Vistamid film-coated tablets 150 mg blister No. 30

Instructions Vistamid film-coated tablets 150 mg blister No. 30

Composition

active ingredient: bicalutamide;

1 film-coated tablet contains 150 mg of bicalutamide;

excipients: lactose monohydrate; povidone; crospovidone; sodium lauryl sulfate; magnesium stearate;

shell: lactose monohydrate; hypromellose; titanium dioxide (E 171); macrogol (PEG 4000).

Dosage form

Film-coated tablets.

Main physicochemical properties: white round biconvex tablets, film-coated; engraved “VSM 150” on one side of the tablets.

Pharmacotherapeutic group

Antiandrogenic agents. ATX code L02B B03.

Pharmacological properties

Pharmacodynamics.

Mechanism of action.

Bicalutamide is a nonsteroidal antiandrogen that has no other effects on the endocrine system. The drug binds to non-mutant androgen receptors ("wild-type") without activating gene expression, thereby inhibiting androgen activity. As a result of such inhibition, regression of prostate tumors is observed. When bicalutamide is discontinued, a certain proportion of patients may experience an antiandrogen withdrawal syndrome.

Clinical efficacy and safety.

Bicalutamide 150 mg was studied in the treatment of patients with localized (T1–T2, N0 or Nx, M0) or locally advanced (T3–T4, N, M0; T1–T2, N+, M0) non-metastatic prostate cancer in three placebo-controlled, double-blind studies involving 8113 patients. In these studies, bicalutamide was administered as emergency hormonal therapy or as an adjuvant to radical prostatectomy or radiotherapy (mainly external beam radiotherapy). At a median follow-up of 9.7 years, 36.6% and 38.17% of all patients receiving bicalutamide and placebo, respectively, had objective disease progression.

The reduction in the risk of objective disease progression was observed in most patients in the groups, but was most pronounced in those at highest risk of disease progression. Therefore, clinicians may decide that the optimal treatment strategy for patients at low risk of disease progression, especially when using the drug in the adjuvant setting after radical prostatectomy, may be hormonal therapy until disease progression.

At a median follow-up of 9.7 years, no difference in overall survival was observed, with a mortality rate of 31.4% (hazard ratio = 1.01; 95% confidence interval 0.94-1.09). However, some trends were evident when subgroup analyses were performed.

Progression-free survival and overall survival data based on Kaplan–Meier analysis in patients with locally advanced prostate cancer are presented in Tables 1 and 2.

The ratio of patients with locally advanced cancer to patients with

disease progression in subgroups with different treatment regimens

Table 1

Overall survival in patients with locally advanced disease

in subgroups with different treatment regimens

Table 2

There was no significant difference in progression-free survival in patients with localized disease who received bicalutamide alone. There was also no significant difference in overall survival 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). There was also a trend towards a reduced survival rate compared with patients with localized disease who would otherwise have been treated with watchful waiting (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 in the treatment of patients with locally advanced, nonmetastatic prostate cancer for whom immediate castration was indicated was demonstrated in two studies involving 480 previously untreated patients with nonmetastatic prostate cancer (M0). 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, the equivalence of the two treatments could not be assessed statistically.

In 2 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 (hazard ratio = 1.30; confidence interval 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 have been conducted in children (see sections “Contraindications” and “Use during pregnancy and breastfeeding”).

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 has a high degree of binding to blood proteins (racemate - 96% (R)-enantiomer - >99%) and is extensively metabolized (by oxidation and glucuronidation), its metabolites are excreted equally in urine and bile.

Biotransformation.

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

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

A plateau concentration of the (R)-enantiomer is observed at approximately 22 μg/mL 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 the semen of men receiving 150 mg was 4.9 μg/ml. The amount of bicalutamide that could potentially be delivered to a female partner during sexual intercourse is low and may be approximately 0.3 μg/ml. This level is below that which has been shown to alter the offspring in laboratory animals.

Special patient groups.

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

Indication

Vistamid 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").

Vistamid 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 unacceptable or cannot be applied.

Contraindication

Vistamid is contraindicated for use in women and children.

Vistamid should not be prescribed to patients who have experienced hypersensitivity reactions to the active substance or any of the excipients included in the medicinal product.

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

Interaction with other medicinal products and other types of interactions

For drugs 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 with compounds such as cyclosporine and calcium channel blockers. It may be necessary to reduce the dose of these drugs, especially if there are signs of increased drug exposure or side effects. When using cyclosporine, it is recommended to carefully monitor its plasma concentration and the patient's clinical condition after starting or stopping treatment with bicalutamide.

Caution should be exercised when prescribing bicalutamide with drugs that may inhibit the oxidation of the drug (such as cimetidine, ketoconazole). Theoretically, this could lead to an increase in bicalutamide plasma concentrations, which could lead to increased side effects of the drug.

In vitro studies have shown that bicalutamide can displace the coumarin anticoagulant warfarin from its protein binding sites. There have been reports of increased effects of warfarin and other coumarin anticoagulants when co-administered 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.

Due to the fact that antiandrogen therapy may lead to prolongation of the QT interval, caution should be exercised when bicalutamide is administered concomitantly with medicinal products that may prolong the QT interval or induce torsade de pointes, such as class IA (quinidine, disopyramide) or class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, methadone, moxifloxacin, neuroleptics (see section "Special warnings and precautions for use").

Children.

Interaction studies have only been conducted in adult patients.

Application features

Treatment should be initiated under the direct supervision of a physician.

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

Due to the possibility of changes in liver function, liver function tests should be monitored periodically. Most changes occur within the first 6 months of bicalutamide use.

Severe liver damage, including fatal cases, has been reported rarely with bicalutamide. If severe damage occurs, bicalutamide should be discontinued.

If there are objective signs of disease progression and an elevated PSA (prostate-specific antigen) level, discontinuation of bicalutamide therapy should be considered.

Bicalutamide has been shown to inhibit cytochrome P450 (CYP3A4) activity, therefore caution should be exercised when co-administered with drugs that are primarily metabolized by CYP3A4.

Photosensitivity reactions have been reported rarely in patients taking bicalutamide 150 mg. Patients should be advised to avoid excessive direct sunlight or ultraviolet light and to use sunscreen while taking bicalutamide 150 mg. If the photosensitivity reaction is more persistent and/or severe, appropriate symptomatic treatment should be initiated.

Antiandrogen therapy may lead to prolongation of the QT interval.

In patients with risk factors or a history of QT prolongation, as well as in patients taking concomitant medications that may prolong the QT interval (see section 4.5), the physician should assess the risk/benefit ratio before initiating treatment with bicalutamide, taking into account the potential risk of torsade de pointes.

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 bicalutamide therapy.

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

Excipients.

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

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

Use during pregnancy or breastfeeding

Vistamid is contraindicated for use in women. Bicalutamide is contraindicated for use in women during pregnancy.

Breast-feeding.

Bicalutamide is contraindicated during breastfeeding.

Fertility.

Reversible impairment of male fertility has been observed in animal studies. A period of subfertility or infertility should be expected in humans.

Ability to influence reaction speed when driving vehicles or other mechanisms

Bicalutamide does not affect the ability to drive or use machines. However, it should be borne in mind that drowsiness and dizziness may occur frequently (see section "Adverse reactions"). Patients taking this medicine should exercise caution.

Method of administration and doses

Adult male patients, including elderly patients: orally one 150 mg tablet once daily.

Vistamid 150 mg should be taken for a long time, at least up to 2 years or until signs of disease progression appear.

Special groups.

Renal insufficiency: No dose adjustment is required for patients with renal insufficiency.

Hepatic impairment: No dose adjustment is required in patients with mild hepatic impairment. Increased drug accumulation may occur in patients with moderate or severe hepatic impairment (see section 4.4).

Children: Bicalutamide is contraindicated for use in children.

Overdose

There are no data on overdose in humans. There is no specific antidote; treatment is symptomatic. Dialysis may be ineffective because bicalutamide is highly protein bound and is not recovered unchanged in the urine. In case of overdose, general supportive care is indicated, including monitoring of vital signs.

Side effects

Adverse reactions are listed by frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, ≤1/100), rare (≥1/10000, ≤1/1000), very rare (≤1/10000), frequency unknown (frequency cannot be estimated from the available data).

1 Hepatic changes are rarely severe and often resolve or improve with continued treatment or after discontinuation.

2 Most patients receiving bicalutamide 150 mg as monotherapy experience gynecomastia and/or breast tenderness. In the study, 5% of patients classified these symptoms as severe. Gynecomastia may not resolve spontaneously after discontinuation of therapy, especially after long-term treatment.

3 According to the coding rules used in the EPC studies, the adverse reaction “dry skin” was coded under the COSTART term “rash”. Therefore, a separate frequency cannot be determined for bicalutamide 150 mg, but the same frequency as for the 50 mg drug is assumed.

4 Included in the list of adverse reactions from post-marketing data. The frequency was determined from the frequency of reports of liver injury in patients receiving bicalutamide 150 mg in the open-label treatment group in the Early Prostate Cancer programme (EPC).

Increased PC/INR: Post-marketing reports have reported interactions between coumarin anticoagulants and bicalutamide.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after the marketing authorisation of a medicinal product is an important procedure. It allows for continued monitoring of the benefit-risk balance of the medicinal product in question. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Expiration date

5 years.

Storage conditions

Does not require any special storage conditions. Keep out of the reach of children.

Packaging

10 tablets in a blister; 3 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Sinton Hispania, S. L.

Address

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