Warfarin Sodium: Interactions
Many compounds interact with warfarin and other oral anticoagulants. Details of these interactions are given below for all oral anticoagulants with different groups of drugs; if the anticoagulant is other than warfarin, then its identity is specified. The major interactions are summarised in the tables, below.
| Drugs generally recognized as diminishing the effects of oral anticoagulants are included in the following list. Further information on the interactions with these drugs and others where the interaction is not so well recognised is provided in the referenced section below. |
|
| acetomenaphthone | ethchlorvynol |
| alcohol (chronic ingestion without liver impairment) | glutethimide |
| griseofulvin | |
| aminoglutethimide | nafcillin |
| barbiturates | phytomenadione |
| bosentan | rifampicin |
| carbamazepine | St John’s wort |
| dichloralphenazone | |
| Drugs recognised or generally reported as enhancing oral anticoagulants are included in the following list. Further information on the interactions with these drugs and others where the interaction is not so well recognised is provided in the referenced section below. | |
| alcohol (acute ingestion or chronic ingestion with liver impairment) | ethylestrenol |
| fluconazole | |
| glucagon | |
| allopurinol | itraconazole |
| amiodarone | ketoconazole |
| aspirin | metronidazole |
| cefamandole | miconazole |
| chloramphenicol | norethandrolone |
| cimetidine | NSAIDs |
| clofibrate | oxymetholone |
| cloral hydrate | quinidine |
| co-trimoxazole | stanozolol |
| danazol | sulfmpyrazone |
| dextropropoxyphene | tamoxifen |
| dextrothyroxine | telithromycin |
| dipyridamole | thyroid agents |
| disulfiram | tramadol |
| erythromycin | triclofos sodium |
| etacrynic acid | |
Interactions of a pharmacodynamic nature occurring with one anticoagulant may well apply to another but this may not be the case with pharmacokinetic interactions. Many food and herbal preparations also have the potential to interact with oral anticoagulants; some are discussed below.
An interaction may be due to increased or decreased anticoagulant metabolism; with warfarin some interacting drugs such as cimetidine, co-trimoxazole, or phenylbutazone have a selective effect on its stereoisomers. Altered absorption may sometimes play a part, as with colestyramine. Displacement of oral anticoagulants from plasma protein binding sites has been reported with many drugs, including some analgesics. Not all reports that have recorded an alteration in the pharmacokinetics of the anticoagulant have, however, shown a corresponding change in clinical response.
Interference with the coagulation process may be responsible for the increased risk of haemorrhage when aspirin, clofibrate, or thyroid hormones are used with anticoagulants. Many other compounds, such as asparaginase, some contrast media, epoprostenol, streptoki-nase, and urokinase also carry this risk; while interactions between these compounds and anticoagulants are not discussed further below, the possibility of an increased risk of haemorrhage should be considered when they are used together.
Where there is a risk of serious haemorrhage from an interaction, then use of both drugs is best avoided. In other instances the anticoagulant activity should be carefully monitored so as to increase or decrease the anticoagulant dose as required. Critical periods are when patients stabilised on an anticoagulant start treatment with an interacting drug, or when patients stabilised on a regimen of an interacting drug and anticoagulant have the interacting drug withdrawn. Depending on the mechanism of the interaction, the clinical response to the interaction may be rapid or may take some days. Interactions involving displacement from plasma protein binding sites are often transient. Some interacting drugs do not produce predictable effects; there have for instance been reports of increased as well as decreased anticoagulant activity with disopyramide, phenytoin, quinidine, and oral contraceptives. Another problem occurs with dipyridamole; it can cause bleeding when given to patients taking anticoagulants but without any changes in the measures used for anticoagulant control.
Alcohol. Alcohol has a variable effect on warfarin. Heavy regular drinkers may have a diminished effect, perhaps through enzyme induction, although the effect of warfarin may be increased in the presence of liver impairment; acute ingestion has enhanced the effect of warfarin. A moderate alcohol intake is generally not considered to cause problems.
Analgesics and NSAIDs. All NSAIDs should be used with caution or not at all in patients on warfarin. Many NSAIDs inhibit platelet function to some extent and have an irritant effect on the gastrointestinal tract, so increasing the risk of haemorrhage. Furthermore, some NSAIDs increase the hypoprothrombinae-mic effect of warfarin, possibly by an intrinsic effect on coagulation or by displacement of warfarin from plasma protein-binding sites. Many studies have compared the relative displacing action of a range of NSAIDs in vitro, but such studies cannot easily be extrapolated to the clinical situation. Changes in plasma concentration of unbound warfarin resulting from displacement from plasma protein-binding sites are usually transient and are most likely to occur in the first few weeks after an NSAID is added to or withdrawn from warfarin therapy; monitoring of anticoagulant therapy is, therefore, most critical during this period.
High doses of aspirin and some other salicylates enhance the hy-poprothrombinaemic effect of warfarin and should generally be avoided in patients on oral anticoagulant therapy. Low-dose aspirin with warfarin may have a role in some patients but the risk of gastrointestinal bleeding is increased. The possibility of an interaction with topical salicylates should also be considered.
Use of phenylbutazone with warfarin has led to serious haemorrhage and should be avoided. Phenylbutazone affects the metabolism of the R- and S- isomers of warfarin in complex and different ways with the net effect of enhancing its anticoagulant activity. Related drugs such as oxyphenbutazone, azapropazone, and feprazone behave similarly and should also be avoided.
For the following NSAIDs there are a few studies or isolated reports suggesting that they may enhance the hypoprothrombinaemic effect of warfarin or other specified oral anticoagulant: diflunisal (with acenocoumarol or warfarin), flurbiprofen (with acenocoumarol), indometacin, ketoprofen, meclofenamate sodium, mefenamic acid, piroxicam, (with warfarin or acenocoumarol), sulindac, tiaprofenic acid (with acenocoumarol), and tolmetin sodium In many cases the result of concomitant therapy was an increased prothrombin time which may or may not be clinically significant; in other cases haemorrhage occurred. It should also be noted that for many of the above NSAIDs, perhaps particularly indometacin, there are studies (not cited) in which no enhancement of warfarin activity was found. NSAIDs with an apparently minimal effect on warfarin activity include etodolac, ibuprofen, and naproxen.
Interactions have also been reported with NSAIDs that are selective inhibitors of cyclo-oxygenase-2. As with other NSAIDs, some studies (not cited) have shown a lack of interaction between warfarin and celecoxib, but there have been several reports of an increase in the INR with concomitant therapy and bleeding has occurred in some patients. Increases in INR have also been reported in studies of warfarin with rofecoxib; and there have also been reports of bleeding. A small increase in INR was also reported with etoricoxib in healthy subjects but was thought unlikely to be of clinical significance in most patients.
In view of the above considerations, paracetamol is recommended as the general analgesic and antipyretic of choice in patients on oral anticoagulant therapy. However, caution should be observed since, although it has no effect on the gastric mucosa or on platelet function, some studies (with warfarin, anisindione, di-coumarol, or phenprocoumon) and isolated reports have found an increased risk of bleeding in patients taking regular doses of paracetamol while on an oral anticoagulant. An increase in INR has also been reported in a controlled study of the use of paracetamol in patients stabilised on warfarin. Increased monitoring of anticoagulant therapy may be appropriate for those also taking paracetamol regularly.
Opioid analgesics do not generally cause problems. However, there have been reports of enhanced anticoagulant activity in patients given tramadol with warfarin including 2 deaths from haemorrhagic stroke, and also with phenprocoumon, although a randomised, double-blind, placebo-controlled study in 19 patients failed to find evidence of an interaction between phenprocoumon and tramadol. Co-proxamol, a combination of dextropropoxyphene and paracetamol, has increased the effect of warfarin. Co-codamol, a combination of codeine and paracetamol, has also enhanced warfarin activity.
Amongst other analgesics, glafenine has been reported to possibly enhance the activity of phenprocoumon. Phenazone, an inducer of enzyme metabolism, reduces plasma concentrations of warfarin and, in contrast with most other analgesics, may necessitate an increase in warfarin dosage
Antiarrhythmics. Amiodarone has been shown in several studies to increase the activity of warfarin and acenocoumarol, probably through inhibition of metabolism. The potentiating effect of amiodarone has been reported to persist for up to 4 months after its withdrawal. Phenprocoumon has been reported to be either unaffected or potentiated by amiodarone. Isolated reports with disopyramide and quinidine have suggested that these drugs can enhance the anticoagulant effect of warfarin. In 7 patients on warfarin or dicoumarol treated with disopyramide or quinidine, however, all but one needed a small increase in the weekly anticoagulant dose suggesting that the antiarrhythmic had reduced the anticoagulant effect. Since the effect was observed after conversion of atrial fibrillation to sinus rhythm an involvement of haemodynamic factors was postulated. Several studies (not cited) have failed to show an effect of quinidine on warfarin. There are also reports indicating that propafenone and moracizine can enhance warfarin.
Antibacterials. Several antibacterials have been involved in interactions with warfarin. Only a few reports are of serious effects and it is unlikely that any of the drugs need to be contra-indicated with warfarin; careful control should suffice. Most of the drugs enhance the effects of warfarin. Apart from possible effects on the metabolism or plasma-protein binding of warfarin, some antibacterials may interfere with platelet function or with the bacterial synthesis of vitamin K in the gastrointestinal tract and thus have an anticoagulant effect of their own. This is generally considered unlikely to be of clinical significance except, perhaps, in patients with an inadequate vitamin K intake. Fever itself may increase the catabolism of clotting factors and exaggerate a potential antibacterial-warfarin interaction.
There are several reports of an enhanced warfarin response with co-trimoxazole stereospecific inhibition of warfarin metabolism is probably responsible. The interaction is generally attributed to the sulfamethoxazole moiety and there are isolated reports suggesting that the activity of warfarin (or other specified oral anticoagulant) may be enhanced by other sulfonamides including sulfafurazote, sulfamethizole, and sulfaphenazole (with phenindione).
There are several reports of potentiation of the effects of warfarin by erythromycin or its salts; inhibition of warfarin metabolism probably occurs. Although no clinically-significant increase in prothrombin time was found in 8 non-infected patients, the potential for an interaction was recognised. An enhanced response to warfarin has also been reported with azithromycin with roxithromycin which included reports of spontaneous bleeding, and with telithromycin including a case of mild haemoptysis. Clarithromycin may potentiate the effect of acenocoumarol and of warfarin, although other factors may also have been involved in this case.
Cefamandole has been reported to enhance the hypoprothrombinaemic response to warfarin. Interference with vitamin K synthesis in the gastrointestinal tract and/or liver has been implicated. Related cephalosporins with an N-methylthiotetrazole side-chain such as cefmetazole, cefmenoxime, cefoperazone, and latamoxef may be expected to behave similarly although there appear to be no reports of an interaction. Cefazolin, which has a similar side-chain, may also enhance the effect of warfarin to some extent.
There have been reports of increased activity of warfarin (or other specified oral anticoagulant) by quinolone antibacterials including nalidixic acid (with warfarin or acenocoumarol), ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, norfloxacin, and ofloxacin although for some of these there are also studies indicating no effect (not cited). Enoxacin has been reported to decrease the clearance of R -warfarin but not S-warfarin; no prolongation of prothrombin time occurred.
There are isolated reports suggesting an enhanced effect of warfarin (or other specified oral anticoagulant) with aminosalicylic acid, benzylpenicillin, chloramphenicol (with dicoumarol), doxycycline, isoniazid, and neomycin Prothrombin times might be prolonged by broad-spectrum antibacterials such as ampicillin, and there has been a report of an increased INR and haematuria in a patient taking warfarin with amoxicillin and cla-vulanic acid. Manufacturers warnings of potentiation of warfarin by aztreonam, trimethoprim, and tetracyclines other than doxycycline appear to have only a theoretical basis. Metronidazole is discussed under Antiprotozoals, below.
Rifampicin diminishes the effect of warfarin by induction of metabolising enzymes in the liver. There are several reports of a similar effect with nafcillin and with dicloxacillin sodium.
Antidepressants. Amitriptyline and nortriptyline have been reported to prolong the half-life of dicoumarol in healthy subjects. The few reports investigating the effect of tricyclic anti-depressants on warfarin have not been able to conclude that a significant interaction exists. Mianserin and phenprocoumon have been reported not to interact.
The BNF considers that there is a possible risk of increased warfarin activity with SSRIs, increased warfarin activity has been reported in a few patients taking fluoxetine in a patient taking fluvoxamine, and another taking the SNRI duloxetine. There has also been a report of increased anticoagulant activity in a patient taking acenocoumarol and citalopram
An increase in the dose of warfarin has been required by patients also taking trazodone, See also St John’s Wort.
Antidiabetics. There have been a few early instances of tolbutamide enhancing the activity of dicoumarol. However, this effect has not been seen in later studies involving dicoumarol, warfarin, and phenprocoumon, although one study did find altered dicoumarol pharmacokinetics. An absence of effect has been documented for phenprocoumon and insulin, glibenclamide, or glibornuride but there is a report of glibenclamide enhancing the effect of warfarin.
There has been an isolated report of bleeding in a patient taking phenformin and warfarin. Metformin has been reported to diminish phenprocoumon activity.
An enhanced response to warfarin has been reported in a patient receiving troglitazone.
Coumarin anticoagulants may increase the hypoglycaemic effect of sulfonylureas.
Antiepileptics. Barbiturates such asphenobarbital andprimi-done diminish the activity of warfarin and other coumarins through increased metabolism. Carbamazepine is reported to have a similar effect. Reports of the effect of phenytoin on anticoagulants do not provide a clear picture. There are reports of phenytoin enhancing the effects of warfarin and a report of initial enhancement followed by decreased anticoagulant action. Phenytoin has been reported to diminish the effect of dicoumarol. Addition of felbamate has been reported to necessitate a reduction in warfarin dosage. In another patient there was a transient increase in response to warfarin when valproic acid was started. Valproate also inhibits platelet function and caution is required with warfarin and other anticoagulants. For the effect of oral anticoagulants on phenytoin.
Antifungals. Griseofulvin has been reported to diminish the activity of warfarin. There are several reports indicating that miconazole, given either systemically or topically as the oral gel, may enhance the activity of oral anticoagulants (warfarin, ethyl biscoumacetate, acenocoumarol, phenindione, and tioclomarol). Absorption of miconazole after intravaginal use may have enhanced the activity of acenocoumarol in 2 patients; it enhanced the activity of warfarin in another. Studies in healthy subjects given a single warfarin dose support case reports suggesting thatfiuconazole may increase the anticoagulant activity of warfarin. There are isolated reports of the potentiation of warfarin by itraconazole and ketoconazole, and of unspecified coumarins by topical bifonazole or econazole There has been a case report of a reduction in the effect of warfarin by terbinafine, although a study in healthy subjects found no clinically significant interaction, and others considered that no interaction usually occurs. A case of potentiation of warfarin by terbinafine has also been reported; the authors speculate that concomitant cimetidine may have contributed to the interaction by increasing plasma-terbinafine concentrations.
Antigout drugs. The two drugs in this group mostly implicated in interactions with anticoagulants are allopurinol and sulfinpyrazone.
With allopurinol there are conflicting reports of patients experiencing no interaction or an enhanced anticoagulant effect with dicoumarol, phenprocoumon, or warfarin. Interactions with sulfinpyrazone have usually involved warfarin and, apart from a case of a mixed response, have involved increased anticoagulant activity, sometimes with haemorrhage, so calling for careful control. It is still not clear how sulfinpyrazone exerts its effect, but studies point to a stereoselective effect on warfarin metabolism where the S-isomer’s metabolic clearance is inhibited; sulfinpyrazone also affects platelets. Sulfinpyrazone has also enhanced the anticoagulant activity of acenocoumarol. A significant interaction with phenprocoumon appears unlikely.
Probenecid has accelerated the elimination of a single dose of phenprocoumon without effect on the prothrombin time. Benziodarone has been reported to enhance the effects of warfarin, diphenadione, ethyl biscoumacetate, and acenocoumarol, but not of dicoumarol, phenindione, or phenprocoumon. A further study confirmed that benziodarone could increase the half-life of ethyl biscoumacetate, but also found that the effect of phenprocoumon was enhanced. A study of benzbromarone, which is structurally related to benziodarone, concluded that it enhanced the effect of warfarin by inhibition of the cytochrome P450 isoenzyme CYP2C9, leading to a stereoselective inhibition of the metabolism of warfarin.
Antihistamines. There has been a report of a raised INR and severe epistaxis in a patient after the addition of cetirizine to long-term acenocoumarol.
Antimalarials. The ingestion of large amounts of tonic water by 2 patients necessitated a reduction in warfarin dosage. The enhanced effect was attributed to the quinine content of the tonic water. A woman stabilised on warfarin developed haematuria and a high prothrombin ratio after taking proguanil for malaria prophylaxis.
Antimuscarinics. There have been 2 cases reported of‘tolterodine enhancing the effect of warfarin. It was stated that the manufacturers of tolterodine were aware of 6 reports of a possible interaction with warfarin.
Anti neoplasties. There have been several reports of interactions between warfarin and antineoplastics. No clear picture emerges from these reports which is not surprising considering that antineoplastics are often given in combination and that they can exert their own haematological effects. Cyclophosphamide for instance has been associated with an increase in warfarin’s activity when given with methotrexate and fluorouracil, but with a decrease when given with non-antineoplastic drugs. An increase in the activity of warfarin and mucous membrane bleeding occurred in a patient who had 4 courses of fluorouracil and folic acid at weekly intervals. The patient was also taking in-dometacin. Warfarin dosage had to be reduced in 5 patients given fluorouracil-based antineoplastic regimens An increase in the effect of warfarin has been reported when given with fluorouracil and levamisole (see Levamisole, below). Capecitabine increases plasma-warfarin concentrations and there have been reports of increased warfarin activity, in 1 case resulting in gastrointestinal bleeding; licensed product information for capecitabine states that altered coagulation parameters and bleeding have also occurred with phenprocoumon. There have been 2 cases reported where trastuzumab enhanced the effect of warfarin. Etoposide with vindesine or with carboplatin, ifosfamide with mesna} and tamoxifen have all produced an increased anticoagulant effect. Aminoglutethimide has led to decreased activity of warfarin or acenocoumarol, probably due to increased warfarin metabolism. Licensed product information for the anti-androgen flutamide states that increases in prothrombin time have been reported after starting flutamide therapy in patients on long-term warfarin. In vitro data indicate a similar reaction is likely with bicalutamide. Mercaptopurine and mitotane have also decreased warfarin activity. Licensed product information for vorinostat states that prolongation of prothrombin time has been seen when the drug is given with coumarin derivatives; prothrombin time and INR should be monitored in patients given both drugs.
Antiplatelets. The interaction between anticoagulants and dipyridamole is unusual as bleeding can occur without any alteration in prothrombin times; special care is therefore required. This interaction has involved a small number of patients taking dipyridamole and warfarin or phenindione; inhibition of platelet function by dipyridamole has been implicated. However, in general it does not appear to increase the risk of bleeding. Paradoxically, addition of ticlopidine was found to significantly increase acenocoumarol requirements. See also under Analgesics and NSAIDs (above).
Antiprotozoals. Metronidazole enhances the activity of warfarin through selective inhibition of the metabolism of its S-isomer.
Antithyroid drugs. See Thyroid and Antithyroid Drugs, below.
Antivirals. Reductions in dosage of either warfarin or acenocoumarol were necessary in 2 patients receiving interferon alfa for hepatitis C. The interactions may have been due to decreased metabolism of the anticoagulant. A similar need for a reduced warfarin dose had also been noted in other patients taking interferon alfa-2b or interferon beta. However, in a patient taking interferon alfa-2b with ribavirin the warfarin dose needed to be increased, probably due to the interaction between ribavirin and warfarin.
An enhanced response to warfarin has been reported in a patient taking saquinavir. The mechanism may involve competitive inhibition of warfarin metabolism and might also occur with other HIV-protease inhibitors. However, a decreased response to warfarin seemed to be caused by ritonavir when it was added to the multidrug therapy of a patient. Ritonavir has also been reported to decrease the response to acenocoumarol.
Up to October 2005 there had been 19 reports received by the Canadian health authorities (Health Canada) of enhanced response to warfarin between 1 and 11 days after starting oseltamivir. The increased INR ranged from 3.2 to 10.9; however, there was not enough information to be certain of causality. In 3 other cases there was a decrease in INR on the addition of oseltamivir.
Anxiolytic sedatives, hypnotics, and antipsychotics. Barbiturates, by inducing liver metabolism, can reduce the activity of anticoagulants; glutethimide has a similar action. The benzodiazepines do not generally have any effect although there is the rare report of increased or decreased activity. Although there is a report suggesting that cloral hydrate may decrease the effect of dicoumarol by enzyme induction, other studies and experience indicate an increase in the anticoagulant activity of warfarin. However, the increase is only transient and is probably the result of displacement of warfarin from plasma protein binding sites by the metabolite trichioroacetic acid. Triclofos sodium appears to increase the activity of warfarin in a similar way.
Reduced anticoagulant activity has been reported with dichloralphenazone, ethchlorvynol (with dicoumarol), and haloperidol (with phenindione). Compounds such as meprobamaie and methaqualone appear to have no effect.
Beta blockers. Beta blockers, particularly those with a high lipid solubility such as propranolol, may inhibit the metabolism of warfarin. Although a number of studies have shown pharma-cokinetic interactions between some beta blockers and oral anticoagulants, no effect on anticoagulant activity has generally been found. However, possible potentiation of the effect of warfarin by propranolol has been reported.
Central stimulants. Methylphenidate has been reported both to increase the half-life of ethyl biscoumacetate, and to have no effect on its half-life or anticoagulant activity. Prolintane had no effect.
Chamomile. A 70-year-old woman stabilised on warfarin developed multiple internal haemorrhages after she increased her use of chamomile lotion and consumption of chamomile tea to 4 or 5 times per day. The interaction was considered to be due to the coumarin constituent of chamomile.
Chinese herbal remedies. There have been a number of reports of increased anticoagulation in patients taking Chinese herbal remedies with warfarin. The remedies have ranged from single ingredient herbal preparations to complex multi-ingredient products, sometimes sold under the same brand name but with very different compositions.
Corticosteroids and corticotropin. Corticosteroids are associated with an increase in blood coagulability, but their extensive use with anticoagulants, and very few reports of interaction, suggests that any problems are rare. However, there are some reports of corticosteroids or corticotropin either enhancing or diminishing the effects of anticoagulants. A retrospective study in patients on long-term warfarin therapy given short courses of oral corticosteroids found that in most cases (29 of 32) there was an increase in INR, suggesting that careful monitoring is required.
Cough suppressants. An increase in the activity of warfarin has been reported in patients taking noscapine, or oxolamine. A subsequent study suggested that the dose of warfarin should be reduced by 50% if oxolamine was started. See also Menthol, below.
Cranberry. Between 1999 and 2003 the UK CSM had received 5 reports suggesting an interaction between warfarin and cranberry juice. In 3 patients the activity of warfarin had been potentiated and one of them had died. In the other patients the INR was either reduced or unstable. By 2004 there had been 7 further reports of suspected interactions and the CSM advised patients to avoid cranberry juice and other cranberry products while taking warfarin. However, despite case reports suggesting an increase in warfarin activity, the potential for a pharmacoki-netic effect has been questioned, and pharmacokinetic studies have failed to confirm an interaction.
Dermatological drugs. A patient’s warfarin dose had to be increased when he started treatment with etretinate.
Dietary supplements. There have been reports of an increased INR in patients taking warfarin and dietary supplements containing glucosamine and chondroitin, and the UK CHM advises that patients on warfarin should not take glucosamine. A similar effect has been reported with poliglusam.
Disulfiram. Two reports suggesting that disulfiram enhances the activity of warfarin were confirmed by a study in 8 healthy subjects. Although inhibition of liver enzymes by disulfiram was considered responsible, a later study suggested that disulfiram acts directly on the liver to increase hypoprothrombinaemia. This interaction is complicated by the variable effects of alcohol on warfarin (see above). Special care is therefore called for when these drugs are used together.
Diuretics. Etacrynic acid has been reported to enhance the activity of warfarin. Chlortalidone and spironolactone have both been associated with a reduction in warfarin’s activity in healthy subjects and it has been suggested that this might be a consequence of the diuresis concentrating the circulating clotting factors. However, bumetanide, furosemide, and the thiazides appear to have no effect on warfarin.
Endothelin receptor antagonists. A study in healthy subjects showed that bosentan decreased the anticoagulant effect of warfarin; a case report confirmed this.
Gastrointestinal drugs. Antacids may or may not interact with warfarin. Bismuth carbonate and magnesium trisilicate for example have been reported to reduce warfarin’s absorption, but aluminium hydroxide has been observed to have no effect on warfarin or dicoumarol. Psyttium and magnesium hydroxide have also been reported to have no effect on warfarin, but the latter has increased the plasma concentrations of dicoumarol. There have been occasional reports of sucralfate diminishing the effect of warfarin.
Histamine H2-antagonists have been widely studied. There are several reports indicating that cimetidine can enhance the anticoagulant effect of warfarin and haemorrhage has occurred. A number of studies show that cimetidine can increase the plasma concentration and half-life of warfarin and that there is a selective inhibitory effect on the metabolism of its R-isomer. Not all these studies have, however, found an increase in prothrombin time. The effect of cimetidine on warfarin appears to be dose-dependent and to be subject to interindividual variation; careful monitoring is needed. Limited evidence suggests that cimetidine has a similar effect on the metabolism of acenocoumarol and phenindione but not of phenprocoumon. Studies with ranitidine have generally been unable to show an effect on the metabolism of warfarin, although in one study warfarin clearance was reduced. There is a case report suggesting that potentiation of warfarin by ranitidine may occasionally occur.
One study has suggested that omeprazole could inhibit the metabolism of R-warfarin although a clinically significant effect was unlikely. No evidence of an interaction was found in a retrospective study of patients on acenocoumarol and omeprazole. Similarly, pantoprazole appears to have no effect on the pharmacokinetics or pharmacodynamics of warfarin or phen-procoumon.
A marked increase in the effect of warfarin has been reported in a patient when cisapride was added.
A study in healthy subjects found that aprepitant caused a small decrease in plasma concentration of the more active S-isomer of warfarin and there was also a decrease in INR. A reduction in the response to warfarin with development of venous thrombosis has been reported in a patient receiving mesalazine, and in another patient receiving sulfasalazine
Ginkgo biloba. There is a report of a woman stabilised on warfarin for 5 years who suffered an intracerebral haemorrhage 2 months after starting Ginkgo biloba, possibly due to the additive effect of the latter’s antiplatelet activity. However, a study in healthy subjects found no evidence that ginkgo affected warfarin pharmacokinetics or coagulation.
Ginseng. A reduction in the response to warfarin was reported in a patient after taking a ginseng preparation. A study in healthy subjects also found a small reduction in response.
Glucagon. A dose-dependent enhancement of warfarin’s anticoagulant activity has been reported with glucagon.
Glucosamine. See Dietary Supplements, above.
Immunosuppressants. Severe bleeding occurred in a patient on long-term warfarin after stopping azathioprine, while another patient required an increased dose of warfarin when it was given with azathioprine.
There have been a few case reports of interaction between warfarin or acenocoumarol and ciclosporin, in which the dose of the anticoagulant or ciclosporin or both needed to be altered (see Anticoagulants under Interactions of Ciclosporin). There has been a report of leflunomide enhancing the effects of warfarin, causing gross haematuria after the second dose; the patient’s INR rose from 3.4 to 11. It was stated that the UK CSM had received 4 reports of increased TNR with leflunomide up to the end of 2002.
Leukotriene antagonists. Zafirlukast is reported to decrease the clearance of S-warfarin. Licensed product information for zafirlukast states that it probably inhibits the cytochrome P450 isoenzyme C YP2C9 which is involved in the metabolism of warfarin. Prothrombin time may be significantly prolonged when zafirlukast is added and warfarin dosage should be adjusted accordingly.
A study of montelukast and warfarin found no significant interaction between the two drugs.
Levamisole. An increased TNR has been reported in a patient taking chronic warfarin therapy after addition of levamisole and fluorouracil, possibly due to inhibition of warfarin metabolism. Interactions between warfarin and other fluorouracil-containing regimens have been reported (see Antineoplastics, above) but levamisole might also be involved. In a second patient, a similar reaction was reported after levamisole and fluorouracil and an episode of bleeding subsequently occurred after levamisole alone.
Lipid regulating drugs. Fibrates have been reported to interact with coumarin anticoagulants. Clqfibrate can enhance the activity of warfarin, sometimes to the point of haemorrhage. The mechanism of this interaction is not clear, but it does not appear to be a pharmacokinetic effect. Similar enhancement of activity has been reported with clofibrate and dicoumarol or phenindione. Bezafibrate has been reported to enhance the effect of phenprocoumon and warfarin, and fenofibrate and gemfibrozil have been reported to enhance the effect of warfarin, although a study in healthy subjects found that gemfibrozil slightly decreased plasma-warfarin concentrations.
Interactions may also occur between statins and coumarin anticoagulants, although there have been conflicting reports in some cases. Hypoprothrombinaemia and bleeding has been reported in 2 patients on warfarin given lovastatin. An increased response to warfarin has also been reported in a number of patients taking fluvastatin. A study with rosuvastatin and warfarin reported an increased TNR in healthy subjects and in patients on long-term warfarin therapy, although another study found no effect. However, there have been reports of haematoma and raised TNR in patients after addition of rosuvastatin to long-term therapy with warfarin or acenocoumarol. An increased response to warfarin has been observed with simvastatin, including a fatal cerebral haemorrhage in a patient who was changed from atorvastatin to simvastatin, and potentiation of the effect of acenocoumarol by simvastatin has also been reported. However, the TNR in another patient on long-term warfarin remained stable on the addition of simvastatin. Licensed product information for pravastatin states that no change in warfarin activity has been seen in patients given both drugs, but there has been a report of bleeding in a patient taking fluindione when pravastatin was added. In a study of 46 patients on warfarin who had been converted from pravastatin to simvastatin, the mean TNR increased, but the median weekly warfarin dose did not differ significantly and no episodes of bleeding were reported.
Dextrothyroxine increases the anticoagulant effect of warfarin sodium and dicoumarol.
Colestyramine has reduced warfarin’s serum concentration and half-life as well as its activity. The mechanisms of this interaction include binding of warfarin to colestyramine and reduced absorption; the enterohepatic recycling of warfarin may also be interrupted. Phenprocoumon’s activity has also been reduced by colestyramine. However, colestyramine can also reduce vitamin K absorption, and this may result in hypoprothrombinaemia and bleeding.
Use of omega-3 fatty acids (as fish oil preparations) in patients taking warfarin and other antithrombotics has been associated with TNR elevation and subdural haematoma. However, controlled studies in patients taking fish oil and warfarin have failed to show an effect on bleeding episodes or bleeding time. Benfluorex and colestipol have been reported not to interact with phenprocoumon.
Menthol. A significant decrease in INR was reported in a patient stabilised on warfarin when he started using a menthol cough preparation.
Pesticides. Chlorinated insecticides diminished the activity of warfarin in a patient.
Piracetam. Piracetam caused an increase in prothrombin time in a patient who had been stabilised on warfarin.
Sex hormones. There have been reports of steroids with anabolic or androgenic properties enhancing the activity of anticoagulants to the point of haemorrhage. Reports have covered oxymetholone and warfarin or acenocoumarol; stanozolol and warfarin or dicoumarol; ethylestrenol and phenindione; norethandrolone and dicoumarol; methyltestosterone and phenprocoumon; and danazol and warfarin. The manufacturer of oxandrolone states that an 80 to 85% reduction in warfarin dose was needed when oxandrolone was added to treatment. The mechanism of this interaction is not clear although it is considered that it is not caused by altered pharmacokinetics. Steroids with a 17-alpha-alkyl substituent appear to be most involved, but there has been a report of topically applied testosterone, which does not have such a substituent, enhancing warfarin. A retrospective study of women receiving anticoagulant therapy who were started on HRT found that tibolone enhanced the effect of warfarin and of phenindione, possibly due to its androgenic properties.
Oral contraceptives have also been implicated in interactions. However, while the effects of dicoumarol were diminished by a combined oral contraceptive, those of acenocoumarol were enhanced by other preparations. Combined oral contraceptives have increased the clearance of phenprocoumon without altering the anticoagulant effect. There has also been a report of a single course of levonorgestrel for emergency contraception increasing the effect of warfarin.
St John’s wort. St John’s wort has been reported to reduce the anticoagulant effect of warfarin.
Thyroid and antithyroid drugs. Since response to oral anticoagulants is dependent on thyroid status an interaction between oral anticoagulants and thyroid or antithyroid drugs might be expected. Thyroid compounds do enhance the activity of oral anticoagulants possibly by increased metabolism of clotting factors. Dextrothyroxine is discussed under Lipid Regulating Drugs, above. Antithyroid compounds have nof however, been reported to diminish the effect of anticoagulants and paradoxically propylthiouracil has been reported to have caused hypoprofhrombinaemia (see Effects on the Blood, under Carbimazole). However, in a patient given thiamazole for Grave’s disease, the response to warfarin varied depending on his thyroid status and thiamazole dose.
Tobacco. Although tobacco smoking may increase warfarin clearance, an appreciable effect on anticoagulant activity appears unlikely. However, there has been a report of an increase in INR in a patient receiving warfarin when he stopped smoking.
Ubidecarenone. Decreased INR values and reduced effect of warfarin has been reported in 3 patients given ubidecarenone.
Vaccines. There have been a few reports of increased pro-fhrombin time and bleeding in warfarin-stabilised patients after influenza vaccination. Studies investigating this possible interaction have found only a small or inconsistent increase in warfarin activity or no effect. One study suggested that influenza vaccine decreases rather than increases the profhrombin time. In a group of patients on long-term acenocoumarol therapy, influenza vaccination had no effect on acenocoumarol activity.
Vitamins. Since vitamin K reverses the effects of oral anticoagulants, it is not surprising that there have been reports of acetomenaphthone and phytomenadione reducing anticoagulant activity, or of foods or nutritional preparations containing vitamin K compounds doing the same.
Occasional reports of ascorbic acid reducing the activity of warfarin have not been confirmed in subsequent studies. There have also been isolated reports suggesting that vitamin E may enhance the activity of warfarin or dicoumarol, although no effect was found in a study of patients receiving warfarin and vitamin E.
Pharmacokinetics
Warfarin sodium is readily absorbed from the gastrointestinal tract; it can also be absorbed through the skin. It is extensively bound to plasma proteins and its plasma half-life is about 37 hours. It crosses the placenta but does not occur in significant quantities in breast milk. Warfarin is used as a racemic mixture; the S-isomer is more potent. The R- and S-isomers are both metabolised in the liver. The S-isomer is metabolised more rapidly than the R-isomer, mainly by the cytochrome P450 isoenzyme CYP2C9, which shows genetic polymorphism; other isoenzymes are also involved in the metabolism of the R-isomer. The stereo-isomers may be affected differently by other drugs (see Interactions, above). Metabolites, with negligible or no anticoagulant activity, are excreted in the urine following reabsorption from the bile.
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