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===Kidney function===
===Kidney function===
Androgen deprivation therapy, including with GnRH agonists and bicalutamide monotherapy, may increase the risk of [[kidney failure]] in men.<ref name="pmid30833616">{{cite journal | vauthors = Peng CC, Chen CY, Chen CR, Chen CJ, Shen KH, Chen KC, Peng RY | title = Renal Damaging Effect Elicited by Bicalutamide Therapy Uncovered Multiple Action Mechanisms As Evidenced by the Cell Model | journal = Sci Rep | volume = 9 | issue = 1 | pages = 3392 | date = March 2019 | pmid = 30833616 | pmc = 6399217 | doi = 10.1038/s41598-019-39533-3 | url = | bibcode = 2019NatSR...9.3392P }}</ref><ref name="pmid31934548">{{cite journal | vauthors = Saito S | title = Successful recovery from multiple organ failure associated with bicalutamide and leuprorelin acetate for prostate cancer | journal = Urol Case Rep | volume = 29 | issue = | pages = 101108 | date = March 2020 | pmid = 31934548 | pmc = 6951477 | doi = 10.1016/j.eucr.2019.101108 | url = }}</ref><ref name="pmid23860987">{{cite journal | vauthors = Lapi F, Azoulay L, Niazi MT, Yin H, Benayoun S, Suissa S | title = Androgen deprivation therapy and risk of acute kidney injury in patients with prostate cancer | journal = JAMA | volume = 310 | issue = 3 | pages = 289–96 | date = July 2013 | pmid = 23860987 | doi = 10.1001/jama.2013.8638 | url = | doi-access = free }}</ref>
Androgens and [[anabolic steroid]]s, including testosterone, have [[hypertrophic|trophic]] and [[anabolic]] effects in the [[kidney]]s.<ref name="Krüskemper2013">{{cite book|author=H.-L. Krüskemper|title=Anabolic Steroids|url=https://books.google.com/books?id=4xIlBQAAQBAJ&pg=PA75%7Cdate%3D22+October+2013%7Cpublisher%3DElsevier%7Cisbn%3D978-1-4832-6504-9%7Cpages%3D75%E2%80%93%7D%7D%3C%2Fref%3E|date=22 October 2013|publisher=Elsevier|isbn=978-1-4832-6504-9|pages=75–}}</ref><ref name="Kochakian1976">{{cite journal|last1=Kochakian|first1=C. D.|title=Body and Organ Weights and Composition|year=1976|pages=73–154|doi=10.1007/978-3-642-66353-6_4}}</ref><ref name="pmid10979040">{{cite journal | vauthors = Starka L, Broulik PD, Hampl R, Nedvidkova J, Hill M | title = Antirenotropic action of antiandrogens cyproterone acetate, casodex, flutamide and epitestosterone | journal = Endocr Regul | volume = 30 | issue = 2 | pages = 93–97 | date = June 1996 | pmid = 10979040 | doi = | url = }}</ref> Androgen deprivation therapy, including with GnRH agonists and bicalutamide monotherapy, may increase the risk of [[kidney failure]] in men.<ref name="pmid30833616">{{cite journal | vauthors = Peng CC, Chen CY, Chen CR, Chen CJ, Shen KH, Chen KC, Peng RY | title = Renal Damaging Effect Elicited by Bicalutamide Therapy Uncovered Multiple Action Mechanisms As Evidenced by the Cell Model | journal = Sci Rep | volume = 9 | issue = 1 | pages = 3392 | date = March 2019 | pmid = 30833616 | pmc = 6399217 | doi = 10.1038/s41598-019-39533-3 | url = | bibcode = 2019NatSR...9.3392P }}</ref><ref name="pmid31934548">{{cite journal | vauthors = Saito S | title = Successful recovery from multiple organ failure associated with bicalutamide and leuprorelin acetate for prostate cancer | journal = Urol Case Rep | volume = 29 | issue = | pages = 101108 | date = March 2020 | pmid = 31934548 | pmc = 6951477 | doi = 10.1016/j.eucr.2019.101108 | url = }}</ref><ref name="pmid23860987">{{cite journal | vauthors = Lapi F, Azoulay L, Niazi MT, Yin H, Benayoun S, Suissa S | title = Androgen deprivation therapy and risk of acute kidney injury in patients with prostate cancer | journal = JAMA | volume = 310 | issue = 3 | pages = 289–96 | date = July 2013 | pmid = 23860987 | doi = 10.1001/jama.2013.8638 | url = | doi-access = free }}</ref> A large [[randomized controlled trial]] in men witih [[prostate cancer]] found that the incidence of kidney failure was 1 to 2% with [[combined androgen blockade]] using bicalutamide or [[flutamide]].<ref name="pmid9428389">{{cite journal | vauthors = Kolvenbag GJ, Blackledge GR, Gotting-Smith K | title = Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development | journal = Prostate | volume = 34 | issue = 1 | pages = 61–72 | date = January 1998 | pmid = 9428389 | doi = 10.1002/(sici)1097-0045(19980101)34:1<61::aid-pros8>3.0.co;2-n | url = }}</ref><ref name="pmid9301693">{{cite journal | vauthors = Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ | title = Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Casodex Combination Study Group | journal = Urology | volume = 50 | issue = 3 | pages = 330–6 | date = September 1997 | pmid = 9301693 | doi = 10.1016/s0090-4295(97)00279-3 | url = }}</ref><ref name="pmid8560681">{{cite journal | vauthors = Kolvenbag GJ, Blackledge GR | title = Worldwide activity and safety of bicalutamide: a summary review | journal = Urology | volume = 47 | issue = 1A Suppl | pages = 70–9; discussion 80–4 | date = January 1996 | pmid = 8560681 | doi = 10.1016/s0090-4295(96)80012-4 | url = }}</ref>


====Anemia====
====Anemia====

Revision as of 22:38, 5 June 2020

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. ^ a b 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. ^ a b 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, gynecomastia, 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.

In men with prostate cancer, bicalutamide monotherapy has been associated with an increased risk of non-cancer death, in part due to an increased incidence of heart failure. This is thought to be a consequence of androgen deprivation. Bicalutamide monotherapy has been found to cause unfavorable liver changes in around 3% of men, with such changes necessitating discontinuation in about 0.3 to 1% of men. Very rarely, bicalutamide has been associated with liver damage, lung disease, and sensitivity to light. It has also uncommonly been associated with hypersensitivity reactions. Bicalutamide has a theoretical risk of birth defects in male fetuses.

Template:Side effects of bicalutamide monotherapy

Template:Side effects of bicalutamide monotherapy by dosage

Side effects of combined androgen blockade with nonsteroidal antiandrogens
Side effect Bicalutamide 50 mg/day +
GnRH agonist (n = 401) (%)a,b		 Flutamide 750 mg/dayc +
GnRH agonist (n = 407) (%)a,b
Hot flashes 52.6 53.3
Pain (general) 35.4 31.2
Back pain 25.4 25.8
Asthenia 22.2 21.4
Constipation 21.7 17.0
Pelvic pain 21.2 17.2
Infection 17.7 14.0
Nausea 14.0 13.6
Peripheral edema 13.2 10.3
Anemiad 12.7 14.7
Dyspnea 12.7 7.9
Diarrhea 12.2 26.3
Nocturia 12.2 13.5
Hematuria 12.0 6.4
Abdominal pain 11.3 11.3
Dizziness 10.2 8.6
Bone pain 9.2 10.6
Gynecomastia 9.0 7.4
Rash 8.7 7.4
Urinary tract infection 8.7 8.8
Chest pain 8.5 8.4
Hypertension 8.5 7.1
Coughing 8.2 5.9
Pharyngitis 8.0 5.7
Paresthesia 7.7 9.8
Elevated liver enzymese 7.5 11.3
  Markedly elevatedf 0.5 2.5
  Leading to withdrawal 1.5 2.0
Weight loss 7.5 9.6
Headache 7.2 6.6
Flu-like symptoms 7.0 4.9
Myasthenia 6.7 4.7
Insomnia 6.7 9.6
Erectile dysfunction 6.7 8.6
Flatulence 6.5 5.4
Hyperglycemia 6.5 6.6
Dyspepsia 6.5 5.7
Decreased appetite 6.2 7.1
Sweating 6.2 4.9
Bronchitis 6.0 2.7
Breast pain/tenderness 5.7 3.7
Urinary frequency 5.7 7.1
Elevated alkaline phosphatase 5.5 5.9
Weight gain 5.5 4.4
Arthritis 5.2 7.1
Anxiety 5.0 2.2
Urinary retention 5.0 3.4
Urinary impairment 4.7 3.7
Pneumonia 4.5 4.7
Pathological fracture 4.2 7.9
Depression 4.0 8.1
Vomiting 4.0 6.9
Rhinitis 3.7 5.4
Urinary incontinence 3.7 7.9
Footnotes: a = Phase III studies of combined androgen blockade (bicalutamide or flutamide + GnRH agonist) in men with advanced prostate cancer. b = Incidence >5% regardless of causality. c = 250 mg three times per day at 8-hour intervals. d = Anemia includes hypochromic anemia and iron deficiency anemia. e = Abnormal liver function tests reported as adverse events. f = Elevated >5 times the normal upper limit. Sources: [8][9][10]

Central nervous system

Hot flashes

In the EPC trial, 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.[11] 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).[11][12]

Sexual dysfunction

Bicalutamide may cause sexual dysfunction, including decreased sex drive and erectile dysfunction.[11] However, the rates of these side effects with bicalutamide monotherapy are very low.[11] 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.[11] 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.[12] About two-thirds of men in these trials, who had advanced prostate cancer and were of almost invariably advanced age,[13] maintained sexual interest, while sexual function was slightly reduced by 18%.[12] Most men experience sexual dysfunction only moderately or not at all with bicalutamide monotherapy, and the same is true during monotherapy with other NSAAs.[14] Bicalutamide monotherapy at a dosage of 50 mg/day had no effect on nocturnal erections in men with prostate cancer.[15][16]

Similarly to in men, bicalutamide has been associated with minimal or no sexual dysfunction in women.[17] 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.[17] Minimal rates of reduced sex drive have also been associated with the related NSAA flutamide.[18][19] 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.[20] 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.[20] It appears that testosterone levels within the normal physiological range are not importantly involved in sexual desire or function in women.[21]

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.[22] Rarely, bicalutamide has been associated with hallucinations.[23] This is thought to be secondary to AR antagonism.[23]

Breasts and reproductive system

Breast changes

Gynecomastia in a 60-year-old man treated with 150 mg/day bicalutamide for prostate cancer.[24]

The most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia.[14] These side effects may occur in as many as 90% of men treated with bicalutamide monotherapy,[25] but gynecomastia is generally reported to occur in 70 to 80% of patients.[26] 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.[11][12] Gynecomastia associated with NSAA monotherapy usually develops within the first 6 to 9 months following initiation of treatment.[24] In more than 90% of affected men, bicalutamide-related breast changes are mild-to-moderate in severity.[12][27] 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.[28] In addition, bicalutamide-associated breast changes improve or resolve in most men upon discontinuation of therapy.[12] 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.[27] The incidence and severity of gynecomastia are reportedly higher with estrogens (e.g., diethylstilbestrol) than with NSAAs like bicalutamide in the treatment of men with prostate cancer.[29]

Template:Bicalutamide monotherapy and breast side effects in dose-ranging studies in men

Management of breast changes

Severe gynecomastia in a 64-year-old man treated with 150 mg/day bicalutamide for prostate cancer. Before (A) and after (B) surgical breast reduction.[30]

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.[31][32] Moreover, in contrast to GnRH analogues (which also alleviate bicalutamide-induced gynecomastia), tamoxifen poses minimal risk of accelerated bone loss and osteoporosis.[31][32] 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.[31][32] A 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.[33] Surgical breast reduction may also be employed to correct bicalutamide-induced gynecomastia.[34]

Tamoxifen doses and rates of bicalutamide-induced breast symptoms in men
Follow-up
timepoint		 Tamoxifen dosage
Placebo 1 mg/day 2.5 mg/day 5 mg/day 10 mg/day 20 mg/day
0 months
–
6 months 98% 90% 80% 54% 22% 10%
12 months 99% 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.[35] Sources: [36][35]

Male breast cancer

A case report of male breast cancer subsequent to bicalutamide-induced gynecomastia has been published.[37] According to the authors, "this is the second confirmed case of breast cancer in association with bicalutamide-induced gynaecomastia (correspondence AstraZeneca)."[37] It is notable, however, that gynecomastia does not seem to increase the risk of breast cancer in men.[37][38] Moreover, the lifetime incidence of breast cancer in men is approximately 0.1%,[39] the average age of diagnosis of prostate cancer and male breast cancer are similar (around 70 years),[13][40] and millions of men have been treated with bicalutamide for prostate cancer,[41] all of which are potentially in support of the notion of chance co-occurrences.[37] In accordance, the authors concluded that "causality cannot be established" and that it was "probable that the association is entirely coincidental and sporadic."[37]

Internal reproductive system and genitals

Bicalutamide reduces the size of the prostate gland and seminal vesicles,[42] though not of the testes.[43] Significantly reduced penile length is also a recognized adverse effect of ADT.[44][45] Reversible hypospermia or aspermia (that is, reduced or absent semen/ejaculate production) may occur.[46][47] However, bicalutamide does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish the capacity/potential for fertility in men.[43][48] 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),[49] but clinical studies indicate that Leydig cell hyperplasia does not occur to a clinically important extent.[50][48][51]

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.[52][53][54][55] 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.[56] 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.[56] As such, bicalutamide is a selective reproductive teratogen in males, and may have the potential to produce undervirilization/sexually ambiguous genitalia in male fetuses.[52][53]

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.[citation needed] Androgens are involved in regulation of the skin (e.g., sebum production), and antiandrogens are known to be associated with skin changes.[50] 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.[50]

Sensitivity to light

A few cases of photosensitivity (hypersensitivity to ultraviolet light-induced skin redness and/or lesions) associated with bicalutamide have been reported.[57][58][59] 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.[57] Flutamide is also associated with photosensitivity, but much more frequently in comparison to bicalutamide.[57][59]

Fat distribution

Antiandrogen therapy and estrogen therapy are known to produce demasculinizing and feminizing effects on fat distribution.[citation needed]

Bone density and fractures

The risk of serious bone fractures is no different with bicalutamide monotherapy than with non-use in men with prostate cancer.[60]

Gastrointestinal system

The incidence of diarrhea with bicalutamide monotherapy in the EPC trial was comparable to placebo (6.3% vs. 6.4%, respectively).[12] 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.[61]

Heart, liver, kidneys, and lungs

Cardiovascular system

See also: Testosterone and the cardiovascular system

In the LPC group of the EPC study, although 150 mg/day bicalutamide monotherapy had reduced mortality due to prostate cancer relative to placebo, there was a trend toward significantly increased overall mortality for bicalutamide relative to placebo at 5.4-year follow-up (25.2% vs. 20.5%).[22][62][63] This was because more bicalutamide than placebo recipients had died due to causes unrelated to prostate cancer in this group (16.8% vs. 9.5% at 5.4-year follow-up; 10.2% vs. 9.2% at 7.4-year follow-up).[22][63][11] At 7.4-year follow-up, there were numerically more deaths from heart failure (1.2% vs. 0.6%; 49 vs. 25 patients) and gastrointestinal cancer (1.3% vs. 0.9%) in the bicalutamide group relative to placebo recipients, although cardiovascular morbidity was similar between the two groups and there was no consistent pattern suggestive of drug-related toxicity for bicalutamide.[11][64] In any case, although the reason for the increased overall mortality with 150 mg/day bicalutamide monotherapy has not been fully elucidated,[26] it has been said that the finding that heart failure was twice as frequent in the bicalutamide group warrants further investigation.[65] In this regard, it is notable that low testosterone levels in men have been associated in epidemiological studies with cardiovascular disease as well as with a variety of other disease states (including hypertension, hypercholesterolemia, diabetes, obesity, Alzheimer's disease, osteoporosis, and frailty).[66]

According to Iversen et al. (2006), the increased non-prostate cancer mortality with bicalutamide monotherapy in LPC patients has also been seen with castration (via orchiectomy or GnRH analogue monotherapy) and is likely a consequence of androgen deprivation in men rather than a specific drug toxicity of bicalutamide:[67]

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.[67]

A study of 300 to 600 mg/day bicalutamide monotherapy 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.[68][69] In addition, at 5-year follow-up, the incidence of cardiovascular events was low, with no differences between the bicalutamide and castration groups.[68][69] There were also no differences in the incidences of arrhythmia, myocardial infarction, or other ischemic cardiac or cerebrovascular conditions.[68][69] These findings suggest that bicalutamide does not cause an excess in cardiovascular events or conditions.[68][69]

A meta-analysis of prospective randomized clinical trials of GnRH agonist-based ADT for the treatment of non-metastatic prostate cancer that included over 4,000 patients found no evidence of increased cardiovascular mortality or overall mortality.[70] Non-prostate cancer mortality was not specifically assessed.[70]

A case report in which bicalutamide was described as a probable cause of heart failure in an elderly man with prostate cancer has been published.[71]

Cardiovascular risks have been reviewed and subjected to meta-analysis.[72][73]

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.[74][75][76][77][78]

Kidney function

Androgens and anabolic steroids, including testosterone, have trophic and anabolic effects in the kidneys.[79][80][81] Androgen deprivation therapy, including with GnRH agonists and bicalutamide monotherapy, may increase the risk of kidney failure in men.[82][83][84] A large randomized controlled trial in men witih prostate cancer found that the incidence of kidney failure was 1 to 2% with combined androgen blockade using bicalutamide or flutamide.[85][86][87]

Anemia

Androgens including testosterone are known to stimulate erythropoiesis (formation of red blood cells) and increase hematocrit (red blood cell levels).[88][89] These effects are mediated by increasing production and secretion of erythropoietin from the kidneys.[89] Erythropoietin in turn stimulates erythropoiesis in hematopoietic tissues such as bone marrow.[90] The high levels of testosterone in males are why hematocrit and hemoglobin levels are higher in men than in women.[91] 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).[89][92] 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.[88][89] Conversely, whether via castration, NSAA monotherapy, or CAB, decreased erythropoiesis resulting in mild anemia is a common side effect of ADT in men.[50][93] The incidence of anemia with bicalutamide as a monotherapy or with castration was about 7.4% in clinical trials.[50] A decrease of hemoglobin levels of 1 to 2 g/dL after approximately six months of treatment may be observed.[93]

Liver toxicity

Bicalutamide may cause liver changes rarely, such as elevated transaminases and jaundice.[94] In the EPC study of 4,052 prostate cancer patients who received 150 mg/day bicalutamide as a monotherapy, the incidence of abnormal liver function tests was 3.4% for bicalutamide and 1.9% for standard care (a 1.5% difference potentially attributable to bicalutamide) at 3-year median follow-up.[11][95] For comparison, the incidences of abnormal liver function tests are 42 to 62% for flutamide, 2 to 3% for nilutamide,[94][96] and (dose-dependently) between 10% and 28% for CPA,[97][98][99] whereas there appears to be no risk with enzalutamide.[100][101] In the EPC trial, bicalutamide-induced liver changes were usually transient and rarely severe.[11] The medication was discontinued due to liver changes (manifested as hepatitis or marked increases in liver enzymes) in approximately 0.3% to 1% of patients treated with it for prostate cancer in clinical trials.[56][102]

The risk of liver changes with bicalutamide is considered to be small but significant, and monitoring of liver function is recommended.[11][103] Elevation of transaminases above twice the normal range or jaundice may be an indication that bicalutamide should be discontinued.[104] Liver changes with bicalutamide usually occur within the first 3 or 4 months of treatment, and it is recommended that liver function be monitored regularly for the first 4 months of treatment and periodically thereafter.[56] Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice.[56]

A total of 7 case reports of bicalutamide-associated hepatotoxicity or liver failure, two of which were fatal, have been published in the literature as of 2018.[105][94][106] One of these cases occurred after two doses of bicalutamide, and has been said to more likely to have been caused by prolonged prior exposure of the patient to flutamide and CPA.[94][96][107][108][109] In the reported cases of bicalutamide-associated hepatotoxicity, the dosages of the drug were 50 mg/day (three), 80 mg/day (one), 100 mg/day (one), and 150 mg/day (two).[105][106] Relative to flutamide (which has an estimated incidence rate of 0.03% or 3 per 10,000), hepatotoxicity is far rarer with bicalutamide and nilutamide, and bicalutamide is regarded as having the lowest risk of the three medications.[110][107][111] For comparison, by 1996, 46 cases of severe cholestatic hepatitis associated with flutamide had been reported, with 20 of the cases resulting in death.[97] Moreover, 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, and the review also cited a report of an additional 96 instances of hepatotoxicity that were attributed to CPA, 33 of which resulted in death.[97]

The clinical studies that have found elevated liver enzymes and the case reports of hepatotoxicity with bicalutamide have all specifically pertained to men of advanced age with prostate cancer.[11][95][94][106] It is notable that older age, for a variety of reasons, appears to be an important risk factor for drug-induced hepatotoxicity.[112][113] As such, the risk of liver changes with bicalutamide may be less in younger patients, for instance young hirsute women and transgender women.[112][113] However, it has been reported on the basis of very limited evidence that this may not be the case with flutamide.[114] There is no evidence of greater liver function changes with higher doses of bicalutamide.[115]

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.[116] However, in contrast to flutamide, hydroxyflutamide, and nilutamide, bicalutamide exhibits much 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 much lower risk of hepatotoxicity in comparison.[117][118][119][120] 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.[107][117][120][121]

Published case reports of bicalutamide-associated liver injury
# Age Sex Dosage Use Onset Outcome Source
1 60 years Male 50 mg/day Prostate cancer 2 days Survived Dawson et al. (1997)
2 79 years Male 80 mg/day Prostate cancer 1.5 months Survived Ikemoto et al. (2000)
3 59 years Male 50 mg/day Prostate cancer 4 days Death O'Bryant et al. (2008)
4 61 years Male 50 mg/day Prostate cancer 3.5 months Death Castro Beza et al. (2008)
5 81 years Male 150 mg/day Prostate cancer 3 weeks Survived Hussain et al. (2014)
6 62 years Male 100 mg/day Prostate cancer 4.5 months Survived Yun et al. (2016)
7 67 years Male 150 mg/day Prostate cancer 3 weeks Survived Gretarsdottir et al. (2018)
8 79 years Male Unknown Prostate cancer 15 days Survived Saito (2020)
9 17 years Trans female Unknown Gender-affirming hormone therapy 1 year Survived Reed (2023)
10 17 years Trans female 50 mg/day Gender-affirming hormone therapy 3 months Survived Wilde 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: [122][123]

Lung toxicity

Several case reports of interstitial pneumonitis (which can progress to pulmonary fibrosis) in association with bicalutamide treatment have been published in the medical literature.[124][125][126][127] Interstitial pneumonitis with bicalutamide is said to be an extremely rare event,[128] and the risk is far less relative to that seen with nilutamide (which has an incidence rate of 0.5–2% of patients).[129]: 81 [125][130] In a very large cohort of prostate cancer patients, the incidence of interstitial pneumonitis with NSAAs was 0.77% for nilutamide but only 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.[131] In addition to interstitial pneumonitis, a single case report of eosinophilic lung disease in association with six months of 200 mg/day bicalutamide treatment exists.[132][133] Side effects associated with the rare potential pulmonary adverse reactions of bicalutamide may include dyspnea (difficult breathing or shortness of breath), cough, and pharyngitis (inflammation of the pharynx, resulting in sore throat).[134]

Published case reports of bicalutamide-associated lung toxicity
# Age Sex Dosage Onset Type of injury Outcome Ref
1 69 years Male 200 mg/day 6 months Eosinophilic lung disease Recovered Wong et al. (1998)
2 ~76 years Male 200 mg/day 8 months Interstitial pneumonitis Recovered McCaffrey & Scher (1998)
3 ~82 years Male 80 mg/day 4 weeks Interstitial pneumonitis Recovered Shioi et al. (2003)
4 ~72 years Male 80 mg/day 2.5 months Interstitial pneumonitis Recovered, then deatha Shioi et al. (2005)
5 84 years Male ? 8 months Interstitial pneumonitis Recovered Kobayashi et al. (2006)
6 76 years Male ? ? Interstitial pneumonitis ? Gifford & DeLong (2008)
7 85 years Male ? 4 months Interstitial pneumonitis Death Kawahara et al. (2009)
8 78 years Male 80 mg/day 8 months Interstitial pneumonitis Recovered Masago et al. (2011)
9 77 years Male ? 7 months Interstitial pneumonitis Death Song et al. (2014)
10 77 years Male >50 mg/day ~12 months Interstitial pneumonitis Death Molina Mancero et al. (2016)
11 79 years Male ? 1 month Interstitial pneumonitis Death Polatoglu et al. (2017)
12 66 years Male ? ? Interstitial pneumonitis Recovered Kim et al. (2018)
13 66 years Male ? ? Interstitial pneumonitis Recovered Derichs et al. (2018)
14 86 years Male 150 mg/day 6 years Eosinophilic pneumonitis Recovered Umeojiako & James (2019)
15 75 years Male ? 2 weeks Interstitial pneumonitis Death Maeda et al. (2019)
16 79 years Male ? 1.5 months Interstitial pneumonitis Recovered Saito (2020)
17 66 years Male 50 mg/day 6 months Interstitial pneumonitis Recovered Smith & 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 FDATooltip 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.

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,[135] while certain other side effects, including hot flashes, depression, fatigue, and sexual dysfunction,[136] occur much more frequently in combination with a GnRH analogue.[15][137][138] 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.[15] 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.[135] However, due to the loss of estrogen, bone loss will accelerate and the risk of osteoporosis developing with long-term therapy will increase.[139]

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  105. ^ a b Gretarsdottir, Helga M.; Bjornsdottir, Elin; Bjornsson, Einar S. (2018). "Bicalutamide-Associated Acute Liver Injury and Migratory Arthralgia: A Rare but Clinically Important Adverse Effect". Case Reports in Gastroenterology. 12 (2): 266–270. doi:10.1159/000485175. ISSN 1662-0631.
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  116. ^ Bunce, Chris M.; Campbell, Moray J. (11 March 2010). Nuclear Receptors: Current Concepts and Future Challenges. Springer Science & Business Media. pp. 160, 167. ISBN 978-90-481-3303-1. Archived from the original on 10 June 2016. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
  117. ^ a b Coe KJ, Jia Y, Ho HK, Rademacher P, Bammler TK, Beyer RP, Farin FM, Woodke L, Plymate SR, Fausto N, Nelson SD (September 2007). "Comparison of the cytotoxicity of the nitroaromatic drug flutamide to its cyano analogue in the hepatocyte cell line TAMH: evidence for complex I inhibition and mitochondrial dysfunction using toxicogenomic screening". Chemical Research in Toxicology. 20 (9): 1277–90. doi:10.1021/tx7001349. PMC 2802183. PMID 17702527.
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  119. ^ Kashimshetty R, Desai VG, Kale VM, Lee T, Moland CL, Branham WS, New LS, Chan EC, Younis H, Boelsterli UA (July 2009). "Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity". Toxicology and Applied Pharmacology. 238 (2): 150–9. doi:10.1016/j.taap.2009.05.007. PMID 19442681.
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