side effects of bicalutamide side effects of bicalutamide 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. major side effects of bicalutamide frequency class of effect effect very common (≥10%) reproductive system and breast disorders• breast tenderness• gynecomastia common (1–10%) general and psychiatric disorders• asthenia • decreased libido • erectile dysfunction • hot flashes skin and subcutaneoustissue disorders • decreased body hair hepato-biliary disorders • elevated liver enzymes uncommon (0.1–1%) immune system disorders and hypersensitivity reactions• angioedema • hives rare (<0.1%) or unknown respiratory disorders• lung disease skin and subcutaneous tissue disorders• sensitivity to light hepato-biliary disorders• liver toxicity 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. usually transient, rarely severe. resolves or improves with continued therapy or on discontinuation. reported in single cases, but not observed in any large, randomized trial. with regular liver monitoring and discontinuation as needed. 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. 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). sexual dysfunction bicalutamide may cause sexual dysfunction, including decreased sex drive and erectile dysfunction. however, the rates of these side effects with bicalutamide monotherapy are very low. 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. 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. about two-thirds of men in these trials, who had advanced prostate cancer and were of almost invariably advanced age, maintained sexual interest, while sexual function was slightly reduced by 18%. most men experience sexual dysfunction only moderately or not at all with bicalutamide monotherapy, and the same is true during monotherapy with other nsaas. bicalutamide monotherapy at a dosage of 50 mg/day had no effect on nocturnal erections in men with prostate cancer. 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. similarly to in men, bicalutamide has been associated with minimal or no sexual dysfunction in women. 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. minimal rates of reduced sex drive have also been associated with the related nsaa flutamide. 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. 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. it appears that testosterone levels within the normal physiological range are not importantly involved in sexual desire or function in women. 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. rarely, bicalutamide has been associated with hallucinations. this is thought to be secondary to ar antagonism. breasts and reproductive system bicalutamide monotherapy and breast side effects in dose-ranging studies in men studyndosagegynecomastiabreast tendernessref tyrrell et al. (1998)a38610 mg/day9%11% 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% 30 mg/day60%64% 50 mg/day52%60% zanardi et al. (2006)c660 mg/week (controls)0%0% 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. the most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia. these side effects may occur in as many as 90% of men treated with bicalutamide monotherapy, but gynecomastia is generally reported to occur in 70 to 80% of patients. 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. 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. this variation is presumably related to factors like duration of therapy, differing patient characteristics, and the specific methods of collection of adverse-event data. 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. gynecomastia associated with nsaa monotherapy usually develops within the first 6 to 9 months following initiation of treatment. in one study, 89% of those who developed gynecomastia and 98% of those who developed breast pain did so within the first 6 months. 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. 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. 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. in more than 90% of affected men, bicalutamide-related breast changes are mild-to-moderate in severity. 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. in addition, bicalutamide-associated breast changes improve or resolve in most men upon discontinuation of therapy. 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. gynecomastia and breast pain improved or resolved upon discontinuation in 70 and 90% of patients, respectively. 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. 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). 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. 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. 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. moreover, in contrast to gnrh analogues (which also alleviate bicalutamide-induced gynecomastia), tamoxifen poses minimal risk of accelerated bone loss and osteoporosis. 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. 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. a 2019 network meta-analysis likewise concluded that tamoxifen was more effective than radiotherapy or anastrozole for preventing bicalutamide-induced gynecomastia. surgical breast reduction may also be employed to correct bicalutamide-induced gynecomastia. tamoxifen doses and rates of bicalutamide-induced breast symptoms in men follow-uptimepointtamoxifen 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. sources: male breast cancer a case report of male breast cancer subsequent to bicalutamide-induced gynecomastia has been published. according to the authors, "this is the second confirmed case of breast cancer in association with bicalutamide-induced gynaecomastia (correspondence astrazeneca)." it is notable, however, that gynecomastia does not seem to increase the risk of breast cancer in men. moreover, the lifetime incidence of breast cancer in men is approximately 0.1%, the average age of diagnosis of prostate cancer and male breast cancer are similar (around 70 years), and millions of men have been treated with bicalutamide for prostate cancer, all of which are potentially in support of the notion of chance co-occurrences. in accordance, the authors concluded that "causality cannot be established" and that it was "probable that the association is entirely coincidental and sporadic." lower reproductive system bicalutamide reduces the size of the prostate gland and seminal vesicles, though not of the testes. slightly but significantly reduced penile length is also a recognized adverse effect of adt. reversible hypospermia or aspermia (that is, reduced or absent semen/ejaculate production) may occur. however, bicalutamide does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish the capacity/potential for fertility in men. 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), but clinical studies indicate that leydig cell hyperplasia does not occur to a clinically important extent. 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. 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. 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. as such, bicalutamide is a selective reproductive teratogen in males, and may have the potential to