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Warfarin Therapy: Evolving Strategies in Anticoagulation

TABLE 3
Selected Warfarin-Drug Interactions

CHARACTERISTICS OF INTERACTION

MANAGEMENT OF
DRUG SEVERITY ONSET EVIDENCE MECHANISM
INTERACTION

Acetaminophen Minor Delayed Poor Inhibits warfarin metabolism Advise patient to limit total
(Tylenol) acetaminophen dosage to less
than 2 g per day; if higher
dosages are used, increased
monitoring may be necessary.

Allopurinol Moderate Delayed Poor Unknown Monitor INR when allopurinol is

(Zyloprim) added or withdrawn.

Amiodarone Moderate Delayed Excellent Decreases warfarin metabolism A 25 percent reduction in the
(Cordarone) within a week of warfarin dosage is
coadministration; effect may recommended when
persist for 1 to 3 months after amiodarone is initiated. Monitor
discontinuation of amiodarone INR closely when amiodarone
May induce hypothyroidism or is added or withdrawn.
hyperthyroidism

Antifungal agents Major Delayed Good Fluconazole (Diflucan), Monitor INR when azole
ketoconazole (Nizoral) and antifungals are added or
miconazole (Monistat) decrease withdrawn.
warfarin metabolism

Antithyroid drugs Moderate Delayed Fair Hyperthyroidism results in Monitor INR when antithyroid
metabolism of vitamin K clotting medications are added or
factors and increased sensitivity withdrawn.
to oral anticoagulants

Barbiturates Major Delayed Excellent Increase warfarin metabolism Monitor INR when barbiturates
and frequently reduce are added or withdrawn; the
hypoprothrombinemic effect of addition of warfarin in patients
warfarin stabilized on a chronic
barbiturate regimen is of less
significance.

Binding resins Moderate Delayed Good Decrease absorption and may Use colestipol (Colestid), which
interrupt enterohepatic has a lower potential for
recirculation of warfarin interaction, instead of
cholestyramine (Questran) in
patients who need a bile
sequestrant.

Carbamazepine Moderate Delayed Fair Increases warfarin metabolism Monitor INR intensively when
(Tegretol) carbamazepine is added or
discontinued.

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CHARACTERISTICS OF INTERACTION

MANAGEMENT OF
DRUG SEVERITY ONSET EVIDENCE MECHANISM
INTERACTION

Increase warfarin doses when

carbamazepine is added, and
reduce doses when
carbamazepine is discontinued
(stabilization occurs after 4 to 6
weeks).

Cephalosporins Moderate Delayed Poor Methylthiotetrazole ring in Avoid concomitant use of

cefoperazone (Cefobid), warfarin and cefoperazone,
cefamandole (Mandol), cefamandole, cefotetan or
cefotetan (Cefotan) and cefmetazole.
cefmetazole (Zefazone) inhibits
production of vitamin
Kdependent clotting factors

Cimetidine Moderate Delayed Excellent Inhibits warfarin metabolism; Use alternative agents in
(Tagamet) predominantly affects R isomer patients receiving warfarin.

Monitor INR when concomitant

use of warfarin and cimetidine
is necessary.

Contraceptives, Minor Delayed Poor May increase clotting factor If possible, avoid oral
oral synthesis May inhibit oxidative contraceptives because of
metabolism increased risk of
thromboembolism Monitor INR
frequently when oral
contraceptives are used
concurrently with warfarin.

Corticosteroids Moderate Delayed Poor Produce hypercoagulability Monitor for gastric toxicity.

May have ulcerogenic effects

Danazol Major Delayed Good May increase endogenous Monitor prothrombin time and
(Danocrine) anticoagulants INR for 2 days to 3 weeks after
danazol is added.

Diflunisal (Dolobid) Moderate Delayed Fair Displaces warfarin from protein If possible, avoid concomitant
binding, inhibits platelet use of warfarin and diflunisal.
aggregation, causes gastric
erosions Monitor INR if concomitant use
is necessary.

Disulfiram Moderate Delayed Fair Inhibits warfarin metabolism If possible, avoid concomitant
(Antabuse) use of warfarin and disulfiram.

Monitor INR if concomitant use

is necessary.

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CHARACTERISTICS OF INTERACTION

MANAGEMENT OF
DRUG SEVERITY ONSET EVIDENCE MECHANISM
INTERACTION

Ethanol Moderate Delayed Excellent Acute ethanol use may inhibit
anticoagulant metabolism.
Chronic ethanol use induces
liver enzymes. Cirrhosis is
associated with reduced
warfarin metabolism.
Caution patients to drink in
moderation and to avoid binge
drinking. Because liver damage
results in greater sensitivity to
warfarin, use lower starting
doses.

Fluvoxamine Moderate Delayed Fair Probably inhibits warfarin Monitor INR more closely for 1
(Luvox) metabolism to 2 weeks after fluvoxamine is
started.

Heparin Moderate Rapid Good Has additive anticoagulant Heparin may prolong INR, and
effects warfarin may prolong partial
thrombin time.

Be aware of small risk of

bleeding events.

HMG CoA Moderate Delayed Poor May inhibit warfarin metabolism Note that lovastatin (Mevacor)
reductase is more commonly associated
inhibitors with hypoprothrombinemia.

Isoniazid Moderate Delayed Poor May inhibit warfarin metabolism Monitor INR when isoniazid is
(Laniazid) added or withdrawn.

Metronidazole Moderate Delayed Fair Inhibits metabolism of S Avoid concomitant use of

(Flagyl) enantiomer of warfarin warfarin and metronidazole.

Monitor INR if concomitant use

is necessary.

Nalidixic acid Moderate Delayed Poor Displaces warfarin from protein- Avoid concomitant
(NegGram) binding sites Inhibits warfarin administration of warfarin and
metabolism nalidixic acid. Monitor INR if
concomitant use is necessary.

NSAIDs Moderate Delayed Fair Inhibit platelet aggregation Advise patients to avoid
Cause gastric erosions NSAIDs or to use them only
intermittently.

Instruct patients to take NSAIDs

with food or antacids.

Consider having patients take

misoprostol (Cytotec) to reduce
risk of gastric erosions.

Paroxetine (Paxil) Moderate Delayed Poor Probably inhibits warfarin Monitor INR frequently when
metabolism paroxetine is added.

Penicillins Moderate Delayed Fair Dicloxacillin (Pathocil) and Monitor INR: dicloxacillin and
nafcillin (Unipen) may enhance nafcillin decrease INR, and
warfarin metabolism. penicillin increases INR.

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CHARACTERISTICS OF INTERACTION

MANAGEMENT OF
DRUG SEVERITY ONSET EVIDENCE MECHANISM
INTERACTION

Penicillin may reduce

gastrointestinal flora synthesis
of vitamin K.

Phenytoin Major Delayed Fair Induces warfarin metabolism Monitor INR frequently for 1
(Dilantin) month or more after phenytoin
Displaces warfarin from protein- is added.
binding sites

Enhances metabolism of
clotting factors

Propafenone Moderate Delayed Fair Probably inhibits warfarin Monitor INR frequently when
(Rythmol) metabolism propafenone is added or
discontinued.

Quinolones Moderate Delayed Poor Possibly inhibit warfarin Monitor INR.

metabolism

Rifampin (Rifadin) Moderate Delayed Poor Induce hepatic enzymes Monitor INR closely for 1 to 2
and rifabutin weeks after rifampin or rifabutin
(Mycobutin) Increase warfarin metabolism is added.

Salicylates Major Delayed Excellent Inhibit platelet aggregation If possible, avoid concurrent
Cause gastric erosions In large use of warfarin and salicylates.
doses, result in
hypoprothrombinemic effect If aspirin is needed, advise
patients to use a small dosage
(325 mg or less per day).

Consider having patients take

misoprostol to reduce the risk of
NSAID-induced ulceration.

Sulfinpyrazone Moderate Delayed Excellent Inhibits warfarin metabolism If possible, avoid concomitant
(Anturane) use of warfarin and
sulfinpyrazone.

Monitor for bleeding when

concomitant use is necessary.

Thyroid hormones Moderate Delayed Excellent Increases catabolism of vitamin Monitor INR frequently for 1 to
Kdependent clotting factors 2 months.

Ticlopidine (Ticlid) Moderate Delayed Poor Inhibits R enantiomer of Monitor for bleeding.
warfarin

Inhibits platelet aggregation

Trimethoprim- Major Delayed Excellent Sulfonamide component may If possible, avoid concurrent
sulfamethoxazole stereoselectively inhibit S use of warfarin and
(Bactrim) isomer metabolism. trimethoprim-sulfamethoxazole.

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CHARACTERISTICS OF INTERACTION

MANAGEMENT OF
DRUG SEVERITY ONSET EVIDENCE MECHANISM
INTERACTION

Monitor INR when concomitant

use is necessary.

Vitamin E Moderate Delayed Fair May interfere with production of Interaction is probably
clotting factors dose-related and more likely to
occur with vitamin E dosages
greater than 800 U per day;
monitor INR if larger dosages
are taken.

Vitamin K Moderate Delayed Excellent Effects of oral anticoagulants Advise patients to eat a
are directly antagonized by the consistent diet and to avoid
excessive ingestion of foods or taking large doses of vitamin
dietary supplements containing supplements containing a great
vitamin K. deal of vitamin K.

INR = International normalized ratio; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; NSAIDs = nonsteroidal anti-inflammatory drugs.

Adapted with permission from Havrda DE, Anderson JR, Talbert RL. Thrombosis. In: Pharmacotherapy self assessment program module 1
cardiovascular. Kansas City, Mo.: American College of Clinical Pharmacy, 1998. Retrieved September 1998 from the World Wide Web at
http:www.accp.com/psap3-des.html. Additional information derived from Warfarin. In: Drugdex. Englewood, Colo.: Micromedex Inc., 1998.

Copyright 1999 by the American Academy of Family Physicians.

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