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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Bicalutamide

Last Update: March 15, 2023.

OVERVIEW

Introduction

Bicalutamide is a second generation, oral nonsteroidal antiandrogen similar in structure to flutamide that has been used widely in the therapy of prostate cancer. Bicalutamide is associated with a low rate of serum enzyme elevations during therapy and has been linked to rare instances of liver injury.

Background

Bicalutamide (bye" ka loo' ta mide) is an orally available nonsteroidal antiandrogen that is similar in structure to flutamide and nilutamide used in the treatment of prostate cancer. Bicalutamide acts by binding to intracellular androgen receptors and competitively inhibiting the action of endogenous androgens on sensitive tissue, including testes, prostate, breast, skin and hypothalamus. Bicalutamide was approved for use in the United States in 1995. Current indications are for the therapy of metastatic prostate cancer in combination with luteinizing hormone releasing hormone (LHRH) analogs such as leuprolide or goserelin. Bicalutamide is available in tablets of 50 mg generically and under the trade name of Casodex. The recommended dose is 50 mg once daily. Common side effects of bicalutamide include fatigue, drowsiness, anxiety, gynecomastia and loss of libido. Rare but potentially severe adverse events include acute liver injury, Stevens Johnson syndrome, and severe hemorrhage when used with warfarin for anticoagulation.

Hepatotoxicity

Bicalutamide therapy is associated with mild, asymptomatic and transient elevations in serum aminotransferase levels in approximately 6% of patients. The frequency and height of the ALT elevations appears to be less with bicalutamide than flutamide. Similarly, there have been rare case reports of clinically apparent liver injury due to bicalutamide, but less frequently than with flutamide. In the Spanish pharmacovigilance study, there were 11 reports of hepatotoxicity from bicalutamide, none of which were fatal. On the other hand, the product label for bicalutamide mentions that a few cases of fatal hepatic failure have been reported. The clinical pattern of liver injury with bicalutamide appears to resemble that of flutamide. The latency to onset is usually 2 to 3 months, but can be shorter with reexposure and occasionally arises 4 to 6 months after starting. The typical pattern of serum enzyme elevations is hepatocellular and severe, fulminant cases have been described. Rash, fever and eosinophilia are not common and autoantibody formation is not described.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of bicalutamide hepatotoxicity is unknown. It is metabolized by the liver via the cytochrome P450 system, largely via CYP 3A4 which it can inhibit and thus cause drug-drug interactions. Thus, liver injury from bicalutamide may be caused by toxic or immunogenic metabolites of the agent. The lower frequency of hepatotoxicity from bicalutamide compared to flutamide may be due to its lower dose or its lower rate of hepatic metabolism.

Outcome and Management

The mild ALT elevations during bicalutamide therapy are usually self-limiting even with continuation of the medication. The rare instances of clinically apparent liver injury have ranged in severity from mild self-limiting cases to fatal acute liver failure. Monitoring of liver tests during therapy is recommended. There is no information on cross sensitivity to hepatic injury among the various antiandrogens. Rechallenge should be avoided and switching therapy to flutamide or nilutamide cannot be recommended.

Drug Class: Antineoplastic Agents, Antiandrogens

CASE REPORTS

Case 1. Acute liver failure arising after two doses of bicalutamide.(1)

A 60 year old man with prostate cancer developed acute liver failure following two doses of bicalutamide and a few days after stopping a 3 month course of flutamide. Liver test results were reported to be normal at the time of diagnosis of prostate cancer. Following an initial month of therapy with cyproterone acetate, flutamide and monthly subcutaneous goserelin acetate was started. Although flutamide was well tolerated, it was discontinued after 3 months and bicalutamide was substituted. After the second dose of bicalutamide, the patient developed jaundice and confusion. All medications were stopped and he was admitted for evaluation and therapy. He had no previous history of liver disease, no risk factors for viral hepatitis and no recent use of alcohol or acetaminophen. Serum bilirubin was 19.5 mg/dL, and serum ALT was markedly elevated with minimal increase in alkaline phosphatase levels (Table). The INR was 2.2. Tests for hepatitis A, B, C and for EBV infection were negative as were autoantibodies. An abdominal ultrasound revealed no evidence of biliary disease or liver metastasis. The patient developed mental obtundation and required intensive care support, vitamin K, and lactulose. After an initial period of worsening, he improved slowly. Eight weeks later, serum enzymes and bilirubin levels were normal.

Key Points

Medication:Bicalutamide, 50 mg, 2 doses, and flutamide, 750 mg daily for 3 months
Pattern:Hepatocellular
Severity:4+ (jaundice, hospitalization, coagulopathy and encephalopathy)
Latency:2 days for bicalutamide, 3 months for flutamide
Recovery:2 months
Other medications:Flutamide, cyproterone acetate, goserelin acetate

Laboratory Values

Time After
Starting		Time After
Stopping		ALT
(U/L)		Alk P
(U/L)		Bilirubin
(mg/dL)		Other
Bicalutamide 50 mg daily for two days
20269018119.5INR=2.2
8 weeks8 weeksNormalNormalNormalAsymptomatic
Normal Values <35 <130 <1.2

Comment

Although widely cited as an example of bicalutamide hepatotoxicity, this case can only be said to be “possibly” related to bicalutamide and is much more likely due to flutamide hepatotoxicity with the typical abrupt hepatocellular pattern of injury arising after 3 months of therapy. Indeed, even with the most severe hepatic injury (in the absence of hemolysis), it would take more than 2 days for serum bilirubin to rise from normal to 19 mg/dL. Cyproterone has also be linked to similar cases of hepatocellular injury, but the appearance of jaundice several months after stopping this agent, makes it unlikely as the cause.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Bicalutamide – Generic, Casodex®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NOMOLECULAR FORMULASTRUCTURE
Bicalutamide 90357-06-5 C18-H14-F4-N2-O4-S image 135014383 in the ncbi pubchem database

CITED REFERENCE

1.
Dawson LA, Chow E, Morton G. Fulminant hepatic failure associated with bicalutamide. Urology. 1997;49:283–4. [PubMed: 9037299]

ANNOTATED BIBLIOGRAPHY

References updated: 15 March 2023

Abbreviations: LHRH, luteinizing hormone releasing hormone; PSA, prostate specific-antigen.

  • Zimmerman HJ. Hepatotoxic effects of oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, p. 699.
    (Expert review of hepatotoxicity published in 1999, mentions that flutamide has led to instances of severe hepatic necrosis and fulminant hepatic failure).
  • DeLeve LD. Flutamide. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd Edition. Amsterdam: Elsevier, 2013. pp. 559.
    (Textbook on drug induced liver injury mentions that flutamide has been implicated in 46 cases of severe liver injury with 20 fatalities; bicalutamide is not discussed).
  • Moy B, Lee RJ, Smith M. Hormone therapy in prostate cancer. Natural products in cancer chemotherapy: hormones and related agents. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1763-9.
    (Textbook of pharmacology and therapeutics; discusses the role of androgen receptor blockers in prostate cancer including bicalutamide, flutamide and nilutamide).
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  • Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patternson AL, Sarosdy M, et al. A controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, in patients with advanced prostate cancer. Casodex Combination Study Group. Urology. 1995;45:745–52. [PubMed: 7538237]
    (Analysis of trial of bicalutamide vs flutamide in 813 men with prostate cancer at 60 sites; abnormal liver function reported in ~12% of flutamide vs ~8% of bicalutamide treated patients, but few details given as to nature, severity or reversibility).
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    (60 year old man with prostate cancer was given cyproterone and flutamide for 3 months and then switched to bicalutamide developing jaundice after 2 doses [bilirubin 19.5 mg/dL, ALT 2690 U/L, Alk P 181 U/L, INR 2.2 and encephalopathy], improving within 2 months: Case 1).
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    (Letter disputing the role of bicalutamide in case described by Dawson [1997] because flutamide had been stopped a few days before and was the more likely culprit).
  • Schellhammer PF. Fulminant hepatic failure associated with bicalutamide. Urology. 1997;50:827. [PubMed: 9372905]
    (Letter regarding case report by Dawson [1997] expressing doubt that the injury was due to bicalutamide [given for 2 days only] rather than flutamide [given for 3 months] or cyproterone [given for 1 month]).
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    (46 year old man with prostate cancer developed ALT elevations [106 U/L] without jaundice after 21 months of flutamide [750 mg/day], which improved on stopping [to 73 U/L] and increased again [108 U/L] with restarting [500 mg/day]. Switching to bicalutamide [50 mg/day] was followed by decrease of ALT but not to normal [53 U/L]).
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    (Review of randomized trials of bicalutamide for prostate cancer with no new information on hepatotoxicity).
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  • Manso G, Thole Z, Salgueiro E, Revuelta P, Hidalgo A. Spontaneous reporting of hepatotoxicity associated with antiandrogens: data from the Spanish pharmacovigilance system. Pharmacoepidemiol Drug Saf. 2006;15:253–9. [PubMed: 16294367]
    (Analysis of spontaneous reporting to Spanish Pharmacovigilance system found 88 cases of flutamide, 11 bicalutamide and 15 cyproterone hepatotoxicity, latency 3-6 months; 2 fatalities, both from flutamide).
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  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J., Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology. 2008;135:1924–34. [PMC free article: PMC3654244] [PubMed: 18955056]
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    (62 year old man with prostate cancer developed jaundice 19 weeks after starting bicalutamide [bilirubin 1.6 mg/dL, ALT 677 U/L, Alk P 87 U/L, INR 1.17], resolving completely within 3 months of stopping).
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    (88 year old man with metastatic prostate cancer developed jaundice one week after stopping a 5 month course of bicalutamide and starting enzalutamide while continuing on leuprolide [bilirubin 3.8 mg/dL, ALT 45 U/L, Alk P 654 U/L, GGT 988 U/L, INR 1.2], with little improvement after stopping all therapy and death from suspected progressive disease 2 weeks later).
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    (79 year old man with metastatic prostate cancer developed renal failure, proteinuria, hypertension, pulmonary dysfunction and liver test abnormalities shortly after starting bicalutamide and leuprorelin [ALT 147 U/L, AST 89 U/L, creatinine 5.6 mg/dL, bilirubin and Alk P not provided], resolving with supportive care).
  • Vaishampayan UN, Heilbrun LK, Monk P 3rd, Tejwani S, Sonpavde G, Hwang C, Smith D, et al. Clinical efficacy of enzalutamide vs bicalutamide combined with androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: a randomized clinical trial. JAMA Netw Open. 2021;4:e2034633. [PMC free article: PMC7838941] [PubMed: 33496795]
    (Among 71 men with advanced prostate cancer treated with either enzalutamide [160 mg] or bicalutamide [50 mg] daily with androgen-depletion therapy using a LHRH analog, the biochemical and overall survival outcomes were greater with enzalutamide than bicalutamide, particularly in Black subjects; no mention of hepatic adverse events).
  • Yanagisawa T, Kimura T, Mori K, Suzuki H, Sano T, Otsuka T, Iwamoto Y, et al. Abiraterone acetate versus nonsteroidal antiandrogen with androgen deprivation therapy for high-risk metastatic hormone-sensitive prostate cancer. Prostate. 2022;82(1):3–12. [PubMed: 34559410]
    (Among 312 men with prostate cancer treated with abiraterone [1000 mg] or bicalutamide [80 mg] daily, overall and cancer specific survival were similar in the two groups, but adverse events were more common with abiraterone [27% vs 21%] as was “impaired liver function” [16% vs 2%], and there were no deaths or severe adverse events attributed to liver injury).

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