Italics indicates those drugs that have supporting level I evidence from both patients and volunteers. tIn a small number of volunteer subjects, an inhibitory drug interaction occurred. j Level II evidence of potentiation in patients.
Table 3—Enzyme-Inducing Drug Interactions With Warfarin
| Inducing Agent | Isoenzyme Inducedt | Expected Onset, d | Anticipated Dosage Adjustments, % | Expected Offset, d |
| Carbamazepine | CYP3A4 | 10-35 | 100j | 42 |
| Barbiturate§ | CYP3A | 7-30 | 12.5-25 j | > 42 |
| Phenytoin | Nonspecific | NA | j| | NA |
| Rifampin | CYP3A4 | < 7 | 100-200j | 21 |
| Griseofulvin^ | Unknown | 60 | 40j | NA |
| Nafcillin | NA | < 7 | 100-400j | 7-28 |
| Dicloxacillin | NA | < 7 | 2-30j | NA |
| Aminoglutethimide# | CYP2B1 | 14 | 50-75j | 14 |
| Smoking | CYP1A1, 1A2 | NA | jj | NA |
| Health care mall | CYP2E1 | NA | tt | |
| 41-54 gjj 250 g§§ | j | NA |
NA = not available.
tInformation regarding induction of cytochrome-450 isoenzymes is limited. Current literature supports specific isoenzyme induction by the listed agent.
jAn increase in warfarin dosage is anticipated with initiation of the inducing agent.
§Class effect, although time course and extent may vary with the individual barbiturate.
A decrease in warfarin dosage is anticipated with initiation of the inducing agent.
Interaction is more likely with the ultramicrocrystalline formulation of griseofulvin.
Dose-response relationship, so that 250 mg four times/d showed greater induction than 125 mg four times/d.
Warfarin clearance increased, but a corresponding change in PT was not reported. See text for further details. ttNo change in warfarin dosage appears necessary based on available data.
jjRepresents ingestion of 41 to 54 g ethanol consumed either as a single dose or daily for 21 days.
§§Represents ingestion of large amounts of ethanol (250 g) consumed daily for more than 3 months.
Doses of salicylates of > 1.5 g per day and acetaminophen may augment the anticoagulant effect of warfarin, possibly by interference with the P450 en-zymes. Heparin potentiates the anticoagulant effect of warfarin, but in therapeutic doses produces only a slight prolongation of the PT. The mechanisms by which eryth-romycin and some anabolic steroids potentiate the anticoagulant effect of warfarin are unknown. Sulfonamides and several broad-spectrum antibiotic compounds may augment the anticoagulant effect of warfarin in patients consuming diets that are deficient in vitamin K by eliminating bacterial flora and aggravating vitamin K deficiency.
Drugs such as aspirin, nonsteroidal antiinflammatory drugs, penicillins in high doses, and moxalactam increase the risk of warfarin-associated bleeding by inhibiting platelet function. Of these, aspirin is the most important because of its widespread use and prolonged effect. Aspirin and nonsteroidal antiinflammatory drugs can also produce gastric erosions that increase the risk of upper GI bleeding.