Warfarin is an oral anticoagulant — a "blood thinner" — used to prevent and treat blood clots in the veins, lungs or heart. It reduces the blood's ability to clot, which requires regular blood tests (INR) to find the right dose for each person.
Also known as: Marevan
Very high bleeding risk. Combined anticoagulation + antiplatelet therapy almost doubles major bleeding rates.
Aspirin irreversibly inhibits platelet COX-1 and warfarin reduces the vitamin K-dependent clotting factors: the two mechanisms add up and the risk of major bleeding — including intracranial and gastrointestinal bleeding — nearly doubles compared with each drug alone. The combination is only indicated in specific situations (e.g. acute coronary syndrome requiring anticoagulation, mechanical valve prosthesis with atherosclerotic disease), always keeping the INR at the lower end of the target range and with gastric protection when indicated. Outside these situations, dual therapy should be avoided, always weighing the individual bleeding risk.
Coumarin + antiplatelet agent: the risk of major bleeding nearly doubles (intracranial and gastrointestinal bleeding). Reserve the combination for specific cardiology indications; otherwise avoid.
Aspirin's irreversible antiplatelet effect added to Warfarin anticoagulation.
Strict INR and regular bleeding surveillance.
GI bleeding; intracranial haemorrhage (sudden severe headache).
Avoid except for specific indications (e.g. mechanical valves) under specialist supervision.
DailyMed/FDA (NIH/NLM) — approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 ; approved Aspirin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3ba0a9f2-062a-401e-82eb-54383a822366
Sulfadoxine (a sulfonamide) may enhance the effect of Warfarin — bleeding risk.
Sulphonamides, such as sulphadoxine, have been associated with increased warfarin effect through multiple mechanisms: CYP2C9 inhibition (metabolism of active S-warfarin), displacement of protein binding and, potentially, reduction of the gut flora producing vitamin K. Pyrimethamine contributes less, but the two are used together in malaria prophylaxis and treatment. The INR should be monitored at the start and end of treatment and the warfarin dose adjusted; watch for bleeding signs.
Sulfadoxine (a sulphonamide) can inhibit warfarin metabolism and displace the free fraction, raising the INR. Monitor the INR during and after the antimalarial.
Possible inhibition of Warfarin metabolism and/or protein-binding displacement.
INR and signs of bleeding.
Bleeding, bruising, dark stools.
Monitor the INR on starting/stopping and adjust the dose.
WHO — WHO Guidelines for malaria: https://www.who.int/teams/global-malaria-programme/guidelines-for-malaria ; DailyMed/FDA (NIH/NLM) — approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Penicillin G benzathine (a β-lactam antibiotic) may alter the INR in patients anticoagulated with warfarin, with a bleeding risk during antibiotic therapy.
The warfarin label identifies antibiotics, including penicillins, as drugs that can alter INR in anticoagulated patients. The mechanism is multiple: reduction of vitamin K-producing gut flora, metabolic inhibition, and the infectious disease itself altering the coagulation state. With benzathine benzylpenicillin (long-acting IM injection, e.g., rheumatic fever prophylaxis), the effect on INR may be less predictable and more delayed. Monitor INR during and after the antibiotic course, watch for bleeding signs and adjust the warfarin dose according to the values.
Warfarin + benzylpenicillin: antibiotics may alter INR (gut flora and enzymes). Monitor INR.
There have been reports of changes in INR in patients taking warfarin and antibiotics; pharmacokinetic studies have not shown consistent effects on plasma warfarin concentrations, so the mechanism is multifactorial (possible reduction of vitamin-K-producing gut flora and altered haemostasis).
INR, signs of bleeding (gums, bruising, melena, haematuria).
Unexplained bleeding, haematuria, melena, INR above the therapeutic range.
Closely monitor the INR when starting and stopping the antibiotic; adjust the warfarin dose as needed during antibiotic therapy.
DailyMed/FDA (NIH/NLM) — approved Warfarin label (section 7.4 Antibiotics and Antifungals): https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 ; approved Bicillin L-A label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=012d46f1-d0a0-4676-a879-cd320297ab16
Warfarin + lipid emulsion: the vitamin K content of lipids may reduce INR.
Soybean oil-based lipid emulsions (such as Intralipid) contain vitamin K, the natural antidote to warfarin: dietary/intravenous vitamin K reactivates the vitamin K-dependent clotting factors and reduces the anticoagulant effect, lowering INR. In anticoagulated patients receiving parenteral nutrition with lipid emulsion, the vitamin K load can make INR lower and more variable, increasing thrombotic risk if not compensated. Monitor INR more frequently after starting (or changing) the lipid emulsion and adjust the warfarin dose according to the values.
Warfarin + lipid emulsion: the vitamin K in soybean lipids may reduce INR. Monitor INR.
Lipid emulsions contain vitamin K, which antagonises the warfarin effect.
Periodic INR.
Signs of thrombosis or sub-therapeutic INR.
Monitor INR during parenteral nutrition with lipids.
DailyMed (FDA) — approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 ; approved Lipid emulsion label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=61e025f1-a38e-4af2-9e18-13ea12977cf5 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Warfarin + vitamin C (high doses): possible INR change.
High-dose vitamin C (several grams per day) has been associated with changes in INR in patients anticoagulated with warfarin — generally a reduced anticoagulant effect, although reports vary. The mechanism is not fully clarified (possible interference with warfarin absorption or metabolism). With usual doses (up to ~500 mg/day) the risk is minimal, but in patients taking megadoses of vitamin C, monitor INR after starting, changing or stopping the supplement, and adjust the warfarin dose as needed.
Warfarin + vitamin C: high-dose vitamin C may alter INR. Monitor INR.
Very high vitamin C doses may interfere with anticoagulation (mechanism not fully clarified).
Periodic INR.
Signs of bleeding or thrombosis.
Avoid high doses (>1 g/day) without monitoring; check INR.
DailyMed (FDA) — approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 ; approved Ascorbic acid (vitamin C) label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1606e29f-0e80-4069-b688-daab9cbff20a — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Taking tamoxifen with warfarin can greatly increase the anticoagulant effect and the risk of bleeding. Your doctor should check the INR more often.
The tamoxifen SmPC (EMC-UK) reports a significant increase in anticoagulant effect when combined with coumarins, and the DailyMed label contraindicates use in patients requiring concomitant coumarin anticoagulation (in the risk-reduction indication). The mechanism involves inhibition of coumarin metabolism and an additive effect on haemostasis. In adjuvant breast cancer therapy, if anticoagulation is essential, monitor INR closely after starting tamoxifen (the anticoagulant dose may need to be reduced).
Tamoxifen significantly potentiates coumarin anticoagulants; in primary prevention of breast cancer the combination is contraindicated. Monitor INR on initiation and after any dose change.
Inhibition of coumarin metabolism and additive effect on haemostasis.
Periodic INR; bleeding symptoms.
Melena, haematemesis, spontaneous bruising, bleeding — seek immediate care.
Combine only if strictly necessary; check INR 1–2 weeks after starting or changing tamoxifen and adjust the anticoagulant dose.
EMC-UK (MHRA) — approved Tamoxifen SmPC: https://www.medicines.org.uk/emc/product/101398/smpc ; DailyMed/FDA (NIH/NLM) — approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Methimazole can increase the effect of warfarin, raising the risk of bleeding. The INR should be monitored more closely during treatment.
The approved methimazole label (DailyMed) states that, through potential inhibition of vitamin K activity, the drug may increase the activity of oral anticoagulants (e.g. warfarin), recommending additional PT/INR monitoring, especially before surgical procedures. The effect is more relevant as hyperthyroidism is controlled, when drug clearance changes.
Methimazole may inhibit vitamin K activity and potentiate oral anticoagulants; monitor PT/INR, especially before surgical procedures.
Inhibition of vitamin K activity and altered hepatic clearance as the euthyroid state is reached.
Periodic INR and bleeding symptoms.
Melena, haematemesis, bruising — seek immediate care.
Monitor INR after starting, adjusting or stopping methimazole; consider reducing the anticoagulant dose.
DailyMed/FDA (NIH/NLM) — approved Methimazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b53f84ac-4263-478c-883d-aca7ab44fef5 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Gliclazide can increase the effect of warfarin and the risk of bleeding. The INR should be checked more often.
The gliclazide SmPC (EMC-UK) states that sulfonylureas may potentiate anticoagulation during concurrent treatment with coumarins (e.g. warfarin), and the anticoagulant dose may need adjustment. The mechanism involves displacement from protein binding and inhibition of coumarin metabolism. The combination is common (type 2 diabetes and atrial fibrillation).
Sulfonylureas may potentiate anticoagulation during concurrent treatment; the anticoagulant dose may need adjustment. Monitor INR.
Displacement from protein binding and inhibition of coumarin metabolism.
Periodic INR and bleeding symptoms.
Melena, haematemesis, bruising — seek immediate care.
Monitor INR when starting, adjusting or stopping gliclazide and adjust the anticoagulant dose.
EMC-UK (MHRA) — approved Gliclazide SmPC: https://www.medicines.org.uk/emc/product/1321/smpc ; DailyMed/FDA (NIH/NLM) — approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 ; Prontuário Terapêutico do INFARMED (11th ed., 2012)
Severe bleeding risk. NSAIDs (Ibuprofen) increase gastrointestinal bleeding and potentiate the anticoagulant effect of Warfarin.
Ibuprofen increases the bleeding risk in anticoagulated patients through two mechanisms: direct injury to the gastrointestinal mucosa and reversible COX-1 inhibition, which reduces thromboxane A2 and impairs platelet aggregation. The effect on the INR is variable, but the increase in bleeding risk — particularly upper gastrointestinal bleeding — is well documented even with occasional NSAID doses. In patients taking warfarin, paracetamol is the first-line analgesic; if an NSAID is indispensable, use the lowest effective dose for the shortest time, consider gastric protection with a proton pump inhibitor, and remain vigilant for bleeding signs (dark stools, spontaneous bruising, bleeding).
NSAID + coumarin: markedly increased bleeding risk (gastrointestinal bleeding and variable INR increase). Prefer paracetamol; if the NSAID is unavoidable, minimal dose, short course and gastric protection; watch for bleeding signs.
Gastric mucosal injury + platelet inhibition + displacement of Warfarin from albumin.
INR and bleeding surveillance; FBC if occult loss is suspected.
Haematemesis, melaena, blood in stool, extensive bruising.
Avoid the combination. Use Paracetamol; if an NSAID is essential, consider gastric protection and strict INR.
DailyMed/FDA (NIH/NLM) — approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 ; approved Ibuprofen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14515409-736f-4119-b6a0-cb19ee2e948e
Amiodarone potentiates Warfarin's anticoagulant effect, raising INR and bleeding risk.
Amiodarone is a potent inhibitor of CYP2C9, the isoenzyme that metabolises S-warfarin (the more active enantiomer), and also inhibits CYP2C19 and CYP3A4. The result is a marked rise in the INR, which can start within the first days but continues to evolve for weeks because amiodarone has a very long half-life (20–100 days) and accumulates in tissues. The approved label recommends reducing the warfarin dose by 30–50% when amiodarone is started and monitoring the INR closely; the effect persists for weeks to months after amiodarone is stopped, so warfarin must be re-adjusted during that phase. This combination is common in atrial fibrillation patients and demands disciplined INR control and vigilance for bleeding.
Amiodarone inhibits CYP2C9 (and CYP2C19/CYP3A4) and can more than double the INR. Reduce warfarin by 30–50% when starting, monitor INR weekly, and re-adjust after amiodarone is stopped (prolonged effect, half-life of weeks).
Inhibits CYP2C9, the main enzyme metabolising Warfarin.
Weekly INR in the first weeks after starting Amiodarone.
Unusual bleeding, spontaneous bruising, gum bleeding.
Reduce the Warfarin dose by 25–50% and monitor INR more frequently.
DailyMed/FDA (NIH/NLM) — approved Amiodarone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51a88e8e-da02-4b97-9e7e-442fbffd908d ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Amoxicillin + Clavulanate (a broad-spectrum antibiotic) may potentiate the anticoagulant effect of Warfarin, raising the INR and the bleeding risk.
Amoxicillin-clavulanate eliminates much of the gut bacterial flora that synthesises vitamin K, reducing the availability of the cofactor needed to carboxylate the vitamin K-dependent coagulation factors (II, VII, IX, X). Since warfarin acts precisely through that pathway (inhibition of vitamin K epoxide reductase), the additional reduction of endogenous vitamin K potentiates the anticoagulant effect and the INR rises. The effect is more evident in patients with marginal dietary vitamin K intake and can appear days after starting the antibiotic. INR monitoring during and after the antibiotic course is essential; in patients with a previously stable INR, consider more frequent checks and alert for bleeding signs (gingival bleeding, bruising, melaena).
Broad-spectrum antibiotics can potentiate warfarin by reducing the gut flora that produces vitamin K and, for some, by enzyme inhibition. Monitor the INR during and after the antibiotic and watch for bleeding.
Reduction of vitamin-K-producing gut flora and altered haemostasis increase the response to the anticoagulant.
INR, signs of bleeding (gums, bruising, melena).
Unexplained bleeding, haematuria, melena.
Monitor the INR when starting and stopping the antibiotic; adjust the warfarin dose as needed.
DailyMed/FDA (NIH/NLM) — approved Amoxicillin + Clavulanate label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5250085e-5509-c577-e063-6294a90a9b87 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Ampicillin (a broad-spectrum antibiotic) may potentiate the anticoagulant effect of Warfarin, raising the INR.
Ampicillin, like other broad-spectrum antibiotics, reduces the gut bacterial flora that synthesises vitamin K. Since warfarin inhibits vitamin K epoxide reductase, the lower availability of endogenous vitamin K translates into a higher INR and bleeding risk. The interaction is more relevant in patients with marginal nutrition, liver disease or prolonged antibiotic therapy. INR should be monitored during treatment and after its completion, with vigilance for bleeding signs; adjust the warfarin dose according to the INR.
Ampicillin can potentiate warfarin by reducing the gut flora that produces vitamin K. Monitor the INR during and after the antibiotic.
Reduction of vitamin-K-producing gut flora increases the response to the anticoagulant.
INR, signs of bleeding.
Unexplained bleeding, melena.
Monitor the INR when starting/stopping ampicillin; adjust the warfarin dose as needed.
DailyMed/FDA (NIH/NLM) — approved Ampicillin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=402e7cc7-5ae8-c113-e063-6394a90aa54a ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Combining Atazanavir with Warfarin may potentiate the anticoagulant effect and increase the risk of serious bleeding.
Atazanavir inhibits CYP3A4 (and UGT1A1), enzymes involved in the metabolism of both warfarin enantiomers. The inhibition can increase warfarin exposure and raise the INR, with increased bleeding risk. Since atazanavir is used with ritonavir or cobicistat (also inhibitors), the effect can be even more pronounced. The INR should be monitored frequently at initiation, during and after antiretroviral discontinuation, and the warfarin dose adjusted accordingly.
Atazanavir inhibits CYP3A4 and UGT1A1 and can raise warfarin levels and the INR. Monitor the INR when starting, adjusting and stopping atazanavir.
Atazanavir inhibits metabolic pathways of Warfarin; the label warns of the potential for serious and/or potentially fatal bleeding with co-administration.
Watch for bleeding signs; regular INR testing at start and dose changes.
A high INR with active bleeding requires immediate discontinuation of the anticoagulant and urgent evaluation.
Monitor the INR frequently and adjust the Warfarin dose during co-administration.
DailyMed/FDA (NIH/NLM) — approved Atazanavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=165cff62-b284-4a27-a65d-9ec8a5bfcdd8 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Proguanil may enhance the anticoagulant effect of Warfarin.
Atovaquone is very highly protein-bound (over 99%) and, by competing for the same binding sites, can displace warfarin and increase the active free fraction, with a transient INR rise. Proguanil does not appear to contribute significantly, but the two are used together. The effect is usually modest and transient, but in patients with a borderline INR it can trigger bleeding. The INR should be monitored at the start and end of prophylaxis and the dose adjusted if necessary.
Atovaquone is extensively protein-bound and can displace warfarin, transiently raising the INR. Monitor the INR when starting and stopping antimalarial prophylaxis.
Possible interaction with hepatic Warfarin metabolism.
INR and signs of bleeding.
Bleeding, bruising, dark stools.
Monitor the INR on starting/stopping and adjust the dose.
DailyMed/FDA (NIH/NLM) — approved Atovaquone + Proguanil label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fc22e8d8-3bfb-4f70-a599-dd81262a4887 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Azithromycin may potentiate the anticoagulant effect of Warfarin, raising the INR and the bleeding risk (variable and sometimes delayed effect).
Azithromycin, like other macrolides, can increase the effect of warfarin through two mechanisms: reduction of the gut flora that produces vitamin K and inhibition (milder than clarithromycin and erythromycin) of CYP3A4, which participates in warfarin metabolism. Clinical reports with azithromycin are less consistent, but cases of elevated INR and bleeding exist. The warfarin label lists macrolides as drugs that can increase the anticoagulant effect. The INR should be monitored during the antibiotic course and in the following weeks, with dose adjustment if needed.
Macrolides can potentiate warfarin (gut flora + enzyme inhibition). Azithromycin's effect is less consistent than clarithromycin/erythromycin, but INR monitoring during and after the antibiotic is still required.
Mechanism not fully established; Azithromycin appears to alter metabolism or gut flora, potentiating Warfarin anticoagulation, usually within the first days or weeks of combined use.
Monitor the INR more frequently and watch for bleeding signs during therapy.
Bleeding, an elevated INR or spontaneous bruising require urgent evaluation.
Monitor the INR and adjust warfarin as needed; watch for bleeding signs during and after the combination.
DailyMed/FDA (NIH/NLM) — approved Azithromycin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=db52b91e-79f7-4cc1-9564-f2eee8e31c45 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Ceftriaxone may prolong prothrombin time and potentiate the anticoagulant effect of Warfarin, especially during prolonged therapy.
Ceftriaxone is a broad-spectrum cephalosporin that reduces the gut flora producing vitamin K. Since warfarin is a vitamin K antagonist, the lower endogenous availability of the cofactor raises the INR and the bleeding risk. The effect is more relevant in malnourished, elderly, liver-disease or prolonged-antibiotic patients. Monitor the INR during and after treatment and adjust the warfarin dose; watch for bleeding signs.
Cephalosporins can potentiate warfarin by reducing the gut flora that produces vitamin K. Monitor the INR during and after the antibiotic.
Risk of vitamin K deficiency and altered clotting-factor synthesis with prolonged use; additive effect with the anticoagulant.
Prothrombin time/INR, signs of bleeding.
Unexplained bleeding, extensive bruising, melena.
Monitor PT/INR; consider vitamin K supplementation with prolonged use or in the elderly.
DailyMed/FDA (NIH/NLM) — approved Ceftriaxone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9efed4c4-72a7-4669-88ae-c80e882c1b37 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Ketoconazole potentiates the anticoagulant effect of Warfarin, increasing the bleeding risk.
Ketoconazole is a potent inhibitor of several cytochrome P450 isoenzymes, including CYP2C9 (which metabolises active S-warfarin) and CYP3A4 (which metabolises R-warfarin). The inhibition results in increased warfarin levels, INR elevation and significant bleeding risk — the ketoconazole and warfarin labels both mention this interaction. Whenever possible the combination should be avoided (alternative antifungals with fewer interactions exist); if unavoidable, reduce the warfarin dose, monitor the INR frequently at initiation and watch for bleeding signs.
Ketoconazole inhibits CYP2C9 and CYP3A4 and can markedly raise the INR. Avoid if possible; if unavoidable, reduce warfarin and monitor the INR closely.
CYP2C9 (and CYP3A4) inhibition by ketoconazole reduces warfarin metabolism and raises the INR.
INR, signs of bleeding (gums, bruising, melena).
Unexplained bleeding, haematuria, melena, intracranial haemorrhage.
Monitor the INR more frequently after starting/stopping ketoconazole; adjust the warfarin dose accordingly.
DailyMed/FDA (NIH/NLM) — approved Ketoconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f162e616-21b4-49b1-b437-15e21001a6f0 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Ciprofloxacin may potentiate the anticoagulant effect of Warfarin, raising the INR and the bleeding risk.
Ciprofloxacin increases the effect of warfarin through three pathways: inhibition of CYP1A2 and CYP3A4 (enzymes that metabolise warfarin), reduction of the gut flora producing vitamin K and, potentially, displacement of protein binding. There are reports of marked INR elevations and severe, sometimes fatal, bleeding, so the warfarin label recommends INR monitoring when a fluoroquinolone is started or stopped. The interaction is more pronounced in the elderly and in patients with multiple comorbidities. Monitor the INR frequently during and after the antibiotic course and adjust the dose.
Ciprofloxacin inhibits CYP1A2/CYP3A4 and reduces gut flora, potentially raising the INR markedly. Monitor the INR during and after the antibiotic.
Ciprofloxacin inhibits CYP1A2 and, to a lesser extent, CYP3A4, reducing Warfarin metabolism; altered vitamin K-producing gut flora also contributes to the enhanced anticoagulant effect.
Monitor the INR more frequently and watch for bleeding signs.
An elevated INR, bleeding or spontaneous bruising require immediate evaluation.
Monitor the INR and adjust the warfarin dose during the combination; reinforce bleeding surveillance.
DailyMed/FDA (NIH/NLM) — approved Ciprofloxacin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=57e5832f-9168-1f24-e063-6294a90aaae6 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Clarithromycin inhibits CYP3A4 and may potentiate the anticoagulant effect of Warfarin, raising the INR and the bleeding risk.
Clarithromycin is a potent CYP3A4 inhibitor, the main enzyme in R-warfarin metabolism, and simultaneously reduces the gut flora producing vitamin K. The result is INR elevation with increased bleeding risk, documented in many reports and mentioned in approved labels. The effect can appear within days of starting and persist after the antibiotic is stopped. Whenever possible, choose an alternative antibiotic (e.g. azithromycin has lower interaction potential); if clarithromycin is needed, monitor the INR frequently and reduce the warfarin dose as needed.
Clarithromycin inhibits CYP3A4 and reduces gut flora, potentially raising the INR and bleeding risk markedly. Monitor the INR during and after the antibiotic; consider an alternative.
Clarithromycin is a potent CYP3A4 inhibitor; it reduces Warfarin metabolism, raising plasma warfarin levels and the INR.
Monitor the INR frequently and watch for bleeding signs during and after the combination.
Active bleeding, a markedly elevated INR or new bruising require urgent intervention.
Adjust the warfarin dose based on the INR; consider an alternative antibiotic when possible.
DailyMed/FDA (NIH/NLM) — approved Clarithromycin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d836ae7e-fdbf-4dcb-a90d-ede1dcbc3e67 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Chloroquine can enhance the effect of Warfarin, raising the INR and the bleeding risk.
Chloroquine and its analogues can inhibit warfarin metabolism and raise the INR, although the exact mechanism is not fully established (possible CYP2C9 inhibition and an effect on gut flora). Reports exist of INR elevation and bleeding when chloroquine is added to warfarin. The INR should be monitored at the start and end of antimalarial treatment and the warfarin dose adjusted; watch for bleeding signs, especially in prolonged treatment (e.g. systemic lupus erythematosus, rheumatoid arthritis).
Chloroquine can increase the effect of warfarin (metabolism inhibition). Monitor the INR when starting and stopping the antimalarial.
Mechanism not fully established; possible reduction of Warfarin clearance.
INR (more often in the first weeks) and signs of bleeding.
Bleeding, easy bruising, dark stools.
Monitor the INR after starting/stopping Chloroquine and adjust the Warfarin dose.
DailyMed/FDA (NIH/NLM) — approved Chloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=06c69e2b-211b-4746-9f3a-f86d36520570 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Combining Efavirenz with Warfarin may increase or decrease the anticoagulant effect, with a risk of bleeding or thrombosis.
Efavirenz induces CYP3A4 and CYP2C9 (among other isoenzymes), accelerating warfarin metabolism and reducing its plasma levels. The usual result is a decrease in the INR, with thrombosis risk if the dose is not adjusted; however, the effect varies between patients and there may be phases of INR instability in both directions. The INR should be monitored frequently at efavirenz initiation and discontinuation and the warfarin dose adjusted accordingly, with vigilance for thromboembolism and bleeding signs.
Efavirenz induces CYP2C9/CYP3A4 and can REDUCE the effect of warfarin. Monitor the INR when starting and stopping the antiretroviral and adjust the dose.
As an enzyme inducer, Efavirenz alters Warfarin metabolism; the net effect is variable between patients.
Frequent INR at start and dose changes.
A high INR or signs of bleeding/thrombosis require anticoagulant adjustment.
Monitor the INR and adjust the Warfarin dose during co-administration.
DailyMed/FDA (NIH/NLM) — approved Efavirenz label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=92603fa5-7a2c-4bfb-9a70-aadb4fba952c ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Erythromycin may potentiate the anticoagulant effect of Warfarin, raising the INR and the bleeding risk.
Erythromycin inhibits CYP3A4, the enzyme that metabolises R-warfarin, and reduces the gut flora producing vitamin K. This dual action increases the anticoagulant effect, with INR elevation and bleeding risk documented in clinical reports and mentioned in approved labels. The effect can be rapid (days) and persist after the antibiotic ends. Monitor the INR frequently during and after treatment and adjust the warfarin dose; consider an alternative antibiotic when possible.
Erythromycin inhibits CYP3A4 and reduces gut flora, potentially raising the INR markedly. Monitor the INR during and after the antibiotic.
Erythromycin inhibits CYP3A4 and CYP1A2, reducing Warfarin metabolism (mainly the active isomer); higher anticoagulant levels raise the INR.
Monitor the INR more frequently and watch for bleeding signs (bruising, gum bleeding, melena).
Bleeding, a very high INR or signs of hemorrhage require discontinuation/adjustment and urgent medical evaluation.
Monitor the INR and adjust the warfarin dose during and after antibiotic therapy; inform the patient of the bleeding risk.
DailyMed/FDA (NIH/NLM) — approved Erythromycin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=49b3ca93-43cc-439c-8f5d-e3ea2e87ad2f ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Fluconazole potentiates the anticoagulant effect of Warfarin, markedly raising the INR and the bleeding risk.
Fluconazole is a potent inhibitor of CYP2C9, the isoenzyme that metabolises active S-warfarin; the effect is dose-dependent and more marked at high doses (e.g. 400 mg/day). The inhibition raises warfarin levels and the INR, with significant bleeding risk — a well-documented interaction mentioned in the approved fluconazole and warfarin labels. Reduce the warfarin dose when starting fluconazole, monitor the INR frequently and re-adjust after the antifungal is stopped; watch for bleeding signs.
Fluconazole inhibits CYP2C9 and can markedly raise the INR. Monitor the INR closely and reduce the warfarin dose when starting the antifungal.
CYP2C9 inhibition by fluconazole reduces the metabolism of the active S-warfarin isomer, raising the INR.
INR, signs of bleeding (gums, bruising, melena).
Unexplained bleeding, haematuria, melena.
Monitor the INR frequently (on starting and stopping fluconazole); reduce the warfarin dose as needed.
DailyMed/FDA (NIH/NLM) — approved Fluconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7961c029-746c-48c3-888b-8f8344102873 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Hydroxychloroquine may increase the effect of Warfarin — bleeding risk.
Hydroxychloroquine, like chloroquine, can inhibit warfarin metabolism and raise the INR, although the mechanism is not fully established. Reports are more frequent in patients with systemic lupus erythematosus or rheumatoid arthritis on chronic treatment, in whom the interaction can manifest weeks after initiation. The INR should be monitored at initiation and discontinuation of hydroxychloroquine and the warfarin dose adjusted; watch for bleeding signs.
Hydroxychloroquine can increase the effect of warfarin. Monitor the INR when starting and stopping, especially in prolonged treatment (lupus, rheumatoid arthritis).
Possible inhibition of Warfarin metabolism (CYP2C9).
INR and signs of bleeding.
Bleeding, bruising, dark stools.
Monitor the INR on starting/stopping and adjust the dose.
DailyMed/FDA (NIH/NLM) — approved Hydroxychloroquine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=34496b43-05a2-45fb-a769-52b12e099341 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Isoniazid may enhance the effect of Warfarin — raised INR and bleeding risk.
Isoniazid inhibits several cytochrome P450 isoenzymes, including CYP2C9 and CYP3A4, and can reduce warfarin metabolism, raising the INR. The effect is variable and coexists with the complexity of antituberculosis regimens (which often include rifampicin, a potent inducer — the interaction network is complex and the INR can swing in both directions). The INR should be monitored frequently when starting, adjusting and stopping each component of the antituberculosis regimen, and the warfarin dose adjusted accordingly.
Isoniazid can inhibit warfarin metabolism and raise the INR. Monitor the INR during tuberculosis treatment and adjust the dose.
CYP2C9 inhibition, the main Warfarin metabolic pathway.
INR, signs of bleeding.
Bleeding, bruising, dark stools.
Monitor the INR when starting/stopping isoniazid and adjust the dose.
DailyMed/FDA (NIH/NLM) — approved Isoniazid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=93252cc8-c8d4-401b-bde5-ca8a3b57651e ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Itraconazole potentiates the anticoagulant effect of Warfarin, increasing the bleeding risk.
Itraconazole is a potent CYP3A4 inhibitor and also affects CYP2C9, enzymes involved in warfarin metabolism. The inhibition results in increased warfarin levels, INR elevation and bleeding risk — an interaction mentioned in approved labels. Whenever possible, choose an alternative antifungal with lower interaction potential; if itraconazole is unavoidable, reduce the warfarin dose, monitor the INR frequently at initiation and during treatment and watch for bleeding signs.
Itraconazole inhibits CYP3A4 (and CYP2C9) and can markedly raise the INR. Avoid if possible; if unavoidable, reduce warfarin and monitor the INR closely.
Metabolic inhibition (CYP2C9/CYP3A4) of warfarin by itraconazole, raising the INR.
INR, signs of bleeding (gums, bruising, melena).
Unexplained bleeding, haematuria, melena.
Monitor the INR frequently after starting/stopping itraconazole; adjust the warfarin dose.
DailyMed/FDA (NIH/NLM) — approved Itraconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a4d555fa-787c-40fb-bb7d-b0d4f7318fd0 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Levofloxacin may potentiate the anticoagulant effect of Warfarin, raising the INR and the bleeding risk.
Levofloxacin, like other fluoroquinolones, can potentiate warfarin by reducing the gut flora producing vitamin K and by inhibiting cytochrome P450 isoenzymes (CYP1A2 and CYP3A4), although its inhibition potential is lower than ciprofloxacin's. Reports exist of INR elevation and bleeding. The INR should be monitored during and after the antibiotic course and the warfarin dose adjusted; the risk is higher in the elderly and in patients with reduced hepatic or renal function.
Levofloxacin can increase the effect of warfarin (enzyme inhibition + gut flora). Monitor the INR during and after the antibiotic.
Quinolones (including levofloxacin) may prolong prothrombin time in patients on oral anticoagulants through metabolic inhibition and possible gut flora changes.
Monitor the INR and bleeding signs during and after therapy.
Bleeding or an elevated INR require urgent medical evaluation.
Monitor the INR and adjust the warfarin dose; inform the patient of the bleeding risk.
DailyMed/FDA (NIH/NLM) — approved Levofloxacin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5c6c117c-9d91-48f4-9aaa-ee70b99218c2 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Metronidazole inhibits Warfarin metabolism, potentiating its anticoagulant effect, with a raised INR and bleeding risk.
Metronidazole is a potent inhibitor of CYP2C9, the enzyme that metabolises active S-warfarin, and has been associated with marked INR elevations and bleeding, including severe cases. The effect can appear within days of starting the antibiotic. The warfarin label lists metronidazole among the drugs that potentiate its effect. The INR should be monitored frequently during and after treatment, a warfarin dose reduction should be considered, and bleeding signs watched for; in patients with a borderline INR the interaction can be particularly dangerous.
Metronidazole inhibits CYP2C9 and can markedly raise the INR. Monitor the INR during and after the antibiotic and consider a warfarin dose reduction.
Metronidazole inhibits the hepatic enzymes (CYP2C9/CYP3A4) that metabolize oral anticoagulants, raising Warfarin levels and prolonging prothrombin time.
Monitor the INR frequently and watch for bleeding signs.
Active bleeding, an elevated INR or new bruising require urgent evaluation.
Adjust the warfarin dose based on the INR and reinforce bleeding surveillance during and after the combination.
DailyMed/FDA (NIH/NLM) — approved Metronidazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d5784eeb-6b99-4e8a-847b-b0d1090ed48a ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Nevirapine with Warfarin reduces the anticoagulant effect of Warfarin, posing a risk of thrombotic events.
Nevirapine induces CYP3A4 and CYP2B6 and can accelerate warfarin metabolism, reducing its levels and the INR. The risk is loss of anticoagulation and thromboembolism if the dose is not adjusted; the inducing effect develops over 2–4 weeks and persists after discontinuation. The INR should be monitored frequently at nevirapine initiation and discontinuation and the warfarin dose adjusted accordingly, with vigilance for thrombosis signs.
Nevirapine induces CYP3A4/CYP2B6 and can REDUCE the effect of warfarin. Monitor the INR when starting and stopping the antiretroviral.
As a cytochrome P450 inducer, Nevirapine increases Warfarin metabolism, lowering its concentrations and its effect.
INR monitoring at start and dose changes; signs of thromboembolism.
A high INR with bleeding or signs of thrombosis requires immediate anticoagulant adjustment.
Monitor the INR and adjust the Warfarin dose whenever Nevirapine is started, stopped or changed.
DailyMed/FDA (NIH/NLM) — approved Nevirapine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fbd628db-4076-4fe0-8323-9cc33ae92e42 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Piperacillin + Tazobactam may potentiate Warfarin and interfere with haemostasis, with a bleeding risk.
Piperacillin-tazobactam is a broad-spectrum antibiotic that reduces the gut flora producing vitamin K, decreasing the availability of the cofactor for carboxylation of the vitamin K-dependent coagulation factors. Since warfarin acts by inhibiting vitamin K epoxide reductase, the anticoagulant effect is potentiated and the INR rises. The risk is higher in critically ill, malnourished, liver-disease patients or with prolonged treatment — a frequent context for this antibiotic. Monitor the INR during and after treatment and adjust the warfarin dose; watch for bleeding.
Piperacillin-tazobactam can potentiate warfarin by reducing the gut flora that produces vitamin K. Monitor the INR during and after the antibiotic.
Reduction of vitamin-K-producing flora and platelet dysfunction (piperacillin may prolong bleeding time), especially at high doses and in renal impairment.
INR, renal function, platelet count, signs of bleeding.
Active bleeding, extensive bruising, haemoptysis/melena.
Monitor the INR and bleeding signs; consider warfarin adjustment and caution in renal patients or at high doses.
DailyMed/FDA (NIH/NLM) — approved Piperacillin + Tazobactam label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7aebc0e6-89db-4ef0-b5ab-d6b3199bcfc4 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Quinine may increase the effect of Warfarin — bleeding risk.
Quinine inhibits warfarin metabolism (CYP2C9 and CYP3A4) and, through its high plasma protein binding, can displace the active free fraction. The result is a marked INR elevation with bleeding risk — a well-documented interaction, with reports of severe bleeding in patients using quinine (or quinine-containing tonic water in large amounts) with warfarin. The INR should be monitored frequently during treatment and after discontinuation, the warfarin dose reduced if needed, and the patient alerted to bleeding signs.
Quinine inhibits CYP2C9/CYP3A4 and is highly protein-bound, potentially raising the INR markedly. Monitor the INR closely and consider a warfarin dose reduction.
Inhibition of Warfarin metabolism (CYP2C9) and possible protein displacement.
Frequent INR and signs of bleeding.
Bleeding, bruising, dark stools.
Monitor the INR and adjust the dose.
DailyMed/FDA (NIH/NLM) — approved Quinine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1f32f05c-a215-40be-b951-e41a7b54a8a0 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Rifampin accelerates Warfarin metabolism and lowers the INR — risk of thrombosis from under-anticoagulation.
Rifampicin is one of the most potent inducers of CYP2C9 and CYP3A4, the enzymes that metabolise warfarin. The induction accelerates warfarin elimination and markedly reduces the INR, with thromboembolism risk; studies show reductions of more than 50% in warfarin exposure. Some patients need the warfarin dose doubled or even tripled, with frequent INR monitoring, and the dose must be re-adjusted in the 1–2 weeks after rifampicin is stopped, because the inducing effect fades gradually and the INR can then rise. This interaction is particularly relevant in tuberculosis treatment in anticoagulated patients.
Rifampicin is a potent CYP2C9/CYP3A4 inducer and can markedly REDUCE the effect of warfarin (low INR, thrombosis risk). Warfarin may need to be doubled or tripled with close monitoring.
CYP2C9 (and CYP3A4) induction, the main Warfarin metabolic pathway.
Weekly INR when starting; signs of thrombosis.
DVT/PE, stroke, limb ischaemia.
Monitor the INR when starting/stopping rifampin and adjust the dose.
DailyMed/FDA (NIH/NLM) — approved Rifampin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b389b1a3-672f-47e3-916c-4a9c044b211b ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Combining Ritonavir with Warfarin can unpredictably alter the anticoagulant effect of Warfarin, posing a risk of bleeding or thrombotic events.
Ritonavir has a complex pharmacokinetic profile: it is a potent inhibitor of CYP3A4 and CYP2D6, but also an inducer of other enzymes and transporters. The net effect on warfarin is variable and unpredictable between patients — most reports show an INR increase, but cases of reduction exist. When ritonavir is used at low boosting doses (with other antiretrovirals), the effect is equally variable. The INR should be monitored frequently at initiation, during and after ritonavir discontinuation, adjusting the warfarin dose according to the result and alerting for bleeding and thrombosis signs.
Ritonavir inhibits and induces several CYP isoenzymes; the net effect on warfarin is unpredictable (usually an INR increase). Monitor the INR closely when starting and stopping.
Ritonavir is a potent inhibitor of CYP3A4 and P-glycoprotein; Warfarin is mainly metabolised by CYP2C9. The net effect on warfarin exposure is variable (increase or decrease) between patients, requiring monitoring.
Frequent INR at start and at each dose change; watch for bleeding signs (spontaneous bruising, gum bleeding, haematuria) and thrombotic symptoms.
INR above 3.5 or active bleeding requires immediate discontinuation or adjustment of the anticoagulant.
Maintain INR monitoring whenever Ritonavir is started, stopped or adjusted; titrate the Warfarin dose based on the INR. When possible, prefer anticoagulants with more predictable pharmacokinetics.
DailyMed/FDA (NIH/NLM) — approved Ritonavir label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2849298e-de6e-47bb-8194-56e075b33fc3 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Voriconazole potentiates the anticoagulant effect of Warfarin, raising the INR and the bleeding risk.
Voriconazole inhibits CYP2C9 (which metabolises active S-warfarin) and CYP3A4, with a clinically relevant documented effect: studies at therapeutic doses showed substantial increases in the INR and warfarin exposure when voriconazole is added. The voriconazole label recommends INR monitoring and warfarin dose adjustment. The interaction is particularly relevant in patients with invasive aspergillosis, often already in a fragile clinical state. Monitor the INR frequently at voriconazole initiation and discontinuation and watch for bleeding signs.
Voriconazole inhibits CYP2C9/CYP3A4 and can markedly raise the INR. Monitor the INR closely and consider a warfarin dose reduction.
CYP2C9 inhibition by voriconazole reduces warfarin metabolism.
INR, signs of bleeding.
Unexplained bleeding, melena.
Monitor the INR frequently; adjust the warfarin dose as needed.
DailyMed/FDA (NIH/NLM) — approved Voriconazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f6a1a792-141b-42e8-8bd1-884e4408eb8a ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Coxib + anticoagulant: increased bleeding risk.
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors such as celecoxib, increase the bleeding risk in anticoagulated patients through mechanisms that add to warfarin's: platelet aggregation inhibition, gastric mucosal injury and, in some cases, interference with warfarin metabolism. Celecoxib has less antiplatelet and gastrointestinal effect than non-selective NSAIDs, but the overall bleeding risk remains increased. Use the lowest effective dose for the shortest time, monitor the INR when celecoxib is started or adjusted, and watch for gastrointestinal bleeding signs; consider gastroprotection in at-risk patients.
NSAID + warfarin: increased bleeding risk (GI and general). Celecoxib is preferable to other NSAIDs, but requires INR monitoring and bleeding vigilance.
Celecoxib may increase gastrointestinal bleeding risk and interact with anticoagulation.
INR and GI symptoms during the combination.
Melena, haematemesis, spontaneous ecchymosis.
Use with caution, consider gastroprotection and watch for bleeding signs.
DailyMed (FDA) — approved Celecoxib label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b06ced10-81c6-4f48-a205-1e0db228cb8b ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Colchicine + anticoagulant: possible increased anticoagulant effect.
Colchicine is a substrate and inhibitor of CYP3A4, an enzyme involved in warfarin metabolism; the inhibition can reduce warfarin clearance and raise the INR. The interaction is especially relevant in prolonged treatment (e.g. gout prophylaxis, familial Mediterranean fever), in which the effect accumulates. Monitor the INR when starting colchicine and after dose changes, and watch for bleeding signs; in renal or hepatic impairment, the toxicity risk of both drugs increases.
Colchicine inhibits CYP3A4 and can raise warfarin levels and the INR. Monitor the INR when starting and adjust the dose.
Colchicine may interfere with warfarin metabolism/effect, raising INR.
Periodic INR during the combination.
Bleeding, spontaneous ecchymosis.
Monitor INR after starting or changing colchicine dose.
DailyMed (FDA) — approved Colchicine label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5ae87893-a065-468e-b8da-f1db86afcaef ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Dabigatran-warfarin transition should follow a protocol to avoid under- or over-anticoagulation.
The combination of warfarin and dabigatran (two anticoagulants with different mechanisms — vitamin K antagonism and direct thrombin inhibition) has no therapeutic indication and multiplies the risk of major bleeding, including intracranial haemorrhage. Switching between the two drugs must follow a protocol: when changing from warfarin to dabigatran, stop warfarin and start dabigatran when the INR is below the threshold; conversely, start warfarin a few days before stopping dabigatran, monitoring the INR. Dual anticoagulation can occur transiently in poorly managed switches or by medication error — alert the patient to bleeding signs.
Two anticoagulants at the same time: additive bleeding risk. Do not combine; switching between warfarin and dabigatran requires a protocol (stop one, start the other with controlled INR/coagulation).
Switching requires coordination between dabigatran's immediate effect and warfarin's delayed onset.
Monitor INR and bleeding signs during the transition.
Supratherapeutic INR or bleeding during transition.
Follow the SmPC transition schedule; adjust with the INR.
DailyMed (FDA) — approved Dabigatran label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f7ea7e2c-ca54-4ecc-9fc7-bd3571b0ebc2 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Corticosteroid + anticoagulant: altered INR and bleeding risk.
Corticosteroids, including dexamethasone, can modify the response to warfarin in both directions: most reports show an INR decrease (possibly through enzyme induction and fluid retention), but cases of increased effect exist, and the response is unpredictable between patients. The interaction is most relevant in prolonged courses or high doses. The INR should be monitored frequently when starting, adjusting and stopping dexamethasone and the warfarin dose adjusted accordingly; the INR must be re-evaluated after corticosteroid discontinuation.
Corticosteroids can alter the effect of warfarin (usually an INR decrease by induction, but variable). Monitor the INR when starting, adjusting and stopping dexamethasone.
Corticosteroids may potentiate or reduce warfarin effect (variable effect on haemostasis and GI mucosa).
Periodic INR and GI symptoms.
Melena, haematemesis, bleeding.
Monitor INR after starting/adjusting corticosteroids; consider gastroprotection.
DailyMed (FDA) — approved Dexamethasone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7cbd9005-7df2-47ee-adb3-7244c1c69bc3 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
NSAID + anticoagulant: increased bleeding risk.
Diclofenac, like other NSAIDs, increases the bleeding risk in warfarin patients through three pathways: reversible platelet aggregation inhibition, gastric mucosal injury (ulcer and GI bleeding risk) and possible interference with warfarin pharmacokinetics. The risk of serious gastrointestinal bleeding with the NSAID + anticoagulant combination is substantial and well documented. Whenever possible, use alternative analgesics (paracetamol at controlled doses); if diclofenac is unavoidable, use the lowest effective dose for the shortest time, consider gastroprotection (PPI) and monitor the INR and bleeding signs.
NSAID + warfarin: increased bleeding risk (GI and general). Avoid NSAIDs in anticoagulated patients; if unavoidable, use the lowest dose, gastroprotection and INR monitoring.
Diclofenac inhibits COX and platelet aggregation and may interact with warfarin, enhancing anticoagulation.
INR and GI symptoms.
Melena, haematemesis, ecchymosis.
Use the lowest NSAID dose; consider gastroprotection and watch for bleeding.
DailyMed (FDA) — approved Diclofenac label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2d45648f-cbea-41a4-8e3e-007b7bb7912c ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Epoetin alfa may alter the response to warfarin; monitor INR when the erythropoietin dose is adjusted.
Epoetin alfa stimulates erythropoiesis and can alter the response to warfarin: the accelerated production of red cells increases vitamin K consumption (needed for synthesis of coagulation factors) and can lower the INR, sometimes requiring a warfarin dose increase. Reports also exist of variation in both directions. The interaction is most relevant in chronic kidney disease patients on prolonged epoetin treatment. The INR should be monitored frequently when starting and adjusting epoetin and during treatment, adjusting the warfarin dose as needed.
Epoetin can reduce the anticoagulant effect of warfarin (possible haematocrit rise and vitamin K consumption). Monitor the INR during erythropoietin treatment.
Improved erythropoiesis and haematocrit changes may alter warfarin pharmacodynamics.
Monitor INR and signs of bleeding or thrombosis.
Unstable INR, thrombotic events (vascular access thrombosis).
Monitor INR more frequently when starting or adjusting epoetin.
DailyMed (FDA) — approved Epoetin alfa label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1f2d0b28-9cc5-4523-80b8-637fdaf3f7a5 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Combining Phenytoin with Warfarin reduces the anticoagulant effect of Warfarin, posing a risk of thrombotic events.
The phenytoin-warfarin interaction is one of the most complex in clinical pharmacology: phenytoin induces CYP2C9 and CYP2C19 (which can reduce warfarin's effect) but also competes with warfarin for plasma protein binding, and warfarin itself inhibits phenytoin metabolism, raising its levels and the risk of neurological toxicity (nystagmus, ataxia, sedation). The net effect on the INR is unpredictable and can oscillate in the first weeks. The INR and serum phenytoin levels should be monitored at initiation and whenever either drug is adjusted, with gradual dose changes.
Complex bidirectional interaction: phenytoin induces and inhibits CYP2C9, and warfarin raises phenytoin levels. Monitor INR and phenytoin levels when starting, adjusting and stopping.
As an enzyme inducer, Phenytoin accelerates Warfarin metabolism, lowering its concentrations and its anticoagulant effect.
Frequent INR at start and dose changes; signs of thromboembolism.
A suboptimal INR or thrombotic events require Warfarin dose adjustment.
Monitor the INR and adjust the Warfarin dose during co-administration.
DailyMed/FDA (NIH/NLM) — approved Phenytoin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ef4e97a7-cd18-47a9-a016-2eca5481a87e ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Combining Phenobarbital with Warfarin reduces the anticoagulant effect of Warfarin, posing a risk of thrombotic events.
Phenobarbital is a potent inducer of CYP2C9, CYP2C19 and CYP3A4, the enzymes that metabolise warfarin, and accelerates its elimination — the anticoagulant effect decreases and the INR falls, with thromboembolism risk if the dose is not adjusted. The inducing effect takes 1–3 weeks to fully develop and persists for several weeks after phenobarbital is stopped, when the INR can rise sharply. The INR should be monitored frequently when starting, during and after phenobarbital, increasing the warfarin dose as needed and re-adjusting it during the withdrawal phase.
Phenobarbital strongly induces CYP2C9/CYP3A4 and can markedly REDUCE the effect of warfarin. The warfarin dose may need to be increased with close monitoring; re-adjust after stopping.
As an enzyme inducer, Phenobarbital accelerates Warfarin metabolism, reducing its anticoagulant effect.
Frequent INR at start and dose changes.
A suboptimal INR or thrombotic events require anticoagulant adjustment.
Monitor the INR and adjust the Warfarin dose during co-administration.
DailyMed/FDA (NIH/NLM) — approved Phenobarbital label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fa09b4f2-edb0-4594-a2d2-b16f7b9686b4 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Phytomenadione (vitamin K1) antagonises the anticoagulant effect of warfarin, lowering the INR.
Phytomenadione (vitamin K1) is the antidote to warfarin: it replenishes the cofactor needed to carboxylate factors II, VII, IX and X and reverses the anticoagulant effect, lowering the INR within hours. This interaction is intentional in the reversal of supratherapeutic INR or bleeding, but accidental (e.g. multivitamin supplements, vitamin-K-rich diet) causes INR instability and thrombosis risk. After vitamin K administration, warfarin may take days to weeks to return to therapeutic effect, and the dose must be re-adjusted with INR monitoring. In anticoagulated patients, advise consistency in vitamin K intake and review supplements.
Vitamin K (phytomenadione) directly antagonises warfarin and lowers the INR — it is the antidote used for reversal. Administer only with an indication (supratherapeutic INR or bleeding) and monitor re-anticoagulation.
Vitamin K replenishes the substrate for factors II, VII, IX and X, reversing warfarin's block.
Monitor INR and signs of thrombosis after reversal.
Subtherapeutic INR or thrombotic events after excessive reversal.
Use vitamin K1 as indicated (reversal, correction of supratherapeutic INR); reassess INR 24 h after.
DailyMed (FDA) — approved Phytomenadione label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c7ef968-2c76-4220-a9ec-3179d243c422 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Leflunomida + anticoagulant: possible increased anticoagulant effect.
Leflunomide (and its active metabolite teriflunomide) has been associated with INR elevation in warfarin-anticoagulated patients, with reports of severe bleeding. The mechanism is not fully established but probably involves interference with warfarin metabolism. The effect can appear weeks after starting leflunomide. The INR should be monitored frequently when starting leflunomide and after dose changes, and bleeding signs watched for; if rapid discontinuation is needed, consider the cholestyramine washout procedure described in the label.
Leflunomide can raise the INR in warfarin patients. Monitor the INR when starting and adjust the dose; cases of severe bleeding described.
Leflunomide may inhibit warfarin metabolism, raising INR.
Periodic INR during the combination.
Bleeding, spontaneous ecchymosis.
Monitor INR after starting or changing leflunomide dose.
DailyMed (FDA) — approved Leflunomide label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fc044417-cd9a-42f6-8a3d-a14e7c2f81a2 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Metamizole may potentiate the effect of oral anticoagulants, increasing bleeding risk.
Metamizole (dipyrone) can increase the effect of warfarin through a pharmacokinetic interaction (metabolism inhibition, with INR elevation) and its own antiplatelet effect; cases of severe bleeding, including gastrointestinal bleeding, have been described. The EMA, in its metamizole review, mentions the need for INR monitoring in anticoagulated patients. Whenever possible, use alternative analgesics (paracetamol at controlled doses); if metamizole is used, monitor the INR frequently and alert for bleeding signs.
Metamizole can potentiate warfarin (pharmacokinetic interaction and antiplatelet effect). Monitor the INR and watch for bleeding; prefer paracetamol as first-line analgesic.
Mechanism not fully established; metamizole may enhance coumarin anticoagulants and increase gastrointestinal bleeding risk.
INR, bruising, bleeding and fall in haemoglobin.
INR above target or active bleeding require anticoagulant adjustment.
Monitor INR and signs of bleeding; where possible prefer paracetamol as analgesic.
EMA — Metamizole (Article 31 referral): https://www.ema.europa.eu/en/medicines/human/referrals/metamizole-containing-medicinal-products ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional references: Prontuário Terapêutico do INFARMED (11th ed., 2012) and national Analgin 500 mg SmPC (HALMED)
NSAID + anticoagulant: increased bleeding risk (gastrointestinal and systemic).
Naproxen, like other NSAIDs, increases the bleeding risk in warfarin patients: it inhibits platelet aggregation (prolongedly, given its long half-life), injures the gastric mucosa and can interfere with warfarin pharmacokinetics. The NSAID + anticoagulant combination is associated with a substantial risk of serious gastrointestinal bleeding. Whenever possible, use alternative analgesics; if naproxen is unavoidable, use the lowest effective dose for the shortest time, consider gastroprotection and monitor the INR and bleeding signs.
NSAID + warfarin: increased bleeding risk (GI and general). Avoid NSAIDs in anticoagulated patients; if unavoidable, lowest dose, gastroprotection and INR monitoring.
NSAIDs inhibit COX and platelet aggregation and may displace warfarin from protein binding, enhancing anticoagulation.
More frequent INR monitoring when starting the NSAID; assess full blood count and GI symptoms.
Blood in stools/melena, haematemesis, skin or mucosal bleeding.
Use the lowest NSAID dose for the shortest time; consider gastroprotection (PPI). Watch for signs of bleeding.
DailyMed (FDA) — approved Naproxen label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=24d44eb6-921e-4150-a6b2-81f42ced32ab ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Omeprazole may slightly increase the effect of warfarin, with a risk of INR elevation.
Omeprazole inhibits CYP2C19, an enzyme involved in R-warfarin metabolism; the inhibition can reduce warfarin clearance and raise the INR, although the effect is generally modest and variable between patients. Other proton pump inhibitors with less CYP2C19 affinity (e.g. pantoprazole) are sometimes preferred in anticoagulated patients. The INR should be monitored when omeprazole is started or stopped, especially in patients with a borderline INR or relevant genetic polymorphisms, and the dose adjusted as needed.
Omeprazole inhibits CYP2C19 and can slightly raise the INR (usually modest, but relevant in sensitive patients). Monitor the INR when starting the PPI.
Omeprazole inhibits CYP2C19 and may alter warfarin metabolism (R-isomer).
Monitor the INR more frequently.
Bleeding from supratherapeutic INR.
Monitor the INR when starting or stopping omeprazole.
DailyMed (FDA) — approved Omeprazole label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6ea9a6f3-b756-4cdf-b3db-f666a2c17d66 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Orlistat may reduce vitamin K absorption and alter the INR in patients taking warfarin.
Orlistat inhibits gastrointestinal lipases and reduces absorption of dietary fats and fat-soluble vitamins, including vitamin K. Since warfarin is a vitamin K antagonist, the lower availability of the cofactor can increase the anticoagulant effect and the INR; cases of elevated INR and bleeding have been described, especially in the first weeks of treatment. The INR should be monitored at initiation and during orlistat treatment and the warfarin dose adjusted; maintain consistent vitamin K intake and watch for bleeding signs.
Orlistat reduces absorption of fats and fat-soluble vitamins, including vitamin K, potentially raising the INR. Monitor the INR when starting and during treatment.
Reduced fat-soluble vitamin K absorption interferes with synthesis of vitamin K-dependent clotting factors.
Monitor bleeding signs and INR.
Bleeding or thrombotic events from unstable INR.
Monitor the INR more frequently when starting, adjusting or stopping orlistat.
DailyMed (FDA) — approved Orlistat label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a2d3bd73-f3af-4ea5-a57c-66b0004cfe4f ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Regular, prolonged use of paracetamol may enhance the anticoagulant effect of warfarin (INR), especially with daily use.
Paracetamol is the preferred analgesic in anticoagulated patients because it lacks the gastrointestinal bleeding risk of NSAIDs, but at high doses or with prolonged use it can raise the INR: the mechanism involves glutathione depletion and interference with the synthesis of vitamin K-dependent coagulation factors (the NAPQI metabolite inhibits vitamin K-dependent carboxylation). Studies show INR elevations with doses ≥ 2 g/day maintained for several days. Use the lowest effective dose, do not exceed 2–3 g/day continuously and monitor the INR in patients using paracetamol chronically.
Paracetamol at high doses or with prolonged use (>2 g/day for days) can raise the INR. Use the lowest effective dose and monitor the INR; paracetamol is preferred over NSAIDs.
Not yet fully established: likely interference with vitamin K and clotting factor metabolism.
Regular INR monitoring in patients taking paracetamol daily for more than a week.
Unusual bleeding, spontaneous bruising, gum bleeding, melaena.
Not contraindicated as a single dose. In chronic use, monitor INR and adjust warfarin if needed.
DailyMed/FDA (NIH/NLM) — approved Paracetamol label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4c737cd6-fe56-4cef-887c-cd6cf83b254c ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057
Corticosteroid + anticoagulant: altered INR and bleeding risk.
Prednisolone, like other corticosteroids, can modify the response to warfarin: most reports show an INR decrease (through enzyme induction and fluid retention with haemodilution), but cases of increased effect exist, and the response is unpredictable. The interaction is most relevant in prolonged courses or high doses (e.g. chronic inflammatory diseases, transplantation). The INR should be monitored frequently when starting, adjusting and stopping prednisolone and the warfarin dose adjusted accordingly, with INR re-evaluation after corticosteroid discontinuation.
Corticosteroids can alter the effect of warfarin (usually an INR decrease, but variable). Monitor the INR when starting, adjusting and stopping prednisolone.
Corticosteroids may potentiate or reduce warfarin effect (variable effect on haemostasis and GI mucosa).
Periodic INR and GI symptoms.
Melena, haematemesis, bleeding.
Monitor INR after starting/adjusting corticosteroids; consider gastroprotection.
DailyMed (FDA) — approved Prednisolone label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=52e6e21d-94b8-41a0-8d13-371c0e66bcee ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Switching between rivaroxaban and warfarin requires controlled overlap; prolonged simultaneous use increases bleeding.
The combination of warfarin and rivaroxaban (vitamin K antagonist + direct factor Xa inhibitor) has no therapeutic indication and substantially increases the risk of major bleeding, including intracranial haemorrhage. Switching between the two drugs must follow a protocol: when changing from warfarin to rivaroxaban, stop warfarin and start rivaroxaban when the INR is below the threshold (usually < 3.0); conversely, start warfarin overlapping with rivaroxaban until the INR is in the therapeutic range, then stop rivaroxaban. Prolonged dual anticoagulation is a medication error — alert the patient to bleeding signs.
Two anticoagulants at the same time: additive bleeding risk. Do not combine; switching between warfarin and rivaroxaban requires a protocol with controlled INR.
Overlap doubles anticoagulation; rivaroxaban's effect overlaps warfarin before it reaches the target INR.
Monitor INR per the transition protocol and bleeding signs.
Supratherapeutic INR, active bleeding during transition.
Follow the SmPC transition schedule: warfarin plus rivaroxaban for 2 days until INR ≥ 2.0 (and vice versa).
DailyMed (FDA) — approved Rivaroxaban label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=481b7802-5093-43e7-bbd9-1532197eb6e6 ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — additional reference: Prontuário Terapêutico do INFARMED (11th ed., 2012)
Combining Valproate with Warfarin may increase the anticoagulant effect and the risk of bleeding.
Valproate is extensively protein-bound (90% or more) and can displace warfarin from its binding sites, increasing the active free fraction and the anticoagulant effect; it can also interfere with warfarin metabolism. Reports exist of INR elevation and bleeding when valproate is added to warfarin. The INR should be monitored at initiation and during treatment and the warfarin dose adjusted; the effect is more relevant in patients with hypoalbuminaemia (elderly, liver disease), in whom the free fraction of both drugs is higher.
Valproate is protein-bound and can displace warfarin, raising the INR. Monitor the INR when starting and adjust the dose.
Valproate displaces Warfarin from plasma proteins, potentially increasing the free fraction and the anticoagulant effect.
Monitor the INR and signs of bleeding.
A high INR or active bleeding require anticoagulant adjustment.
Monitor the INR and watch for bleeding signs.
DailyMed/FDA (NIH/NLM) — approved Valproic acid label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a33f7657-ad0f-43e9-ba48-024746e6d08e ; approved Warfarin label: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=541c9a70-adaf-4ef3-94ba-ad4e70dfa057 — with additional reference: Prontuário Terapêutico do INFARMED, INFARMED (11th ed., 2012)
Foods rich in vitamin K (broccoli, leafy greens, spinach, liver) counteract warfarin's effect on vitamin K-dependent clotting factor synthesis, shifting the INR as dietary intake varies.
Keep dietary vitamin K intake stable and consistent; seek professional guidance before significant dietary changes; monitor INR after any change.
EMC-UK (MHRA) — approved Warfarin SmPC: https://www.medicines.org.uk/emc/product/2803/smpc
Case reports associate cranberry intake with INR elevation and bleeding risk; the mechanism is not fully established.
Advise avoiding cranberry products; if regular intake continues, reinforce INR monitoring.
EMC-UK (MHRA) — approved Warfarin SmPC: https://www.medicines.org.uk/emc/product/2803/smpc
Acute heavy alcohol intake may inhibit warfarin metabolism and raise INR, while chronic heavy intake may induce metabolism and reduce the anticoagulant effect.
Advise against heavy or binge drinking; moderate intake is acceptable if consistent, with INR monitoring if drinking habits change.
EMC-UK (MHRA) — approved Warfarin SmPC: https://www.medicines.org.uk/emc/product/2803/smpc
Warfarin is contraindicated in patients with cerebral haemorrhage because the risk of further bleeding outweighs any anticoagulant benefit.
Do not use warfarin after haemorrhagic stroke; after ischaemic stroke, reintroduction must balance infarct size and blood pressure control.
EMC-UK (MHRA) — approved Warfarin SmPC: https://www.medicines.org.uk/emc/product/2803/smpc
Any clinically significant bleeding, or a condition where bleeding risk outweighs clinical benefit, contraindicates anticoagulation.
Do not start warfarin in actively bleeding patients or those at high bleeding risk; reassess the need for anticoagulation regularly.
EMC-UK (MHRA) — approved Warfarin SmPC: https://www.medicines.org.uk/emc/product/2803/smpc
Protein C or S deficiency predisposes to skin necrosis during warfarin initiation.
Start warfarin without a loading dose in these patients, with close monitoring.
EMC-UK (MHRA) — approved Warfarin SmPC: https://www.medicines.org.uk/emc/product/2803/smpc
Active peptic ulceration carries a high risk of serious gastrointestinal bleeding during anticoagulation.
Weigh risk-benefit, educate the patient on bleeding signs and keep INR within the therapeutic range.
EMC-UK (MHRA) — approved Warfarin SmPC: https://www.medicines.org.uk/emc/product/2803/smpc
Warfarin is teratogenic (fetal warfarin syndrome in the 1st trimester) and is associated with fetal bleeding or fetal death in the 3rd trimester.
Contraindicated in the 1st and 3rd trimesters; also contraindicated within 48 hours after delivery.
Warfarin is excreted into breast milk in small amounts and, at therapeutic doses, has shown no adverse effects in the infant.
Women of child-bearing age must use effective contraception during treatment.
EMC-UK (MHRA) — approved Warfarin SmPC: https://www.medicines.org.uk/emc/product/2803/smpc
Clinical and educational support tool. The information does not replace a medical prescription or the opinion of a qualified healthcare professional.
Oral anticoagulant: the anticoagulant effect usually appears within 24 hours of administration, but peak effect may be delayed 72 to 96 hours. The duration of action of a single dose is 2 to 5 days. The half-lives of the vitamin K-dependent clotting factors explain this profile: factor II about 60 h, factor VII 4 to 6 h, factor IX 24 h, factor X 48 to 72 h, and the anticoagulant proteins C and S about 8 h and 30 h, respectively.
Warfarin inhibits the synthesis of the vitamin K-dependent clotting factors (II, VII, IX and X) and of the anticoagulant proteins C and S. Inhibition of the C1 subunit of the VKORC1 enzyme complex (vitamin K epoxide reductase) reduces the regeneration of vitamin K from its epoxide, decreasing the gamma-carboxylation of the vitamin K-dependent factors.
Warfarin is essentially completely absorbed after oral administration, with peak plasma concentrations usually reached within the first 4 hours. The volume of distribution is about 0.14 L/kg and approximately 99% of the drug is bound to plasma proteins.
Elimination is almost entirely by hepatic metabolism, stereoselectively: S-warfarin (2 to 5 times more active) is hydroxylated mainly by CYP2C9 (a polymorphic enzyme; the *2 and *3 variant alleles reduce its clearance), as well as CYP2C19, 2C8, 2C18, 1A2 and 3A4, yielding inactive hydroxylated metabolites; reductases convert it into warfarin alcohols with minimal activity. Very little warfarin is excreted unchanged in urine.
The terminal half-life after a single dose is about 1 week; however, the effective half-life ranges from 20 to 60 hours (mean about 40 hours). R-warfarin has a half-life of 37 to 89 hours and S-warfarin of 21 to 43 hours. Up to 92% of the oral dose is recovered in urine, mainly as metabolites.
Medicines from the same therapeutic group (ATC classification) or the same pharmacological class.
