease in clearance of substrate). For many medications, strength of inhibition in vivo is undetermined.

^bStrong inhibitors (≥5-fold increase in exposure or >80% decrease in clearance of substrate)

^cDabigafran is not a substrate, inducer, or inhibitor of CYP450 enzymes. Edoxaban is only minimally metabolized by CYP450.

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5 . Which of the following medications is a strong inducer of P-gp?

	A)		Amiodarone
	B)		Diltiazem
	C)		Erythromycin
	D)		Phenytoin

REVIEW OF CYP450 AND TRANSPORTER INTERACTIONS

SELECT P-GLYCOPROTEIN DRUG INTERACTIONS

DOAC Substrates

Select Inhibitors

Select Inducers^a

Apixaban

Dabigatran

Edoxaban

Rivaroxaban

Amiodarone (moderate or strong inhibitor)

Atorvastatin

Azithromycin

Canagliflozin (weak inhibitor)

Captopril

Carvedilol

Clarithromycin^c (strong inhibitor)

Cobicistat

Conivaptan^b

Cyclosporine^b (strong inhibitor)

Diclofenac

Diltiazem^b

Dronedarone^b (strong inhibitor)

Erythromycin^b (strong inhibitor)

Esomeprazole

Ibuprofen

Indomethacin

Itraconazole^c

Ketoconazole^c (strong inhibitor)

Lansoprazole

Lopinavir/ritonavir^c

Lovastatin

Mirabegron

Naproxen

Nefazodone^c

Nelfinavir^c

Nifedipine

Omeprazole

Posaconazole^c

Propafenone

Quinidine (strong inhibitor)

Quinine

Rabeprazole

Ranolazine

Ritonavir^c

Saquinavir/ritonavir^c

Simvastatin

Spironolactone

Telmisartan

Tetracycline

Ticagrelor

Trimethoprim

Tipranavir/ritonavir^c

Verapamil^b (strong inhibitor)

Vilazodone

Voriconazole (strong inhibitor)

Carbamazepine

Phenobarbital

Phenytoin

Rifabutin

Rifampin

St. John's wort

Venlafaxine

^aAll are strong inducers, except venlafaxine.

^bModerate CYP3A inhibitors

^cStrong CYP3A inhibitors

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6 . Which medication is most likely to decrease levels of a DOAC and increase thrombosis risk?

	A)		Rifampin
	B)		Ritonavir
	C)		Ranolazine
	D)		Ranitidine

MANAGING DOAC INTERACTIONS

Drug experts from Pharmacist's Letter and Prescriber Insights provide the following practical approach to managing DOAC interactions [11]:

Pinpoint critical DOAC interactions, and act if necessary.
Generally avoid combining DOACs with strong CYP3A4 and P-glycoprotein inducers (e.g., phenytoin, rifampin, St. John's wort). These may lower DOAC levels and increase thrombosis risk.
If these interacting medications cannot be avoided, switch to warfarin, because it is easier to monitor than a DOAC.
Watch for strong CYP3A4 and P-glycoprotein inhibitors (e.g., ritonavir, itraconazole), as these may raise DOAC levels and increase bleeding risk.

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7 . Which of the following medications is most likely to raise levels of a direct oral anticoagulant (DOAC) and increase bleeding risk?

	A)		Itraconazole
	B)		Levofloxacin
	C)		Phenytoin
	D)		Ranitidine

MANAGING DOAC INTERACTIONS

Drug experts from Pharmacist's Letter and Prescriber Insights provide the following practical approach to managing DOAC interactions [11]:

Pinpoint critical DOAC interactions, and act if necessary.
Generally avoid combining DOACs with strong CYP3A4 and P-glycoprotein inducers (e.g., phenytoin, rifampin, St. John's wort). These may lower DOAC levels and increase thrombosis risk.
If these interacting medications cannot be avoided, switch to warfarin, because it is easier to monitor than a DOAC.
Watch for strong CYP3A4 and P-glycoprotein inhibitors (e.g., ritonavir, itraconazole), as these may raise DOAC levels and increase bleeding risk.

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8 . Which of the following statements regarding DOAC interactions with nirmatrelvir/ritonavir is TRUE?

	A)		All DOACs should be held during treatment with nirmatrelvir/ritonavir.
	B)		Nirmatrelvir/ritonavir may be a concern with DOACs because it inhibits CYP3A4 and P-gp.
	C)		DOAC doses should generally be increased during treatment with nirmatrelvir/ritonavir.
	D)		Nirmatrelvir/ritonavir may be a concern with DOACs because it induces CYP1A2 and P-gp.

MANAGING DOAC INTERACTIONS

To manage these drug interactions, consider the specific DOAC, dose, and indication (Table 3). One example that blends consideration of these factors is use of nirmatrelvir/ritonavir for treatment of COVID-19 in patients receiving a DOAC. This combination introduces potential risk for drug interactions, because ritonavir is a strong CYP3A4 and P-glycoprotein inhibitor. For instance, when a patient is receiving nirmatrelvir/ritonavir for COVID-19, apixaban being given for atrial fibrillation should be reduced to 2.5 mg twice per day during treatment and for three days after. However, coadministration of nirmatrelvir/ritonavir and rivaroxaban should be avoided [12].

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9 . What is advised for patients receiving apixaban for venous thromboembolism treatment if a strong CYP3A4 and P-gp inducer is required?

	A)		Reduce the apixaban dose by 50%.
	B)		Change apixaban to rivaroxaban.
	C)		Change apixaban to warfarin.
	D)		Continue apixaban at the standard dose.

MANAGING DOAC INTERACTIONS

COMPARISON OF DOACs

Drug

Approved Indications and Dosing (Adults)

Select Interactions

Apixaban (Eliquis)

Thromboembolism (e.g., stroke) prevention in nonvalvular atrial fibrillation: 5 mg BID or 2.5 mg BID for patients with ≥2 of the following:

Age ≥80 years
Weight ≤60 kg
Serum creatinine ≥1.5 mg/dL

VTE prevention post-hip or knee replacement: 2.5 mg BID for 35 days (hip) or 12 days (knee) starting 12 to 24 hours post-operative

DVT/PE treatment: 10 mg BID for seven days, then 5 mg BID

DVT/PE prevention of recurrence: 2.5 mg BID after at least six months of treatment

Atrial fibrillation: A reasonable anticoagulant choice for patients with CrCl <15 mL/min or on dialysis

Reduce dose by 50% with strong inhibitors of both CYP3A4 and P-gp (e.g., itraconazole, ketoconazole, ritonavir). Avoid in patients already taking 2.5 mg BID. Resume usual dose three days after the last dose of nirmatrelvir/ritonavir (Paxlovid).

Avoid strong inducers of both CYP3A4 and P-gp (e.g., phenobarbital, carbamazepine, phenytoin, St. John's wort, rifampin).

Caution with antiplatelets and anticoagulants.

Dual antiplatelet therapy about doubles bleeding risk.

Dabigatran (Pradaxa)

Thromboembolism (e.g., stroke) prevention in nonvalvular atrial fibrillation: 150 mg BID

DVT/PE treatment (following 5 to 10 days' treatment with a parenteral anticoagulant) or prevention of recurrence: 150 mg BID. Start 0 to 2 hours before the next dose of parenteral anticoagulant would have been due, or at the time of discontinuation of heparin drip.

VTE prevention post-hip replacement: 220 mg once daily for 28 to 35 days. If started on day of surgery (1 to 4 hours post-surgery, assuming hemostasis achieved), initial dose is 110 mg.

Atrial fibrillation: Use 75 mg BID if CrCl 15 to 30 mL/min. No dosing information for CrCl <15 mL/min or dialysis.

DVT/PE treatment/prevention (adults) and VTE prevention post-hip replacement: No dosing information for CrCl ≤30 mL/min or dialysis

P-gp inhibitors may increase dabigatran levels.

For atrial fibrillation indication: Avoid P-gp inhibitors (e.g., amiodarone) if CrCl <30 mL/min. Reduce dose to 75 mg BID with ketoconazole or dronedarone if CrCl 30–50 mL/min.

For VTE/PE treatment/prevention (including post-hip replacement): Avoid use of P-gp inhibitors if CrCl <50 mL/min. Consider separating by several hours if CrCl ≥50 mL/min (hip replacement indication).

P-gp inducers could decrease dabigatran efficacy. Avoid P-gp inducers per labeling.

Use caution with antiplatelets. Co-administration with aspirin or clopidogrel about doubles bleeding risk.

Drugs that increase gastric pH could reduce efficacy. Take dabigatran at least two hours before antacids.

Edoxaban (Savaysa)

Thromboembolism (e.g., stroke) prevention in nonvalvular atrial fibrillation: 60 mg once daily in patients with CrCl 50 to ≤95 mL/min

DVT/PE treatment (following 5 to 10 days' treatment with a parenteral anticoagulant): 60 mg once daily, or 30 mg once daily if body weight ≤60 kg

Atrial fibrillation: 60 mg once daily for CrCl 50 to ≤95 mL/min, or 30 mg once daily for CrCl 15–50 mL/min. Not for use in patients with CrCl 95 mL/min.

DVT/PE treatment: 30 mg once daily for CrCl 15–50 mL/min (after 5 to 10 days of parenteral anticoagulant)

Not recommended if CrCl <15 mL/min

Use with other anticoagulants is not recommended, except when switching.

Caution with antiplatelets. Can use with aspirin ≤100 mg/day, with caution.

Avoid rifampin (a P-gp inducer).

Reduce dose to 30 mg once daily for DVT/PE indication in patients taking certain P-gp inhibitors (e.g., azithromycin, clarithromycin, erythromycin, itraconazole [oral], ketoconazole [oral], quinidine, verapamil).

Rivaroxaban (Xarelto)

VTE prevention post-hip or knee replacement: 10 mg once daily for 35 days [hip] or 12 days [knee] starting 6 to 10 hours post-surgery, assuming hemostasis achieved. Avoid if CrCl <15 mL/min.

Thromboembolism (e.g., stroke) prevention in nonvalvular atrial fibrillation: 20 mg once daily with evening meal to improve absorption. Dose is 15 mg with evening meal for CrCl ≤50 mL/min. Consider rivaroxaban 10 mg or 15 mg once daily in patients undergoing hemodialysis based on pharmacokinetic and limited clinical outcome data.

DVT/PE treatment or prevention of recurrence: 15 mg BID (with food to improve absorption) for three weeks, then 20 mg once daily with food for at least six months, then 10 mg once daily. Avoid if CrCl <15 mL/min.

VTE prevention in acutely ill medical patients at risk for VTE but without high risk of bleeding: 10 mg once daily for 31 to 39 days. Avoid if CrCl <15 mL/min.

Cardiovascular risk reduction in patients with CAD or PAD: 2.5 mg BID, with aspirin 75–100 mg once daily. (Patients with eGFR <15 mL/min were excluded from clinical trial, and <1% of included patients had eGFR <30 mL/min.)

Avoid use with drugs that are both P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, posaconazole, ritonavir, cobicistat).

In patients with CrCl 15 to <80 mL/min, the decision to use a combined P-gp/moderate CYP3A4 inhibitor (e.g., erythromycin) is a risk/benefit determination. Avoid with amiodarone or verapamil if CrCl is <80 mL/min.

Drugs that are P-gp and strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) may decrease efficacy and should be avoided.

Avoid use with other anticoagulants. Caution with antiplatelets, including clopidogrel.

BID = twice per day, CAD = coronary artery disease, CrCl = creatinine clearance, DVT = deep vein thrombosis, eGFR = estimated glomerular filtration rate, PAD = peripheral arterial disease, PE = pulmonary embolism, VTE = venous thromboembolism.

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10 . What is generally advised for patients receiving apixaban for stroke prevention in atrial fibrillation and aspirin for cardiovascular primary prevention?

	A)		Continue apixaban and aspirin.
	B)		Stop aspirin.
	C)		Change aspirin to clopidogrel.
	D)		Reduce the apixaban dose by 50%.

MANAGING DOAC INTERACTIONS

Caution should be exercised when prescribing DOAC and medications that increase the risk of bleeding (e.g., antiplatelets, non-steroidal anti-inflammatory drugs [NSAIDs]). Ensuring the need for both agents is the first step. For example, aspirin used for cardiovascular primary prevention can usually be discontinued; aspirin for cardiovascular primary prevention is no longer routinely recommended, regardless of DOAC use [13; 14]. Duration of combination therapy is another concern. For instance, clopidogrel can be discontinued one-year post-stent placement for most patients with atrial fibrillation on a long-term DOAC. Limited evidence suggests that DOAC monotherapy is often sufficient at this point [15].

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