Bicalutamide Heumann

Bicalutamide Heumann 150 mg tablets are indicated either alone or as adjuvant to radical prostatectomy or radiotherapy in patients with locally advanced prostate cancer at high risk for disease progression.

Bicalutamide Heumann 150 mg tablets are also indicated for the management of patients with locally advanced, non-metastatic prostate cancer for whom surgical castration or other medical intervention is not considered appropriate or acceptable.

- Bicalutamide Heumann is contraindicated in women and children.

- Co-administration of terfenadine, astemizole or cisapride with Bicalutamide Heumann is contra-indicated.

Initiation of treatment should be under the direct supervision of a specialist.

Bicalutamide Heumann is extensively metabolised in the liver. Data suggests that its elimination may be slower in subjects with severe hepatic impairment and this could lead to increased accumulation of Bicalutamide Heumann. Therefore, Bicalutamide Heumann should be used with caution in patients with moderate to severe hepatic impairment.

Periodic liver function testing should be considered due to possibility of hepatic changes. The majority of changes are expected to occur within the first 6 months of Bicalutamide Heumann therapy.

Severe hepatic changes and hepatic failure have been observed rarely with Bicalutamide Heumann, and fatal outcomes have been reported. Bicalutamide Heumann therapy should be discontinued if changes are severe.

For patients who have an objective progression of disease together with elevated PSA, cessation of Bicalutamide Heumann therapy should be considered.

Bicalutamide Heumann has been shown to inhibit cytochrome P450 (CYP 3A4), as such, caution should be exercised when co-administered with drugs metabolised predominantly by CYP 3A4.

Androgen deprivation therapy may prolong the QT interval

In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating Bicalutamide Heumann.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Bicalutamide Heumann is unlikely to impair the ability of patients to drive or operate machinery. However, it should be noted that occasionally dizziness or somnolence may occur. Any affected patients should exercise caution.

Pharmacotherapeutic group: Hormone antagonists and related agents, anti-androgens.

ATC code: L02BB03

Bicalutamide Heumann is a non-steroidal anti-androgen, devoid of other endocrine activity. It binds to the androgen receptors without activating gene expression, and thus inhibits the androgen stimulus. Regression of prostatic tumours results from this inhibition. Clinically discontinuation of Bicalutamide Heumann can result in the “anti-androgen withdrawal syndrome” in a sub-set of patients.

Bicalutamide Heumann was studied as a treatment for patients with localised (T1 - T2, N0 or NX, M0) or locally advanced (T3 - T4, any N, M0; T1 - T2, N+, M0) non-metastatic prostate cancer in a combined analysis of 3 placebo controlled double-blind studies in 8113 patients, where Bicalutamide Heumann was given as immediate hormonal therapy or as adjuvant to radical prostatectomy or radiotherapy (primarily external beam radiation). At 9.7 years median follow up, 36.6% and 38.17% of all Bicalutamide Heumann and placebo-treated patients respectively had experienced objective disease progression.

A reduction in risk of objective disease progression was seen across most patient groups but was most evident in those at highest risk of disease progression. Therefore, clinicians may decide that the optimum medical strategy for a patient at low risk of disease progression, particularly in the adjuvant setting following radical prostatectomy, may be to defer hormonal therapy until signs that the disease is progressing.

No overall survival difference was seen at 9.7 years median follow up with 31.4% mortality (HR = 1.01; 95% CI 0.94 to 1.09). However, some trends were apparent in exploratory subgroup analyses.

Data on progression-free survival and overall survival over time based on Kaplan-Meier estimates for patients with locally advanced disease are summarised in the following tables:

Table 1 Proportion of locally advanced disease patients with disease progression over time by therapy sub-group

Table 2 Overall survival in locally advanced disease by therapy sub-group

For patients with localised disease receiving Bicalutamide Heumann alone, there was no significant difference in progression free survival. There was no significant difference in overall survival in patients with localised disease who received Bicalutamide Heumann as adjuvant therapy, following radiotherapy (HR = 0.98; 95% CI 0.80 to 1.20) or radical prostatectomy (HR = 1.03; 95% CI 0.85 to 1.25). In patients with localised disease, who would otherwise have been managed by watchful waiting, there was also a trend toward decreased survival compared with placebo patients (HR = 1.15; 95% CI 1.00 to 1.32). In view of this, the benefit-risk profile for the use of Bicalutamide Heumann is not considered favourable in patients with localised disease.

In a separate programme, the efficacy of Bicalutamide Heumann 150mg for the treatment of patients with locally advanced non-metastatic prostate cancer for whom immediate castration was indicated, was demonstrated in a combined analysis of two studies with 480 previously untreated patients with non-metastatic (M0) prostate cancer. At 56% mortality and a median follow-up of 6.3 years, there was no significant difference between Bicalutamide Heumann and castration in survival (HR = 1.05; CI = 0.81 to 1.36); however, equivalence of the two treatments could not be concluded statistically.

In a combined analysis of 2 clinical studies with 805 previously untreated patients with metastatic (M1) disease at 43% mortality, Bicalutamide Heumann 150mg was demonstrated to be less effective than castration in survival time (HR = 1.30; CI 1.04 to 1.65), with a numerical difference in estimated time to death of 42 days (6 weeks) over a median survival time of 2 years.

Bicalutamide Heumann is a racemate with its antiandrogen activity being almost exclusively in the (R)-enantiomer.

Bicalutamide Heumann is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.

The (S)-enantiomer is rapidly cleared relative to the (R)-enantiomer, the latter having a plasma elimination half-life of about 1 week.

On daily administration of Bicalutamide Heumann, the (R)-enantiomer accumulates about 10-fold in plasma, as a consequence of its long half-life.

Steady state plasma concentrations of the (R)-enantiomer, of approximately 22μg/ml are observed during daily administration of Bicalutamide Heumann 150mg. At steady state, the predominantly active (R)-enantiomer accounts for 99 % of the total circulating enantiomers.

The pharmacokinetics of the (R)-enantiomer are unaffected by age, renal impairment or mild to moderate hepatic impairment. There is evidence that for subjects with severe hepatic impairment, the (R)-enantiomer is more slowly eliminated from plasma in patients with severe hepatic impairment.

Bicalutamide Heumann is highly protein bound (racemate 96%, enantiomer-(R) > 99%) and extensively metabolised (via oxidation and glucuronidation). Its metabolites are eliminated via the kidneys and bile in approximately equal proportions.

In clinical study, the mean concentration of (R)-enantiomer in semen of men receiving Bicalutamide Heumann 150 mg was 4.9µg/ml. The amount of Bicalutamide Heumann potentially delivered to a female partner during intercourse is low and equates to approximately 0.3µg/kg. This is below that required to induce changes in offspring of laboratory animals.

Not applicable.

Dispose of the medication in accordance with local regulations for medical waste.