Bicalutamide is an oral nonsteroidal antiandrogen agent. It is indicated in combination with an LHRH analog as an antihormonal agent in the treatment of metastatic prostatic cancer. Unlike flutamide, another nonsteroidal antiandrogen, bicalutamide has a long plasma half-life that allows once-daily dosing compared with three times daily for flutamide. Severe hepatotoxicity has been observed in clinical trials; regularly monitor liver function tests. While a 150 mg dosage form was once under investigation as monotherapy or in combination with other drugs for select stages of prostate cancer, this dosage is not FDA-approved and select clinical trials have found significant trends in terms of increased mortality/decreased survival in the bicalutamide-treated group at the 150 mg-dosage versus patients undergoing castration or other treatments. Due to strong evidence supporting the use of docetaxel, abiraterone plus prednisone, apalutamide, or enzalutamide in combination with androgen deprivation therapy in men with newly diagnosed metastatic hormone-sensitive prostate cancer, the long-term use of first-generation antiandrogens such as bicalutamide is not recommended in American Urological Association guidelines for the treatment of advanced prostate cancer.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Route-Specific Administration
Oral Administration
-Bicalutamide should be taken at the same time every day.
-May be administered without regard to meals.
-If a dose is missed, skip that dose and take the next dose at the usual time; do not take the missed dose and do not take a double dose.
Chest pain (unspecified) occurred in 8% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog compared with 8%, of those who received flutamide plus an LHRH analog in a randomized clinical trial. In this study, angina, myocardial infarction, cardiac arrest, and coronary artery disease occurred in 2% to less than 5% of men treated with bicalutamide plus a LHRH analog.
Constipation (22%), diarrhea (12%), abdominal pain (11%), and flatulence (6%) were reported in men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial. Additionally, hernia, melena, rectal bleeding (GI bleeding), and gastrointestinal disorder were each reported in 2% to less than 5% of bicalutamide-treated patients in this trial.
Anemia was reported in 11% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial; decreased hemoglobin levels and decreased white blood cell count (leukopenia) were also reported in patients who received bicalutamide in this trial.
Generalized pain was reported in 35% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial. Additional musculoskeletal adverse reactions included back pain (25%), bone pain (9%), myasthenia (7%), arthritis (5%), and pathologic bone fractures (4%). In this study, myalgia, leg muscle cramps, and neck pain each occurred in 2% to less than 5% of men who received with bicalutamide.
Dizziness occurred in 10% and headache in 7% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial; syncope was also reported in 2% to less than 5% of bicalutamide-treated patients in this trial.
Dyspnea was reported in 13% and increased cough in 8% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial; lung disorders and asthma occurred in 2% to 5% of bicalutamide-treated patients in this study. Interstitial lung disease/pneumonitis, including fatalities, and pulmonary fibrosis have been reported in postmarketing experience with bicalutamide, most often at doses greater than 50 mg.
Rash occurred in 9% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial. Xerosis, pruritus, skin disorder, and cysts were each reported in 2% to less than 5% of bicalutamide-treated patients in this trial. Photosensitivity has been reported in postmarketing experience with bicalutamide.
Pelvic pain (21%), nocturia (12%), hematuria (12%), increased urinary frequency (6%), urinary retention (5%), urinary impaired (5%), and urinary incontinence (3%) were reported in 7% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial; dysuria, urinary urgency, hydronephrosis, and urinary tract disorder were each reported in 2% to 5% of bicalutamide-treated patients in this trial.
Anxiety occurred in 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog (n = 401) compared with 2% of those who received flutamide plus an LHRH analog (n = 407) in a multicenter, double-blind, comparative trial; depression was reported in 4% vs. 8%, respectively. In this study, nervousness also occurred in 2% to less than 5% of men treated with bicalutamide plus a LHRH analog.
Gynecomastia (9% vs. 7%) and breast pain (6% vs. 4%) were reported in men with advanced prostate cancer who received oral bicalutamide plus a luteinizing hormone-releasing hormone analog (n = 401) compared with flutamide plus an LHRH analog (n = 407) in a multicenter, double-blind, comparative trial. Additionally, gynecomastia and breast pain occurred in up to 38% and 39% of patients, respectively, who received single-agent bicalutamide in clinical studies.
Infection was reported in 18% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial including urinary tract infections (9%), pharyngitis (8%), influenza (7%), bronchitis (6%), pneumonia (4%), and rhinitis (4%). Herpes zoster, periodontal abscess, sinusitis, and sepsis were each reported in 2% to 5% of bicalutamide-treated patients.
Serious hepatotoxicity including hepatitis and hepatic failure have been reported in postmarketing surveillance in patients who received bicalutamide, some cases resulted in hospitalization or death. In a multicenter, double-blind, comparative trial, elevated hepatic enzymes occurred in 7% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog (n = 401) compared with 11% of those who received flutamide plus an LHRH analog (n = 407); alkaline phosphatase levels were increased in 5% vs. 6%, respectively. In this study, elevated AST and ALT levels and elevated bilirubin levels (hyperbilirubinemia) have been reported in men treated with both flutamide and bicalutamide plus a LHRH analog. Obtain liver transaminase levels prior to starting bicalutamide therapy, at regular intervals for the first 4 months of therapy, and periodically thereafter; measure serum transaminase levels immediately if patients develop signs or symptoms of liver dysfunction. Discontinue therapy in patients who have transaminase levels increases to greater than 2 times the upper limit of normal or jaundice.
Hypersensitivity reactions including angioedema and urticaria have been reported in postmarketing surveillance in patients who received bicalutamide.
Hyperglycemia occurred in 6% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial. Consider monitoring blood glucose levels in patients receiving bicalutamide plus an LHRH analog.
Peripheral edema was reported in 13% of men with advanced prostate cancer who received oral bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog (n = 401) compared with 10% of those who received flutamide plus an LHRH analog (n = 407) in a multicenter, double-blind, comparative trial. In this study, edema occurred in 2% to less than 5% of men treated with bicalutamide plus a LHRH analog.
Hot flashes (53%) were the most frequently reported adverse reaction in men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial; diaphoresis was also reported in 6% of bicalutamide-treated patients in this trial.
Asthenia was reported in 22% of men with advanced prostate cancer who received oral bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog (n = 401) and 21% of those who received flutamide plus an LHRH analog (n = 407) in a multicenter, double-blind, comparative trial.
Anorexia was reported in 6% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial; weight loss occurred in 7% of patients. Weight gain was conversely been reported in 5% of bicalutamide-treated patients in this trial. Xerostomia and dysphagia were reported in 2% to less than 5% of patients who received bicalutamide in this study.
Cataracts occurred in 2% to less than 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone analog (n = 401) in a multicenter, double-blind, comparative trial.
Fever and chills occurred in 2% to less than 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone analog (n = 401) in a multicenter, double-blind, comparative trial.
Dehydration, increased BUN, and increased creatinine were each reported in 2% to less than 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial.
Gout occurred in 2% to less than 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone analog (n = 401) in a multicenter, double-blind, comparative trial.
Hypercholesterolemia occurred in 2% to less than 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone analog (n = 401) in a multicenter, double-blind, comparative trial.
New primary malignancy or neoplasm occurred in 2% to less than 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial. Specifically, gastric cancer and skin cancer were each reported in 2% to 5% of bicalutamide-treated patients in this study.
Hypertension occurred in 8% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog compared with 7% of those who received flutamide plus an LHRH analog in a randomized clinical trial.
Nausea (15%) and vomiting (6%) were reported in men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial; dyspepsia was also reported in 7% of patients in this trial.
Insomnia was reported in 7% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial. Conversely, drowsiness was reported in 2% to less than 5% of bicalutamide-treated patients in this study.
Paresthesias occurred in 8% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial. Neuropathy was additionally reported in 2% to less than 5% of bicalutamide-treated patients in this trial.
Hypertonia occurred in 2% to less than 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial.
Confusion occurred in 2% to less than 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial.
Alopecia was reported in 2% to less than 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial.
Impotence (erectile dysfunction) occurred in 27% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog compared with 35%, of those who received flutamide plus an LHRH analog in a randomized clinical trial (grade 3 or 4, 7% vs. 9%). In this study, a libido decrease occurred in 2% to less than 5% of men treated with bicalutamide plus an LHRH analog.
Epistaxis was reported in 2% to less than 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial.
Congestive heart failure was reported in 2% to less than 5% of men with advanced prostate cancer treated with bicalutamide plus a luteinizing hormone-releasing hormone (LHRH) analog in a randomized clinical trial.
Use bicalutamide with caution in patients with moderate to severe hepatic disease; limited data suggest that excretion may be delayed in patients with severe hepatic impairment leading to further accumulation. Cases of death or hospitalization due to severe liver injury (hepatic failure) have been reported in postmarketing experience with bicalutamide; hepatotoxicity in these reports generally occurred within the first 3 to 4 months of treatment. Monitor transaminase concentrations at baseline, at regular intervals for the first 4 months of treatment, and periodically thereafter. Immediately measure serum transaminases and particularly serum ALT if clinical signs or symptoms of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, dark urine, jaundice, or right upper quadrant tenderness). Immediately discontinue treatment if a patient develops jaundice or their ALT rises above 2 times the upper limit of normal and closely monitor hepatic function.
Use bicalutamide with caution in patients with diabetes mellitus or glucose intolerance. A reduction in glucose tolerance has been observed in males receiving LHRH agonists, which are given concomitantly with bicalutamide. This may manifest as diabetes or loss of glycemic control in patients who have pre-existing diabetes. Monitor blood glucose in patients who are receiving bicalutamide in combination with LHRH agonists.
The safe and effective use of bicalutamide in children has not been established. Additionally, in adolescents with stuttering priapism, bicalutamide should not be used until sexual maturation is fully completed and they have reached adult stature.
Bicalutamide is contraindicated in females as well as during pregnancy; it has no indication for women, and should not be used in this population. Although there are no adequately controlled studies in pregnant women, bicalutamide can cause fetal harm or death when administered during pregnancy based on its mechanism of action and animal studies. The administration of bicalutamide (approximately 0.7 to 2 times the human exposure at the recommended dose) during organogenesis resulted in reduced anogenital distance, smaller secondary sex organs, cryptorchidism, and hypospadias resulting in an inability to mate and impregnate female partners in male fetuses in an embryo-fetal development study in pregnant rats. Female offspring of rats receiving approximately 0.7 times the human exposure at the recommended dose or more had reduced pregnancy rates. Survival and weights of offspring during lactation were reduced for litters from maternal rats receiving doses approximating 2 times the human exposure at the recommended dose.
Counsel patients about the reproductive risk and contraception requirements during bicalutamide treatment. Antiandrogen therapy may cause morphological changes in spermatozoa. Due to the risk of male-mediated teratogenicity, males with female partners of reproductive potential should use effective contraception during and for at least 130 days after treatment with bicalutamide. Although there are no data regarding the effect of bicalutamide on human fertility, male infertility has been observed in animal studies. The long-term effects of bicalutamide on male fertility have not been studied.
Bicalutamide is not indicated for use in women; therefore, it should not be used in women who are breast-feeding. It is not known whether bicalutamide is present in human milk, although many drugs are excreted in human milk.
For the treatment of prostate cancer:
-for the treatment of stage D2 metastatic prostate cancer, in combination with a luteinizing hormone-releasing hormone (LHRH) analog:
Oral dosage:
Adults: 50 mg PO once daily. Treatment with bicalutamide should be started at the same time as treatment with an LHRH analog. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. There was no significant difference in survival between previously untreated patients with advanced prostate cancer who received bicalutamide compared with flutamide, each in combination with LHRH analogs. Additionally, there was no significant difference in time to objective tumor progression. Assessment of quality of life questionnaires did not indicate consistent significant differences between the 2 treatment groups. Due to strong evidence supporting the use of docetaxel, abiraterone plus prednisone, apalutamide, or enzalutamide in combination with androgen deprivation therapy in men with newly diagnosed metastatic hormone-sensitive prostate cancer, the long-term use of first-generation antiandrogens such as bicalutamide is not recommended in American Urological Association guidelines for the treatment of advanced prostate cancer.
For prevention of stuttering priapism* (i.e., recurrent priapism):
Oral dosage:
Adult males: Case reports suggest 50 mg PO once every other day is effective; additionally, a lower dose of 1 to 2 doses per week has also been successful. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In 2 patients (both with sickle cell anemia), an initial dose of 50 mg PO once daily eliminated stuttering priapism; due to financial reasons or adverse effects (e.g., gynecomastia), the dose was reduced to 50 mg PO every other day with continued successful prevention of priapism. The patient experiencing gynecomastia further reduced his dosage to 50 mg PO 1 to 2 times per week with success. A third patient, with a spinal cord injury, experienced complete elimination of priapism after initiating therapy with 50 mg PO every other day. All 3 patients have been treated chronically (i.e., greater than 2 years) without recurrence of priapism or significant adverse effects; all 3 patients are able to engage in sexual activity. The American Urological Association recommends antiandrogen therapy as a first-line option in the prevention of stuttering priapism; however, do not use bicalutamide in patients who have not achieved full sexual maturation and adult stature.
For the treatment of peripheral precocious puberty* (e.g., McCune-Albright Syndrome, familial male-limited precocious puberty):
Oral dosage:
Children 2 to 12 years: 2 mg/kg/dose PO once daily. An acceptable alternative dosing regimen is 12.5 to 100 mg PO once daily. Max: 100 mg/day. Use bicalutamide in combination with an aromatase inhibitor.
Maximum Dosage Limits:
-Adults
50 mg/day PO.
-Elderly
50 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is necessary.
Jaundice, or ALT greater than 2 times the upper limit of normal: Discontinue bicalutamide treatment.
Patients with Renal Impairment Dosing
No dosage adjustment is necessary.
*non-FDA-approved indication
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with bicalutamide may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of bicalutamide could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If bicalutamide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Bicalutamide is a weak inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like bicalutamide can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If bicalutamide is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. If bicalutamide is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like bicalutamide can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If bicalutamide is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. If bicalutamide is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like bicalutamide can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If bicalutamide is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alprazolam: (Major) Avoid coadministration of alprazolam and bicalutamide due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with bicalutamide, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor. Coadministration with another weak CYP3A4 inhibitor, increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of bicalutamide. Patients receiving both a CYP2D6 inhibitor plus bicalutamide may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; bicalutamide is a weak CYP3A inhibitor.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. If bicalutamide is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like bicalutamide can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If bicalutamide is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with bicalutamide may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of bicalutamide in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If bicalutamide is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Bicalutamide is a weak inhibitor of CYP3A4.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with bicalutamide is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
Carbamazepine: (Major) Monitor for increased carbamazepine-related adverse reactions if coadministered with bicalutamide. Taking these drugs together may increase carbamazepine plasma concentrations, potentially resulting in adverse events. Bicalutamide is a weak CYP3A4 inhibitor; carbamazepine is a substrate of CYP3A4 with a narrow therapeutic index.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with bicalutamide is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of bicalutamide, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like bicalutamide can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If bicalutamide is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cisapride: (Moderate) Use caution when administering bicalutamide with cisapride. Taking these drugs together may increase cisapride plasma concentrations, potentially resulting in adverse events. Bicalutamide is a weak CYP3A4 inhibitor; cisapride is a substrate of CYP3A4 with a narrow therapeutic index.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with bicalutamide and monitor for adverse reactions. If bicalutamide is discontinued, monitor for lack of clozapine effect and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4. Bicalutamide is a weak CYP3A4 inhibitor.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with bicalutamide is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with bicalutamide is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and bicalutamide is a CYP3A4 inhibitor.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with bicalutamide is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate and strong CYP3A4 inhibitors.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with bicalutamide is necessary as concurrent use may increase dofetilide exposure. Bicalutamide is a weak CYP3A inhibitor. Dofetilide is a minor CYP3A substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A inhibitors may increase the risk of arrhythmia (torsade de pointes).
Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of bicalutamide and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of bicalutamide and eliglustat requires dosage reduction of eliglustat to 84 mg PO once daily. Bicalutamide is a weak CYP3A4 inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration with CYP3A4 inhibitors, such as bicalutamide, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Felodipine: (Moderate) Concurrent use of felodipine and bicalutamide should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor. Concurrent use of another weak CYP3A4 inhibitor increased felodipine AUC and Cmax by approximately 50%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. If bicalutamide is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like bicalutamide can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If bicalutamide is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or bicalutamide; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and bicalutamide is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including bicalutamide, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with bicalutamide is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A4 substrate and bicalutamide is a CYP3A4 inhibitor.
Grapefruit juice: (Moderate) Substances that are potent inhibitors of CYP3A4 activity decrease the metabolism of bicalutamide and increase bicalutamide concentrations. This increase may be clinically relevant as adverse reactions to bicalutamide are related to dose and exposure; therefore caution should be used when administering CYP3A4 inhibitors, such as grapefruit juice. with bicalutamide.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like bicalutamide can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If bicalutamide is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like bicalutamide can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If bicalutamide is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like bicalutamide can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If bicalutamide is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. If bicalutamide is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like bicalutamide can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If bicalutamide is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Isradipine: (Minor) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with bicalutamide is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and bicalutamide is a weak CYP3A inhibitor.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of bicalutamide is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and bicalutamide is a weak CYP3A inhibitor.
Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with bicalutamide as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; bicalutamide is a weak CYP3A4 inhibitor. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with bicalutamide is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with bicalutamide is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with bicalutamide is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
Lomitapide: (Major) Concomitant use of lomitapide and bicalutamide may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Bicalutamide is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and bicalutamide; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing bicalutamide. Lonafarnib is a sensitive CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with bicalutamide is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A4 and bicalutamide is a weak CYP3A4 inhibitor.
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. If bicalutamide is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; bicalutamide is a weak CYP3A4 enzyme inhibitor. Concomitant use with bicalutamide can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
Midazolam: (Moderate) Use caution when midazolam is coadministered with bicalutamide. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor. Clinical studies have shown that bicalutamide may increase mean midazolam exposure by 1.5-fold for Cmax and 1.9-fold for AUC.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of bicalutamide. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and bicalutamide is a weak CYP3A inhibitor.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with bicalutamide is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with bicalutamide due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. If bicalutamide is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like bicalutamide can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If bicalutamide is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Pimozide: (Major) Concurrent use of pimozide and bicalutamide should be avoided. Coadministration may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is metabolized primarily through CYP3A4, and bicalutamide is a weak CYP3A4 inhibitor.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with bicalutamide; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and bicalutamide with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate; bicalutamide is a weak CYP3A4 inhibitor.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of bicalutamide. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and bicalutamide is a weak CYP3A inhibitor.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if bicalutamide must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of bicalutamide is necessary. If bicalutamide is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like bicalutamide can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If bicalutamide is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with bicalutamide is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; bicalutamide is a weak CYP3A4 inhibitor.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with bicalutamide is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of bicalutamide, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with bicalutamide is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of bicalutamide, a weak CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with bicalutamide and consider appropriate dose reduction of triazolam if clinically indicated. Coadministration may increase triazolam exposure. Triazolam is a sensitive CYP3A substrate and bicalutamide is a weak CYP3A inhibitor.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with bicalutamide. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; bicalutamide is a weak CYP3A4 inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with bicalutamide is necessary. Vinorelbine is a CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
Warfarin: (Moderate) Closely monitor the PT/INR if coadministration of warfarin with bicalutamide is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. In vitro protein-binding studies have shown that bicalutamide can displace coumarin anticoagulants from binding sites. There have been reports of excessive prolongation of the PT/INR days to weeks after the introduction of bicalutamide in patients who were previously stable on coumarin anticoagulants. Some patients had serious bleeding including intracranial, retroperitoneal, and gastrointestinal requiring blood transfusion and/or administration of vitamin K. Additionally, bicalutamide is a weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate; the S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Bicalutamide is a nonsteroidal androgen receptor inhibitor. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. When bicalutamide is combined with 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 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 PSA and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.
Bicalutamide is administered orally; it is 96% protein-bound. Bicalutamide undergoes stereospecific metabolism. The S isomer (inactive) is primarily metabolized by glucuronidation. The active R isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. The S-enantiomer is rapidly cleared relative to the R-enantiomer, with the R-enantiomer accounting for about 99% of total steady-state plasma concentrations. Both the parent and metabolite glucuronides are eliminated in the urine and feces. The half-life of the R-enantiomer is roughly 5.8 days (+/- 2.29 days) for adults without liver disease. The mean apparent oral clearance is 0.32 L/hour (+/- 0.103 L/hour).
Affected cytochrome P450 isoenzymes: CYP3A4, CYP2C9, CYP2C19, CYP2D6
R-bicalutamide is a weak CYP3A4 inhibitor in vitro; it has lesser inhibitory effects on CYP2C9, CYP2C19, and CYP2D6.
-Route-Specific Pharmacokinetics
Oral Route
The absolute bioavailability of bicalutamide is not known despite being well-absorbed orally. The single-dose peak concentration of bicalutamide is 0.768 mcg/mL (+/- 0.178 mcg/mL) in healthy males and the single-dose time to peak concentration is 31.3 hours (+/- 14.6 hours). In patients with prostate cancer, the concentration at steady-state is 8.939 mcg/mL (+/- 3.504 mcg/mL). Coadministration of bicalutamide with food has no clinically significant effect on the rate or extent of absorption.
-Special Populations
Hepatic Impairment
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, in patients with severe liver disease, the half-life of the R-enantiomer was increased approximately 76% to roughly 10.4 days.
Renal Impairment
Renal impairment (as measured by creatinine clearance) had no significant effect on the elimination of total bicalutamide or the active R-enantiomer.
Pediatrics
In an open-label, noncomparative, multicenter study in patients 2 years of age or older treated with once-daily bicalutamide, the majority of patients attained steady-state trough concentrations of R-bicalutamide by day 21. The safety and effectiveness of bicalutamide in pediatric patients have not been established.
Geriatric
No significant relationship between age and steady-state levels of total bicalutamide or the active R-enantiomer was shown in two studies in patients given bicalutamide 50 mg or 150 mg by mouth daily.