CLINICAL PHARMACOLOGY R O U N D S

A case of bleeding requiring hospitalization that was likely caused by an interaction between warfarin and levamisole

Warfarin is one of the most commonly used oral anticoagulants. Many medications have been shown to influence the prothrombin time in patients treated with warfarin by various mechanisms. We observed a major bleeding episode that resulted from a probable interaction between levamisole (Ergamisol), 5-fluorouracil, and warfarin. It is conceivable that many patients who are predisposed to thromboembolism because of cancer and surgery will be taking this combination of medications. (CLm PHA~tACOL THrR 1996;59:360"2.)

T a r e k W. W e h b e , M D , a n d J a m e s A. W a r t h , M D Boston, Mass.

The patient was a 60-year-old woman found to have stage C2 rectal carcinoma according to the modified Astler-Coller staging system. Postopera- tively she developed a lower extremity deep vein thrombosis and pulmonary embolus for which she received the anticoagulant heparin. She then began treatment with warfarin.

The patient was subsequently randomized to re- ceive 5-fluorouracil and levamisole under the East- ern Cooperative Oncology Group study protocol 4290, which compares the use of these medications, leucovorin alone, and radiation therapy in different combinations as adjuvant treatment for resected stages B2 and C rectal carcinoma.

At the time of enrollment, she was receiving war- farin 5 mg per day with a prothrombin time (PT) fluctuating between 13.6 and 19.7 seconds (control, 10 to 13 seconds). Ten days after completion of the first cycle of levamisole and 5-fluorouracil, her PT increased to 22.6 seconds (April 18). Two days after the completion of a 3-day course of levamisole (April 26), the patient had right flank pain for 1 day,

From the Faulkner Hospital and Tufts Medical School. Received for publication Feb. 10, 1995; accepted Sept. 30, 1995. Reprint requests: Tarek W. Wehbe, MD, 309 Greenwich Ave.,

C316, Warwick, RI 02886. Copyright © 1996 by Mosby-Year Book, Inc. 0009-9236/96/$5.00 + 0 13/1/69621

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accompanied by gross hematuria noted by the pa- tient and her visiting nurse. The PT when the patient came to the hospital was greater than 40 seconds. Cystoscopy was performed and showed the site of bleeding to be from both ureters. She was treated with fresh frozen plasma and vitamin K, with reso- lution of the hematuria. Her only other medication at that time was 325 mg ferrous sulfate three times a day. She received no radiation, growth factors, or other medications during this period. Urine culture at admission (April 26) showed no bacterial growth. The patient was followed up without anticoagula- tion because the hypercoagulable state was elimi- nated with surgery and chemotherapy. No clinically obvious deep vein thrombosis or pulmonary embo- lus was detected during follow-up. Table I summa- rizes the patient information.

DISCUSSION

Warfarin is the most commonly used oral antico- agulant in the United States. It has 100% bioavail- ability, and 99% is bound to albumin with a half-life of 37 hours) The mechanism of action is thought to be interference with the posttranslational vitamin K-dependen t modification of coagulation factors II, VII, IX, and X in the liver. 2 The stereoselectivity of warfarin metabolism has been used to assess structure-function relationships of cytochrome P450 (CYP450) family members. 3 A number of enzymes

CI.I NICAL PHAI~,MA('OLOGY & TH I-I~kI'EUTICS VOI.UME 59, NUMBER 3 Wehbe and Warth 361

40 Warfarin dose (rag/day)

I 2.5/d t 5.O/d

0

v

E

0

30

20

1 0 d -

t~

FU/Lev m /

Lev i = I I

I I I I

2 ~4 6 ~ 8 ~

Weeks Since Start of Warfarin o,

Fig. 1. Change of prothrombin time (PT) with time.

FU/Lev

1 0 3 12 (,o

in this family are involved in metabolism to different enantiomers. These are oxidized in turn by CYP4502C subfamily members.

Many drugs have been shown to interact with warfarin by different mechanisms resulting in an increase or decrease in its activity. Our patient had a rapid prolongation of the prothronbin time mea- sured 10 days after the first dose of 5-fluorouracil and levamisole and 4 days after levamisole alone (Fig. 1, data point for April 26). There have been a number of reports showing an interaction between 5-fluorouracil and warfarin resulting in prolonga- tion of PT. 4"5 Levamisole administration without 5-fluorouracil (April 22) was closer in time to the PT prolongation, which makes 5-fluorouracil a less likely cause, especially when one considers that 5-fluorouracil can no longer be detected in the plasma 3 hours after its intravenous injection, r' Nonetheless, it is not possible to exclude 5-fluorouracil completely on the basis of the current data.

Scarfe and Israel 7 reported a potential interac-

tion between warfarin and the combination of levamisole and 5-fluorouracil in an elderly pa- tient. The prolongation of the international nor- malization ratio occurred 4 weeks after therapy was started, which makes a displacement reaction unlikely. To our knowledge, that was the first report to suggest an interaction between levami- sole and warfarin.

Levamisole is distributed extensively in the tis- sues, with the highest concentration occurring in the liver and kidneys. In the plasma, it binds to both albumin and oh-acid glycoprotein (Scarfe and IsraelT). It has been shown s to induce CYP450 in mice when given as 20 mg/kg/day for 4 days. One may speculate that while levamisole induces some members of the CYP450 family, it may inhibit others that are involved in warfarin metabolism. However, this remains to be proven. The level of different cytochrome enzymes varies from one individual to another, as well as with the state of induction in the same person. For example, some medications that induce CYP450 (such as phenobarbital) increase the

3 6 2 Wehbe a n d W a r t h CLINICAL I'HAILMACOLOGY & THEIL'~.PEUTI(-q

MARCH 1996

Table I. Change of PT over time

Date PT (sec) Comments

2/11 10.9 2/13 10.9 2/28 11.5 3/2 19.7 3/3 18.1 3/6 17.5 3/14 13.6 3/25 18.5 4/8-4/12

4/18 22.6 4/22-4/24 - -

4/26 >40

4/27 23 4/28 14 5/6--5/10

5/7 11 5/13 10.9

2.5 mg/day warfarin

Warfarin increased to 5 mg/day

150 mg intravenous levamisole over 2 hours daily for 3 days; 808 mg 5-FU as an intrave- nous bolus daily for 5 days

150 mg intravenous levamisole over 2 hours daily for 3 days

Warfarin stopped; FFP and vitamin K given

150 mg intravenous levamisole over 2 hours daily for 3 days; 565 mg 5-FU as intravenous bolus daily for 5 days

PT, Prothrombin time; FFP, fresh frozen plasma; 5-FU, 5-fluorouracil.

rate of formation of 4'- and 7-hydroxy-R-warfarin metabolites, 9'1° probably by up-regulating certain enzymes in the family over others.

Other possible mechanisms of interaction be- tween levamisole and warfarin can not be ruled out and have been shown to take place in other drug- warfarin interactions. Both warfarin and levamisole are bound in the plasma to albumin; therefore le- vamisole may displace warfarin from albumin and increase its free plasma concentration. This seems to be a less likely possibility because the prolongation of PT did not occur shortly after levamisole admin- istration on April 8.

Ano the r possibility is an effect of levamisole on the half-life of one or more clotting factors in the coagulation cascade or interference with vitamin K binding, without necessarily interacting with warfarin. 1~ We are unable to rule out insufficient oral intake of vitamin K during the same period, which is of potential importance in patients with cancer who are receiving chemotherapy. How- ever, this patient was not receiving antibiotics and did not lose weight.

In conclusion, thromboembolism is not an un- common postoperative problem in patients with cancer. It is conceivable that other patients receiving levamisole and warfarin treatment will have signifi- cant bleeding. In fact, we have received correspon- dence from the manufacturer of levamisole that indicates that a report of a similar interaction has been received (Personal communication, Irene Long, RN, BSN, Jansen Research Foundation, Pis- cataway, N.J., July 14, 1991). Our report will hope- fully alert physicians whose patients are receiving levamisole to monitor warfarin therapy closely to avoid bleeding.

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2. Nagashima R, O'Reily AA, Levy G. Kinetics of phar- macologic effects in man: anticoagulant action of war- farin. CLIN PHARMACOL THER 1969;10:22-5.

3. Kaminsky LS, de Morals SM, Faletto MB, Dunbar DA, Goldstein JA. Correlation of human cytochrome P4502C substrate specificities with primary structure: warfarin as a probe. Mol Pharmacol 1993;43:234-9.

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8. DalviRR, Terse PS. Induction of hepatic microsomal drug metabolizing enzyme system by levamisole in male mice. J Pharm Pharmacol 1990;42:58-9.

9. Sutcliffe FA, MacNicoll AD, Gibson GG. Hepatic microsomal warfarin metabolism in warfarin-resistant and susceptible mouse strains: influence of pretreat- ment with cytochrome P-450 inducers. Chem Biol Interactions 1990;75:171-84.

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