Bicalutamide-vista ac

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

Composition:

Active substance: bicalutamide;

One film-coated tablet contains 150 mg of bicalutamide;

Excipients: lactose monohydrate; povidone K-25; sodium starch glycolate (type A); magnesium stearate;

Tablet coating Opadry OY-S-9622: hypromellose (5 cP), titanium dioxide (E 171), propylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: round, biconvex, white tablets with a score line, coated with a film coating.

Pharmacotherapeutic group. Hormonal antagonists and related agents. Antiandrogens. Bicalutamide. ATC code L02BB03

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Bicalutamide is a nonsteroidal antiandrogen with no other effects on the endocrine system. It binds to wild-type (non-mutated) or normal androgen receptors without activating gene expression, thereby inhibiting androgen activity. As a result of this inhibition, regression of prostate tumor tissue is observed. After discontinuation of bicalutamide, a post-antiandrogen therapy syndrome may occur in some patients.

Clinical efficacy and safety

Bicalutamide 150 mg was used as a treatment for patients with localized (T1–T2N0 or NX, M0) or locally advanced (T3–T4, any N, M0; T1–T2, N+, M0) prostate cancer without metastases in three placebo-controlled, double-blind studies involving 8,113 patients. Bicalutamide was administered either as immediate hormonal therapy or as adjuvant therapy following radical prostatectomy or radiotherapy (mostly 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 the majority of patients across treatment groups, but this effect was most pronounced in individuals at high risk of disease progression. Therefore, for patients at low risk of disease progression, particularly those receiving adjuvant bicalutamide after radical prostatectomy, a strategy of deferring hormonal therapy until signs of disease progression may be optimal.

At a median follow-up of 9.7 years, no difference in overall survival was observed, with mortality rates of 31.4% in both groups (relative risk (RR) = 1.01; 95% confidence interval (CI) = 0.94–1.09). However, subgroup analyses revealed certain trends.

Kaplan-Meier estimates of progression-free survival and overall survival in patients with locally advanced prostate cancer are presented in the following tables:

Table 1

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

Table 2

Overall survival of patients with locally advanced disease 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 watchful waiting approach, there remains a trend toward reduced survival compared to patients receiving placebo (HR 1.15; 95% CI 1.00–1.32). Considering the benefit/risk ratio, the use of bicalutamide in patients with localized disease is not considered appropriate.

In another program, the efficacy of bicalutamide 150 mg for the treatment of patients with locally advanced prostate cancer without metastases (M0), who were candidates for immediate castration, was demonstrated in a combined analysis of two studies involving 480 patients with prostate cancer without metastases (M0) who had not received prior therapy. At a median follow-up 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 a combined analysis of two studies involving 805 patients with metastases (M1) who had not received prior therapy, at a mortality rate of 43%, bicalutamide 150 mg 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 racemic mixture with antiandrogenic activity residing almost exclusively in the (R)-enantiomer.

Children. No studies have been conducted in pediatric patients (see sections "Contraindications" and "Use in Pregnancy and Breastfeeding").

Pharmacokinetics

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

Distribution. Bicalutamide is highly protein-bound (racemate 96%, (R)-enantiomer >99%) and undergoes extensive metabolism (via oxidation and glucuronidation); its metabolites are excreted in urine and bile in approximately equal amounts.

Biotransformation. The (S)-enantiomer is rapidly eliminated compared to the (R)-enantiomer; elimination of the latter from plasma takes approximately 1 week.

With daily administration of bicalutamide 150 mg, the (R)-enantiomer accumulates in plasma due to its long elimination half-life, reaching a 10-fold concentration. A steady-state concentration plateau of the (R)-enantiomer at approximately 22 μg/mL is achieved with a daily dose of 150 mg bicalutamide. In the steady state, the predominant active (R)-enantiomer accounts for 99% of the total circulating enantiomers.

Excretion. During a clinical study, the mean concentration of (R)-bicalutamide in semen of men receiving bicalutamide 150 mg was 4.9 μg/mL. The amount of bicalutamide potentially transferred to a female partner during sexual intercourse is low and estimated to be approximately 0.3 μg/mL, which is below the level shown to affect offspring in laboratory animals.

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

Clinical characteristics

Indications

BICALUTAMIDE-VISTA AS 150 mg is indicated as monotherapy and 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 AS 150 mg is also indicated for the treatment of patients with locally advanced non-metastatic prostate cancer when surgical castration or other medical interventions are not acceptable or cannot be applied.

Contraindications

• BICALUTAMIDE-VISTA AS is contraindicated in women and children (see section "Use in pregnancy and lactation").
• Hypersensitivity to the active substance or to any of the excipients.
• Concomitant administration of BICALUTAMIDE-VISTA AS with terfenadine, astemizole, or cisapride is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction

In vitro studies have shown that R-bicalutamide is an inhibitor of CYP3A4 and has 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% after concomitant administration for 28 days with bicalutamide. For medicinal products with a narrow therapeutic range, such an increase may be clinically significant. Therefore, concomitant use with terfenadine, astemizole, and cisapride is contraindicated (see section "Contraindications"). Bicalutamide should also be used with caution when administered concomitantly with agents such as cyclosporine and calcium channel blockers. A 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 treatment.

Bicalutamide should be prescribed with caution when used concomitantly with medicinal products that may inhibit the oxidation of other agents (e.g., cimetidine, ketoconazole). Theoretically, this may lead to increased plasma concentrations of bicalutamide and result in an increased risk of adverse effects.

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 using this medicinal product in patients receiving coumarin anticoagulants, careful monitoring of prothrombin time (PT) and international normalized ratio (INR) is recommended, and dose adjustment of anticoagulants should be considered (see sections "Special precautions for use" and "Adverse reactions").

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

Paediatric population. Interaction studies have been conducted only in adults.

Special precautions for use

Treatment with this medicinal product should be initiated under direct medical supervision. Bicalutamide is extensively metabolized in the liver. Available data suggest that in patients with severe hepatic impairment, elimination of bicalutamide is slowed, which may lead to its accumulation. Therefore, bicalutamide should be used with caution in patients with moderate or severe hepatic impairment. Since changes in liver function may occur, liver function tests should be monitored periodically. Most changes are expected to occur within the first 6 months of bicalutamide treatment. Rarely, severe hepatic dysfunction has been observed during treatment with this medicinal product, including fatal cases (see section "Adverse reactions"). If severe liver function abnormalities occur, bicalutamide treatment should be discontinued. In patients with objective disease progression accompanied by rising PSA (prostate-specific antigen) levels, discontinuation of bicalutamide should be considered.

Bicalutamide has been shown to inhibit CYP3A4 activity; therefore, it should be used cautiously with medicinal products that are primarily metabolized by CYP3A4 (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Rarely, photosensitivity reactions have been reported in patients receiving bicalutamide. Patients should be advised to avoid excessive exposure to direct sunlight or ultraviolet light and to use sun protection measures during treatment. If photosensitivity reactions are persistent and/or severe, appropriate symptomatic treatment should be initiated.

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 receiving 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 treatment, considering the potential risk of developing torsade 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 sexual partners should use effective contraception during treatment and for 130 days after the last dose of the medicinal product.

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 is recommended, and dose adjustment of anticoagulants should be considered (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Important information on excipients.
The medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially sodium-free.

BICALUTAMIDE-VISTA AS contains lactose. Patients with rare hereditary problems of galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy and breastfeeding

Pregnancy. Bicalutamide is contraindicated for use in women. It is contraindicated during pregnancy.

Breastfeeding. Bicalutamide is contraindicated during breastfeeding.

Fertility. Reversible impairment of male fertility was observed in animal studies. A period of subfertility or infertility may also be expected in men.

Ability to influence reaction speed when driving or operating machinery

The medicinal product does not affect the ability to drive or operate complex machinery. However, it should be noted that somnolence is common and dizziness is very common (see section "Adverse reactions"). Patients taking this medicinal product should therefore exercise caution.

Method of Administration and Dosage

For adult men, including elderly patients: take 1 tablet (150 mg) once daily.

The medicinal product should be taken long-term, for at least 2 years or until signs of disease progression appear.

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.

In patients with moderate and severe hepatic impairment, increased accumulation is possible (see section "Special Warnings and Precautions for Use").

Children. The medicinal product is contraindicated in children.

Overdose.

Symptoms. Data on overdose in humans are lacking.

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 functions.

Side effects

The frequency of adverse reactions is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (≤ 1/10,000), frequency not known (cannot be estimated based on available data).

Changes in the liver are rarely severe and often resolve or diminish with continued treatment or after discontinuation.

b Gynaecomastia and/or breast pain occurred in the majority of patients receiving bicalutamide 150 mg as monotherapy. In clinical trials, these symptoms were considered severe in 5% of patients. Gynaecomastia may persist after discontinuation of therapy, particularly following prolonged treatment.

c Due to the coding standards used in the EPC (Early Prostate Cancer programme) trials, adverse events of "dry skin" were coded as "rash" according to COSTART terminology. Therefore, the frequency cannot be determined separately for the 150 mg bicalutamide dose; however, the frequency is expected to be the same as that for the 50 mg dose.

d Included in the list of adverse drug reactions after evaluation of post-marketing data. The frequency was determined based on the rate of reports of hepatic failure as an adverse event in patients receiving treatment in the open EPC trials receiving 150 mg bicalutamide.

e Included in the list of adverse drug reactions after evaluation of post-marketing data. The frequency was determined based on the rate of reports of interstitial pneumonia as an adverse event in patients receiving treatment in the open EPC trials receiving 150 mg bicalutamide.

Increase in PT/INR: During post-marketing surveillance, interactions between coumarin anticoagulants and bicalutamide have been reported (see sections "Dosage and Administration" and "Interaction with other medicinal products and other forms of interaction"). Reporting of suspected adverse reactions

Reporting of adverse reactions after drug authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 5 years.

Storage conditions. Store in the original packaging, at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging. 10 tablets per blister, 3 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. JENEPHARM, S.A.

Manufacturer's address and place of business. 18th km Marathon Avenue, Pallini, 153 51, Greece