Bicalutamide genefarm

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

Composition:

Active substance: bicalutamide;

One film-coated tablet contains 50 mg of bicalutamide;

Excipients: lactose monohydrate; povidone K-25; sodium starch glycolate (type A); magnesium stearate;

Coating of the tablet: hypromellose (5 cP); titanium dioxide (E 171); propylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: round, biconvex, white film-coated tablets.

Pharmacotherapeutic group. Antiandrogens. ATC code L02B B03.

Pharmacological Properties

Pharmacodynamics

Bicalutamide is a non-steroidal antiandrogen with 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 tumor is observed. Discontinuation of Bicalutamide Geneferm in some patients may lead to a withdrawal syndrome.

Bicalutamide Geneferm is a racemic mixture with antiandrogenic activity primarily attributed to the (R)-enantiomer.

Pharmacokinetics

Absorption

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

Distribution

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

Biotransformation

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 Geneferm, the (R)-enantiomer accumulates in plasma due to its long elimination half-life, reaching 10-fold higher concentrations.

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

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 intercourse is low, estimated at approximately 0.3 µg/mL, which is below the level shown to affect offspring in laboratory animals.

Special patient groups

The pharmacokinetics of the (R)-enantiomer are independent of age, renal impairment, or presence of 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.

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

Contraindications.

Bicalutamide Genepharm is contraindicated in women and children (see section "Use in pregnancy and lactation").

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 "Interaction with other medicinal products and other forms of interaction").

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 exhibits a lesser inhibitory effect on the activity of CYP 2C9, 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% after concomitant administration for 28 days with bicalutamide. In the case of drugs with a narrow therapeutic range, such an increase may be clinically significant. Therefore, concomitant use with terfenadine, astemizole and cisapride is contraindicated (see section "Contraindications"). Bicalutamide should also be used with caution when administered concomitantly with such compounds as cyclosporine and calcium channel blockers. Dose reduction of these drugs 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 treatment with Bicalutamide Genepharm.

Bicalutamide Genepharm should be prescribed with caution when used concomitantly with drugs that may inhibit drug 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 protein-binding sites. Enhanced effects of warfarin and other coumarin anticoagulants have been reported when administered concomitantly with bicalutamide. Therefore, during treatment with Bicalutamide Genepharm in patients receiving concomitant coumarin anticoagulants, careful monitoring of prothrombin time (PT) and international normalized ratio (INR) is recommended; dose adjustment of anticoagulants may be necessary (see sections "Special precautions for use" and "Adverse reactions").

Since antiandrogen therapy may lead to QT interval prolongation, Bicalutamide Genepharm should be used with caution when administered concomitantly with medicinal products known to prolong the QT interval or induce torsade de pointes ventricular tachycardia, such as class IA (quinidine, disopyramide) or class III (amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, methadone, moxifloxacin, neuroleptics, etc. (see section "Special precautions for use").

Children.

Interaction studies have been conducted only in adults.

Special precautions for use

Treatment with the medicinal product should be initiated under the direct supervision of a physician. Bicalutamide is extensively metabolized in the liver. Available data suggest that in patients with severe hepatic impairment, elimination of the drug is slowed, which may lead to its accumulation. Therefore, bicalutamide should be used with caution in patients with moderate or severe liver impairment.

Due to the potential for changes in liver function, liver function tests should be monitored periodically. Most changes are expected to occur during the first 6 months of treatment with Bicalutamide GenePharm.

Rarely, severe hepatic function changes have been observed during bicalutamide treatment, and fatal cases have been reported (see section "Adverse reactions"). If severe hepatic dysfunction occurs, treatment with Bicalutamide GenePharm should be discontinued.

In patients who have objective disease progression together with increased prostate-specific antigen (PSA) levels, discontinuation of bicalutamide therapy should be considered.

In men receiving luteinizing hormone-releasing hormone (LHRH) agonists, glucose tolerance may be reduced. This may manifest as diabetes mellitus or loss of glycemic control in patients with pre-existing diabetes. Therefore, blood glucose levels should be monitored in patients receiving Bicalutamide GenePharm in combination with LHRH agonists.

Bicalutamide has been shown to inhibit CYP3A4 enzyme 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 interaction").

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

Antiandrogen therapy may lead to QT interval prolongation.

In patients with risk factors or a history of QT interval prolongation, as well as in patients receiving concomitant medicinal products that may prolong the QT interval (see section "Interaction with other medicinal products and other forms of interactions"), the physician should assess the benefit-risk ratio before initiating treatment with Bicalutamide GenePharm, 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 contraception during treatment and for 130 days after treatment with Bicalutamide GenePharm.

Enhanced effects of coumarin anticoagulants have been reported in patients receiving bicalutamide concomitantly, 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 the need for anticoagulant dose adjustment should be evaluated (see sections "Interaction 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., essentially sodium-free.

Use during pregnancy and 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 was observed. A period of impaired reproductive function or infertility in men should therefore be considered possible.

Ability to affect reaction speed when driving vehicles or operating machinery

Bicalutamide GenePharm does not affect 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

Dosage

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

Treatment with Bicalutamide Jenefarm should be initiated at least 3 days prior to the start of therapy with luteinizing hormone-releasing hormone (LHRH) analogs or concurrently 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 is possible in patients with moderate to severe hepatic impairment (see section "Special Warnings and Precautions for Use").

Children

Bicalutamide Jenefarm is contraindicated in pediatric patients.

Overdose

Data on overdose in humans are lacking. 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 signs.

Side effects.

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 ≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (based on available data, it is not possible to estimate the frequency of occurrence).

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

2 Included in the list of adverse drug reactions following evaluation of post-marketing data. The frequency was determined based on reports of liver failure as an adverse event in patients receiving bicalutamide 150 mg treatment in the open-label studies of the Early Prostate Cancer programme (EPC).

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. 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 drug reactions following evaluation of post-marketing data. The frequency was determined based on reports of interstitial lung disease as an adverse event in patients receiving bicalutamide 150 mg in the open-label EPC studies.

Increased PT/INR: During post-marketing surveillance, interactions between coumarin anticoagulants and bicalutamide have been reported (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Reporting of suspected adverse reactions.

It is important to report suspected adverse reactions after a medicinal product has been authorized. This enables continued monitoring of the benefit-risk balance 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 per blister pack, 2 blister packs in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Generics S.A., Greece

Manufacturer's address and location of operations.

18th km Marathon Avenue, Pallini Attiki, 15351, Greece