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
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| - 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 NSAIDS | Increase 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
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Alcohol | Argatroban contains ethanol; possible interaction with metronidazole or disulfiram |
Dabigatran
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Amiodarone | Increase the risk of bleeding | Amiodarone 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 drugs | Increase 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 | |
| Chemotherapy drugs:
- Abiraterone - Crizotinib - Doxorrubicin - Enzalutamide - Ibrutinib - Imatinib - Lapatinib - Sunitinib - Vandetanib - Vemurafenib - Vinblastine | Increase the risk of bleeding | The combination is contraindicated/not recommended | |
| Chemotherapy drugs:
- Axitinib - Dexametasone - Lapatinib - Nilotinib - Tamoxifen | Increase the risk of bleeding | Caution in case of polypharmacy or in the presence of ≥2 bleeding risk factors | |
| Clarithromycin | Close monitoring, particularly in patients with mild-moderate renal impairment | ||
| Dronedarone | Inhibits CYP3A4 and P-gp and markedly increase dabigatran plasma levels | Avoid the combination | |
| Immunusuppessive drugs:
- Ciclosporin - Tacrolimus | Inhibit P-gp. Increase dabigatran plasma levels | Avoid the combination | |
| Ketoconazole | Avoid the combination | ||
| Macrolides:
- Clarithromycin - Erythromycin | Inhibit CYP3A4 and increase dabigatran plasma levels (15-20%) | With caution | |
| NSAIDs | Increases the risk of bleeding | ||
| Posaconazole | Increases the risk of bleeding | Increases 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 events | They 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 bleeding | Close 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 | ||
| Quinidine | Increases dabigatran plasma levels (50%) | Caution. No reduction of dose required | |
| Verapamil | Increases the risk of bleeding | Increases 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
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Azole antifungals:
- Itraconazole - Ketoconazole - Posaconazole - Voriconazole | Potent inhibitors of P-gp/BCRP and CYP 3A4 . Increase apixaban plasma levels (105%) | Avoid the combination | |
| Diltizem | Increases 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 levels | With caution | |
| Naproxen | Competes 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 events | They are P-gp/BCRP and CYP 3A4 and 2J2 inducers. Decrease exposure to apixaban (50%) | Avoid the combination |
Edoxaban
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Amiodarone | Amiodarone 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 | |
| Dronedarone | Increases 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 events | They 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 of bleeding | Reduce the dose of edoxaban to 30 mg od. | |
| Quinidine | Increases dabigatran plasma levels (70%) | Caution. No reduction of dose required | |
| Strong dual inducers of CYP3A4 and P-gp | Decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events | Avoid the combination if possible | |
| Verapamil | Increases 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
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Amiodarone | Amiodarone inhibits CYP 2C9, 2D6 and 3A4, and P-gp. Increases rivaroxaban plasma levels | Minor 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 | |
| Fluconazole | Inhibits CYP3A4 and increases rivaroxaban plasma levels (40%) is systemically administered | With 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 events | They are P-gp/BCRP and CYP 3A4 and 2J2 inducers. Decrease the plasma levels of rivaroxaban (50%) | Avoid the combination |
| Diltiazem | Use with caution if CrCl is 15-50 ml/min | ||
| Dronedarone | Increases rivaroxaban plasma levels | With caution and try to avoid the combination | |
| Verapamil | Use with caution if CrCl is 15-50 ml/min |
Apixaban, Edoxaban, RIvaroxaban
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Chemotherapy drugs:
- Abiraterone - Aprepitant - Crizotinib - Doxorrubicin - Enzalutamide - Idelasilib - Imatinib - Sunitinib - Sandetanib - Vinblastine | The combination is contraindicated/not recommended | ||
| Chemotherapy drugs:
- Axitinib - Ciclosporina - Dexametasone - Lapatinib - Nilotinib - Tacrolimus - Tamoxifen | Caution in case of polypharmacy or in the presence of ≥2 bleeding risk factors |
Apixaban, Rivaroxaban
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
- Paclitaxel - Pazopanib - Prednisone - Sirolimus - Temsirolimus - Vermurafenib | Consider dose adjustment. Caution in case of polypharmacy or in the presence of ≥2 bleeding risk factors | ||
- Anastrozol - Bicalutamida - Cyclophosphamide - Dasatinib - Docetaxel - Etoposide - Idarubicin - Ifosfamide - Lomustine - Vincristine - Vinorelbine | Caution in case of polypharmacy or in the presence of ≥2 bleeding risk factors |
No interactions with ranitidine, antacid aluminum hydroxide/magnesium hydroxide, atorvastatin, digoxin, midazolam or omeprazole
2. Synthetic pentasaccharide inhibitors of factor Xa: Fonfaparinux
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Anticoagulants
- Alprostadil - Antiplatelet agents - Aspirin - Dextran - Dipyridamole - Iloprost - NSAIDs - Prostacyclin - Thrombolytics - Warfarin | Increase the risk of bleeding | Co-administration should be undertaken under close monitoring of the patient
|
3. Heparins
3.1. Unfractiones heparin (UFH)
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Alcohol | Heavy drinkers were at greater risk of major heparin-associated bleeding than moderate drinkers or non-drinkers | May increase the risk of bleeding | |
| Aspirin | Anti-platelet effect of aspirin is substantially reduced after administration of heparin during carotid endarterectomy | Certain patients are at increased risk for acute cardiovascular events after major vascular surgery, despite aspirin therapy | |
| Benzodiazepines | UFH displaces the benzodiazepines from plasma proteins and increase their effects | Use with caution. Use lorazepam | |
| Capecitabine | Increases the risk of bleeding | Avoid the combination | |
| 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 action | Monitor 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 bleeding | These 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 | |
| Fluvoxamine | Increase INR | With 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 tendency | People taking heparin should consult with a physician knowledgeable about botanical medicines. | |
| K supplements
K salts | Heparin may cause hyperkalemia | Risk of hyperkalemia | |
| Nicotine | It may partially counteract the anticoagulant effect of heparin | Increased 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 route | Monitor patients closely to ensure anticoagulation. When nitroglycerin therapy is stopped, a decrease in heparin dosage may be necessary | |
| Oral anticoagulants | Oral 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 inhibitors | Increased risk of hyperkalaemia | Monitor serum potassium levels | |
| Streptokinase | Patients 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 | |
| Sulphonilureas | Increased risk of hypoglycaemia | Coadministration with caution. Monitor the APTT | |
| Tobacco | Smoking activates thrombosis | Reduced half-life and increased elimination of heparin in smokers | Aumentar la dosis de heparina |
| Tenecteplase | Tenecteplase may attenuate the intensity of anticoagulation of UFH in vitro | Monitor the APTT | |
| Vitamine D | Heparin may interfere with activation of vitamin D in the body | Osteoporosis 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
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Anticoagulants
- Alprostadil - Antiplatelet agents - Dextran - Dipyridamole - Iloprost - NSAIDs - Prostacyclin - Thrombolytics - Warfarin | Increase the risk of bleeding | Concomitant use should be undertaken with caution |
4. Vitamine K antagonists (Warfarin)
| Drug | Pharmacodynamic interaction | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Acarbose | Increases the risk of bleeding | Possibly by increasing warfarin absorption | Monitor 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 system | This 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 |
| Alcohol | Increases/decreases the INR | The 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 warfarin | Moderate alcohol intake can be permitted. |
| Allopurinol | Potentiates the effect of warfarin and increases the risk of bleeding | Allopurinol inhibits the hepatic metabolism of VKAs and prolong their half-lives | Monitor INR in patients on an VKAs when allopurinol is first added. |
| Amiodarone | Potentiates the effect of warfarin and increases the risk of bleeding. Patients who develop hyperthyroidism secondary to amiodarone may have an increased anticoagulant effect | Amiodarone and desethylamiodarone, its active metabolite, inhibit CYP2C9 and CYP3A4 and increases plasma warfarin levels | The 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 metabolism | Monitor 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 factors | Monitor 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 effect | Anticoagulants 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 bleeding | Dicumarol inhibits the metabolism and increases the exposure to tolbutamide | Avoid 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 requirements | Decrease 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 | ||
| Aprepitant | Decreases the PT/INR | Induces cytochrome P450 2C9-mediated metabolism of S(-) warfarin | The INR should be monitored |
| Aromatase inhibitors:
- Aminoglutethimide | Reduce the effects of VKAs | Increase the hepatic metabolism and clearance of VKAs | INR should be monitored and the dose of VKAs increased to maintain the desired level of anticoagulation.
Anastrozole and letrozole do not interact with warfarin |
| Aspirin | Inhibits 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 metabolism | The 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 |
| Atenolol | Increases the INR | Use caution if atenolol and warfarin are used concomitantly | |
| Azathioprine | Antagonise the effect of warfarin | Inhibits warfarin absorption and enhances its metabolism | Monitor 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 metabolism | The INR should be closely monitored. Adjustment of the dose of VKA may be necessary to maintain the desired level of anticoagulation.
|
| Barbiturates | Antagonise the effect of warfarin | Interfere with intestinal absorption of dicumarol and are potent CYP enzyme inducers increasing the metabolism of VKA | INR 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 |
| Benzbromarone | Increases 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% |
| Bicalutamide | Increase the risk of bleeding | Bicalutamide can displace coumarin anticoagulants from binding sites. | Monitor the INR |
| Bile-acid binding resins:
- Cholestyramine - Colesevelam - Colestipol | Reduces the effects of VKAs | Colestyramine 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 warfarin | Patients 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 effects | Diltiazem and verapamil inhibit CYP3A4 and slightly decrease the metabolism of warfarin | No special precaution would be needed |
| Carbamazepine | Reduces the anticoagulant effect of warfarin
| Carbamazepine increases the hepatic metabolism of warfarin | The 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 |
| Carbimazole | Reduces the anticoagulant effect of VKAs | Decreases the metabolism of clotting factors | Increased 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 |
| Chemotherapy drugs:
- Alkylating agents: Carboplatine, Cisplatin, Cyclophosphamide, Ifosfamide, Procarbazine, Tiotepa - Antimetabolites: Capecitabine, Cytarabine, 5-fluorouracil, Methotrexate - Bicalutamide - Carbozantinib - Ceritinib - Dasatinib - Doxorubicin - Erlotinib - Etoposide - Gefitinib - Ibritumomab - Ibrutinib - Imatinib - Interferons - Ipilimumab - Irinotecan - Nintedanib - Obinutuzumab - Paclitaxel - Regorafenib - Romidepsin - Rucaparib - Sorafenib - Sunitinib - Tegafur - VEGF/VEGFR inhibitors - Vorinostat - Tyrosine kinase inhibitors | Increase the anticoagulant effects of warfarin and the risk of bleeding | Monitor the INR
Avoid the commbination with capecitabine, etoposido+carboplatine, 5-fluorouracil, ifosfamide, imatinib, paclitaxel or tamoxifeno | |
| Chemotherapy drugs:
- Dabrafenib - Ivosidenib - Mercaptopurine - Mitotane - Nilotinib | Decrease the anticoagulant effects of warfarin | Monitor the INR
Avoid the combination with dabrafenib or ivosidenib | |
| Chloramphenicol | Increases the risk of bleeding | Inhibits hepatic metabolism and decreases vitamin K production by bacteria in the gut. It may increase the half-life of bishydroxycumarin | Avoid the use of chloramphenicol if possible |
| Cilostazol | Increases the risk of bleeding. Additive anticaugulant effect | Avoid the combination | |
| Coenzyme Q | Reduces the anticaogulant effect. Chemical similarity between coenzyme Q10 and vitamin K2 | Avoid the combination | |
| COMT inhibitors:
- Entacapone | Increase the INR values | Increases 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 VKAs | They 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 |
| Corticosteroids | They may slightly increase or decrease the effect of VKA. They increase the risk of gastrointestinal ulceration and bleeding | Close monitoring of coagulation parameters is recommended if high-doses of corticosteroids | |
| Dexmethylphenidate | Increases the risk of bleeding | Inhibits the metabolism of coumarin anticoagulants | Consider reducing the warfarin dose during concomitant therapy |
| Dextropropoxyphene | Increases the risk of bleeding | Inhibits the metabolism of warfarin | May be prudent to monitor the INR during concurrent therapy |
| Diazoxide | Increases the risk of bleeding | Displaces VKAs from plasma binding sites | Monitor the INR. Adjustments in the dose of VKAs may be necessary to maintain the desired level of anticoagulation |
| Dipyridamole | Inhibits platelet aggregation and increases the effect of VKAs | Avoid the combination.
If they are coadministered, monitor the INR. Adjustments in the warfarin dose may be necessary to maintain the desired level of anticoagulation | |
| Disulfiram | Potentiates the effect of warfarin and increases the risk of bleeding | It 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 bleeding | Avoid 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-warfarin | The INR should be closely monitored and reassessed periodically during concurrent therapy. Reduce the dose of sitaxentan. Ambrisentan does not present this interaction |
| Fibrates | Fibrates may increase the effects of warfarin, prolong the PT/INR and increase the risk of bleeding | Displace warfarin from protein binding sites | The dose of warfarin should be reduced (30-50%) and the INR should be monitorized |
| Fondaparinux | Increases 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 | |
| Glucagon | Increases 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 site | Monitor additive the INR and reduce the dosage of warfarin |
| Glucosamine | Increased the INR | This combination is not recommended | |
| Glutethimide | Reduces the anticoagulant effect of warfarin | Induces the metabolism of warfarin | Monitor the INR. Adjustments of the warfarin dose may be necessary. Benzodiazepines are an alternative hypnotic class without warfarin interactions |
| Griseofulvin | Antagonise 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 cetirizine | Temporary 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 warfarin | Inhibits 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 bleeding | Danazol inhibits the metabolism of warfarin | Close monitoring of the INR. Dose reductions of warfarin (30–50%) |
| Influenza virus vaccine | Increases the risk of bleeding in some patients treated with warfarin | Monitor the INR within one to two weeks following the vaccine. Acenocumarol also does not normally interact | |
| Interferons | May increase the effect of VKA | Interferons reduce the hepatic metabolism of VKA | It would seem prudent to monitor the INR and to reduce the dosage of VKA if necessary |
| Isoniazid | Increases the risk of bleeding | It may reduce the hepatic metabolism of VKA | Monitor the INR |
| Laxatives | They can reduce the effect of warfarin | They may reduce absorption of vitamin K | It may be necessary to monitor the INR |
| Leflunomide | Increases the risk of bleeding | Inhibits CYP2C9-mediated metabolism of warfarin | Close 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 bleeding | Zafirlukast inhibits CYP2C9-mediated warfarin metabolism. Zileuton decreases the clearance of warfarin | Even when the clinical significance of this is unclear, the INR should be monitored and the warfarin dose should be adjusted accordingly |
| Lomitapide | Lomitapide increases the INR | Lomitapide increases (30%) plasma concentrations of both R(+)- warfarin and S(-)-warfarin | Monitor 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 |
| Metformin | Decreases the effects of phenprocoumon | Possibly increases bile excretion of phenprocoumon | Increase the dose of phenprocoumon |
| Methylphenidate | Potentiates the effect of warfarin and increase the risk of bleeding | Inhibits the metabolism of warfarin | Monitor the INR |
| Metronidazole | Potentiates the effect of warfarin and increases the risk of bleeding | Inhibits the matabolism of (S)-warfarin | The INR should be closely monitored and should be reassessed periodically during concurrent therapy |
| Nalidixic acid | Increases the risk of bleeding. | Displacement of warfarin from protein binding sites | Monitor the INR. Adjustments in the warfarin dose may be necessary to maintain the desired level of anticoagulation |
| Neomycin | Increases the risk of bleeding. | Possible inhibits vitamin K synthesis by the gut flora or reduces the absorption of vitamin K | The 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 |
| Nilutamide | Increases the risk of bleeding. | Inhibits liver cytochrome P450 isoenzymes and causes a reduction of warfarin metabolism | Monitor 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 VKA | Displace warfarin from plasma proteins binding sites. They may also decrease VKA mtabolism | Caution 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 bleeding | Patients receiving anticoagulant therapy should be monitored periodically | |
| Orlistat | Reduces the effect of warfarin | Decreases vitamin K absorption | The INR should be monitored |
| Paracetamol | It may increase the incidence of upper gastrointestinal bleeding | It may compete with the metabolism of R-warfarin | Small 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 |
| Penicillins | Amoxicillin, 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 colon | Interactions 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 Sodium | Increases the risk of bleeding. Additive anticoagulant effect | Close clinical and laboratory monitoring is advised | |
| Pentoxifylline | Pentoxifylline, alone and in the presence of VKA, increases the risk of bleeding | Monitor 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 metabolism | Monitor the INR. Higher doses of warfarin are required. |
| Phosphodiesterase 5 (PDE5) inhibitors:
- Sildenafil - Taladafil - Verdenafil | Increases nosebleeds in patients with pulmonary hypertension treated with VKAs | There 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 effect | This 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 | |
| Primidone | Antagonise the effect of warfarin | Increases warfarin metabolism | The INR should be closely monitored. Adjustments of the warfarin dose may be necessary |
| Propafenone | Potentiates the effect of warfarin and increases the risk of bleeding | May reduce the metabolism of VKA | INR should be closely monitored. Warfarin dosage adjustment may be required |
| Propranolol | May increase the risk of bleeding | Inhibits the metabolism of warfarin and increases plasma levels | Monitor 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 bleeding | Inhibit the hepatic metabolism of (R)-warfarin | Monitor the INR and adjust the warfarin dose accordingly.
Pantoprazole does not affect the pharmacokinetics of warfarin |
| Quetiapine | Increases the risk of bleeding. | Inhibits cytochrome P450 3A4 and 2C9 | INR should be closely monitored. Adjustments of the warfarin dose may be necessary |
| Quinidine | Increases the risk of bleeding | Decreases the synthesis of vitamin K dependent clotting factors | Monitor 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 bleeding | Are 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 |
| Raloxifene | Loss of anticoagulation control | Decreases in the clearance and the volume of distribution) of R- and S-warfarin | Monitor the INR |
| Rifabutin | Antagonise the effect of warfarin | Induces warfarin metabolism | Doses of warfarin may need to be increased when rifabutin is given concomitantly |
| Rifamycin | Antagonise the effect of warfarin | Induces hepatic cytochrome P450 enzymes and increases the metabolism of VKA | Closely 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 bleeding | Fluvoxamine 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 |
| Spironolactone | Decreases VKA effectiveness | Hypovolemia increases the concentration of clotting factors | Monitor 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 |
| Sucralfate | Decreases VKA effectiveness | Decreases the absorption of warfarin | The INR should be monitored periodically during concurrent therapy. Adjustments of the warfarin dose may be necessary |
| Sulfamethoxazole | Potentiates the effect of warfarin and increases the risk of bleeding | ||
| Sulfasalazine | Decreases VKA effectiveness | Warfarin 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 bleeding | Displaces 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 sites | The 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 sulfonilureas | Dicoumarol inhibits the hepatic metabolism of tolbutamide and increases its effects. Tolbutamide can displace dicumarol from plasma proteins | Monitor 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 activity | They 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 levels | Monitor the INR with the addition or withdrawal of tetracyclins. Adjustments in the warfarin dose may be necessary to maintain the desired level of anticoagulation |
| Thiazides | May decrease the effect of warfarin | Hypovolemia increases concentrations of circulating clotting factors. In patients with hepatic congestion thiazides may improve hepatic function and increase clotting factor synthesis | Combination 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 requirements | Monitor the INR in patients treated with VKAs and receiving these drugs
Manufacturers indicate to replace VKAs by heparins (UFH, LMWH) | |
| Tibolone | Increases the risk of bleeding | Monitor the INR | |
| Tobacco | Increase 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 bleeding | They 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 effect | They 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 hormones | Increase the risk of bleeding. The response to VKA is increased in hyperthyroidism, while hypothyroid patients are relatively resistant to the effects of VKA | 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 |
| Tolterodine | Increases the risk of bleeding | Inhibits cytochrome P450 3A4-mediated metabolism | Monitor the INR. Warfarin dose should be adjusted to maintain the desired level of anticoagulation |
| Trastuzumab | Increases the risk of bleeding | Monitor 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 bleeding | Decreases 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 |
| Vancomycin | Increases the risk of bleeding | Monitor the INR. Adjust the dose of warfarin dose to maintain the desired level of anticoagulation | |
| Vitamine A | Increases the risk of bleeding | Caution is advised. Monitor the INR. VKA dose adjustments may be necessary | |
| Vitamin K (Phytonadione) | It decreases VKA effectiveness
| Antagonism of the VKA mechanism of action | Vitamin K is the treatment of acute bleeding due to VKA overdosage |
| Vitamin E | Large doses of vitamin E (> 300 IU daily) may interfere with the vitamin K-dependent clotting factors and increase the risk of bleeding | INR 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 | |
| Vorinostat | Increases the risk of bleeding | Monitor the INR | |
| Zafirlukast | Potentiates the effect of warfarin and Increases the risk of bleeding | Inhibits the metabolism of warfarin via CYP2C9 | Monitor the patient's INR and adjust (reduce) the warfarin dose accordingly |
| Zotepine | Increases the risk of bleeding | The INR should be closely monitored |
Drug-Food combinations
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Food | The 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 warfarin | Avoid 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 VKA | Avoid 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 unaffected | It 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
| Drug | Pharmacodynamic interactions | Pharmacokinetic 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 exposure | Most 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 activity | Monitor the INR. Adjustments of the warfarin dose may be necessary | |
| Ginger | Increases the risk of bleeding. Ginger may inhibit thromboxane B2 formation and thromboxane synthetase and increase prostacyclin levels | Even when the clinical significance of this interaction is undetermined, caution is advised if ginger and an anticoagulant are taken concomitantly | |
| Ginkgo biloba | Increases 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 bleeding | Soy isoflavones (genistein and daidzein) may alter drug absorption by interacting with the P-gp efflux system and OATP drug transporter | Avoid concomitant administration of VKA with tan-shen |
Herbal medicines: Medicines that decrease warfarin effectiveness
| Drug | Pharmacodynamic interactions | Pharmacokinetic interactions | Cautions |
|---|---|---|---|
| Green tea | Reduces 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 levels | Avoid 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