Drug Interactions between dicumarol and Phenytoin Sodium, Prompt

ADJUST DOSING INTERVAL: Phenytoin bioavailability may decrease to subtherapeutic levels when the suspension is given concomitantly with enteral feedings. The mechanism may be related to phenytoin binding to substances in the enteral formula (e.g., calcium, protein) and/or binding to the tube lumen. Data have been conflicting and some studies have reported no changes in phenytoin levels, while others have reported significant reductions.

MONITOR: Acute consumption of alcohol may increase plasma phenytoin levels. Chronic consumption of alcohol may decrease plasma phenytoin levels. The mechanism of this interaction is related to induction of phenytoin metabolism by ethanol during chronic administration. Other hydantoin derivatives may be similarly affected by ethanol.

MANAGEMENT: Some experts have recommended interrupting the feeding for 2 hours before and after the phenytoin dose, giving the phenytoin suspension diluted in water, and flushing the tube with water after administration; however, this method may not entirely avoid the interaction and is not always clinically feasible. Patients should be closely monitored for clinical and laboratory evidence of altered phenytoin efficacy and levels upon initiation and discontinuation of enteral feedings. Dosage adjustments or intravenous administration may be required until therapeutic serum levels are obtained. In addition, patients receiving phenytoin therapy should be warned about the interaction between phenytoin and ethanol and they should be advised to notify their physician if they experience worsening of seizure control or symptoms of toxicity, including drowsiness, visual disturbances, change in mental status, nausea, or ataxia.

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MONITOR: Vitamin K may antagonize the hypoprothrombinemic effect of oral anticoagulants. Vitamin K is a cofactor in the synthesis of blood clotting factors that are inhibited by oral anticoagulants, thus intake of vitamin K through supplements or diet can reverse the action of oral anticoagulants. Resistance to oral anticoagulants has been associated with consumption of foods or enteral feedings high in vitamin K content. Likewise, a reduction of vitamin K intake following stabilization of anticoagulant therapy may result in elevation of the INR and bleeding complications. Foods rich in vitamin K include beef liver, broccoli, Brussels sprouts, cabbage, collard greens, endive, kale, lettuce, mustard greens, parsley, soy beans, spinach, Swiss chard, turnip greens, watercress, and other green leafy vegetables. Moderate to high levels of vitamin K are also found in other foods such as asparagus, avocados, dill pickles, green peas, green tea, canola oil, margarine, mayonnaise, olive oil, and soybean oil. Snack foods containing the fat substitute, olestra, are fortified with 80 mcg of vitamin K per each one ounce serving so as to offset any depletion of vitamin K that may occur due to olestra interference with its absorption. Whether these foods can alter the effect of oral anticoagulants has not been extensively studied. One small study found that moderate consumption (1.5 servings/day) does not significantly affect the INR after one week in patients receiving long-term anticoagulation.

Consumption of large amounts of mango fruit has been associated with enhanced effects of warfarin. The exact mechanism of interaction is unknown but may be related to the vitamin A content, which may inhibit metabolism of warfarin. In one report, thirteen patients with an average INR increase of 38% reportedly had consumed one to six mangos daily 2 to 30 days prior to their appointment. The average INR decreased by 17.7% after discontinuation of mango ingestion for 2 weeks. Rechallenge in two patients appeared to confirm the interaction.

Limited data also suggest a potential interaction between warfarin and cranberry juice resulting in changes in the INR and/or bleeding complications. The mechanism is unknown but may involve alterations in warfarin metabolism induced by flavonoids contained in cranberry juice. At least a dozen reports of suspected interaction have been filed with the Committee on Safety of Medicines in the U.K. since 1999, including one fatality. In the fatal case, the patient's INR increased dramatically (greater than 50) six weeks after he started drinking cranberry juice, and he died from gastrointestinal and pericardial hemorrhage. However, the patient was also taking cephalexin for a chest infection and had not eaten for two weeks prior to hospitalization, which may have been contributing factors. Other cases involved less dramatic increases or instabilities in INR following cranberry juice consumption, and a decrease was reported in one, although details are generally lacking. In a rare published report, a 71-year-old patient developed hemoptysis, hematochezia, and shortness of breath two weeks after he started drinking 24 ounces of cranberry juice a day. Laboratory test results on admission revealed a decrease in hemoglobin, an INR greater than 18, and prothrombin time exceeding 120 seconds. The patient recovered after warfarin doses were withheld for several days and he was given packed red blood cells, fresh-frozen plasma, and subcutaneous vitamin K. It is not known if variations in the constituents of different brands of cranberry juice may affect the potential for drug interactions.

There have been several case reports in the medical literature of patients consuming grapefruit, grapefruit juice, or grapefruit seed extract who experienced increases in INR. R(+) warfarin, the less active of the two enantiomers of warfarin, is partially metabolized by CYP450 3A4. Depending on brand, concentration, dose and preparation, grapefruit juice may be considered a moderate to strong inhibitor of CYP450 3A4, thus coadministration with warfarin may decrease the clearance of R(+) warfarin. However, the clinical significance of this effect has not been established. A pharmacokinetic study found no effect on the PT or INR values of nine warfarin patients given 8 oz of grapefruit juice three times a day for one week.

A patient who was stabilized on warfarin developed a large hematoma in her calf in association with an elevated INR of 14 following consumption of approximately 3 liters of pomegranate juice in the week prior to admission. In vitro data suggest that pomegranate juice can inhibit CYP450 2C9, the isoenzyme responsible for the metabolic clearance of the biologically more active S(-) enantiomer of warfarin. In rats, pomegranate juice has also been shown to inhibit intestinal CYP450 3A4, the isoenzyme that contributes to the metabolism of R(+) warfarin.

Black currant juice and black currant seed oil may theoretically increase the risk of bleeding or bruising if used in combination with anticoagulants. The proposed mechanism is the antiplatelet effects of the gamma-linolenic acid constituent in black currants.

Soy protein in the form of soy milk was thought to be responsible for a case of possible warfarin antagonism in an elderly male stabilized on warfarin. The exact mechanism of interaction is unknown, as soy milk contains only trace amounts of vitamin K. Subtherapeutic INR values were observed approximately 4 weeks after the patient began consuming soy milk daily for the treatment of hypertriglyceridemia. No other changes in diet or medications were noted during this time. The patient's INR returned to normal following discontinuation of the soy milk with no other intervention.

An interaction with chewing tobacco was suspected in a case of warfarin therapy failure in a young male who was treated with up to 25 to 30 mg/day for 4.5 years. The inability to achieve adequate INR values led to eventual discontinuation of the chewing tobacco, which resulted in an INR increase from 1.1 to 2.3 in six days. The authors attributed the interaction to the relatively high vitamin K content in smokeless tobacco.

MANAGEMENT: Intake of vitamin K through supplements or diet should not vary significantly during oral anticoagulant therapy. The diet in general should remain consistent, as other foods containing little or no vitamin K such as mangos and soy milk have been reported to interact with warfarin. Some experts recommend that continuous enteral nutrition should be interrupted for one hour before and one hour after administration of the anticoagulant dose and that enteral formulas containing soy protein should be avoided. Patients should also consider avoiding or limiting the consumption of cranberry juice or other cranberry formulations (e.g., encapsulated dried cranberry powder), pomegranate juice, black currant juice, and black currant seed oil.

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