Instructions for Casodex film-coated tablets 50 mg No. 28
Composition
active ingredient: bicalutamide;
1 film-coated tablet contains 50 mg of bicalutamide;
Excipients: lactose monohydrate; magnesium stearate; hypromellose; macrogol 300; povidone; sodium starch glycolate (type A); titanium dioxide (E 171).
Dosage form
Film-coated tablets.
Main physicochemical properties: round, biconvex, white film-coated tablets, embossed with Cdx 50 on one side and the logo on the other.
Pharmacotherapeutic group
Antiandrogenic agents. ATX code L02B B03.
Pharmacological properties
Pharmacodynamics.
Casodex is a nonsteroidal antiandrogen that has no other effect on the endocrine system. The drug binds to androgen receptors without activating gene expression, thus suppressing androgenic stimuli. As a result of such suppression, regression of the prostate tumor is observed. When Casodex is discontinued, a certain proportion of patients may experience a withdrawal syndrome.
Casodex is a racemic mixture with antiandrogenic activity represented almost exclusively by the (R)-enantiomer.
Pharmacokinetics.
Absorption
Casodex 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
Casodex is highly protein bound (racemate 96%, (R)-enantiomer > 99%) and is extensively metabolized (by oxidation and glucuronidation); its metabolites are excreted renally and biliarily in approximately equal amounts.
Biotransformation
The (S)-enantiomer is eliminated very rapidly compared to the (R)-enantiomer; the latter is eliminated from plasma in approximately 1 week.
With daily administration of the drug Casodex, the (R)-enantiomer accumulates in blood plasma in a 10-fold concentration due to its long half-life.
A plateau concentration of the (R)-enantiomer at approximately 9 μg/ml is observed with a daily dose of 50 mg Casodex. At steady state, the predominantly active (R)-enantiomer accounts for 99% of the total circulating enantiomers.
Elimination (extraction)
In a clinical study, the mean concentration of (R)-bicalutamide in the semen of men treated with Casodex 150 mg was 4.9 μg/ml. The amount of bicalutamide potentially delivered to a female partner during sexual intercourse is low and may be approximately 0.3 μg/ml, which is below the level that has been 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. There is evidence that the (R)-enantiomer is cleared from plasma more slowly in patients with severe hepatic impairment.
Indication
Treatment of advanced prostate cancer in combination with luteinizing hormone-releasing factor (LHRH) analogues or surgical castration.
Contraindication
Casodex is contraindicated for use in women and children (see section “Use during pregnancy and lactation”).
Hypersensitivity to the active substance or to any of the excipients.
Concomitant use of Casodex with terfenadine, astemizole or cisapride is contraindicated (see section “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
There is no evidence of a pharmacodynamic or pharmacokinetic interaction between Casodex and luteinizing hormone-releasing factor analogues.
In vitro studies have shown that R-bicalutamide is an inhibitor of CYP3A4 and has a lesser inhibitory effect on the activity of CYP 2C9, 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 midazolam concentration (area under the pharmacokinetic curve) increased by up to 80% after co-administration for 28 days with Casodex. For drugs with a narrow therapeutic window, this increase may be significant. Accordingly, concomitant use with terfenadine, astemizole and cisapride is contraindicated (see section 4.3). Casodex should also be used with caution with compounds such as ciclosporin and calcium channel blockers. A dose reduction of these drugs may be necessary, especially if there is evidence of increased drug exposure or adverse effects.
When using cyclosporine, careful monitoring of its plasma concentration and the patient's clinical condition is recommended after starting or stopping treatment with Casodex.
In vitro studies have shown that Casodex can displace the coumarin anticoagulant warfarin from its protein binding sites. Therefore, when prescribing Casodex to patients already receiving coumarin anticoagulants, careful monitoring of prothrombin time is recommended.
In vitro studies have shown that bicalutamide can displace the coumarin anticoagulant warfarin from its protein binding sites. There have been reports of increased effects of warfarin and other coumarin anticoagulants when co-administered with Casodex. Therefore, careful monitoring of the IRR/PTT is recommended when Casodex is used in patients receiving coumarin anticoagulants and dose adjustment of the anticoagulant should be considered (see sections 4.4 and 4.8).
Due to the fact that antiandrogen therapy may lead to prolongation of the QT interval, caution should be exercised when prescribing Casodex concomitantly with medicinal products that may prolong the QT interval or induce torsade de pointes, 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.
Application features
Treatment with the drug should be started under the direct supervision of a physician. Casodex is extensively metabolized in the liver. Certain data suggest that in patients with severe liver damage, the elimination of the drug is slowed down, which may lead to its cumulation. Therefore, Casodex should be used with caution in patients with moderate or severe liver damage.
Because of the possibility of changes in liver function, liver function tests should be monitored periodically. It is expected that most changes will occur within the first 6 months of Casodex use.
Rarely, severe changes in liver function have been observed with Casodex, and fatal cases have been reported (see section 4.8). If severe changes in liver function occur, Casodex treatment should be discontinued.
For patients who have objective disease progression along with an elevated PSA level, discontinuation of Casodex therapy should be considered.
Glucose tolerance has been reported to be impaired in men taking luteinizing hormone-releasing factor agonists. This may result in diabetes mellitus or loss of glycemic control in patients with pre-existing diabetes. Therefore, blood glucose levels should be monitored in patients receiving Casodex in combination with luteinizing hormone-releasing factor agonists.
Casodex has been shown to inhibit P450 (CYP3A4) activity, therefore caution should be exercised when co-administering it with drugs that are primarily metabolized by CYP3A4 (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”).
Patients with rare hereditary forms of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Antiandrogen therapy may lead to prolongation of the QT interval.
In patients with risk factors or a history of QT prolongation, as well as in patients taking 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 risk/benefit ratio before initiating Casodex treatment, taking into account the potential risk of torsade de pointes.
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 Casodex therapy.
Increased effects of coumarin anticoagulants have been reported in patients receiving Casodex concomitantly, which may lead to increases in prothrombin time (PT) and international normalized ratio (INR). Some cases have been associated with a risk of bleeding. Close monitoring of PT/INR levels is recommended and dose adjustment of anticoagulants should be considered (see sections 4.5 and 4.8).
This medicinal product contains less than 1 mmol (23 mg) sodium/dose, i.e. essentially sodium-free.
Use during pregnancy and breastfeeding
Pregnancy
Bicalutamide is contraindicated for use in women. It is contraindicated during pregnancy.
Breast-feeding
Bicalutamide is contraindicated during breastfeeding.
Fertility
Reversible impairment of male fertility has been observed in animal studies. It should be assumed that men may also experience a period of reproductive failure or infertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
Casodex does not affect the ability to drive or use machines. However, it should be borne in mind that drowsiness may occur frequently, and dizziness very commonly (see section "Adverse reactions"). Patients taking this drug should be careful.
Method of administration and doses
Dosage
Adult men, including elderly patients: one tablet (50 mg) once daily.
Casodex treatment should be initiated at least 3 days before starting therapy with luteinizing hormone-releasing factor analogues or simultaneously with surgical castration.
Renal impairment: No dose adjustment is required for patients with renal impairment.
Hepatic impairment: No dose adjustment is required for patients with mild hepatic impairment.
Increased accumulation is possible in patients with moderate and severe hepatic insufficiency (see section "Special warnings and precautions for use").
Children
Casodex is contraindicated for use in children.
Overdose
There are no data on overdose in humans. There is no specific antidote; treatment is symptomatic. Dialysis may be ineffective because Casodex is highly protein bound and is not excreted unchanged in the urine. In case of overdose, general supportive care is indicated, including monitoring of vital signs.
Side effects
Adverse reactions are listed by frequency 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), frequency unknown (frequency cannot be estimated from the available data).
| Organ system | Frequency | Adverse reaction |
| Blood and lymphatic system disorders | Very often | Anemia |
| Immune system disorders | Infrequently | Hypersensitivity, angioedema, urticaria |
| Metabolic and nutritional disorders | Often | Decreased appetite |
| Mental disorders | Often | Decreased libido, depression |
| Nervous system disorders | Very often | Dizziness |
| Often | Drowsiness |
| Heart disorders | Often | Myocardial infarction (fatal cases reported)4, heart failure4 |
| Frequency unknown | QT prolongation (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other types of interactions”) |
| Vascular disorders | Very often | Tides |
| Mediastinal, thoracic and respiratory disorders | Infrequently | Interstitial lung disease5 (fatal cases have been reported) |
| Digestive system disorders | Very often | Abdominal pain, constipation, nausea |
| Often | Dyspepsia, flatulence |
| Hepatobiliary disorders | Often | Hepatotoxicity, jaundice, increased transaminases1 |
| Rarely | Hepatic failure2 (fatal cases have been reported). |
| Skin and subcutaneous tissue disorders | Often | Alopecia, hirsutism/hair regrowth, dry skin, itching, rash |
| Infrequently | Hypersensitivity reaction to light |
| Kidney and urinary system disorders | Very often | Hematuria |
| Reproductive system and mammary gland disorders | Very often | Gynecomastia and breast tenderness3 |
| Often | Erectile dysfunction |
| General disorders and administration site conditions | Very often | Asthenia |
| Often | Swelling, chest pain |
| Examination | Often | Weight gain |
1 Hepatic changes are rarely severe and often resolve or improve with continued treatment or after discontinuation.
2 Included in the list of adverse drug reactions after review of post-marketing data. The frequency was determined from the frequency of reports of adverse events of hepatic failure in patients treated in the open-label Early Prostate Cancer programme (EPC) trials in the Casodex 150 mg groups.
3 May be reduced with concomitant castration.
4 Observed in a pharmacoepidemiological study of the use of luteinizing hormone-releasing factor agonists and antiandrogens for the treatment of prostate cancer. The risk was increased when Casodex 50 mg was used in combination with luteinizing hormone-releasing factor agonists, but no increased risk was observed when Casodex 150 mg was used as monotherapy for the treatment of prostate cancer.
Increased PC/INR: Interactions of coumarin anticoagulants with Casodex have been reported in post-marketing experience (see sections 4.4 and 4.5).
Reporting of suspected adverse reactions.
It is important to report suspected adverse reactions after a medicinal product has been authorised. This allows for continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
Expiration date
5 years.
Storage conditions
Store at a temperature not exceeding 30 ° C. Keep out of the reach of children.
Packaging
14 tablets in a blister, 2 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
AstraZeneca UK Limited.
Address
Silk Road Business Park, Macclesfield, SK10 2NA, United Kingdom.
