Bicalutamide-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BICALUTAMIDE-VISTA (BICALUTAMIDE-VISTA)

Composition:

Active substance: bicalutamide;

One film-coated tablet contains 150 mg of bicalutamide;

Excipients: lactose monohydrate, povidone, crospovidone, sodium lauryl sulfate, magnesium stearate; coating: lactose monohydrate, hypromellose, titanium dioxide (E 171), macrogol (PEG 4000).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets. On one side of the tablet there is an imprint "ВСМ 150".

Pharmacotherapeutic group. Antiandrogen agents. ATC code L02B B03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Bicalutamide is a non-steroidal antiandrogen that has no other effect on the endocrine system. The drug binds to non-mutant (wild-type) androgen receptors without activating gene expression, thereby inhibiting androgen activity. As a result of this inhibition, regression of prostate tumors is observed. Upon discontinuation of bicalutamide, withdrawal syndrome may occur in a certain proportion of patients.

Clinical efficacy and safety. Bicalutamide 150 mg was evaluated in patients with localized (T1–T2, N0 or Nx, M0) or locally advanced (T3–T4, N, M0; T1–T2, N+, M0) prostate cancer without metastases in three placebo-controlled, double-blind studies involving 8113 patients. In these studies, bicalutamide was administered as immediate hormonal therapy or as an adjuvant to radical prostatectomy or radiotherapy (primarily external beam radiation therapy). At a median follow-up of 9.7 years, objective disease progression was observed in 36.6% of patients receiving bicalutamide and 38.17% of those receiving placebo. A reduction in the risk of objective disease progression was observed in most patients across the groups, but was most pronounced in those with the highest risk of disease progression. Therefore, clinicians may determine that the optimal treatment strategy for patients at low risk of disease progression, particularly when the drug is used adjuvantly after radical prostatectomy, may be to defer hormonal therapy until disease progression occurs. At the median follow-up of 9.7 years, no difference in overall survival was observed, with mortality rates of 31.4% (hazard ratio (HR) = 1.01; 95% confidence interval (CI) 0.94–1.09). However, trends were evident during subgroup analyses of study outcomes. Data on progression-free survival and overall survival based on Kaplan-Meier analysis in patients with locally advanced prostate cancer are presented in Tables 1 and 2.

Table 1

Proportion of patients with locally advanced prostate cancer and patients with disease progression in subgroups according to different treatment regimens

Table 2

Overall survival in patients with locally advanced cancer in subgroups with different treatment regimens

In patients with localized disease who received bicalutamide alone, there was no statistically significant difference in progression-free survival. Also, in patients with localized disease who received bicalutamide as adjuvant therapy after radiotherapy (HR=0.98; 95% CI 0.80–1.20) or radical prostatectomy (HR=1.03; 95% CI 0.85–1.25), no statistically significant difference in overall survival was observed. In patients with localized disease who otherwise would have been managed with a strategy of watchful waiting, a trend toward reduced survival was observed compared to patients receiving placebo (HR=1.15; 95% CI 1.00–1.32). Given this risk/benefit ratio, the use of bicalutamide in patients with localized disease is not considered appropriate.

In another program, the efficacy of bicalutamide for the treatment of patients with locally advanced prostate cancer without metastases (M0), for whom immediate castration was indicated, was demonstrated in two studies involving 480 previously untreated patients with non-metastatic prostate cancer. At the median follow-up time of 6.3 years, the mortality rate was 56% and did not differ significantly between the bicalutamide and castration groups (HR=1.05; CI 0.81–1.36); however, statistical equivalence of the two treatment methods cannot be established.

In the course of two studies involving 805 previously untreated patients with metastatic disease (M1) and a mortality rate of 43%, bicalutamide was found to be less effective than castration in terms of survival time (HR=1.30; CI 1.04–1.65), with a numerical difference in time to death of 42 days (6 weeks) and a median survival of 2 years. Bicalutamide is a racemate with antiandrogenic activity, represented almost exclusively by the R-enantiomer.

Children. No studies in children have been conducted (see sections "Contraindications" and "Use in pregnancy or lactation").

Pharmacokinetics.

Absorption. Bicalutamide is well absorbed after oral administration. There is no evidence of a clinically significant effect of food intake on the bioavailability of the drug.

Distribution. Bicalutamide is highly protein-bound (racemate - 96%, (R)-enantiomer - >99%) and is extensively metabolized (by oxidation and glucuronidation), with metabolites excreted equally in urine and bile.

Biotransformation. The (S)-enantiomer is rapidly eliminated compared to the (R)-enantiomer; the latter has an elimination half-life in plasma of approximately 1 week.

With daily administration of bicalutamide, the (R)-enantiomer accumulates in plasma due to its long half-life, reaching concentrations 10-fold higher.

A plateau concentration of the (R)-enantiomer at approximately 22 μg/mL is observed with a daily dose of 150 mg bicalutamide. At steady state, the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.

Elimination. In a clinical study, the mean concentration of (R)-bicalutamide in semen of men receiving 150 mg was 4.9 μg/mL. The amount of bicalutamide potentially transferred to a female partner during sexual intercourse is low and may be approximately 0.3 μg/mL. This level is lower than that which in laboratory animals causes offspring alterations.

Special patient groups. The pharmacokinetics of the (R)-enantiomer are independent of age, renal impairment, or mild to moderate hepatic impairment. Evidence exists that in patients with severe hepatic impairment, the (R)-enantiomer is eliminated more slowly from plasma.

Clinical characteristics.

Indications.

Bicalutamide-Vista 150 mg is indicated for monotherapy or as adjuvant therapy in combination with radical prostatectomy or radiotherapy in patients with locally advanced prostate cancer at high risk of disease progression (see section "Pharmacological properties").

Bicalutamide-Vista 150 mg is also indicated for the treatment of patients with locally advanced non-metastatic prostate cancer for whom surgical castration or other medical interventions are inappropriate or cannot be applied.

Contraindications.

Bicalutamide-Vista is contraindicated in women and children.

Bicalutamide-Vista must not be administered to patients who have shown hypersensitivity reactions to the active substance or to any of the excipients contained in the medicinal product.

Concomitant administration of bicalutamide with terfenadine, astemizole, or cisapride is contraindicated.

Interaction with other medicinal products and other forms of interaction.

In vitro studies have shown that R-bicalutamide is an inhibitor of CYP 3A4 and exhibits a lesser inhibitory effect on the activity of CYP 2C9, 2C19, and 2D6. Although clinical studies using antipyrine as a marker for cytochrome P450 (CYP) activity did not indicate a potential interaction with bicalutamide, the mean concentration of midazolam (area under the pharmacokinetic curve) increased by up to 80% following concomitant administration for 28 days with bicalutamide.

For medicinal products with a narrow therapeutic range, such an increase may be significant. Therefore, concomitant use with terfenadine, astemizole, and cisapride is contraindicated. Bicalutamide should also be used with caution when administered with compounds such as cyclosporines and calcium channel blockers. Dose reduction of these medicinal products may be necessary, especially if signs of enhanced drug effect or adverse effects occur. When cyclosporine is used, careful monitoring of its plasma concentration and the patient's clinical status is recommended upon initiation or discontinuation of bicalutamide therapy.

Bicalutamide-Vista should be prescribed with caution when used concomitantly with medicinal products that may inhibit its oxidation (such as cimetidine, ketoconazole). Theoretically, this may lead to increased plasma concentrations of bicalutamide, potentially resulting in enhanced adverse effects of the drug.

In vitro studies have shown that bicalutamide may displace the coumarin anticoagulant warfarin from its protein-binding sites. Enhanced effects of warfarin and other coumarin anticoagulants have been reported when administered concomitantly with bicalutamide. Therefore, when bicalutamide is prescribed to patients already receiving coumarin anticoagulants, careful monitoring of prothrombin time is recommended, and consideration should be given to adjusting the anticoagulant dose.

Since antiandrogen therapy may lead to QT interval prolongation, bicalutamide should be used with caution when administered concomitantly with medicinal products capable of prolonging the QT interval or inducing ventricular tachycardia of the torsade de pointes type, such as class IA (quinidine, disopyramide) or class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, methadone, moxifloxacin, and neuroleptics (see section "Special precautions").

Children. Interaction studies have been conducted only in adults.

Special precautions for use

Treatment should be initiated under direct medical supervision.

Bicalutamide is extensively metabolized in the liver. Some data suggest that elimination of the drug may be slowed in patients with severe hepatic impairment, which could lead to accumulation of bicalutamide. Therefore, bicalutamide should be used with caution in patients with moderate or severe liver impairment.

Due to the potential for changes in liver function, periodic monitoring of liver function tests is recommended. Most abnormalities occur within the first 6 months of bicalutamide treatment. Rarely, severe hepatic reactions have been observed during bicalutamide use, including fatal cases. If severe liver function abnormalities occur, treatment with bicalutamide should be discontinued.

In the presence of objective signs of disease progression or elevated PSA (prostate-specific antigen) levels, discontinuation of bicalutamide therapy should be considered.

Bicalutamide has been shown to inhibit cytochrome P450 (CYP3A4) activity. Therefore, caution should be exercised when co-administering bicalutamide with medicinal products that are primarily metabolized by CYP3A4.

Rare cases of photosensitivity reactions have been reported in patients receiving bicalutamide 150 mg. Patients should be advised to avoid excessive exposure to direct sunlight or ultraviolet light and to use sun protection measures during treatment with bicalutamide 150 mg. If a photosensitivity reaction is persistent and/or severe, appropriate symptomatic treatment should be initiated.

Patients with rare hereditary conditions such as galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. If intolerance to certain sugars is established, medical advice should be sought before taking this medicinal product.

Antiandrogen therapy may prolong the QT interval. In patients with risk factors or a history of QT interval prolongation, as well as in patients concurrently taking medicinal products that may prolong the QT interval (see section "Interaction with other medicinal products and other forms of interaction"), the physician should assess the benefit-risk ratio before initiating bicalutamide therapy, considering the potential risk of torsades de pointes ventricular tachycardia. Antiandrogen therapy may cause changes in sperm morphology. Although the effect of bicalutamide on sperm morphology has not been evaluated and such changes have not been reported in patients receiving bicalutamide, patients and/or their partners should use effective contraception during treatment and for 130 days after the end of bicalutamide therapy.

Enhanced effects of coumarin anticoagulants have been reported in patients receiving bicalutamide concomitantly, which may lead to increased prothrombin time (PT) and international normalized ratio (INR). Some cases were associated with a risk of bleeding. Careful monitoring of PT/INR levels is recommended, and dose adjustment of anticoagulants should be considered.

Excipients:

The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

Bicalutamide-Vista is contraindicated in women. Bicalutamide is contraindicated in women during pregnancy.

Breastfeeding.

Bicalutamide-Vista is contraindicated during breastfeeding.

Fertility.

Reversible impairment of male fertility has been observed in animal studies. In humans, a period of subfertility or infertility should be assumed.

Ability to affect reaction speed while driving or operating machinery.

Bicalutamide-Vista has no influence on the ability to drive a vehicle or operate complex machinery. However, it should be noted that somnolence and dizziness may occur frequently (see section "Adverse reactions"). Patients taking this medicinal product should exercise caution.

Method of Administration and Dosage.

Adult male patients, including elderly patients: orally, one 150 mg tablet once daily. Bicalutamide-Vista 150 mg should be administered long-term, for at least 2 years or until signs of disease progression occur.

Special populations.

Renal impairment: Dose adjustment is not required in patients with renal impairment.

Hepatic impairment: Dose adjustment is not required in patients with mild hepatic impairment. Increased accumulation of the medicinal product may occur in patients with moderate or severe hepatic impairment (see section "Special instructions").

Children.

Bicalutamide-Vista is contraindicated in pediatric patients.

Overdose.

There are no data regarding overdose in humans.

Treatment. There is no specific antidote; treatment is symptomatic. Dialysis may be ineffective because bicalutamide is highly protein-bound and is not excreted unchanged in urine. In case of overdose, general supportive therapy is indicated, including monitoring of vital signs.

Side effects.

Side effects are listed by frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (based on available data, the frequency of occurrence cannot be estimated).

1 Liver changes are rarely severe and often resolve or diminish with continued treatment or after discontinuation of therapy.

2 Most patients receiving bicalutamide 150 mg as monotherapy experience gynecomastia and/or breast tenderness. In clinical trials, 5% of patients classified these symptoms as severe. Gynecomastia may not resolve spontaneously after discontinuation of therapy, particularly following prolonged treatment.

3 According to coding rules used in the EPC trials, the adverse reaction "dry skin" was coded under the COSTART term "rash". Therefore, the individual frequency of occurrence cannot be determined for bicalutamide 150 mg; however, the frequency is expected to be the same as that for the 50 mg dosage.

4 Included in the list of adverse reactions following post-marketing data. The frequency was estimated based on the rate of reported cases of liver injury in patients receiving bicalutamide 150 mg in the open-treatment arm of the Early Prostate Cancer (EPC) programme studies.

5 Included in the list of adverse reactions following post-marketing data. The frequency was estimated based on the rate of reported cases of interstitial pneumonia during the randomized treatment period with bicalutamide 150 mg in the EPC studies.

Increase in PT/INR: Post-marketing reports have indicated an interaction between coumarin anticoagulants and bicalutamide.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 5 years.

Storage conditions.

Store in the original packaging at temperatures not exceeding 25 °C. Keep out of the reach of children.

Packaging.

10 tablets per blister; 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Sicant Spain, S.L.

Manufacturer's address and place of business.

C/Castello, no 1, Sant Boi de Llobregat, Barcelona, 08830, Spain.