Bicalutamide-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BICALUTAMIDE-TEVA

Composition:

Active substance: bicalutamide;

One film-coated tablet contains 50 mg of bicalutamide;

Excipients: microcrystalline cellulose, povidone, sodium croscarmellose, sodium lauryl sulfate, lactose monohydrate, colloidal anhydrous silicon dioxide, magnesium stearate, hypromellose, polidextrose, titanium dioxide (E 171), polyethylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: white or almost white, round, biconvex, film-coated tablets, embossed with "93" on one side and "220" on the other; without cracks or chips.

Pharmacotherapeutic group. Antiandrogens. ATC code L02B B03.

Pharmacological properties.

Pharmacodynamics.

Bicalutamide is a non-steroidal antiandrogen agent devoid of other endocrine activity. It binds to androgen receptors without activating gene expression, thereby blocking androgen stimulation. This leads to regression of prostate tumors. In some patients, discontinuation of bicalutamide therapy may provoke a withdrawal syndrome.

It is a racemic compound; antiandrogenic activity is exhibited exclusively by the (R)-enantiomer.

Pharmacokinetics.

Absorption

Bicalutamide is well absorbed after oral administration. Food does not exert any clinically significant effect on bioavailability.

Compared to the (R)-enantiomer, the (S)-enantiomer is rapidly eliminated from the body, with a half-life of approximately 1 week.

Distribution

With daily administration of bicalutamide, plasma concentrations of the (R)-enantiomer increase 10-fold due to its long elimination half-life.

With daily administration of bicalutamide at a dose of 50 mg, the steady-state concentration plateau of the (R)-enantiomer is approximately 9 µg/mL. The active (R)-enantiomer accounts for 99% of the total circulating enantiomers at steady state.

Biotransformation and elimination

The pharmacokinetics of the (R)-enantiomer are not influenced by age or by mild to moderate impairment of renal or hepatic function. In cases of severe hepatic impairment, elimination of the (R)-enantiomer from plasma is slower.

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

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 intercourse is low, estimated at approximately 0.3 µg/mL, which is below the level associated with effects on offspring in laboratory animals.

Clinical characteristics.

Indications.

Treatment of advanced prostate cancer in combination with a luteinizing hormone-releasing hormone (LHRH) analogue or surgical castration.

Contraindications.

− Hypersensitivity to bicalutamide or to any of the excipients;

− concomitant treatment with terfenadine, astemizole, or cisapride (see section "Interaction with other medicinal products and other forms of interaction");

− contraindicated in women and children (see section "Use during pregnancy or breastfeeding").

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 exhibits a weaker inhibitory effect on the activity of CYP2C9, 2C19, and 2D6.

Although clinical studies using antipyrine as a marker for cytochrome P450 (CYP) activity did 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 drugs with a narrow therapeutic index, such an increase may be clinically significant. Therefore, concomitant administration with terfenadine, astemizole, and cisapride is contraindicated (see section "Contraindications"). Caution is advised when prescribing concomitantly 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.

Caution should also be exercised when co-administering substances that may inhibit bicalutamide oxidation, i.e., medicinal products containing ketoconazole or cimetidine. This may lead to increased plasma levels of bicalutamide, potentially resulting in enhanced adverse reactions.

In vitro studies have shown that bicalutamide can displace the coumarin-type anticoagulant warfarin from its protein-binding sites. Therefore, prothrombin time should be closely monitored in patients receiving concomitant treatment with coumarin anticoagulants.

Medicinal products that may prolong the QT interval or provoke torsades de pointes ventricular tachycardia should be used with caution, given that antiandrogen therapy may prolong the QT interval. Such medicinal products include: Class IA (e.g., quinidine, disopyramide) and Class III (e.g., amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmics, methadone, moxifloxacin, and antipsychotics (see section "Special precautions").

Special precautions for use

Initiation of treatment should be carried out under direct medical supervision.

Bicalutamide-Teva is extensively metabolized in the liver. In patients with severe impairment of liver function, elimination of the drug may be slowed, potentially leading to increased accumulation of bicalutamide. Therefore, bicalutamide-Teva should be used with caution in patients with moderate to severe hepatic dysfunction.

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

Rare cases of severe liver disorders and liver failure, sometimes fatal, have been reported during bicalutamide use (see section "Adverse reactions"). If severe liver disorders occur during treatment with Bicalutamide-Teva, the treatment should be discontinued.

For patients with objective disease progression together with rising PSA levels, discontinuation of bicalutamide therapy should be considered.

Bicalutamide is an inhibitor of cytochrome P450 (CYP3A4); therefore, caution should be exercised when administering this drug concomitantly with medicinal products metabolized by CYP3A4 (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Reduced glucose tolerance has been observed in male patients receiving GnRH agonists, manifesting as development of diabetes mellitus or loss of glycemic control in patients with pre-existing diabetes. Therefore, blood glucose levels should be closely monitored in patients receiving bicalutamide in combination with GnRH agonists.

Antiandrogen therapy may prolong the QT interval.

In patients with risk factors or a history of QT interval prolongation, and in patients receiving concomitant medicinal products 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 treatment, taking into account the potential risk of developing bidirectional or 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.

This medicinal product contains 35 mg of lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or breastfeeding

Pregnancy

Bicalutamide is contraindicated in women and 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 anticipated.

Ability to affect reaction speed when driving or operating machinery

Impairment of patients' ability to drive or operate machinery due to bicalutamide is unlikely. However, it should be noted that somnolence is common and dizziness is very common (see section "Adverse reactions"). Patients taking this medication should exercise caution.

Method of Administration and Dosage

For adult men, including elderly: 1 tablet once daily, at the same time each day (in the morning or evening).

Treatment should be initiated within 1 week prior to starting LHRH analogs or concurrently with surgical castration.

Renal impairment. Dose adjustment is not required.

Hepatic impairment. Dose adjustment is not required in patients with mild hepatic impairment. Increased accumulation of bicalutamide may occur in patients with moderate to severe hepatic impairment (see section "Special Warnings and Precautions for Use").

Pediatric population.

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

Overdose.

There is no clinical experience with overdose in humans. There is no specific antidote; treatment should be symptomatic. Dialysis is likely to be ineffective because bicalutamide is highly protein-bound and is not excreted unchanged in urine. Supportive therapy, including monitoring of vital functions, is recommended.

Side effects

Side effects are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders. Very common: anaemia.

Immune system disorders. Uncommon: hypersensitivity, angioedema, urticaria.

Psychiatric disorders. Common: decreased libido, depression.

Nervous system disorders. Very common: dizziness. Common: somnolence.

Cardiac disorders. Common: myocardial infarction (fatal cases reported), heart failure. Frequency not known: QT interval prolongation (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Vascular disorders. Very common: hot flushes.

Respiratory system disorders. Uncommon: interstitial lung disease (fatal cases reported)*.

Gastrointestinal disorders. Very common: abdominal pain, constipation, nausea. Common: dyspepsia, flatulence.

Hepatobiliary disorders. Common: hepatotoxicity, jaundice, increased levels of transaminases**. Rare: hepatic failure (fatal cases reported)***.

Skin and subcutaneous tissue disorders. Common: alopecia, hirsutism/regrowth of hair, dry skin, pruritus, rash. Uncommon: photosensitivity reactions.

Renal and urinary disorders. Very common: haematuria.

Reproductive system and breast disorders. Very common: gynaecomastia, breast tenderness****. Common: erectile dysfunction.

Metabolism and nutrition disorders. Common: decreased appetite.

Investigations. Common: weight gain.

General disorders. Very common: asthenia. Common: oedema, chest pain.

* Included in the list of adverse reactions based on post-marketing data. Frequency was determined from case reports of interstitial pneumonia in patients receiving bicalutamide 150 mg during randomized Early Prostate Cancer (EPC) trials.

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

*** Included in the list of adverse reactions based on post-marketing data. Frequency was determined from reported cases of hepatic failure in patients receiving bicalutamide 150 mg in an open EPC trial.

**** May decrease with concomitant castration.

***** Observed in a pharmacoepidemiological study of luteinizing hormone-releasing hormone agonists and antiandrogens used in the treatment of prostate cancer. Risk increased when bicalutamide 50 mg was used in combination with luteinizing hormone-releasing hormone agonists, but an increased risk was not observed with bicalutamide 150 mg used as monotherapy for prostate cancer.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after marketing authorization. This allows continued 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 package in a place inaccessible to children.

Packaging.

7 tablets in a blister, 4 blisters in a carton.

10 tablets in a blister, 3 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. Teva Pharmaceutical Industries Ltd.

Manufacturer's address.
18 Hameyasdim Street, Industrial Zone, Kefar Sava, Israel