Bicalutamide, a nonsteroidal antiandrogen, is an antineoplastic agent.1, 3, 4, 14, 40, 43
Bicalutamide 50 mg daily is used in combination with a luteinizing hormone-releasing hormone (LHRH) analog (e.g., goserelin or leuprolide acetate) for the treatment of metastatic (stage D2) prostate cancer.1
Guidelines state that clinicians should not offer first-generation antiandrogens, including bicalutamide, in combination with LHRH agonists in patients with metastatic hormone-sensitive prostate cancer, except to block testosterone flare.3017
Bicalutamide 150 mg daily should not be used alone or in combination with other treatments; this dosage regimen was associated with a potentially increased risk of mortality compared to castration in studies enrolling patients with locally advanced (T3-4, NX, M0) or metastatic (M1) prostate cancer† .1
Safety and efficacy of bicalutamide for this use are based principally on the results of a double-blind, multicenter, randomized study in 813 patients with previously untreated advanced prostate cancer.1, 42 Patients were randomized to receive bicalutamide 50 mg once daily or flutamide 250 mg 3 times daily, each in combination with an LHRH analog (goserelin acetate implant or leuprolide acetate depot).1 The mean age of patients in the trial was 70 years, and approximately 71% of patients were white.42 Approximately 39% of patients had 6 or more metastases.42 The final analysis of this trial was conducted after a median follow-up time of 160 weeks.1, 42 At the time of final analysis, 52.7% of bicalutamide-treated patients had died, and 57.5% of flutamide-treated patients had died.1 There was no difference in survival between treatment groups (hazard ratio, 0.87; 95% confidence interval, 0.72-1.05).1 Quality of life measurements were also found to be similar among treatment groups.1
A phase 2, double-blind, randomized controlled trial (TERRAIN) compared bicalutamide 50 mg daily to enzalutamide 160 mg daily (each in combination with LHRH agonist or antagonist therapy) in patients with metastatic castration-resistant prostate cancer.45 The primary endpoint was progression-free survival.45 The mean age of patients in this trial was 71 years, and approximately 93% were white.45 The median follow-up time was 20 months in the enzalutamide group and 16.7 months in the bicalutamide group.45 Median progression-free survival was substantially prolonged among patients who received enzalutamide compared with bicalutamide (15.7 versus 5.8 months, respectively).45
According to a joint guideline from the American Urological Association (AUA), American Society for Radiation Oncology (ASTRO), and Society of Urologic Oncology (SUO), clinicians should not offer first-generation antiandrogens (i.e., bicalutamide, flutamide, nilutamide) in combination with LHRH agonists in patients with metastatic hormone-sensitive prostate cancer, except to block testosterone flare.3017 In light of the compelling evidence to support the use of other therapies (i.e., docetaxel, abiraterone acetate plus prednisone, apalutamide, or enzalutamide) in combination with androgen deprivation therapy in men with newly diagnosed metastatic hormone-sensitive prostate cancer, long-term use of first-generation antiandrogens in lieu of these agents cannot be supported.3017 Androgen pathway-directed therapy (e.g., abiraterone plus prednisone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, nilutamide) should not be offered without concomitant androgen deprivation therapy in metastatic hormone-sensitive prostate cancer.3017
Bicalutamide is administered orally once daily at the same time each day (morning or evening) without regard to meals.1
If a dose of bicalutamide is missed, the prescribed dose should be taken at the next scheduled time; an additional dose should not be administered to replace the missed dose.1
Store bicalutamide tablets between 20-25°C.1
For use in combination with a luteinizing hormone-releasing hormone (LHRH) analog in the treatment of metastatic (stage D2) prostate cancer, the usual adult dosage of bicalutamide is 50 mg once daily in the morning or evening.1 Treatment with bicalutamide and the LHRH analog should be initiated concomitantly.1
No adjustment of bicalutamide dosage is necessary in patients with mild to moderate hepatic impairment.1 Although data indicate that delayed excretion and accumulation of bicalutamide can occur in severe hepatic impairment, no dosage adjustment is necessary.1
No adjustment of bicalutamide dosage is necessary in patients with renal impairment.1
The manufacturer provides no recommendations regarding modification of bicalutamide dosage in geriatric patients.1
Severe liver injury, in some cases leading to hospitalization and/or death, has been reported rarely in association with bicalutamide therapy.1 Hepatotoxicity generally occurred within the first 3-4 months of bicalutamide therapy.1 Hepatitis or marked increases in serum concentrations of hepatic transaminases leading to discontinuance of bicalutamide therapy were reported in 1% of patients receiving the drug in controlled clinical trials.1
Serum transaminase concentrations should be measured prior to initiation of bicalutamide therapy, at regular intervals during the first 4 months of treatment, and periodically thereafter.1 If clinical signs or symptoms suggestive of liver dysfunction (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, “flu-like” symptoms, dark urine, jaundice, or right upper quadrant tenderness) occur, serum transaminase (especially ALT) concentrations should be measured immediately.1 Bicalutamide should be discontinued immediately in any patient who develops jaundice or an increase in serum ALT concentration to greater than 2 x ULN, and liver function should be monitored closely.1
Hemorrhage with Concomitant Use of Coumarin Anticoagulant
Post-marking reports of excessive prolongation of the prothrombin time (PT) and international normalized ratio (INR) occurring days to weeks after introduction of bicalutamide have been reported in patients who were previously stable on anticoagulation with coumarin anticoagulants.1 Some cases resulted in serious intracranial, retroperitoneal, or GI bleeding that required blood transfusion and/or vitamin K administration.1 When patients on warfarin are started on bicalutamide, closely monitor the PT/INR and adjust the dosage of warfarin as necessary.1
In clinical trials, gynecomastia and breast pain were reported in 38 and 39% of patients, respectively, who were receiving bicalutamide 150 mg as monotherapy for prostate cancer.1
A reduction of glucose tolerance, presenting as diabetes or loss of glycemic control has occurred in patients receiving luteinizing hormone-releasing hormone (LHRH) agonists.1 Consider monitoring blood glucose in patients on bicalutamide and LHRH analog combination therapy.1
Regular monitoring of prostate specific antigen (PSA) concentrations can be helpful when assessing response to therapy.1 If PSA levels rise while on bicalutamide, the patient should undergo evaluation for clinical disease progression.1, 17
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.1
Bicalutamide is contraindicated for use in pregnancy due to the risk of fetal harm and is not indicated for use in females.1 No human data are available evaluating bicalutamide in pregnancy; in animal studies, abnormal development of male reproductive organs occurred when bicalutamide was administered during organogenesis.1
Bicalutamide is not indicated for use in females.1 It is not known whether bicalutamide or its metabolites are distributed into human milk.1 The effects of the drug on the breast-fed infant or on the production of milk are unknown.1 The presence of bicalutamide has been detected in rat milk.1
Females and Males of Reproductive Potential
Morphological changes of spermatozoa may occur with antiandrogen therapy.1 Advise male patients with female partners of reproductive potential to use effective contraception during treatment with bicalutamide and for 130 days after the final dose.1 Bicalutamide can inhibit spermatogenesis and impair fertility in males of reproductive potential; the long-term effects of bicalutamide on male fertility have not been evaluated.1
The safety and efficacy of bicalutamide have not been established in pediatric patients.1
No significant relationship has been shown between age and steady state levels of bicalutamide or the active R -enantiomer of bicalutamide.1
Use bicalutamide with caution in patients with moderate to severe hepatic impairment.1 Bicalutamide is extensively metabolized in the liver; however, the pharmacokinetics of the drug do not appear to be altered in patients with mild to moderate hepatic impairment.1 Limited pharmacokinetic data in severe hepatic impairment indicate that the half-life of the bicalutamide R -enantiomer is increased by approximately 76%.1 Consider periodic liver function tests in patients with hepatic impairment receiving long-term therapy.1
Renal impairment has no significant impact on the elimination of bicalutamide or its active R -enantiomer.1
Adverse effects reported in ≥10% of patients in clinical trials receiving bicalutamide plus a LHRH analog include hot flashes, pain (including general, back, pelvic, and abdominal), asthenia, constipation, infection, nausea, peripheral edema, dyspnea, diarrhea, hematuria, nocturia, and anemia.1
Bicalutamide does not induce cytochrome P-450 (CYP) isoenzymes.1 In vitro, the R -enantiomer of bicalutamide has been shown to inhibit CYP3A4 to a greater extent than CYP2C9, CYP2C19, and CYP2D6.1 Clinical data have not demonstrated an interaction between LHRH analogs (eg, leuprolide, goserelin) and bicalutamide.1
Drugs Metabolized by Hepatic Microsomal Enzymes
CYP3A4 substrates
Use caution with coadministration of bicalutamide and CYP3A4 substrates.1 Studies have shown that concomitant use of bicalutamide with midazolam, a sensitive CYP3A4 substrate, can increase the maximum serum concentration (Cmax) and AUC of midazolam by 1.5- and 1.9-fold, respectively.1
Bicalutamide is highly protein bound (96%); in vitro, studies have shown bicalutamide to displace coumarin anticoagulants from protein binding sites.1 Monitor the PT/INR closely and adjust the warfarin dosage as necessary in patients receiving concomitant bicalutamide and warfarin.1
Bicalutamide is a nonsteroidal antiandrogen1, 3, 4, 14, 40, 43 that is structurally and pharmacologically related to flutamide and nilutamide.3, 9, 14, 17, 40, 43
Bicalutamide inhibits the action of androgens by competitively blocking nuclear androgen receptors in target tissues such as the prostate, seminal vesicles, and adrenal cortex; blockade of androgen receptors in the hormone-sensitive tumor cells may result in growth arrest or transient tumor regression through inhibition of androgen-dependent DNA and protein synthesis.1, 11, 12, 14, 16, 34, 43 Bicalutamide is a selective antiandrogen with no androgenic or progestational activity in various animal models.12, 17, 43 The relative binding affinity of bicalutamide at the androgen receptor is more than that of nilutamide and approximately 4 times that of hydroxyflutamide, the active metabolite of flutamide.3, 9, 10, 22, 34, 39, 43
Common pharmacologic therapies for prostate cancer (i.e., gonadotropin-releasing hormone [GnRH] analogs, nonsteroidal antiandrogens) when used as monotherapy initially result in increased serum testosterone concentrations, which may limit the effects of the drugs.8, 10, 16, 17, 18, 21, 23, 27 Androgen receptors in the hypothalamus are blocked by bicalutamide, which disrupts the inhibitory feedback of testosterone on luteinizing hormone (LH) release, resulting in a temporary increase in secretion of LH; the increase in LH stimulates an increase in the production of testosterone.3, 10, 12, 14, 16, 34 As GnRH analogs have potent GnRH agonist properties, testicular steroidogenesis continues during the first few weeks after initiating therapy.8 However, the combination of orchiectomy or GnRH analog therapy to suppress testicular androgen production and an antiandrogen to block response of remaining adrenal androgens provides maximal androgen blockade.8, 9, 10, 16, 24, 40, 43 Concomitant administration of antiandrogens such as bicalutamide in patients initiating therapy with a GnRH analog can inhibit initial androgenic stimulation and potential exacerbation of symptoms (e.g., bone pain, urinary obstruction, liver pain, impending spinal cord compression) that may occur during the first month of GnRH analog therapy.8, 10, 14, 16, 18, 21, 23, 25, 40
Although the absolute bioavailability is not known, bicalutamide is well absorbed following oral administration.1 Administration of bicalutamide with food does not affect the rate or extent of drug absorption.1 Bicalutamide exhibits high protein-binding (96%).1 The S (inactive) enantiomer of bicalutamide is metabolized primarily by glucuronidation.1 The R (active) enantiomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation.1 Metabolites are eliminated in the urine or feces.1 The S -enantiomer undergoes rapid clearance in comparison to the R -enantiomer; the R -enantiomer accounts for the majority of steady-state plasma levels (99%).1 In healthy males, the half-life of the R -enantiomer of bicalutamide is approximately 5.8 days.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film- coated | 50 mg | ANI Pharmaceuticals |
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