Side effects of bicalutamide

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Major side effects of bicalutamide [1] [2] [3] [4] [5] [6] [7]
Frequency Class of effect Effect
Very common (≥10%) Reproductive system and breast disorders •  Breast tenderness [a]
•  Gynecomastia [a]
Common (1–10%) General and psychiatric disorders •  Asthenia
•  Decreased libido
•  Erectile dysfunction
•  Hot flashes
Skin and subcutaneous
tissue disorders 		•  Decreased body hair
Hepato-biliary disorders •  Elevated liver enzymes [b]
Uncommon (0.1–1%) Immune system disorders and hypersensitivity reactions •  Angioedema
•  Hives
Rare (<0.1%) or unknown Respiratory disorders •  Lung disease [c]
Skin and subcutaneous tissue disorders •  Sensitivity to light
Hepato-biliary disorders •  Liver toxicity [c]
  1. 1 2 May occur as often as 90% of those taking bicalutamide, but is mild-to-moderate in 90% of occurrences. Incidence greatly decreased in combination with castration.
  2. ↑ Usually transient, rarely severe. Resolves or improves with continued therapy or on discontinuation.
  3. 1 2 Reported in single cases, but not observed in any large, randomized trial. With regular liver monitoring and discontinuation as needed.

The side effects of bicalutamide, a nonsteroidal antiandrogen (NSAA), including its frequent and rare side effects, have been well-studied and characterized. The most common side effects of bicalutamide monotherapy in men include breast tenderness, breast growth, feminization, demasculinization, and hot flashes. Less common side effects of bicalutamide monotherapy in men include sexual dysfunction, depression, fatigue, weakness, and anemia. Bicalutamide is well tolerated and has few side effects in women. General side effects of bicalutamide that may occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash.

Contents

In men with prostate cancer, bicalutamide monotherapy has been found to increase the likelihood of death due to causes other than prostate cancer. Bicalutamide has been found to cause unfavorable liver changes in around 3 to 11% of people, with such changes necessitating discontinuation in approximately 1%. Rarely, bicalutamide has been associated with serious liver toxicity and lung disease, as well as sensitivity to light. It has also uncommonly been associated with hypersensitivity reactions. Bicalutamide has a theoretical risk of birth defects in male fetuses.

Central nervous system

Hot flashes

In the Early Prostate Cancer (EPC) clinical trial programme, at 7.4 years follow-up, the rate of hot flashes was 9.2% for bicalutamide monotherapy relative to 5.4% for placebo, which was regarded as relatively low. [8] In the LAPC subgroup of the EPC trial, the rate of hot flashes with bicalutamide monotherapy was 13.1% (relative to 50.0% for castration). [8] [9]

Sexual dysfunction

Bicalutamide may cause sexual dysfunction, including decreased sex drive and erectile dysfunction. [8] However, the rates of these side effects with bicalutamide monotherapy are very low. [8] In the EPC trial, at 7.4 years follow-up, the rates of decreased libido and impotence were only 3.6% and 9.3% in the 150 mg/day bicalutamide monotherapy group relative to 1.2% and 6.5% for placebo, respectively. [8] Similarly, in the trials of 150 mg/day bicalutamide monotherapy for advanced prostate cancer, fewer than 10% of men reported decreased sex drive or reduced erectile function as a side effect. [9] About two-thirds of men in these trials, who had advanced prostate cancer and were of almost invariably advanced age, [10] maintained sexual interest, while sexual function was slightly reduced by 18%. [9] Most men experience sexual dysfunction only moderately or not at all with bicalutamide monotherapy, and the same is true during monotherapy with other NSAAs. [11] Bicalutamide monotherapy at a dosage of 50 mg/day had no effect on nocturnal erections in men with prostate cancer. [12] [13] The preservation of sexual desire and function with NSAA monotherapy may be related to testosterone metabolites such as estradiol and the 3α-androstanediol maintaining these functions rather than the androgen receptor or to bicalutamide and other NSAAs possibly incompletely blocking the androgen receptor in the brain. [14] [15]

Similarly to in men, bicalutamide has been associated with minimal or no sexual dysfunction in women. [16] A phase III clinical study of 50 mg/day bicalutamide in conjunction with a combined oral contraceptive in women with severe hirsutism due to polycystic ovary syndrome (PCOS) carefully assessed the side effect of decreased libido and found that the incidence with bicalutamide did not differ from the control group. [16] Minimal rates of reduced sex drive have also been associated with the related NSAA flutamide. [17] [18] These findings are in accordance with the fact that women with complete androgen insensitivity syndrome (CAIS) show normal sexual function in spite of complete loss of androgen receptor (AR) signaling. [19] They are also in accordance with a variety of findings concerning testosterone levels and sexual function in premenopausal women, in which no change in parameters of sexual function, including libido, have been observed in association with increases or decreases in testosterone levels. [19] It appears that testosterone levels within the normal physiological range are not importantly involved in sexual desire or function in women. [20]

Psychiatric conditions

At 5.3 years follow-up, the incidence of depression was 5.5% for bicalutamide monotherapy relative to 3.0% for placebo in the EPC trial, and the incidence of asthenia (weakness or fatigue) was 10.2% for bicalutamide monotherapy relative to 5.1% for placebo. [21] Rarely, bicalutamide has been associated with hallucinations. [22] This is thought to be secondary to AR antagonism. [22]

Breasts and reproductive system

Bicalutamide monotherapy and breast side effects in dose-ranging studies in men
StudyNDosage Gynecomastia Breast tenderness Ref
Tyrrell et al. (1998)a38610 mg/day9%11% [23]
30 mg/day26%42%
50 mg/day36%48%
100 mg/day79%86%
150 mg/day78%89%
200 mg/day79%79%
Kennealey & Furr (1991)b21010 mg/day29%38% [24]
30 mg/day60%64%
50 mg/day52%60%
Zanardi et al. (2006)c660 mg/week (controls)0%0% [25] [26] [27]
50 mg/week (~7 mg/day)44%32%
100 mg/week (~14 mg/day)50%64%
Footnotes:a = Testosterone levels increased to ~460–610 ng/dL and estradiol levels to ~32–51 pg/mL. b = Testosterone levels increased to ~505–715 ng/dL and estradiol levels to ~32–53 pg/mL. c = Testosterone levels increased to ~540–600 ng/dL and estradiol levels to ~29–34 pg/mL.

Breast changes

Gynecomastia in a 60-year-old man treated with 150 mg/day bicalutamide for prostate cancer. Severe bicalutamide-induced gynecomastia.jpg
Gynecomastia in a 60-year-old man treated with 150 mg/day bicalutamide for prostate cancer.

The most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia. [11] These side effects may occur in as many as 90% of men treated with bicalutamide monotherapy, [29] but gynecomastia is generally reported to occur in 70 to 80% of patients. [30] In the EPC trial, at a median follow-up of 7.4 years, breast pain and gynecomastia respectively occurred in 73.6% and 68.8% of men treated with 150 mg/day bicalutamide monotherapy. [8] [9]

Rates of gynecomastia with bicalutamide monotherapy and monotherapy with other NSAA varies significantly across different trials, in reviews ranging from 38 to 85% with bicalutamide, 21 to 80% with flutamide, and 50 to 79% with nilutamide. [31] [32] This variation is presumably related to factors like duration of therapy, differing patient characteristics, and the specific methods of collection of adverse-event data. [32] [23] One review noted that rates of breast side effects were much lower with open questioning (23–26% for gynecomastia and 26–31% for breast tenderness at 50–150 mg/day bicalutamide) as opposed to direct questioning in studies of bicalutamide monotherapy for prostate cancer. [23]

Gynecomastia associated with NSAA monotherapy usually develops within the first 6 to 9 months following initiation of treatment. [28] [33] [34] In one study, 89% of those who developed gynecomastia and 98% of those who developed breast pain did so within the first 6 months. [33] Of those who developed gynecomastia, around 55% did so in the first 3 months, around 35% between 3 and 6 months, and 10% after more than 6 months. [33] For breast pain, rates were around 75% in the first 3 months, 25% between 3 and 6 months, and less than 5% after more than 6 months. [33] In the EPC programme, 85% who developed breast pain did so in the first 6 months and 80% who developed gynecomastia did so in the first 9 months. [34]

In more than 90% of affected men, bicalutamide-related breast changes are mild-to-moderate in severity. [9] [35] [34] It is only rarely and in severe and extreme cases of gynecomastia that the proportions of the male breasts become so marked that they are comparable to those of women. [36] In addition, bicalutamide-associated breast changes improve or resolve in most men upon discontinuation of therapy. [9] In the EPC trial, 16.8% of bicalutamide patients relative to 0.7% of controls withdrew from the study due to breast pain and/or gynecomastia. [35] [34] Gynecomastia and breast pain improved or resolved upon discontinuation in 70 and 90% of patients, respectively. [34] Resolution of breast symptoms was dependent on duration of bicalutamide therapy, with resolution rates ranging from 29% with >18 months of treatment to 64% for <6 months of treatment. [34]

Gynecomastia and breast pain/tenderness with NSAA monotherapy is due to increased estradiol levels and unopposed estrogen action in the breasts due to androgen receptor blockade (as androgens inhibit the effects of estrogens in the breasts). [32]

The incidence and severity of gynecomastia are reportedly slightly higher with estrogens (e.g., diethylstilbestrol) (40–80%) than with NSAAs like bicalutamide (40–70%) in the treatment of men with prostate cancer. [37] [31]

Management of breast changes

Severe gynecomastia with 150 mg/day bicalutamide monotherapy in a 64-year-old man with prostate cancer. Before (left) and after (right) surgical breast reduction. Severe bicalutamide-induced gynecomastia before and after surgical breast reduction.jpg
Severe gynecomastia with 150 mg/day bicalutamide monotherapy in a 64-year-old man with prostate cancer. Before (left) and after (right) surgical breast reduction.

Tamoxifen, a selective estrogen receptor modulator (SERM) with antiestrogenic actions in breast tissue and estrogenic actions in bone, has been found to be highly effective in preventing and reversing bicalutamide-induced gynecomastia in men. [39] [40] Moreover, in contrast to GnRH analogues (which also alleviate bicalutamide-induced gynecomastia), tamoxifen poses minimal risk of accelerated bone loss and osteoporosis. [39] [40] For reasons that are unclear, anastrozole, an aromatase inhibitor (or an inhibitor of estrogen biosynthesis), has been found to be much less effective in comparison to tamoxifen for treating bicalutamide-induced gynecomastia. [39] [40] A 2015 systematic review of NSAA-induced gynecomastia and breast tenderness concluded that tamoxifen (10–20 mg/day) and radiotherapy could effectively manage the side effect without relevant adverse effects, though with tamoxifen showing superior effectiveness. [41] A 2019 network meta-analysis likewise concluded that tamoxifen was more effective than radiotherapy or anastrozole for preventing bicalutamide-induced gynecomastia. [42] Surgical breast reduction may also be employed to correct bicalutamide-induced gynecomastia. [31]

Tamoxifen doses and rates of bicalutamide-induced breast symptoms in men
Follow-up
timepoint		Tamoxifen dosage
Placebo1 mg/day2.5 mg/day5 mg/day10 mg/day20 mg/day
0 months
–
6 months98%90%80%54%22%10%
12 months99%95%84%56%38%19%
Notes: Prevention of breast symptoms—specifically gynecomastia and breast pain—induced by 150 mg/day bicalutamide monotherapy with tamoxifen in 282 men with prostate cancer. Bicalutamide and tamoxifen were initiated at the same time (0 months). Estradiol levels were in the range of about 22 to 47 pg/mL in the treated group. [43] Sources: [44] [43]

Male breast cancer

A case report of male breast cancer subsequent to bicalutamide-induced gynecomastia has been published. [45] According to the authors, "this is the second confirmed case of breast cancer in association with bicalutamide-induced gynaecomastia (correspondence AstraZeneca)." [45] It is notable, however, that gynecomastia does not seem to increase the risk of breast cancer in men. [45] [46] Moreover, the lifetime incidence of breast cancer in men is approximately 0.1%, [47] the average age of diagnosis of prostate cancer and male breast cancer are similar (around 70 years), [10] [48] and millions of men have been treated with bicalutamide for prostate cancer, [49] all of which are potentially in support of the notion of chance co-occurrences. [45] In accordance, the authors concluded that "causality cannot be established" and that it was "probable that the association is entirely coincidental and sporadic." [45]

Lower reproductive system

Bicalutamide reduces the size of the prostate gland and seminal vesicles, [50] though not of the testes. [51] Slightly but significantly reduced penile length is also a recognized adverse effect of ADT. [52] [53] Reversible hypospermia or aspermia (that is, reduced or absent semen/ejaculate production) may occur. [54] [55] However, bicalutamide does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish the capacity/potential for fertility in men. [51] [56] Due to the induction of chronic overproduction of LH and testosterone, there was concern that long-term bicalutamide monotherapy might induce Leydig cell hyperplasia and tumors (usually benign), [57] but clinical studies indicate that Leydig cell hyperplasia does not occur to a clinically important extent. [58] [56] [59]

Male birth defects

Because bicalutamide blocks the AR, like all antiandrogens, it can interfere with the androgen-mediated sexual differentiation of the genitalia (and brain) during prenatal development. [60] [61] [62] [63] In pregnant rats given bicalutamide at a dosage of 10 mg/kg/day (resulting in circulating drug levels approximately equivalent to two-thirds of human therapeutic concentrations) and above, feminization of male offspring, such as reduced anogenital distance and hypospadias, as well as impotence, were observed. [64] No other teratogenic effects were observed in rats or rabbits receiving up to very high dosages of bicalutamide (that corresponded to up to approximately two times human therapeutic levels), and no teratogenic effects of any sort were observed in female rat offspring at any dosage. [64] As such, bicalutamide is a selective reproductive teratogen in males, and may have the potential to produce undervirilization/sexually ambiguous genitalia in male fetuses. [60] [61] Due to its teratogenic capacity, contraception should be used in women taking bicalutamide who are fertile and sexually active. [65]

Skin, fat, and bone

Skin changes

Antiandrogen therapy and estrogen therapy are known to produce demasculinizing and feminizing effects in the skin and on hair follicle distribution in people assigned male at birth. [66] Androgens are involved in regulation of the skin (e.g., sebum production), and antiandrogens are known to be associated with skin changes. [58] Skin-related side effects, which included dry skin, itching, and rash, were reported at a rate of 2% in both monotherapy and CAB clinical studies of bicalutamide in men. [58]

Sensitivity to light

A few cases of photosensitivity (hypersensitivity to ultraviolet light-induced skin redness and/or lesions) associated with bicalutamide have been reported. [67] [68] [69] In one of the cases, bicalutamide was continued due to effectiveness in treating prostate cancer in the patient, and in combination with strict photoprotection (in the form of avoidance/prevention of ultraviolet light exposure). Eventually, the symptoms disappeared and did not recur. [67] Flutamide is also associated with photosensitivity, but much more frequently in comparison to bicalutamide. [67] [69]

Fat distribution

Antiandrogen therapy and estrogen therapy are known to produce demasculinizing and feminizing effects on fat distribution in people assigned male at birth. [66]

Bone density and fractures

Bicalutamide monotherapy preserves bone mineral density in men with prostate cancer relative to surgical or medical castration. [7] [70] [71] [72] [73] This is considered to be due to preservation of gonadal estradiol production with bicalutamide monotherapy, in contrast to castration which greatly reduces estradiol levels. [7] The risk of osteoporosis and serious bone fractures with bicalutamide monotherapy appears to be no different than with non-use in men with prostate cancer. [74]

Gastrointestinal system

The incidence of diarrhea with bicalutamide monotherapy in the EPC trial was comparable to placebo (6.3% vs. 6.4%, respectively). [9] In phase III studies of bicalutamide monotherapy for LAPC, the rates of diarrhea for bicalutamide and castration were 6.4% and 12.5%, respectively, the rates of constipation were 13.7% and 14.4%, respectively, and the rates of abdominal pain were 10.5% and 5.6%, respectively. [75]

Heart, liver, kidneys, and lungs

Cardiovascular system

A study of high-dose bicalutamide monotherapy (300–600 mg/day) in 248 men with LAPC or metastatic prostate cancer found that there were no effects of bicalutamide on heart rate, blood pressure, or electrocardiogram parameters. [76] [77] At the 5-year follow-up of the study, the incidence of cardiovascular events was low, with no differences between the bicalutamide group and the castration group. [76] [77] There were also no differences in the incidences of arrhythmia, myocardial infarction, or other ischemic cardiac or cerebrovascular conditions. [76] [77]

In the LPC group of the EPC study, which compared 150 mg/day bicalutamide monotherapy versus placebo/standard care, there were numerically more deaths from heart failure (1.2% vs. 0.6%; 49 vs. 25 patients) in the bicalutamide group. [8] [78] This contributed to a trend toward significantly increased mortality due to causes other than prostate cancer in the bicalutamide group. [21] [79] [80] Cardiovascular morbidity, on the other hand, was similar between the bicalutamide and placebo groups. [8] [78] In the NRG/RTOG 9601 trial, bicalutamide monotherapy significantly increased the risk of grade 3 to 5 cardiovascular incidents after a median 13 years of follow-up. [81]

A systematic review and meta-analysis of randomized controlled trials of ADT and risk of cardiovascular death in men with non-metastatic prostate cancer was published in 2011. [82] It assessed ADT in the form of a GnRH agonist or surgical castration alone or in combination with a NSAA and included over 4,000 patients. [82] The meta-analysis found no evidence of increased cardiovascular mortality or overall mortality. [82] Non-prostate cancer mortality was not specifically assessed. [82] A limitation of the meta-analysis was that of the trials included in the meta-analysis, only flutamide was employed and not bicalutamide. [82] Subsequent reviews and meta-analyses, published between 2014 and 2022, have reported positive though inconsistent associations of ADT with cardiovascular complications and death. [83] [84] [85] [86] [87] [88] [89]

A case report in which bicalutamide was described as a probable cause of heart failure in a man with prostate cancer has been published. [90]

Lipid profile

Bicalutamide has been found to increase total cholesterol and LDL cholesterol levels in women with polycystic ovary syndrome and hirsutism taking a combined birth control pill. [16] [91] [92] There was also a non-significant trend toward increased triglyceride levels. [16] [91] [92] Lipid changes with bicalutamide in men with prostate diseases have also been studied, but no significant changes have been found in studies in this population. [93] [72] [94] Heightened LDL cholesterol and triglyceride levels are potential risk factors for atherosclerosis or coronary heart disease. [95] Unfavorable blood lipid profile changes have also been seen with other antiandrogens in women, for instance cyproterone acetate [96] and spironolactone, [97] [98] and with androgenic medications. [99] [100] [101]

Coagulation

NSAA monotherapy is associated with a greater risk of venous thromboembolism (VTE) than non-use, although not to the same extent as surgical or medical castration or particularly high-dose estrogen therapy. [102] [103] [104] [105] [106]

Kidney function

Androgens and anabolic steroids, including testosterone, have trophic and anabolic effects in the kidneys. [107] [108] [109] [110] Androgen deprivation therapy, including with GnRH agonists and bicalutamide monotherapy, may increase the risk of kidney failure in men. [111] [112] [113] A large randomized controlled trial in men with prostate cancer found that the incidence of kidney failure was 1 to 2% in men treated with combined androgen blockade using bicalutamide or flutamide, although this study had no placebo group. [114] [115] [58] Several preclinical studies are suggestive that bicalutamide may have toxic effects on kidney cells. [116] [117] [111] [118] [119] [120] This may be secondary to androgen deprivation. [116] [117] [111] [118] [119] [120] Kidney toxicity with bicalutamide and ADT has yet to be fully assessed clinically. [116] [117]

Anemia

Androgens including testosterone are known to stimulate erythropoiesis (formation of red blood cells) and increase hematocrit (red blood cell levels). [121] [122] [123] These effects are mediated by increasing production and secretion of erythropoietin from the kidneys. [122] Erythropoietin in turn stimulates erythropoiesis in hematopoietic tissues such as bone marrow. [124] The high levels of testosterone in males are why hematocrit and hemoglobin levels are higher in men than in women. [125] Due to stimulation of erythropoiesis, anabolic–androgenic steroids (AAS) such as oxymetholone and nandrolone decanoate are effective for and used in the treatment of severe anemia (very low hematocrit). [122] [126] High doses or levels of AAS, including testosterone, can cause polycythemia—high red blood cell and/or hemoglobin levels that increase the risk of stroke—as an adverse effect. [121] [122] Conversely, whether via castration, NSAA monotherapy, or CAB, decreased erythropoiesis resulting in mild anemia is a common side effect of ADT in men. [58] [127] [123] The incidence of anemia with bicalutamide either as a monotherapy or with castration was about 7.3 to 7.5% in clinical trials, which was similar to the rate with castration of about 7.1%. [58] [123] A decrease of hemoglobin levels of 1 to 2 g/dL after about 6 months of treatment may be observed. [127]

Greater decreases in hemoglobin levels and anemia incidences have been reported with flutamide relative to bicalutamide (e.g., 9.8% anemia rate with flutamide plus a GnRH agonist). [128] [58] [123] Flutamide has been associated with cases of hemolytic anemia, macrocytic anemia, methemoglobinemia, sulfhemoglobinemia, leukopenia, neutropenia, and thrombocytopenia, whereas such complications may not be associated with bicalutamide. [123] [129]

Liver toxicity

Bicalutamide can cause adverse liver changes rarely, such as elevated transaminases, jaundice, hepatitis, and liver failure. [130] In the EPC trial, in which bicalutamide monotherapy (150 mg/day) was evaluated for treatment of early prostate cancer in 8,113 men, the incidence of abnormal liver function tests at 3-year median follow-up was 3.4% for bicalutamide plus standard care (n=4,052) and 1.9% for standard care alone (n=4,061). [8] [131] However, in a phase 3 clinical trial of bicalutamide (50 mg/day) plus a GnRH agonist versus flutamide (750 mg/day) plus a GnRH agonist for metastatic prostate cancer, the rate of abnormal liver function tests was 7.5% with bicalutamide (n=401) and 11.3% with flutamide (n=407). [132] [133] [134] [123] [58] Markedly elevated liver enzymes occurred at rates of 0.5% with bicalutamide and 2.5% with flutamide in this trial, whereas rates of drug discontinuation due to elevated liver enzymes were 1.5% with bicalutamide and 2.0% with flutamide. [58] [135] In clinical trials, bicalutamide-induced liver changes have usually been transient and have rarely been severe. [8] [58] Bicalutamide was discontinued due to liver changes (manifested as hepatitis or marked increases in liver enzymes) in clinical trials in 0.3% to 1.5% of patients, or approximately 1% overall. [64] [8] [136] [137] [135] Aside from men with prostate cancer, liver changes have also been observed in women treated with low doses of bicalutamide (10–50 mg/day) for scalp hair loss. [138] Rates of elevated liver enzymes have ranged from 2.9 to 11.4% in these studies, which spontaneously resolved in some women and necessitated discontinuation of treatment in others. [138] [139]

No cases of liver failure or death due to liver toxicity were seen with bicalutamide in the initial clinical development programme for prostate cancer which included over 3,900 men treated with bicalutamide. [58] [134] [140] [141] [114] These trials employed bicalutamide alone (as a monotherapy) and in combination with castration at doses ranging from 10 to 450 mg/day (with most patients receiving 50 to 150 mg/day). [134] [58] Five cases of jaundice, including one man who died of prostate cancer, chronic renal failure, and jaundice, were recorded in the programme. [58] [140] [141] Rates of jaundice with bicalutamide in the programme were similar to comparator therapies. [58] No instances of fatal hepatotoxicity occurred with 150 mg/day bicalutamide monotherapy in the SPCG-6 Tooltip Scandinavian Prostate Cancer Group 6 substudy of the EPC programme, in which 607 men received bicalutamide. [21] Following the initial clinical development programme of bicalutamide for prostate cancer and the EPC programme, cases of grade 3 to 4 (severe or life-threatening/disabling) adverse liver changes have been reported with bicalutamide in subsequent individual trials of bicalutamide for treatment of various types of cancer. [142] [143] [144] [145]

The risk of liver changes with bicalutamide is considered to be small but significant, and monitoring of liver function is recommended. [8] [146] Elevation of transaminases above twice the normal range or jaundice may be an indication that bicalutamide should be discontinued. [147] Liver changes with bicalutamide usually occur within the first 3 to 6 months of treatment, and it is recommended that liver function be monitored regularly for the first 4 months of treatment and periodically thereafter. [64] [58] Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice. [64]

As of 2022, at least 10 case reports of bicalutamide-associated hepatotoxicity or liver failure, two of which were fatal, have been published in the literature. [148] [149] [130] [150] [112] [151] The dosages of bicalutamide in the cases ranged from 50 to 150 mg/day and the onsets were all within 6 months of therapy. [149] [130] [150] [112] [151] One of the cases onset after only two doses of bicalutamide and may have been more related to prolonged prior exposure to flutamide and CPA. [130] [152] Aside from published case reports, hundreds of additional cases of liver complications in people taking bicalutamide exist in the FDA Adverse Event Reporting System (FAERS) database. [153] Similarly, additional cases exist in and have been described in published research for other pharmacovigilance systems, such as the Spanish pharmacovigilance system. [154]

Liver toxicity is considered to be much more rare with bicalutamide than with flutamide, and bicalutamide is also regarded as having a lower risk than nilutamide. [155] [156] [157] Rates of abnormal liver function tests have varied widely between studies, with reported ranges of 4 to 62% with flutamide and 2 to 33% with nilutamide. [123] [158] [159] The risk of serious or fatal liver toxicity with flutamide has been estimated to be 3 in 10,000 cases, and other studies suggest an even higher incidence. [32] [158] By 1996, 46 cases of severe cholestatic hepatitis associated with flutamide had been reported, with 20 of the cases resulting in death. [160] A 2002 review reported that there were 18 reports of hepatotoxicity associated with CPA in the medical literature, with 6 of the reported cases resulting in death. [160] The review also cited a report of an additional 96 instances of hepatotoxicity that were attributed to CPA, of which 33 resulted in death. [160] However, clinically significant liver toxicity has almost exclusively been associated with high doses of CPA in men with prostate cancer (≥100 mg/day). [161] [162] [163]

There is no evidence of greater liver function changes with higher doses of bicalutamide, and hence the liver toxicity of bicalutamide is not currently known to be dose-dependent across its clinically used dosage range. [164] Older age, for a variety of reasons, appears to be an important risk factor for drug-induced hepatotoxicity. [165] [166] As such, the risk of liver changes with bicalutamide may be lower in younger individuals, for instance women with hirsutism and transgender women. [165] [166] However, it has been reported on the basis of very limited evidence that this may not be the case with flutamide. [167]

From a theoretical standpoint (on the basis of structure–activity relationships), it has been suggested that flutamide, bicalutamide, and nilutamide, to varying extents, all have the potential to cause liver toxicity. [168] However, in contrast to flutamide, hydroxyflutamide, and nilutamide, bicalutamide exhibits less or no mitochondrial toxicity and inhibition of enzymes in the electron transport chain such as respiratory complex I (NADH ubiquinone oxidoreductase), and this may be the reason for its lower risk of hepatotoxicity in comparison. [169] [170] [171] [172] The activity difference may be related to the fact that flutamide, hydroxyflutamide, and nilutamide all possess a nitroaromatic group, whereas in bicalutamide, a cyano group is present in place of this nitro group, potentially reducing toxicity. [156] [169] [172] [173] A potential biological target mediating hepatotoxicity with antiandrogens, such as flutamide and cyproterone acetate, is the aryl hydrocarbon receptor. [174] [175] [176]

Published case reports of bicalutamide-associated liver injury
#AgeSexDosageUseOnsetOutcomeSource
160 yearsMale50 mg/dayProstate cancer2 daysSurvivedDawson et al. (1997)
279 yearsMale80 mg/dayProstate cancer1.5 monthsSurvivedIkemoto et al. (2000)
359 yearsMale50 mg/dayProstate cancer4 daysDeathO'Bryant et al. (2008)
461 yearsMale50 mg/dayProstate cancer3.5 monthsDeathCastro Beza et al. (2008)
581 yearsMale150 mg/dayProstate cancer3 weeksSurvivedHussain et al. (2014)
662 yearsMale100 mg/dayProstate cancer4.5 monthsSurvivedYun et al. (2016)
767 yearsMale150 mg/dayProstate cancer3 weeksSurvivedGretarsdottir et al. (2018)
879 yearsMaleUnknownProstate cancer15 daysSurvivedSaito (2020)
917 yearsTrans femaleUnknownGender-affirming hormone therapy1 yearSurvivedReed (2023)
1017 yearsTrans female50 mg/dayGender-affirming hormone therapy3 monthsSurvivedWilde et al. (2023)
Notes: Additional cases of bicalutamide-associated adverse liver changes have been reported. These include 11 cases in a 2006 Spanish pharmacovigilance system report (including 1 case of hepatitis, 2 cases of cholestatic hepatitis, 1 case of jaundice, 4 cases of elevated liver enzymes, and 1 case of elevated bilirubin; no deaths) and a number of cases in the FDA Adverse Event Reporting System (FAERS). Also 5 cases of jaundice were reported out of ~3,700 men in clinical trials but no cases of liver failure or of liver-toxicity-related death clearly attributable to bicalutamide were observed. Sources:Main: [177] [178]

Lung toxicity

Case reports of interstitial pneumonitis associated with bicalutamide treatment have been published in the medical literature. [179] [180] [181] [182] Hundreds of additional cases of interstitial lung disease in people taking bicalutamide exist in the FDA Adverse Event Reporting System (FAERS) database. [153] Interstitial pneumonitis can progress to pulmonary fibrosis and can be fatal. Interstitial pneumonitis with bicalutamide is said to be a very rare event. [183] The risk is much lower than that with nilutamide (which has an incidence rate of 0.5–2% of patients). [184] : 81  [180] [185] In a large cohort of prostate cancer patients, the incidence of interstitial pneumonitis with NSAAs was 0.77% for nilutamide, 0.04% (4 per 10,000) for flutamide, and 0.01% (1 per 10,000) for bicalutamide. [3] An assessment done prior to the publication of the aforementioned study estimated the rates of pulmonary toxicity with flutamide, bicalutamide, and nilutamide as 1 case, 5 cases, and 303 cases per million, respectively. [186] Strong safety signals of bicalutamide with interstitial lung disease have been observed in pharmacovigilance databases such as the FAERS and Japanese Adverse Drug Event Report (JADER) databases (e.g., ROR Tooltip reporting odds ratio = 9.2, 95% CI Tooltip confidence interval = 7.9–10.6; ROR = 8.2, 95% CI = 6.0–11.2). [187] [188] [189] Similar safety signals have been observed for certain other antiandrogens, like nilutamide and flutamide. [187] [189] In addition to interstitial pneumonitis, there is a smaller number of published case reports of eosinophilic lung disease associated with bicalutamide. [190] [191] Side effects associated with the rare lung toxicity of bicalutamide may include dyspnea (difficult breathing or shortness of breath), cough, and pharyngitis (inflammation of the pharynx, resulting in sore throat). [192]

Published case reports of bicalutamide-associated lung toxicity
#AgeSexDosageOnsetType of injuryOutcomeRef
169 yearsMale200 mg/day6 monthsEosinophilic lung diseaseRecoveredWong et al. (1998)
2~76 yearsMale200 mg/day8 monthsInterstitial pneumonitisRecoveredMcCaffrey & Scher (1998)
3~82 yearsMale80 mg/day4 weeksInterstitial pneumonitisRecoveredShioi et al. (2003)
4~72 yearsMale80 mg/day2.5 monthsInterstitial pneumonitisRecovered, then deathaShioi et al. (2005)
584 yearsMale ?8 monthsInterstitial pneumonitisRecoveredKobayashi et al. (2006)
676 yearsMale ? ?Interstitial pneumonitis ?Gifford & DeLong (2008)
785 yearsMale ?4 monthsInterstitial pneumonitisDeathKawahara et al. (2009)
878 yearsMale80 mg/day8 monthsInterstitial pneumonitisRecoveredMasago et al. (2011)
977 yearsMale ?7 monthsInterstitial pneumonitisDeathSong et al. (2014)
1077 yearsMale>50 mg/day~12 monthsInterstitial pneumonitisDeathMolina Mancero et al. (2016)
1179 yearsMale ?1 monthInterstitial pneumonitisDeathPolatoglu et al. (2017)
1266 yearsMale ? ?Interstitial pneumonitisRecoveredKim et al. (2018)
1366 yearsMale ? ?Interstitial pneumonitisRecoveredDerichs et al. (2018)
1486 yearsMale150 mg/day6 yearsEosinophilic pneumonitisRecoveredUmeojiako & James (2019)
1575 yearsMale ?2 weeksInterstitial pneumonitisDeathMaeda et al. (2019)
1679 yearsMale ?1.5 monthsInterstitial pneumonitisRecoveredSaito (2020)
1766 yearsMale50 mg/day6 monthsInterstitial pneumonitisRecoveredSmith & Antonarakis (2020)
Footnotes:a = Died of pneumothorax followed by spontaneous rupture of bulla induced by previous interstitial pneumonitis 14 months after discontinuation of bicalutamide and recovery from interstitial pneumonitis. Notes: Twelve additional cases of bicalutamide-associated interstitial pneumonitis, three of which resulted in death, were observed in an 87,000-patient cohort from MedWatch (U.S. Tooltip United States FDA Tooltip Food and Drug Administration passive adverse-event reporting database) between 1998 and 2000 (0.01% incidence). The median age of the patients was 73.5 years (range 59 to 91 years), and median duration of bicalutamide exposure was 7.5 weeks (range 1 to 312 weeks). Cases of interstitial pneumonitis have also been reported in association with flutamide, nilutamide, and gonadotropin-releasing hormone (GnRH) agonists.

Risk of death

In men with early prostate cancer, bicalutamide has been shown to increase the likelihood of death due to causes other than prostate cancer. [81] This was shown in the SPCG-6 Tooltip Scandinavian Prostate Cancer Group 6 substudy (n=1218) of the EPC programme, in which overall survival was significantly worse in the 150 mg/day bicalutamide monotherapy group compared to the placebo/standard care group (HR Tooltip hazard ratio = 1.47; 95% CI Tooltip confidence interval = 1.06–2.03). [81] There was also a near-significant trend toward increased overall mortality in the combined programme (n=8113) (HR = 1.16; 95% CI = 0.99–1.37; p=0.07). [81] At 5.4 years of follow-up for the EPC programme, the overall incidence of death was 25.2% in the bicalutamide group and 20.5% in the placebo/standard care group. [21] [79] [80] This was because more bicalutamide than placebo/standard care recipients had died due to causes unrelated to prostate cancer (16.8% vs. 9.5% at 5.4-year follow-up; 10.2% vs. 9.2% at 7.4-year follow-up). [21] [80] [8] Bicalutamide reduced mortality due to prostate cancer, but this was not sufficient to overcome the increase in mortality due to non-prostate-cancer causes. [21] [79] [80] Other trials, such as NRG/RTOG 9601, have also reported increased mortality with bicalutamide. [81] Consequent to the EPC programme findings, authorization of bicalutamide for the treatment of LPC was revoked, and use of bicalutamide for this indication was discontinued. [8] [80] [79] [193] Bicalutamide continues to be authorized and used in the treatment of LAPC and mPC, where the benefits of bicalutamide against prostate cancer outweigh any influence on non-prostate-cancer mortality. [8]

The reasons for the increased overall mortality with bicalutamide seen in the EPC programme have not been fully elucidated. [30] In any case, at 7.4-year follow-up, there were numerically more deaths from heart failure (1.2% vs. 0.6%) and gastrointestinal cancer (1.3% vs. 0.9%) in the bicalutamide group relative to placebo/standard care recipients. [8] [78] [194] It has been said that there was no consistent pattern suggestive of drug-related toxicity for bicalutamide and that the causes were likely a consequence of androgen deprivation: [195] [196] [8] [78] [197]

The increased number of deaths in patients with localized disease receiving bicalutamide was meticulously investigated and they appeared to be due to a number of small imbalances rather than a specific cause. In addition, no direct toxic effect on any organ system could be identified. From this it may be speculated that the excess deaths in patients who are at low risk from prostate cancer mortality reflect the impact of endocrine therapy (rather than bicalutamide in particular). [...] The increased number of non-prostate cancer deaths in the early castration therapy arm [(via orchiectomy or GnRH monotherapy)] in the [Medical Research Council] study suggests that the trend towards an increased number of deaths in patients with localized disease in the present study is a reflection of early endocrine therapy as a concept rather than a bicalutamide-related phenomenon. [195]

The increased number of deaths in bicalutamide-treated patients under watchful waiting with localized disease appears to be due to the accumulation of several small imbalances in various causes of death rather than an identifiable specific cause. However, an indirect effect from androgen receptor blockade, or some other unknown hormonally mediated effect, can neither be confirmed nor refuted with current data. [196]

Low testosterone levels in men have been associated in epidemiological studies with cardiovascular disease as well as with a variety of other disease states. [198] These include hypertension, hypercholesterolemia, diabetes, obesity, Alzheimer's disease, osteoporosis, and frailty. [198] In any case, although bicalutamide monotherapy blocks the actions of androgens, it simultaneously preserves relatively high estradiol levels in men. [199] [200] [136] This would potentially be expected to reduce or offset many of the risks of sex hormone deprivation. [201] [202] [203] [204] Yet increased mortality has still been seen with bicalutamide monotherapy in men in clinical trials. [81] [8]

Modification of side effects by castration

Combination of bicalutamide with medical (i.e., a GnRH analogue) or surgical castration modifies the side-effect profile of bicalutamide. Some of its side effects, including breast pain/tenderness and gynecomastia, are far less likely to occur when the drug is combined with a GnRH analogue, [205] while certain other side effects, including hot flashes, depression, fatigue, and sexual dysfunction, [206] occur much more frequently in combination with a GnRH analogue. [12] [207] [208] It is thought that this is due to the suppression of estrogen levels (in addition to androgen levels) by GnRH analogues, as estrogens may compensate for various negative central effects of androgen deprivation. [12] If bicalutamide is combined with a GnRH analogue or surgical castration, the elevation of androgen and estrogen levels in men caused by bicalutamide will be prevented and the side effects of excessive estrogens, namely gynecomastia, will be reduced. [205] However, due to the loss of estrogen, bone loss will accelerate and the risk of osteoporosis developing with long-term therapy will increase. [209]

Related Research Articles

<span class="mw-page-title-main">Antiandrogen</span> Class of pharmaceutical drugs

Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.

<span class="mw-page-title-main">Bicalutamide</span> Antiandrogen medication

Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC). To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women, as a puberty blocker and component of feminizing hormone therapy for transgender girls and women, to treat gonadotropin-independent early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.

<span class="mw-page-title-main">Polyestradiol phosphate</span> Chemical compound

Polyestradiol phosphate (PEP), sold under the brand name Estradurin, is an estrogen medication which is used primarily in the treatment of prostate cancer in men. It is also used in women to treat breast cancer, as a component of hormone therapy to treat low estrogen levels and menopausal symptoms, and as a component of feminizing hormone therapy for transgender women. It is given by injection into muscle once every four weeks.

<span class="mw-page-title-main">Flutamide</span> Chemical compound

Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.

<span class="mw-page-title-main">Nilutamide</span> Chemical compound

Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. It is taken by mouth.

<span class="mw-page-title-main">Gonadotropin-releasing hormone agonist</span> Drug class affecting sex hormones

A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.

Feminizing hormone therapy, also known as transfeminine hormone therapy or male-to-female (MTF) is a hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine. It is a common type of transgender hormone therapy and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences.

<span class="mw-page-title-main">Enzalutamide</span> Antiandrogen medication used in treatment of prostate cancer

Enzalutamide, sold under the brand name Xtandi, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is indicated for use in conjunction with castration in the treatment of metastatic castration-resistant prostate cancer (mCRPC), nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer (mCSPC). It is taken by mouth.

The first antiandrogen was discovered in the 1960s. Antiandrogens antagonise the androgen receptor (AR) and thereby block the biological effects of testosterone and dihydrotestosterone (DHT). Antiandrogens are important for men with hormonally responsive diseases like prostate cancer, benign prostatic hyperplasia (BHP), acne, seborrhea, hirsutism and androgen alopecia. Antiandrogens are mainly used for the treatment of prostate diseases. Research from 2010 suggests that ARs could be linked to the disease progression of triple-negative breast cancer and salivary duct carcinoma and that antiandrogens can potentially be used to treat it.

Sexual motivation is influenced by hormones such as testosterone, estrogen, progesterone, oxytocin, and vasopressin. In most mammalian species, sex hormones control the ability and motivation to engage in sexual behaviours.

<span class="mw-page-title-main">Cyproterone acetate</span> Chemical compound

Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent conditions such as acne, excessive body hair growth, early puberty, and prostate cancer, as a component of feminizing hormone therapy for transgender individuals, and in birth control pills. It is formulated and used both alone and in combination with an estrogen. CPA is taken by mouth one to three times per day.

<span class="mw-page-title-main">Nonsteroidal antiandrogen</span> Antiandrogen with a nonsteroidal chemical structure

A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like testosterone and dihydrotestosterone (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.

Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration. The medication is taken by mouth twice per day with food.

<span class="mw-page-title-main">Apalutamide</span> Chemical compound

Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication used for the treatment of prostate cancer. It is an androgen receptor inhibitor. It is taken by mouth.

The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Indications for bicalutamide include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.

Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.

<span class="mw-page-title-main">Pharmacology of bicalutamide</span> Pharmaceutical compound

The pharmacology of bicalutamide is the study of the pharmacodynamic and pharmacokinetic properties of the nonsteroidal antiandrogen (NSAA) bicalutamide. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility.

<span class="mw-page-title-main">Pharmacology of cyproterone acetate</span> Pharmaceutical compound

The pharmacology of cyproterone acetate (CPA) concerns the pharmacology of the steroidal antiandrogen and progestin medication cyproterone acetate.

The side effects of cyproterone acetate (CPA), a steroidal antiandrogen and progestin, including its frequent and rare side effects, have been studied and characterized. It is generally well-tolerated and has a mild side-effect profile, regardless of dosage, when it used as a progestin or antiandrogen in combination with an estrogen such as ethinylestradiol or estradiol valerate in women. Side effects of CPA include hypogonadism and associated symptoms such as demasculinization, sexual dysfunction, infertility, and osteoporosis; breast changes such as breast tenderness, enlargement, and gynecomastia; emotional changes such as fatigue and depression; and other side effects such as vitamin B12 deficiency, weak glucocorticoid effects, and elevated liver enzymes. Weight gain can occur with CPA when it is used at high doses. Some of the side effects of CPA can be improved or fully prevented if it is combined with an estrogen to prevent estrogen deficiency. Few quantitative data are available on many of the potential side effects of CPA. Pooled tolerability data for CPA is not available in the literature.

The Early Prostate Cancer (EPC) programme was a large clinical trial programme of monotherapy with the nonsteroidal antiandrogen bicalutamide (Casodex) plus standard care versus standard care alone in men with early prostate cancer. It was started in August 1995, with the first analysis published in 2002 and the final follow-up published in 2010. The programme consisted of three large randomized, double-blind, placebo-controlled trials in which a total of 8,113 men with localized or locally advanced prostate cancer were treated with 150 mg/day bicalutamide plus standard care (n=4052) or given placebo (n=4061). It constituted the largest clinical trial of prostate cancer treatment to have ever been conducted at the time.

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  23. 1 2 3 Tyrrell CJ, Denis L, Newling D, Soloway M, Channer K, Cockshott ID (1998). "Casodex 10-200 mg daily, used as monotherapy for the treatment of patients with advanced prostate cancer. An overview of the efficacy, tolerability and pharmacokinetics from three phase II dose-ranging studies. Casodex Study Group". Eur. Urol. 33 (1): 39–53. doi:10.1159/000019526. PMID   9471040. S2CID   71758492. The relatively high incidence of breast tenderness and gynaecomastia seen in these studies is likely to be a consequence of the direct questioning which was used to elicit these adverse events. Previously published studies using a dose of Casodex of 50, 100 and 150 mg daily [23-26] where these events were elicited by open questioning during Casodex therapy, found the incidence of gynaecomastia (23-26%) and breast tenderness (26-31 %) to be much lower.
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  25. ↑ Zanardi S, Puntoni M, Maffezzini M, Bandelloni R, Branchi D, Argusti A, Campodonico F, Turbino L, Mori M, Decensi A (1 December 2006). "A biomarker trial of intermittent, low-dose bicalutamide in subjects at high risk for prostate cancer: Updated results". Cancer Epidemiol Biomarkers Prev. 15 (12 Supplement): A145. Testosterone (T), LH, E2 and SHBG levels increased on Bic, although only T changes on both doses and LH changes on Bic 100 mg were significantly different to controls (p<0.001). Changes in circulating hormones and biomarkers were evident after 3 months, and persisted through the 6th month of treatment. No change in circulating hormones or biomarkers was observed in the control group. [...] Treatment was well tolerated, although breast pain was recorded in 0/19 (0%), 8/25 (32%) and 14/22 (64%), and gynecomastia in 0/19 (0%), 11/25 (44%) and 11/22 (50%) of subjects on no treatment, Bic 50 or 100 mg, respectively.
  26. ↑ Zanardi, S.; Puntoni, M.; Maffezzini, M.; Bandelloni, R.; Mori, M.; Argusti, A.; Campodonico, F.; Turbino, L.; Branchi, D.; Montironi, R.; Decensi, A. (2009). "Phase I-II Trial of Weekly Bicalutamide in Men with Elevated Prostate-Specific Antigen and Negative Prostate Biopsies". Cancer Prevention Research. 2 (4): 377–384. doi: 10.1158/1940-6207.CAPR-08-0205 . ISSN   1940-6207. PMID   19336728.
  27. ↑ Decensi A, Zanardi S, Puntoni M, Bandelloni R, Branchi D, Argusti A, Campodonico F, Turbino L, Mori M, Maffezzini M (20 June 2007). "Phase I-II trial of weekly bicalutamide in men with high PSA and negative biopsy". Journal of Clinical Oncology. 25 (18_suppl): 1500. doi:10.1200/jco.2007.25.18_suppl.1500. T, LH, estradiol and SHBG increased on Bic by 50–60%. [...] Treatment was well tolerated, mild (G1) breast pain and gynecomastia being recorded in 40% of treated subjects.
  28. 1 2 Michalopoulos NV, Keshtgar MR (2012). "Images in clinical medicine. Gynecomastia induced by prostate-cancer treatment". The New England Journal of Medicine. 367 (15): 1449. doi:10.1056/NEJMicm1209166. PMID   23050528. Gynecomastia occurs in up to 80% of patients who receive nonsteroidal antiandrogens (eg, bicalutamide, flutamide, or nilutamide), usually within the first 6 to 9 months after the initiation of treatment.
  29. ↑ Fradet Y, Egerdie B, Andersen M, Tammela TL, Nachabe M, Armstrong J, Morris T, Navani S (2007). "Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide 150 mg monotherapy in patients with prostate cancer: a randomised, placebo-controlled, dose-response study". European Urology. 52 (1): 106–14. doi:10.1016/j.eururo.2007.01.031. PMID   17270340.
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  32. 1 2 3 4 Fourcade, R.-O.; McLeod, D. (March 2004). "Tolerability of Antiandrogens in the Treatment of Prostate Cancer". UroOncology. 4 (1): 5–13. doi:10.1080/1561095042000191655. ISSN   1561-0950. The risk of fatal or serious hepatic toxicity associated with flutamide was estimated to be 3 of 10,000 based on cases reported to the Food and Drug Administration in the USA [59], although others suggest that the incidence may be higher than this [57].
  33. 1 2 3 4 Van Poppel H, Tyrrell CJ, Haustermans K, Cangh PV, Keuppens F, Colombeau P, Morris T, Garside L (May 2005). "Efficacy and tolerability of radiotherapy as treatment for bicalutamide-induced gynaecomastia and breast pain in prostate cancer". Eur Urol. 47 (5): 587–92. doi:10.1016/j.eururo.2004.12.003. PMID   15826748. 3.2. Incidence, time to onset and intensity of symptoms. Of the 51 patients, 37 (72.5%) experienced gynaecomastia and 41 (80.4%) experienced breast pain within the 12 months following initiation of bicalutamide 150 mg. Time to onset of these symptoms is illustrated in Fig. 1. Generally, gynaecomastia and breast pain were reported within the first 6 months of treatment (89.2% [33/37] and 97.6% [40/41], respectively).
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  37. ↑ Deepinder F, Braunstein GD (2012). "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety. 11 (5): 779–95. doi:10.1517/14740338.2012.712109. PMID   22862307. S2CID   22938364. Treatment with estrogen has the highest incidence of gynecomastia, at 40 – 80%, anti-androgens, including flutamide, bicalutamide and nilutamide, are next, with a 40 – 70% incidence, followed by GnRH analogs (goserelin, leuprorelin) and combined androgen deprivation, both with incidences of 13% each.
  38. ↑ Nakabayashi M, Bartlett RA, Oh WK (2006). "Treatment of bicalutamide-induced gynecomastia with breast-reduction surgery in prostate cancer". Journal of Clinical Oncology. 24 (18): 2958–9. doi: 10.1200/JCO.2005.03.8505 . PMID   16782932.
  39. 1 2 3 Saltzstein D, Sieber P, Morris T, Gallo J (2005). "Prevention and management of bicalutamide-induced gynecomastia and breast pain: randomized endocrinologic and clinical studies with tamoxifen and anastrozole". Prostate Cancer and Prostatic Diseases. 8 (1): 75–83. doi: 10.1038/sj.pcan.4500782 . PMID   15685254.
  40. 1 2 3 Boccardo F, Rubagotti A, Battaglia M, Di Tonno P, Selvaggi FP, Conti G, Comeri G, Bertaccini A, Martorana G, Galassi P, Zattoni F, Macchiarella A, Siragusa A, Muscas G, Durand F, Potenzoni D, Manganelli A, Ferraris V, Montefiore F (February 2005). "Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer". Journal of Clinical Oncology. 23 (4): 808–15. doi: 10.1200/JCO.2005.12.013 . PMID   15681525.
  41. ↑ Fagerlund A, Cormio L, Palangi L, Lewin R, Santanelli di Pompeo F, Elander A, Selvaggi G (2015). "Gynecomastia in Patients with Prostate Cancer: A Systematic Review". PLOS ONE. 10 (8): e0136094. Bibcode:2015PLoSO..1036094F. doi: 10.1371/journal.pone.0136094 . PMC   4550398 . PMID   26308532.
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  57. ↑ Scialli AR, Clegg ED (9 June 1992). Reversibility in Testicular Toxicity Assessment. CRC Press. pp. 107–. ISBN   978-0-8493-5980-4.
  58. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Kolvenbag GJ, Blackledge GR (January 1996). "Worldwide activity and safety of bicalutamide: a summary review". Urology. 47 (1A Suppl): 70–9, discussion 80–4. doi:10.1016/S0090-4295(96)80012-4. PMID   8560681. [...] In the combination study,9 the incidence of hepatic adverse events was lower in bicalutamide plus LHRH-A group than in the flutamide plus LHRH-A group (6.7% versus 12%; P = 0.07). [...] In the clinical trial program, evaluation of biochemistry assessments showed that increases in the liver function test values for serum glutamic oxaloacetic transaminase (SGOT; aspartate aminotransferase) and serum glutamic pyruvic transaminase (SGPT; alanine aminotransaminase) occurred with greater frequency in the flutamide plus LHRH-A group than in the bicalutamide plus LHRH-A group (49 [12.0%] and 28 [7.0%] patients, respectively). The difference between groups was observed for both test results that were less than twice the upper limit of normal (ULN) and for test results that were greater than two times the ULN. [\n\n] In the combination study, 77 patients (28 [7.0%], bicalutamide plus LHRH-A; 49 [12.0%], flutamide plus LHRH) had at least one liver enzyme test result (SGOT or SGPT) that exceeded twice the ULN. For these patients, there was no clear pattern to distinguish between SGOT versus SGPT changes as drug induced; changes were observed for both enzymes (either alone or together) while patients received study therapy. Of these 77 patients, 52 had an increase in SGOT and/or SGPT levels >2 ✕ ULN on only one occasion. [\n\n] Drug-induced changes were more likely when liver function test values were above the ULN at more than one assessment. This finding was observed more often for flutamide-treated patients than for bicalutamide-treated patients (17 [4.2%] vs 8 [2.0%]). Liver function test values >5 ✕ ULN (SGOT >325 U/L [patients >65 years]; SGPT >265 U/L) after the start of therapy were more frequently observed for patients who received flutamide plus LHRH-A (10 of 407 patients) [2.5%] than patients who received bicalutamide plus LHRH-A (2 of 401 patients) [0.5%].
  59. ↑ Jones HB, Betton GR, Bowdler AL, McFarquhar RL, Middleton BJ, Lunglmayr G (1994). "Pathological and morphometric assessment of testicular parameters in patients with metastatic prostate cancer following treatment with either the antiandrogen Casodex (ZM176,334) or bilateral orchidectomy". Urol. Res. 22 (3): 191–5. doi:10.1007/BF00571849. PMID   7992465. S2CID   19540140.
  60. 1 2 Iswaran TJ, Imai M, Betton GR, Siddall RA (May 1997). "An overview of animal toxicology studies with bicalutamide (ICI 176,334)". The Journal of Toxicological Sciences. 22 (2): 75–88. doi: 10.2131/jts.22.2_75 . PMID   9198005.
  61. 1 2 Smith RE (4 April 2013). Medicinal Chemistry – Fusion of Traditional and Western Medicine. Bentham Science Publishers. pp. 306–. ISBN   978-1-60805-149-6. Archived from the original on 29 May 2016.
  62. ↑ Sex Differences in the Human Brain, their underpinnings and implications. Elsevier. 3 December 2010. pp. 44–45. ISBN   978-0-444-53631-0. Archived from the original on 26 May 2016.
  63. ↑ Paoletti R (6 December 2012). Chemistry and Brain Development: Proceedings of the Advanced Study Institute on "Chemistry of Brain Development," held in Milan, Italy, September 9–19, 1970. Springer Science & Business Media. pp. 218–. ISBN   978-1-4684-7236-3.
  64. 1 2 3 4 5 "Casodex® (bicalutamide) Tablets" (PDF). FDA. Archived (PDF) from the original on 27 February 2017.
  65. ↑ Papadimitriou, Kasiani; Anagnostis, Panagiotis; Goulis, Dimitrios G. (2022). "The challenging role of antiandrogens in the management of polycystic ovary syndrome". Polycystic Ovary Syndrome. Elsevier. pp. 297–314. doi:10.1016/B978-0-12-823045-9.00013-4. ISBN   9780128230459. S2CID   244697776.
  66. 1 2 Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ, Murad MH, Rosenthal SM, Safer JD, Tangpricha V, T'Sjoen GG (December 2017). "Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society* Clinical Practice Guideline". Endocr Pract. 23 (12): 1437. doi:10.4158/1934-2403-23.12.1437. PMID   29320642. S2CID   3639218.
  67. 1 2 3 Lee K, Oda Y, Sakaguchi M, Yamamoto A, Nishigori C (May 2016). "Drug-induced photosensitivity to bicalutamide – case report and review of the literature". Photodermatology, Photoimmunology & Photomedicine. 32 (3): 161–4. doi:10.1111/phpp.12230. PMID   26663090. S2CID   2761388.
  68. ↑ Lee K, et al. (2016). "Drug-induced photosensitivity to bicalutamide – case report and review of the literature". Reactions Weekly. 1612 (1): 161–4. doi:10.1007/s40278-016-19790-1. PMID   26663090. S2CID   261402820.
  69. 1 2 Sasada K, Sakabe J, Tamura A, Kasuya A, Shimauchi T, Ito T, Hirakawa S, Tokura Y (2012). "Photosensitive drug eruption induced by bicalutamide within the UVB action spectrum". European Journal of Dermatology. 22 (3): 402–3. doi:10.1684/ejd.2012.1719. PMID   22503957.
  70. ↑ Tyrrell CJ, Blake GM, Iversen P, Kaisary AV, Melezinek I (May 2003). "The non-steroidal antiandrogen, bicalutamide ('Casodex'), may preserve bone mineral density as compared with castration: results of a preliminary study". World J Urol. 21 (1): 37–42. doi:10.1007/s00345-003-0322-7. PMID   12756493. S2CID   13355134.
  71. ↑ Smith MR, Goode M, Zietman AL, McGovern FJ, Lee H, Finkelstein JS (July 2004). "Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: effects on bone mineral density and body composition". J. Clin. Oncol. 22 (13): 2546–53. doi: 10.1200/JCO.2004.01.174 . PMID   15226323.
  72. 1 2 Sieber PR, Keiller DL, Kahnoski RJ, Gallo J, McFadden S (June 2004). "Bicalutamide 150 mg maintains bone mineral density during monotherapy for localized or locally advanced prostate cancer". J. Urol. 171 (6 Pt 1): 2272–6, quiz 2435. doi:10.1097/01.ju.0000127738.94221.da. PMID   15126801.
  73. ↑ Wadhwa VK, Weston R, Parr NJ (June 2011). "Bicalutamide monotherapy preserves bone mineral density, muscle strength and has significant health-related quality of life benefits for osteoporotic men with prostate cancer". BJU Int. 107 (12): 1923–9. doi:10.1111/j.1464-410X.2010.09726.x. PMID   20950306. S2CID   205543615.
  74. ↑ Thorstenson A, Bratt O, Akre O, Hellborg H, Holmberg L, Lambe M, Bill-Axelson A, Stattin P, Adolfsson J (July 2012). "Incidence of fractures causing hospitalisation in prostate cancer patients: results from the population-based PCBaSe Sweden". Eur. J. Cancer. 48 (11): 1672–81. doi: 10.1016/j.ejca.2012.01.035 . PMID   22386317.
  75. ↑ Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Van Poppel H, Tammela TL, Chamberlain M, Carroll K, Melezinek I (2000). "Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup". The Journal of Urology. 164 (5): 1579–82. doi:10.1016/s0022-5347(05)67032-2. PMID   11025708.
  76. 1 2 3 Chodak G, Gomella L, Phung de H (September 2007). "Combined androgen blockade in advanced prostate cancer: looking back to move forward". Clin Genitourin Cancer. 5 (6): 371–8. doi:10.3816/CGC.2007.n.019. PMID   17956709.
  77. 1 2 3 Tyrrell CJ, Iversen P, Tammela T, Anderson J, Björk T, Kaisary AV, Morris T (September 2006). "Tolerability, efficacy and pharmacokinetics of bicalutamide 300 mg, 450 mg or 600 mg as monotherapy for patients with locally advanced or metastatic prostate cancer, compared with castration". BJU Int. 98 (3): 563–72. doi:10.1111/j.1464-410X.2006.06275.x. PMID   16771791. S2CID   41672303.
  78. 1 2 3 4 Pagliarulo V, Bracarda S, Eisenberger MA, Mottet N, Schröder FH, Sternberg CN, Studer UE (2012). "Contemporary role of androgen deprivation therapy for prostate cancer". European Urology. 61 (1): 11–25. doi:10.1016/j.eururo.2011.08.026. PMC   3483081 . PMID   21871711.
  79. 1 2 3 4 Bowsher W, Carter A (15 April 2008). Challenges in Prostate Cancer. John Wiley & Sons. pp. 146–. ISBN   978-1-4051-7177-9.
  80. 1 2 3 4 5 Shahani R, Fleshner NE, Zlotta AR (2007). "Pharmacotherapy for prostate cancer: the role of hormonal treatment". Discovery Medicine. 7 (39): 118–24. PMID   18093474.
  81. 1 2 3 4 5 6 Jia AY, Spratt DE (June 2022). "Bicalutamide Monotherapy With Radiation Therapy for Localized Prostate Cancer: A Non-Evidence-Based Alternative". Int J Radiat Oncol Biol Phys. 113 (2): 316–319. doi:10.1016/j.ijrobp.2022.01.037. PMID   35569476. S2CID   248765294. Four other randomized trials using BICmono have also raised concerns about either lack of efficacy or even harm from this treatment approach compared with placebo or no hormone therapy. SPCG-6 randomized 1218 patients to either 150 mg of BICmono daily or placebo. In the subset of patients with LPCa managed with observation, survival was significantly worse with BIC than placebo (hazard ratio [HR], 1.47; 95% confidence interval, 1.06-2.03).10 Two other randomized trials were part of the early prostate cancer program,11 which conducted 3 randomized trials that were pooled together to determine the benefit of BICmono (SPCG-6 was one of the 3 trials). Overall, in the combined 8113 patient pooled cohort, after a median follow-up of 7 years, there was no improvement even in progression-free survival from the use of adjuvant BIC in LPCa, and there was a trend for worse overall survival (HR, 1.16; 95% confidence interval, 0.99-1.37; P = .07). [...] Although not in LPCa, NRG/RTOG 9601 demonstrated findings consistent with the prior trials.12 This trial randomized men to postprostatectomy salvage radiation therapy plus placebo versus 150 mg of BICmono daily for 2 years. After a median follow-up of 13 years, the trial showed that there were significantly more grade 3 to 5 cardiac events in the BICmono arm. In patients with less aggressive disease with lower PSAs (prostate-specific antigens; more analogous to LPCa), other-cause mortality was significantly higher in the BICmono arm. In patients with high PSAs >1.5 ng/mL (which with modern molecular positron emission tomography imaging would be expected to have high rates of regional and distant metastatic disease), a survival benefit from the addition of BIC was observed. This is consistent with results from the early prostate cancer studies that showed that only patients with more advanced disease derived benefit from BICmono.10 Thus, all the randomized evidence from 5 trials (Table 1) demonstrates that, in LPCa, BICmono had no clinically significant oncologic activity over placebo/no treatment, and consistent trends with long-term use resulted in worse survival.
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  85. ↑ Poljak Z, Hulin I, Maruscakova L, Carter A, Mladosievicova B (2016). "Androgen deprivation therapy and cardiovascular complications". Bratisl Lek Listy. 117 (10): 557–561. doi: 10.4149/BLL_2016_109 . PMID   28621142.
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  135. 1 2 Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G (January 1996). "Maximal androgen blockade for patients with metastatic prostate cancer: outcome of a controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy. Casodex Combination Study Group". Urology. 47 (1A Suppl): 54–60, discussion 80–4. doi:10.1016/s0090-4295(96)80010-0. PMID   8560679. The tolerability evaluation included 808 patients (401 in the bicalutamide plus LHRH-A group and 407 in the flutamide plus LHRH-A group) and was performed after a median follow-up of 49 weeks. Five patients refused therapy; 88 patients (32 [8.0%] in the bicalutamide plus LHRH-A group and 56 [13.8%] in the flutamide plus LHRH-A group) had study therapy withdrawn because of safety reasons (Table II). [...] TABLE II. Adverse events leading to withdrawal: [...] Liver function abnormalities: Bicalutamide plus LHRH-A (n = 401): 6 [1.5%]; Flutamide plus LHRH-A (n = 407): 8 [2.0%]. [...]
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  138. 1 2 Carvalho RM, Santos LD, Ramos PM, Machado CJ, Acioly P, Frattini SC, Barcaui CB, Donda AL, Melo DF (October 2022). "Bicalutamide and the new perspectives for female pattern hair loss treatment: What dermatologists should know". J Cosmet Dermatol. 21 (10): 4171–4175. doi:10.1111/jocd.14773. PMID   35032336. S2CID   253239337.
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  142. ↑ Shipley, W.U.; Hunt, D.; Lukka, H.; Major, P.; Heney, N.M.; Grignon, D.; Patel, M.; Bahary, J.; Lawton, C.; Sandler, H. (November 2010). "Initial Report of RTOG 9601: A Phase III Trial in Prostate Cancer: Anti-androgen Therapy (AAT) with Bicalutamide during and after Radiation Therapy (RT) Improves Freedom from Progression and Reduces the Incidence of Metastatic Disease in Patients following Radical Prostatectomy (RP) with pT2-3, N0 Disease, and Elevated PSA Levels". International Journal of Radiation Oncology, Biology, Physics. 78 (3): S27. doi: 10.1016/j.ijrobp.2010.07.103 . ISSN   0360-3016. In the [radiation therapy (RT)] plus [anti-androgen Therapy (AAT)] arm Grade III was the highest liver toxicity observed which occurred in 3 of 387 patients.
  143. ↑ Akaza H, Yamaguchi A, Matsuda T, Igawa M, Kumon H, Soeda A, Arai Y, Usami M, Naito S, Kanetake H, Ohashi Y (January 2004). "Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients". Jpn J Clin Oncol. 34 (1): 20–8. doi: 10.1093/jjco/hyh001 . PMID   15020659. Two patients in the MAB group had a grade 4 ADR relating to hepatic function, while one patient in each group had a grade 3 ADR. [...] Reassuringly in our study, neither the total number of patients with any abnormal hepatic function test result nor the frequency of elevations of individual enzymes was markedly higher in the MAB group than in the monotherapy group. However, as two grade 4 events did occur in the MAB group, we do recommend periodic testing of hepatic function.
  144. ↑ Fushimi C, Tada Y, Takahashi H, Nagao T, Ojiri H, Masubuchi T, Matsuki T, Miura K, Kawakita D, Hirai H, Hoshino E, Kamata S, Saotome T (April 2018). "A prospective phase II study of combined androgen blockade in patients with androgen receptor-positive metastatic or locally advanced unresectable salivary gland carcinoma". Ann Oncol. 29 (4): 979–984. doi:10.1093/annonc/mdx771. PMC   5913639 . PMID   29211833. Elevated grade 3 liver transaminases and increased serum creatinine were reported in two patients, respectively. [...] Regarding the grade 3 liver dysfunction patients, one incident was due to bicalutamide and another was due to liver metastasis progression.
  145. ↑ Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, Blackwell K, Rugo H, Nabell L, Forero A, Stearns V, Doane AS, Danso M, Moynahan ME, Momen LF, Gonzalez JM, Akhtar A, Giri DD, Patil S, Feigin KN, Hudis CA, Traina TA (October 2013). "Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer". Clin Cancer Res. 19 (19): 5505–12. doi:10.1158/1078-0432.CCR-12-3327. PMC   4086643 . PMID   23965901. There were few grade 2 or 3 adverse events associated with bicalutamide (Table 3). All grade 3 liver enzyme abnormalities (elevation in AST, bilirubin, and alkaline phosphatase) were documented in 1 patient with known liver metastases who had progressed on therapy. Thus, it remains unclear whether these laboratory findings were attributable to bicalutamide therapy or disease progression.
  146. ↑ Lehne RA (2013). Pharmacology for Nursing Care. Elsevier Health Sciences. pp. 1297–. ISBN   978-1-4377-3582-6.
  147. ↑ Tripathi KD (30 September 2013). Essentials of Medical Pharmacology. JP Medical Ltd. pp. 302–. ISBN   978-93-5025-937-5.
  148. ↑ Trüeb RM, Luu NC, Uribe NC, Régnier A (December 2022). "Comment on: Bicalutamide and the new perspectives for female pattern hair loss treatment: What dermatologists should know". J Cosmet Dermatol. 21 (12): 7200–7201. doi:10.1111/jocd.14936. PMID   35332669. S2CID   247677549. Indeed, due to the minimal biological importance of androgens in women, the adverse effects of bicalutamide are few. And yet, bicalutamide has been associated with elevated liver enzymes, and as of 2021, there have been 10 case reports of liver toxicity associated with bicalutamide, with fatality occurring in 2 cases.2
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  151. 1 2 Ikemoto I, Kiyota H, Abe K, Hasegawa T, Ohishi Y, Aizawa Y (20 May 2000), "ビカルタミドにより惹起された重症肝障害" [Bicalutamide-induced Liver Toxicity in a Patient with Prostate Cancer], 臨床泌尿器科[Rinsho Hinyokika (Clinical Urology)], 54: 489–491, doi:10.11477/mf.1413902997
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  153. 1 2 "FDA Adverse Event Reporting System (FAERS) Public Dashboard". FDA. 22 October 2021.
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  156. 1 2 Danseuse P, Snyder RR, Monks TJ, Jollow DJ, Sipes IG, Greim H, Gibson GG, Delaforge M (6 December 2012). Biological Reactive Intermediates Vi: Chemical and Biological Mechanisms in Susceptibility to and Prevention of Environmental Diseases. Springer Science & Business Media. pp. 37–. ISBN   978-1-4615-0667-6. Archived from the original on 28 April 2016.
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  158. 1 2 Kolvenbag, Geert J. C. M.; Furr, Barrington J.A. (2009). "Nonsteroidal Antiandrogens". Hormone Therapy in Breast and Prostate Cancer. Humana Press. pp. 347–368. doi:10.1007/978-1-59259-152-7_16. ISBN   978-1-60761-471-5. Differences between the NSAAs are also apparent with respect to liver toxicity. Abnormal liver-function tests have been reported with all three NSAAs. The incidence of abnormalities varies widely, from 2–3% with nilutamide (67,94,95) and 4–62% with flutamide (45,69,91,96–98). Many, but not all, cases may be at least partly due to underlying diseases and/or concomitant drug therapy. In the double-blind comparative study of flutamide and bicalutamide, the incidence of elevated transaminases was higher, but not significantly so, in the flutamide group (56). Symptomatic and, in some cases, serious hepatotoxicity has also been reported for NSAAs. It has been estimated that the risk of severe, potentially fatal, hepatic failure with flutamide is 3/10000 patients (99). Nilutamide hepatotoxicity is less well-documented, but can also have a fatal outcome (100).
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