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1. INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BICALUTAMIDE GENEPHARM (BICALUTAMIDE GENEPHARM)
   1. Composition
   2. Pharmaceutical Form
   3. Main Physical and Chemical Properties
   4. Pharmacotherapeutic Group
   5. Pharmacological Properties
   6. Special Patient Groups
   7. Clinical Characteristics
   8. Special Warnings and Precautions for Use
   9. Use During Pregnancy and Breastfeeding
   10. Ability to Influence the Speed of Reaction When Driving Vehicles or Working with Complex Mechanisms
   11. Method of Administration and Dosage
   12. Overdose
   13. Adverse Reactions
   14. Reporting of Suspected Adverse Reactions
   15. Shelf Life
   16. Storage Conditions
   17. Packaging
   18. Release Category
   19. Manufacturer
   20. Manufacturer's Location and Address of Business

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BICALUTAMIDE GENEPHARM (BICALUTAMIDE GENEPHARM)

Composition

active substance: bicalutamide; 1 film-coated tablet contains 50 mg of bicalutamide; excipients: lactose, monohydrate; povidone K-25; sodium starch glycolate (type A); magnesium stearate; tablet coating: hypromellose (5cP); titanium dioxide (E 171); propylene glycol.

Pharmaceutical Form

Tablets, film-coated.

Main Physical and Chemical Properties

Round, biconvex, white tablets, film-coated.

Pharmacotherapeutic Group

Antiandrogenic agents. ATC code L02B B03.

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 stimuli. As a result of this inhibition, regression of prostate tumors is observed. Upon discontinuation of Bicalutamide Genepharm, a withdrawal syndrome may occur in some patients.

Bicalutamide Genepharm is a racemic mixture with antiandrogenic activity, represented almost exclusively by 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 bioavailability of the drug.

Distribution: Bicalutamide has a high degree of binding to proteins (racemate 96%, (R)-enantiomer > 99%) and undergoes extensive metabolism (by oxidation and glucuronidation); its metabolites are excreted by the kidneys and with bile in approximately equal amounts.

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

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

A plateau concentration of the (R)-enantiomer of approximately 9 μg/mL is observed when a daily dose of 50 mg of bicalutamide is administered. In the steady state, the (R)-enantiomer accounts for 99% of the total amount of circulating enantiomers.

Elimination (Excretion)

During a clinical study, the mean concentration of (R)-bicalutamide in the semen of men who received bicalutamide 150 mg was 4.9 μg/mL. The amount of bicalutamide that can potentially enter the body of a female partner during sexual intercourse is low and may be approximately 0.3 μg/mL, which is lower than the level that affects offspring in laboratory animals.

Special Patient Groups

The pharmacokinetics of the (R)-enantiomer do not depend on age, presence of renal impairment, or presence of mild or moderate liver impairment. There is evidence that in patients with severe liver impairment, the (R)-enantiomer is eliminated more slowly from the blood plasma.

Clinical Characteristics

Indications

For the treatment of advanced prostate cancer in combination with luteinizing hormone-releasing factor analogs (LHRH) or surgical castration.

Contraindications

Bicalutamide Genepharm is contraindicated for use in women and children (see section "Use during pregnancy and breastfeeding").

Hypersensitivity to the active substance or to any of the excipients.

Concomitant administration of Bicalutamide Genepharm with terfenadine, astemizole, or cisapride is contraindicated (see section "Interactions with other medicinal products and other forms of interaction").

Interactions with Other Medicinal Products and Other Forms of Interaction

There is no evidence of pharmacodynamic or pharmacokinetic interaction between bicalutamide and luteinizing hormone-releasing factor analogs.

In vitro studies have shown that R-bicalutamide is an inhibitor of CYP3A4 and has a weaker inhibitory effect on the activity of CYP 2C9, 2C19, and 2D6.

Although clinical studies using antipyrine as a marker of cytochrome P450 (CYP) activity do not indicate a potential interaction with bicalutamide, the mean concentration of midazolam (area under the pharmacokinetic curve) increased by 80% after concomitant administration with bicalutamide for 28 days. In the case of drugs with a narrow therapeutic range, such an increase may be significant. Therefore, concomitant use with terfenadine, astemizole, and cisapride is contraindicated (see section "Contraindications"). 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 effect or adverse reactions occur as a result of its use.

When using cyclosporine, it is recommended to carefully monitor its concentration in plasma and the patient's clinical condition after starting or stopping treatment with Bicalutamide Genepharm.

Bicalutamide Genepharm should be prescribed with caution when using drugs that can inhibit the oxidation of drugs, such as cimetidine, ketoconazole. This may theoretically lead to an increase in the concentration of bicalutamide in the plasma, which can cause an increase in the side effects of the drug.

In vitro studies have shown that bicalutamide can displace the coumarin anticoagulant warfarin from its binding sites. There have been reports of increased effects of warfarin and other coumarin anticoagulants when used concomitantly with bicalutamide. Therefore, during the use of Bicalutamide Genepharm in patients who are also receiving coumarin anticoagulants, it is recommended to carefully monitor prothrombin time (PT) and international normalized ratio (INR) and adjust the dose of anticoagulants if necessary (see sections "Special warnings and precautions for use" and "Adverse reactions").

Due to the fact that antiandrogen therapy can lead to prolongation of the QT interval, Bicalutamide Genepharm should be used with caution when administered concomitantly with drugs that can prolong the QT interval or cause the development of ventricular tachycardia of the pirouette type (torsade de pointes), such as antiarrhythmic drugs of class IA (quinidine, disopyramide) or class III (amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, neuroleptics, etc. (see section "Interactions with other medicinal products and other forms of interaction").

Children

Interaction studies were conducted only in adults.

Special Warnings and Precautions for Use

Treatment with the drug should be started under the direct supervision of a doctor. Bicalutamide is actively metabolized in the liver. Certain data suggest that in patients with severe liver damage, the elimination of the drug is slowed down, which can lead to its accumulation. Therefore, bicalutamide should be used with caution in patients with moderate or severe liver damage.

Due to the possibility of changes in liver function, liver function tests should be periodically monitored. It is expected that most changes are possible within the first 6 months of using Bicalutamide Genepharm.

Rarely, when using bicalutamide, severe changes in liver function have been observed, and there have been reports of fatal cases (see section "Adverse reactions"). If severe changes in liver function occur, treatment with Bicalutamide Genepharm should be discontinued.

For patients who have objective disease progression along with an increased level of prostate-specific antigen (PSA), the possibility of discontinuing bicalutamide therapy should be considered.

In men who are taking luteinizing hormone-releasing factor agonists, glucose tolerance is reduced. This can manifest as diabetes or loss of glycemic control in patients with already diagnosed diabetes. In connection with this, it is necessary to monitor the blood glucose level in patients who are receiving Bicalutamide Genepharm in combination with luteinizing hormone-releasing factor agonists.

It has been shown that bicalutamide inhibits the activity of CYP3A4, so caution should be exercised when using it concomitantly with drugs that are metabolized mainly by CYP3A4 (see sections "Contraindications" and "Interactions with other medicinal products and other forms of interaction").

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

Antiandrogen therapy can lead to prolongation of the QT interval.

In patients with risk factors or a history of QT interval prolongation, as well as in patients who are concomitantly taking drugs that can prolong the QT interval (see section "Interactions with other medicinal products and other forms of interaction"), the doctor should assess the risk/benefit ratio before starting treatment with Bicalutamide Genepharm, taking into account the potential risk of developing ventricular tachycardia of the pirouette type (torsade de pointes).

Antiandrogen therapy can 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 therapy with Bicalutamide Genepharm.

There have been reports of increased effects of coumarin anticoagulants in patients who concomitantly took bicalutamide, which can lead to an increase in prothrombin time (PT) and international normalized ratio (INR). Some cases were associated with an increased risk of bleeding. It is recommended to carefully monitor PT/INR levels and assess the need to adjust the dose of anticoagulants (see sections "Interactions with other medicinal products and other forms of interaction" and "Adverse reactions").

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

Use During Pregnancy and Breastfeeding

Pregnancy

Bicalutamide is contraindicated for use in women. It is contraindicated to prescribe it during pregnancy.

Breastfeeding

Bicalutamide is contraindicated during breastfeeding.

Fertility

In animal studies, reversible impairment of male fertility was observed. It should be assumed that in men, a period of insufficient reproductive function or infertility is also possible.

Ability to Influence the Speed of Reaction When Driving Vehicles or Working with Complex Mechanisms

Bicalutamide Genepharm does not affect the ability to drive a car or work with complex mechanisms. However, it should be taken into account that drowsiness often occurs, and very often - dizziness (see section "Adverse reactions"). Patients taking this medicinal product should be careful.

Method of Administration and Dosage

Dosage

Adult men, including elderly patients: one tablet (50 mg) once daily.

Treatment with Bicalutamide Genepharm should be started at least 3 days before the start of therapy with luteinizing hormone-releasing factor analogs or simultaneously with surgical castration.

Renal insufficiency: dose adjustment for patients with renal insufficiency is not required.

Hepatic insufficiency: dose adjustment for patients with mild hepatic insufficiency is not required.

Increased accumulation is possible in patients with moderate and severe hepatic insufficiency (see section "Special warnings and precautions for use").

Children

Bicalutamide Genepharm is contraindicated for use in children.

Overdose

Data on overdose in humans are not available. There is no specific antidote; treatment is symptomatic. Dialysis may be ineffective, as bicalutamide is highly bound to proteins and is not excreted in the urine in its unchanged form. In case of overdose, general supportive therapy is indicated, including monitoring of vital signs.

Adverse Reactions

The frequency of adverse reactions is defined as follows: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to ≤1/100), rare (from ≥1/10000 to ≤1/1000), very rare (≤1/10 000), frequency not known (based on available data, it is not possible to establish the frequency of occurrence).

1 Changes in liver function are rarely severe and often resolve or decrease after continuing or discontinuing treatment.

2 Included in the list of adverse reactions to the medicinal product after reviewing post-registration data. The frequency was determined based on the frequency of reports of liver failure in patients who received treatment with bicalutamide 150 mg in open studies of the Early Prostate Cancer program (EPC).

3 May decrease with concurrent castration.

4 Observed during a pharmacoeepidemiological study of the use of luteinizing hormone-releasing factor analogs and antiandrogens for the treatment of prostate cancer. The risk increased if bicalutamide 50 mg was used in combination with luteinizing hormone-releasing factor analogs, but an increased risk was not noted when bicalutamide 150 mg was used as monotherapy for the treatment of prostate cancer.

5 Included in the list of adverse reactions to the medicinal product after reviewing post-registration data. The frequency was determined based on the frequency of reports of interstitial pneumonia as an adverse reaction in patients who received treatment with bicalutamide 150 mg in open studies of the EPC.

Increased PT/INR: in reports during post-registration surveillance, an interaction between coumarin anticoagulants and bicalutamide was reported (see sections "Special warnings and precautions for use" and "Interactions with other medicinal products and other forms of interaction").

Reporting of Suspected Adverse Reactions

It is important to report suspected adverse reactions after the registration of a medicinal product. This allows for the continued monitoring of the benefit/risk ratio of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf Life

3 years.

Storage Conditions

The medicinal product does not require special storage conditions.

Packaging

14 tablets in a blister pack, 2 blister packs in a carton box.

Release Category

By prescription only.

Manufacturer

Genepharm S.A., Greece

Manufacturer's Location and Address of Business

18th km Marathons Ave, Pallini Attiki, 15351, Greece