Anticoagulants

Drug interaction

1. Directly acting oral anticoagulants
• 1.1 Direct thrombin inhibitors: a) divalent drugs (Bivalirudin) and b) monovalent drugs (Argatroban and Dabigatran)
• 1.2 Direct factor Xa inhibitors: Apixaban, Edoxaban, Rivroxaban

2. Synthetic pentasaccharide inhibitors of factor Xa: Fonfaparinux

3. Heparin and derivative substances
• 3.1 Unfractiones heparin
• 3.2 Low molecular weight heparin: Bemiparin, Dalteparin, Enoxaparin, Nadroparin, Tinzaparin

4. Vitamin K antagonists: acenocoumarol, phenprocoumon, warfarin

General interactions

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
- Alcohol
- Anticoagulants
- Antiplatelet agents
- dextran
- Dipyridamole
- Sulfinpyrazone
- Thrombolytics
Increase the risk of bleeding.Close observation for signs and symptoms of bleeding is recommended
Edoxaban can be co-administered with low dose ASA (≤ 100 mg/day).
Aspirin, and NSAIDSIncrease the risk of bleeding. A 50-60% increase in anti-FXa activity when apixaban was coadministered with enoxaparin or naproxen. Close observation for signs and symptoms of bleeding is recommended
Edoxaban can be co-administered with low dose ASA (≤ 100 mg/day).
Selective serotonin re-uptake inhibitors (SSRIs)
Selective serotonin norepinephrine re-uptake inhibitors (SNRIs)
Increase the risk of bleeding.Close observation for signs and symptoms of bleeding is recommended
Edoxaban can be co-administered with low dose ASA (≤ 100 mg/day).

1. Directly acting oral anticoagulants


1.1 Direct thrombin inhibitors

Argotraban

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AlcoholArgatroban contains ethanol; possible interaction with metronidazole or disulfiram.

Dabigatran

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AmiodaroneIncreases the risk of bleedingAmiodarone inhibits CYP 2C9, 2D6 and 3A4, and P-gp and increases plasma concentration of dabigatran (50-60%)With caution
- Antiacids
- Histamine H2-receptor antagonists
- Proton pump inhibitors
Reduce the absorption and exposure of dabigatran (12-30%)Monitor the drug response
Antipletelet drugsIncreases the risk of bleeding
Azole antifungals:
- Itraconazole
- Ketoconazole
- Posaconazole
- Voriconazole
Potent inhibitors of P-gp/BCRP and CYP 3A4 . Increase dabigatan plasma levels (145%)Avoid the combination
ClarithromycinClose monitoring, particularly in patients with mild-moderate renal impairment.
DronedaroneInhibits CYP3A4 and P-gp and markedly increase dabigatran plasma levels Avoid the combination
Immunusuppessive drugs:
- Ciclosporin
- Tacrolimus
Inhibit P-gp. Increase dabigatran plasma levelsAvoid the combination
KetoconazoleAvoid the combination
Macrolides:
- Clarithromycin
- Erythromycin
Inhibit CYP3A4 and increase dabigatran plasma levels (15-20%)With caution
NSAIDsIncreases the risk of bleeding
PosaconazoleIncreases the risk of bleedingIncreases dabigatran plasma levels
Potent dual inducers of CYP3A4 and P-gp:
- Carbamazepine
- Phenobarbital
- Phenytoin
- Rifampicin
- St John´s worth
Increase the risk of stroke and other thromboembolic eventsThey are P-gp/BCRP and CYP 3A4 and 2J2 inducers. Decrease exposure to dabigatran (60%)Avoid the combination
Potent P-gp inhibitors:
- Quinidine
Increase dabigatran exposure and the risk of bleedingClose clinical surveillance is recommended
Separate the administration of dabigatran and the P-gp inhibitor by several hours
P-gp inducers:
- Rifampin
- St. John´s wort
Decrease dabigatran exposure
QuinidineIncreases dabigatran plasma levels (50%)Caution. No reduction of dose required
VerapamilIncreases the risk of bleedingIncreases dabigatran plasma levels (12-180%)Reduce the dose of dabigatran.
No interaction when verapamil was given 2 h after dabigatran etexilate, because at this time dabigatran absorption has been completed

Dabigatran etexilate and dabigatran are not metabolised by the cytochrome P450 system; thus, related medicinal product interactions are not expected with dabigatran


1.2 Direct factor Xa inhibitors

Apixaban

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Azole antifungals:
- Itraconazole
- Ketoconazole
- Posaconazole
- Voriconazole
Potent inhibitors of P-gp/BCRP and CYP 3A4 . Increase apixaban plasma levels (105%)Avoid the combination
DiltizemIncreases apixaban plasma levels (40%)With caution
HIV-protease inhibitors:
- Ritonavir
They are P-gp/BCRP inducers and CYP 3A4 inhibitors. Markedly increase the apixaban plasma levelsWith caution
NaproxenCompetes with P-gp and increases apixaban plasma levels (50%)With caution
Potent inhibitors of both CYP3A4 and P-gp.Increasethe exposure to apixaban Avoid the combination if possible
Potent dual inducers of CYP3A4 and P-gp:
- Carbamazepine
- Phenobarbital
- Phenytoin
- Rifampicin
- St John´s worth
Increase the risk of stroke and other thromboembolic eventsThey are P-gp/BCRP and CYP 3A4 and 2J2 inducers. Decrease exposure to apixaban (50%)Avoid the combination

Edoxaban

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AmiodaroneAmiodarone inhibits CYP 2C9, 2D6 and 3A4, and P-gp. Increases edoxaban plasma levels (40%)Monitor the drug effect.
Azole antifungals:
- Itraconazole
- Ketoconazole
- Posaconazole
- Voriconazole
Potent inhibitors of P-gp/BCRP and CYP 3A4 . Increase edoxaban plasma levels (85%)Reduce the dose of rivaroxaban by 50%. With caution
DronedaroneIncreases edoxaban plasma levels (85%)Reduce the dose of edoxaban (50%)
Immunusuppessive drugs:
- Ciclosporin
- Tacrolimus
Inhibit P-gp. Increase edoxaban plasma levels (73%)With caution
Macrolides:
- Clarithromycin
- Erythromycin
Inhibit CYP3A4 and increase edoxaban plasma levels (90%)Reduce the dose of edoxaban (50%)
Potent dual inducers of CYP3A4 and P-gp:
- Carbamazepine
- Phenobarbital
- Phenytoin
- Rifampicin
- St John´s worth
Increase the risk of stroke and other thromboembolic eventsThey are P-gp/BCRP and CYP 3A4 and 2J2 inducers. Decrease the plasma levels of edoxaban 350%)With caution. Monitor closely the patient
Potent inhibitors of both CYP3A4 and P-gp:
- Quinidine
- Verapamil
Increase the exposure to apixaban Avoid the combination if possible
Potent P-gp inhibitors:
- Ciclosporin
- Dronedarone
- Erythromycin
- Ketoconazole
- Quinidine
- Verapamil
Increase plasma levels of edoxaban and the risk f bleedingReduce the dose of edoxaban to 30 mg od.
QuinidineIncreases dabigatran plasma levels (70%)Caution. No reduction of dose requiered
Strong dual inducers of CYP3A4 and P-gpDecrease exposure to apixaban and increase the risk of stroke and other thromboembolic events Avoid the combination if possible
VerapamilIncreases dabigatran plasma levels (50%)Increases dabigatran plasma levels (50%) No dose reduction required by label

No dose modification is necessary when edoxaban is administered with digoxin, quinidine or proton-pump inhibitors


Rivaroxaban

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
AmiodaroneAmiodarone inhibits CYP 2C9, 2D6 and 3A4, and P-gp. Increases rivaroxaban plasma levelsMinor effect. Use with caution if CrCl <50 ml/min
Azole antifungals:
- Itraconazole
- Ketoconazole
- Posaconazole
- Voriconazole
Potent inhibitors of P-gp/BCRP and CYP 3A4 . Increase apixaban plasma levels (150%)Avoid the combination
FluconazoleInhibits CYP3A4 and increases rivaroxaban plasma levels (40%) is systemically administeredWith caution
HIV-protease inhibitors:
- Ritonavir
They are P-gp/BCRP inducers and CYP 3A4 inhibitors. Markedly increase the apixaban plasma levels (150%)With caution
Macrolides:
- Clarithromycin
- Erythromycin
Inhibit CYP3A4 and increase dabigatran plasma levels (30-50%)With caution
Strong inhibitors of both CYP3A4 and P-gp:
- Azole-antimycotics: Fluconazole, Ketoconazole, Posaconazole, Voriconazole
- HIV inhibitors: Indinavir, Lopinavir, Ritonavir
- Macrolides: Erythromycin, Clarithromycin
- Quinidine
- Verapamil
Increase the exposure to apixaban Avoid the combination if possible
Potent dual inducers of CYP3A4 and P-gp:
- Carbamazepine
- Phenobarbital
- Phenytoin
- Rifampicin
- St John´s worth
Increase the risk of stroke and other thromboembolic eventsThey are P-gp/BCRP and CYP 3A4 and 2J2 inducers. Decrease the plasma levels of rivaroxaban (50%)Avoid the combination
DiltiazemUse with caution if CrCl is 15-50 ml/min
DronedaroneIncreases rivaroxaban plasma levelsWith caution and try to avoid the combination
VerapamilUse with caution if CrCl is 15-50 ml/min

No interactions with ranitidine, antacid aluminum hydroxide/magnesium hydroxide, atorvastatin, digoxin, midazolam or omeprazole


2. Synthetic pentasaccharide inhibitors of factor Xa: Fonfaparinux

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Anticoagulants
Alprostadil
Antiplatelet agents
Aspirin
Dextran
Dipyridamole
Iloprost
NSAIDs
Prostacyclin
Thrombolytics
Warfarin
Increase the risk of bleedingCo-administration should be undertakenunder close monitoring of the patient

3. Heparins

3.1. Unfractiones heparin (UFH)

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Alcohol Heavy drinkers were at greater risk of major heparin-associated bleeding than moderate drinkers or non-drinkersMay increase the risk of bleeding
AspirinAnti-platelet effect of aspirin is substantially reduced after administration of heparin during carotid endarterectomyCertain patients are at increased risk for acute cardiovascular events after major vascular surgery, despite aspirin therapy
BenzodiazepinesUFH displaces the benzodiazepines from plasma proteins and increase their effects Use with caution. Use lorazepam
Cephalosporins:
- Cefaclor
- Cefixim
- Ceftriaxone
They may increase the risk of bleeding when used concurrently with heparin.Monitor the patient for signs of bleeding. Readjust the dose of UFH
Digitalis Digitalis may interfere with the anticoagulant action of heparin, reducing its actionMonitor the APTT
Drugs that can counteract the effect of UFH:
- Digoxin
- Epopoetin
- Tetracyclines
Careful monitoring of aPPT and adjustment of heparin dosage are recommended.
Drugs that increase the risk of bleeding:
- Alprostadil
- Anticoagulants
- Antiplatelet agents
- Dextrans
- Dipyridamole
- Iloprost
- NSAIDs
- Prostacyclins
- Thrombolytics
- Warfarin
Interfere with platelet aggregation which increases the risk of bleedingThese drugs should be used with caution in patients receiving heparin. Monitor APTT for signs of hemorrhage and heparin dosage may be need to be reduced duribng concurrent use to prevent bleeding.
When UFH is given with dicumarol or warfarin, a period of at least 5 h after the last IV dose should elapse before blood is drawn to determine the PT
FluvoxamineIncrease INRWith caution
Glyceryl trinitrate
The activity of UFH is reduced when combined with IV glyceryl trinitrate infusion.Monitor the clinical response
Herbal medicines:
- Dasshen
- Dong quai
- Feverfew
- Garlic
- Ginger
- Ginkgo
- Horse chesnut
Herbs produce platelet dysfunction and increase bleeding tendencyPeople taking heparin should consult with a physician knowledgeable about botanical medicines.
K supplements
K salts
Heparin may cause hyperkalemiaRisk of hyperkalemia
NicotineIt may partially counteract the anticoagulant effect of heparinIncreased heparin dosage may be required in smokers.
Nitroglycerin, i.v In some studies, nitroglycerin may reduce the activity of heparin when both drugs are administered simultaneously by the intravenous routeMonitor patients closely to ensure anticoagulation. When nitroglycerin therapy is stopped, a decrease in heparin dosage may be necessary
Oral anticoagulantsOral anticoagulants can contribute to an increase in APTT and heparin to an increase in PT.When both drugs are given together a period of at least 5 hours after the last i.v. dose or 24 hours after the last s.c. dose should elapse before a valid PT is to be obtained.
RAAS inhibitorsIncreased risk of hyperkalaemiaMonitor serum potassium levels
StreptokinasePatients treated with streptokinase appear to be partially resistent to the anticoagulant effects of heparin Use higher doses of heparin and more frequent dose adjustements if streptokinase is given
SulphonilureasIncreased risk of hypoglycaemiaCoadministration with caution. Monitor the APTT
Tabaco Smoking activates thrombosisReduced half-life and increased elimination of heparin in smokersAumentar la dosis de heparina
TenecteplaseTenecteplase may attenuate the intensity of anticoagulation of UFH in vitroMonitor the APTT
Vitamine D Heparin may interfere with activation of vitamin D in the bodyOsteoporosis has been reported in patients receiving high doses of heparin for several months
Drugs incompatible with heparin:
- Alteplase
- Amikacin
- Amiodarone
- Ampicillin
- Aprotinin
- Cephalotin
- Ciprofloxaci
- Cytarabine
- Daunorubicin
- Diazepam
- Dobutamine
- Doxorrubicin
- Droperidol
- Erythromycin
- Gentamicin
- Haloperidol
- Hyaluronidase
- Hydrocortisone
- Kanamycin
- Methicillin
- Nesiritide
- Netilmicin
- Opiod analgesics
- Oxytetracycline
- Some phenothiazines
- Polymyxin
- Streptomycin
- Tetracycline
- Tobramycin
- Vancomycin
- Vinblastine
They may form a precipitate:Heparin sodium Injection should not be mixed with these drugs

3.2 Low-molecular weight heparins

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Anticoagulants
- Alprostadil
- Antiplatelet agents
- Dextran
- Dipyridamole
- Iloprost
- NSAIDs
- Prostacyclin
- Thrombolytics
- Warfarin
Increase the risk of bleedingConcomitant use should be undertaken with caution

4. Vitamine K antagonists (Warfarin)

DrugPharmacodynamic interactionPharmacokinetic interactionsCautions
AcarboseIncreases the risk of bleedingPossibly by increasing warfarin absorptionMonitor INR following initiation or discontinuation of acarbose
Adenosine diphosphate (ADP) receptor inhibitors:
- Cangrelor
- Clopidogrel
- Prasugrel
- Ticagrelor
- Ticlopidine
Inhibit platelet aggregation and increase the risk of bleeding Inhibit the CYP2C9 enzyme systemThis combination should be avoided, unless the potential benefit outweighs the risk of bleeding. Monitor the INR closely and patients should report any signs or symptoms for inappropriate bleeding
AlcoholIncreases/decreases the INRThe acute ingestion of large amounts of alcohol may inhibit the metabolism of warfarin and increase INR. Chronic heavy alcohol intake may induce the metabolism of warfarinModerate alcohol intake can be permitted.
AllopurinolPotentiates the effect of warfarin and increases the risk of bleeding Allopurinol inhibits the hepatic metabolism of VKAs and prolong their half-livesMonitor INR in patients on an VKAs when allopurinol is first added.
AmiodaronePotentiates the effect of warfarin and increases the risk of bleeding. Patients who develop hyperthyroidism secondary to amiodarone may have an increased anticoagulant effectAmiodarone and desethylamiodarone, its active metabolite, inhibit CYP2C9 and CYP3A4 and increases plasma warfarin levelsThe dosage of warfarin should be reduced. The interaction begins within 2 weeks and may persist for 6-16 weeks after the withdrawal of amiodarone. The possibility of amiodarone-induced thyrotoxicosis should be considered if an abrupt increase in INR occurs
Anabolic steroids:
- Medroxyprogesterone
- Methandienone
- Methyltestosterone
- Methandrostenolone
- Nandrolone
- Oxandrolone
- Oxymetholone
- Stanozolol
- Testosterone
Increase the risk of bleeding.
Testosterone suppresses clotting factors IIa, Va, VIIa and Xa.
Reduce the synthesis and/or increase the metabolic destruction of blood clotting factors This combination should be avoided if possible. The INR should be closely monitored and reassessed periodically during concurrent therapy. It might be necessary to reduce the dose of VKAs
Anticancer drugs:
- Azathioprine
- Mercaptopurine
- Mesna
- Mitotane
These drugs increase the synthesis of prothrombin and antagonise the effect of warfarin
Probably inhibit warfarin absorption and induces its metabolismMonitor closely the INR. Adjustments of the warfarin dose may be necessary during concurrent therapy.
Anticancer drugs:
- Capecitabine
- Carboplatin
- Cyclophosphamide
- Doxorubicin
- Erlotibib
- Etoposide
- 5-flurouracil
- Gefitinib
- Gemcitabine
- Ifosfamide
- Imatinib
- Mesna
- Methotrexate
- Nilotinib
- Procarbazine
- Vincristine
- Vindesine
Potentiate the effect of warfarin and increase the risk of bleeding.
Multiple mechanisms: poor appetite, vomiting and alterations in the gastrointestinal mucosa that can alter the absorption of VKAs
Probably decrease the activity and/or inhibit the activity of CYP 2C9 and 2D6 enzymes responsible of warfarin metabolism and the synthesis of clotting factorsMonitor closely the INR. Adjustments of the warfarin dose may be necessary.
Patients who require anticoagulation should receive low-molecular weight or standard heparin.
Anticoagulants:
- Direct thrombin inhibitors: Bivalirudin, Dabigatran
- Fondaparinux
- Low-molecular-weight heparins
- Non-vitamin K Non oral anticoagulants: Apixaban, Dabigatran, Edoxabann Ribaroxaban
- Unfractionated heparin
Increases the risk of bleeding. Additive anticoagulant effectAnticoagulants should not be used concurrently with warfarin unless the potential benefit outweighs the risk of bleeding. Caution should be exercised when warfarin is administered concomitantly. Close clinical (for external bleeding and signs and symptoms of internal bleeding) and laboratory monitoring is advised.
Antidiabetics:
- Tolbutamide
Increases the risk of bleedingDicumarol inhibits the metabolism and increases the exposure to tolbutamideAvoid the combination. Monitor the INR if both drugs are coadministered.
Antiestrogens:
- Tamoxifen
- Toremifene
Potentiates the effect of warfarin and increases the risk of bleeding Tamoxifen is contraindicated with concomitant VKAs in women with breast cnacer on tamoxifen. When concurrent therapy with antiestrogens and warfarin is justified, the INR should be closely monitored
Antithyroid agents:
- Carbimazole
- Dextrothyroxine
- Methimazole
- Methylthiouracil
- Propylthiouracil
Decrease the anticoagulant effectiveness and increase warfarin requirementsDecrease the metabolism of clotting factors Hypothyroid patients are relatively resistant to VKAs and higher doses of VKAs may be required to maintain the desired level of anticoagulation.. Monitor the INR.
If the thyroid status of the hyperthyroid patients is normalized an increase in VKA dosage would be expected.
Thyroid hormones increase the affinity of VKA for their binding sites and increase the metabolism of vitamin K-depending clotting factors.
Hypothyroidism reduces the catabolism of blood clotting fators II, VII, IX and X
INR should be closely monitored and reassessed periodically during concurrent therapy. Warfarin dose should be adjusted to maintain the desired level of anticoagulation.
AprepitantDecreases the PT/INRInduces cytochrome P450 2C9-mediated metabolism of S(-) warfarinThe INR should be monitored
Aromatase inhibitors:
- Aminoglutethimide
Reduce the effects of VKAsIncrease the hepatic metabolism and clearance of VKAsINR should be monitored and the dose of VKAs increased to maintain the desired level of anticoagulation.
Anastrozole and letrozole do not interact with warfarin.
AspirinInhibits platelet aggregation and has a direct irritant effect on the stomach. At high doses, it has a direct hypoprothrombinaemic effect. Thus, aspirin can be additive with the effects of VKA and increases the risk of bleeding.Displaces warfarin from plasma albumin and inhibits its metabolismThe combination should be avoided whenever possible. If given together, carefully monitor the INR and watch the patient for signs of bleeding, especially in the gastrointestinal tract. Adjustments of the VKA dose may be necessary in order to maintain the desired level of anticoagulation. Non-acetylated salicylates or acetaminophen are alternatives for analgesia
AtenololIncreases the INRUse caution if atenolol and warfarin are used concomitantly
AzathioprineAntagonise the effect of warfarinInhibits warfarin absorption and enhances its metabolismMonitor the INR
Azole anifungals:
- Fluconazole
- Itraconazol
- Ketoconazole
- Miconazole
- Voriconazole
Potentiate the effect of warfarin and increase the risk of bleeding
They inhibit cytochrome P450 CYP2C9 and CYP2C9 involved in the warfarin metabolismThe INR should be closely monitored. Adjustment of the dose of VKA may be necessary to maintain the desired level of anticoagulation.
BarbituratesAntagonise the effect of warfarinInterfere with intestinal absorption of dicumarol and are potent CYP enzyme inducers increasing the metabolism of VKAINR should be closely monitored. The dose of VKA must be increased (30- 60%). If the barbiturate is later withdrawn, the VKA dosage should be reduced to avoid the risk of bleeding. Alternative non-interacting sedatives include nitrazepam, diazepam, and flurazepam
BenzbromaroneIncreases the risk of bleeding.Inhibits CYP2C9 and the metabolism of (S)-warfarin INR should be closely monitored. The dose of warfarin should be reduced approximately 30%
BicalutamideIncrease the risk of bleedingBicalutamide can displace coumarin anticoagulants from binding sites.Monitor the INR
Bile-acid binding resins:
- Cholestyramine
- Colesevelam
- Colestipol
Reduces the effects of VKAsColestyramine decreases the absorption of vitamin K and may interrupt the enterohepatic recirculation of VKAs. Colestipol does not alter the absorption of or effect of phenprocoumon or warfarin. Colestipol does not interact with warfarinPatients taking warfarin should not receive cholestyramine concurrently. Give the resin 3 hours before or 3 and 6 hours after the warfarin dose minimizes the interaction. Colesevelam or colestipol are an alternative to cholestyramine.
Calcium channel blockers (CCBs)Some CCBs exhibit antiplatelet effectsDiltiazem and verapamil inhibit CYP3A4 and slightly decrease the metabolism of warfarinNo special precaution would be needed.
CarbamazepineReduces the anticoagulant effect of warfarin
Carbamazepine increases the hepatic metabolism of warfarinThe INR should be closely monitored. It may be necessary to increase the dose of warfarin if coadministered with carbamazepine; a reduction in the dose of warfarin is frequently required upon the discontinuation of carbamazepine. Stabilization of the warfarin dosage and anticoagulant effect may require four to six weeks. Oxcarbazepine appears to be a relatively non-interacting alternative.
CarbimazoleReduces the anticoagulant effect of VKAsDecreases the metabolism of clotting factorsIncreased anticoagulant doses may be required to maintain the desired level of anticoagulation
Cephalosporins:
- Cefalexin
- Cefalotin
- Cefamandole
- Cefazolin
- Cefminox
- Cefoperazone
- Cefotetan
- Cefpiramide
- Ceftriaxone
- Cefuroxime
Cephalosporins with an N-methylthiotetrazole side-chain inhibit platelet function and decrease the synthesis of vitamin K-dependent clotting factors. The may increase the risk of bleeding.They reduce the gut flora which produce vitamin K The INR should be closely and regularly monitored. Adjustment of the warfarin dosage is frequently necessary.
ChloramphenicolIncreases the risk of bleedingInhibits hepatic metabolism and decreases vitamin K production by bacteria in the gut. It may increase the half-life of bishydroxycumarinAvoid the use of chloramphenicol if possible
CilostazolIncreases the risk of bleeding. Additive anticaugulant effectAvoid the combination
Coenzyme QReduces the anticaogulant effect. Chemical similarity between coenzyme Q10 and vitamin K2Avoid the combination
COMT inhibitors:
- Entacapone
Increase the INR valuesIncreases the AUC for R-warfarin by 18%Uncertain clinical relevance. No interaction with tolcapone
Contraceptives
- Ethinyl estradiol
- Etonogestrel
- Levonorgestrel
- Medroxyprogesterone
- Megestrol
- Mestranol
- Norelgestromin
- Norethindrone
- Norgestrel
Antagonise the effect of warfarin. They increase the concentrations of certain clotting factors and fibrinogen and reduce levels of antithrombin III. Decrease the effect of VKAsThey can increase the glucuronidation of phenprocoumon and displace warfarin from its binding sites.Concurrent use should generally be avoided, but if these drugs are used together, monitor the INR closely.
It may require discontinuation of estrogen therapy and/or a higher level of anticoagulation.
CorticosteroidsThey may slightly increase or decrease the effect of VKA. They increase the risk of gastrointestinal ulceration and bleedingClose monitoring of coagulation parameters is recommended if high-doses of corticosteroids
DexmethylphenidateIncreases the risk of bleeding.Inhibits the metabolism of coumarin anticoagulantsConsider reducing the warfarin dose during concomitant therapy
DextropropoxypheneIncreases the risk of bleeding.Inhibits the metabolism of warfarinMay be prudent to monitor the INR during concurrent therapy
DiazoxideIncreases the risk of bleedingDisplaces VKAs from plasma binding sites Monitor the INR. Adjustments in the dose of VKAs may be necessary to maintain the desired level of anticoagulation
DipyridamoleInhibits platelet aggregation and increases the effect of VKAsAvoid the combination.
If they are coadministered, monitor the INR. Adjustments in the warfarin dose may be necessary to maintain the desired level of anticoagulation
DisulfiramPotentiates the effect of warfarin and increases the risk of bleedingIt may chelate the metal ions necessary for the production of thrombin from prothrombin.If the combination is used, the INR should be monitored and dose adjustments made as appropriate
Drugs with adverse effects on hemostasis:
- Anticoagulants
- Heparins
- Heparin derivatives
- NSAIDs
- Platelet antiaggregants
- Prostacyclins analogues
- Thrombolytic drugs
Additive effects. Increase the risk of bleedingAvoid the combination unless the potential benefit outweighs the risk of bleeding.
Close clinical (for external bleeding and signs and symptoms of internal bleeding) and laboratory monitoring is advised.
Endothelin receptor blockers:
- Ambrisentan
- Bosentan
- Sitaxentan
Reduces warfarin efficacy
Bosentan induces CYP3A4, and possibly 2C9 enzymes. Sitaxentan increases the exposure to S-warfarinThe INR should be closely monitored and reassessed periodically during concurrent therapy. Reduce the dose of sitaxentan. Ambrisentan does not present this interaction.
FibratesFibrates may increase the effects of warfarin, prolong the PT/INR and increase the risk of bleedingDisplace warfarin from protein binding sitesThe dose of warfarin should be reduced (30-50%) and the INR should be monitorized
FondaparinuxIncreases the risk of bleeding.This combination should be avoided. Monitor the INR and observe patients for external bleeding and be alert for signs and symptoms of internal bleeding
GlucagonIncreases the anticoagulant effects of VKA of warfarin and the risk of bleeding
Probably decreases liver clotting factor production or increases sensitivity of the VKA for its receptor siteMonitor additive the INR and reduce the dosage of warfarin
GlucosamineIncreased the INRThis combination is not recommended
GlutethimideReduces the anticoagulant effect of warfarin Induces the metabolism of warfarinMonitor the INR. Adjustments of the warfarin dose may be necessary. Benzodiazepines are an alternative hypnotic class without warfarin interactions.
GriseofulvinAntagonise the effect of VKAs
Induce the metabolism of warfarin and reduces its plasma levels Monitor the INR and increase the dose of warfarin to maintain the desired level of anticoagulation.
Histamine H1-receptor antagonists The effects of acenocoumarol may be reduced by loratadine, ebastine, or cetirizineTemporary increases in the dosage of VKA may be required.
Histamine H2-receptor antagonists:
- Cimetidine
- Famotidine
- Nizatidine
- Ranitidine
- Roxatidine
Cimetidine increases the effect of warfarin and the risk of bleeding. Famotidine, ranitidine, nizatidine and roxatidine do not appear to interact with warfarinInhibits hepatic metabolism of (R)-warfarin and increases warfarin levels by 20-30%. Avoid the use of cimetidine in patients treated with warfarin. If given in combination, the INR should be monitored and it may be neccessary to reduce the dose of warfarin.
Famotidine, ranitidine, or nizatidine do not appear to interact with warfarin
Heparins:
- LMW
- Heparinoids
- UFH
Additive anticoagulation
Increases the risk of bleeding.
VKA should be discontinued prior to the initiation of therapy with heparins, unless the potential benefit outweighs the risk of bleeding. If this is not possible, INR should be closely monitored. The increased risk of bleeding with this combination will not be fully reflected by the activated partial thromboplastin time.
Warfarin may initially be given with a heparin in the initial treatment of thrombosis, until the INR is in the correct range.
HIV-protease inhibitors
- Amprenavir
- Atazanavir
- Fosamprevir
- Indinavir
- Nelfinavir
- Ritonavir
- Saquinavir
Atazanavir, fosamprevire, ritonavir and saquinavir increase the risk of bleeding.
Amprenavir, indinavir and nelfinavir can reduce the effects of VKA
Atazanavir, fosamprevire, ritonavir and saquinavir inhibit CYP3A4 (and CYP2C9) and increase serum concentrations of warfarin.
Amprenavir inhibit citochrome P450-induced VKA metabolism
Monitor closely the INR and adjust the dose of warfarin as required.
Hormone antagonists:
- Danazol
- Flutamide
- Tamoxifen
Direct effects on the coagulation and fibrinolytic systems. Increase the risk of bleedingDanazol inhibits the metabolism of warfarinClose monitoring of the INR. Dose reductions of warfarin (30–50%)
Influenza virus vaccineIncreases the risk of bleeding in some patients treated with warfarinMonitor the INR within one to two weeks following the vaccine. Acenocumarol also does not normally interact.
InterferonsMay increase the effect of VKAInterferons reduce the hepatic metabolism of VKAIt would seem prudent to monitor the INR and to reduce the dosage of VKA if necessary.
IsoniazidIncreases the risk of bleedingIt may reduce the hepatic metabolism of VKAMonitor the INR
LaxativesThey can reduce the effect of warfarinThey may reduce absorption of vitamin KIt may be necessary to monitor the INR
LeflunomideIncreases the risk of bleeding Inhibits CYP2C9-mediated metabolism of warfarinClose monitoring of the INR and adjust the warfarin dose accordingly to achieve desired level of anticoagulation
Leucotriene antagonists:
- Zafirlukast
- Zileuton
Increase the effects of warfarin and the risk of bleedingZafirlukast inhibits CYP2C9-mediated warfarin metabolism. Zileuton decreases the clearance of warfarinEven when the clinical significance of this is unclear, the INR should be monitored and the warfarin dose should be adjusted accordingly
LomitapideLomitapide increases the INRLomitapide increases (30%) plasma concentrations of both R(+)- warfarin and S(-)-warfarinMonitor the INR, INR, particularly after any changes in lomitapide dosage
Macrolides:
- Azithromycin
- Clarithromycin
- Erythromycin
- Roxithromycin
- Telithomycin
Potentiate the effect of warfarin and increase the risk of bleeding Inhibit cytochrome P450 isoenzymes and decrease warfarin metabolism INR should be closely monitored. The dose of warfarin should be reduced in order to maintain the desired level of anticoagulation.
MetforminDecreases the effects of phenprocoumonPossibly increases bile excretion of phenprocoumonIncrease the dose of phenprocoumon
MethylphenidatePotentiates the effect of warfarin and increase the risk of bleedingInhibits the metabolism of warfarin Monitor the INR
MetronidazolePotentiates the effect of warfarin and increases the risk of bleedingInhibits the matabolism of (S)-warfarinThe INR should be closely monitored and should be reassessed periodically during concurrent therapy
Nalidixic acidIncreases the risk of bleeding. Displacement of warfarin from protein binding sitesMonitor the INR. Adjustments in the warfarin dose may be necessary to maintain the desired level of anticoagulation
NeomycinIncreases the risk of bleeding.Possible inhibits vitamin K synthesis by the gut flora or reduces the absorption of vitamin KThe INR should be monitored and should be periodically reassessed during concurrent therapy. Warfarin dosage adjustments may be required to maintain the desired level of anticoagulation
NilutamideIncreases the risk of bleeding.Inhibits liver cytochrome P450 isoenzymes and causes a reduction of warfarin metabolismMonitor the prothrombin time (PT) or the INR and adjust the warfarin dose accordingly.
Non-nucleoside reverse transcriptase inhibitors:
- Delavirdine
- Efavirenz
- Etravirine
- Nevirapine
Increase the risk of bleeding.Inhibit the metabolism of warfarin via CYP3A4 and/or 2C9.With caution. Monitor the INR. The dose of warfarin should be increased
NSAIDs (including aspirin and COX-2 specific NSAIDS)NSAIDs inhibit the synthesis of prothrombin and platelet aggregation, and may cause gastric erosion and bleeding, which can further increase the risk of a gastrointestinal bleed when combined with an VKADisplace warfarin from plasma proteins binding sites. They may also decrease VKA mtabolismCaution when VKA are administered concurrently with NSAIDs. INR should be closely monitored and watch patients for signs of bleeding especially from the gastrointestinal tract. Adjustments of the VKA dose may be necessary to maintain the desired level of anticoagulation.
NSAID agents which lack platelet inhibition and acetaminophen can be used in patients requiring only analgesia
Omega-3 fatty acids High doses (4 g/daily) of omega-3 prolong the bleeding time and increase the risk of bleedingPatients receiving anticoagulant therapy should be monitored periodically.
OrlistatReduces the effect of warfarinDecreases vitamin K absorptionThe INR should be monitored
ParacetamolIt may increase the incidence of upper gastrointestinal bleeding.It may compete with the metabolism of R-warfarinSmall doses of paracetamol (up to 3 g weekly) are unlikely to cause important INR rises in patients on VKA, but if larger amounts are taken the INR should be monitored.
PenicillinsAmoxicillin, ampipicillin, carbenicillin, methicillim, talampicillin and ticarcillin may increase the risk of bleeding. Carbenicillin can prolong prothrombin times.
Dicloxacillin, mofloxacin and nafcillin, and possibly amoxicillin reduce the effect of warfarin.
Some penicillins can modify antithrombin III activity, platelet aggregation and the conversion of fibrinogen to fibrin
Nafcillin increases in the metabolism of warfarin by the liver. Broad-spectrum penicillins can potentiate the effect of warfarin by reducing the gut flora which produce vitamin K in the colonInteractions are relatively rare. The INR should be closely monitored in patients treated with cloxacillin, and the dose of VKA adjusted as needed. If the INR cannot be maintained within the desired therapeutic range, alternative antimicrobial therapy is indicated.
Pentosan Polysulfate SodiumIncreases the risk of bleeding. Additive anticoagulant effectClose clinical and laboratory monitoring is advised
PentoxifyllinePentoxifylline, alone and in the presence of VKA, increases the risk of bleedingMonitor the INR. The combination should be avoided because of the potential risk of bleeding
Phenytoin Antagonise the effect of warfarin. Increases the risk of bleeding Warfarin can increase the plasma levels of warfarin. Phenytoin can displace warfarin from protein binding sites and increases its metabolismMonitor the INR. Higher doses of warfarin are required.
Phosphodiesterase 5 (PDE5) inhibitors:
- Sildenafil
- Taladafil
- Verdenafil
Increases nosebleeds in patients with pulmonary hypertension treated with VKAsThere are no PK/PD interaction between (PDE5) inhibitors and VKAs
Platelet antiaggregants:
- Adenosine diphosphate (ADP) P2Y12 receptor inhibitors: Cangrelor, Clopidogrel, Prasugrel, Ticagrelor
- Adenosine reuptake inhibitors: Dipyridamole
- Glycoprotein IIB/IIIA inhibitors: Abciximab, Eptifibatide, Tirofiban
- Phosphodiesterase inhibitors: Cilostazol
- Protease-activated receptor-1 (PAR-1) antagonists: Vorapaxar
They inhibit platelet aggregation and increase the risk of bleeding. Additive anticoagulant effectThis combination should be avoided. The combination should be undertaken with caution and only when the potential benefit outweighs the risk of bleeding. Monitor the PT/INR. Observe patients for external bleeding and be alert for signs and symptoms of internal bleeding.
Warfarin should not be given within seven days of abciximab use
PrimidoneAntagonise the effect of warfarinIncreases warfarin metabolismThe INR should be closely monitored. Adjustments of the warfarin dose may be necessary
PropafenonePotentiates the effect of warfarin and increases the risk of bleedingMay reduce the metabolism of VKAINR should be closely monitored. Warfarin dosage adjustment may be required
PropranololMay increase the risk of bleedingInhibits the metabolism of warfarin and increases plasma levelsMonitor the INR. This interaction has not been described with atenolol, bisoprolol or metoprolol
Prostacyclin and analogues:
- Beraprost
- Epoprostenol
- Iloprost
- Treprostinil
They may increase the risk of pulmonary haemorrhage when combined with warfarin
Prostacyclins inhibits inhibit platelet aggregation
Avoid the combination
Proton pump inhibitors:
- Esomeprazole
- Lansoprazole
- Omeprazole
- Pantoprazole
- Rabeprazole
Omeprazole potentiate the effect of warfarin and increase the risk of bleedingInhibit the hepatic metabolism of (R)-warfarinMonitor the INR and adjust the warfarin dose accordingly.
Pantoprazole does not affect the pharmacokinetics of warfarin
QuetiapineIncreases the risk of bleeding.Inhibits cytochrome P450 3A4 and 2C9INR should be closely monitored. Adjustments of the warfarin dose may be necessary
QuinidineIncreases the risk of bleedingDecreases the synthesis of vitamin K dependent clotting factorsMonitor the INR. Adjustments of the warfarin dose may be necessary
Quinolones:
- Ciprofloxacin
- Enoxacin
- Gatifloxacin
- Gemifloxacin
- Levofloxacin
- Moxifloxacin
- Nalidixic acid
- Norfloxacin
- Ofloxacin
The may suppress vitamin K-producing bacteria in the colon increasing the effects of VKA and the risk of bleedingAre potent inhibitors of the P450 hepatic enzyme system that metabolizes warfarin. Nalidixic acid can displace warfarin from its binding sites on human plasma protein. The first days of treatment the INR should be monitored and adjustments of the warfarin dose may be necessary in order to maintain the desired level of anticoagulation.
RaloxifeneLoss of anticoagulation controlDecreases in the clearance and the volume of distribution) of R- and S-warfarinMonitor the INR
RifabutinAntagonise the effect of warfarinInduces warfarin metabolismDoses of warfarin may need to be increased when rifabutin is given concomitantly
RifamycinAntagonise the effect of warfarinInduces hepatic cytochrome P450 enzymes and increases the metabolism of VKAClosely monitor the INR. Doses of warfarin may need to be increased when rifabutin is given concomitantly
Serotonin-norepinephrine reuptake inhibitors (SNRI):
- Duloxetine
- Levomilnacipran
- Milnacipran
- Venlafaxine
Increase the pharmacological effect of warfarin and the risk of bleeding
Possible inhibition of the metabolism of warfarin by CYP1A2, 2C9, 2C19 y 2D6
Avoid the combination.
Monitor the INR. Adjustments of the warfarin dose may be necessary
Selective serotonin reuptake inhibitors (SSRIs):
- Citalopram,
- Dapoxetine
- Escitalopram
- Fluoxetine
- Fluvoxamine,
- Paroxetine
- Sertraline
Increase the pharmacological effect of warfarin and the risk of bleedingFluvoxamine inhibits the metabolism of warfarin by CYP1A2, 2C9, 2C19 y 2D6
Avoid the combination.
Monitor the INR. Adjustments of the warfarin dose may be necessary
SpironolactoneDecreases VKA effectivenessHypovolemia increases the concentration of clotting factorsMonitor periodically the INR. Adjustments of the warfarin dose may be necessary
Statins:
- Atorvastatin
- Fluvastatin
- Lovastatin
- Pitavastatin
- Pravastatin
- Rosuvastatin
- Simvastatin
In patients treated with VKAs, initiation of treatment or dosage up-titration of statins doses may result in an increase in INR.
Fluvastatin and rosuvastatin can increase the effects of warfarin
Fluvastatin is a weak inhibitor of CYP2C.The INR should be monitored following the initiation of a statin or a change in statin dose. Adjustments of the warfarin dose may be necessary. Atorvastatin, lovastatin, pitavastatin and pravastatin do not appear to interact with warfarin.
With simvastatin also monitor the patient for signs and symptoms of myopathy or rhabdomyolysis.
SucralfateDecreases VKA effectiveness Decreases the absorption of warfarinThe INR should be monitored periodically during concurrent therapy. Adjustments of the warfarin dose may be necessary.
SulfamethoxazolePotentiates the effect of warfarin and increases the risk of bleeding
SulfasalazineDecreases VKA effectivenessWarfarin resistance may occur due to this interaction. The INR should be closely monitored and reassessed periodically and adjustments of the warfarin dose may be necessary.
Sulfinpyrazone Increases the effects of VKA and the risk of bleedingDisplaces VKA from their plasma protein binding sites and inhibits the metabolism of (S)-warfarin via CYP2C9.Monitor the INR and reduce the dosage of VKA as needed
Sulfonamides:
- Sulfisoxazole
- Sulfamethoxazole+trimwtroprim
- Sulfametizole
- Sulfaphenazole
Increase the effects of VKA and the risk of bleeding
Sulfonamides reduce the intestinal bacterial synthesis of vitamin K, inhibit the hepatic metabolism of S-warfarin and displace VKA from plasma protein binding sitesThe INR should be closely monitored and the VKA dosage reduced appropriately to maintain the desired level of anticoagulation.
Sulfonilureas:
- Clorpropamide
- Glipizide
- Glyburide
- Tolbutamide
Increase the effects of VKA and VKA increase the hypoglycaemic effects of sulfonilureasDicoumarol inhibits the hepatic metabolism of tolbutamide and increases its effects. Tolbutamide can displace dicumarol from plasma proteinsMonitor the INR and adjustments of the warfarin dose may be necessary. Patients receiving warfarin and glipizide concurrently should be monitored closely for hypoglycemia.
The combination of dicoumarol with tolbutamide, may result in diabetic coma and serious bleeding
Tetracyclins:
- Dicloxacillin
- Doxycycline
- Oxytetracycline
- Tetracycline
- Tigecycline
Reduce plasma prothrombin activity, presumably by reducing plasa prothrombin activityThey can potentiate the effect of warfarin by reducing the gut flora which produce vitamin K in the colon. Tigecycline decreases the metabolism of warfarin and increases its plasma levelsMonitor the INR with the addition or withdrawal of tetracyclins. Adjustments in the warfarin dose may be necessary to maintain the desired level of anticoagulation
ThiazidesMay decrease the effect of warfarinHypovolemia increases concentrations of circulating clotting factors. In patients with hepatic congestion thiazides may improve hepatic function and increase clotting factor synthesisCombination of warfarin and thiazides can be undertaken with the usual monitoring of the INR
Thyrosine kinase inhibitor:
- Dasatinib
- Erlotinib
- Gefitinib
- Imatinib
- Pazopanib
- Sorafenib
- Sunitinib
Potentiate the effect of warfarin and increase the risk of bleeding. Ilness-related factors (anorexia) may alter warfarin requirementsMonitor the INR in patients treated with VKAs and receiving these drugs
Manufacturers indicate to replace VKAs by heparins (UFH, LMWH)
TiboloneIncreases the risk of bleedingMonitor the INR
TobaccoIncrease or decrease the effect of VKA. Tobacco contains phylloquinone (vitamin K1), an isomer of vitamin K Tobacco contains substances that may increase/decrease the metabolism of warfarin.Warfarine dose requirements are higher in smokers
Thrombin inhibitors:
- Argatroban
- Bivaluridin
- Desidurin
- Lepidurin
They inhibit platelet aggregation and increase the risk of bleedingThey are contra-indicated in patients receiving warfarin.
Monitor the INR closely. Observe patients for external bleeding and be alert for signs and symptoms of internal bleeding
Thrombolytic agents:
- Alteplase
- Anistgreplase
- Reteplase
- Streptokinase
- Tenecteplase
- Urokinase
Increase the risk of bleeding. Additive anticoagulant effectThey are contra-indicated in patients receiving warfarin.
The combination should be undertaken with caution and only when the potential benefit outweighs the risk of bleeding. Close INR monitoring is advised. VKA should not be coadministered with intravenous doses of urokinase.
Thyroid hormonesIncrease the risk of bleeding. The response to VKA is increased in hyperthyroidism, while hypothyroid patients are relatively resistant to the effects of VKAThyroid hormones increase the affinity of VKA for their binding sites and increase the metabolism of vitamin K-depending clotting factors.
Hypothyroidism reduces the catabolism of blood clotting fators II, VII, IX and X
INR should be closely monitored and reassessed periodically during concurrent therapy. Warfarin dose should be adjusted to maintain the desired level of anticoagulation.
TolterodineIncreases the risk of bleedingInhibits cytochrome P450 3A4-mediated metabolismMonitor the INR. Warfarin dose should be adjusted to maintain the desired level of anticoagulation
TrastuzumabIncreases the risk of bleedingMonitor the INR. Warfarin dosage adjustments may be required.
Tricyclic or tetracyclic antidepressants:
- Amitriptyline
- Clomipramine
- Desipramine
- Imipramine
- Nortriptyline
They can increase the risk of bleeding
The tricyclics slow gastroitestinal motility and increase the absorption and may inhibit the metabolism of VKA INR should be monitored and the VKA dosage adjusted. Considerable interindividual differences may be found. Maprotiline and mianserin do not usually interact with VKA.
Cotrimoxazole (Trimethoprim/sulfamethoxazole)Increases the risk of bleedingDecreases intestinal bacteria responsible for production of vitamin K, inhibits warfarin metabolism and displaces warfarin from protein binding sites. Increases serum levels of the (S)-warfarin The INR should be closely monitored and reassessed periodically during concurrent therapy. Adjustments of the warfarin dose may be necessary to maintain the desired level of anticoagulation.
VancomycinIncreases the risk of bleedingMonitor the INR. Adjust the dose of warfarin dose to maintain the desired level of anticoagulation
Vitamine AIncreases the risk of bleedingCaution is advised. Monitor the INR. VKA dose adjustments may be necessary
Vitamin K (Phytonadione)It decreases VKA effectiveness
Antagonism of the VKA mechanism of actionVitamin K is the treatment of acute bleeding due to VKA overdosage
Vitamin ELarge doses of vitamin E (> 300 IU daily) may interfere with the vitamin K-dependent clotting factors and increase the risk of bleedingINR should be closely monitored in patients receiving high doses of vitamin E, and reassessed periodically during concurrent therapy. Adjustments of the warfarin dose may be necessary.
VorinostatIncreases the risk of bleedingMonitor the INR
ZafirlukastPotentiates the effect of warfarin and Increases the risk of bleedingInhibits the metabolism of warfarin via CYP2C9Monitor the patient's INR and adjust (reduce) the warfarin dose accordingly
ZotepineIncreases the risk of bleedingThe INR should be closely monitored

Drug-Food combinations

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
FoodThe total amount of drug absorbed is unaffected when administered with food.
Avocado and soybean may reduce the effects of VKA.
Food may increase the absorption of dicumarol. Avocado may interfere with the absorption of warfarin and induce microsomal liver enzymes and increase warfarin metabolism. Brussels sprouts increase the metabolism of warfarinAvoid sudden changes in diet with a high content in vitamin K. If not, INR monitoring might be neccessary.
The diet of any patient who shows ‘warfarin resistance’ should be investigated. Patients on vitamin K-rich diets should not change their eating habits without a reduction in VKAA dosage
Patients should be informed of the need to seek medical advice before undertaking any major changes in diet.
Grapefruit juice
Cranberry juice
They may cause a modest rise in INR in some patients taking warfarin.They shoud be avoided in patients on warfarin. Increased INR monitoring should be considered for any patient taking warfarin and cranberry or grapefruit juice
Papaya Papain may damage the membranes of the gastrointestinal tract, leading to increased bleeding if combined with VKAAvoid concomitant use of papaya extract and VKA. If taken together, monitor the INR closely
Vitamin K containing foods Liver, broccoli, Brussel sprouts, spinach, chick peas, watercress and green leafy vegetables contain large amounts of vitamin K.
May antagonize the effect of warfarin
Serum levels of warfarin tend to be lower when administered with food, the total amount of drug absorbed is unaffectedIt may be necessary to increase the dosage of warfarin. Monitor the INR.
Patients taking warfarin should avoid drastic changes in dietary habits

Herbal medicines: medicines that increase warfarin effectiveness

DrugPharmacodynamic interactionsPharmacokinetic interactions Cautions
Other herbal medicines:
- Agrimony
- Alfalfa
- Aniseed
- Arnica
- Asafetida
- Astragallus
- Bilberry
- Boldo (Peumus boldus)
- Caparral
- Chamomile
- Cranberry
- Curcumin
- Dandelion
- Danshen
- Devil´s claw
- Dong quai (Angelica sinensis),
- Fenugreek (foenum-graecum) Ginseng
- Guggul
- Kava
- Licorice root
- Nettle
- Parsley
- Passion flower
- Red clover
- Safflower oil
- Skullcap (Scutellariae radix)
- Tonka beans
Potentiate the effects of VKA and increase the risk of bleeding.
Alfalfa, boldo, don-quai, licoric and skullcap contain coumarins an/or flavonoids with antiplatelet activity which counteracts the effectiveness of VKA.
Astragalus may increase fibrinolysis, inhibits the synthesis of thromboxane A2 and increases prostaglandin I2
Caparral, curculin, ginseg, guggul, kava and safflower oil inhibit platelet aggregation
Dandelion inhibits platelet aggregation and increases the risk of bleeding. It contains vitamin A.
Fenugreek contains coumarins which may affect blood coagulation
Danshen and guggul increases fibrinolytic activity .
Ginseng decreases warfarin exposureMost of these interactions are not proven.
Caution is advised when these remedies and anticoagulants are used concomitantly. Monitor bleeding time and signs and symptoms of excessive bleeding.
Garlic
- Evening primrose oil
- Feverfew (Tanacetum parthenium)
Inhibit thromboxane A2 formation and platelet aggregation and increase the risk of bleeding. Garlic also increases the fibrinolytic activityMonitor the INR. Adjustments of the warfarin dose may be necessary
GingerIncreases the risk of bleeding. Ginger may inhibit thromboxane B2 formation and thromboxane synthetase and increase prostacyclin levelsEven when the clinical significance of this interaction is undetermined, caution is advised if ginger and an anticoagulant are taken concomitantly.
Ginkgo bilobaIncreases the risk of bleeding. Ginkgo inhibits platelet aggregation by increasing the levels of NO and prostacyclin. Ginkgolide B directly inhibits the binding of platelet-activating factor to its receptors on platelet membranes.Avoid concomitant use of ginkgo and VKA. Monitor the INR. Adjust VKA dosages only if the patient takes a consistent dosage of ginkgo with a consistent and standardized brand.
Tan-Shen (Salvia miltiorrhiza)Increase the risk of bleedingSoy isoflavones (genistein and daidzein) may alter drug absorption by interacting with the P-gp efflux system and OATP drug transporterAvoid concomitant administration of VKA with tan-shen

Herbal medicines: Medicines that decrease warfarin effectiveness

DrugPharmacodynamic interactionsPharmacokinetic interactionsCautions
Green teaReduces VKA effectiveness. Dry green tea leaves contain vitamin K Patients should be advised to consume a consistent amount and use a consistent brand and method of brewing
Soy bean Natto, a common soybean-based food in Japan, may increase the activity of vitamin K
St. John's Worth (Hypericum perforatum)Reduces the anticoagulant effects of phenprocoumon and warfarin Inhibits the absorption of VKA from the gut, induces cytochrome P450 CYP1A2 and 2C9 and decreases the warfarin plasma levelsAvoid the combination. Monitor the INR

Warfarin is a mixture of two enantiomers. R-warfarin is metabolized primarily by CYP1A2 and CYP3A4; S-warfarin is metabolized primarily by CYP2C9. The efficacy of warfarin is affected primarily when the metabolism of S-warfarin is altered.

  • Careful when stopping or reducing the dose of a metabolic inhibitor or inducer, once the patient is stable on this combination
  • Drugs that compete as substrates for these cytochromes or inhibit their activity may increase warfarin plasma concentrations and INR and can increase the risk of bleeding. When these drugs are co-administered, the dose of warfarin may need to be reduced and the INR monitored more closely.
  • Patients should generally avoid taking any herbal medicines or food supplements whilst taking warfarin, and should be told to advise their doctor if they are taking any, as more frequent monitoring is advisable.

Abbreviations

ADP: adenosine diphosphate
CCBs: calcium channel blockers
COMT: catechol-O-methyltransferase
COX-2: cyclooxygenase 2
CrCl: creatinine clearance
CYP: cytochrome P450 family
INR: international normalized ratios
i.v.: intravenous
LMWH: low-molecular weight heparins
NSAIDs: nonsteroidal anti-inflammatory drugs
PAR-1: protease-activated receptor-1
PDE5: phosphodiesterase 5
PK/PD: pharmacokinetic/pharmacodynamic
PT: prothrombin time
RAAS: renin-angiotensin-aldosterone
s.c.: subcutaneous
SNRI: serotonin-norepinephrine reuptake inhibitors
SSRIs: selective serotonin reuptake inhibitors
UFH: unfractioned heparin
VKA: vitamin K antagonists