【药物名称】比卡鲁胺 bicalutamide
【中文别名】N-[4-氰基-3-(三氟甲基)苯基]-3-(4-氟苯硫酰基)-2-甲基-2-羟基丙酰胺
【英文名称】Bicalutamide
【英文别名】Bicalutamide (Subject to patent free); 4-cyano-3-trifluoromethyl-N-(3-p-fluorophenylsulfonyl-2-hydroxy-2-methylpropionyl)aniline; N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methyl-propanamid
【CAS号】90357-06-5
【分子式成分】分子式：C18H14F4N2O4S。
【分子量】430.37
【分子结构】
【性状】为白色薄膜衣片。
【药理作用】
比卡鲁胺属于非甾体类抗雄激素药物，没有其它激素的作用，它与雄激素受体结合而使其无有效的基因表达，从而抑制了雄激素的刺激，导致前列腺肿瘤的萎缩。比卡鲁胺是消旋物，其抗雄激素作用仅仅出现在（R）-结构对应体上。
【药代动力学】
比卡鲁胺经口服吸收良好。没有证据表明食物对其生物利用度存在任何临床相关的影响。（S）-异构体相对（R）-异构体消除较为迅速，后者的血浆半衰期为1周。在比卡鲁胺的每日用量下，R）-异构体因其半衰期长，在血浆中蓄积了约10倍，因此非常适合每日1次的日服。比卡鲁胺与血浆蛋白高度结合（96%），并被广泛代谢（经氧化及葡萄糖醛酸化），其代谢产物以几乎相同的比例经肾及胆消除。
【适应症】与黄体生成素释放激素（LHRH）类似物或外科睾丸切除术联合应用于晚期前列腺癌的治疗。
用法用量
【用法用量】
成人：成人男性包括老年人：一片（50mg），每日1次，用比卡鲁胺治疗应与LHRH类似物或外科睾丸切除术治疗同时开始。
儿童：比卡鲁胺禁用于儿童
肾损害：对于肾损害的病人无需调整剂量。
肝损害：对于轻度肝损害的病人无需调整剂量，中重度肝操作的病人可能发生药物蓄积。
【不良反应】
面色潮红，瘙痒，乳房触痛和男性乳房女性化，腹泻、恶心、呕吐，乏力。暂时性肝功改变（转氨酶升高，黄疸）。康士得与LHRH类似物联用，进行临床研究期间还观察到下列副作用（可能与药物相关且发生率大于1%），这些副作用与药物的使用没有因果关系，有些是老年人日常固有的
心血管系统 ：心力衰竭。消化系统 ：厌食、口干、消化不良、便秘、腹痛、胃肠胀气。中枢神经系统 ：头晕、失眠、嗜睡、性欲减低。呼吸系统 ：呼吸困难。泌尿生殖系统 ：阳痿、夜尿增多。
血液系统 ：贫血。皮肤 ：脱发、皮疹、出汗、多毛。代谢及营养 ：糖尿病、高血糖、周围性水肿、体重增加或减轻。其他 ：胸痛、头痛、骨盆痛、寒战。
【禁忌症】
对比卡鲁胺过敏者，以及妇女、儿童。
【注意事项】
中、重度肝损伤病人可能发生药物蓄积，因此应慎用。
【药物相互作用】
比卡鲁胺与黄体生成素释放激素（LHRH）类似物之间无任何药效学或药代动力学方面的相互作用。与常见的处方药合用未出现相互作用。在每天剂量高达150 mg时未发现酶诱导作用。体外研究表明，比卡鲁胺可以与双香豆素类抗凝剂，如华法令竞争其血浆蛋白结合点，因此建议在已经接受双香豆素类抗凝剂治疗的病人，如果开始服用比卡鲁胺，应密切监测凝血酶原时间。
【药物过量】
没有人类过量的经验，没有特效的解药，应该对症治疗。透析可能无效，因为比卡鲁胺与血浆蛋白高度结合，且在尿液中以非原形排泄。但一般的支持疗法是需要的，这包括生命体征的密切监测。
新研究提示，放疗后每日比卡鲁胺，（Casodex）治疗似乎可改善局部晚期前列腺癌男性的生存。然而，这种生存益处似乎与内科去雄疗法加入放疗的结果类似。
根据这些发现，作者相信抗雄激素药比卡鲁胺可能是去雄疗法的一种合适的、较好耐受的替代；去雄疗法对生活质量有不利影响。如同在8月的《癌症研究和临床肿瘤学杂志》（J Cancer Res Clin Oncol 2006;132:S7-S16.）上所报告的，美国Milwaukee医学院的William A. See博士及其同事评估了在放疗后被随机分配接受比卡鲁胺（150 mg）或安慰剂每日1次的1370例早期前列腺癌（T1-4, N any, M0）患者的生存结果。中位随访期为7.2年。
报告指出，比卡鲁胺治疗与无进展和总生存显著改善相关。与单用放疗比较，加用比卡鲁胺使客观进展风险降低44%。同样，这种药物治疗使总死亡风险降低35%。进一步分析显示，比卡鲁胺引起的总生存改善主要是由于其降低前列腺癌相关死亡的作用。与局部晚期疾病患者不同，有局灶性疾病的患者未从放疗加比卡鲁胺治疗中受益。
作者指出，这是非去雄疗法用于这类患者的总生存益处的首个证据。与去雄疗法比较，比卡鲁胺在维持性欲、体能和骨矿密度方面提供附加的生活质量益处。
其他说明
【贮藏/有效期】 小心贮存30°C以下。五年。
【规    格】50mg*90片
【生产厂家】 德国Stada

比卡鲁胺属于非甾体类抗雄激素药物，与黄体生成素释放激素（LHRH）类似物或外科睾丸切除术联合应用于晚期前列腺癌的治疗。比卡鲁胺经口服吸收良好。与黄体生成素释放激素（LHRH）类似物之间无任何药效学或药代动力学方面的相互作用。与常见的处方药合用未出现相互作用。在每天剂量高达150mg时未发现酶诱导作用。

Bicalutamide
BICALUTAMIDE- bicalutamide tablet
Accord Healthcare Inc
1. INDICATIONS AND USAGEBicalutamide tablets 50 mg daily is indicated for use in combination therapy with a luteinizing hormone-releasing hormone (LHRH) analog for the treatment of Stage D2 metastatic carcinoma of the prostate.
Bicalutamide tablets 150 mg daily is not approved for use alone or with other treatments [see Clinical Studies (14.2)].
2. DOSAGE AND ADMINISTRATIONThe recommended dose for bicalutamide tablets therapy in combination with an LHRH analog is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that bicalutamide tablets be taken at the same time each day. Treatment with bicalutamide tablets should be started at the same time as treatment with an LHRH analog.
2.1. Dosage Adjustment in Renal ImpairmentNo dosage adjustment is necessary for patients with renal impairment [see Use in Specific Populations(8.7)].
2.2. Dosage Adjustment in Hepatic Impairment
No dosage adjustment is necessary for patients with mild to moderate hepatic impairment. In patients with severe liver impairment (n=4), although there was a 76% increase in the half-life (5.9 and 10.4 days for normal and impaired patients, respectively) of the active enantiomer of bicalutamide no dosage adjustment is necessary [see Use in Specific Populations (8.6)].
3. DOSAGE FORMS & STRENGTHSBicalutamide tablets 50 mg for oral administration are white to off-white, round, biconvex, film coated tablets, debossed ‘B 50’ on one side and plain on other side.
4. CONTRAINDICATIONS4.1. HypersensitivityBicalutamide is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or any of the tablet’s components. Hypersensitivity reactions including angioneurotic edema and urticaria have been reported [see Adverse Reactions (6.2)].
4.2. WomenBicalutamide has no indication for women, and should not be used in this population.
4.3. PregnancyBicalutamide may cause fetal harm when administered to a pregnant woman. Bicalutamide is contraindicated in women, including those who are or may become pregnant. There are no studies in pregnant women using bicalutamide. If this drug is used during pregnancy, or if 1 the patient becomes pregnant while taking this drug, the patient should be appraised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
5. WARNINGS AND PRECAUTIONS5.1. HepatitisCases of death or hospitalization due to severe liver injury (hepatic failure) have been reported post-marketing in association with the use of bicalutamide. Hepatotoxicity in these reports generally occurred within the first three to four months of treatment. Hepatitis or marked increases in liver enzymes leading to drug discontinuation occurred in approximately 1% of bicalutamide patients in controlled clinical trials.
Serum transaminase levels should be measured prior to starting treatment with bicalutamide, at regular intervals for the first four months of treatment, and periodically thereafter. If clinical symptoms or signs suggestive of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, dark urine, jaundice, or right upper quadrant tenderness), the serum transaminases, in particular the serum ALT, should be measured immediately. If at any time a patient has jaundice, or their ALT rises above two times the upper limit of normal, bicalutamide should be immediately discontinued with close follow-up of liver function.
5.2. Gynecomastia and Breast PainIn clinical trials with bicalutamide 150 mg as a single agent for prostate cancer, gynecomastia and breast pain have been reported in up to 38% and 39% of patients, respectively.
5.3. Glucose ToleranceA reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycemic control in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists.
5.4. Laboratory TestsadvertisementRegular assessments of serum Prostate Specific Antigen (PSA) may be helpful in monitoring the patient’s response.
If PSA levels rise during bicalutamide therapy, the patient should be evaluated for clinical progression. For patients who have objective progression of disease together with an elevated PSA, a treatment-free period of antiandrogen, while continuing the LHRH analog, may be considered.
6. ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
6.1. Clinical Trials ExperienceIn patients with advanced prostate cancer treated with bicalutamide in combination with an LHRH analog, the most frequent adverse reaction was hot flashes (53%).
In the multicenter, double-blind, controlled clinical trial comparing bicalutamide 50 mg once daily with flutamide 250 mg three times a day, each in combination with an LHRH analog, the following adverse reactions with an incidence of 5% or greater, regardless of causality, have been reported.
Other adverse reactions (greater than or equal to 2%, but less than 5%) reported in the bicalutamide-LHRH analog treatment group are listed below by body system and are in order of decreasing frequency within each body system regardless of causality.
Body as a Whole:
Neoplasm; Neck Pain; Fever; Chills; Sepsis; Hernia; Cyst
Cardiovascular:
Angina Pectoris; Congestive Heart Failure; Myocardial Infarct; Heart Arrest; Coronary Artery Disorder; Syncope
Digestive:
Melena; Rectal Hemorrhage; Dry Mouth; Dysphagia; Gastrointestinal Disorder; Periodontal Abscess; Gastrointestinal Carcinoma
Metabolic and Nutritional:
Edema; BUN Increased; Creatinine Increased; Dehydration; Gout; Hypercholesteremia
Musculoskeletal:
Myalgia; Leg Cramps
Nervous:
Hypertonia; Confusion; Somnolence; Libido Decreased; Neuropathy; Nervousness
Respiratory:
Lung Disorder; Asthma; Epistaxis; Sinusitis
Skin and Appendages:
Dry Skin; Alopecia; Pruritus; Herpes Zoster; Skin Carcinoma; Skin Disorder
Special Senses:
Cataract specified
Urogenital:
Dysuria; Urinary Urgency; Hydronephrosis; Urinary Tract Disorder
Abnormal Laboratory Test Values:
Laboratory abnormalities including elevated AST, ALT, bilirubin, BUN, and creatinine and decreased hemoglobin and white cell count have been reported in both bicalutamide-LHRH analog treated and flutamide-LHRH analog treated patients.
6.2. Postmarketing ExperienceThe following adverse reactions have been identified during postapproval use of bicalutamide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Uncommon cases of hypersensitivity reactions, including angioneurotic edema and urticaria have been seen [see Contraindications (4.1)]. Cases of interstitial lung disease (some fatal), including interstitial pneumonitis and pulmonary fibrosis, have been reported with bicalutamide. Interstitial lung disease has been reported most often at doses greater than 50 mg. A few cases of fatal hepatic failure have been reported.
Reduction in glucose tolerance, manifesting as diabetes or a loss of glycemic control in those with pre-existing diabetes, has been reported during treatment with LHRH agonists.
7. DRUG INTERACTIONSClinical studies have not shown any drug interactions between bicalutamide and LHRH analogs (goserelin or leuprolide). There is no evidence that bicalutamide induces hepatic enzymes.
In vitro studies have shown that R-bicalutamide is an inhibitor of CYP 3A4 with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity. Clinical studies have shown that with co-administration of bicalutamide, mean midazolam (a CYP 3A4 substrate) levels may be increased 1.5 fold (for Cmax ) and 1.9 fold (for AUC). Hence, caution should be exercised when bicalutamide is co-administered with CYP 3A4 substrates.
In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants from binding sites. Prothrombin times should be closely monitored in patients already receiving coumarin anticoagulants who are started on bicalutamide and adjustment of the anticoagulant dose may be necessary.
8. USE IN SPECIFIC POPULATIONS8.1. PregnancyPREGNANCY CATEGORY X[see Contraindications (4.3)]. Based on its mechanism of action, bicalutamide may cause fetal harm when administered to a pregnant woman. Bicalutamide is contraindicated in women, including those who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
While there are no human data on the use of bicalutamide in pregnancy and bicalutamide is not for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus.
In animal reproduction studies, male offspring of rats receiving doses of 10 mg/kg/day (approximately 2/3 of clinical exposure at the recommended dose) and above, were observed to have reduced anogenital distance and hypospadias. These pharmacological effects have been observed with other antiandrogens. No other teratogenic effects were observed in rabbits receiving doses up to 200 mg/kg/day (approximately 1/3 of clinical exposure at the recommended dose) or rats receiving doses up to 250 mg/kg/day (approximately 2 times the clinical exposure at the recommended dose).
8.3. Nursing Mothers
Bicalutamide is not indicated for use in women.
8.4. Pediatric UseThe safety and effectiveness of bicalutamide in pediatric patients have not been established.
Bicalutamide orodispersible tablet was studied in combination with anastrozole orodispersible tablet in an open-label, non-comparative, multi-center study that assessed the efficacy and safety of this combination regimen over 12 months in the treatment of gonadotropin-independent precocious puberty in boys with familial male-limited precocious puberty, also known as testotoxicosis. Patients were enrolled in the study if they had a baseline age ≥ 2 years and a diagnosis of testotoxicosis based on clinical features of progressive precocious puberty, symmetrical testicular enlargement, advanced bone age, pubertal levels of serum testosterone, prepubertal pattern of gonadotropin secretion following a GnRH stimulation test, and absence of other clinical and biochemical causes of testosterone excess. Thirteen out of the 14 patients enrolled completed 12 months of combination treatment (one patient was lost to follow-up). If central precocious puberty (CPP) developed an LHRH analog was to be added. Four patients were diagnosed with CPP during the 12-month study and received LHRH analog treatment and 2 additional patients were diagnosed at the end of the 12 months and received treatment subsequently. Mean ± SD characteristics at baseline were as follows: chronological age: 3.9±1.9 years; bone age 8.8±2.5; bone age/chronological age ratio: 2.06 ± 0.51; growth rate (cm/yr): 10.81 ± 4.22; growth rate standard deviation score (SDS): 0.41 ± 1.36.
The starting bicalutamide dose was 12.5 mg. Bicalutamide was titrated in each patient until steady-state R-bicalutamide (the active isomer of bicalutamide) trough plasma concentration reached 5 to 15 mcg/mL, which is the range of therapeutic concentrations achieved in adults with prostate cancer following the administration of the currently approved bicalutamide dose of 50 mg. The starting daily dose of anastrozole was 0.5 mg. Anastrozole was independently titrated in each patient until it reached at steady-state a serum estradiol concentration of <10 pmol/L (2.7 pg/mL). The following ascending doses were used for bicalutamide: 12.5 mg, 25 mg, 50 mg, and 100 mg. For anastrozole there were two ascending doses: 0.5 mg and 1 mg. At the end of the titration phase 1 patient was on 12.5 mg bicalutamide, 8 patients were on 50 mg bicalutamide, and 4 patients were on 100 mg bicalutamide; 10 patients were on 0.5 mg anastrozole and 3 patients were on 1 mg anastrozole. In the majority of patients, steady-state trough concentrations of R-bicalutamide appeared to be attained by Day 21 with once daily dosing. Steady-state trough plasma anastrozole concentrations appeared to be attained by Day 8.
The primary efficacy analysis of the study was to assess the change in growth rate after 12 months of treatment, relative to the growth rate during the ≥6 months prior to entering the study. Pre-study growth rates were obtained retrospectively. There was no statistical evidence that the growth rate was reduced during treatment. During bicalutamide /anastrozole treatment the mean growth rate (cm/yr) decreased by 1.6 cm/year, 95% CI (-4.7 to 1.5) p=0.28; the mean growth rate SDS decreased by 0.1 SD, 95% CI (–1.2 to 1.0) p=0.88. Table 2 shows descriptive data for growth rates for the overall population and for subgroups defined by history of previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors.
Change compared to pre-study growth rate
PT = Previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrazole or other aromatase inhibitors
Median calculated as midpoint of 3rd and 4th ranked observations
NPT = no previous treatment for testotoxicosis with ketoconazole, spironolactone, anastrozole or other aromatase inhibitors
Total testosterone concentrations increased by a mean of 5 mmol/L over the 12 months of treatment from a baseline mean of 10 mmol/L. Estradiol concentrations were at or below the level of quantification (9.81 pmol/L) for 11 of 12 patients after 12 months of treatment. Six of the 12 patients started treatment at an estradiol concentration below the level of quantification.
There were no deaths, serious adverse events, or discontinuations due to adverse events during the study. Of the 14 patients exposed to study treatment, 13 (92.9%) experienced at least one adverse event. The most frequently reported (>3 patients) adverse events were gynecomastia (7/14, 50%), central precocious puberty (6/14, 43%), vomiting (5/14, 36%), headache (3/14, 21%), pyrexia (3/14, 21%) and upper respiratory tract infection (3/14, 21%). Adverse reactions considered possibly related to bicalutamide by investigators included gynecomastia (6/14, 43%), central precocious puberty (2/14, 14%), breast tenderness (2/14, 14%), breast pain (1/14, 7%), asthenia (1/14, 7%), increased alanine aminotransferase [ALT] (1/14, 7%), increased aspartate aminotransferase [AST] (1/14, 7%), and musculoskeletal chest pain (1/14, 7%). Headache was the only adverse reaction considered possibly related to anastrazole by investigators. For the patient who developed elevated ALT and AST, the elevation was <3X ULN, and returned to normal without stopping treatment; there was no concomitant elevation in total bilirubin.
8.5. Geriatric UseIn two studies in patients given 50 or 150 mg daily, no significant relationship between age and steady-state levels of total bicalutamide or the active R-enantiomer has been shown.
8.6. Hepatic ImpairmentBicalutamide should be used with caution in patients with moderate-to-severe hepatic impairment. Bicalutamide is extensively metabolized by the liver. Limited data in subjects with severe hepatic impairment suggest that excretion of bicalutamide may be delayed and could lead to further accumulation. Periodic liver function tests should be considered for hepatic-impaired patients on long-term therapy [see Warnings and Precautions (5.1)].
No clinically significant difference in the pharmacokinetics of either enantiomer of bicalutamide was noted in patients with mild-to-moderate hepatic disease as compared to healthy controls. However, the half-life of the R-enantiomer was increased approximately 76% (5.9 and 10.4 days for normal and impaired patients, respectively) in patients with severe liver disease (n=4).
8.7. Renal ImpairmentRenal impairment (as measured by creatinine clearance) had no significant effect on the elimination of total bicalutamide or the active R-enantiomer.
8.8. Women
Bicalutamide has not been studied in women.
10. OVERDOSAGELong-term clinical trials have been conducted with dosages up to 200 mg of bicalutamide daily and these dosages have been well tolerated. A single dose of bicalutamide that results in symptoms of an overdose considered to be life threatening has not been established.
There is no specific antidote; treatment of an overdose should be symptomatic.
In the management of an overdose with bicalutamide, vomiting may be induced if the patient is alert. It should be remembered that, in this patient population, multiple drugs may have been taken. Dialysis is not likely to be helpful since bicalutamide is highly protein bound and is extensively metabolized. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.
11. DESCRIPTIONBicalutamide tablets contain 50 mg of bicalutamide, a non-steroidal androgen receptor inhibitor with no other known endocrine activity. The chemical name is propanamide, N [4 cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-,(+-). The structural and empirical formulas are:
C18 H14 N2 O4 F4 S
Bicalutamide has a molecular weight of 430.37. The pKa’ is approximately 12. Bicalutamide is a fine white to off-white powder which is practically insoluble in water at 37°C (5 mg per 1000 mL), slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and soluble in acetone and tetrahydrofuran.
Bicalutamide is a racemate with its antiandrogenic activity being almost exclusively exhibited by the R-enantiomer of bicalutamide; the S-enantiomer is essentially inactive.
The inactive ingredients of bicalutamide tablets are lactose monohydrate, magnesium stearate, hypromellose E5, polyethylene glycol 400, povidone K30, sodium starch glycolate, and titanium dioxide.
Bicalutamide tablets 50 mg meets USP Dissolution Test 2.
12. CLINICAL PHARMACOLOGY
12.1. Mechanism of ActionBicalutamide is a non-steroidal androgen receptor inhibitor. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen.
When bicalutamide is combined with luteinizing hormone releasing hormone (LHRH) analog therapy, the suppression of serum testosterone induced by the LHRH analog is not affected. However, in clinical trials with bicalutamide as a single agent for prostate cancer, rises in serum testosterone and estradiol have been noted.
In a subset of patients who have been treated with bicalutamide and an LHRH agonist, and who discontinue bicalutamide therapy due to progressive advanced prostate cancer, a reduction in Prostate Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.
12.3. PharmacokineticsAbsorptionBicalutamide is well-absorbed following oral administration, although the absolute bioavailability is unknown. Co-administration of bicalutamide with food has no clinically significant effect on rate or extent of absorption.
DistributionBicalutamide is highly protein-bound (96%) [see Drug Interactions (7)].
Metabolism/Elimination
Bicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. Both the parent and metabolite glucuronides are eliminated in the urine and feces. The S-enantiomer is rapidly cleared relative to the R-enantiomer, with the R-enantiomer accounting for about 99% of total steady-state plasma levels.
Pharmacokinetics of the active enantiomer of bicalutamide in normal males and patients with prostate cancer are presented in Table 3.
13. NONCLINICAL TOXICOLOGY13.1. Carcinogenesis, Mutagenesis, Impairment of FertilityTwo-year oral carcinogenicity studies were conducted in both male and female rats and mice at doses of 5, 15 or 75 mg/kg/day of bicalutamide. A variety of tumor target organ effects were identified and were attributed to the antiandrogenicity of bicalutamide, namely, testicular benign interstitial (Leydig) cell tumors in male rats at all dose levels (the steady-state plasma concentration with the 5 mg/kg/day dose is approximately 2/3 human therapeutic concentrations 1) and uterine adenocarcinoma in female rats at 75 mg/kg/day (approximately 1 1/2 times the human therapeutic concentrations 1). There is no evidence of Leydig cell hyperplasia in patients; uterine tumors are not relevant to the indicated patient population.
A small increase in the incidence of hepatocellular carcinoma in male mice given 75 mg/kg/day of bicalutamide (approximately 4 times human therapeutic concentrations 1) and an increased incidence of benign thyroid follicular cell adenomas in rats given 5 mg/kg/day (approximately 2/3 human therapeutic concentrations 1) and above were recorded. These neoplastic changes were progressions of non-neoplastic changes related to hepatic enzyme induction observed in animal toxicity studies. Enzyme induction has not been observed following bicalutamide administration in man. There were no tumorigenic effects suggestive of genotoxic carcinogenesis.
A comprehensive battery of both in vitro and in vivo genotoxicity tests (yeast gene conversion, Ames, E.coli, CHO/HGPRT, human lymphocyte cytogenetic, mouse micronucleus, and rat bone marrow cytogenetic tests) has demonstrated that bicalutamide does not have genotoxic activity.
Administration of bicalutamide may lead to inhibition of spermatogenesis. The long-term effects of bicalutamide on male fertility have not been studied.
In male rats dosed at 250 mg/kg/day (approximately 2 times human therapeutic concentrations 1), the precoital interval and time to successful mating were increased in the first pairing but no effects on fertility following successful mating were seen. These effects were reversed by 7 weeks after the end of an 11-week period of dosing.
No effects on female rats dosed at 10, 50 and 250 mg/kg/day (approximately 2/3, 1 and 2 times human therapeutic concentrations, respectively 1)) or their female offspring were observed. Administration of bicalutamide to pregnant females resulted in feminization of the male offspring leading to hypospadias at all dose levels. Affected male offspring were also impotent.
1 Based on a maximum dose of 50 mg/day of bicalutamide for an average 70 kg patient.
14. CLINICAL STUDIES14.1. Bicalutamide Tablets 50 mg Daily in Combination with an LHRH-AIn a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive bicalutamide 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with LHRH analogs (either goserelin acetate implant or leuprolide acetate depot).
In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) patients treated with bicalutamide -LHRH analog therapy and 235 (57.5%) patients treated with flutamide-LHRH analog therapy had died. There was no significant difference in survival between treatment groups (see Figure 1). The hazard ratio for time to death (survival) was 0.87 (95% confidence interval 0.72 to 1.05).
Figure 1 -- The Kaplan-Meier probability of death for both antiandrogen treatment groups.
There was no significant difference in time to objective tumor progression between treatment groups (see Figure 2 ).
Objective tumor progression was defined as the appearance of any bone metastases or the worsening of any existing bone metastases on bone scan attributable to metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal metastases. The hazard ratio for time to progression of bicalutamide plus LHRH analog to that of flutamide plus LHRH analog was 0.93 (95% confidence interval, 0.79 to 1.10).
Figure 2 -- Kaplan-Meier curve for time to progression for both antiandrogen treatment groups.
Quality of life was assessed with self-administered patient questionnaires on pain, social functioning, emotional well being, vitality, activity limitation, bed disability, overall health, physical capacity, general symptoms, and treatment related symptoms. Assessment of the Quality of Life questionnaires did not indicate consistent significant differences between the two treatment groups.
14.2. Safety Data from Clinical Studies using Bicalutamide Tablets 150 mgBicalutamide tablet 150 mg is not approved for use either alone or with other treatments.
Two identical multicenter, randomized, open-label trials comparing bicalutamide 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, MO) or metastatic (M1) prostate cancer.
Monotherapy – M1 GroupBicalutamide 150 mg daily is not approved for use in patients with M1 cancer of the prostate. Based on an interim analysis of the two trials for survival, the Data Safety Monitoring Board recommended that bicalutamide treatment be discontinued in the M1 patients because the risk of death was 25% (HR 1.25, 95% CI 0.87 to 1.81) and 31% (HR 1.31, 95% CI 0.97 to 1.77) higher in the bicalutamide treated group compared to that in the castrated group, respectively.
Locally Advanced (T3-4, NX, MO) GroupBicalutamide 150 mg daily is not approved for use in patients with locally advanced (T3-4, NX, M0) cancer of the prostate. Following discontinuation of all M1 patients, the trials continued with the T3-4, NX, MO patients until study completion. In the larger trial (N=352), the risk of death was 25% (HR 1.25, 95% CI 0.92 to 1.71) higher in the bicalutamide group and in the smaller trial (N=140), the risk of death was 36% (HR 0.64, 95% CI, 0.39 to 1.03) lower in the bicalutamide group.
In addition to the above two studies, there are three other on-going clinical studies that provide additional safety information for bicalutamide 150 mg, a dose that is not approved for use. These are three multicenter, randomized, double-blind, parallel group trials comparing bicalutamide 150 mg daily monotherapy (adjuvant to previous therapy or under watchful waiting) with placebo, for death or time to disease progression, in a population of 8113 patients with localized or locally advanced prostate cancer.
Bicalutamide 150 mg daily is not approved for use as therapy for patients with localized prostate cancer who are candidates for watchful waiting. Data from a planned subgroup analysis of two of these trials in 1627 patients with localized prostate cancer who were under watchful waiting, revealed a trend toward decreased survival in the bicalutamide arm after a median follow-up of 7.4 years. There were 294 (37.7%) deaths in the bicalutamide treated patients versus 279 (32.9%) deaths in the placebo treated patients (localized watchful waiting group) for a hazard ratio of 1.16 (95% CI 0.99 to 1.37).
16. HOW SUPPLIED/STORAGE AND HANDLING
Bicalutamide tablets 50 mg are white to off-white, round, biconvex, film coated tablets, debossed ‘B 50’ on one side and plain on other side and supplied in bottles of 30 tablets (NDC 16729-023-10) and bottles of 100 tablets (NDC 16729-023-01).
16.1. Storage and Handling“Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature]”