Bicaluplex

Bicaluplex 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.

Bicaluplex 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.

Adult males including the elderly

One 150 mg tablet once a day.

The tablets should be swallowed whole with liquid.

Bicaluplex 150 mg tablets should be taken continuously for at least 2 years or until disease progression.

Children and adolescents

Bicaluplex is contraindicated in children and adolescents.

Renal impairment

No dose adjustment is necessary for patients with renal impairment

Hepatic impairment

No dose adjustment is necessary for patients with mild hepatic impairment.

Increased accumulation may occur in patients with moderate to severe hepatic impairment.

- Bicaluplex is contraindicated in women and children.

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

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

Bicaluplex 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 Bicaluplex. Therefore, Bicaluplex 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 Bicaluplex therapy.

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

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

Bicaluplex 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 Bicaluplex.

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

Bicaluplex 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.

In this section, undesirable effects are defined as follows: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

¹ Listed as an adverse drug reaction following review of post-marketed data. Frequency has been determined from the incidence of reported adverse events of interstitial pneumonia in the randomised treatment period of the 150 mg EPC studies.

² Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.

³ Listed as an adverse drug reaction following review of post-marketed data. Frequency has been determined from the incidence of reported adverse events of hepatic failure in patients receiving treatment in the open-label Bicaluplex arm of the 150 mg EPC studies.

⁴ Due to the coding conventions used in the EPC studies, adverse events of 'dry skin' were coded under the COSTART term of 'rash'. No separate frequency descriptor can therefore be determined for the 150 mg Bicaluplex dose however the same frequency as the 50 mg dose is assumed.

⁵ The majority of patients receiving Bicaluplex 150 mg as monotherapy experience gynaecomastia and/or breast pain. In studies these symptoms were considered to be severe in up to 5% of the patients. Gynaecomastia may not resolve spontaneously following cessation of therapy, particularly after prolonged treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

No case of overdose has been reported. There is no specific antidote; treatment should be symptomatic. Dialysis is unlikely to be helpful, since Bicaluplex is highly protein bound and is not recovered unchanged in the urine. General supportive care, including frequent monitoring of vital signs, is indicated.

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

ATC code: L02BB03

Bicaluplex 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 Bicaluplex can result in the “anti-androgen withdrawal syndrome” in a sub-set of patients.

Bicaluplex 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 Bicaluplex 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 Bicaluplex 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 Bicaluplex 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 Bicaluplex 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 Bicaluplex is not considered favourable in patients with localised disease.

In a separate programme, the efficacy of Bicaluplex 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 Bicaluplex 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, Bicaluplex 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.

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

Bicaluplex 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 Bicaluplex, 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 Bicaluplex 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.

Bicaluplex 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 Bicaluplex 150 mg was 4.9µg/ml. The amount of Bicaluplex 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.

Bicaluplex is a potent antiandrogen and a mixed function oxidase enzyme inducer in animals.

Target organ changes, including tumour induction (Leydig cells, thyroid, liver) observed in animals are related to these activities. Enzyme induction has not been observed in man and none of these findings is considered to have relevance to the treatment of patients with prostate cancer.

Atrophy of seminiferous tubules is a predicted class effect with antiandrogens and has been observed for all the species examined.

Full reversal of the testicular atrophy was 24 weeks after a 12-month repeated dose toxicity study in rats, although the function reversion was evident in reproduction studies of 7 weeks, after the end of an 11 week dosing. A period of subfertility or infertility should be assumed in man.

Not applicable.

No special requirements.