Vistamid

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VISTAMID (VISTAMID)

Composition:

active substance: bicalutamide;

1 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 tablets, film-coated; on one side of the tablets there is an imprint "VSM 150".

Pharmacotherapeutic group. Hormone therapy preparations. Hormone antagonists and their analogues. Antiandrogen agents. Bicalutamide. ATC code L02B B03.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Bicalutamide is a non-steroidal antiandrogen with no other endocrine effects. 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, some patients may experience an antiandrogen withdrawal syndrome.

Clinical Efficacy and Safety

Bicalutamide 150 mg was evaluated in three placebo-controlled, double-blind studies involving 8,113 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 these studies, bicalutamide was administered either as immediate hormonal therapy or as an adjuvant following radical prostatectomy or radiotherapy (primarily external beam radiation therapy). At the median observation time 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 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 = 1.01; 95% confidence interval 0.94–1.09). However, subgroup analyses revealed certain trends.

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 proportion of patients with disease progression in subgroups receiving different treatment regimens

Table 2

Overall survival in patients with locally advanced disease

in subgroups with different treatment regimens

In patients with localized disease who received bicalutamide alone, there was no 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 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 decreased survival was observed compared to patients receiving placebo (HR = 1.15; 95% CI 1.00–1.32). Given this risk/benefit profile, 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 evaluated in two studies involving 480 previously untreated patients with non-metastatic prostate cancer. 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 demonstration of equivalence between the two treatment modalities was not achieved.

In 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 (hazard ratio = 1.30; confidence interval 1.04–1.65), with a numerical difference in time to death of 42 days (6 weeks) at a median survival of 2 years.

Bicalutamide is a racemate with antiandrogenic activity attributable almost exclusively to the R-enantiomer.

Children

No studies have been conducted in children (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 the drug.

Distribution

Bicalutamide is highly bound to plasma proteins (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 of approximately 22 µg/mL is achieved 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 estimated to be approximately 0.3 µg/mL. This level is lower than that which caused offspring changes in laboratory animals.

Special patient groups

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

Clinical characteristics.

Indications

Vistamid 150 mg is indicated for monotherapy or as an 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 inappropriate or cannot be applied.

Contraindications

Vistamid is contraindicated in women and children.

Vistamid should not be administered to patients who have experienced hypersensitivity reactions to the active substance or to any of the excipients contained in the medicinal product. Concomitant use 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 CYP3A4 and has a lesser inhibitory effect on the activity of CYP2C9, 2C19, and 2D6. Although clinical studies using antipyrine as a marker of 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% when co-administered for 28 days with bicalutamide.

For medicinal products with a narrow therapeutic index, such an increase may be clinically significant. Therefore, concomitant use with terfenadine, astemizole, and cisapride is contraindicated. Bicalutamide should also be used with caution when administered with drugs such as cyclosporine and calcium channel blockers. It may be necessary to reduce the dose of these agents, especially if signs of enhanced drug effect or adverse reactions occur. When cyclosporine is used, careful monitoring of its plasma concentration and the patient's clinical status is recommended following the initiation or discontinuation of bicalutamide therapy. Bicalutamide 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 enhancing its adverse effects.

In vitro studies have shown that bicalutamide may displace the coumarin anticoagulant warfarin from its plasma protein binding sites. Enhanced effects of warfarin and other coumarin anticoagulants have been reported when co-administered with bicalutamide. Therefore, when prescribing bicalutamide to patients already receiving coumarin anticoagulants, careful monitoring of prothrombin time is recommended, and consideration should be given to adjusting the anticoagulant dose. Because antiandrogen therapy may prolong the QT interval, bicalutamide should be used with caution when administered concomitantly with medicinal products capable of prolonging the QT interval or inducing torsades de pointes ventricular tachycardia, such as Class IA antiarrhythmics (quinidine, disopyramide) or Class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, and neuroleptics (see section "Special warnings and precautions for use").

Children

Interaction studies have been conducted only in adult patients.

Special precautions for use

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

Bicalutamide is actively metabolized in the liver. Some data suggest that in patients with severe hepatic impairment, elimination of the drug is slowed, 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 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 changes have been observed during bicalutamide use, including fatal cases. If severe liver changes occur, bicalutamide treatment should be discontinued.

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

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

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

Antiandrogen therapy may lead to QT interval prolongation.

For patients with risk factors or a history of QT prolongation, as well as for 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 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 partners should use effective contraceptive methods during treatment and for 130 days after the end of bicalutamide therapy.

Enhanced effects of coumarin anticoagulants have been reported in patients receiving bicalutamide concurrently, 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.

Important information about excipients

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

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

Use during pregnancy or breastfeeding

Pregnancy

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

Breastfeeding

Bicalutamide 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 anticipated.

Ability to influence reaction rate while driving or operating machinery

Bicalutamide does not affect the ability to drive a vehicle or operate complex machinery. However, it should be noted that somnolence and dizziness may commonly occur (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.

Vistamid 150 mg should be taken long-term, at least for 2 years or until signs of disease progression appear.

Special patient groups

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 or severe hepatic impairment, increased accumulation of the drug may occur (see section "Special precautions for use").

Children. Bicalutamide is contraindicated in children.

Overdose

Symptoms. There is 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 functions.

Adverse reactions

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 not known (cannot be estimated from the available data).

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. During clinical studies, 5% of patients classified these symptoms as severe. Gynecomastia may not resolve spontaneously after discontinuation of therapy, especially following prolonged 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, the individual frequency of occurrence cannot be determined for bicalutamide 150 mg; however, it is expected to be similar to that observed with the 50 mg dose of the drug.

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

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

Increase in PT/INR. Post-marketing surveillance reports have described interactions between coumarin anticoagulants and bicalutamide.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 5 years.

Storage conditions

No special storage conditions required. Keep out of reach of children.

Packaging. 10 tablets per blister; 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer

Sicton España, S.L.

Manufacturer's address and place of business

C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.