Casodex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CASODEX® (CASODEX)

Composition:

Active substance: bicalutamide;

One film-coated tablet contains 150 mg of bicalutamide;

Excipients: lactose monohydrate; magnesium stearate; hypromellose; macrogol 300; povidone; sodium starch glycolate (type A); titanium dioxide (E 171).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, round, biconvex, film-coated tablets, with a logo embossed on one side and the strength on the other.

Pharmacotherapeutic group. Antiandrogens. ATC code: L02B B03.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Bicalutamide is a non-steroidal antiandrogen that has no other effects on the endocrine system. It binds to wild-type (non-mutated) or normal androgen receptors without activating gene expression, thereby inhibiting androgen activity. As a result of this inhibition, regression of prostate tumors is observed. Upon discontinuation of Casodex, some patients may experience an antiandrogen withdrawal syndrome.

Clinical efficacy and safety

Casodex 150 mg was studied as a treatment for 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 8,113 patients. Casodex was administered either 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 Casodex 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, although 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 in the adjuvant setting after radical prostatectomy—deferring hormonal therapy until signs of disease progression may be an optimal treatment strategy.

At a median follow-up of 9.7 years, no difference in overall survival was observed, with mortality rates of 31.4% (relative risk (RR) = 1.01; 95% confidence interval (CI) = 0.94–1.09). However, subgroup analyses revealed certain trends.

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

Table 1

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

Table 2

Overall survival of patients with locally advanced disease

in subgroups with different treatment regimens

In patients with localized disease who received only Casodex, there was no statistically significant difference in progression-free survival. Also, in patients with localized disease who received Casodex 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 statistically significant difference in overall survival was observed. In patients with localized disease who otherwise would have been managed with a strategy of active surveillance, a trend toward reduced survival was maintained compared to patients who received placebo (HR 1.15; 95% CI 1.00–1.32). Considering the benefit/risk ratio, the use of Casodex in patients with localized disease is not considered appropriate.

In another program, the efficacy of Casodex 150 mg for the treatment of patients with locally advanced prostate cancer without metastases, for whom immediate castration was indicated, was demonstrated in a combined analysis of two studies involving 480 patients with non-metastatic (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 Casodex and castration groups (HR 1.05; 95% CI 0.81–1.36); however, statistical equivalence between the two treatment methods could not be established.

In a combined analysis of two studies involving 805 patients with metastatic disease (M1) who had not received prior therapy, at a mortality rate of 43%, Casodex 150 mg was found to be less effective than castration in terms of survival time (HR 1.30; 95% 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.

Bicalutamide is a racemic mixture with antiandrogenic activity, primarily represented by the (R)-enantiomer.

Children.

No studies in pediatric populations have been conducted (see sections "Contraindications" and "Use in Pregnancy and Breast-feeding").

Pharmacokinetics

Absorption

Bicalutamide 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 protein-bound (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 elimination half-life of the latter from plasma is approximately 1 week.

With daily administration of Casodex 150 mg, the (R)-enantiomer accumulates in plasma due to its long elimination half-life, reaching a 10-fold higher concentration.

A steady-state concentration plateau of the (R)-enantiomer at approximately 22 µg/mL is achieved with a daily dose of 150 mg of Casodex. 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 Casodex 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 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.

Casodex 150 mg is indicated as monotherapy and as 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").

Casodex 150 mg is also indicated for the treatment of patients with locally advanced non-metastatic prostate cancer when surgical castration or other medical interventions are unacceptable or cannot be applied.

Contraindications.

Casodex 150 mg is contraindicated in women and children (see section "Use in pregnancy and lactation").

Casodex 150 mg is contraindicated in patients who have experienced hypersensitivity reactions to the active substance or to any of the excipients.

Concomitant administration of Casodex 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.

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 Casodex, the mean concentration of midazolam (area under the pharmacokinetic curve) increased by up to 80% following concomitant administration with Casodex for 28 days. For 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"). Casodex should also be used with caution when administered concomitantly with drugs such as cyclosporine and calcium channel blockers.

Dosage reduction of these drugs may be necessary, particularly 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 following initiation or discontinuation of Casodex therapy.

Casodex should be prescribed with caution when used concomitantly with drugs that may inhibit drug oxidation, such as cimetidine and ketoconazole. Theoretically, this may lead to increased plasma concentrations of Casodex, potentially resulting in enhanced 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 Casodex. Therefore, careful monitoring of INR/PT is recommended in patients receiving Casodex together with coumarin anticoagulants, and dose adjustment of anticoagulants should be considered (see sections "Special warnings and precautions for use" and "Undesirable effects").

Since antiandrogen therapy may lead to QT interval prolongation, Casodex 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 antiarrhythmics (quinidine, disopyramide) or class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide), 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 the drug should be initiated under direct medical supervision.

Bicalutamide is extensively metabolized in the liver. Available data suggest that in patients with severe hepatic impairment, drug elimination may be slowed, potentially leading to bicalutamide accumulation. Therefore, Casodex 150 mg 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 within the first 6 months of Casodex treatment.

Rarely, severe liver function abnormalities have been observed with Casodex 150 mg, and fatal cases have been reported (see section "Adverse reactions"). If severe liver function abnormalities occur, treatment with Casodex 150 mg should be discontinued.

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

Bicalutamide 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 taking Casodex 150 mg. Patients should be advised to avoid excessive exposure to sunlight or ultraviolet light and to use sun protection measures during treatment with Casodex 150 mg. If photosensitivity reactions are 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 for or a history of QT interval 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 Casodex 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 evaluated and such changes have not been reported in patients receiving Casodex, patients and/or their partners should use effective contraception during treatment and for 130 days after discontinuation of Casodex.

Enhanced effects of coumarin anticoagulants have been reported in patients receiving Casodex concomitantly, which may lead to increased prothrombin time (PT) and international normalized ratio (INR). Some cases were associated with a risk of bleeding. Close 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").

The medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during pregnancy and breastfeeding

Pregnancy

Bicalutamide is contraindicated in women and should not be used 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.

Effect on ability to drive and use machines

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

Dosage and Administration

Dosage

Adult males, including elderly: one 150 mg tablet orally once daily.

Casodex 150 mg should be administered long-term, for at least 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").

Pediatric Patients

Casodex is contraindicated in children (see section "Contraindications").

Overdose

There is no human experience with overdose. There is no specific antidote; treatment should be symptomatic. Dialysis is likely to be ineffective because Casodex is highly protein-bound and is not excreted unchanged in urine. In case of overdose, general supportive therapy is recommended, including monitoring of vital functions.

Side effects.

Side effects 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 (cannot be estimated from the available data).

Table 3

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

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

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

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

e Included in the list of drug adverse reactions following review of post-marketing data. The frequency was determined based on the rate of reports of interstitial lung disease as an adverse event in patients receiving treatment in open-label EPC studies in the Casodex 150 mg groups.

Prolongation of PT/INR: interaction between coumarin anticoagulants and Casodex has been reported in post-marketing surveillance (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 the medicine has been registered. This enables continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life.

4 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of the reach of children.

Packaging. 14 tablets per blister pack, 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

AstraZeneca UK Limited.

Manufacturer's address.

Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom.