Bikatero

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

Composition:

Active substance: bicalutamide;

One film-coated tablet contains 150 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 characteristics: white, round, biconvex film-coated tablets, with "11" engraved on one side and "H" on the other.

Pharmacotherapeutic group. Antiandrogens. ATC code L02B B03.

Pharmacological properties

Pharmacodynamics

Mechanism of action

BICATERO is a nonsteroidal 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. Upon discontinuation of BICATERO, withdrawal syndrome may occur in a certain proportion of patients.

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

Clinical efficacy and safety

Bicalutamide at a dose of 150 mg was investigated as therapy in patients with localized (T1–T2N0 or NX, M0) or locally advanced (T3–T4, any N, M0; T1–T2, N+, M0) prostate cancer without metastases, in a combined analysis of three placebo-controlled, double-blind studies involving 8113 patients. In these studies, bicalutamide was administered as immediate hormonal therapy or as adjuvant therapy following radical prostatectomy or radiotherapy (mostly external beam radiation therapy). At a median follow-up of 9.7 years, objective disease progression was observed in 36.6% of patients receiving bicalutamide and 38.17% of those receiving placebo.

A reduction in the risk of objective disease progression was observed in the majority of patients across treatment groups, but this reduction was most pronounced in individuals at high risk of disease progression. Therefore, clinicians may consider that for patients at low risk of disease progression, particularly when the drug is used adjuvantly after radical prostatectomy, the optimal treatment strategy may be to defer hormonal therapy until signs of disease progression appear.

At a median follow-up of 9.7 years, no difference in overall survival rates was observed, with mortality rates of 31.4% in both groups (hazard ratio = 1.01; 95% confidence interval 0.94–1.09). However, during subgroup analyses of study outcomes, certain trends were evident.

Data on progression-free survival and overall survival are based on Kaplan–Meier analysis and are presented in the following tables for patients with locally advanced prostate cancer:

Table 1

Proportion of patients with locally advanced prostate cancer and disease progression in subgroups according to treatment regimen

Table 2

Overall survival of patients with locally advanced disease

in subgroups with different treatment regimens

In patients with localized disease who received bicalutamide alone, there was no significant difference in progression-free survival. Also, in patients with localized disease who received bicalutamide as adjuvant therapy after radiotherapy (HR 0.98; 95% CI 0.80–1.20) or radical prostatectomy (HR 1.03; 95% CI 0.85–1.25), no significant difference in overall survival was observed. In patients with localized disease who otherwise would have been managed with a strategy of active surveillance, there remains a trend toward reduced survival compared to patients who received placebo (HR 1.15; 95% CI 1.00–1.32). Considering the benefit/risk ratio, the use of bicalutamide in patients with localized disease is not considered appropriate.

In another program, the efficacy of bicalutamide 150 mg for the treatment of patients with locally advanced prostate cancer without metastases, for whom immediate castration was indicated, was demonstrated in a pooled analysis of two studies involving 480 patients with metastasis-free (M0) prostate cancer who had not received prior therapy. At a median follow-up of 6.3 years, the mortality rate was 56% and did not differ significantly between the bicalutamide and castration groups (HR 1.05; CI 0.81–1.36); however, statistical equivalence of the two treatment methods cannot be established.

In a combined analysis of two studies involving 805 patients with metastases (M1) who had not received prior therapy, at a mortality rate of 43%, bicalutamide 150 mg was found to be less effective than castration in terms of survival time (HR 1.30; CI 1.04–1.65), with a numerical difference in time to death of 42 days (6 weeks) at a median survival of 2 years.

Children.

No studies have been conducted in children (see sections "Contraindications" and "Use in pregnancy or lactation").

Pharmacokinetics.

Absorption

BICATERO is well absorbed after oral administration. There is no evidence of a clinically significant food effect 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 rapidly eliminated compared to the (R)-enantiomer; the latter has an elimination half-life from plasma of approximately 1 week.

With daily administration of bicalutamide, the (R)-enantiomer accumulates in plasma due to its long elimination half-life, reaching concentrations 10 times higher.

A steady-state concentration plateau of the (R)-enantiomer at approximately 22 µg/mL is achieved with a daily dose of 150 mg bicalutamide. In 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 bicalutamide 150 mg 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, 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 indicates that in patients with severe hepatic impairment, the (R)-enantiomer is eliminated more slowly from plasma.

Clinical characteristics.

Indications.

BICATERO, 150 mg tablets, is indicated for:

monotherapy or adjuvant therapy in combination with radical prostatectomy or radiotherapy in patients with locally advanced prostate cancer at high risk of disease progression (see section "Pharmacological properties");

treatment of patients with locally advanced non-metastatic prostate cancer when surgical castration or other medical interventions are inappropriate or unacceptable.

Contraindications.

BICATERO is contraindicated in women and children.

BICATERO 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 use of BICATERO with terfenadine, astemizole, or cisapride is contraindicated.

Interaction with other medicinal products and other forms of interaction.

In vitro studies have shown that R-bicalutamide is an inhibitor of CYP3A4 and exhibits 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 significant for drugs with a narrow therapeutic index. Therefore, concomitant use of BICATERO with terfenadine, astemizole, and cisapride is contraindicated. BICATERO should also be used with caution when co-administered with cyclosporine and calcium channel blockers. Dose reduction of these agents may be necessary, especially if signs of enhanced drug effect or adverse effects 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 BICATERO.

BICATERO should be prescribed with caution when used concomitantly with drugs that may inhibit its 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. 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 cautiously 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 precautions").

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 extensively 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 possibility of changes in liver function, liver function tests should be monitored periodically. Most changes are expected to occur during the first 6 months of BICATERO treatment.

Rarely, severe hepatic dysfunction has been observed with bicalutamide administration, and fatal cases have been reported (see section "Adverse reactions"). If severe liver function abnormalities occur, treatment with BICATERO should be discontinued.

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

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

Rare cases of photosensitivity reactions have been reported in patients receiving bicalutamide. Patients should be advised to avoid excessive direct exposure to sunlight or ultraviolet light and to use sun protection measures during treatment with BICATERO. If a photosensitivity reaction is persistent and/or severe, appropriate symptomatic treatment should be initiated.

Patients with rare hereditary conditions of galactose intolerance, congenital lactase deficiency, or glucose-galactose malabsorption should not take this medication.

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 interaction"), the physician should assess the benefit-risk ratio before initiating BICATERO treatment, 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 discontinuation of BICATERO.

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 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.

Pregnancy

Bicalutamide is contraindicated for use in women and should not be administered during pregnancy.

Breastfeeding

Bicalutamide is contraindicated during breastfeeding.

Fertility

Reversible impairment of male fertility has been observed in animal studies. In humans, a period of subfertility or infertility should be assumed.

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

Dosing

Adult men, including elderly: 1 tablet of 150 mg orally once daily.

BICATERO should be taken long-term, at least for 2 years or until signs of disease progression appear.

Special Populations

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 may occur in patients with moderate to severe hepatic impairment (see section "Special Warnings and Precautions for Use").

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 ≥1/10000 to <1/1000), very rare (≤1/10000), frequency not known (based on available data, the frequency of occurrence cannot be estimated).

Table 3

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

b Gynaecomastia and/or breast tenderness have been reported in the majority of patients receiving bicalutamide 150 mg as monotherapy. In clinical trials, these symptoms were considered severe in 5% of patients. Gynaecomastia may not resolve spontaneously after stopping therapy, particularly after prolonged treatment.

c Due to the coding standards used in the EPC trials, adverse events of "dry skin" were coded as "rash" according to COSTART terminology. Therefore, a separate frequency description cannot be provided for the 150 mg dose of bicalutamide; however, the frequency is expected to be the same as that for the 50 mg dose.

d The frequency was determined based on the incidence of reported cases of hepatic failure in patients treated with bicalutamide 150 mg in open-label trials (Early Prostate Cancer programme (EPC)).

e The frequency was determined based on the incidence of reported cases of interstitial lung disease as an adverse event in patients treated with bicalutamide 150 mg in open-label EPC trials. Increase in INR/PT: post-marketing reports have described interactions between coumarin anticoagulants and bicalutamide (see sections "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 marketing authorization of the medicinal product. This enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked 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 the reach of children.

Packaging.

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

Prescription status. Prescription only.

Manufacturer.

HETERO LABS LIMITED.

Address of the manufacturer and location of its business operations.

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