Bicalutamide-vista

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BICALUTAMIDE-VISTA

Composition:

Active substance: 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 physico-chemical properties: white, round, biconvex film-coated tablets. Tablets are engraved with "BCM 50" on one side.

Pharmacotherapeutic group. Antiandrogens. ATC code L02B B03.

Pharmacological Properties.

Pharmacodynamics.

Bicalutamide is a non-steroidal antiandrogen that has no other effects 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 cancer is observed. Upon discontinuation of bicalutamide, a withdrawal syndrome may occur in some patients. Bicalutamide is a racemic mixture with antiandrogenic activity, present almost exclusively as the (R)-enantiomer.

Pharmacokinetics.

Absorption.

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

Distribution.

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

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, the (R)-enantiomer accumulates in plasma due to its long elimination half-life, reaching concentrations 10-fold higher than initial levels. A steady-state concentration plateau of the (R)-enantiomer at approximately 9 µg/mL is achieved with a daily dose of 50 mg bicalutamide. In the 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 bicalutamide at a dose of 150 mg was 4.9 µg/mL. The amount of bicalutamide potentially transferred to a woman's body during sexual intercourse is low, estimated at approximately 0.3 µg/mL. This level is lower than that which causes offspring effects in laboratory animals.

Special patient groups.

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

Clinical characteristics.

Indications.

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

Contraindications.

Bicalutamide-Vista is contraindicated in women and children.

Bicalutamide-Vista should not be prescribed to patients who have experienced 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 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 do 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 agents such as cyclosporine and calcium channel blockers. Dose reduction of these agents may be necessary, 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 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, during bicalutamide use in patients receiving coumarin anticoagulants, careful monitoring of prothrombin time (PT)/international normalized ratio (INR) is recommended, and dose adjustment of anticoagulants should be considered.

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

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

Special precautions for use.

Treatment with Bicalutamide-Vista 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 liver impairment. Due to the possibility of 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 dysfunction has been observed during bicalutamide therapy, and fatal cases have been reported (see section "Adverse reactions"). If severe liver function abnormalities occur, bicalutamide treatment should be discontinued.

In patients who have objective disease progression accompanied by rising PSA levels, discontinuation of bicalutamide therapy should be considered.

In men receiving GnRH agonists, glucose intolerance may develop. This may manifest as diabetes mellitus or loss of glycemic control in patients with pre-existing diabetes. Therefore, monitoring of blood glucose levels should be considered in patients receiving bicalutamide in combination with GnRH agonists.

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 (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interactions").

Patients with rare hereditary conditions of galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. If you have been diagnosed with intolerance to certain sugars, consult your doctor before taking this medicinal product.

Antiandrogen therapy may lead to QT interval prolongation. In patients with risk factors or a history of QT prolongation, as well as in patients receiving concomitant medications that may prolong the QT interval (see section "Interaction with other medicinal products and other forms of interactions"), physicians should assess the benefit-risk ratio before initiating bicalutamide therapy, considering the potential risk of developing 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 PT and 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 is contraindicated in women and should not be administered during pregnancy.

Breastfeeding.

Bicalutamide is contraindicated during breastfeeding.

Fertility.

In animal studies, reversible impairment of male fertility was observed. A transient impairment of reproductive function or infertility in men should therefore be considered possible.

Effects on ability to drive and use machines.

Bicalutamide-Vista has no known influence on the ability to drive a vehicle 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 be initiated at least 3 days before starting therapy with luteinizing hormone-releasing hormone analogues 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. Increased accumulation of the drug may occur in patients with moderate or severe hepatic impairment.

Children.

Bicalutamide-Vista is contraindicated for use in children.

Overdose.

There is no data on 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. General supportive therapy, including monitoring of vital signs, is indicated in case of overdose.

Adverse reactions.

Adverse reactions 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 (cannot be estimated from the available data).

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

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 trials of the Early Prostate Cancer programme (EPC) with 150 mg bicalutamide.

3 May decrease when combined with concomitant castration.

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

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

INR/PT increase: During post-marketing surveillance, reports have indicated an interaction between coumarin anticoagulants and bicalutamide.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug authorization 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 a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

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

Prescription status. Prescription only.

Manufacturer.

Sinteo España, S.L.

Manufacturer's address and location of operations.

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