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  • CLASSES

    Anti-Androgens
    Cytostatic Anti-androgens

    DEA CLASS

    Rx

    DESCRIPTION

    Oral nonsteroidal antiandrogen structurally related to flutamide; used in the treatment of metastatic prostatic carcinoma; unlike flutamide, bicalutamide can be dosed once-daily; also, bicalutamide is more selective for the peripheral androgen receptor and has less activity at the central (HPA) androgen receptor.

    COMMON BRAND NAMES

    Casodex

    HOW SUPPLIED

    Bicalutamide/Casodex Oral Tab: 50mg

    DOSAGE & INDICATIONS

    For the treatment of stage D-2 metastatic prostate cancer in combination with a luteinizing hormone-releasing hormone (LHRH) analog.
    Oral dosage
    Adult males

    50 mg PO once daily. Treatment with bicalutamide should be started at the same time as treatment with a LHRH analog. A multicenter, double-blind, controlled clinical trial compared bicalutamide and flutamide, each in combination with LHRH analogues (e.g., goserelin acetate implant or leuprolide acetate depot). At a median of 160 weeks of therapy, 52.7% of the bicalutamide-LHRH analogue therapy arm and 57.5% of the flutamide-LHRH analogue therapy arm had died [NS]. No significant difference in quality of life parameters was noted between treatment arms.

    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—2 doses/week has also been successful. 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—2 times/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., > 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment guidelines are available. Bicalutamide should not be used in patients with jaundice or elevated ALT levels.

    Renal Impairment

    No dosage adjustment needed.

    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.

    STORAGE

    Casodex:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Contraception requirements, females, infertility, male-mediated teratogenicity, pregnancy, reproductive risk

    Bicalutamide has no indication in females, and should not be used for non-serious or non-life threatening situations. The manufacturer lists females as a contraindicated population for the use of bicalutamide. Further, bicalutamide is contraindicated for use during pregnancy. Bicalutamide has been shown to cause fetal harm in animal studies at plasma concentrations similar to those achieved in humans. If this drug is used during pregnancy, or if a female of childbearing potential becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Antiandrogen therapy may cause morphological changes in sperm and there is potential for male-mediated teratogenicity. Counsel male patients with female partners of reproductive potential about the reproductive risk and contraception requirements for men; effective contraception must be used during therapy and for 130 days following the last dose. In addition, based on animal studies, bicalutamide can lead to sperm inhibition and may cause infertility in males of reproductive potential. The long-term effects of bicalutamide on male fertility have not been studied.

    Breast-feeding

    Given its indication for use, bicalutamide would not be expected to be used during lactation; the drug is not for use in females. Use of bicalutamide during breast-feeding is not indicated, and if excreted in milk, would be expected to have the potential for adverse effects in a nursing infant due to the anti-androgenic activity. Bicalutamide has been detected in rat milk.

    Hepatic disease, hepatitis, jaundice

    The liver extensively metabolizes bicalutamide, and limited data suggest that in subjects with moderate to severe hepatic disease, excretion could be delayed, leading to accumulation. Rare cases of death or hospitalization due to severe hepatotoxicity have been reported with the clinical use of bicalutamide. Serum transaminase levels should be measured prior to starting therapy with bicalutamide and at regular intervals for the first 4 months of treatment and then periodically thereafter. If clinical signs and symptoms suggestive of liver dysfunction occur (e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, flu-like symptoms, dark urine, jaundice, hepatitis, or right upper quadrant tenderness), the serum transaminases, in particular the ALT, should be measured immediately. If at any time a patient has jaundice or their ALT rises above 2-times the upper limit of normal, bicalutamide should be discontinued with close follow-up of liver function.

    Children

    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.

    Diabetes mellitus

    A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This effect may manifest as diabetes or loss of glycemic control in patients who have diabetes. LHRH agonists are given concomitantly with bicalutamide. Use with caution in patients with glucose intolerance or diabetes mellitus. Monitor blood glucose in patients who are receiving bicalutamide in combination with LHRH agonists.

    ADVERSE REACTIONS

    Severe

    myocardial infarction / Delayed / 2.0-5.0
    heart failure / Delayed / 2.0-5.0
    cardiac arrest / Early / 2.0-5.0
    GI bleeding / Delayed / 2.0-5.0
    new primary malignancy / Delayed / 2.0-5.0
    bone fractures / Delayed / 4.0-4.0
    pulmonary fibrosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known

    Moderate

    hot flashes / Early / 53.0-53.0
    constipation / Delayed / 22.0-22.0
    dyspnea / Early / 13.0-13.0
    peripheral edema / Delayed / 13.0-13.0
    hematuria / Delayed / 12.0-12.0
    anemia / Delayed / 11.0-11.0
    bone pain / Delayed / 9.0-9.0
    chest pain (unspecified) / Early / 8.0-8.0
    hypertension / Early / 8.0-8.0
    myasthenia / Delayed / 7.0-7.0
    impotence (erectile dysfunction) / Delayed / 7.0-7.0
    elevated hepatic enzymes / Delayed / 0-7.0
    hyperglycemia / Delayed / 6.0-6.0
    angina / Early / 2.0-5.0
    dysphagia / Delayed / 2.0-5.0
    melena / Delayed / 2.0-5.0
    hypertonia / Delayed / 2.0-5.0
    confusion / Early / 2.0-5.0
    urinary retention / Early / 5.0-5.0
    dysuria / Early / 2.0-5.0
    edema / Delayed / 2.0-5.0
    cataracts / Delayed / 2.0-5.0
    dehydration / Delayed / 2.0-5.0
    gout / Delayed / 2.0-5.0
    hypercholesterolemia / Delayed / 2.0-5.0
    urinary incontinence / Early / 4.0-4.0
    depression / Delayed / 4.0-4.0
    neutropenia / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    diabetes mellitus / Delayed / Incidence not known

    Mild

    gynecomastia / Delayed / 9.0-38.0
    back pain / Delayed / 25.0-25.0
    asthenia / Delayed / 22.0-22.0
    infection / Delayed / 2.0-18.0
    nausea / Early / 15.0-15.0
    diarrhea / Early / 12.0-12.0
    nocturia / Early / 12.0-12.0
    abdominal pain / Early / 11.0-11.0
    dizziness / Early / 10.0-10.0
    rash / Early / 9.0-9.0
    paresthesias / Delayed / 8.0-8.0
    pharyngitis / Delayed / 8.0-8.0
    cough / Delayed / 8.0-8.0
    dyspepsia / Early / 2.0-7.0
    headache / Early / 7.0-7.0
    insomnia / Early / 7.0-7.0
    weight loss / Delayed / 7.0-7.0
    flatulence / Early / 6.0-6.0
    anorexia / Delayed / 6.0-6.0
    vomiting / Early / 6.0-6.0
    diaphoresis / Early / 6.0-6.0
    increased urinary frequency / Early / 6.0-6.0
    syncope / Early / 2.0-5.0
    xerostomia / Early / 2.0-5.0
    muscle cramps / Delayed / 2.0-5.0
    myalgia / Early / 2.0-5.0
    arthralgia / Delayed / 5.0-5.0
    drowsiness / Early / 2.0-5.0
    sinusitis / Delayed / 2.0-5.0
    epistaxis / Delayed / 2.0-5.0
    pruritus / Rapid / 2.0-5.0
    alopecia / Delayed / 2.0-5.0
    xerosis / Delayed / 2.0-5.0
    libido decrease / Delayed / 2.0-5.0
    urinary urgency / Early / 2.0-5.0
    anxiety / Delayed / 5.0-5.0
    weight gain / Delayed / 5.0-5.0
    chills / Rapid / 2.0-5.0
    fever / Early / 2.0-5.0
    rhinitis / Early / 4.0-4.0
    photosensitivity / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    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; 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.
    Amiodarone: (Moderate) Bicalutamide is metabolized by CYP3A4. Drugs that are inhibitors of CYP3A4 activity, like amiodarone, may decrease the metabolism of bicalutamide and increase bicalutamide concentrations.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as clarithromycin, 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.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as clarithromycin, 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.
    Aspirin, ASA; 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.
    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.
    Barbiturates: (Moderate) Bicalutamide is metabolized by CYP3A4. Barbiturates induce CYP3A4 activity and will decrease the plasma concentrations of bicalutamide.
    Bosentan: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Drugs that are potent inducers of CYP3A4 activity, such as bosentan, will decrease the plasma concentrations of bicalutamide. Clinical trials have not been conducted to determine if bicalutamide dosing adjustments are necessary.
    Carbamazepine: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Drugs that are potent inducers of CYP3A4 activity, such as carbamazepine, will decrease the plasma concentrations of bicalutamide. It is unknown if dosing adjustments are necessary.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (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.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (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.
    Clarithromycin: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as clarithromycin, 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.
    Delavirdine: (Major) Caution is advised during coadministration of bicalutamide and delavirdine. Bicalutamide is metabolized by CYP3A4. Potent inhibitors of CYP3A4, such as delaviridine, decrease the metabolism and increase the serum concentrations of bicalutamide. This increase may be clinically relevant as adverse reactions to bicalutamide are related to dose and exposure.
    Dexamethasone: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Drugs that are potent inducers of CYP3A4 activity, such as dexamethasone, will decrease the plasma concentrations of bicalutamide.It is not known if bicalutamide dosing adjustments are necessary.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (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.
    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).
    Erythromycin: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as erythromycin, 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
    Erythromycin; Sulfisoxazole: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as erythromycin, 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
    Fluconazole: (Moderate) Bicalutamide is metabolized by cytochrome CYP3A4. Substances that are inhibitors of CYP3A4 activity, like fluconazole, decrease the metabolism of bicalutamide and increase bicalutamide concentrations.
    Fluoxetine: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as fluoxetine, 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.
    Fluoxetine; Olanzapine: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as fluoxetine, 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.
    Fosphenytoin: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Drugs that are potent inducers of CYP3A4 activity, such as fosphenytoin, will decrease the plasma concentrations of bicalutamide. Clinical trials have not been conducted to determine if bicalutamide dosing adjustments are necessary.
    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.
    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.
    Imatinib: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as imatinib, 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.
    Itraconazole: (Moderate) Bicalutamide is metabolized by cytochrome CYP3A4. Substances that are inhibitors of CYP3A4 activity, like itraconazole, decrease the metabolism of bicalutamide and increase bicalutamide concentrations.
    Ketoconazole: (Moderate) Bicalutamide is metabolized by cytochrome CYP3A4. Substances that are inhibitors of CYP3A4 activity, like ketoconazole, decrease the metabolism of bicalutamide and increase bicalutamide concentrations.
    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.
    Mifepristone: (Moderate) Bicalutamide is a CYP3A4 inhibitor. Moderate CYP3A4 inhibitors should be used with caution with mifepristone.Medications that inhibit CYP3A could increase plasma mifepristone concentrations and dose reduction of mifepristone, when used chronically for treatment of Cushing's disease or hormonal disorders, may be required.
    Nefazodone: (Moderate) Bicalutamide is metabolized by cytochrome CYP3A4. Substances that are inhibitors of CYP3A4 activity, like nefazodone, decrease the metabolism of bicalutamide and increase bicalutamide concentrations.
    Nevirapine: (Major) Bicalutamide is metabolized by CYP3A4. Drugs that are potent inducers of CYP3A4 activity, like nevirapine, will decrease the plasma concentrations of bicalutamide. Clinical trials have not been conducted to determine if bicalutamide dosing adjustments are necessary.
    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.
    Phenytoin: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Drugs that are potent inducers of CYP3A4 activity, such as hydantoin anticonvulsants, will decrease the plasma concentrations of bicalutamide.
    Protease inhibitors: (Major) Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as protease inhibitors, 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.
    Rifamycins: (Major) Bicalutamide is metabolized by CYP3A4. Drugs that are potent inducers of CYP3A4 activity, like the rifamycins, will decrease the plasma concentrations of bicalutamide.
    St. John's Wort, Hypericum perforatum: (Major) Bicalutamide is metabolized by CYP3A4. Drugs that are potent inducers of CYP3A4 activity, like St. John's Wort, will decrease the plasma concentrations of bicalutamide.
    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.
    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.
    Voriconazole: (Moderate) Bicalutamide is metabolized by cytochrome CYP3A4. Substances that are inhibitors of CYP3A4 activity, like voriconazole, decrease the metabolism of bicalutamide and increase bicalutamide concentrations.
    Warfarin: (Moderate) Bicalutamide has been shown in vitro to displace coumarin anticoagulants such as warfarin from protein-binding sites. Prothrombin times should be closely monitored in patients receiving warfarin and subsequently started on bicalutamide.

    PREGNANCY AND LACTATION

    Pregnancy

    Given its indication for use, bicalutamide would not be expected to be used during lactation; the drug is not for use in females. Use of bicalutamide during breast-feeding is not indicated, and if excreted in milk, would be expected to have the potential for adverse effects in a nursing infant due to the anti-androgenic activity. Bicalutamide has been detected in rat milk.

    MECHANISM OF ACTION

    Bicalutamide competitively inhibits the action of androgens by binding to cytoplasmic androgen receptors, primarily in the prostate. There is some central androgen blockade but not as much as flutamide. Serum LH and testosterone are not elevated because of bicalutamide's central activity. Bicalutamide exists as a racemic mixture, with the activity being exhibited by the R-enantiomer only. Prostatic carcinoma is often androgen sensitive and responds to treatments that counteract the effects of androgens or remove their source. Combination therapy with a luteinizing hormone-releasing hormone analog achieves a nearly complete antagonism of testosterone (i.e., the LHRH analog suppresses testosterone output, while bicalutamide interferes with binding of remaining testosterone at the testosterone receptor). In a subset of patients who have been treated with non-steroidal antiandrogen therapy and an LHRH agonist, and whom discontinue the antiandrogen therapy due to progressive advanced prostate cancer, a reduction in prostate specific antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.

    PHARMACOKINETICS

    Bicalutamide is administered orally. It does not cross the blood-brain barrier and is therefore devoid of CNS effects on testosterone. Bicalutamide is 96% protein-bound. The active R-enantiomer is metabolized mainly by oxidation 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 5.9 days for adults without liver disease. This half-life of nearly 6 days affords once-daily dosing. Plasma concentrations are linearly related to dose up to 150 mg given once.
     
    Affected cytochrome P450 isoenzymes: CYP3A4, CYP2C9, CYP2C19, CYP2D6
    In vitro studies have shown that R-bicalutamide is an inhibitor of hepatic CYP3A4 with lesser inhibitory effects on CYP2C9, CYP2C19, and CYP2D6 activity.

    Oral Route

    The absolute bioavailability is not known despite being well absorbed orally. Coadministration of bicalutamide with food has no clinically significant effect.