Flutamide Hepatotoxicity

0022-5347/96/155 1-0209$03.00/0 THE JOURNAL OF UROLOGY Copyright @ 1996 by AMERICAN UROLOGICAL ~ I A T l O N , INC.

Vol. 155. 209-212. January 1996 Printed in U.S.A

FLUTAMIDE HEPATOTOXICITY

DIANE K. WYSOWSKI AND JEAN L. FOURCROY From the Divisions of Epidemiology and Surveillance, and Metabolism and Endocrine Drug Products, Center for Drug Evaluation and

Research, Food and Drug Administration, Rockville, Maryland

ABSTRACT

Purpose: Observed and expected reporting rates were compared in patients who died or were hospitalized due to hepatotoxicity associated with the use of flutamide.

Materials and Methods: Case series were submitted to the MedWatch Spontaneous Reporting System of the Food and Drug Administration. Reporting rates for serious hepatotoxicity due to flutamide were calculated and compared to rates for hospitalized patients with acute idiopathic hepatitis in the medical literature.

Results: After the marketing of flutamide in the United States, between February 1989 and December 1994 the Food and Drug Administration received reports of 20 patients who died and 26 who were hospitalized for hepatotoxicity due to flutamide. The rate of approximately 3 per 10,000 flutamide users exceeds by 10-fold or more the expected rate of hospitalizations for acute noninfectious liver injury of 2.5 per 100,000 men 65 years and older. Autopsies in 6 cases revealed marked to massive hepatic necrosis as the predominant feature.

Conclusions: Flutamide is a potent hepatotoxin in certain patients. Serial blood aminotransferase levels should be monitored during the first few months of flutamide treatment. Before beginning use of this drug patients should be instructed to report immediately to physicians any episodes of nausea, vomiting, fatigue and jaundice so that flutamide can be promptly discontinued to avoid progression of possible liver injury.

KEY WORDS: flutamide, hepatitis, toxicity, liver diseases, liver failure

Flutamide, an oral antiandrogen agent, was marketed in February 1989 in the United States for treatment of patients with prostate cancer (stage D2). It is indicated for use in combination with an analogue of luteinizing hormone-releasing hormone.

In a randomized double-blind trial 303 prostate cancer patients treated with an analogue of luteinizing hormone- releasing hormone and flutamide had a 7-month increase in median survival compared to 300 treated with a luteinizing hormone-releasing hormone analogue and placebo.' Diar- rhea was the only adverse event that was statistically signif- icantly more frequent in the flutamide group. However, data on side effects were not available for 71 eligible patients because of early death or failure to report such data. In a second randomized trial 155 patients with metastatic prostate cancer treated by a luteinizing hormone-releasing hormone analogue and flutamide experienced a 7-month increase in median survival compared to 155 who underwent bilateral orchiectomy.2 Flutamide was withdrawn due to liver toxicity in 4 patients. Also, abnormal values of serum glutamic pyruvic transaminase (alanine aminotransferase) were reported more frequently (p=0.07) in the patients who received drug therapy.

From the time flutamide was marketed through March 1991, the Food and Drug Administration (FDA) received reports of 19 patients in the United States who suffered serious hepatotoxicity while using this drug.3 In 14 patients the abnormal liver function test results resolved after discon- tinuing or decreasing the dose of flutamide but 5 died of progressive liver disease. We updated information and sum- marized additional reports of patients with hepatotoxicity caused by flutamide.

Accepted for publication July 21, 1995. This article represents the views of the authors and does not

constitute an official position of the Food and Drug Administration.

MATERIALS AND METHODS

Since 1969 approximately 1 million reports of adverse drug events have been submitted to the FDA MedWatch Sponta- neous Reporting System. Reports are submitted principally by physicians and pharmacists to pharmaceutical companies, who must by law forward the information to the FDA

A computer-assisted search of adverse event reports received by the FDA h m the marketing of flutamide in Feb- ruary 1989 through December 1994 in which flutamide was listed as the suspect drug was performed using 33 terms indicative of liver disorders. Foreign, literature and con- sumer reports were excluded, and only those from domestic patient care settings were reviewed. We also excluded dupli- cates and paired initial and followup reports. We then de- scribed patients whose illnesses resulted in serious outcomes (death or hospitalization).

To estimate the extent of serious hepatotoxicity due to flutamide, we compared the reporting rate of hepatotoxicity with flutamide to expected rates of serious acute idiopathic hepatotoxicity in the United States. The numerator of the reporting rate was the annual number of patients reported to the FDA with serious hepatotoxicity due to flutamide and the denominator was the estimated annual number of outpatient prescriptions dispensed through retail channels, including chain and independent pharmacies and food stores.4 Report- ing rates were calculated for each year from 1989 through 1994 and were averaged for the 6-year period. The average reporting rate was then compared to the baseline rate of hospitalization for noninfectious acute liver iqjury in the general population not exposed to drugs.6 While the denominator of the reporting rate does not include the total number of prescriptions (excluding those from Federal facilities, health maintenance organizations and mail order houses), even small underreporting of the numerator would probably more than offset the predicted small underreporting of the denominator.

209

2 10 FLUTAMIDE HEPATOTOXICITY

Next we calculated annual rates of death and hospitalization due to flutamide hepatotoxicity using spontaneously reported cases as the numerators and the estimated annual number of persons using flutamide as the denominators. Since patients are usually prescribed flutamide on a monthly basis,4 the estimated annual number of flutamide users was obtained by dividing the annual number of prescriptions by 12. Reporting rates were calculated for each year from 1989 through 1994 and averaged for the 6-year period. The average reporting rate was then compared to the annual incidence rate of validated hospital cases of acute idiopathic symptomatic hepatitis.6

We also attempted to obtain rates of older men hospitalized for acute noninfectious hepatitis from the investigators who had reported the aforementioned expected rates for compar- ison with the reporting rates of serious hepatotoxicity in older men due to flutamide use.

RESULTS

Deaths. A total of 20 men 47 to 85 years old (mean and median ages approximately 71 years) was reported to the FDA as having died of liver damage while undergoing flutamide therapy for prostate cancer. Patients presented to the physician with nausea, vomiting, lethargy and jaundice. For all but 3 patients flutamide was reportedly discontinued but hepatitis was often fulminant, resulting in hepatic failure, hepatorenal failure, encephalopathy and death.

Duration of flutamide use to onset of symptoms ranged from 5 days to 9 months (mean nearly 3 months). All patients for whom doses were recorded were taking the standard dose of 750 mg. flutamide per day. Liver function studies reportedly ranged from 200 to 5,760 units per 1. (mean 1,638) for aspartate aminotransferase, 200 to 2,974 units per 1. (mean 1,095) for alanine aminotransferase and 3 to 49.6 mg./dl. (mean 30.7) for bilirubin. Reports also mentioned prolonged prothrombin times in 3 patients but it is likely that others had abnormal values that were not reported. Autopsies in 6 cases revealed marked to massive hepatic necrosis as the predominant feature.

No other factors besides flutamide use explained the acute onset of liver dysfunction. Hepatitis serology was negative except in 2 patients with evidence of old disease. Computer- ized tomography (CT) and ultrasound studies were negative for metastases. There were no reported histories of drug abuse or intravenous drug use and there were no reported toxic exposures or blood transfusions. Only 2 patients had histories of 2 to 3 drinks of alcohol per day and 1 had a history of 6 drinks per day. Concomitant medications were not known to be hepatotoxic and only 7 of the 19 patients were taking a luteinizing hormone-releasing hormone agc- nist.

Hospitalized cases. Of the patients reported 26 were hospitalized for treatment of hepatotoxicity associated with the u8e of flutamide, including 25 men 52 to 81 years old (mean age 69) undergoing therapy for prostate cancer and a 47- year-old woman given a higher than standard dose of flutamide (1,OOO mg. per day) for alopecia and oily skin. Patients presented with the same symptoms as those who died but in 20 diecontinuation of the drug resulted in resolution of symptoms. In 3 patients it was not known whether flutamide was discontinued and in 3 discontinuation did not decrease the symptoms after a short followup. Duration of flutamide use to onset of symptoms ranged from 14 to 300 days (mean approximately 3 months). Except for the woman who was taking 1,OOO mg. per day, 18 men were taking 750 mg. per day and 3 were taking less than 750 mg. per day, while the doses were unknown in 4. Liver function studies ranged from 54 to 2,590 units per 1. (mean 762) for aspartate aminotrans- feraee, 63 to 2,700 (mean 993) for alanine aminotransferase, and 6.2 to 44 mgJdl. (mean 19.9) for bilirubin. The aspartate

aminotransferase and bilirubin levels were statistically sig- nificantly lower (t test p=0.049 for differences in aspartab aminotransferase levels and p=0.007 for differences in b& irubin levels) than those of the patients who died. Prolonged prothrombin times were reported in 5 patients.

Results of liver biopsies in men included hepatic necrosis in 1; acute and subacute cholestatic jaundice in 1; cirrhosis, acute hepatitis and ascites in 1, and severe acute and subacute cholestatic hepatitis with extensive bridging necrosb and bile duct proliferation in 1. In 1 patient biopsy w ~ g consistent with obstruction but a sonogram and CT showed hepatomegaly, cholestasis, bile thrombi and hepatic necrosis. The predominant features of these biopsies were cholestasb and hepatic necrosis.

One patient tested positive for hepatitis C but he also had a positive de-challenge with flutamide discontinuation. Sero- logical results indicated a history of exposure to hepatitis A and B in 2 patients. All other viral hepatitis studies reported were negative. Except for 1 patient whose CT and sonogram showed hepatomegaly, cholestasis, bile thrombi and hepatic necrosis, Liver CT and abdominal ultrasound studies were negative. One patient underwent exploratory surgery and cholecystectomy, and no pancreatic lesions or abdominal obstruction was found. One patient also underwent cholecystectomy but there was no mention of gallstones. Three patients had a history of alcohol use or misuse, including 1 currently abstinent patient with a history of ingesting 1 pint of hard liquor per day. Except for 1 patient who was taking diethylstilbestrol and 1 who was taking glyburide, there were no other known concomitant hepatotoxic drugs.

Reporting rates compared to expected rates. According to the reported 46 cases of serious hepatotoxicity in flutamide users that resulted in hospitalization or death and an estimated 1.87 million dispensed outpatient flutamide prescrip tions,4 the reporting rate for flutamide hepatotoxicity was calculated as 2.5 per 100,000 prescriptions, The baseline rate of hospitalization for noninfectious acute liver injury was low in the population not exposed to any drugs and was estimated as 0.2 case per person-time, equivalent to 0.2 case per 100,000 prescriptions in a recent epidemiology study.5 Thus, the observed reporting rate of hepatotoxicity in flutamide users was 12.5 times the expected rate in the nondrug using general population and it was even greater if underreporting of cases to the FDA is considered.

Calculating annual rates of death and hospitalization due to flutamide hepatotoxicity as the numerator and the estimated number of persons using flutamide as the denominator yields annual reporting rates of 2.1 to 3.6 per 10,000 patients (mean 3.0 per 10,000). The annual incidence rate of validated hospital cases of acute idiopathic symptomatic h e p atitis has been reported as 2.2 per 100,000 persons in Mich- igan and Florida Medicaid programs.6 Thus, the annual reporting rate of serious hepatotoxicity in flutamide users of 3.0 per 10,000 is 13.6 times the expected annual incidence rate of 2.2 per 100,000 persons.

The rate of hospitalization for acute idiopathic hepatitis was not available for patients with metastatic prostate cancer. However, from a previous study the rate of hospitalization for noninfectious acute liver injury in men 65 years and older was estimated as 2.5 per 100,000.5.7 Comparing the observed rate of serious hepatotoxicity in flutamide users of 3.0 per 10,000 to this expected rate in older men yields a 12-fold increase, which is close to the aforementioned results using general population rates.

DISCUSSION

From the time flutamide was marketed in February 1989 to December 1994 the FDA received reports of 20 patients who died and 26 who were hospitalized for hepatotoxicity due to flutamide. These 46 cases along with prescription data

FLUTAMIDE HEPATOTOXICITY 211 yield a reporting rate of 3 per 10,000 flutamide users, which is 10 or more times the expected rate of hospital cases of acute noninfectious liver injury in men 65 years and older. Since there is underreporting of adverse drug events to the FDA, it is likely that the reporting rate is higher and the observed-to-expected ratio is even greater than that reported.

Because the rate of hepatotoxicity in flutamide users is low, no statistically significant differences in frequencies of abnormal liver function studies between the flutamide and placebo arms were found in the pivotal study of approximately 600 patients required for FDA approval of flutamide.1.s Also, inability to observe a difference may have been due to incomplete data on side effects, since according to the investigators such data were not available for 71 patients (due to either early death or failure to report resultsl.1 In a second randomized clinical trial comparing 155 patients who received a luteinizing hormone-releasing hormone analogue and flutamide and 155 who underwent bilateral orchiectomy, flutamide had to be withdrawn due to liver toxicity in 4.2 Furthermore, abnormal values of serum glutamic pyruvic transaminase (alanine aminotransferase) were reported more frequently (p=0.07) in the patients who received drug therapy. Also in a study of 1,091 consecutive patients with stage C or D prostate cancer treated with flutamide and a luteinizing hormone-releasing hormone agonist an increase in aspartate aminotransferase and alanine aminotransferase of 4-fold or more above the upper limit of normal occurred in 4 (0.36% or 36 per lO,OOO).9 Two of the 4 patients (0.18% or 18 per 10,000) had clinical manifestations of h e r disease.

In 1993 we reported our first series of 19 patients in the United States who had serious hepatotoxicity while using flutamide.3 The symptoms resolved with drug discontinuation in 14 patients but 5 died. The present study includes these cases and provides information on 27 reported through 1994.

In addition to the aforementioned patients who had liver toxicity in the clinical trial: at least 16 patients have been reported with hepatotoxicity while on flutamide the rap^.^-^^ Two reports concerned women who received flutamide for hirsutism.12.16 A 20-year-old East Indian woman with men- strual irregularity and hirsutism suffered hepatotoxicity approximately 1.5 months after beginning 500 mg. flutamide per day. Flutamide was discontinued, the liver enzymes re- turned to normal and the symptoms resolved. In addition to these cases, there have been at least 4 reports of flutamide in which 1 or more cases of hepatotoxicity developed during the study.g.24-26 Frequencies of hepatotoxicity ranged from less than 1 to 10%.

A recent study of flutamide in rats confirmed that the drug was toxic to rat hepatocytes as a result of the cytochrome p450 mediated formation of metabolite^.^^ Flutamide also inhibited mitochondria1 respiration and adenosine triphosphate formation.

on drug therapy. Also, there have been reports in the literature of 16 patients (including 2 women treated for hirsutism) and at least 4 studies of 1 or more patients in whom hepatotoxicity developed while on flutamide. A recent study in rats revealed that flutamide was toxic to rat hepatocytes due to the cytochrome P450 mediated formation of metabolites. Flu- tamide was also found to inhibit mitochondrial respiration and adenosine triphosphate formation.

Flutamide is a potent hepatotoxin in certain patients. Se- rial blood aminotransferase levels should be monitored during the first few months of treatment. Before beginning use of this drug, patients should be instructed to report immediately to physicians any episodes of nausea, vomiting, fatigue and jaundice so that flutamide can be promptly discontinued to avoid progression of possible liver injury.

CONCLUSIONS

From the marketing of flutamide in the United States in February 1989 through December 1994, the FDA received reports of 20 patients who died and 26 who were hospitalized for hepatotoxicity due to flutamide. The estimated reporting rate of approximately 3 per 10,000 flutamide users exceeds by 10-fold or more the expected rate of hospitalizations for acute noninfectious liver injury of 2.5 per 100,000 in men 65 Years and older. Autopsies in 6 cases revealed marked to massive hepatic necrosis.

In addition to this series, in a randomized trial that com- Pared patients treated with a luteinizing hormone-releasing hormone analogue and flutamide to those who underwent bilateral orchiectomy, flutamide was withdrawn in 4 due to %r toxicity and elevated serum g l u t d c pyr~Vic trans-- mase levels were reported more frequently (p=0.07) m those

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18. Dankoff, J. S.: Near fatal liver dysfunction secondary to administration of flutamide for prostate cancer. J. Urol., 148: 1914, 1992.

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EDITORIAL COMMENT

The authors underscore the importance of continuous and diligent monitoring of potential side effecte associated with drugs that are being prescribed in larger patient populations following initial approval. They reviewed the safety profile of flutamide and indicate that the understanding of liver toxicity, which has accrued with larger patient exposure. continues to be refined. Post-marketing surveillance of drug safety often provides important information to maximize the correct and safest use of new drugs. The current case is no exception. The incidence of abnormal Liver function tests and hepatotoxicity, now with 6 years of post-marketing experience, continues to demand our attention. More importantly, the authors note critical guidelines for improved monitoring of liver function testing and drug administration, which should further minimize adverse events and maximize safety.

It is also equally important to place a new drug or class of drugs in proper clinical perspective, especially in light of emerging safety data. In multiple randomized studies the addition of an antiandm gen. such as flutamide, to either a luteinizing hormone-releasing hormone agonist or orchiectomy has consistently improved the overall survival of patients with metastatic prostate cancer (references 1 and 2 in article). Moreover. the benefit of the antiandrogen is a u g mented in patients with low volume metastatic disease with good performance status. This latter point is especially important, since many patients now being diagnosed with prostate cancer in the 1- have earlier stage disease and those with metastatic disease often demonstrate only minimal disease. Thus. the use of an antian-

of safety versus efficacy. The initial approval by the Food and Drug Administration of flutamide in combination with a Iuteinizing her- mone-releasing hormone agonist, based upon improvement in overall survival, was an important advance. The curtailing of its use, based upon this report, I believe would be inappropriate and would not be in the best interest of our patients. Moreover, the additional years of life saved in patients treated with flutamide are vastly greater than life lost resulting from drug induced morbidity and mortality.

The data reported by the authors also underscore the necessity for physicians to understand the proper use of new drugs. I t is of interest that the doses administered to several patients were not withn prescribing guidelines, some of the patients were women taking flutamide for nonappmved indications and a majority of patients were not receiving a luteinizing hormone-releasing hormone agonist as recommended in the prescribing information suggested by the manufacturer. Moreover, in a recent survey conducted by the Hams poll on prescribing practices of physicians caring for patients with prostate cancer, an antiandrogen was given inappropriately to 62% of patients with refractory disease (when i t is not indicated) and in only 408 of those with newly diagnosed metastatic disease, which i5 the appropriate use.' We all must do better in understanding the appropriate and proper use of drugs to assure that those who can benefit from the drug receive it and those who are unlikely to benefit do not.

There is also no reason to believe that the hepatotoxicity of other antiandrogens will be any different than that of flutamide. In the randomized study of flutamide plus luteinizing hormone-releasing hormone agonist versus bicalutamide plus luteinizing hormone- releasing hormone agonist, there was no statistically significant difference in abnormal liver function tests.' With the recent approvaj and more widespread availability of bicalutamide, it will be critical for physicians, the Food and Drug Administration and manufactur- ers to continue to monitor safety with great diligence until a larger exposed patient population has been studied.

Marc B. Garnick Department of Urology Harvard Medical School Boston, Massachusetts

1. Perspectives on prostate cancer treatments: awareness, atti- tudes and relationships. Conducted by Louis Harris and As- sociates, Inc., July 31-August 17, 1995.

2. Schellhammer, P., Sharifi, R., Block, N., Soloway, M., Venner, P., Patterson, A. L., Sarosdy, M., Vogelzang, N., Jones, J . and Kolvenbag, G. for the Casodex Combination Study Group: A controlled trial of bicalutamide versus flutamide each in combination with a luteinizing hormone-releasing hormone ana-

drogen in these patients would be expected to show continuous improvement in overall survival. Therefore, the balance becomes one

logue therapy, in patients with advanced prostate cancer. Urology, 45: 745, 1995.

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Flutamide Hepatotoxicity