Vistamed

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

Composition:

Active ingredient: bicalutamide;

One film-coated tablet contains 50 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 tablets there is an imprint "ВСМ 50".

Pharmacotherapeutic group. Hormonal therapy agents. Hormone antagonists and their analogues. Antiandrogen agents. Bicalutamide. ATC code L02BB03.

Pharmacological Properties

Pharmacodynamics

Bicalutamide is a non-steroidal antiandrogen that has no other effect on the endocrine system. The drug binds to androgen receptors without activating gene expression, thereby inhibiting androgenic stimulation. As a result of this inhibition, regression of prostate tumor occurs. Upon discontinuation of bicalutamide, a withdrawal syndrome may occur in some patients. Bicalutamide is a racemic mixture with antiandrogenic activity residing almost exclusively in the (R)-enantiomer.

Pharmacokinetics

Absorption

Bicalutamide is well absorbed after oral administration. There is no evidence of clinically significant food effects on the drug's bioavailability.

Distribution

The (S)-enantiomer is rapidly eliminated compared to the (R)-enantiomer; the plasma elimination half-life of the latter is approximately 1 week. With daily administration of bicalutamide, the (R)-enantiomer accumulates in plasma due to its long half-life, reaching concentrations about 10 times higher than initial levels. A steady-state concentration plateau of approximately 9 µg/mL of the (R)-enantiomer is achieved with a daily dose of 50 mg bicalutamide. At steady state, the predominantly active (R)-enantiomer accounts for 99% of total circulating enantiomers. The pharmacokinetics of the (R)-enantiomer are independent of patient age, presence of renal impairment, or mild to moderate hepatic impairment. Evidence suggests that in patients with severe hepatic impairment, the (R)-enantiomer is eliminated more slowly from plasma. Bicalutamide is highly bound to plasma proteins (racemate – 96%; (R)-enantiomer – >99%) and is extensively metabolized (via oxidation and glucuronidation); metabolites are excreted equally in urine and bile.

Elimination

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

Special patient populations

The pharmacokinetics of the (R)-enantiomer are independent of patient age, presence of 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

Treatment of metastatic prostate cancer in combination with luteinizing hormone-releasing hormone (LHRH) analogue therapy or surgical castration.

Contraindications

Bicalutamide is contraindicated in women and children.

Bicalutamide 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

There is no evidence of pharmacodynamic or pharmacokinetic interaction between bicalutamide and luteinizing hormone-releasing hormone (LHRH) analogues.

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 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 28 days of concomitant administration 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 compounds such as cyclosporines and calcium channel blockers. It may be necessary to reduce the dose of these medicinal products, 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 initiation or discontinuation of bicalutamide treatment.

Bicalutamide should be prescribed with caution when used 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 in the blood. Enhanced effects of warfarin and other coumarin anticoagulants have been reported when administered concomitantly with bicalutamide. Therefore, during bicalutamide treatment in patients receiving coumarin anticoagulants, careful monitoring of PT/INR is recommended, and dose adjustment of anticoagulants should be considered.

Since antiandrogen therapy may prolong the QT interval, bicalutamide should be administered with caution in combination with medicinal products capable of causing QT prolongation or inducing torsade de pointes ventricular tachycardia, such as Class IA (e.g. quinidine, disopyramide) or Class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, methadone, moxifloxacin, neuroleptics, etc. (see section "Special precautions").

Children

Interaction studies have been conducted only in adult patients.

Special precautions for use

Treatment with Vistamid 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 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 liver function abnormalities have been observed during bicalutamide use, and fatal cases have been reported (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 levels, discontinuation of bicalutamide therapy should be considered.

In men receiving luteinizing hormone-releasing hormone (LHRH) agonists, decreased glucose tolerance has been observed. This may manifest as diabetes mellitus or loss of glycemic control in patients with pre-existing diabetes. Therefore, monitoring of blood glucose levels is recommended in patients receiving bicalutamide in combination with LHRH agonists.

Bicalutamide has been shown to inhibit cytochrome P450 (CYP3A4) activity; therefore, caution should be exercised when co-administering bicalutamide with drugs primarily metabolized by CYP3A4 (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Antiandrogen therapy may lead to QT interval prolongation.

For patients with risk factors or history of QT interval 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"), physicians should assess the benefit-risk ratio before initiating bicalutamide therapy, considering the potential risk of torsade de pointes ventricular tachycardia.

Antiandrogen therapy may cause changes in sperm morphology. Although the effect of bicalutamide on sperm morphology has not been specifically 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 concurrently receiving bicalutamide, 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

This medicinal product is contraindicated in patients with rare hereditary disorders such as galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption.

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

Breastfeeding

Bicalutamide is contraindicated during breastfeeding.

Fertility

In animal studies, reversible impairment of male fertility has been observed. A period of impaired reproductive function or infertility in men should also be considered possible.

Ability to influence the speed of reactions when driving or operating machinery

Bicalutamide has no influence on the ability to drive or operate 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 exercise caution.

Method of Administration and Dosage

Adult male patients, including elderly patients: orally, 1 tablet of 50 mg once daily. Treatment with bicalutamide should begin at least 3 days before starting therapy with luteinizing hormone-releasing hormone analogs or simultaneously with surgical castration.

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 drug accumulation may occur.

Children. Bicalutamide is contraindicated for use in children.

Overdose

Symptoms. 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 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 Included in the list of adverse drug reactions following review of post-marketing data. The frequency was determined based on reports of hepatic failure in patients receiving treatment in the open-label studies of the Early Prostate Cancer programme (EPC) in the bicalutamide 150 mg groups.

3 May decrease when combined with castration.

4 Observed during a pharmacoepidemiological study of luteinizing hormone-releasing hormone agonists and antiandrogens for the treatment of prostate cancer. The risk increased when bicalutamide 50 mg was used in combination with luteinizing hormone-releasing hormone agonists; however, an increased risk was not observed with bicalutamide 150 mg used as monotherapy for the treatment of prostate cancer.

5 Included in the list of adverse reactions following analysis of post-marketing data. The frequency was determined based on reports of interstitial lung disease during the randomized treatment period with the 150 mg dose in EPC studies.

Elevated PT/INR. Interaction between coumarin anticoagulants and bicalutamide has been reported during post-marketing surveillance.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via 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 and sight of children.

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

Prescription status. Prescription only.

Manufacturer.

Sicor España, S.L.

Manufacturer's address and location of its operations

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