Side effects of bicalutamide
The side effects of bicalutamide, a nonsteroidal antiandrogen, 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.
Overview
Central nervous system
Hot flashes
In the 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. In the subgroup of the trial, the rate of hot flashes with bicalutamide monotherapy was 13.1%.Sexual dysfunction
Bicalutamide may cause sexual dysfunction, including decreased sex drive and erectile dysfunction. However, the rates of these side effects with bicalutamide monotherapy are very low. In the trial, at 7.4 years follow-up, the rates of decreased libido and impotence were only 3.6% and 9.3% in the 150 mg/day bicalutamide monotherapy group relative to 1.2% and 6.5% for placebo, respectively. Similarly, in the trials of 150 mg/day bicalutamide monotherapy for advanced prostate cancer, fewer than 10% of men reported decreased sex drive or reduced erectile function as a side effect. About two-thirds of men in these trials, who had advanced prostate cancer and were of almost invariably advanced age, maintained sexual interest, while sexual function was slightly reduced by 18%. Most men experience sexual dysfunction only moderately or not at all with bicalutamide monotherapy, and the same is true during monotherapy with other. Bicalutamide monotherapy at a dosage of 50 mg/day had no effect on nocturnal erections in men with prostate cancer.Similarly to in men, bicalutamide has been associated with minimal or no sexual dysfunction in women. A phase III clinical study of 50 mg/day bicalutamide in conjunction with a combined oral contraceptive in women with severe hirsutism due to polycystic ovary syndrome carefully assessed the side effect of decreased libido and found that the incidence with bicalutamide did not differ from the control group. Minimal rates of reduced sex drive have also been associated with the related NSAA flutamide. These findings are in accordance with the fact that women with complete androgen insensitivity syndrome show normal sexual function in spite of complete loss of androgen receptor signaling. They are also in accordance with a variety of findings concerning testosterone levels and sexual function in premenopausal women, in which no change in parameters of sexual function, including libido, have been observed in association with increases or decreases in testosterone levels. It appears that testosterone levels within the normal physiological range are not importantly involved in sexual desire or function in women.
Psychiatric conditions
At 5.3 years follow-up, the incidence of depression was 5.5% for bicalutamide monotherapy relative to 3.0% for placebo in the trial, and the incidence of asthenia was 10.2% for bicalutamide monotherapy relative to 5.1% for placebo. Rarely, bicalutamide has been associated with hallucinations. This is thought to be secondary to AR antagonism.Breasts and reproductive system
Breast changes
The most common side effects of bicalutamide monotherapy in men are breast pain/tenderness and gynecomastia. These side effects may occur in as many as 90% of men treated with bicalutamide monotherapy, but gynecomastia is generally reported to occur in 70 to 80% of patients. In the 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. Gynecomastia associated with monotherapy usually develops within the first 6 to 9 months following initiation of treatment. In more than 90% of affected men, bicalutamide-related breast changes are mild-to-moderate in severity. It is only rarely and in severe and extreme cases of gynecomastia that the proportions of the male breasts become so marked that they are comparable to those of women. In addition, bicalutamide-associated breast changes improve or resolve in most men upon discontinuation of therapy. In the trial, 16.8% of bicalutamide patients relative to 0.7% of controls withdrew from the study due to breast pain and/or gynecomastia. The incidence and severity of gynecomastia are reportedly higher with estrogens than with like bicalutamide in the treatment of men with prostate cancer.Management of breast changes
, a selective estrogen receptor modulator with antiestrogenic actions in breast tissue and estrogenic actions in bone, has been found to be highly effective in preventing and reversing bicalutamide-induced gynecomastia in men. Moreover, in contrast to analogues, tamoxifen poses minimal risk of accelerated bone loss and osteoporosis. For reasons that are unclear, anastrozole, an aromatase inhibitor, has been found to be much less effective in comparison to tamoxifen for treating bicalutamide-induced gynecomastia. A systematic review of -induced gynecomastia and breast tenderness concluded that tamoxifen and radiotherapy could effectively manage the side effect without relevant adverse effects, though with tamoxifen showing superior effectiveness. Surgical breast reduction may also be employed to correct bicalutamide-induced gynecomastia.Male breast cancer
A case report of male breast cancer subsequent to bicalutamide-induced gynecomastia has been published. According to the authors, "this is the second confirmed case of breast cancer in association with bicalutamide-induced gynaecomastia." It is notable, however, that gynecomastia does not seem to increase the risk of breast cancer in men. Moreover, the lifetime incidence of breast cancer in men is approximately 0.1%, the average age of diagnosis of prostate cancer and male breast cancer are similar, and millions of men have been treated with bicalutamide for prostate cancer, all of which are potentially in support of the notion of chance co-occurrences. In accordance, the authors concluded that "causality cannot be established" and that it was "probable that the association is entirely coincidental and sporadic."Lower reproductive system
Bicalutamide reduces the size of the prostate gland and seminal vesicles, though not of the testes. Slightly but significantly reduced penile length is also a recognized adverse effect of. Reversible hypospermia or aspermia may occur. However, bicalutamide does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish the capacity/potential for fertility in men. Due to the induction of chronic overproduction of and testosterone, there was concern that long-term bicalutamide monotherapy might induce Leydig cell hyperplasia and tumors, but clinical studies indicate that Leydig cell hyperplasia does not occur to a clinically important extent.Male birth defects
Because bicalutamide blocks the, like all antiandrogens, it can interfere with the androgen-mediated sexual differentiation of the genitalia during prenatal development. In pregnant rats given bicalutamide at a dosage of 10 mg/kg/day and above, feminization of male offspring, such as reduced anogenital distance and hypospadias, as well as impotence, were observed. No other teratogenic effects were observed in rats or rabbits receiving up to very high dosages of bicalutamide, and no teratogenic effects of any sort were observed in female rat offspring at any dosage. As such, bicalutamide is a selective reproductive teratogen in males, and may have the potential to produce undervirilization/sexually ambiguous genitalia in male fetuses.Skin, fat, and bone
Skin changes
Antiandrogen therapy and estrogen therapy are known to produce demasculinizing and feminizing effects in the skin and on hair follicle distribution in people assigned male at birth. Androgens are involved in regulation of the skin, and antiandrogens are known to be associated with skin changes. Skin-related side effects, which included dry skin, itching, and rash, were reported at a rate of 2% in both monotherapy and clinical studies of bicalutamide in men.Sensitivity to light
A few cases of photosensitivity associated with bicalutamide have been reported. In one of the cases, bicalutamide was continued due to effectiveness in treating prostate cancer in the patient, and in combination with strict photoprotection. Eventually, the symptoms disappeared and did not recur. Flutamide is also associated with photosensitivity, but much more frequently in comparison to bicalutamide.Fat distribution
Antiandrogen therapy and estrogen therapy are known to produce demasculinizing and feminizing effects on fat distribution in people assigned male at birth.Bone density and fractures
Bicalutamide monotherapy preserves bone mineral density in men with prostate cancer relative to surgical or medical castration. This is considered to be due to preservation of gonadal estradiol production with bicalutamide monotherapy, in contrast to castration which greatly reduces estradiol levels. The risk of osteoporosis and serious bone fractures with bicalutamide monotherapy appears to be no different than with non-use in men with prostate cancer.Gastrointestinal system
The incidence of diarrhea with bicalutamide monotherapy in the trial was comparable to placebo. In phase III studies of bicalutamide monotherapy for, 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.Heart, liver, kidneys, and lungs
Cardiovascular system
In the group of the 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. This was because more bicalutamide than placebo recipients had died due to causes unrelated to prostate cancer in this group. At 7.4-year follow-up, there were numerically more deaths from heart failure and gastrointestinal cancer 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. In any case, although the reason for the increased overall mortality with 150 mg/day bicalutamide monotherapy has not been fully elucidated, it has been said that the finding that heart failure was twice as frequent in the bicalutamide group warrants further investigation. 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.According to Iversen et al., the increased non-prostate cancer mortality with bicalutamide monotherapy in patients has also been seen with castration and is likely a consequence of androgen deprivation in men rather than a specific drug toxicity of bicalutamide:
A study of 300 to 600 mg/day bicalutamide monotherapy in 248 men with or metastatic prostate cancer found that there were no effects of bicalutamide on heart rate, blood pressure, or electrocardiogram parameters. In addition, at 5-year follow-up, the incidence of cardiovascular events was low, with no differences between the bicalutamide and castration groups. There were also no differences in the incidences of arrhythmia, myocardial infarction, or other ischemic cardiac or cerebrovascular conditions. These findings suggest that bicalutamide does not cause an excess in cardiovascular events or conditions.
A meta-analysis of prospective randomized clinical trials of agonist-based for the treatment of non-metastatic prostate cancer that included over 4,000 patients found no evidence of increased cardiovascular mortality or overall mortality. Non-prostate cancer mortality was not specifically assessed.
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.
Cardiovascular risks have been reviewed and subjected to meta-analysis.
Coagulation
monotherapy is associated with a greater risk of venous thromboembolism than non-use, although not to the same extent as surgical or medical castration or particularly high-dose estrogen therapy.Kidney function
Androgens and anabolic steroids, including testosterone, have trophic and anabolic effects in the kidneys. Androgen deprivation therapy, including with GnRH agonists and bicalutamide monotherapy, may increase the risk of kidney failure in men. A large randomized controlled trial in men witih prostate cancer found that the incidence of kidney failure was 1 to 2% with combined androgen blockade using bicalutamide or flutamide.Anemia
Androgens including testosterone are known to stimulate erythropoiesis and increase hematocrit. These effects are mediated by increasing production and secretion of erythropoietin from the kidneys. Erythropoietin in turn stimulates erythropoiesis in hematopoietic tissues such as bone marrow. The high levels of testosterone in males are why hematocrit and hemoglobin levels are higher in men than in women. Due to stimulation of erythropoiesis, anabolic–androgenic steroids such as oxymetholone and nandrolone decanoate are effective for and used in the treatment of severe anemia. High doses or levels of AAS, including testosterone, can cause polycythemia—high red blood cell and/or hemoglobin levels that increase the risk of stroke—as an adverse effect. Conversely, whether via castration, monotherapy, or, decreased erythropoiesis resulting in mild anemia is a common side effect of in men. The incidence of anemia with bicalutamide as a monotherapy or with castration was about 7.4% in clinical trials. A decrease of hemoglobin levels of 1 to 2 g/dL after approximately six months of treatment may be observed.Liver toxicity
Bicalutamide may cause liver changes rarely, such as elevated transaminases and jaundice. In the 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 at 3-year median follow-up. For comparison, the incidences of abnormal liver function tests are 42 to 62% for flutamide, 2 to 3% for nilutamide, and between 10% and 28% for, whereas there appears to be no risk with enzalutamide. In the trial, bicalutamide-induced liver changes were usually transient and rarely severe. The medication was discontinued due to liver changes in approximately 0.3% to 1% of patients treated with it for prostate cancer in clinical trials.The risk of liver changes with bicalutamide is considered to be small but significant, and monitoring of liver function is recommended. Elevation of transaminases above twice the normal range or jaundice may be an indication that bicalutamide should be discontinued. 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. Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice.
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. 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. In the reported cases of bicalutamide-associated hepatotoxicity, the dosages of the drug were 50 mg/day, 80 mg/day, 100 mg/day, and 150 mg/day. Relative to flutamide, hepatotoxicity is far rarer with bicalutamide and nilutamide, and bicalutamide is regarded as having the lowest risk of the three medications. For comparison, by 1996, 46 cases of severe cholestatic hepatitis associated with flutamide had been reported, with 20 of the cases resulting in death. Moreover, a 2002 review reported that there were 18 reports of hepatotoxicity associated with 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, 33 of which resulted in death.
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. It is notable that older age, for a variety of reasons, appears to be an important risk factor for drug-induced hepatotoxicity. As such, the risk of liver changes with bicalutamide may be less in younger patients, for instance young hirsute women and transgender women. However, it has been reported on the basis of very limited evidence that this may not be the case with flutamide. There is no evidence of greater liver function changes with higher doses of bicalutamide.
From a theoretical standpoint, it has been suggested that flutamide, bicalutamide, and nilutamide, to varying extents, all have the potential to cause liver toxicity. 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, and this may be the reason for its much lower risk of hepatotoxicity in comparison. 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.