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bicalutamide
Bicalutamide is a selective, non-steroidal antiandrogen. It binds to the androgen receptors in target tissue and competitively inhibits the action of androgen, resulting in regression of prostatic tumours. Bicalutamide is a racemate and the (R)-enantiomer is primarily responsible for its anti-androgenic activity.
Oral: Well absorbed. Food does not appear to affect the rate or extent of absorption.
The (R)-enantiomer accumulates about 10-fold with daily administration.
| Cross blood brain barrier? | Probably poor penetration |
| PPB | > 96 % |
Bicalutamide undergoes stereospecific metabolism, with hepatic biotransformation via glucuronidation and oxidation. The (S)-enantiomer is very rapidly cleared relative to the (R)-enantiomer.
| Active metabolites | R-enantiomer |
Metabolites are eliminated equally via renal and biliary routes.
| Feces | 43 % over 9 days |
| Urine | 36 % over 9 days |
| Half-life | 1 week |
For use in combination with LHRH analogue or surgical castration in the treatment of metastatic (stage D2) prostate cancer.
Emetogenic Potential:
Extravasation Potential: Not applicable
The following adverse effects were observed in metastatic prostate cancer patients, in combination with a LHRH agonist.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (<5%) | D | |||
| Arterial thromboembolism (<5%) | E D | ||||
| Cardiotoxicity (4%) | D | ||||
| Hypertension (8%) | D | ||||
| Venous thromboembolism (<5%) | E D | ||||
| Dermatological | Alopecia (4%) | E | |||
| Hirsutism (2%) | D | ||||
| Photosensitivity (rare) | E | ||||
| Rash (9%) | E | ||||
| Gastrointestinal | Abdominal pain (11%) | E | |||
| Anorexia (6%) | E | ||||
| Constipation (22%) | E | ||||
| Diarrhea (12%) | I | ||||
| Dyspepsia (7%) | E | ||||
| GI hemorrhage (<5%) | E | ||||
| GI obstruction (<5%) | E | ||||
| Nausea, vomiting (14%) | I | ||||
| Weight changes (7%) | D | ||||
| General | Edema (13%) | D | |||
| Fatigue (22%) | E | ||||
| Hematological | Anemia (13%) | D | |||
| Hepatobiliary | ↑ LFTs (7%) (may be severe) | D | |||
| Hypersensitivity | Hypersensitivity (1%) (angioedema, urticaria) | I | |||
| Infection | Infection (18%) | D | |||
| Metabolic / Endocrine | ↑ Ca (<5%) | D | |||
| ↑ Cholesterol (<5%) | D | ||||
| Hyperglycemia (7%) | D | ||||
| Musculoskeletal | Musculoskeletal pain (35%) | E | |||
| Osteoporosis (4%) /Fractures | D | ||||
| Nervous System | Anxiety (5%) | E | |||
| Cognitive disturbance (<5%) | E | ||||
| Depression (4%) | E | ||||
| Dizziness (10%) | I E | ||||
| Headache (7%) | E | ||||
| Insomnia (7%) | I E | ||||
| Neuropathy (8%) | E | ||||
| Ophthalmic | Cataract (<5%) | E D | |||
| Conjunctivitis (<5%) | E D | ||||
| Renal | Creatinine increased (<5%) | E | |||
| Reproductive and breast disorders | Androgen deprivation symptoms (53%) | D | |||
| Respiratory | Cough, dyspnea (13%) | D | |||
| Pneumonitis (rare) | D | ||||
| Urinary | Urinary symptoms (12%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
Dose-limiting side effects are underlined.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
Bicalutamide is well-tolerated in general, with expected adverse effects including hot flashes, breast tenderness and gynecomastia, which may be reduced by concomitant surgical or medical castration. Bicalutamide may also be associated with occurrence of diarrhea, nausea, vomiting and fatigue. Fluid retention may occur.
In the pivotal trial comparing bicalutamide to flutamide, an imbalance in cardiac deaths was noted (18 patients vs. 9 patients receiving flutamide). The combined use of anti-androgen plus LHRH analogue / surgical castration increases risk of cardiovascular disease and osteoporosis or the potential of QT prolongation. (especially in patients with risk factors). Assess benefit-risk ratio in these patients before starting treatment. Use bicalutamide with caution in patients with cardiac disease as well as in patients at risk for prolonged QTc.
Bone loss may occur during the hypoandrogenic state caused by long-term combined androgen blockade. Risk factors such as older patients, pre-existing osteopenia, family history of osteoporosis, chronic use of corticosteroids or anticonvulsants, or chronic alcohol/tobacco abuse should be carefully considered before starting treatment. Reduction of glucose tolerance has also been observed in patients receiving combined androgen blockade.
Severe, sometimes fatal hepatic failure and hepatic changes have been observed rarely. Hepatotoxicity generally occurs within the first 3-4 months of treatment. Interstitial lung disease (ILD), including fatal reports, has been reported rarely, especially at doses of over 50mg.
In some patients, antiandrogens may increase rather than inhibit growth of prostate cancer; patients with increasing PSA or worsening symptoms should discontinue bicalutamide and be assessed for 6-8 weeks for an antiandrogen withdrawal response.
Photosensitivity reactions have been reported rarely. If the reaction is persistent and/or severe, appropriate symptomatic treatment should be given.
Refer to protocol by which patient is being treated. Bicalutamide should be started at the same time as the LHRH analogue for patients who have not had surgical castration. Bicalutamide doses of 150 mg/day should not be used as this increases mortality (phase III localized prostate trials).
Patients should be advised to avoid direct exposure to excessive sunlight and may consider the use of sunscreens.
| Toxicity | Action |
| Myelosuppression | No adjustment required |
| Pneumonitis | Hold; investigate. If confirmed, discontinue. |
| Cardiac failure, arterial or venous thromboembolism | Discontinue |
| Grade 3 or 4 LFT increases | Discontinue |
No adjustment required in the presence of mild hepatic impairment. Caution should be exercised in moderate to severe hepatic impairment, as bicalutamide is extensively metabolized in the liver. Elimination is lower in subjects with severe hepatic impairment, leading to increased accumulation.
No adjustment required.
No adjustment required.
CONTRAINDICATED in children
- Outpatient prescription for home administration
- May be taken with or without food
- in patients with hypersensitivity to the drug or any of its components
- in localized prostate cancer undergoing ”watchful waiting”
- in females and children
- contains lactose; use should be carefully considered in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption
- results in fluid retention and should be used with caution in patients with cardiac disease as well as in patients at risk for prolonged QTc
-
Genotoxicity:
No
-
Fetotoxicity:
Yes
Bicalutamide is CONTRAINDICATED in pregnancy and breastfeeding. Patients and their partners should use adequate contraception for at least 130 days after the last dose.
-
Fertility effects:
Probable
Male fertility impairment may be reversible.
No drug/drug interactions were observed with LHRH analogues.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Drugs metabolized by CYP3A4 | Bicalutamide (R-enantiomer) inhibits CYP3A4 (and 2C9, 2C19, 2D6 to a lesser extent) | ↑ levels of drugs | Caution when using with drugs with narrow therapeutic index |
| warfarin | ↑ PT/INR | Increased anticoagulant effect and risk of bleeding; bicalutamide displaces warfarin from protein binding | Monitor PT/INR closely; warfarin dose may require adjustment |
| Drugs that may prolong QT interval | Potential risk in ↑ QT interval | Additive effects when combined with LHRH analogue and anti-androgen | Caution and monitor |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
| Liver function tests | baseline and regular |
Electrolytes |
baseline, also during treatment for patients at risk of electrolyte abnormality and QT prolongation |
| Blood glucose | especially in diabetic patients; baseline and regular |
ECG |
baseline; also during treatment for patients at risk of QT prolongation |
Bone density |
as clinically indicated |
INR, for patients on warfarin |
as clinically indicated |
Clinical assessment for fluid retention, pneumonitis, androgen withdrawal effects, cardiovascular, hepatic effects and thromboembolism |
at each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
Hemoglobin |
baseline and as clinically indicated |
Prescribing Information: Casodex® (bicalutamide). AstraZeneca US Inc., December 2008.
November 2017 modified contraception, interactions and monitoring sections
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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