Biculide

Bikulide is a non-steroidal antiandrogenic drug. It does not affect the endocrine system.

The drug is synthesized with androgenic endings, without causing active gene expression, which leads to the suppression of androgenic stimuli. Such suppression leads to the development of regression of neoplasm in the prostate area. In case of drug withdrawal, some patients may develop drug withdrawal syndrome.

Indications Biculida

It is used for prostate carcinoma (at late stages) in combination with the use of lutropin-releasing factor analogues or with surgical castration.

Release form

The medicinal component is released in tablets - 50 pieces in bottles. It is also sold in cellular packages - 15 pieces. There are 2 such packages in a box.

Pharmacodynamics

Biculide is a racemic mixture with antiandrogenic properties. It appears almost exclusively in the form of the (R)-enantiomer.

Pharmacokinetics

The drug is well absorbed when taken orally. There is no proven information that food has a clinically significant effect on the bioavailability of the drug.

The (S)-enantiomer is excreted much more rapidly than the (R)-enantiomer; the plasma half-life of the latter is approximately 7 days.

In case of daily administration of the drug, the (R)-enantiomer (due to the long half-life) accumulates in the blood plasma in a 10-fold amount.

A plateau of approximately 9 μg/mL for the (R)-enantiomer is observed after administration of 50 mg of the drug per day. At steady state, the predominantly active (R)-enantiomer constitutes 99% of the total circulating enantiomers.

There is information that in individuals with severe liver disease, the (R)-enantiomer is excreted from plasma more slowly.

Biculide has a high protein synthesis rate (racemate is 96%, and (R)-enantiomer is >99%); it also participates in intensive metabolic processes (glucuronidation with oxidation). Metabolic components are excreted equally with bile and urine.

In clinical tests, mean levels of (R)-bicalutamide in male sperm (patients took 0.15 g of the drug) were 4.9 μg/mL. The amounts of bicalutamide that are theoretically absorbed into the female body during sexual intercourse are low, approximately 0.3 μg/mL. This is below the level that has caused adverse effects on the fetus in animals.

Dosing and administration

Adult men (including the elderly) are required to take 50 mg orally (equivalent to 1 tablet), 1 time per day.

Taking Biculide should be started no earlier than 3 days before starting treatment with lutropin-releasing factor analogues, or simultaneously with surgical castration.

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Use Biculida during pregnancy

Biculide is used to treat the prostate, so it is not prescribed to women.

Contraindications

Among the contraindications:

• the presence of symptoms of intolerance to the active element or other auxiliary components that are part of the drug;
• combined use with astemizole, terfenadine or cisapride.

Side effects Biculida

The drug is usually tolerated without complications. Only occasionally developing disorders required discontinuation of the medication.

Main side effects:

Lesions of the lymph and blood system: anemia (this includes iron deficiency and hypochromic forms);

Immune disorders: Quincke's edema, personal intolerance and urticaria;

Disorders of metabolic and nutritional processes: loss of appetite;

Mental health problems: depression, decreased libido and anxiety;

NS related disorders: drowsiness or insomnia, dizziness, paresthesia and headaches;

Cardiovascular disorders: prolongation of the QT interval, hot flashes, myocardial infarction (there are reports of fatal outcomes) ⁴, hypertension and CHF ⁴;

Lesions of the sternum, mediastinum and respiratory tract: dyspnea, pharyngitis, ILD (there are reports of fatal outcomes), pneumonia, increased cough, runny nose, bronchitis and flu-like syndrome;

Digestive problems: vomiting, bloating, abdominal pain, dyspepsia, nausea, diarrhea and constipation;

Hepatobiliary disorders: liver failure ² (there is information about deaths), hepatotoxicity, increased alkaline phosphatase values, jaundice and increased action of transaminases ¹;

Lesions of the subcutaneous layers and epidermis: itching, alopecia, dry epidermis, hirsutism or hair regrowth, photosensitivity and rashes;

Renal and urinary disorders: infection of the urethra, retention, incontinence or increased frequency of urination, nocturia or hematuria;

Problems with the functioning of the mammary glands and reproductive organs: impotence, gynecomastia and pain affecting the mammary glands ³;

Systemic manifestations: pain in the sternum area, systemic pain and asthenia;

Test results: weight loss or gain;

Endocrine dysfunction: hyperglycemia or diabetes mellitus;

Lesions of the musculoskeletal structure: pain arising in the back, pelvis or bones, pathological fractures, arthritis or myasthenia.

¹ liver damage is only rarely severe and often disappears or is relieved with continued therapy or after its discontinuation.

² liver failure has been observed occasionally with Biculide administration, but no connection with the drug has been established in this case. Periodic monitoring of liver function should be considered.

³ When castration is performed, weakening is possible.

⁴ noted in pharmaco-epidemiological testing of the use of luteinizing hormone-releasing factor agonists and antiandrogens during prostate carcinoma therapy. The risk increases when the drug is used together with luteinizing hormone-releasing factor agonists. No increased risk was observed with monotherapy with 0.15 g of Biculide for the treatment of prostate carcinoma.

In addition, it is necessary to indicate adverse events that occurred during clinical trials with the administration of the drug together with a lutropin-releasing factor analogue, but the connection with the drug was not clearly established:

• disorders associated with the cardiovascular system: fainting, angina pectoris, cerebral or coronary blood flow disorder, arrhythmia, bleeding, deep thrombophlebitis, atrial fibrillation, cerebral ischemia and bradycardia;
• problems with nervous system function: neuropathy or confusion;
• gastrointestinal disorders: dry mouth, gastrointestinal cancer, melena, periodontal abscess, rectal hemorrhage, dysphagia, gastritis, rectal disease and intestinal obstruction;
• lymph and blood lesions: thrombocytopenia or ecchymosis;
• metabolic disorders: increased creatinine or blood urea levels, gout, hypercalcemia or -cholesterolemia, dehydration and hypoglycemia;
• problems with musculoskeletal function: myalgia, bone disease and cramps affecting the legs;
• respiratory disorders: sinusitis, voice changes, pulmonary disorders, pleural effusion or asthma;
• epidermal lesions: skin cancer, herpes zoster, as well as epidermal hypertrophy or skin ulcers;
• visual impairment: vision problems, cataracts or conjunctivitis;
• problems with urinary or renal function: balanitis, hydronephrosis, renal calculus, dysuria, disorders related to the prostate, and stenosis affecting the bladder;
• Systemic signs: neck pain or stiffness, chills, swelling, hernia, facial swelling, cysts, fever, and sepsis.

Overdose

There is no information regarding poisoning by the drug in humans.

There is no antidote; symptomatic treatment is performed. Dialysis will not have an effect, because the drug is largely synthesized with protein, not being determined in the urine in an unchanged state. In case of intoxication, general supportive measures are performed (also monitoring the work of vital systems).

Interactions with other drugs

There is no information confirming the pharmacokinetic or -dynamic interaction of the drug and analogs of lutein-releasing factor.

In vitro tests have shown that R-bicalutamide inhibits the action of CYP 3A4, while also exerting a less pronounced inhibitory effect on the activity of CYP 2C9, as well as 2C19 and 2D6.

Although clinical trials using antipyrine as a marker of hemoprotein P450 (CYP) activity do not show a theoretical interaction with drugs, the mean midazolam values (AUC) increased by up to 80% when combined with Bikulide over a 28-day cycle. For drugs with a narrow pharmaceutical spectrum, such an increase may be important. Therefore, the drug should not be combined with cisapride, astemizole or terfenadine.

At the same time, the drug is very carefully combined with blockers of Ca channel activity and cyclosporines. It is possible that there will be a need to reduce the dose of these drugs, especially in the presence of symptoms of potentiation of drug activity or when negative signs appear during its administration. During the administration of cyclosporine, its plasma parameters and the clinical condition of the patient (after the start and completion of therapy with Biculide) should be closely monitored.

Caution is required when administering the drug with medications that can inhibit oxidation of products (including ketoconazole with cimetidine). In theory, this may cause an increase in the plasma level of Biculide, potentiating its side effects.

In vitro tests have shown that the drug is capable of displacing coumarin anticoagulants (warfarin) from their protein synthesis sites. Because of this, when administering the drug to people already using such anticoagulants, it is necessary to closely monitor the PT values. If necessary, the dose of the anticoagulant is changed.

The combination of androgen blockers, an antiandrogen, and a lutein-releasing factor analogue with drugs that prolong the QTc interval may lead to the development of tachycardia (torsades de pointes). This factor must be taken into account when using bicalutamide together with substances that are theoretically capable of prolonging the QTc interval. Among such drugs (the list is incomplete):

• antidepressants (nortriptyline with amitriptyline);
• antiarrhythmic substances of subcategory IA (disopyramide with quinidine);
• subcategory III (dofetilide, dronedarone with amiodarone, ibutilide and sotalol);
• subcategory IC (propafenone with flecainide);
• antimalarial substances (quinine);
• neuroleptics (for example, chlorpromazine);
• 5-hydroxytryptamine ending antagonists (including ondansetron);
• opioids (eg methadone);
• macrolides with their analogues (clarithromycin with erythromycin and azithromycin), as well as quinolines (for example, moxifloxacin);
• antifungals from the azole subgroup;
• β2-adrenergic receptor analogues (for example, salbutamol).

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Storage conditions

Bikulide should be stored in a place closed to small children. Temperature indicators - no more than 30 ° C.

Shelf life

Biculirid can be used within a 5-year (vials) and 3-year (blisters) period from the date of manufacture of the drug.

Application for children

There is no data on the therapeutic efficacy and safety of bicalutamide (non-steroidal antiandrogen) administration to children. For this reason, Biculirid is not used in pediatrics.

Analogues

The analogs of the drug are the substances Casodex, Flutamide, Areclok, Flutazine with Calumid, and in addition Bicalutamide-Teva, Xtandi and Flutafarm.