Side effects of bicalutamide: Difference between revisions

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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]
^ ^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. ^ Usually transient, rarely severe. Resolves or improves with continued therapy or on discontinuation. ^ ^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

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Side effects of combined androgen blockade with nonsteroidal antiandrogens
Side effect	Bicalutamide 50 mg/day + GnRH agonist (n = 401) (%)^a,b	Flutamide 750 mg/day^c + 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
Anemia^d	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 enzymes^e	7.5	11.3
Markedly elevated^f	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]

Breast changes

The most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia.^[12] These side effects may occur in as many as 90% of men treated with bicalutamide monotherapy,^[13] but gynecomastia is generally reported to occur in 70 to 80% of patients.^[14] 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.^[15]^[16] Gynecomastia associated with NSAA monotherapy usually develops within the first 6 to 9 months following initiation of treatment.^[11] In more than 90% of affected men, bicalutamide-related breast changes are mild-to-moderate in severity.^[16]^[17] 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.^[18] In addition, bicalutamide-associated breast changes improve or resolve in most men upon discontinuation of therapy.^[16] 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.^[17] 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.^[19]

Management

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.^[21]^[22] Moreover, in contrast to GnRH analogues (which also alleviate bicalutamide-induced gynecomastia), tamoxifen poses minimal risk of accelerated bone loss and osteoporosis.^[21]^[22] 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.^[21]^[22] 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.^[23] Surgical breast reduction may also be employed to correct bicalutamide-induced gynecomastia.^[24]

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Tamoxifen doses and rates of bicalutamide-induced breast symptoms in men
Follow-up timepoint	Tamoxifen dosage
Follow-up timepoint	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.^[25] Sources: ^[26]^[25]

Sexual dysfunction

Bicalutamide may cause sexual dysfunction, including decreased sex drive and erectile dysfunction.^[15] However, the rates of these side effects with bicalutamide monotherapy are very low.^[15] 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.^[15] 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.^[16] About two-thirds of men in these trials, who had advanced prostate cancer and were of almost invariably advanced age,^[27] maintained sexual interest, while sexual function was slightly reduced by 18%.^[16] Most men experience sexual dysfunction only moderately or not at all with bicalutamide monotherapy, and the same is true during monotherapy with other NSAAs.^[12] Bicalutamide monotherapy at a dosage of 50 mg/day had no effect on nocturnal erections in men with prostate cancer.^[28]^[29]

Similarly to in men, bicalutamide has been associated with minimal or no sexual dysfunction in women.^[30] 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.^[30] Minimal rates of reduced sex drive have also been associated with the related NSAA flutamide.^[31]^[32] 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,^[33] as well as 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.^[33] It appears that testosterone levels within the normal physiological range are not importantly involved in sexual desire or function in women.^[34]

Reproductive changes

Bicalutamide reduces the size of the prostate gland and seminal vesicles,^[35] though not of the testes.^[36] Significantly reduced penile length is also a recognized adverse effect of ADT.^[37]^[38] Reversible hypospermia or aspermia (that is, reduced or absent semen/ejaculate production) may occur.^[39]^[40] However, bicalutamide does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish the capacity/potential for fertility in men.^[36]^[41] 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),^[42] but clinical studies indicate that Leydig cell hyperplasia does not occur to a clinically important extent.^[43]^[41]^[44]

Gastrointestinal

The incidence of diarrhea with bicalutamide monotherapy in the EPC trial was comparable to placebo (6.3% vs. 6.4%, respectively).^[16] 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.^[45]

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.^[15] 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).^[15]^[16]

Psychological

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.^[46]

Anemia

Androgens are known to stimulate the formation of red blood cells and increase the red blood cell count and circulating hematocrit levels, effects which they mediate by increasing production of erythropoietin in the kidneys.^[47] In accordance, anabolic–androgenic steroids (AAS) such as oxymetholone and nandrolone decanoate are approved and used in the treatment of severe anemia,^[47]^[48] and AAS can cause polycythemia as an adverse effect in high dosages.^[47] Conversely, whether via castration, NSAA monotherapy, or CAB, mild anemia is a common side effect of ADT in men.^[43]^[49] The incidence of anemia with bicalutamide as a monotherapy or with castration was about 7.4% in clinical trials.^[43] A decrease of hemoglobin levels of 1–2 g/dL after approximately six months of treatment may be observed.^[49]

Skin changes

Androgens are involved in regulation of the skin (e.g., sebum production), and antiandrogens are known to be associated with skin changes.^[43] 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.^[43]

With 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,^[50] while certain other side effects, including hot flashes, depression, fatigue, and sexual dysfunction,^[51] occur much more frequently in combination with a GnRH analogue.^[28]^[52]^[53] 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.^[28] 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.^[50] However, due to the loss of estrogen, bone loss will accelerate and the risk of osteoporosis developing with long-term therapy will increase.^[54]

Increased mortality

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%).^[46]^[55]^[56] 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).^[46]^[56]^[15] 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.^[15]^[57] In any case, although the reason for the increased overall mortality with 150 mg/day bicalutamide monotherapy has not been fully elucidated,^[14] it has been said that the finding that heart failure was twice as frequent in the bicalutamide group warrants further investigation.^[58] 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).^[59]

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:^[60]

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.^[60]

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.^[61]^[62] In addition, at 5-year follow-up, the incidence of cardiovascular events was low, with no differences between the bicalutamide and castration groups.^[61]^[62] There were also no differences in the incidences of arrhythmia, myocardial infarction, or other ischemic cardiac or cerebrovascular conditions.^[61]^[62] These findings suggest that bicalutamide does not cause an excess in cardiovascular events or conditions.^[61]^[62]

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.^[63] Non-prostate cancer mortality was not specifically assessed.^[63]

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.^[64]

Renal toxicity

As a result of androgen deprivation therapy, bicalutamide may increase the risk of kidney failure in men.^[65]

Liver toxicity

Bicalutamide may cause liver changes rarely, such as elevated transaminases and jaundice.^[66] 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.^[15]^[67] For comparison, the incidences of abnormal liver function tests are 42 to 62% for flutamide, 2 to 3% for nilutamide,^[66]^[68] and (dose-dependently) between 10% and 28% for CPA,^[69]^[70]^[71] whereas there appears to be no risk with enzalutamide.^[72]^[73] In the EPC trial, bicalutamide-induced liver changes were usually transient and rarely severe.^[15] 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.^[74]^[75]

The risk of liver changes with bicalutamide is considered to be small but significant, and monitoring of liver function is recommended.^[15]^[76] Elevation of transaminases above twice the normal range or jaundice may be an indication that bicalutamide should be discontinued.^[77] 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.^[74] Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice.^[74]

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.^[78]^[66]^[79] 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.^[66]^[68]^[80]^[81]^[82] 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).^[78]^[79] 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.^[83]^[80]^[84] For comparison, by 1996, 46 cases of severe cholestatic hepatitis associated with flutamide had been reported, with 20 of the cases resulting in death.^[69] 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.^[69]

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.^[15]^[67]^[66]^[79] It is notable that older age, for a variety of reasons, appears to be an important risk factor for drug-induced hepatotoxicity.^[85]^[86] As such, the risk of liver changes with bicalutamide may be less in younger patients, for instance young hirsute women and transgender women.^[85]^[86] However, it has been reported on the basis of very limited evidence that this may not be the case with flutamide.^[87]

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.^[88] 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.^[89]^[90]^[91]^[92] 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.^[80]^[89]^[92]^[93]

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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: ^[78]^[94]

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.^[95]^[96]^[97]^[98] Interstitial pneumonitis with bicalutamide is said to be an extremely rare event,^[99] and the risk is far less relative to that seen with nilutamide (which has an incidence rate of 0.5–2% of patients).^[100]^: 81^[96]^[101] 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.^[102] 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.^[103]^[104] 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).^[105]

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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 death^a	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.

Sensitivity to light

A few cases of photosensitivity (hypersensitivity to ultraviolet light-induced skin redness and/or lesions) associated with bicalutamide have been reported.^[106]^[107]^[108] 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), the symptoms disappeared and did not recur.^[106] Flutamide is also associated with photosensitivity, but much more frequently in comparison to bicalutamide.^[106]^[108]

Male breast cancer

A case report of male breast cancer subsequent to bicalutamide-induced gynecomastia has been published.^[109] According to the authors, "this is the second confirmed case of breast cancer in association with bicalutamide-induced gynaecomastia (correspondence AstraZeneca)."^[109] It is notable, however, that gynecomastia does not seem to increase the risk of breast cancer in men.^[109]^[110] Moreover, the lifetime incidence of breast cancer in men is approximately 0.1%,^[111] the average age of diagnosis of prostate cancer and male breast cancer are similar (around 70 years),^[27]^[112] and millions of men have been treated with bicalutamide for prostate cancer,^[113] all of which are potentially in support of the notion of chance co-occurrences.^[109] In accordance, the authors concluded that "causality cannot be established" and that it was "probable that the association is entirely coincidental and sporadic."^[109]

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.^[114]^[115]^[116]^[117] 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.^[74] 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.^[74] As such, bicalutamide is a selective reproductive teratogen in males, and may have the potential to produce undervirilization/sexually ambiguous genitalia in male fetuses.^[114]^[115]

References

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^ ^a ^b Iversen P, Johansson JE, Lodding P, Kylmälä T, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Armstrong J (2006). "Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer: updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years". Scandinavian Journal of Urology and Nephrology. 40 (6): 441–52. doi:10.1080/00365590601017329. PMID 17130095.
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^ ^a ^b Craig, Jordon V.; Furr, B.J.A. (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 356–. ISBN 978-1-59259-152-7. A case of near-fatal fulminant hepatic failure in a patient on bicalutamide therapy (50 mg) has recently been published (101), but it is uncertain whether this can be attributed to bicalutamide, as the symptoms developed after only two doses in a patient previously exposed to both cyproterone acetate and flutamide (101). {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
^ ^a ^b ^c Kaplowitz, Neil (16 October 2002). Drug-Induced Liver Disease. CRC Press. pp. 618–. ISBN 978-0-203-90912-6. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
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[breast-8] 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.

[9] Usually transient, rarely severe. Resolves or improves with continued therapy or on discontinuation.

[case-10] Reported in single cases, but not observed in any large, randomized trial. With regular liver monitoring and discontinuation as needed.

[pmid12231039-1] Mcleod DG (September 2002). "Emerging role of adjuvant hormonal therapy". Urology. 60 (3 Suppl 1): 13–20, discussion 21. doi:10.1016/S0090-4295(02)01562-5. PMID 12231039.

[PMS-Bicalutamide-Label-2] "Bicalutamide" (PDF). Richmond Hill, Ontario: Nu-Pharm Inc. October 2009.

[pmid12353966-3] Bennett CL, Raisch DW, Sartor O (October 2002). "Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect". Annals of Internal Medicine. 137 (7): 625. doi:10.7326/0003-4819-137-7-200210010-00029. PMID 12353966. An estimated 0.77% of the 6,480 nilutamide-treated patients, 0.04% of the 41,700 flutamide-treated patients, and 0.01% of the 86,800 bicalutamide-treated patients developed pneumonitis during the study period. Cite error: The named reference "pmid12353966" was defined multiple times with different content (see the help page).

[Molina_ManceroPicón2016-4] Molina Mancero G, Picón X, Di Tullio F, Ernst G, Dezanzo P, Salvado A, Chertcoff JF (October 2016). "Neumonía intersticial inducida por bloqueo androgénico máximo como tratamiento de cáncer de próstata avanzado" [Fatal interstitial lung disease associated with maximum androgen blockade. Report of one case]. Revista médica de Chile (in Spanish). 144 (10): 1356–1359. doi:10.4067/S0034-98872016001000017. PMID 28074993.

[pmid26663090-5] 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): 161–164. doi:10.1111/phpp.12230. PMID 26663090. S2CID 2761388.

[6] Gretarsdottir HM, Bjornsdottir E, Bjornsson ES (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. S2CID 81661015.

[pmid12603397-7] Anderson J (March 2003). "The role of antiandrogen monotherapy in the treatment of prostate cancer". BJU International. 91 (5): 455–461. doi:10.1046/j.1464-410X.2003.04026.x. PMID 12603397. S2CID 8639102.

[Casodex-Label-US-11] "Casodex Product Monograph" (PDF). Retrieved 24 September 2018. Table 1 Incidence of Adverse Reactions (≥ 5% in Either Treatment Group) Regardless of Causality [...] Increased Liver Enzyme Test: [...] [Number of Patients (%)] [...] CASODEX Plus LHRH Analog (n=401): 30 (7 [7.5%) [...] Flutamide Plus LHRH Analog (n=407): 46 (11 [11.3%]).

[Casodex-Label-CA-12] "NU-Bicalutamide Product Monograph" (PDF). Retrieved 24 September 2018. Adverse event reports of abnormal liver function test results occurred in 7% of patients. These changes were frequently transient and rarely severe, resolving or improving with continued therapy or following cessation of therapy. Hepatic failure and interstitial lung disease (see WARNINGS AND PRECAUTIONS) have been observed in post-marketed data and fatal outcomes have been reported for both. [...] The most common adverse events leading to withdrawal of study medication were abnormal liver function tests (1.5%) [...] Table 1 Incidence Of Adverse Events (≥ 5% In Either Treatment Group) Regardless Of Causality [...] Increased Liver Enzyme Test^b [Number of Patients (%)] [...] CASODEX Plus LHRH Analogue (n=401): 30 (7 [7.5%]) [...] Flutamide Plus LHRH Analogue (n=407): 46 (11 [11.3%]) [...] During the first few months of use, you may be monitored by your physician for signs of changes in your liver function. In approximately 2.0% of patients, such changes may lead to withdrawal of therapy.

[pmid8717470-13] Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". Eur. Urol. 29 Suppl 2: 96–104. doi:10.1159/000473847. PMID 8717470. Casodex has been administered to over 3,900 subjects and patients and, in general, has been well tolerated. [...] Elevations of liver transaminases have been seen with Casodex, but these are usually transient, resolving either on continued therapy or on temporary cessation of therapy. In a randomised comparison with flutamide, elevations of transaminases were both less frequent and less severe than with flutamide. No cases of fulminant hepatic failure or death due to hepatic failure have been seen with Casodex in any of the clinical trials.

[pmid23050528-14] 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.

[Aronson2009-15] Aronson, Jeffrey K. (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 150–152. ISBN 978-0-08-093292-7. In contrast [to flutamide and nilutamide], no specific non-pharmacological complications have been linked to bicalutamide, while diarrhea and abnormal liver function occur less often than with flutamide. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)

[FradetEgerdie2007-16] 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.

[WirthHakenberg2007-17] Wirth MP, Hakenberg OW, Froehner M (February 2007). "Antiandrogens in the treatment of prostate cancer". European Urology. 51 (2): 306–13, discussion 314. doi:10.1016/j.eururo.2006.08.043. PMID 17007995.

[Wellington2006-18] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l Wellington K, Keam SJ (2006). "Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer" (PDF). Drugs. 66 (6): 837–50. doi:10.2165/00003495-200666060-00007. PMID 16706554. Archived (PDF) from the original on 28 August 2016.

[Anderson2003-19] ^ ^a ^b ^c ^d ^e ^f ^g Anderson J (March 2003). "The role of antiandrogen monotherapy in the treatment of prostate cancer". BJU International. 91 (5): 455–61. doi:10.1046/j.1464-410X.2003.04026.x. PMID 12603397.

[WellingtonKeam2006-20] Wellington K, Keam SJ (2006). "Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer". Drugs. 66 (6): 837–50. doi:10.2165/00003495-200666060-00007. PMID 16706554.

[pmid4812899-21] Brown JS, Rubenfeld S (1974). "Irradiation in preventing gynecomastia induced by estrogens". Urology. 3 (1): 51–3. doi:10.1016/s0090-4295(74)80060-9. PMID 4812899. Infrequently, the breast hypertrophy can become so marked that it attains proportions comparable to that in female breasts.

[DeepinderBraunstein2012-22] 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. 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.

[pmid16782932-23] 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.

[SaltzsteinSieber2005-24] 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.

[Boccardo2005-25] 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.

[pmid26308532-26] 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[pmid16321765-27] Di Lorenzo G, Autorino R, Perdonà S, De Placido S (2005). "Management of gynaecomastia in patients with prostate cancer: a systematic review". Lancet Oncol. 6 (12): 972–9. doi:10.1016/S1470-2045(05)70464-2. PMID 16321765.

[pmid17270340-28] Fradet Y, Egerdie B, Andersen M, Tammela TL, Nachabe M, Armstrong J, Morris T, Navani S (July 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". Eur. Urol. 52 (1): 106–14. doi:10.1016/j.eururo.2007.01.031. PMID 17270340.

[pmid29322112-29] Fentiman IS (January 2018). "Managing Male Mammary Maladies". Eur J Breast Health. 14 (1): 5–9. doi:10.5152/ejbh.2017.3841. PMC 5758064. PMID 29322112.

[pmid27194038-30] Rahman HP, Hofland J, Foster PA (2016). "In touch with your feminine side: how oestrogen metabolism impacts prostate cancer" (PDF). Endocrine-Related Cancer. 23 (6): R249–66. doi:10.1530/ERC-16-0118. PMID 27194038. Prostate cancer primarily affects the elderly with 99.9% of patients diagnosed over the age of 50 and the mean age at diagnosis being 73 (Parkin, et al. 1997).

[IversenMelezinek2001-31] Iversen P, Melezinek I, Schmidt A (January 2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU International. 87 (1): 47–56. doi:10.1046/j.1464-410x.2001.00988.x. PMID 11121992.

[pmid1378907-32] Migliari R, Muscas G, Usai E (August 1992). "Effect of Casodex on sleep-related erections in patients with advanced prostate cancer". J. Urol. 148 (2 Pt 1): 338–41. doi:10.1016/S0022-5347(17)36588-6. PMID 1378907.

[pmid29211888-33] Moretti C, Guccione L, Di Giacinto P, Simonelli I, Exacoustos C, Toscano V, Motta C, De Leo V, Petraglia F, Lenzi A (March 2018). "Combined Oral Contraception and Bicalutamide in Polycystic Ovary Syndrome and Severe Hirsutism: A Double-Blind Randomized Controlled Trial". J. Clin. Endocrinol. Metab. 103 (3): 824–838. doi:10.1210/jc.2017-01186. PMID 29211888.

[pmid21117864-34] Paradisi R, Fabbri R, Porcu E, Battaglia C, Seracchioli R, Venturoli S (October 2011). "Retrospective, observational study on the effects and tolerability of flutamide in a large population of patients with acne and seborrhea over a 15-year period". Gynecol. Endocrinol. 27 (10): 823–9. doi:10.3109/09513590.2010.526664. PMID 21117864. Among the slight and temporary adverse events [of flutamide], most frequently reported and not requesting treatment discontinuation were headache (7.8%), respiratory tract disorders (7.0%), nausea and/or vomiting (4.0%), diarrhea (4.0%), dry skin (9.5%), and reduction of libido (4.5%).

[pmid11815724-35] Venturoli S, Paradisi R, Bagnoli A, Colombo FM, Ravaioli B, Vianello F, Mancini F, Gualerzi B, Porcu E, Seracchioli R (2001). [[...] changes in serum levels of the aminotransferases [11] or side effects (stomach pain, headache, dry skin, nausea, increased appetite, decrease of libido) are only occasionally seen [with flutamide] [10, 11]. "Low-dose flutamide (125 mg/day) as maintenance therapy in the treatment of hirsutism"]. Horm. Res. 56 (1–2): 25–31. doi:10.1159/000048086. PMID 11815724. {{cite journal}}: Check |url= value (help)

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[Paoletti2012-120] Paoletti, Rodolfo (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. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)

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@@ Line 16: / Line 16: @@
 [[File:Severe bicalutamide-induced gynecomastia.jpg|thumb|right|200px|Gynecomastia in a 60-year-old man treated with 150&nbsp;mg/day bicalutamide for prostate cancer.<ref name="pmid23050528">{{cite journal |vauthors=Michalopoulos NV, Keshtgar MR |title=Images in clinical medicine. Gynecomastia induced by prostate-cancer treatment |journal=The New England Journal of Medicine |volume=367 |issue=15 |pages=1449 |year=2012 |pmid=23050528 |doi=10.1056/NEJMicm1209166 |df=dmy-all | quote = 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.}}</ref>]]
-The most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia.<ref name="Aronson2009">{{cite book |first=Jeffrey K. |last=Aronson | name-list-format = vanc |title=Meyler's Side Effects of Endocrine and Metabolic Drugs |url=https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA150 |date=21 February 2009 |publisher=Elsevier |isbn=978-0-08-093292-7 |pages=150–152 |quote=In contrast [to flutamide and nilutamide], no specific non-pharmacological complications have been linked to bicalutamide, while diarrhea and abnormal liver function occur less often than with flutamide.}}</ref> These side effects may occur in as many as 90% of men treated with bicalutamide monotherapy,<ref name="FradetEgerdie2007">{{cite journal |vauthors=Fradet Y, Egerdie B, Andersen M, Tammela TL, Nachabe M, Armstrong J, Morris T, Navani S |title=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 |journal=European Urology |volume=52 |issue=1 |pages=106–14 |year=2007 |pmid=17270340 |doi=10.1016/j.eururo.2007.01.031}}</ref> but gynecomastia is generally reported to occur in 70 to 80% of patients.<ref name="WirthHakenberg2007">{{cite journal |vauthors=Wirth MP, Hakenberg OW, Froehner M |title=Antiandrogens in the treatment of prostate cancer |journal=European Urology |volume=51 |issue=2 |pages=306–13; discussion 314 |date=February 2007 |pmid=17007995 |doi=10.1016/j.eururo.2006.08.043}}</ref> In the {{abbr|EPC|Early Prostate Cancer}} trial, at a median follow-up of 7.4&nbsp;years, breast pain and gynecomastia respectively occurred in 73.6% and 68.8% of men treated with 150&nbsp;mg/day bicalutamide monotherapy.<ref name=Wellington2006>{{cite journal |vauthors=Wellington K, Keam SJ |title=Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer |journal=Drugs |volume=66 |issue=6 |pages=837–50 |year=2006 |pmid=16706554 |doi=10.2165/00003495-200666060-00007 |url=http://www.antialabs.com/reference/21018026.pdf |deadurl=no |archiveurl=https://web.archive.org/web/20160828024232/http://www.antialabs.com/reference/21018026.pdf |archivedate=28 August 2016 |df=dmy-all}}</ref><ref name="Anderson2003" /> Gynecomastia associated with {{abbr|NSAA|nonsteroidal antiandrogen}} monotherapy usually develops within the first 6 to 9&nbsp;months following initiation of treatment.<ref name="pmid23050528" /> In more than 90% of affected men, bicalutamide-related [[breast]] changes are mild-to-moderate in severity.<ref name="Anderson2003" /><ref name="WellingtonKeam2006">{{cite journal |vauthors=Wellington K, Keam SJ |title=Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer |journal=Drugs |volume=66 |issue=6 |pages=837–50 |year=2006 |pmid=16706554 |doi=10.2165/00003495-200666060-00007}}</ref> 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.<ref name="pmid4812899">{{cite journal |vauthors=Brown JS, Rubenfeld S |title=Irradiation in preventing gynecomastia induced by estrogens |journal=Urology |volume=3 |issue=1 |pages=51–3 |year=1974 |pmid=4812899 |doi=10.1016/s0090-4295(74)80060-9 |url= |quote=Infrequently, the breast hypertrophy can become so marked that it attains proportions comparable to that in female breasts.}}</ref> In addition, bicalutamide-associated breast changes improve or resolve in most men upon discontinuation of therapy.<ref name="Anderson2003" /> In the {{abbr|EPC|Early Prostate Cancer}} trial, 16.8% of bicalutamide patients relative to 0.7% of controls withdrew from the study due to breast pain and/or gynecomastia.<ref name="WellingtonKeam2006" /> The incidence and severity of gynecomastia are reportedly higher with estrogens (e.g., [[diethylstilbestrol]]) than with {{abbr|NSAAs|nonsteroidal antiandrogens}} like bicalutamide in the treatment of men with prostate cancer.<ref name="DeepinderBraunstein2012">{{cite journal |vauthors=Deepinder F, Braunstein GD |title=Drug-induced gynecomastia: an evidence-based review |journal=Expert Opinion on Drug Safety |volume=11 |issue=5 |pages=779–95 |year=2012 |pmid=22862307 |doi=10.1517/14740338.2012.712109 |quote=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.}}</ref>
+The most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia.<ref name="Aronson2009">{{cite book |first=Jeffrey K. |last=Aronson | name-list-format = vanc |title=Meyler's Side Effects of Endocrine and Metabolic Drugs |url=https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA150 |date=21 February 2009 |publisher=Elsevier |isbn=978-0-08-093292-7 |pages=150–152 |quote=In contrast [to flutamide and nilutamide], no specific non-pharmacological complications have been linked to bicalutamide, while diarrhea and abnormal liver function occur less often than with flutamide.}}</ref> These side effects may occur in as many as 90% of men treated with bicalutamide monotherapy,<ref name="FradetEgerdie2007">{{cite journal |vauthors=Fradet Y, Egerdie B, Andersen M, Tammela TL, Nachabe M, Armstrong J, Morris T, Navani S |title=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 |journal=European Urology |volume=52 |issue=1 |pages=106–14 |year=2007 |pmid=17270340 |doi=10.1016/j.eururo.2007.01.031}}</ref> but gynecomastia is generally reported to occur in 70 to 80% of patients.<ref name="WirthHakenberg2007">{{cite journal |vauthors=Wirth MP, Hakenberg OW, Froehner M |title=Antiandrogens in the treatment of prostate cancer |journal=European Urology |volume=51 |issue=2 |pages=306–13; discussion 314 |date=February 2007 |pmid=17007995 |doi=10.1016/j.eururo.2006.08.043}}</ref> In the {{abbr|EPC|Early Prostate Cancer}} trial, at a median follow-up of 7.4&nbsp;years, breast pain and gynecomastia respectively occurred in 73.6% and 68.8% of men treated with 150&nbsp;mg/day bicalutamide monotherapy.<ref name=Wellington2006>{{cite journal |vauthors=Wellington K, Keam SJ |title=Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer |journal=Drugs |volume=66 |issue=6 |pages=837–50 |year=2006 |pmid=16706554 |doi=10.2165/00003495-200666060-00007 |url=http://www.antialabs.com/reference/21018026.pdf |url-status=live |archiveurl=https://web.archive.org/web/20160828024232/http://www.antialabs.com/reference/21018026.pdf |archivedate=28 August 2016 |df=dmy-all}}</ref><ref name="Anderson2003" /> Gynecomastia associated with {{abbr|NSAA|nonsteroidal antiandrogen}} monotherapy usually develops within the first 6 to 9&nbsp;months following initiation of treatment.<ref name="pmid23050528" /> In more than 90% of affected men, bicalutamide-related [[breast]] changes are mild-to-moderate in severity.<ref name="Anderson2003" /><ref name="WellingtonKeam2006">{{cite journal |vauthors=Wellington K, Keam SJ |title=Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer |journal=Drugs |volume=66 |issue=6 |pages=837–50 |year=2006 |pmid=16706554 |doi=10.2165/00003495-200666060-00007}}</ref> 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.<ref name="pmid4812899">{{cite journal |vauthors=Brown JS, Rubenfeld S |title=Irradiation in preventing gynecomastia induced by estrogens |journal=Urology |volume=3 |issue=1 |pages=51–3 |year=1974 |pmid=4812899 |doi=10.1016/s0090-4295(74)80060-9 |url= |quote=Infrequently, the breast hypertrophy can become so marked that it attains proportions comparable to that in female breasts.}}</ref> In addition, bicalutamide-associated breast changes improve or resolve in most men upon discontinuation of therapy.<ref name="Anderson2003" /> In the {{abbr|EPC|Early Prostate Cancer}} trial, 16.8% of bicalutamide patients relative to 0.7% of controls withdrew from the study due to breast pain and/or gynecomastia.<ref name="WellingtonKeam2006" /> The incidence and severity of gynecomastia are reportedly higher with estrogens (e.g., [[diethylstilbestrol]]) than with {{abbr|NSAAs|nonsteroidal antiandrogens}} like bicalutamide in the treatment of men with prostate cancer.<ref name="DeepinderBraunstein2012">{{cite journal |vauthors=Deepinder F, Braunstein GD |title=Drug-induced gynecomastia: an evidence-based review |journal=Expert Opinion on Drug Safety |volume=11 |issue=5 |pages=779–95 |year=2012 |pmid=22862307 |doi=10.1517/14740338.2012.712109 |quote=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.}}</ref>
 ===Management===
@@ Line 31: / Line 31: @@
 ==Reproductive changes==
-Bicalutamide reduces the size of the prostate gland and [[seminal vesicles]],<ref name="FurrTucker1996">{{cite journal |vauthors=Furr BJ, Tucker H |title=The preclinical development of bicalutamide: pharmacodynamics and mechanism of action |journal=Urology |volume=47 |issue=1A Suppl |pages=13–25; discussion 29–32 |date=January 1996 |pmid=8560673 |doi=10.1016/S0090-4295(96)80003-3}}</ref> though not of the [[testes]].<ref name="MorganteGradini2001">{{cite journal |vauthors=Morgante E, Gradini R, Realacci M, Sale P, D'Eramo G, Perrone GA, Cardillo MR, Petrangeli E, Russo M, Di Silverio F |title=Effects of long-term treatment with the anti-androgen bicalutamide on human testis: an ultrastructural and morphometric study |journal=Histopathology |volume=38 |issue=3 |pages=195–201 |date=March 2001 |pmid=11260298 |doi=10.1046/j.1365-2559.2001.01077.x}}</ref> Significantly reduced penile length is also a recognized adverse effect of {{abbr|ADT|androgen deprivation therapy}}.<ref name="pmid23008326">{{cite journal |vauthors=Higano CS |title=Sexuality and intimacy after definitive treatment and subsequent androgen deprivation therapy for prostate cancer |journal=Journal of Clinical Oncology |volume=30 |issue=30 |pages=3720–5 |year=2012 |pmid=23008326 |doi=10.1200/JCO.2012.41.8509 |url=}}</ref><ref name="NguyenAlibhai2015">{{cite journal |vauthors=Nguyen PL, Alibhai SM, Basaria S, D'Amico AV, Kantoff PW, Keating NL, Penson DF, Rosario DJ, Tombal B, Smith MR |title=Adverse effects of androgen deprivation therapy and strategies to mitigate them |journal=European Urology |volume=67 |issue=5 |pages=825–36 |date=May 2015 |pmid=25097095 |doi=10.1016/j.eururo.2014.07.010|url=http://www.europeanurology.com/article/S0302283814006502/pdf }}</ref> Reversible [[hypospermia]] or [[aspermia]] (that is, reduced or absent [[semen]]/[[ejaculate]] production) may occur.<ref name="MazzolaMulhall2012">{{cite journal |vauthors=Mazzola CR, Mulhall JP |title=Impact of androgen deprivation therapy on sexual function |journal=Asian Journal of Andrology |volume=14 |issue=2 |pages=198–203 |date=March 2012 |pmid=22231298 |pmc=3735098 |doi=10.1038/aja.2011.106}}</ref><ref name="Mulcahy2001">{{cite book |first=John J. |last=Mulcahy | name-list-format = vanc |title=Male Sexual Function |url=https://books.google.com/books?id=j1lDBAAAQBAJ&pg=RA3-PA49 |date=1 January 2001 |publisher=Springer Science & Business Media |isbn=978-1-59259-098-8 |pages=3– |deadurl=no |archiveurl=https://web.archive.org/web/20160520025701/https://books.google.com/books?id=j1lDBAAAQBAJ&pg=RA3-PA49 |archivedate=20 May 2016 |df=dmy-all}}</ref> However, bicalutamide does not appear to adversely affect [[spermatogenesis]], and thus may not necessarily abolish the capacity/potential for [[fertility]] in men.<ref name="MorganteGradini2001" /><ref name="pmid8009196">{{cite journal | vauthors = Bjerklund Johansen TE, Majak M, Nesland JM | title = Testicular histology after treatment with the new antiandrogen Casodex for carcinoma of the prostate. A preliminary report | journal = Scand. J. Urol. Nephrol. | volume = 28 | issue = 1 | pages = 67–70 | date = March 1994 | pmid = 8009196 | doi = 10.3109/00365599409180473 | url = }}</ref> Due to the induction of chronic overproduction of {{abbr|LH|luteinizing hormone}} and testosterone, there was concern that long-term bicalutamide monotherapy might induce [[Leydig cell hyperplasia]] and [[Leydig cell tumour|tumors]] (usually benign),<ref name="ScialliClegg1992">{{cite book |first1=Anthony R. |last1=Scialli |first2=Eric D. |last2=Clegg | name-list-format = vanc |title=Reversibility in Testicular Toxicity Assessment |url=https://books.google.com/books?id=ZDtMkgPlAhsC&pg=PA107 |date=9 June 1992 |publisher=CRC Press |isbn=978-0-8493-5980-4 |pages=107–}}</ref> but clinical studies indicate that Leydig cell hyperplasia does not occur to a clinically important extent.<ref name="Kolvenbag1996">{{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|quote=Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.}}</ref><ref name="pmid8009196" /><ref name="pmid7992465">{{cite journal | vauthors = Jones HB, Betton GR, Bowdler AL, McFarquhar RL, Middleton BJ, Lunglmayr G | title = 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 | journal = Urol. Res. | volume = 22 | issue = 3 | pages = 191–5 | date = 1994 | pmid = 7992465 | doi = 10.1007/BF00571849 | url = }}</ref>
+Bicalutamide reduces the size of the prostate gland and [[seminal vesicles]],<ref name="FurrTucker1996">{{cite journal |vauthors=Furr BJ, Tucker H |title=The preclinical development of bicalutamide: pharmacodynamics and mechanism of action |journal=Urology |volume=47 |issue=1A Suppl |pages=13–25; discussion 29–32 |date=January 1996 |pmid=8560673 |doi=10.1016/S0090-4295(96)80003-3}}</ref> though not of the [[testes]].<ref name="MorganteGradini2001">{{cite journal |vauthors=Morgante E, Gradini R, Realacci M, Sale P, D'Eramo G, Perrone GA, Cardillo MR, Petrangeli E, Russo M, Di Silverio F |title=Effects of long-term treatment with the anti-androgen bicalutamide on human testis: an ultrastructural and morphometric study |journal=Histopathology |volume=38 |issue=3 |pages=195–201 |date=March 2001 |pmid=11260298 |doi=10.1046/j.1365-2559.2001.01077.x}}</ref> Significantly reduced penile length is also a recognized adverse effect of {{abbr|ADT|androgen deprivation therapy}}.<ref name="pmid23008326">{{cite journal |vauthors=Higano CS |title=Sexuality and intimacy after definitive treatment and subsequent androgen deprivation therapy for prostate cancer |journal=Journal of Clinical Oncology |volume=30 |issue=30 |pages=3720–5 |year=2012 |pmid=23008326 |doi=10.1200/JCO.2012.41.8509 |url=}}</ref><ref name="NguyenAlibhai2015">{{cite journal |vauthors=Nguyen PL, Alibhai SM, Basaria S, D'Amico AV, Kantoff PW, Keating NL, Penson DF, Rosario DJ, Tombal B, Smith MR |title=Adverse effects of androgen deprivation therapy and strategies to mitigate them |journal=European Urology |volume=67 |issue=5 |pages=825–36 |date=May 2015 |pmid=25097095 |doi=10.1016/j.eururo.2014.07.010|url=http://www.europeanurology.com/article/S0302283814006502/pdf }}</ref> Reversible [[hypospermia]] or [[aspermia]] (that is, reduced or absent [[semen]]/[[ejaculate]] production) may occur.<ref name="MazzolaMulhall2012">{{cite journal |vauthors=Mazzola CR, Mulhall JP |title=Impact of androgen deprivation therapy on sexual function |journal=Asian Journal of Andrology |volume=14 |issue=2 |pages=198–203 |date=March 2012 |pmid=22231298 |pmc=3735098 |doi=10.1038/aja.2011.106}}</ref><ref name="Mulcahy2001">{{cite book |first=John J. |last=Mulcahy | name-list-format = vanc |title=Male Sexual Function |url=https://books.google.com/books?id=j1lDBAAAQBAJ&pg=RA3-PA49 |date=1 January 2001 |publisher=Springer Science & Business Media |isbn=978-1-59259-098-8 |pages=3– |url-status=live |archiveurl=https://web.archive.org/web/20160520025701/https://books.google.com/books?id=j1lDBAAAQBAJ&pg=RA3-PA49 |archivedate=20 May 2016 |df=dmy-all}}</ref> However, bicalutamide does not appear to adversely affect [[spermatogenesis]], and thus may not necessarily abolish the capacity/potential for [[fertility]] in men.<ref name="MorganteGradini2001" /><ref name="pmid8009196">{{cite journal | vauthors = Bjerklund Johansen TE, Majak M, Nesland JM | title = Testicular histology after treatment with the new antiandrogen Casodex for carcinoma of the prostate. A preliminary report | journal = Scand. J. Urol. Nephrol. | volume = 28 | issue = 1 | pages = 67–70 | date = March 1994 | pmid = 8009196 | doi = 10.3109/00365599409180473 | url = }}</ref> Due to the induction of chronic overproduction of {{abbr|LH|luteinizing hormone}} and testosterone, there was concern that long-term bicalutamide monotherapy might induce [[Leydig cell hyperplasia]] and [[Leydig cell tumour|tumors]] (usually benign),<ref name="ScialliClegg1992">{{cite book |first1=Anthony R. |last1=Scialli |first2=Eric D. |last2=Clegg | name-list-format = vanc |title=Reversibility in Testicular Toxicity Assessment |url=https://books.google.com/books?id=ZDtMkgPlAhsC&pg=PA107 |date=9 June 1992 |publisher=CRC Press |isbn=978-0-8493-5980-4 |pages=107–}}</ref> but clinical studies indicate that Leydig cell hyperplasia does not occur to a clinically important extent.<ref name="Kolvenbag1996">{{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|quote=Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.}}</ref><ref name="pmid8009196" /><ref name="pmid7992465">{{cite journal | vauthors = Jones HB, Betton GR, Bowdler AL, McFarquhar RL, Middleton BJ, Lunglmayr G | title = 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 | journal = Urol. Res. | volume = 22 | issue = 3 | pages = 191–5 | date = 1994 | pmid = 7992465 | doi = 10.1007/BF00571849 | url = }}</ref>
 ==Gastrointestinal==
@@ Line 49: / Line 49: @@
 ==With castration==
-Combination of bicalutamide with medical (i.e., a {{abbr|GnRH|gonadotropin-releasing hormone}} 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 {{abbr|GnRH|gonadotropin-releasing hormone}} analogue,<ref name="DrozAudisio2012">{{cite book |first1=Jean-Pierre |last1=Droz |first2=Riccardo A. |last2=Audisio |name-list-format=vanc |title=Management of Urological Cancers in Older People |url=https://books.google.com/books?id=-P2wi-xVk_gC&pg=PA84 |date=2 October 2012 |publisher=Springer Science & Business Media |isbn=978-0-85729-986-4 |pages=84– |deadurl=no |archiveurl=https://web.archive.org/web/20160511211354/https://books.google.com/books?id=-P2wi-xVk_gC&pg=PA84 |archivedate=11 May 2016 |df=dmy-all}}</ref> while certain other side effects, including hot flashes, depression, fatigue, and sexual dysfunction,<ref name="pmid16896883">{{cite journal |vauthors=Mason M |title=What implications do the tolerability profiles of antiandrogens and other commonly used prostate cancer treatments have on patient care? |journal=Journal of Cancer Research and Clinical Oncology |volume=132 Suppl 1 |issue= |pages=S27-35 |date=August 2006 |pmid=16896883 |doi=10.1007/s00432-006-0134-4}}</ref> occur much more frequently in combination with a {{abbr|GnRH|gonadotropin-releasing hormone}} analogue.<ref name="IversenMelezinek2001">{{cite journal |vauthors=Iversen P, Melezinek I, Schmidt A |title=Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function |journal=BJU International |volume=87 |issue=1 |pages=47–56 |date=January 2001 |pmid=11121992 |doi=10.1046/j.1464-410x.2001.00988.x}}</ref><ref name="CherHonn2006">{{cite book |first1=Michael L. |last1=Cher |first2=Kenneth V. |last2=Honn |first3=Avraham |last3=Raz |name-list-format=vanc |title=Prostate Cancer: New Horizons in Research and Treatment |url=https://books.google.com/books?id=AGYKBwAAQBAJ&pg=PA382 |date=11 April 2006 |publisher=Springer Science & Business Media |isbn=978-0-306-48143-7 |pages=382– |deadurl=no |archiveurl=https://web.archive.org/web/20160505105536/https://books.google.com/books?id=AGYKBwAAQBAJ&pg=PA382 |archivedate=5 May 2016 |df=dmy-all}}</ref><ref name="FeldmanMarcus2007">{{cite book |first1=David |last1=Feldman |first2=Robert |last2=Marcus |first3=Dorothy |last3=Nelson |first4=Clifford J. |last4=Rosen |name-list-format=vanc |title=Osteoporosis |url=https://books.google.com/books?id=blFlkDHffW8C&pg=PA1354 |date=8 November 2007 |publisher=Academic Press |isbn=978-0-08-055347-4 |pages=1354– |deadurl=no |archiveurl=https://web.archive.org/web/20160611031603/https://books.google.com/books?id=blFlkDHffW8C&pg=PA1354 |archivedate=11 June 2016 |df=dmy-all}}</ref> It is thought that this is due to the suppression of estrogen levels (in addition to androgen levels) by {{abbr|GnRH|gonadotropin-releasing hormone}} analogues, as estrogens may compensate for various negative central effects of androgen deprivation.<ref name="IversenMelezinek2001" /> If bicalutamide is combined with a {{abbr|GnRH|gonadotropin-releasing hormone}} 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.<ref name="DrozAudisio2012" /> However, due to the loss of estrogen, bone loss will accelerate and the risk of osteoporosis developing with long-term therapy will increase.<ref name="pmid18438173">{{cite journal |vauthors=Vanderschueren D, Gaytant J, Boonen S, Venken K |title=Androgens and bone |journal=Current Opinion in Endocrinology, Diabetes and Obesity |volume=15 |issue=3 |pages=250–4 |date=June 2008 |pmid=18438173 |doi=10.1097/MED.0b013e3282fe6ca9}}</ref>
+Combination of bicalutamide with medical (i.e., a {{abbr|GnRH|gonadotropin-releasing hormone}} 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 {{abbr|GnRH|gonadotropin-releasing hormone}} analogue,<ref name="DrozAudisio2012">{{cite book |first1=Jean-Pierre |last1=Droz |first2=Riccardo A. |last2=Audisio |name-list-format=vanc |title=Management of Urological Cancers in Older People |url=https://books.google.com/books?id=-P2wi-xVk_gC&pg=PA84 |date=2 October 2012 |publisher=Springer Science & Business Media |isbn=978-0-85729-986-4 |pages=84– |url-status=live |archiveurl=https://web.archive.org/web/20160511211354/https://books.google.com/books?id=-P2wi-xVk_gC&pg=PA84 |archivedate=11 May 2016 |df=dmy-all}}</ref> while certain other side effects, including hot flashes, depression, fatigue, and sexual dysfunction,<ref name="pmid16896883">{{cite journal |vauthors=Mason M |title=What implications do the tolerability profiles of antiandrogens and other commonly used prostate cancer treatments have on patient care? |journal=Journal of Cancer Research and Clinical Oncology |volume=132 Suppl 1 |issue= |pages=S27-35 |date=August 2006 |pmid=16896883 |doi=10.1007/s00432-006-0134-4}}</ref> occur much more frequently in combination with a {{abbr|GnRH|gonadotropin-releasing hormone}} analogue.<ref name="IversenMelezinek2001">{{cite journal |vauthors=Iversen P, Melezinek I, Schmidt A |title=Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function |journal=BJU International |volume=87 |issue=1 |pages=47–56 |date=January 2001 |pmid=11121992 |doi=10.1046/j.1464-410x.2001.00988.x}}</ref><ref name="CherHonn2006">{{cite book |first1=Michael L. |last1=Cher |first2=Kenneth V. |last2=Honn |first3=Avraham |last3=Raz |name-list-format=vanc |title=Prostate Cancer: New Horizons in Research and Treatment |url=https://books.google.com/books?id=AGYKBwAAQBAJ&pg=PA382 |date=11 April 2006 |publisher=Springer Science & Business Media |isbn=978-0-306-48143-7 |pages=382– |url-status=live |archiveurl=https://web.archive.org/web/20160505105536/https://books.google.com/books?id=AGYKBwAAQBAJ&pg=PA382 |archivedate=5 May 2016 |df=dmy-all}}</ref><ref name="FeldmanMarcus2007">{{cite book |first1=David |last1=Feldman |first2=Robert |last2=Marcus |first3=Dorothy |last3=Nelson |first4=Clifford J. |last4=Rosen |name-list-format=vanc |title=Osteoporosis |url=https://books.google.com/books?id=blFlkDHffW8C&pg=PA1354 |date=8 November 2007 |publisher=Academic Press |isbn=978-0-08-055347-4 |pages=1354– |url-status=live |archiveurl=https://web.archive.org/web/20160611031603/https://books.google.com/books?id=blFlkDHffW8C&pg=PA1354 |archivedate=11 June 2016 |df=dmy-all}}</ref> It is thought that this is due to the suppression of estrogen levels (in addition to androgen levels) by {{abbr|GnRH|gonadotropin-releasing hormone}} analogues, as estrogens may compensate for various negative central effects of androgen deprivation.<ref name="IversenMelezinek2001" /> If bicalutamide is combined with a {{abbr|GnRH|gonadotropin-releasing hormone}} 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.<ref name="DrozAudisio2012" /> However, due to the loss of estrogen, bone loss will accelerate and the risk of osteoporosis developing with long-term therapy will increase.<ref name="pmid18438173">{{cite journal |vauthors=Vanderschueren D, Gaytant J, Boonen S, Venken K |title=Androgens and bone |journal=Current Opinion in Endocrinology, Diabetes and Obesity |volume=15 |issue=3 |pages=250–4 |date=June 2008 |pmid=18438173 |doi=10.1097/MED.0b013e3282fe6ca9}}</ref>
 ==Increased mortality==
@@ Line 70: / Line 70: @@
 ==Liver toxicity==
-Bicalutamide may cause liver changes rarely, such as [[elevated transaminases]] and jaundice.<ref name="pmid24967002" /> In the {{abbr|EPC|Early Prostate Cancer}} study of 4,052 prostate cancer patients who received 150&nbsp;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.<ref name="Wellington2006" /><ref name="SeeWirth2002">{{cite journal |vauthors=See WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, Chodak G, Montie J, Tyrrell C, Wallace DM, Delaere KP, Vaage S, Tammela TL, Lukkarinen O, Persson BE, Carroll K, Kolvenbag GJ | display-authors = 6 |title=Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program |journal=The Journal of Urology |volume=168 |issue=2 |pages=429–35 |date=August 2002 |pmid=12131282 |doi=10.1016/S0022-5347(05)64652-6}}</ref> For comparison, the incidences of abnormal liver function tests are 42 to 62% for flutamide, 2 to 3% for nilutamide,<ref name="pmid24967002" /><ref name="CRAIGFurr2010" /> and (dose-dependently) between 10% and 28% for {{abbr|CPA|cyproterone acetate}},<ref name="Kaplowitz2002">{{cite book |first=Neil |last=Kaplowitz | name-list-format = vanc |title=Drug-Induced Liver Disease |url=https://books.google.com/books?id=d8cgCAAAQBAJ&pg=PA618 |date=16 October 2002 |publisher=CRC Press |isbn=978-0-203-90912-6 |pages=618–}}</ref><ref name="KimYoo2014">{{cite journal |vauthors=Kim JH, Yoo BW, Yang WJ |title=Hepatic failure induced by cyproterone acetate: A case report and literature review |journal=Canadian Urological Association Journal |volume=8 |issue=5–6 |pages=E458-61 |date=May 2014 |pmid=25024808 |pmc=4081269 |doi=10.5489/cuaj.1753}}</ref><ref name="Savidou2006">{{cite journal |vauthors=Savidou I, Deutsch M, Soultati AS, Koudouras D, Kafiri G, Dourakis SP |title=Hepatotoxicity induced by cyproterone acetate: a report of three cases |journal=World Journal of Gastroenterology |volume=12 |issue=46 |pages=7551–5 |date=December 2006 |pmid=17167851 |pmc=4087608 |doi=10.3748/wjg.v12.i46.7551}}</ref> whereas there appears to be no risk with enzalutamide.<ref name="Keating2015">{{cite journal |vauthors=Keating GM |title=Enzalutamide: a review of its use in chemotherapy-naïve metastatic castration-resistant prostate cancer |journal=Drugs & Aging |volume=32 |issue=3 |pages=243–9 |date=March 2015 |pmid=25711765 |doi=10.1007/s40266-015-0248-y}}</ref><ref name="BeerArmstrong2014">{{cite journal |vauthors=Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B |title=Enzalutamide in metastatic prostate cancer before chemotherapy |journal=The New England Journal of Medicine |volume=371 |issue=5 |pages=424–33 |date=July 2014 |pmid=24881730 |pmc=4418931 |doi=10.1056/NEJMoa1405095}}</ref> In the {{abbr|EPC|Early Prostate Cancer}} trial, bicalutamide-induced liver changes were usually transient and rarely severe.<ref name="Wellington2006" /> 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.<ref name=FDALabel>{{cite web |title=Casodex® (bicalutamide) Tablets |publisher=FDA |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020498s016lbl.pdf |deadurl=no |archiveurl=https://web.archive.org/web/20170227211300/http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020498s016lbl.pdf |archivedate=27 February 2017 |df=dmy-all}}</ref><ref name="MahlerVerhelst1998">{{cite journal |vauthors=Mahler C, Verhelst J, Denis L |title=Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer |journal=Clinical Pharmacokinetics |volume=34 |issue=5 |pages=405–17 |date=May 1998 |pmid=9592622 |doi=10.2165/00003088-199834050-00005}}</ref>
+Bicalutamide may cause liver changes rarely, such as [[elevated transaminases]] and jaundice.<ref name="pmid24967002" /> In the {{abbr|EPC|Early Prostate Cancer}} study of 4,052 prostate cancer patients who received 150&nbsp;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.<ref name="Wellington2006" /><ref name="SeeWirth2002">{{cite journal |vauthors=See WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, Chodak G, Montie J, Tyrrell C, Wallace DM, Delaere KP, Vaage S, Tammela TL, Lukkarinen O, Persson BE, Carroll K, Kolvenbag GJ | display-authors = 6 |title=Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program |journal=The Journal of Urology |volume=168 |issue=2 |pages=429–35 |date=August 2002 |pmid=12131282 |doi=10.1016/S0022-5347(05)64652-6}}</ref> For comparison, the incidences of abnormal liver function tests are 42 to 62% for flutamide, 2 to 3% for nilutamide,<ref name="pmid24967002" /><ref name="CRAIGFurr2010" /> and (dose-dependently) between 10% and 28% for {{abbr|CPA|cyproterone acetate}},<ref name="Kaplowitz2002">{{cite book |first=Neil |last=Kaplowitz | name-list-format = vanc |title=Drug-Induced Liver Disease |url=https://books.google.com/books?id=d8cgCAAAQBAJ&pg=PA618 |date=16 October 2002 |publisher=CRC Press |isbn=978-0-203-90912-6 |pages=618–}}</ref><ref name="KimYoo2014">{{cite journal |vauthors=Kim JH, Yoo BW, Yang WJ |title=Hepatic failure induced by cyproterone acetate: A case report and literature review |journal=Canadian Urological Association Journal |volume=8 |issue=5–6 |pages=E458-61 |date=May 2014 |pmid=25024808 |pmc=4081269 |doi=10.5489/cuaj.1753}}</ref><ref name="Savidou2006">{{cite journal |vauthors=Savidou I, Deutsch M, Soultati AS, Koudouras D, Kafiri G, Dourakis SP |title=Hepatotoxicity induced by cyproterone acetate: a report of three cases |journal=World Journal of Gastroenterology |volume=12 |issue=46 |pages=7551–5 |date=December 2006 |pmid=17167851 |pmc=4087608 |doi=10.3748/wjg.v12.i46.7551}}</ref> whereas there appears to be no risk with enzalutamide.<ref name="Keating2015">{{cite journal |vauthors=Keating GM |title=Enzalutamide: a review of its use in chemotherapy-naïve metastatic castration-resistant prostate cancer |journal=Drugs & Aging |volume=32 |issue=3 |pages=243–9 |date=March 2015 |pmid=25711765 |doi=10.1007/s40266-015-0248-y}}</ref><ref name="BeerArmstrong2014">{{cite journal |vauthors=Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B |title=Enzalutamide in metastatic prostate cancer before chemotherapy |journal=The New England Journal of Medicine |volume=371 |issue=5 |pages=424–33 |date=July 2014 |pmid=24881730 |pmc=4418931 |doi=10.1056/NEJMoa1405095}}</ref> In the {{abbr|EPC|Early Prostate Cancer}} trial, bicalutamide-induced liver changes were usually transient and rarely severe.<ref name="Wellington2006" /> 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.<ref name=FDALabel>{{cite web |title=Casodex® (bicalutamide) Tablets |publisher=FDA |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020498s016lbl.pdf |url-status=live |archiveurl=https://web.archive.org/web/20170227211300/http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020498s016lbl.pdf |archivedate=27 February 2017 |df=dmy-all}}</ref><ref name="MahlerVerhelst1998">{{cite journal |vauthors=Mahler C, Verhelst J, Denis L |title=Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer |journal=Clinical Pharmacokinetics |volume=34 |issue=5 |pages=405–17 |date=May 1998 |pmid=9592622 |doi=10.2165/00003088-199834050-00005}}</ref>
 The risk of liver changes with bicalutamide is considered to be small but significant, and monitoring of liver function is recommended.<ref name="Wellington2006" /><ref name="Lehne2013">{{cite book |first=Richard A. |last=Lehne | name-list-format = vanc |title=Pharmacology for Nursing Care |url=https://books.google.com/books?id=_4SwO2dHcAIC&pg=PA1297 |year=2013 |publisher=Elsevier Health Sciences |isbn=978-1-4377-3582-6 |pages=1297–}}</ref> Elevation of [[transaminase]]s above twice the normal range or jaundice may be an indication that bicalutamide should be discontinued.<ref name="Tripathi2013">{{cite book |first=KD |last=Tripathi | name-list-format = vanc |title=Essentials of Medical Pharmacology |url=https://books.google.com/books?id=FfG8AQAAQBAJ&pg=PA302 |date=30 September 2013 |publisher=JP Medical Ltd |isbn=978-93-5025-937-5 |pages=302–}}</ref> Liver changes with bicalutamide usually occur within the first 3 or 4&nbsp;months of treatment, and it is recommended that liver function be monitored regularly for the first 4&nbsp;months of treatment and periodically thereafter.<ref name="FDALabel" /> Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice.<ref name="FDALabel" />
-A total of 7&nbsp;case reports of bicalutamide-associated hepatotoxicity or liver failure, two of which were fatal, have been published in the literature as of 2018.<ref name="GretarsdottirBjornsdottir2018">{{cite journal | last1 = Gretarsdottir | first1 = Helga M. | last2 = Bjornsdottir | first2 = Elin | last3 = Bjornsson | first3 = Einar S. | title = Bicalutamide-Associated Acute Liver Injury and Migratory Arthralgia: A Rare but Clinically Important Adverse Effect | journal = Case Reports in Gastroenterology | volume = 12 | issue = 2 | year = 2018 | pages = 266–270 | issn = 1662-0631 | doi = 10.1159/000485175}}</ref><ref name="pmid24967002">{{cite journal | vauthors = Hussain S, Haidar A, Bloom RE, Zayouna N, Piper MH, Jafri SM | title = Bicalutamide-induced hepatotoxicity: A rare adverse effect | journal = Am J Case Rep | volume = 15 | issue = | pages = 266–70 | date = 2014 | pmid = 24967002 | pmc = 4068966 | doi = 10.12659/AJCR.890679 | url = }}</ref><ref name="pmid27099451">{{cite journal | vauthors = Yun GY, Kim SH, Kim SW, Joo JS, Kim JS, Lee ES, Lee BS, Kang SH, Moon HS, Sung JK, Lee HY, Kim KH | title = Atypical onset of bicalutamide-induced liver injury | journal = World J. Gastroenterol. | volume = 22 | issue = 15 | pages = 4062–5 | date = April 2016 | pmid = 27099451 | pmc = 4823258 | doi = 10.3748/wjg.v22.i15.4062 | url = }}</ref> 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 {{abbr|CPA|cyproterone acetate}}.<ref name="pmid24967002" /><ref name="CRAIGFurr2010">{{cite book |first1=Jordon V. |last1=Craig |first2=B.J.A. |last2=Furr | name-list-format = vanc |title=Hormone Therapy in Breast and Prostate Cancer |url=https://books.google.com/books?id=dM0uvBnxiN0C&pg=PA356 |date=5 February 2010 |publisher=Springer Science & Business Media |isbn=978-1-59259-152-7 |pages=356– |quote=A case of near-fatal fulminant hepatic failure in a patient on bicalutamide therapy (50 mg) has recently been published (101), but it is uncertain whether this can be attributed to bicalutamide, as the symptoms developed after only two doses in a patient previously exposed to both cyproterone acetate and flutamide (101).}}</ref><ref name="DansetteSnyder2012" /><ref name="pmid9372905">{{cite journal | vauthors = Schellhammer PF | title = Fulminant hepatic failure associated with bicalutamide | journal = Urology | volume = 50 | issue = 5 | pages = 827 | date = November 1997 | pmid = 9372905 | doi = 10.1016/S0090-4295(97)80116-1 | url = }}</ref><ref name="pmid18657023">{{cite journal | vauthors = O'Bryant CL, Flaig TW, Utz KJ | title = Bicalutamide-associated fulminant hepatotoxicity | journal = Pharmacotherapy | volume = 28 | issue = 8 | pages = 1071–5 | date = August 2008 | pmid = 18657023 | doi = 10.1592/phco.28.8.1071 | url = }}</ref> In the reported cases of bicalutamide-associated hepatotoxicity, the dosages of the drug were 50&nbsp;mg/day (three), 80&nbsp;mg/day (one), 100&nbsp;mg/day (one), and 150&nbsp;mg/day (two).<ref name="GretarsdottirBjornsdottir2018" /><ref name="pmid27099451" /> 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.<ref name="JordanFurr2010">{{cite book |first1=Virgil Craig |last1=Jordan |first2=B. J. A. |last2=Furr |name-list-format=vanc |title=Hormone Therapy in Breast and Prostate Cancer |url=https://books.google.com/books?id=dM0uvBnxiN0C&pg=PA350 |date=5 February 2010 |publisher=Springer Science & Business Media |isbn=978-1-59259-152-7 |pages=350– |deadurl=no |archiveurl=https://web.archive.org/web/20160529061703/https://books.google.com/books?id=dM0uvBnxiN0C&pg=PA350 |archivedate=29 May 2016 |df=dmy-all}}</ref><ref name="DansetteSnyder2012" /><ref name="RamonDenis2007">{{cite book |first1=J. |last1=Ramon |first2=L.J. |last2=Denis |name-list-format=vanc |title=Prostate Cancer |url=https://books.google.com/books?id=Bg6ZbqhhboUC&pg=PA256 |date=5 June 2007 |publisher=Springer Science & Business Media |isbn=978-3-540-40901-4 |pages=256– |deadurl=no |archiveurl=https://web.archive.org/web/20160427075934/https://books.google.com/books?id=Bg6ZbqhhboUC&pg=PA256 |archivedate=27 April 2016 |df=dmy-all}}</ref> For comparison, by 1996, 46&nbsp;cases of severe [[cholestasis|cholestatic]] hepatitis associated with flutamide had been reported, with 20 of the cases resulting in death.<ref name="Kaplowitz2002" /> Moreover, a 2002 review reported that there were 18&nbsp;reports of hepatotoxicity associated with {{abbr|CPA|cyproterone acetate}} 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 {{abbr|CPA|cyproterone acetate}}, 33 of which resulted in death.<ref name="Kaplowitz2002" />
+A total of 7&nbsp;case reports of bicalutamide-associated hepatotoxicity or liver failure, two of which were fatal, have been published in the literature as of 2018.<ref name="GretarsdottirBjornsdottir2018">{{cite journal | last1 = Gretarsdottir | first1 = Helga M. | last2 = Bjornsdottir | first2 = Elin | last3 = Bjornsson | first3 = Einar S. | title = Bicalutamide-Associated Acute Liver Injury and Migratory Arthralgia: A Rare but Clinically Important Adverse Effect | journal = Case Reports in Gastroenterology | volume = 12 | issue = 2 | year = 2018 | pages = 266–270 | issn = 1662-0631 | doi = 10.1159/000485175}}</ref><ref name="pmid24967002">{{cite journal | vauthors = Hussain S, Haidar A, Bloom RE, Zayouna N, Piper MH, Jafri SM | title = Bicalutamide-induced hepatotoxicity: A rare adverse effect | journal = Am J Case Rep | volume = 15 | issue = | pages = 266–70 | date = 2014 | pmid = 24967002 | pmc = 4068966 | doi = 10.12659/AJCR.890679 | url = }}</ref><ref name="pmid27099451">{{cite journal | vauthors = Yun GY, Kim SH, Kim SW, Joo JS, Kim JS, Lee ES, Lee BS, Kang SH, Moon HS, Sung JK, Lee HY, Kim KH | title = Atypical onset of bicalutamide-induced liver injury | journal = World J. Gastroenterol. | volume = 22 | issue = 15 | pages = 4062–5 | date = April 2016 | pmid = 27099451 | pmc = 4823258 | doi = 10.3748/wjg.v22.i15.4062 | url = }}</ref> 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 {{abbr|CPA|cyproterone acetate}}.<ref name="pmid24967002" /><ref name="CRAIGFurr2010">{{cite book |first1=Jordon V. |last1=Craig |first2=B.J.A. |last2=Furr | name-list-format = vanc |title=Hormone Therapy in Breast and Prostate Cancer |url=https://books.google.com/books?id=dM0uvBnxiN0C&pg=PA356 |date=5 February 2010 |publisher=Springer Science & Business Media |isbn=978-1-59259-152-7 |pages=356– |quote=A case of near-fatal fulminant hepatic failure in a patient on bicalutamide therapy (50 mg) has recently been published (101), but it is uncertain whether this can be attributed to bicalutamide, as the symptoms developed after only two doses in a patient previously exposed to both cyproterone acetate and flutamide (101).}}</ref><ref name="DansetteSnyder2012" /><ref name="pmid9372905">{{cite journal | vauthors = Schellhammer PF | title = Fulminant hepatic failure associated with bicalutamide | journal = Urology | volume = 50 | issue = 5 | pages = 827 | date = November 1997 | pmid = 9372905 | doi = 10.1016/S0090-4295(97)80116-1 | url = }}</ref><ref name="pmid18657023">{{cite journal | vauthors = O'Bryant CL, Flaig TW, Utz KJ | title = Bicalutamide-associated fulminant hepatotoxicity | journal = Pharmacotherapy | volume = 28 | issue = 8 | pages = 1071–5 | date = August 2008 | pmid = 18657023 | doi = 10.1592/phco.28.8.1071 | url = }}</ref> In the reported cases of bicalutamide-associated hepatotoxicity, the dosages of the drug were 50&nbsp;mg/day (three), 80&nbsp;mg/day (one), 100&nbsp;mg/day (one), and 150&nbsp;mg/day (two).<ref name="GretarsdottirBjornsdottir2018" /><ref name="pmid27099451" /> 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.<ref name="JordanFurr2010">{{cite book |first1=Virgil Craig |last1=Jordan |first2=B. J. A. |last2=Furr |name-list-format=vanc |title=Hormone Therapy in Breast and Prostate Cancer |url=https://books.google.com/books?id=dM0uvBnxiN0C&pg=PA350 |date=5 February 2010 |publisher=Springer Science & Business Media |isbn=978-1-59259-152-7 |pages=350– |url-status=live |archiveurl=https://web.archive.org/web/20160529061703/https://books.google.com/books?id=dM0uvBnxiN0C&pg=PA350 |archivedate=29 May 2016 |df=dmy-all}}</ref><ref name="DansetteSnyder2012" /><ref name="RamonDenis2007">{{cite book |first1=J. |last1=Ramon |first2=L.J. |last2=Denis |name-list-format=vanc |title=Prostate Cancer |url=https://books.google.com/books?id=Bg6ZbqhhboUC&pg=PA256 |date=5 June 2007 |publisher=Springer Science & Business Media |isbn=978-3-540-40901-4 |pages=256– |url-status=live |archiveurl=https://web.archive.org/web/20160427075934/https://books.google.com/books?id=Bg6ZbqhhboUC&pg=PA256 |archivedate=27 April 2016 |df=dmy-all}}</ref> For comparison, by 1996, 46&nbsp;cases of severe [[cholestasis|cholestatic]] hepatitis associated with flutamide had been reported, with 20 of the cases resulting in death.<ref name="Kaplowitz2002" /> Moreover, a 2002 review reported that there were 18&nbsp;reports of hepatotoxicity associated with {{abbr|CPA|cyproterone acetate}} 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 {{abbr|CPA|cyproterone acetate}}, 33 of which resulted in death.<ref name="Kaplowitz2002" />
 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.<ref name="Wellington2006" /><ref name="SeeWirth2002" /><ref name="pmid24967002" /><ref name="pmid27099451" /> It is notable that older age, for a variety of reasons, appears to be an important risk factor for drug-induced hepatotoxicity.<ref name="LemkeWilliams2012B">{{cite book |author1=Thomas L. Lemke |author2=David A. Williams |title=Foye's Principles of Medicinal Chemistry |url=https://books.google.com/books?id=Sd6ot9ul-bUC&pg=PA169 |date=24 January 2012 |publisher=Lippincott Williams & Wilkins |isbn=978-1-60913-345-0 |pages=169–}}</ref><ref name="Rustgi2016">{{cite book |author=Vinod Rustgi |title=Drug Hepatotoxicity, An Issue of Clinics in Liver Disease, E-Book |url=https://books.google.com/books?id=IfoTDgAAQBAJ&pg=PT89 |date=16 November 2016 |publisher=Elsevier Health Sciences |isbn=978-0-323-49662-9 |pages=89–}}</ref> As such, the risk of liver changes with bicalutamide may be less in younger patients, for instance young hirsute women and transgender women.<ref name="LemkeWilliams2012B" /><ref name="Rustgi2016" /> However, it has been reported on the basis of very limited evidence that this may not be the case with flutamide.<ref name="pmid28379593">{{cite journal |vauthors=Giorgetti R, di Muzio M, Giorgetti A, Girolami D, Borgia L, Tagliabracci A |title=Flutamide-induced hepatotoxicity: ethical and scientific issues |journal=European Reviews for Medical and Pharmacological Sciences |volume=21 |issue=1 Suppl |pages=69–77 |year=2017 |pmid=28379593 |doi= |url=}}</ref>
-From a theoretical standpoint (on the basis of [[structure–activity relationship]]s), it has been suggested that flutamide, bicalutamide, and nilutamide, to varying extents, all have the potential to cause [[hepatotoxicity|liver toxicity]].<ref name="BunceCampbell2010">{{cite book |first1=Chris M. |last1=Bunce |first2=Moray J. |last2=Campbell |name-list-format=vanc |title=Nuclear Receptors: Current Concepts and Future Challenges |url=https://books.google.com/books?id=U_1I616STa4C&pg=PA160 |date=11 March 2010 |publisher=Springer Science & Business Media |isbn=978-90-481-3303-1 |pages=160, 167 |deadurl=no |archiveurl=https://web.archive.org/web/20160610112652/https://books.google.com/books?id=U_1I616STa4C&pg=PA160 |archivedate=10 June 2016 |df=dmy-all}}</ref> However, in contrast to flutamide, [[hydroxyflutamide]], and nilutamide, bicalutamide exhibits much less or no [[mitochondrial toxicity]] and inhibition of [[enzyme]]s in the [[electron transport chain]] such as [[Electron transport chain#Complex I|respiratory complex I]] ([[NADH:ubiquinone reductase (H+-translocating)|NADH ubiquinone oxidoreductase]]), and this may be the reason for its much lower risk of hepatotoxicity in comparison.<ref name="CoeJia2007">{{cite journal |vauthors=Coe KJ, Jia Y, Ho HK, Rademacher P, Bammler TK, Beyer RP, Farin FM, Woodke L, Plymate SR, Fausto N, Nelson SD |title=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 |journal=Chemical Research in Toxicology |volume=20 |issue=9 |pages=1277–90 |date=September 2007 |pmid=17702527 |doi=10.1021/tx7001349 |pmc=2802183}}</ref><ref name="MarroquinHynes2007">{{cite journal |vauthors=Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y |title=Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants |journal=Toxicological Sciences |volume=97 |issue=2 |pages=539–47 |date=June 2007 |pmid=17361016 |doi=10.1093/toxsci/kfm052 |quote=Apoptosis induced by the androgen antagonist bicalutamide is receptor mediated (Lin et al., 2006), and hence a dominant effect at low concentrations, and hepatoxicity is a rare event (Dawson et al., 1997), in accord with its relative lack of toxicity to galactose-grown cells.}}</ref><ref name="KashimshettyDesai2009">{{cite journal |vauthors=Kashimshetty R, Desai VG, Kale VM, Lee T, Moland CL, Branham WS, New LS, Chan EC, Younis H, Boelsterli UA |title=Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity |journal=Toxicology and Applied Pharmacology |volume=238 |issue=2 |pages=150–9 |date=July 2009 |pmid=19442681 |doi=10.1016/j.taap.2009.05.007}}</ref><ref name="BallKamalian2016">{{cite journal |vauthors=Ball AL, Kamalian L, Alfirevic A, Lyon JJ, Chadwick AE |title=Identification of the Additional Mitochondrial Liabilities of 2-Hydroxyflutamide When Compared With its Parent Compound, Flutamide in HepG2 Cells |journal=Toxicological Sciences |volume=153 |issue=2 |date=July 2016 |pmid=27413113 |doi=10.1093/toxsci/kfw126 |pages=341–351|pmc=5036617 }}</ref> The activity difference may be related to the fact that flutamide, hydroxyflutamide, and nilutamide all possess a [[nitro compound|nitroaromatic]] [[functional group|group]], whereas in bicalutamide, a [[cyanide|cyano group]] is present in place of this nitro group, potentially reducing toxicity.<ref name="DansetteSnyder2012">{{cite book |first1=Patrick |last1=Danseuse |first2=Robert R. |last2=Snyder |first3=Terrence J. |last3=Monks |first4=David J. |last4=Jollow |first5=I. Glenn |last5=Sipes |first6=Helmut |last6=Greim |first7=G. Gordon |last7=Gibson |first8=Marcel |last8=Delaforge | name-list-format = vanc |title=Biological Reactive Intermediates Vi: Chemical and Biological Mechanisms in Susceptibility to and Prevention of Environmental Diseases |url=https://books.google.com/books?id=xRflBwAAQBAJ&pg=PA37 |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-1-4615-0667-6 |pages=37– |deadurl=no |archiveurl=https://web.archive.org/web/20160428014548/https://books.google.com/books?id=xRflBwAAQBAJ&pg=PA37 |archivedate=28 April 2016 |df=dmy-all}}</ref><ref name="CoeJia2007" /><ref name="BallKamalian2016" /><ref name="BoelsterliHo2006">{{cite journal |vauthors=Boelsterli UA, Ho HK, Zhou S, Leow KY |title=Bioactivation and hepatotoxicity of nitroaromatic drugs |journal=Current Drug Metabolism |volume=7 |issue=7 |pages=715–27 |date=October 2006 |pmid=17073576 |doi=10.2174/138920006778520606}}</ref>
+From a theoretical standpoint (on the basis of [[structure–activity relationship]]s), it has been suggested that flutamide, bicalutamide, and nilutamide, to varying extents, all have the potential to cause [[hepatotoxicity|liver toxicity]].<ref name="BunceCampbell2010">{{cite book |first1=Chris M. |last1=Bunce |first2=Moray J. |last2=Campbell |name-list-format=vanc |title=Nuclear Receptors: Current Concepts and Future Challenges |url=https://books.google.com/books?id=U_1I616STa4C&pg=PA160 |date=11 March 2010 |publisher=Springer Science & Business Media |isbn=978-90-481-3303-1 |pages=160, 167 |url-status=live |archiveurl=https://web.archive.org/web/20160610112652/https://books.google.com/books?id=U_1I616STa4C&pg=PA160 |archivedate=10 June 2016 |df=dmy-all}}</ref> However, in contrast to flutamide, [[hydroxyflutamide]], and nilutamide, bicalutamide exhibits much less or no [[mitochondrial toxicity]] and inhibition of [[enzyme]]s in the [[electron transport chain]] such as [[Electron transport chain#Complex I|respiratory complex I]] ([[NADH:ubiquinone reductase (H+-translocating)|NADH ubiquinone oxidoreductase]]), and this may be the reason for its much lower risk of hepatotoxicity in comparison.<ref name="CoeJia2007">{{cite journal |vauthors=Coe KJ, Jia Y, Ho HK, Rademacher P, Bammler TK, Beyer RP, Farin FM, Woodke L, Plymate SR, Fausto N, Nelson SD |title=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 |journal=Chemical Research in Toxicology |volume=20 |issue=9 |pages=1277–90 |date=September 2007 |pmid=17702527 |doi=10.1021/tx7001349 |pmc=2802183}}</ref><ref name="MarroquinHynes2007">{{cite journal |vauthors=Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y |title=Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants |journal=Toxicological Sciences |volume=97 |issue=2 |pages=539–47 |date=June 2007 |pmid=17361016 |doi=10.1093/toxsci/kfm052 |quote=Apoptosis induced by the androgen antagonist bicalutamide is receptor mediated (Lin et al., 2006), and hence a dominant effect at low concentrations, and hepatoxicity is a rare event (Dawson et al., 1997), in accord with its relative lack of toxicity to galactose-grown cells.}}</ref><ref name="KashimshettyDesai2009">{{cite journal |vauthors=Kashimshetty R, Desai VG, Kale VM, Lee T, Moland CL, Branham WS, New LS, Chan EC, Younis H, Boelsterli UA |title=Underlying mitochondrial dysfunction triggers flutamide-induced oxidative liver injury in a mouse model of idiosyncratic drug toxicity |journal=Toxicology and Applied Pharmacology |volume=238 |issue=2 |pages=150–9 |date=July 2009 |pmid=19442681 |doi=10.1016/j.taap.2009.05.007}}</ref><ref name="BallKamalian2016">{{cite journal |vauthors=Ball AL, Kamalian L, Alfirevic A, Lyon JJ, Chadwick AE |title=Identification of the Additional Mitochondrial Liabilities of 2-Hydroxyflutamide When Compared With its Parent Compound, Flutamide in HepG2 Cells |journal=Toxicological Sciences |volume=153 |issue=2 |date=July 2016 |pmid=27413113 |doi=10.1093/toxsci/kfw126 |pages=341–351|pmc=5036617 }}</ref> The activity difference may be related to the fact that flutamide, hydroxyflutamide, and nilutamide all possess a [[nitro compound|nitroaromatic]] [[functional group|group]], whereas in bicalutamide, a [[cyanide|cyano group]] is present in place of this nitro group, potentially reducing toxicity.<ref name="DansetteSnyder2012">{{cite book |first1=Patrick |last1=Danseuse |first2=Robert R. |last2=Snyder |first3=Terrence J. |last3=Monks |first4=David J. |last4=Jollow |first5=I. Glenn |last5=Sipes |first6=Helmut |last6=Greim |first7=G. Gordon |last7=Gibson |first8=Marcel |last8=Delaforge | name-list-format = vanc |title=Biological Reactive Intermediates Vi: Chemical and Biological Mechanisms in Susceptibility to and Prevention of Environmental Diseases |url=https://books.google.com/books?id=xRflBwAAQBAJ&pg=PA37 |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-1-4615-0667-6 |pages=37– |url-status=live |archiveurl=https://web.archive.org/web/20160428014548/https://books.google.com/books?id=xRflBwAAQBAJ&pg=PA37 |archivedate=28 April 2016 |df=dmy-all}}</ref><ref name="CoeJia2007" /><ref name="BallKamalian2016" /><ref name="BoelsterliHo2006">{{cite journal |vauthors=Boelsterli UA, Ho HK, Zhou S, Leow KY |title=Bioactivation and hepatotoxicity of nitroaromatic drugs |journal=Current Drug Metabolism |volume=7 |issue=7 |pages=715–27 |date=October 2006 |pmid=17073576 |doi=10.2174/138920006778520606}}</ref>
 {{Published case reports of bicalutamide-associated liver injury}}
 ==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.<ref name="Dart2004b">{{cite book |first1=Richard C. |last1=Dart |name-list-format=vanc |title=Medical Toxicology |url=https://books.google.com/books?id=BfdighlyGiwC&pg=PA497 |year=2004 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-2845-4 |pages=497– |deadurl=no |archiveurl=https://web.archive.org/web/20160511213240/https://books.google.com/books?id=BfdighlyGiwC&pg=PA497 |archivedate=11 May 2016 |df=dmy-all}}</ref><ref name="MasagoWatanabe2011">{{cite journal |vauthors=Masago T, Watanabe T, Nemoto R, Motoda K |title=Interstitial pneumonitis induced by bicalutamide given for prostate cancer |journal=International Journal of Clinical Oncology |volume=16 |issue=6 |pages=763–5 |date=December 2011 |pmid=21537882 |doi=10.1007/s10147-011-0239-x}}</ref><ref name="Aronson2014">{{cite book |first=Jeffrey K |last=Aronson |name-list-format=vanc |title=Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions |url=https://books.google.com/books?id=jTc3AAAAQBAJ&pg=PA740 |date=4 March 2014 |publisher=Newnes |isbn=978-0-444-62636-3 |pages=740– |deadurl=no |archiveurl=https://web.archive.org/web/20160506202559/https://books.google.com/books?id=jTc3AAAAQBAJ&pg=PA740 |archivedate=6 May 2016 |df=dmy-all}}</ref><ref name="UmeojiakoHamid2014">{{cite journal | vauthors = Umeojiako WI, James M | title = Bicalutamide-induced Eosinophilic Pneumonitis-A Serendipitous Diagnosis | journal = Journal of Case Reports in Medicine | year = 2019 | volume = 8 | issue = 1 | pages = 6 | issn = 2090-5351 | doi = 10.25149/case-reports.v8i1.164| pmid = | url = http://www.oakhillspub.com/index.php/jcrm/article/view/164}}</ref> Interstitial pneumonitis with bicalutamide is said to be an extremely rare event,<ref name="RicciBuzzatti2014">{{cite journal |vauthors=Ricci F, Buzzatti G, Rubagotti A, Boccardo F |title=Safety of antiandrogen therapy for treating prostate cancer |journal=Expert Opinion on Drug Safety |volume=13 |issue=11 |pages=1483–99 |date=November 2014 |pmid=25270521 |doi=10.1517/14740338.2014.966686}}</ref> and the risk is far less relative to that seen with nilutamide (which has an incidence rate of 0.5–2% of patients).<ref name="Gulley2011">{{cite book |first1=James Leonard |last1=Gulley |name-list-format=vanc |title=Prostate Cancer |url=https://books.google.com/books?id=WJkjgbRJe3EC&pg=PT81 |year=2011 |publisher=Demos Medical Publishing |isbn=978-1-935281-91-7 |pages=81– |deadurl=no |archiveurl=https://web.archive.org/web/20160425141102/https://books.google.com/books?id=WJkjgbRJe3EC&pg=PT81 |archivedate=25 April 2016 |df=dmy-all}}</ref>{{rp|81}}<ref name="MasagoWatanabe2011" /><ref name="CamusIII2010">{{cite book |first1=Phillipe |last1=Camus |first2=Edward C |last2=Rosenow III | name-list-format = vanc |title=Drug-induced and Iatrogenic Respiratory Disease |url=https://books.google.com/books?id=QlJsBgAAQBAJ&pg=PA235 |date=29 October 2010 |publisher=CRC Press |isbn=978-1-4441-2869-7 |pages=235–}}</ref> In a very large cohort of prostate cancer patients, the incidence of interstitial pneumonitis with {{abbr|NSAAs|nonsteroidal antiandrogens}} was 0.77% for nilutamide but only 0.04% (4 per 10,000) for flutamide and 0.01% (1 per 10,000) for bicalutamide.<ref name="pmid12353966">{{cite journal | vauthors = Bennett CL, Raisch DW, Sartor O | title = Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect |journal=Annals of Internal Medicine | volume = 137 | issue = 7 | pages = 625 | date = October 2002 | pmid = 12353966 | doi = 10.7326/0003-4819-137-7-200210010-00029 | quote = An estimated 0.77% of the 6,480 nilutamide-treated patients, 0.04% of the 41,700 flutamide-treated patients, and 0.01% of the 86,800 bicalutamide-treated patients developed pneumonitis during the study period.}}</ref> 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.<ref name="pmid11802586">{{cite journal |vauthors=Rodriguez EM, Staffa JA, Graham DJ |title=The role of databases in drug postmarketing surveillance |journal=Pharmacoepidemiology and Drug Safety |volume=10 |issue=5 |pages=407–10 |year=2001 |pmid=11802586 |doi=10.1002/pds.615 |url=https://zenodo.org/record/1229314}}</ref> In addition to interstitial pneumonitis, a single case report of [[eosinophilic lung disease]] in association with six months of 200&nbsp;mg/day bicalutamide treatment exists.<ref name=Dart2004>{{cite book |first1=Richard C. |last1=Dart |name-list-format=vanc |title=Medical Toxicology |url=https://books.google.com/books?id=BfdighlyGiwC&pg=PA497 |year=2004 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-2845-4 |pages=497, 521 |deadurl=no |archiveurl=https://web.archive.org/web/20160511213240/https://books.google.com/books?id=BfdighlyGiwC&pg=PA497 |archivedate=11 May 2016 |df=dmy-all}}</ref><ref name="WongMaoris1998">{{cite journal |vauthors=Wong PW, Macris N, DiFabrizio L, Seriff NS |title=Eosinophilic lung disease induced by bicalutamide: a case report and review of the medical literature |journal=Chest |volume=113 |issue=2 |pages=548–50 |date=February 1998 |pmid=9498983 |doi=10.1378/chest.113.2.548}}</ref> 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).<ref name="pmid15195196">{{cite journal |vauthors=Daba MH, El-Tahir KE, Al-Arifi MN, Gubara OA |title=Drug-induced pulmonary fibrosis |journal=Saudi Medical Journal |volume=25 |issue=6 |pages=700–6 |date=June 2004 |pmid=15195196 |doi=}}</ref>
+Several case reports of interstitial pneumonitis (which can progress to pulmonary fibrosis) in association with bicalutamide treatment have been published in the medical literature.<ref name="Dart2004b">{{cite book |first1=Richard C. |last1=Dart |name-list-format=vanc |title=Medical Toxicology |url=https://books.google.com/books?id=BfdighlyGiwC&pg=PA497 |year=2004 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-2845-4 |pages=497– |url-status=live |archiveurl=https://web.archive.org/web/20160511213240/https://books.google.com/books?id=BfdighlyGiwC&pg=PA497 |archivedate=11 May 2016 |df=dmy-all}}</ref><ref name="MasagoWatanabe2011">{{cite journal |vauthors=Masago T, Watanabe T, Nemoto R, Motoda K |title=Interstitial pneumonitis induced by bicalutamide given for prostate cancer |journal=International Journal of Clinical Oncology |volume=16 |issue=6 |pages=763–5 |date=December 2011 |pmid=21537882 |doi=10.1007/s10147-011-0239-x}}</ref><ref name="Aronson2014">{{cite book |first=Jeffrey K |last=Aronson |name-list-format=vanc |title=Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions |url=https://books.google.com/books?id=jTc3AAAAQBAJ&pg=PA740 |date=4 March 2014 |publisher=Newnes |isbn=978-0-444-62636-3 |pages=740– |url-status=live |archiveurl=https://web.archive.org/web/20160506202559/https://books.google.com/books?id=jTc3AAAAQBAJ&pg=PA740 |archivedate=6 May 2016 |df=dmy-all}}</ref><ref name="UmeojiakoHamid2014">{{cite journal | vauthors = Umeojiako WI, James M | title = Bicalutamide-induced Eosinophilic Pneumonitis-A Serendipitous Diagnosis | journal = Journal of Case Reports in Medicine | year = 2019 | volume = 8 | issue = 1 | pages = 6 | issn = 2090-5351 | doi = 10.25149/case-reports.v8i1.164| pmid = | url = http://www.oakhillspub.com/index.php/jcrm/article/view/164}}</ref> Interstitial pneumonitis with bicalutamide is said to be an extremely rare event,<ref name="RicciBuzzatti2014">{{cite journal |vauthors=Ricci F, Buzzatti G, Rubagotti A, Boccardo F |title=Safety of antiandrogen therapy for treating prostate cancer |journal=Expert Opinion on Drug Safety |volume=13 |issue=11 |pages=1483–99 |date=November 2014 |pmid=25270521 |doi=10.1517/14740338.2014.966686}}</ref> and the risk is far less relative to that seen with nilutamide (which has an incidence rate of 0.5–2% of patients).<ref name="Gulley2011">{{cite book |first1=James Leonard |last1=Gulley |name-list-format=vanc |title=Prostate Cancer |url=https://books.google.com/books?id=WJkjgbRJe3EC&pg=PT81 |year=2011 |publisher=Demos Medical Publishing |isbn=978-1-935281-91-7 |pages=81– |url-status=live |archiveurl=https://web.archive.org/web/20160425141102/https://books.google.com/books?id=WJkjgbRJe3EC&pg=PT81 |archivedate=25 April 2016 |df=dmy-all}}</ref>{{rp|81}}<ref name="MasagoWatanabe2011" /><ref name="CamusIII2010">{{cite book |first1=Phillipe |last1=Camus |first2=Edward C |last2=Rosenow III | name-list-format = vanc |title=Drug-induced and Iatrogenic Respiratory Disease |url=https://books.google.com/books?id=QlJsBgAAQBAJ&pg=PA235 |date=29 October 2010 |publisher=CRC Press |isbn=978-1-4441-2869-7 |pages=235–}}</ref> In a very large cohort of prostate cancer patients, the incidence of interstitial pneumonitis with {{abbr|NSAAs|nonsteroidal antiandrogens}} was 0.77% for nilutamide but only 0.04% (4 per 10,000) for flutamide and 0.01% (1 per 10,000) for bicalutamide.<ref name="pmid12353966">{{cite journal | vauthors = Bennett CL, Raisch DW, Sartor O | title = Pneumonitis associated with nonsteroidal antiandrogens: presumptive evidence of a class effect |journal=Annals of Internal Medicine | volume = 137 | issue = 7 | pages = 625 | date = October 2002 | pmid = 12353966 | doi = 10.7326/0003-4819-137-7-200210010-00029 | quote = An estimated 0.77% of the 6,480 nilutamide-treated patients, 0.04% of the 41,700 flutamide-treated patients, and 0.01% of the 86,800 bicalutamide-treated patients developed pneumonitis during the study period.}}</ref> 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.<ref name="pmid11802586">{{cite journal |vauthors=Rodriguez EM, Staffa JA, Graham DJ |title=The role of databases in drug postmarketing surveillance |journal=Pharmacoepidemiology and Drug Safety |volume=10 |issue=5 |pages=407–10 |year=2001 |pmid=11802586 |doi=10.1002/pds.615 |url=https://zenodo.org/record/1229314}}</ref> In addition to interstitial pneumonitis, a single case report of [[eosinophilic lung disease]] in association with six months of 200&nbsp;mg/day bicalutamide treatment exists.<ref name=Dart2004>{{cite book |first1=Richard C. |last1=Dart |name-list-format=vanc |title=Medical Toxicology |url=https://books.google.com/books?id=BfdighlyGiwC&pg=PA497 |year=2004 |publisher=Lippincott Williams & Wilkins |isbn=978-0-7817-2845-4 |pages=497, 521 |url-status=live |archiveurl=https://web.archive.org/web/20160511213240/https://books.google.com/books?id=BfdighlyGiwC&pg=PA497 |archivedate=11 May 2016 |df=dmy-all}}</ref><ref name="WongMaoris1998">{{cite journal |vauthors=Wong PW, Macris N, DiFabrizio L, Seriff NS |title=Eosinophilic lung disease induced by bicalutamide: a case report and review of the medical literature |journal=Chest |volume=113 |issue=2 |pages=548–50 |date=February 1998 |pmid=9498983 |doi=10.1378/chest.113.2.548}}</ref> 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).<ref name="pmid15195196">{{cite journal |vauthors=Daba MH, El-Tahir KE, Al-Arifi MN, Gubara OA |title=Drug-induced pulmonary fibrosis |journal=Saudi Medical Journal |volume=25 |issue=6 |pages=700–6 |date=June 2004 |pmid=15195196 |doi=}}</ref>
 {{Published case reports of bicalutamide-associated lung toxicity}}
@@ Line 91: / Line 91: @@
 ==Male breast cancer==
-A case report of [[male breast cancer]] subsequent to bicalutamide-induced gynecomastia has been published.<ref name="Aronson2009-1">{{cite book |first=Jeffrey K. |last=Aronson | name-list-format = vanc |title=Meyler's Side Effects of Endocrine and Metabolic Drugs |url=https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA155 |date=21 February 2009 |publisher=Elsevier |isbn=978-0-08-093292-7 |pages=155–}}</ref> According to the authors, "this is the second confirmed case of breast cancer in association with bicalutamide-induced gynaecomastia (correspondence AstraZeneca)."<ref name="Aronson2009-1" /> It is notable, however, that gynecomastia does not seem to increase the risk of breast cancer in men.<ref name="Aronson2009-1" /><ref name="PolatCuhaci2014">{{cite journal |vauthors=Cuhaci N, Polat SB, Evranos B, Ersoy R, Cakir B |title=Gynecomastia: Clinical evaluation and management |journal=Indian Journal of Endocrinology and Metabolism |volume=18 |issue=2 |pages=150–8 |date=March 2014 |pmid=24741509 |doi=10.4103/2230-8210.129104 |pmc=3987263}}</ref> Moreover, the lifetime incidence of breast cancer in men is approximately 0.1%,<ref name="NussbaumMcInnes2015">{{cite book |first1=Robert L. |last1=Nussbaum |first2=Roderick R. |last2=McInnes |first3=Huntington F. |last3=Willard | name-list-format = vanc |title=Thompson & Thompson Genetics in Medicine |url=https://books.google.com/books?id=KMaNCgAAQBAJ&pg=PA319 |date=21 May 2015 |publisher=Elsevier Health Sciences |isbn=978-1-4377-0696-3 |pages=319–}}</ref> the average age of diagnosis of prostate cancer and male breast cancer are similar (around 70 years),<ref name="pmid27194038" /><ref name="Li2009">{{cite book |author=Christopher Li |title=Breast Cancer Epidemiology |url=https://books.google.com/books?id=m3MtuTKbkbUC&pg=PA261 |date=11 November 2009 |publisher=Springer Science & Business Media |isbn=978-1-4419-0685-4 |pages=261–}}</ref> and millions of men have been treated with bicalutamide for prostate cancer,<ref name="HHS2010">{{citation |title=Bicalutamide BPCA Drug Use Review in the Pediatric Population |first=Stephen |last=Chang | name-list-format = vanc |publisher=[[United States Department of Health and Human Services|U.S. Department of Health and Human Service]] |date=10 March 2010 |accessdate=20 July 2016 |url=http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM214400.pdf |deadurl=no |archiveurl=https://web.archive.org/web/20161024181831/http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM214400.pdf |archivedate=24 October 2016 |df=dmy-all}}</ref> all of which are potentially in support of the notion of chance co-occurrences.<ref name="Aronson2009-1" /> In accordance, the authors concluded that "causality cannot be established" and that it was "probable that the association is entirely coincidental and sporadic."<ref name="Aronson2009-1" />
+A case report of [[male breast cancer]] subsequent to bicalutamide-induced gynecomastia has been published.<ref name="Aronson2009-1">{{cite book |first=Jeffrey K. |last=Aronson | name-list-format = vanc |title=Meyler's Side Effects of Endocrine and Metabolic Drugs |url=https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA155 |date=21 February 2009 |publisher=Elsevier |isbn=978-0-08-093292-7 |pages=155–}}</ref> According to the authors, "this is the second confirmed case of breast cancer in association with bicalutamide-induced gynaecomastia (correspondence AstraZeneca)."<ref name="Aronson2009-1" /> It is notable, however, that gynecomastia does not seem to increase the risk of breast cancer in men.<ref name="Aronson2009-1" /><ref name="PolatCuhaci2014">{{cite journal |vauthors=Cuhaci N, Polat SB, Evranos B, Ersoy R, Cakir B |title=Gynecomastia: Clinical evaluation and management |journal=Indian Journal of Endocrinology and Metabolism |volume=18 |issue=2 |pages=150–8 |date=March 2014 |pmid=24741509 |doi=10.4103/2230-8210.129104 |pmc=3987263}}</ref> Moreover, the lifetime incidence of breast cancer in men is approximately 0.1%,<ref name="NussbaumMcInnes2015">{{cite book |first1=Robert L. |last1=Nussbaum |first2=Roderick R. |last2=McInnes |first3=Huntington F. |last3=Willard | name-list-format = vanc |title=Thompson & Thompson Genetics in Medicine |url=https://books.google.com/books?id=KMaNCgAAQBAJ&pg=PA319 |date=21 May 2015 |publisher=Elsevier Health Sciences |isbn=978-1-4377-0696-3 |pages=319–}}</ref> the average age of diagnosis of prostate cancer and male breast cancer are similar (around 70 years),<ref name="pmid27194038" /><ref name="Li2009">{{cite book |author=Christopher Li |title=Breast Cancer Epidemiology |url=https://books.google.com/books?id=m3MtuTKbkbUC&pg=PA261 |date=11 November 2009 |publisher=Springer Science & Business Media |isbn=978-1-4419-0685-4 |pages=261–}}</ref> and millions of men have been treated with bicalutamide for prostate cancer,<ref name="HHS2010">{{citation |title=Bicalutamide BPCA Drug Use Review in the Pediatric Population |first=Stephen |last=Chang | name-list-format = vanc |publisher=[[United States Department of Health and Human Services|U.S. Department of Health and Human Service]] |date=10 March 2010 |accessdate=20 July 2016 |url=http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM214400.pdf |url-status=live |archiveurl=https://web.archive.org/web/20161024181831/http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/UCM214400.pdf |archivedate=24 October 2016 |df=dmy-all}}</ref> all of which are potentially in support of the notion of chance co-occurrences.<ref name="Aronson2009-1" /> In accordance, the authors concluded that "causality cannot be established" and that it was "probable that the association is entirely coincidental and sporadic."<ref name="Aronson2009-1" />
 ==Male birth defects==
-Because bicalutamide blocks the {{abbr|AR|androgen receptor}}, like all antiandrogens, it can interfere with the androgen-mediated [[sexual differentiation]] of the [[genitalia]] (and brain) during [[prenatal development]].<ref name="IswaranImai1997">{{cite journal |vauthors=Iswaran TJ, Imai M, Betton GR, Siddall RA |title=An overview of animal toxicology studies with bicalutamide (ICI 176,334) |journal=The Journal of Toxicological Sciences |volume=22 |issue=2 |pages=75–88 |date=May 1997 |pmid=9198005 |doi=10.2131/jts.22.2_75}}</ref><ref name="Smith2013">{{cite book |first1=Robert E. |last1=Smith |name-list-format=vanc |title=Medicinal Chemistry – Fusion of Traditional and Western Medicine |url=https://books.google.com/books?id=RkDcAwAAQBAJ&pg=PA306 |date=4 April 2013 |publisher=Bentham Science Publishers |isbn=978-1-60805-149-6 |pages=306– |deadurl=no |archiveurl=https://web.archive.org/web/20160529034219/https://books.google.com/books?id=RkDcAwAAQBAJ&pg=PA306 |archivedate=29 May 2016 |df=dmy-all}}</ref><ref>{{cite book |title=Sex Differences in the Human Brain, their underpinnings and implications |url=https://books.google.com/books?id=JFpq6hYQRhQC&pg=PA44 |date=3 December 2010 |publisher=Elsevier |isbn=978-0-444-53631-0 |pages=44–45 |deadurl=no |archiveurl=https://web.archive.org/web/20160526221656/https://books.google.com/books?id=JFpq6hYQRhQC |archivedate=26 May 2016 |df=dmy-all}}</ref><ref name="Paoletti2012">{{cite book |first=Rodolfo |last=Paoletti | name-list-format = vanc |title=Chemistry and Brain Development: Proceedings of the Advanced Study Institute on "Chemistry of Brain Development," held in Milan, Italy, September 9–19, 1970 |url=https://books.google.com/books?id=8YbgBwAAQBAJ&pg=PA218 |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-1-4684-7236-3 |pages=218–}}</ref> In pregnant rats given bicalutamide at a dosage of 10&nbsp;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.<ref name="FDALabel" /> 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 [[teratogen]]ic effects of any sort were observed in female rat offspring at any dosage.<ref name="FDALabel" /> As such, bicalutamide is a selective reproductive teratogen in males, and may have the potential to produce [[undervirilization]]/sexually [[ambiguous genitalia]] in male [[fetus]]es.<ref name="IswaranImai1997" /><ref name="Smith2013" />
+Because bicalutamide blocks the {{abbr|AR|androgen receptor}}, like all antiandrogens, it can interfere with the androgen-mediated [[sexual differentiation]] of the [[genitalia]] (and brain) during [[prenatal development]].<ref name="IswaranImai1997">{{cite journal |vauthors=Iswaran TJ, Imai M, Betton GR, Siddall RA |title=An overview of animal toxicology studies with bicalutamide (ICI 176,334) |journal=The Journal of Toxicological Sciences |volume=22 |issue=2 |pages=75–88 |date=May 1997 |pmid=9198005 |doi=10.2131/jts.22.2_75}}</ref><ref name="Smith2013">{{cite book |first1=Robert E. |last1=Smith |name-list-format=vanc |title=Medicinal Chemistry – Fusion of Traditional and Western Medicine |url=https://books.google.com/books?id=RkDcAwAAQBAJ&pg=PA306 |date=4 April 2013 |publisher=Bentham Science Publishers |isbn=978-1-60805-149-6 |pages=306– |url-status=live |archiveurl=https://web.archive.org/web/20160529034219/https://books.google.com/books?id=RkDcAwAAQBAJ&pg=PA306 |archivedate=29 May 2016 |df=dmy-all}}</ref><ref>{{cite book |title=Sex Differences in the Human Brain, their underpinnings and implications |url=https://books.google.com/books?id=JFpq6hYQRhQC&pg=PA44 |date=3 December 2010 |publisher=Elsevier |isbn=978-0-444-53631-0 |pages=44–45 |url-status=live |archiveurl=https://web.archive.org/web/20160526221656/https://books.google.com/books?id=JFpq6hYQRhQC |archivedate=26 May 2016 |df=dmy-all}}</ref><ref name="Paoletti2012">{{cite book |first=Rodolfo |last=Paoletti | name-list-format = vanc |title=Chemistry and Brain Development: Proceedings of the Advanced Study Institute on "Chemistry of Brain Development," held in Milan, Italy, September 9–19, 1970 |url=https://books.google.com/books?id=8YbgBwAAQBAJ&pg=PA218 |date=6 December 2012 |publisher=Springer Science & Business Media |isbn=978-1-4684-7236-3 |pages=218–}}</ref> In pregnant rats given bicalutamide at a dosage of 10&nbsp;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.<ref name="FDALabel" /> 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 [[teratogen]]ic effects of any sort were observed in female rat offspring at any dosage.<ref name="FDALabel" /> As such, bicalutamide is a selective reproductive teratogen in males, and may have the potential to produce [[undervirilization]]/sexually [[ambiguous genitalia]] in male [[fetus]]es.<ref name="IswaranImai1997" /><ref name="Smith2013" />
 ==References==

v t e Bicalutamide
Topics	Medical uses of bicalutamide Side effects of bicalutamide Pharmacology of bicalutamide Comparison of bicalutamide with other antiandrogens
Related drugs	Nonsteroidal antiandrogens: First-generation: Flutamide Nilutamide Topilutamide; Second-generation: Apalutamide Enzalutamide