Bikatero

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BICATERO (BICATERO)

Composition:

Active substance: bicalutamide;

One film-coated tablet contains 50 mg of bicalutamide;

Excipients: lactose monohydrate, crospovidone, povidone, magnesium stearate, Opadry White Y-1-7000: hypromellose (E 464), titanium dioxide (E 171), polyethylene glycol 400.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex film-coated tablets, with "2" engraved on one side and "H" on the other.

Pharmacotherapeutic group. Antiandrogens. ATC code L02B B03.

Pharmacological properties.

Pharmacodynamics.

BICATERO 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 is observed. Discontinuation of BICATERO may lead to a withdrawal syndrome in some patients.

BICATERO is a racemic mixture with antiandrogenic activity attributable almost exclusively to the (R)-enantiomer.

Pharmacokinetics.

Absorption

BICATERO 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 is highly bound to plasma proteins (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 eliminated very rapidly compared to the (R)-enantiomer; the 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 10-fold higher concentrations.

A steady-state concentration plateau of the (R)-enantiomer of approximately 9 mcg/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

During a clinical study, the mean concentration of (R)-bicalutamide in semen of men receiving 150 mg bicalutamide was 4.9 mcg/mL. The amount of bicalutamide potentially transferred to a female partner during intercourse is low, estimated at approximately 0.3 mcg/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 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 advanced prostate cancer in combination with luteinizing hormone-releasing hormone (LHRH) analogues or surgical castration.

Contraindications.

BICATERO is contraindicated in women and children.

BICATERO must not be administered to patients who have previously shown hypersensitivity reactions to the active substance or to any of the excipients of the medicinal product.

Concomitant administration of BICATERO 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 BICATERO 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 of cytochrome P450 (CYP) activity did not indicate a potential interaction with bicalutamide, the mean midazolam concentration (area under the pharmacokinetic curve) increased by up to 80% after concomitant administration for 28 days with bicalutamide. Such an increase is clinically significant for drugs with a narrow therapeutic index. Therefore, concomitant use with terfenadine, astemizole, and cisapride is contraindicated. BICATERO should also be used with caution when administered concomitantly with cyclosporine and calcium channel blockers. Dose reduction of these agents may be necessary, especially if signs of enhanced effect or adverse reactions occur. When cyclosporine is used, careful monitoring of its plasma concentration and the patient's clinical status is recommended during initiation or discontinuation of BICATERO therapy.

BICATERO should be prescribed with caution when used concomitantly with drugs that may inhibit its oxidation (e.g., cimetidine, ketoconazole). In theory, this could 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. Therefore, when BICATERO is prescribed to patients already receiving coumarin anticoagulants, careful monitoring of prothrombin time (PT/INR) is recommended, and dose adjustment of anticoagulants should be considered.

Since antiandrogen therapy may lead to QT interval prolongation, BICATERO should be used with caution when administered concomitantly with medicinal products capable of prolonging the QT interval or inducing 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 warnings and precautions for use").

Children.

Interaction studies have been conducted only in adults.

Special precautions for use.

Treatment with BICATERO should be initiated under direct medical supervision.

BICATERO is actively metabolized in the liver. Some data suggest that in patients with severe hepatic impairment, elimination of the drug may be slowed, potentially leading to accumulation of bicalutamide. Therefore, BICATERO should be used with caution in patients with moderate or severe hepatic impairment.

Due to the potential for changes in liver function, periodic liver function tests should be performed. Most abnormalities occur within the first 6 months of treatment with BICATERO.

Rarely, severe hepatic dysfunction has been observed during bicalutamide treatment, and fatal cases have been reported (see section "Adverse reactions"). If severe liver function abnormalities occur, treatment with BICATERO 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, glucose tolerance may be reduced. This may manifest as new-onset diabetes mellitus or loss of glycemic control in patients with pre-existing diabetes. Therefore, monitoring of blood glucose levels is required in patients receiving BICATERO in combination with LHRH agonists.

BICATERO has been shown to inhibit cytochrome P450 (CYP3A4) activity; therefore, caution should be exercised when co-administering with drugs that are primarily metabolized by CYP3A4.

This medication is contraindicated in patients with rare hereditary conditions of galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption.

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 concurrently receiving medications 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 specifically 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 BICATERO therapy.

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 have been associated with a risk of bleeding. Careful monitoring of PT/INR levels is recommended, and dose adjustment of anticoagulants should be considered (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Use during pregnancy or breastfeeding.

BICATERO is contraindicated for use in women. It is contraindicated during pregnancy and 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 affect reaction speed while driving or operating machinery.

BICATERO does not affect the ability to drive a vehicle or operate complex machinery. However, it should be noted that somnolence may rarely occur, and dizziness is very common (see section "Adverse reactions"). Patients taking this medication should therefore exercise caution.

Method of Administration and Dosage.

Dosage

Adults, including elderly patients: orally, 1 tablet (50 mg) once daily.

Treatment with BICATERO should be initiated at least 3 days prior to the start of therapy with luteinizing hormone-releasing factor 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 drug accumulation may occur in patients with moderate or severe hepatic impairment.

Children. The drug is contraindicated for use in children (see section "Contraindications").

Overdose.

There is no data on overdose in humans. There is no specific antidote; treatment is symptomatic. Dialysis may be ineffective because BICATERO 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 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 <1/1000), very rare (≤1/10,000), frequency not known (based on available data, the frequency of occurrence cannot be determined).

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

2 The frequency was determined based on reports of hepatic failure as an adverse reaction in patients receiving bicalutamide 150 mg in open-label studies of the Early Prostate Cancer programme (EPC).

3 May decrease when used concomitantly with castration.

4 Observed during a pharmacoepidemiological study of luteinizing hormone-releasing hormone agonists and antiandrogens used in 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 prostate cancer.

5 The frequency was determined based on reports of interstitial pneumonia as an adverse reaction in patients receiving bicalutamide 150 mg in open-label EPC studies. Increased INR/PT: During post-marketing surveillance, interactions between coumarin anticoagulants and bicalutamide have been reported (see section "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").

Reporting of suspected adverse reactions.

It is important to report suspected adverse reactions after a medicinal product is marketed. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets per blister, 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

HETERO LABS LIMITED.

Manufacturer's address and location of operation.

Unit-VI, TSIIC, Formulation SEZ, Sy No. 410 & 411, Polepally Village, Jadcherla Mandal, Mahaboobnagar-District, Telangana, Pin-509301, India.