Calubia

Each film-coated tablet contains: Bicalutamide 50 mg.

Pharmacotherapeutic group: Endocrine therapy, hormone antagonists and related agents, anti-androgens.
Pharmacology: Pharmacodynamics: Mechanism of action: Bicalutamide is a non-steroidal antiandrogen, devoid of other endocrine activity. It binds to androgen receptors without activating gene expression, and thus inhibits the androgen stimulus. Regression of prostatic tumours results from this inhibition. Clinically, discontinuation of bicalutamide can result in antiandrogen withdrawal syndrome in a subset of patients.
Bicalutamide is a racemate with its antiandrogenic activity being almost exclusively in the (R)-enantiomer.
Clinical efficacy and safety: Bicalutamide 150 mg was studied as a treatment for patients with localised (T1-T2, N0 or NX, M0) or locally advanced (T3-T4, any N, M0; T1-T2, N+, M0) non metastatic prostate cancer in a combined analysis of three placebo controlled, double-blind studies in 8,113 patients, where bicalutamide 150 mg was given as immediate hormonal therapy or as adjuvant to radical prostatectomy or radiotherapy, (primarily external beam radiation). At 7.4 years median follow up, 27.4% and 30.7% of all bicalutamide and placebo treated patients, respectively, had experienced objective disease progression.
A reduction in risk of objective disease progression was seen across most patient groups but was most evident in those at highest risk of disease progression. Therefore, clinicians may decide that the optimum medical strategy for a patient at low risk of disease progression, particularly in the adjuvant setting following radical prostatectomy, may be to defer hormonal therapy until signs that the disease is progressing.
No overall survival difference was seen at 7.4 years median follow up with 22.9% mortality (HR=0.99; 95% CI 0.91 to 1.09). However, some trends were apparent in exploratory subgroup analyses.
Progression-free survival and overall survival data for patients with locally advanced disease are summarised in the following tables: See Tables 1 and 2.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

For patients with localised disease receiving bicalutamide alone, there was no significant difference in progression free survival. In these patients there was also a trend toward decreased survival compared with placebo patients (HP = 1.16; 95% Cl 0.99 to 1.37). In view of this, the benefit-risk profile for the use of bicalutamide is not considered favourable in this group of patients.
Pharmacokinetics: Absorption and Distribution: Bicalutamide is well absorbed following oral administration. There is no evidence of any clinically relevant effect of food on bioavailability.
The (S)-enantiomer is rapidly cleared relative to the (R)-enantiomer, the latter having a plasma elimination half-life of about 1 week.
On daily administration of bicalutamide, the (R)-enantiomer accumulates about 10 fold in plasma as a consequence of its long half-life.
Steady state plasma concentrations of the (R)-enantiomer of approximately 9 μg/mL are observed during daily administration of 50 mg doses of bicalutamide.
At steady state the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.
The pharmacokinetics of the (R)-enantiomer are unaffected by age, renal impairment or mild to moderate hepatic impairment. There is evidence that for subjects with severe hepatic impairment, the (R)-enantiomer is more slowly eliminated from plasma.
Biotransformation and elimination: Bicalutamide is highly protein bound (racemate 96%, R-bicalutamide 99.6%) and extensively metabolised (via oxidation and glucuronidation): Its metabolites are eliminated via the kidneys and bile in approximately equal proportions.
After excretion in the bile, hydrolysis of the glucuronides takes place. In the urine scarcely altered bicalutamide is found.
In 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 delivered to a female partner during intercourse is low and equates to approximately 0.3 μg/kg.
This is below that required to induce changes in offspring of laboratory animals.
Toxicology: Preclinical safety data: Bicalutamide is a potent antiandrogen and a mixed function oxidase enzyme inducer in animals.
Target organ changes, including tumour induction, in animals, are related to these activities. None of the findings in the preclinical testing is considered to have relevance to the treatment of advanced prostate cancer patients.

Combination therapy with bicalutamide 50 mg: Treatment of advanced prostate cancer in combination with luteinising hormone-releasing hormone (LHRH) analogue therapy or surgical castration.
Monotherapy with 3 tablets of bicalutamide 50 mg (150 mg bicalutamide): Bicalutamide at a dose of 150 mg is indicated either alone or as adjuvant to radical prostatectomy or radiotherapy in patients with locally advanced prostate cancer at high risk for disease progression.

Combination therapy with bicalutamide 50 mg: Adult males including the elderly: One tablet (50 mg) once daily with or without food.
Treatment with bicalutamide may be started either 3 days before or at the same time as commencing treatment with an LHRH analogue, or at the same time as surgical castration.
Monotherapy with 3 tablets of bicalutamide 50 mg (150 mg bicalutamide): Adult males including the elderly: Three tablets (150 mg) once daily with or without food.
Bicalutamide 150 mg should be taken continuously for at least 2 years or until disease progression.
Renal impairment: No dosage adjustment is necessary for patients with renal impairment.
Hepatic impairment: No dosage adjustment is necessary for patients with mild hepatic impairment. Increased accumulation may occur in patients with moderate to severe hepatic impairment.

There is no human experience of overdose. There is no specific antidote; treatment should be symptomatic. Dialysis may not be helpful, since bicalutamide is highly protein bound and is not recovered unchanged in the urine. General supportive care, including frequent monitoring of vital signs, is indicated.

Bicalutamide is contraindicated in females and children.
Hypersensitivity to the active substance or to any of the excipients.
Co-administration of terfenadine, astemizole or cisapride with bicalutamide.

Initiation of treatment should be under the direct supervision of a specialist.
Bicalutamide is extensively metabolised in the liver. Data suggests that its elimination may be slower in subjects with severe hepatic impairment and this could lead to increased accumulation of bicalutamide. Therefore, bicalutamide should be used with caution in patients with moderate to severe hepatic impairment.
Periodic liver function testing should be considered due to the possibility of hepatic changes. The majority of changes are expected to occur within the first 6 months of bicalutamide therapy.
Severe hepatic changes and hepatic failure have been observed rarely with bicalutamide and fatal outcomes have been reported. Bicalutamide therapy should be discontinued if changes are severe.
A reduction in glucose tolerance has been observed in males receiving LHRH agonists. This may manifest as diabetes or loss of glycaemic control in those with pre-existing diabetes. Consideration should therefore be given to monitoring blood glucose in patients receiving bicalutamide in combination with LHRH agonists.
Bicalutamide has been shown to inhibit cytochrome P450 (CYP3A4), as such caution should be exercised when co-administered with medicinal products metabolised predominantly by CYP3A4.
Androgen deprivation therapy may prolong the QT interval.
In patients with a history of or risk factors for QT prolongation and in patients receiving concomitant medicinal products that might prolong the QT interval physicians should assess the benefit risk ratio including the potential for Torsade de pointes prior to initiating bicalutamide.
Potentiation of the effects of coumarin anticoagulants in patients concomitantly receiving bicalutamide may result in an increase in prothrombin time (PT) and International Normalised Ratio (INR).
Some of these cases have been associated with a bleeding risk.
Close monitoring of PT/INR is therefore recommended and adjustment of the anticoagulant dose should be considered.
Antiandrogen therapy may cause morphological changes in spermatozoa. Although the effect of bicalutamide on sperm morphology has not been evaluated and no such changes have been reported for patients who received bicalutamide, patients and/or their partners should follow adequate contraception during and for 130 days after bicalutamide therapy.
Effects on Ability to Drive and Use Machines: Bicalutamide is unlikely to impair the ability of patients to drive or operate machinery. However, it should be noted that occasionally somnolence may occur. Any affected patients should exercise caution.

Bicalutamide is contraindicated in females and must not be given to pregnant women.
Bicalutamide is contraindicated during breast-feeding.
Reversible impairment of male fertility has been observed in animal studies. A period of sub-fertility or infertility should be assumed in man.

In this section undesirable effects are defined as follows: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to ≤ 1/100); rare (≥ 1/10,000 to ≤ 1/1,000); very rare (≤ 1/10,000), not known (cannot be estimated from the available data).
Blood and lymphatic system disorders: Bicalutamide 150 mg (monotherapy): Common: Anaemia.
Bicalutamide 50 mg (combination therapy): Very common: Anaemia.
Immune system disorders: Bicalutamide 150 mg (monotherapy): Uncommon: Hypersensitivity, angioedema and urticaria.
Bicalutamide 50 mg (combination therapy): Uncommon: Hypersensitivity, angioedema and urticaria.
Metabolism and nutrition disorders: Bicalutamide 150 mg (monotherapy): Common: Decreased appetite.
Bicalutamide 50 mg (combination therapy): Common: Decreased appetite.
Psychiatric disorders: Bicalutamide 150 mg (monotherapy): Common: Decreased libido, depression.
Bicalutamide 50 mg (combination therapy): Common: Decreased libido, depression.
Nervous system disorders: Bicalutamide 150 mg (monotherapy): Common: Dizziness, somnolence.
Bicalutamide 50 mg (combination therapy): Very common: Dizziness. Common: Somnolence.
Cardiac disorders: Bicalutamide 150 mg (monotherapy): Not known: QT prolongation.
Bicalutamide 50 mg (combination therapy): Common: Myocardial infarction (fatal outcomes have been reported), cardiac failure. Not known: QT prolongation.
Vascular disorders: Bicalutamide 150 mg (monotherapy): Common: Hot flush.
Bicalutamide 50 mg (combination therapy): Very common: Hot flush.
Respiratory, thoracic and mediastinal disorders: Bicalutamide 150 mg (monotherapy): Uncommon: Interstitial lung disease (fatal outcomes have been reported).
Bicalutamide 50 mg (combination therapy): Uncommon: Interstitial lung disease (fatal outcomes have been reported).
Gastrointestinal disorders: Bicalutamide 150 mg (monotherapy): Common: Abdominal pain, constipation, dyspepsia, flatulence, nausea.
Bicalutamide 50 mg (combination therapy): Very common: Abdominal pain, constipation, nausea. Common: Dyspepsia, flatulence.
Hepato-biliary disorders: Bicalutamide 150 mg (monotherapy): Common: Hepatotoxicity, jaundice, hypertransaminasaemia. Rare: Hepatic failure (fatal outcomes have been reported).
Bicalutamide 50 mg (combination therapy): Common: Hepatotoxicity, jaundice, hypertransaminasaemia. Rare: Hepatic failure (fatal outcomes have been reported).
Skin and subcutaneous tissue disorders: Bicalutamide 150 mg (monotherapy): Very common: Rash. Common: Alopecia, hirsutism/hair re-growth, dry skin, pruritus. Rare: Photosensitivity reaction.
Bicalutamide 50 mg (combination therapy): Common: Alopecia, hirsutism/hair re-growth, dry skin, pruritus, rash. Rare: Photosensitivity reaction.
Renal and urinary disorders: Bicalutamide 150 mg (monotherapy): Common: Haematuria.
Bicalutamide 50 mg (combination therapy): Very common: Haematuria.
Reproductive system and breast disorders: Bicalutamide 150 mg (monotherapy): Very common: Gynaecomastia and breast tenderness. Common: Erectile dysfunction.
Bicalutamide 50 mg (combination therapy): Very common: Gynaecomastia and breast tenderness. Common: Erectile dysfunction.
General disorders and administration site conditions: Bicalutamide 150 mg (monotherapy): Very common: Asthenia. Common: Chest pain, oedema.
Bicalutamide 50 mg (combination therapy): Very common: Asthenia, oedema. Common: Chest pain.
Investigations: Bicalutamide 150 mg (monotherapy): Common: Weight increased.
Bicalutamide 50 mg (combination therapy): Common: Weight increased.
The majority of patients receiving bicalutamide 150 mg as monotherapy experience gynaecomastia and/or breast pain. In studies these symptoms were considered to be severe in up to 5% of the patients. Gynaecomastia may not resolve spontaneously following cessation of therapy, particularly after prolonged treatment.
Hepatic changes are rarely severe and were frequently transient, resolving or improving with continued therapy or following cessation of therapy.
Increase of PT/INR: During post-marketing cases of interactions between coumarin anticoagulants and bicalutamide have been reported.

There is no evidence of any pharmacodynamic or pharmacokinetic interactions between bicalutamide and LHRH analogues.
In vitro studies have shown that R-bicalutamide is an inhibitor of CYP 3A4, with lesser inhibitory effects on CYP 2C9, 2C19 and 2D6 activity.
Although clinical studies using antipyrine as a marker of cytochrome P450 (CYP) activity showed no evidence of a drug interaction potential with bicalutamide, mean midazolam exposure (AUC) was increased by up to 80%, after co-administration of bicalutamide for 28 days.
For medicinal products with a narrow therapeutic index such an increase could be of relevance. As such, concomitant use of terfenadine, astemizole and cisapride is contraindicated and caution should be exercised with the co-administration of bicalutamide with compounds such as ciclosporin and calcium channel blockers. Dose reduction may be required for these medicinal products particularly if there is evidence of enhanced or adverse events.
For ciclosporin, it is recommended that plasma concentrations and clinical condition are closely monitored following initiation or cessation of bicalutamide therapy.
Caution should be exercised when prescribing bicalutamide with other medicinal products which may inhibit drug oxidation e.g. cimetidine and ketoconazole. In theory, this could result in increased plasma concentrations of bicalutamide which theoretically could lead to an increase in side effects.
There have been reports of an increased effect of warfarin and other coumarin anticoagulants when administered concomitantly with bicalutamide. It is therefore recommended that in patients who are receiving coumarin anticoagulants, prothrombin time should be closely monitored. A dose adjustment of the anticoagulant medicinal product should be considered.
Since androgen deprivation treatment may prolong the QT interval, the concomitant use of bicalutamide with medicinal products known to prolong the QT interval or medicinal products able to induce Torsade de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc. should be carefully evaluated.

Store at temperatures not exceeding 25°C.

Cancer Hormone Therapy

L02BB03 - bicalutamide ; Belongs to the class of anti-androgens. Used in treatment of neoplastic diseases.

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