Bicalutamide was patented in 1982 and approved for medical use in 1995.[35] It is on theWorld Health Organization's List of Essential Medicines.[36] Bicalutamide is available as ageneric medication.[37] The drug is sold in more than 80 countries, including mostdeveloped countries.[38][39][40] It was at one time the most widely used antiandrogen in the treatment of prostate cancer, with millions of men with the disease having been prescribed it.[23][41][42][43][44] Although bicalutamide is also used for other indications besides prostate cancer, the vast majority of prescriptions appear to be for treatment of prostate cancer.[44]
In Japan, bicalutamide is uniquely used at a dosage of 80 mg/day both in combination with castration and as a monotherapy in the treatment of prostate cancer.[48][49]
Bicalutamide is also employed for the followingoff-label (non-approved) indications:
To reduce the effects of the testosterone flare at the initiation ofGnRH agonist therapy in men[50][51]
Bicalutamide ispregnancy category X, or "contraindicated in pregnancy", in theU.S.,[27] andpregnancy category D, the second most restricted rating, in Australia.[89] As such, it is contraindicated in women during pregnancy, and women who are sexually active and who can or may become pregnant are strongly recommended to take bicalutamide only in combination with adequatecontraception.[90][91] It is unknown whether bicalutamide is excreted inbreast milk, but many drugs are excreted in breast milk, and for this reason, bicalutamide treatment is similarly not recommended whilebreastfeeding.[3][27]
In individuals with severe, though not mild-to-moderatehepatic impairment, there is evidence that the elimination of bicalutamide is slowed, and hence, caution may be warranted in these patients as circulating levels of bicalutamide may be increased.[2][92] In severe hepatic impairment, the elimination half-life of the active (R)-enantiomer of bicalutamide is increased by about 1.75-fold (76% increase; elimination half-life of 5.9 and 10.4 days for normal and impaired patients, respectively).[13][93][94] The elimination half-life of bicalutamide is unchanged inrenal impairment.[84]
^abMay 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.
^abReported in single cases, but not observed in any large, randomized trial. With regular liver monitoring and discontinuation as needed.
A single oral dose of bicalutamide in humans that results in symptoms of overdose or that is considered to be life-threatening has not been established.[27][163] Dosages of up to 600 mg/day have been well tolerated in clinical trials,[164] and it is notable that there is a saturation of absorption with bicalutamide such that circulating levels of its active (R)-enantiomer do not further increase above a dosage of 300 mg/day.[2][164] Overdose is considered unlikely to be life-threatening with bicalutamide or other first-generationNSAAs (i.e., flutamide and nilutamide).[165] A massive overdose of nilutamide (13 grams, or 43 times the normal maximum 300 mg/day clinical dosage) in a 79-year-old man was uneventful, producing no clinical signs, symptoms, or toxicity.[166] There is no specificantidote for bicalutamide orNSAA overdose, and treatment should be based on symptoms, if any are present.[27][163]
Bicalutamide is almost exclusivelymetabolized byCYP3A4.[4] As such, its levels in the body may be altered byinhibitors andinducers of CYP3A4.[7] (For a list of CYP3A4 inhibitors and inducers, seehere.) However, in spite of the fact bicalutamide is metabolized by CYP3A4, there is no evidence of clinically significantdrug interactions when bicalutamide at a dosage of 150 mg/day or less is co-administered with drugs that inhibit or inducecytochrome P450enzyme activity.[13]
In-vitro studies suggest that bicalutamide may be able to inhibit CYP3A4 and, to a lesser extent,CYP2C9,CYP2C19, andCYP2D6.[2] Conversely, animal studies suggest that bicalutamide may induce cytochrome P450 enzymes.[2] In a clinical study, bicalutamide co-administered with the CYP3A4 substrate midazolam caused only a small and statistically non-significant increase in midazolam levels (+27%) presumably due to CYP3A4 inhibition.[2] However, this was well below increases in midazolam exposure with potent CYP3A4 inhibitors likeketoconazole (+1500%),itraconazole (+1000%), anderythromycin (+350%), and is considered to not be clinically important.[2] There is no indication of clinically significant enzyme inhibition or induction with bicalutamide at doses of 150mg/day or below.[2]
Because bicalutamide circulates at relatively high concentrations and is highly protein-bound, it has the potential to displace other highly protein-bound drugs likewarfarin,phenytoin,theophylline, andaspirin fromplasma binding proteins.[103][107] This could, in turn, result in increased free concentrations of such drugs and increased effects and/or side effects, potentially necessitating dosage adjustments.[103] Bicalutamide has specifically been found to displacecoumarinanticoagulants like warfarin from their plasma binding proteins (namelyalbumin)in vitro, potentially resulting in an increased anticoagulant effect, and for this reason, close monitoring ofprothrombin time and dosage adjustment as necessary is recommended when bicalutamide is used in combination with these drugs.[167][168][169] However, in spite of this, no conclusive evidence of an interaction between bicalutamide and other drugs was found in clinical trials of nearly 3,000 patients.[107]
Bicalutamide monotherapy seems to have minimal effect ontesticularspermatogenesis, testicularultrastructure, and certain aspects ofmale fertility.[218][90][219] This seems to be because testosterone levels in the testes (where ~95% of testosterone in males is produced) are extremely high (up to 200-fold higher than circulating levels) and only a small fraction (less than 10%) of the normal levels of testosterone in the testes are actually necessary to maintain spermatogenesis.[220][221][222] As a result, bicalutamide appears to not be able to compete with testosterone in this sole part of the body to an extent sufficient to considerably interfere with androgen signaling and function.[220][221][222] However, while bicalutamide does not seem to be able to adversely influence testicular spermatogenesis, it may interfere withAR-dependent sperm maturation and transport outside of the testes in theepididymides andvas deferens where androgen levels are far lower, and hence may still be able to impair male fertility.[223] In addition, the combination of bicalutamide with other medications, such as estrogens, progestogens, andGnRH analogues, can compromise spermatogenesis due to their own adverse effects on male fertility.[224][225][226][227][228][229] These medications are able to strongly suppress gonadal androgen production, which can severely impair or abolish testicular spermatogenesis, and estrogens also appear to have direct and potentially long-lastingcytotoxic effects in the testes at sufficiently high concentrations.[224][225][226][227][228][229]
Though its absolutebioavailability in humans is unknown, bicalutamide is known to be extensively and well-absorbed.[2][3] Its absorption is not affected byfood.[3][167] The absorption of bicalutamide is linear at doses up to 150 mg/day and is saturable at doses above this, with no further increases insteady-state levels of bicalutamide occurring at doses above 300 mg/day.[2][13][237][164] Whereas absorption of (R)-bicalutamide is slow, with levelspeaking at 31 to 39 hours after a dose, (S)-bicalutamide is much more rapidly absorbed.[13][27][2] Steady-state concentrations of the drug are reached after 4 to 12 weeks of treatment independently of dosage, with a 10- to 20-fold progressive accumulation in levels of (R)-bicalutamide.[13][238][239][185] The long time to steady-state levels is the result of bicalutamide's very longelimination half-life.[185] There is wideinterindividual variability in (R)-bicalutamide levels (up to 16-fold) with bicalutamide regardless of dosage.[2]
Thetissue distribution of bicalutamide is not well-characterized.[240] The amount of bicalutamide insemen that could potentially be transferred to a female partner duringsexual intercourse is low and is not thought to be important.[89] Based onanimal studies with rats and dogs it was thought that bicalutamide could not cross theblood–brain barrier and hence could not enter the brain.[241][34][242][243] As such, it was initially thought to be aperipherally selective antiandrogen.[241][34] However, subsequent clinical studies found that this was not also the case for humans, indicating species differences; bicalutamide crosses into the human brain and, in accordance, produces effects and side effects consistent with central antiandrogenic action.[2][109][244][245][246] In any case, there is indication that bicalutamide might have at least some peripheral selectivity in humans.[247] Bicalutamide is highlyplasma protein bound (96.1% for racemic bicalutamide, 99.6% for (R)-bicalutamide) and is bound mainly toalbumin, with negligible binding toSHBG andcorticosteroid-binding globulin.[4][2][240][176]
Bicalutamide ismetabolized in theliver.[4][167] (R)-Bicalutamide is metabolized slowly and almost exclusively viahydroxylation byCYP3A4 into (R)-hydroxybicalutamide.[167][2][4][248] Thismetabolite is thenglucuronidated byUGT1A9.[167][2][9][6] In contrast to (R)-bicalutamide, (S)-bicalutamide is metabolized rapidly and mainly by glucuronidation (without hydroxylation).[167] None of the metabolites of bicalutamide are known to be active and levels of the metabolites are low in plasma, where unchanged biclautamide predominates.[4][5][2] Due to the stereoselective metabolism of bicalutamide, (R)-bicalutamide has a far longer terminal half-life than (S)-bicalutamide and its levels are about 10- to 20-fold higher in comparison following a single dose and 100-fold higher at steady-state.[13][248][249] (R)-Bicalutamide has a relatively long elimination half-life of 5.8 days with a single dose and 7 to 10 days following repeated administration.[8]
Bicalutamide iseliminated in similar proportions infeces (43%) andurine (34%), while its metabolites are eliminated roughly equally inurine andbile.[4][167][250][251] The drug isexcreted to a substantial extent in unmetabolized form, and both bicalutamide and its metabolites are eliminated mainly asglucuronideconjugates.[173] The glucuronide conjugates of bicalutamide and its metabolites are eliminated from the circulation rapidly, unlike unconjugated bicalutamide.[2][167][252]
The second-generationNSAAs enzalutamide andapalutamide were derived from and are analogues of the first-generationNSAAs,[167][262] while another second-generationNSAA,darolutamide, is said to be structurally distinct and chemically unrelated to the otherNSAAs.[263] Enzalutamide is a modification of bicalutamide in which the inter-ring linkingchain has been altered andcyclized into a 5,5-dimethyl-4-oxo-2-thioxoimidazolidine moiety. In apalutamide, the 5,5-dimethyl groups of the imidazolidine ring of enzalutamide are cyclized to form an accessorycyclobutane ring and one of its phenyl rings is replaced with apyridine ring.
A number ofchemical syntheses of bicalutamide have been published in the literature.[253][271][272][273][274] The procedure of the first published synthesis of bicalutamide can be seen below.[271]
Bicalutamide is thegeneric name of the drug in English and French and itsINNTooltip INN,USANTooltip United States Adopted Name,USPTooltip United States Pharmacopeia,[299]BANTooltip British Approved Name,DCFTooltip Dénomination Commune Française,AANTooltip Australian Approved Name,[89] andJANTooltip Japanese Accepted Name.[38][300][80][301] It is also referred to asbicalutamidum inLatin,bicalutamida in Spanish andPortuguese,bicalutamid in German, andbikalutamid in Russian and otherSlavic languages.[38][80] The "bica-" prefix corresponds to the fact that bicalutamide is abicyclic compound, while the "-lutamide" suffix is the standard suffix forNSAAs.[302][303] Bicalutamide is also known by its formerdevelopmental code nameICI-176,334.[300][80][38]
Bicalutamide is marketed by AstraZeneca in oral tablet form under the brand names Casodex, Cosudex, Calutide, Calumid, and Kalumid in many countries.[38][80][304][305] It is also marketed under the brand names Bicadex, Bical, Bicalox, Bicamide, Bicatlon, Bicusan, Binabic, Bypro, Calutol, and Ormandyl among others in various countries.[38] The drug is sold under a large number of generic trade names such as Apo-Bicalutamide, Bicalutamide Accord, Bicalutamide Actavis, Bicalutamide Bluefish, Bicalutamide Kabi, Bicalutamide Sandoz, and Bicalutamide Teva as well.[38] A combination formulation of bicalutamide and goserelin is marketed by AstraZeneca in Australia and New Zealand under the brand name ZolaCos-CP.[81][86][87][88]
Bicalutamide is off-patent and available as a generic.[292] Unlike bicalutamide, the newerNSAA enzalutamide is stillon-patent, and for this reason, is considerably more expensive in comparison.[306]
Sales of bicalutamide (as Casodex) worldwide peaked atUS$1.3 billion in 2007,[311] and it has been described as a "billion-dollar-a-year" drug prior to losing its patent protection starting in 2007.[43][312][259] In 2014, despite the introduction of abiraterone acetate in 2011 and enzalutamide in 2012, bicalutamide was still the most commonly prescribed drug in the treatment ofmetastatic castration-resistant prostate cancer (mCRPC).[43] Moreover, in spite of being off-patent, bicalutamide was said to still generate a few hundred million dollars in sales per year for AstraZeneca.[43] Total worldwide sales of brand name Casodex were approximatelyUS$13.4 billion as of the end of 2018.[313][314][40][315][316][311][317][318][319][320][321][excessive citations]
Bicalutamide has been studied in the treatment ofbenign prostatic hyperplasia (BPH) in a 24-week trial of 15 patients at a dosage of 50 mg/day.[340][341] Prostate volume decreased by 26% in patients taking bicalutamide andurinary irritative symptom scores significantly decreased.[340][341] Conversely, peakurine flow rates andurine pressure flow examinations were not significantly different between bicalutamide and placebo.[340][341] The decrease in prostate volume achieved with bicalutamide was comparable to that observed with the 5α-reductase inhibitorfinasteride, which is approved for the treatment of BPH.[342][343] Breast tenderness (93%), gynecomastia (54%), and sexual dysfunction (60%) were all reported as side effects of bicalutamide at the dosage used in the study, although no treatment discontinuations due to adverse effects occurred and sexual functioning was maintained in 75% of patients.[341][107]
Antiandrogens have been suggested for treatingCOVID-19 in men and as of May 2020 high-dose bicalutamide is in a phase II clinical trial for this purpose.[344][345]
Bicalutamide may be used to treat hyperandrogenism and associated benign prostatic hyperplasia secondary tohyperadrenocorticism (caused by excessive adrenal androgens) in maleferrets.[346][347][348] However, it has not been formally assessed in controlled studies for this purpose.[348][349]
^abDole EJ, Holdsworth MT (1997). "Nilutamide: an antiandrogen for the treatment of prostate cancer".The Annals of Pharmacotherapy.31 (1):65–75.doi:10.1177/106002809703100112.PMID8997470.S2CID20347526.page 67: Currently, information is not available regarding the activity of the major urinary metabolites of bicalutamide, bicalutamide glucuronide, and hydroxybicalutamide glucuronide.
^abSchellhammer PF (September 2002). "An evaluation of bicalutamide in the treatment of prostate cancer".Expert Opinion on Pharmacotherapy.3 (9):1313–28.doi:10.1517/14656566.3.9.1313.PMID12186624.S2CID32216411.The clearance of bicalutamide occurs pre- dominantly by hepatic metabolism and glucuronidation, with excretion of the resulting inactive metabolites in the urine and faces.
^abNargund VH, Raghavan D, Sandler HM (17 January 2015).Urological Oncology. Springer. pp. 823–.ISBN978-0-85729-482-1.On the other hand, the 150 mg dose of bicalutamide has been associated with some safety concerns, such as a higher death rate when added to active surveillance in the early prostate cancer trialists group study [29], which has led the United States and Canada to recommend against prescribing the 150 mg dose [30].
^abElliott S, Latini DM, Walker LM, Wassersug R, Robinson JW (2010). "Androgen deprivation therapy for prostate cancer: recommendations to improve patient and partner quality of life".The Journal of Sexual Medicine.7 (9):2996–3010.doi:10.1111/j.1743-6109.2010.01902.x.PMID20626600.
^abHammerer P, Manka L (2019). "Androgen Deprivation Therapy for Advanced Prostate Cancer".Urologic Oncology. Springer International Publishing. pp. 255–276.doi:10.1007/978-3-319-42623-5_77.ISBN978-3-319-42622-8.Bicalutamide is the most widely used antiandrogen in the treatment of prostate cancer. [...] Common side effects [of bicalutamide] include breast enlargement, breast tenderness, hot flashes, and constipation as well as feminization and changes in mood and liver as well as lung toxicity; monitoring of liver enzymes is recommended during treatment (Schellhammer and Davis 2004).
^abJia AY, Spratt DE (June 2022). "Bicalutamide Monotherapy With Radiation Therapy for Localized Prostate Cancer: A Non-Evidence-Based Alternative".Int J Radiat Oncol Biol Phys.113 (2):316–319.doi:10.1016/j.ijrobp.2022.01.037.PMID35569476.S2CID248765294.Four other randomized trials using BICmono have also raised concerns about either lack of efficacy or even harm from this treatment approach compared with placebo or no hormone therapy. SPCG-6 randomized 1218 patients to either 150 mg of BICmono daily or placebo. In the subset of patients with LPCa managed with observation, survival was significantly worse with BIC than placebo (hazard ratio [HR], 1.47; 95% confidence interval, 1.06-2.03).10 Two other randomized trials were part of the early prostate cancer program,11 which conducted 3 randomized trials that were pooled together to determine the benefit of BICmono (SPCG-6 was one of the 3 trials). Overall, in the combined 8113 patient pooled cohort, after a median follow-up of 7 years, there was no improvement even in progression-free survival from the use of adjuvant BIC in LPCa, and there was a trend for worse overall survival (HR, 1.16; 95% confidence interval, 0.99-1.37; P = .07). [...] Although not in LPCa, NRG/RTOG 9601 demonstrated findings consistent with the prior trials.12 This trial randomized men to postprostatectomy salvage radiation therapy plus placebo versus 150 mg of BICmono daily for 2 years. After a median follow-up of 13 years, the trial showed that there were significantly more grade 3 to 5 cardiac events in the BICmono arm. In patients with less aggressive disease with lower PSAs (prostate-specific antigens; more analogous to LPCa), other-cause mortality was significantly higher in the BICmono arm. In patients with high PSAs >1.5 ng/mL (which with modern molecular positron emission tomography imaging would be expected to have high rates of regional and distant metastatic disease), a survival benefit from the addition of BIC was observed. This is consistent with results from the early prostate cancer studies that showed that only patients with more advanced disease derived benefit from BICmono.10 Thus, all the randomized evidence from 5 trials (Table 1) demonstrates that, in LPCa, BICmono had no clinically significant oncologic activity over placebo/no treatment, and consistent trends with long-term use resulted in worse survival.
^abLee K, Oda Y, Sakaguchi M, Yamamoto A, Nishigori C (May 2016). "Drug-induced photosensitivity to bicalutamide – case report and review of the literature".Photodermatology, Photoimmunology & Photomedicine.32 (3):161–4.doi:10.1111/phpp.12230.PMID26663090.S2CID2761388.
^abcdeFurr BJ, Tucker H (January 1996). "The preclinical development of bicalutamide: pharmacodynamics and mechanism of action".Urology.47 (1A Suppl):13–25, discussion 29–32.doi:10.1016/S0090-4295(96)80003-3.PMID8560673.
^World Health Organization (2019).World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^Hamilton R (2015).Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 381.ISBN9781284057560.
^abAkaza H (1999). "[A new anti-androgen, bicalutamide (Casodex), for the treatment of prostate cancer—basic clinical aspects]".Gan to Kagaku Ryoho. Cancer & Chemotherapy (in Japanese).26 (8):1201–7.PMID10431591.
^abcdCampbell T (22 January 2014)."Slowing Sales for Johnson & Johnson's Zytiga May Be Good News for Medivation". The Motley Fool.Archived from the original on 26 August 2016. Retrieved20 July 2016.[...] the most commonly prescribed treatment for metastatic castration resistant prostate cancer: bicalutamide. That was sold as AstraZeneca's billion-dollar-a-year drug Casodex before losing patent protection in 2008. AstraZeneca still generates a few hundred million dollars in sales from Casodex, [...]
^Klotz L, Schellhammer P (March 2005). "Combined androgen blockade: the case for bicalutamide".Clinical Prostate Cancer.3 (4):215–9.doi:10.3816/cgc.2005.n.002.PMID15882477.
^Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ (September 1997). "Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Casodex Combination Study Group".Urology.50 (3):330–6.doi:10.1016/S0090-4295(97)00279-3.PMID9301693.
^abcSuzuki H, Kamiya N, Imamoto T, Kawamura K, Yano M, Takano M, Utsumi T, Naya Y, Ichikawa T (October 2008). "Current topics and perspectives relating to hormone therapy for prostate cancer".International Journal of Clinical Oncology.13 (5):401–10.doi:10.1007/s10147-008-0830-y.PMID18946750.S2CID32859879.
^abMelmed S (1 January 2016).Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 752–.ISBN978-0-323-29738-7.GnRH analogues, both agonists and antagonists, severely suppress endogenous gonadotropin and testosterone production [...] Administration of GnRH agonists (e.g., leuprolide, goserelin) produces an initial stimulation of gonadotropin and testosterone secretion (known as a "flare"), which is followed in 1 to 2 weeks by GnRH receptor downregulation and marked suppression of gonadotropins and testosterone to castration levels. [...] To prevent the potential complications associated with the testosterone flare, AR antagonists (e.g., bicalutamide) are usually coadministered with a GnRH agonist for men with metastatic prostate cancer.399
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^Haddad NG, Eugster EA (2012). "Peripheral Precocious Puberty: Interventions to Improve Growth".Handbook of Growth and Growth Monitoring in Health and Disease. Springer. pp. 1199–1212.doi:10.1007/978-1-4419-1795-9_71.ISBN978-1-4419-1794-2.
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^abcdeChabner BA, Longo DL (8 November 2010).Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 679–680.ISBN978-1-60547-431-1.Archived from the original on 10 January 2023. Retrieved27 September 2016.From a structural standpoint, antiandrogens are classified as steroidal, including cyproterone [acetate] (Androcur) and megestrol [acetate], or nonsteroidal, including flutamide (Eulexin, others), bicalutamide (Casodex), and nilutamide (Nilandron). The steroidal antiandrogens are rarely used.
^Kolvenbag GJ, Furr BJ, Blackledge GR (December 1998). "Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity".Prostate Cancer Prostatic Dis.1 (6):307–314.doi:10.1038/sj.pcan.4500262.PMID12496872.S2CID33497597.In addition, since bicalutamide has a low solubility, authentic Casodex® is micronised to ensure a small and consistent particle size to optimise bioavailability.
^"Bicalutamide"(PDF). Richmond Hill, Ontario: Nu-Pharm Inc. October 2009.
^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.PMID12353966.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.
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^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.ISSN1662-0631.S2CID81661015.
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^Higano CS (February 2003). "Side effects of androgen deprivation therapy: monitoring and minimizing toxicity".Urology.61 (2 Suppl 1):32–8.doi:10.1016/S0090-4295(02)02397-X.PMID12667885.
^Higano CS (2012). "Sexuality and intimacy after definitive treatment and subsequent androgen deprivation therapy for prostate cancer".Journal of Clinical Oncology.30 (30):3720–5.doi:10.1200/JCO.2012.41.8509.PMID23008326.
^abcdefghKolvenbag GJ, Blackledge GR (January 1996). "Worldwide activity and safety of bicalutamide: a summary review".Urology.47 (1A Suppl):70–9, discussion 80–4.doi:10.1016/s0090-4295(96)80012-4.PMID8560681.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.
^Kathryn Korkidakis A, Reid RL (2017). "Testosterone in Women: Measurement and Therapeutic Use".Journal of Obstetrics and Gynaecology Canada.39 (3):124–130.doi:10.1016/j.jogc.2017.01.006.PMID28343552.
^Davis SR, Wahlin-Jacobsen S (2015). "Testosterone in women--the clinical significance".The Lancet Diabetes & Endocrinology.3 (12):980–92.doi:10.1016/S2213-8587(15)00284-3.PMID26358173.
^Luque-Ramírez M, Ortiz-Flores AE, Nattero-Chávez L, Escobar-Morreale HF (December 2020). "A safety evaluation of current medications for adult women with the polycystic ovarian syndrome not pursuing pregnancy".Expert Opin Drug Saf.19 (12):1559–1576.doi:10.1080/14740338.2020.1839409.PMID33070640.S2CID224784192.
^Fourcade RO, McLeod D (March 2004). "Tolerability of Antiandrogens in the Treatment of Prostate Cancer".UroOncology.4 (1):5–13.doi:10.1080/1561095042000191655.ISSN1561-0950.Based on the available evidence, bicalutamide appears to have a better profile of non-pharmacological side effects than either flutamide or nilutamide; no specific nonpharmacological complications have yet been linked to this agent, while the incidence of the side effects such as diarrhoea and abnormal liver function appears to be lower than for the other two non-steroidal compounds. Furthermore, the recent data from the EPC programme suggest that the non-pharmacological side-effect profile of bicalutamide is not dissimilar to that of placebo (Table m [3].
^Lunglmayr G (August 1995). "Efficacy and tolerability of Casodex in patients with advanced prostate cancer. International Casodex Study Group".Anti-Cancer Drugs.6 (4):508–13.doi:10.1097/00001813-199508000-00003.PMID7579554.
^Tyrrell CJ, Iversen P, Tammela T, Anderson J, Björk T, Kaisary AV, Morris T (September 2006). "Tolerability, efficacy and pharmacokinetics of bicalutamide 300 mg, 450 mg or 600 mg as monotherapy for patients with locally advanced or metastatic prostate cancer, compared with castration".BJU International.98 (3):563–72.doi:10.1111/j.1464-410X.2006.06275.x.PMID16771791.S2CID41672303.
^abSee WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, et al. (August 2002). "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".The Journal of Urology.168 (2):429–35.doi:10.1016/S0022-5347(05)64652-6.PMID12131282.
^Schellhammer P, Sharifi R, Block N, Soloway M, Venner P, Patterson AL, Sarosdy M, Vogelzang N, Jones J, Kolvenbag G (January 1996). "Maximal androgen blockade for patients with metastatic prostate cancer: outcome of a controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy. Casodex Combination Study Group".Urology.47 (1A Suppl):54–60, discussion 80–4.doi:10.1016/s0090-4295(96)80010-0.PMID8560679.
^Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K (November 2004). "Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6".The Journal of Urology.172 (5 Pt 1):1871–6.doi:10.1097/01.ju.0000139719.99825.54.PMID15540741.
^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.PMID17130095.S2CID25862814.
^abTrüeb RM, Luu NC, Uribe NC, Régnier A (December 2022). "Comment on: Bicalutamide and the new perspectives for female pattern hair loss treatment: What dermatologists should know".J Cosmet Dermatol.21 (12):7200–7201.doi:10.1111/jocd.14936.PMID35332669.S2CID247677549.Indeed, due to the minimal biological importance of androgens in women, the adverse effects of bicalutamide are few. And yet, bicalutamide has been associated with elevated liver enzymes, and as of 2021, there have been 10 case reports of liver toxicity associated with bicalutamide, with fatality occurring in 2 cases.2
^Masago T, Watanabe T, Nemoto R, Motoda K (December 2011). "Interstitial pneumonitis induced by bicalutamide given for prostate cancer".International Journal of Clinical Oncology.16 (6):763–5.doi:10.1007/s10147-011-0239-x.PMID21537882.S2CID24068787.
^Daba MH, El-Tahir KE, Al-Arifi MN, Gubara OA (June 2004). "Drug-induced pulmonary fibrosis".Saudi Medical Journal.25 (6):700–6.PMID15195196.
^Thole Z, Manso G, Salgueiro E, Revuelta P, Hidalgo A (2004). "Hepatotoxicity induced by antiandrogens: a review of the literature".Urologia Internationalis.73 (4):289–95.doi:10.1159/000081585.PMID15604569.S2CID24799765.
^Ricci F, Buzzatti G, Rubagotti A, Boccardo F (November 2014). "Safety of antiandrogen therapy for treating prostate cancer".Expert Opinion on Drug Safety.13 (11):1483–99.doi:10.1517/14740338.2014.966686.PMID25270521.S2CID207488100.
^Boccardo F (2000). "Hormone therapy of prostate cancer: is there a role for antiandrogen monotherapy?".Crit. Rev. Oncol. Hematol.35 (2):121–32.doi:10.1016/s1040-8428(00)00051-2.PMID10936469.
^Thole Z, Manso G, Salgueiro E, Revuelta P, Hidalgo A (2004). "Hepatotoxicity induced by antiandrogens: a review of the literature".Urol. Int.73 (4):289–95.doi:10.1159/000081585.PMID15604569.S2CID24799765.
^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.PMID12353966.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.
^Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, Arezzo JC, Powlin SS, Dinchuk JE, Balog A, Salvati ME, Attar RM, Gottardis MM (2011). "Drug safety is a barrier to the discovery and development of new androgen receptor antagonists".Prostate.71 (5):480–8.doi:10.1002/pros.21263.PMID20878947.S2CID24620044.
^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 (2014)."Enzalutamide in metastatic prostate cancer before chemotherapy".N. Engl. J. Med.371 (5):424–33.doi:10.1056/NEJMoa1405095.PMC4418931.PMID24881730.
^Furr BJ, Tucker H (1996). "The preclinical development of bicalutamide: pharmacodynamics and mechanism of action".Urology.47 (1A Suppl):13–25, discussion 29–32.doi:10.1016/S0090-4295(96)80003-3.PMID8560673.
^Greenblatt DJ, Koch-Weser J (July 1973). "Adverse reactions to spironolactone. A report from the Boston Collaborative Drug Surveillance Program".JAMA.225 (1):40–3.doi:10.1001/jama.1973.03220280028007.PMID4740303.
^Bahceci M, Tuzcu A, Canoruc N, Tuzun Y, Kidir V, Aslan C (2004). "Serum C-reactive protein (CRP) levels and insulin resistance in non-obese women with polycystic ovarian syndrome, and effect of bicalutamide on hirsutism, CRP levels and insulin resistance".Hormone Research.62 (6):283–7.doi:10.1159/000081973 (inactive 2 December 2024).PMID15542929.S2CID46261843.{{cite journal}}: CS1 maint: DOI inactive as of December 2024 (link)
^abcTyrrell CJ, Iversen P, Tammela T, Anderson J, Björk T, Kaisary AV, Morris T (September 2006). "Tolerability, efficacy and pharmacokinetics of bicalutamide 300 mg, 450 mg or 600 mg as monotherapy for patients with locally advanced or metastatic prostate cancer, compared with castration".BJU International.98 (3):563–72.doi:10.1111/j.1464-410X.2006.06275.x.PMID16771791.S2CID41672303.
^Genrx (1999).1999 Mosby's GenRx. Mosby.ISBN978-0-323-00625-5.A 79-year-old man attempted suicide by ingesting 13g of nilutamide (i.e., 43 times the maximum recommended dose). Despite immediate gastric lavage and oral administration of activated charcoal, plasma nilutamide levels peaked at 6 times the normal range 2 hours after ingestion. There were no clinical signs or symptoms or changes in parameters such as transaminases or chest x-ray. Maintenance treatment (150 mg/day) was resumed 30 days later.
^abcdefghiWeber GF (22 July 2015).Molecular Therapies of Cancer. Springer. pp. 318–.ISBN978-3-319-13278-5.Compared to flutamide and nilutamide, bicalutamide has a 2-fold increased affinity for the Androgen Receptor, a longer half-life, and substantially reduced toxicities. Based on a more favorable safety profile relative to flutamide, bicalutamide is indicated for use in combination therapy with a Gonadotropin Releasing Hormone analog for the treatment of advanced metastatic prostate carcinoma.
^Mosby's GenRx: A Comprehensive Reference for Generic and Brand Prescription Drugs. Mosby. 2001. p. 290.ISBN978-0-323-00629-3.In vitro studies have shown bicalutamide can displace coumarin anticoagulants, such as warfarin, from their protein-binding sites. It is recommended that if bicalutamide is started in patients already receiving coumarin anticoagulants, prothrombin times should be closely monitored and adjustment of the anticoagulant dose may be necessary.
^Furr BK (1997). "Relative potencies of flutamide and 'Casodex'".Endocrine-Related Cancer.4 (2):197–202.doi:10.1677/erc.0.0040197 (inactive 1 November 2024).ISSN1351-0088.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
^Furr BJ (1996). "The development of Casodex (bicalutamide): preclinical studies".European Urology.29 (Suppl 2):83–95.doi:10.1159/000473846.PMID8717469.
^abcdDenis L, Mahler C (January 1996). "Pharmacodynamics and pharmacokinetics of bicalutamide: defining an active dosing regimen".Urology.47 (1A Suppl):26–8, discussion 29–32.doi:10.1016/S0090-4295(96)80004-5.PMID8560674.
^Eri LM, Haug E, Tveter KJ (March 1995). "Effects on the endocrine system of long-term treatment with the non-steroidal anti-androgen Casodex in patients with benign prostatic hyperplasia".British Journal of Urology.75 (3):335–40.doi:10.1111/j.1464-410X.1995.tb07345.x.PMID7537602.
^abBouchard P, Caraty A (15 November 1993).GnRH, GnRH Analogs, Gonadotropins and Gonadal Peptides. CRC Press. pp. 455–456.ISBN978-0-203-09205-7.[...] when male levels of androgens are achieved in plasma, their effects on gonadotropin secretion are similar in women and men. [...] administration of flutamide in a group of normally-cycling women produced a clinical improvement of acne and hirsutism without any significant hormonal change. [...] All these data emphasize that physiological levels of androgens have no action on the regulation of gonadotropins in normal women. [...] Androgens do not directly play a role in gonadotropin regulation [in women].
^Asscheman H, Gooren LJ, Peereboom-Wynia JD (1989). "Reduction in undesired sexual hair growth with anandron in male-to-female transsexuals—experiences with a novel androgen receptor blocker".Clinical and Experimental Dermatology.14 (5):361–3.doi:10.1111/j.1365-2230.1989.tb02585.x.PMID2612040.S2CID45303518.
^Rao BR, de Voogt HJ, Geldof AA, Gooren LJ, Bouman FG (1988). "Merits and considerations in the use of anti-androgen".Journal of Steroid Biochemistry.31 (4B):731–7.doi:10.1016/0022-4731(88)90024-6.PMID3143862.
^abWibowo E, Schellhammer P, Wassersug RJ (January 2011). "Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy".The Journal of Urology.185 (1):17–23.doi:10.1016/j.juro.2010.08.094.PMID21074215.
^abMotofei IG, Rowland DL, Popa F, Kreienkamp D, Paunica S (July 2011). "Preliminary study with bicalutamide in heterosexual and homosexual patients with prostate cancer: a possible implication of androgens in male homosexual arousal".BJU International.108 (1):110–5.doi:10.1111/j.1464-410X.2010.09764.x.PMID20955264.S2CID45482984.
^abWibowo E, Wassersug RJ (September 2013). "The effect of estrogen on the sexual interest of castrated males: Implications to prostate cancer patients on androgen-deprivation therapy".Critical Reviews in Oncology/Hematology.87 (3):224–38.doi:10.1016/j.critrevonc.2013.01.006.PMID23484454.
^Huang Q, Zhu H, Fischer DF, Zhou JN (June 2008). "An estrogenic effect of 5alpha-androstane-3beta, 17beta-diol on the behavioral response to stress and on CRH regulation".Neuropharmacology.54 (8):1233–8.doi:10.1016/j.neuropharm.2008.03.016.PMID18457850.S2CID9052079.
^Mahler C, Verhelst J, Denis L (May 1998). "Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer".Clinical Pharmacokinetics.34 (5):405–417.doi:10.2165/00003088-199834050-00005.PMID9592622.S2CID25200595.If used in monotherapy, libido and potency are largely preserved. Although the mechanisms to explain this are not completely understood, it seems that at the central level pure antiandrogens are unable to completely inhibit the effect of the increased amount of androgens.
^Morgante E, Gradini R, Realacci M, Sale P, D'Eramo G, Perrone GA, Cardillo MR, Petrangeli E, Russo M, Di Silverio F (March 2001). "Effects of long-term treatment with the anti-androgen bicalutamide on human testis: an ultrastructural and morphometric study".Histopathology.38 (3):195–201.doi:10.1046/j.1365-2559.2001.01077.x.hdl:11573/387981.PMID11260298.S2CID36892099.
^abJones CA, Reiter L, Greenblatt E (2016). "Fertility preservation in transgender patients".International Journal of Transgenderism.17 (2):76–82.doi:10.1080/15532739.2016.1153992.ISSN1553-2739.S2CID58849546.Traditionally, patients have been advised to cryopreserve sperm prior to starting cross-sex hormone therapy as there is a potential for a decline in sperm motility with high-dose estrogen therapy over time (Lubbert et al., 1992). However, this decline in fertility due to estrogen therapy is controversial due to limited studies.
^abPayne AH, Hardy MP (28 October 2007).The Leydig Cell in Health and Disease. Springer Science & Business Media. pp. 422–431.ISBN978-1-59745-453-7.Estrogens are highly efficient inhibitors of the hypothalamic-hypophyseal-testicular axis (212–214). Aside from their negative feedback action at the level of the hypothalamus and pituitary, direct inhibitory effects on the testis are likely (215,216). [...] The histology of the testes [with estrogen treatment] showed disorganization of the seminiferous tubules, vacuolization and absence of lumen, and compartmentalization of spermatogenesis.
^abSalam MA (2003).Principles & Practice of Urology: A Comprehensive Text. Universal-Publishers. pp. 684–.ISBN978-1-58112-412-5.Estrogens act primarily through negative feedback at the hypothalamic-pituitary level to reduce LH secretion and testicular androgen synthesis. [...] Interestingly, if the treatment with estrogens is discontinued after 3 yr. of uninterrupted exposure, serum testosterone may remain at castration levels for up to another 3 yr. This prolonged suppression is thought to result from a direct effect of estrogens on the Leydig cells.
^abFoster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, Arezzo JC, Powlin SS, Dinchuk JE, Balog A, Salvati ME, Attar RM, Gottardis MM (April 2011). "Drug safety is a barrier to the discovery and development of new androgen receptor antagonists".The Prostate.71 (5):480–8.doi:10.1002/pros.21263.PMID20878947.S2CID24620044.
^Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)".Eur. Urol.29 (Suppl 2):96–104.doi:10.1159/000473847.PMID8717470.
^Furr BJ (1989). ""Casodex" (ICI 176,334)--a new, pure, peripherally-selective anti-androgen: preclinical studies".Hormone Research.32 (Suppl 1):69–76.doi:10.1159/000181315 (inactive 11 November 2024).PMID2533159.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
^Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen".The Journal of Endocrinology.113 (3): R7-9.doi:10.1677/joe.0.113R007.PMID3625091.
^Soloway MS, Schellhammer PF, Smith JA, Chodak GW, Vogelzang NJ, Kennealey GT (December 1995). "Bicalutamide in the treatment of advanced prostatic carcinoma: a phase II noncomparative multicenter trial evaluating safety, efficacy and long-term endocrine effects of monotherapy".The Journal of Urology.154 (6):2110–4.doi:10.1016/S0022-5347(01)66709-0.PMID7500470.
^Mason M (August 2006). "What implications do the tolerability profiles of antiandrogens and other commonly used prostate cancer treatments have on patient care?".Journal of Cancer Research and Clinical Oncology.132 (Suppl 1): S27-35.doi:10.1007/s00432-006-0134-4.PMID16896883.S2CID19685819.
^Fradet Y (February 2004). "Bicalutamide (Casodex) in the treatment of prostate cancer".Expert Review of Anticancer Therapy.4 (1):37–48.doi:10.1586/14737140.4.1.37.PMID14748655.S2CID34153031.In contrast, the incidence of diarrhea was comparable between the bicalutamide and placebo groups (6.3 vs. 6.4%, respectively) in the EPC program [71].
^Sharma K, Pawar GV, Giri S, Rajagopal S, Mullangi R (2012). "Development and validation of a highly sensitive LC-MS/MS-ESI method for the determination of bicalutamide in mouse plasma: application to a pharmacokinetic study".Biomedical Chromatography.26 (12):1589–95.doi:10.1002/bmc.2736.PMID22495777.
^Anderson PO, Knoben JE, Troutman WG (22 August 2001).Handbook of Clinical Drug Data. Canadian Medical Association Journal. Vol. 128. McGraw Hill Professional. p. 245.ISBN978-0-07-138942-6.PMC1875767.PMID20313924.With an oral dose of 50 mg/day, bicalutamide attains a peak serum level of 8.9 mg/L (21 μmol/L) 31 hr after a dose at steady state. CI of (R)-bicalutamide is 0.32 L/hr. The active (R)-enantiomer of bicalutamide is oxidized to an inactive metabolite, which, like the inactive (S)-enantiomer, is glucuronidated and cleared rapidly by elimination in the urine and feces.165
^abcdeMohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, Hwang DJ, Dalton JT, Miller DD (June 2009). "Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit".Journal of Medicinal Chemistry.52 (12):3597–617.doi:10.1021/jm900280m.PMID19432422.[C]linically relevant antiandrogens currently are nonsteroidal anilide derivatives. Antiandrogens used for prostate cancer include the monoarylpropionamide flutamide (1) (a prodrug of hydroxyflutamide (2)),29–31 the hydantoin nilutamide(3),32–34 and the diarylpropionamide bicalutamide (4) (Chart1).35–37
^Kawahara T, Minamoto H (2014). "Androgen Receptor Antagonists in the Treatment of Prostate Cancer".Clinical Immunology, Endocrine & Metabolic Drugs.1 (1):11–19.doi:10.2174/22127070114019990002.
^abcSegal S, Narayanan R, Dalton JT (April 2006). "Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery".Expert Opinion on Investigational Drugs.15 (4):377–87.doi:10.1517/13543784.15.4.377.PMID16548787.S2CID31787187.Structural modifications of bicalutamide led to the discovery of the first nonsteroidal androgens (the aryl propionamides) in 1998. Lead compounds in this class (denoted S1 and S4 in published literature) not only bind to the AR with high affinity (low nanomolar range), but also demonstrate tissue selectivity in animal models [46,50].
^abcdParent EE, Dence CS, Jenks C, Sharp TL, Welch MJ, Katzenellenbogen JA (2007). "Synthesis and biological evaluation of [18F]bicalutamide, 4-[76Br]bromobicalutamide, and 4-[76Br]bromo-thiobicalutamide as non-steroidal androgens for prostate cancer imaging".J. Med. Chem.50 (5):1028–40.doi:10.1021/jm060847r.PMID17328524.
^Chand M, Shukla AK (2012). Novel Synthesis of Bicalutamide Drug Substance and their Impurities using Imidazolium Type of Ionic Liquid (Report).doi:10.2139/ssrn.2160199.SSRN2160199.
^Diamanti-Kandarakis E (September 1999)."Current aspects of antiandrogen therapy in women".Current Pharmaceutical Design.5 (9):707–23.doi:10.2174/1381612805666230111201150.PMID10495361.Archived from the original on 10 January 2023. Retrieved27 September 2016.Several trials demonstrated complete clearing of acne with flutamide [62,77]. Flutamide used in combination with an [oral contraceptive], at a dose of 500mg/d, flutamide caused a dramatic decrease (80%) in total acne, seborrhea and hair loss score after only 3 months of therapy [53]. When used as a monotherapy in lean and obese PCOS, it significantly improves the signs of hyperandrogenism, hirsutism and particularly acne [48]. [...] flutamide 500mg/d combined with an [oral contraceptive] caused an increase in cosmetically acceptable hair density, in sex of seven women suffering from diffuse androgenetic alopecia [53].
^Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen".The Journal of Endocrinology.113 (3): R7-9.doi:10.1677/joe.0.113r007.PMID3625091.
^Newling DW (1990). "The response of advanced prostatic cancer to a new non-steroidal antiandrogen: results of a multicenter open phase II study of Casodex. European/Australian Co-operative Group".European Urology.18 (Suppl 3):18–21.doi:10.1159/000463973.PMID2094607.
^Kolvenbag GJ, Iversen P, Newling DW (2001). "Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer".Urology.58 (2 Suppl 1):16–23.doi:10.1016/s0090-4295(01)01237-7.PMID11502439.
^Bono AV (2004). "Overview of Current Treatment Strategies in Prostate Cancer".European Urology Supplements.3 (1):2–7.doi:10.1016/j.eursup.2003.12.002.The Canadian Health Authorities have withdrawn the approval for antiandrogen monotherapy with bicalutamide for the treatment of localised prostate cancer [5]. Several European countries have also withdrawn approval for bicalutamide for this indication.
^Dhas NL, Ige PP, Kudarha RR (2015). "Design, optimization and in-vitro study of folic acid conjugated-chitosan functionalized PLGA nanoparticle for delivery of bicalutamide in prostate cancer".Powder Technology.283:234–245.doi:10.1016/j.powtec.2015.04.053.
^Emans SJ, Laufer MR (5 January 2012).Emans, Laufer, Goldstein's Pediatric and Adolescent Gynecology. Lippincott Williams & Wilkins. pp. 365–.ISBN978-1-4511-5406-1.Archived from the original on 16 May 2016.Therapy with GnRH analogs is expensive and requires intramuscular injections of depot formulations, the insert of a subcutaneous implant yearly, or, much less commonly, daily subcutaneous injections.
^Wang LG, Mencher SK, McCarron JP, Ferrari AC (2004). "The biological basis for the use of an anti-androgen and a 5-alpha-reductase inhibitor in the treatment of recurrent prostate cancer: Case report and review".Oncology Reports.11 (6):1325–9.doi:10.3892/or.11.6.1325.PMID15138573.
^Merrick GS, Butler WM, Wallner KE, Galbreath RW, Allen ZA, Kurko B (2006). "Efficacy of neoadjuvant bicalutamide and dutasteride as a cytoreductive regimen before prostate brachytherapy".Urology.68 (1):116–20.doi:10.1016/j.urology.2006.01.061.PMID16844453.
^Sartor O, Gomella LG, Gagnier P, Melich K, Dann R (2009). "Dutasteride and bicalutamide in patients with hormone-refractory prostate cancer: the Therapy Assessed by Rising PSA (TARP) study rationale and design".The Canadian Journal of Urology.16 (5):4806–12.PMID19796455.
^Chu FM, Sartor O, Gomella L, Rudo T, Somerville MC, Hereghty B, Manyak MJ (2015). "A randomised, double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate-resistant prostate cancer".European Journal of Cancer.51 (12):1555–69.doi:10.1016/j.ejca.2015.04.028.PMID26048455.
^Gaudet M, Vigneault É, Foster W, Meyer F, Martin AG (2016). "Randomized non-inferiority trial of Bicalutamide and Dutasteride versus LHRH agonists for prostate volume reduction prior to I-125 permanent implant brachytherapy for prostate cancer".Radiotherapy and Oncology.118 (1):141–7.doi:10.1016/j.radonc.2015.11.022.PMID26702991.
^Ho TH, Nunez-Nateras R, Hou YX, Bryce AH, Northfelt DW, Dueck AC, et al. (April 2017). "A Study of Combination Bicalutamide and Raloxifene for Patients With Castration-Resistant Prostate Cancer".Clinical Genitourinary Cancer.15 (2): 196–202.e1.doi:10.1016/j.clgc.2016.08.026.PMID27771244.S2CID19043552.
^abcdLepor H (1993). "Medical therapy for benign prostatic hyperplasia".Urology.42 (5):483–501.doi:10.1016/0090-4295(93)90258-c.PMID7694413.The clinically significant adverse events reported in the casodex group included breast tenderness (93%), breast enlargement (54%), and sexual dysfunction (60%). In none of the patients in the placebo group did any of these adverse events develop. None of the subjects discontinued therapy owing to an adverse event.
^Kenny B, Ballard S, Blagg J, Fox D (1997). "Pharmacological options in the treatment of benign prostatic hyperplasia".J. Med. Chem.40 (9):1293–315.doi:10.1021/jm960697s.PMID9135028.
^Fox JG, Marini RP (26 March 2014).Biology and Diseases of the Ferret. Wiley. p. 980.ISBN978-1-118-78273-6.Other agents have been proposed for medical management of [adrenal-associated endocrinopathy] but have not been studied. Possibly medications include the androgen receptor blockers flutamide and bicalutamide, the anti-androgen finasteride, estrogen-inhibiting anastrozole, and another GnRH analog, goserelin. [...] None of these drugs have been tested in controlled clinical trials in ferrets.
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