Bikalutamid

General characteristics. Structure:

Active ingredient: 50 mg or 150 mg of a bikalutamid.

Excipients: lactoses monohydrate, sodium carboxymethylstarch, povidone, magnesium stearate.

Tablet cover: Опадрай белый*.
 
* Опадрай white contains: macrogoal, titanium dioxide, gipromelloz.

Pharmacological properties:

Pharmacodynamics. Bikalutamid represents racemic mix with nonsteroid anti-androgenic activity preferential (R) - an enantiomer, has no other endocrine activity. Bikalutamid contacts androgenic receptors and, without activating an expression of genes, suppresses the stimulating influence of androgens. Regression of malignant new growths of a prostate is result of it.
 
At some patients the termination of reception of a bikalutamid can lead to development of a clinical syndrome of "cancellation" of anti-androgens.
 
At use of a bikalutamid in a daily dose of 150 mg daily for treatment of patients with locally-spread (T3-T4, any N, M0; T1-T2, N+, M0) a prostate cancer, as immediate hormonal therapy or as adjuvant therapy, considerably decreases risk of progressing of a disease and metastasises in a bone. At a locally-spread prostate cancer the tendency to improvement of indicators of life expectancy without signs of progressing of a disease in groups of the patients accepting бикалутамид in a dose of 150 mg as immediate therapy or adjuvant therapy on comparison with standard therapy (surgical treatment, radiation therapy) is noted.
 
Increase in life expectancy among the patients with a locally-spread prostate cancer receiving бикалутамид in a dose of 150 mg as immediate monotherapy or adjuvant treatment in a combination with radiation therapy is shown.

Pharmacokinetics. After intake it is quickly and completely soaked up from digestive tract. Meal does not influence absorption.
 
(S) - the enantiomer is brought out of an organism much quicker (R) - an enantiomer, an elimination half-life of the last - about 7 days.
 
At daily reception of a bikalutamid concentration (R) - an enantiomer in a blood plasma increases approximately by 10 times owing to a long elimination half-life that does possible administration of drug once a day.
 
At reception of 150 mg of a bikalutamid daily equilibrium concentration (R) - an enantiomer makes about 22 mkg/ml. At an equilibrium state about 99% of all enantiomer circulating in blood make active (R) - an enantiomer.
 
The pharmacokinetics (R) - an enantiomer is not influenced by age, a renal failure, a lung and average degree an abnormal liver function. There are data that at patients with heavy degree of abnormal liver functions elimination (R) - an enantiomer from a blood plasma is slowed down.
 
Communication with proteins of a blood plasma high (for racemic mix of 96%, for (R) - an enantiomer of 99,6%). It is intensively metabolized in a liver (by oxidation and formation of conjugates with glucuronic acid). Metabolites are removed by kidneys and intestines approximately in equal ratios.
 
Average concentration (R) - an enantiomer in sperm of the men receiving бикалутамид in a dose of 150 mg makes 4,9 mkg/ml.

Indications to use:

- Bikalutamid in a dose of 150 mg is shown for treatment of a locally-spread prostate cancer (T3-T4, any N, M0; T1-T2, N+, M0) as monotherapy or adjuvant therapy in combination with a radical prostatectomy or radiation therapy.
 
- Bikalutamid in a dose of 150 mg is also shown for treatment of a locally-spread not metastatic prostate cancer in cases when surgical castration or other medical interventions are not acceptable or do not suit the patient.

Route of administration and doses:

Adult men (including elderly). At a locally-spread prostate cancer: inside on 150 mg once a day. Bikalutamid it is necessary to accept it is long, at least within 2 years. At emergence of signs of progressing of a disease administration of drug should be stopped.

Correction of the mode of dosing.

Renal failures. Dose adjustment is not required.
 
Abnormal liver functions. At easy degree of abnormal liver functions dose adjustment is not required. At patients with average and heavy degree of abnormal liver functions the increased cumulation of a bikalutamid can be observed (see the section "Special Instructions").

Features of use:

Pregnancy and lactation. Bikalutamid is contraindicated to women and should not be appointed pregnant or during breastfeeding.

At patients with progressing of a disease against the background of increase in concentration of prostatspetsifichesky antigen (DOG) it is necessary to consider a question of the treatment termination bikalutamidy.
 
At purpose of a bikalutamid the patients receiving anticoagulants of a coumarinic row are recommended to control a prothrombin time regularly.
 
Considering a possibility of inhibition bikalutamidy activities of P450 cytochrome (CYP 3A4 isoenzyme) it is necessary to show care at co-administration of a bikalutamid with the drugs which are preferential metabolized with participation of an isoenzyme of CYP 3A4 (see sections of "Contraindication" and "Interaction with Other Medicines"),
 
At the patients accepting GNRG agonists decrease in portability of glucose was observed. This effect can lead to development of a diabetes mellitus or decrease in tolerance to glucose at patients with a diabetes mellitus. In this connection at the patients accepting бикалутамид in a combination with GNRG agonists it is necessary to control concentration of glucose in blood.
 
Patients with a lactose intolerance need to be informed that each tablet of a bikalutamid of 150 mg contains 183 mg of monohydrate of lactose, respectively.
 
Use for patients with abnormal liver functions. Bikalutamid is intensively metabolized in a liver. Considering a possibility of delay of removal of a bikalutamid and cumulation of a bikalutamid at patients with an abnormal liver function, it is reasonable to estimate function of a liver periodically. The majority of changes of function of a liver meet within the first 6 months of treatment bikalutamidy.
 
Bikalutamid it is necessary to apply with care at patients with average and heavy degree of abnormal liver functions.
 
Changes of function of a liver of heavy degree when using a bikalutamid arise seldom (see the section "Side effect"), there are messages on cases with a lethal outcome.
 
In case of development of the expressed changes of function of a liver reception of a bikalutamid needs to be stopped.
 
Precautionary measures at use. At the treatment of drug of special precautionary measures it is not required.

Influence on ability to manage vehicles and mechanisms. At use of a bikalutamid drowsiness and dizziness can be observed. At emergence of the described undesirable phenomena it is necessary to refrain from performance of the specified types of activity.

Side effects:

Bikalutamid in general has good tolerance. Only in rare instances use of a bikalutamid is cancelled because of the side effects caused by drug. According to WHO recommendations side effects which can cause бикалутамид are classified according to the frequency of their development as follows: very often - ≥ 10%, are frequent - ≥ 1% and <10%, infrequently - ≥ 0,1% and <1%, is rare - ≥ 0,01% and <0,1%, is very rare - <0,01%, is unknown (it is impossible to estimate on the basis of the available data).
 
Side effects which met at use of a bikalutamid on 150 mg once a day and at simultaneous use of a bikalutamid on 50 mg GNRG analogs once a day are included below:
 
Disturbances from blood and lymphatic system: often: anemia.
 
Disturbances from immune system: infrequently: hypersensitivity reactions (including Quincke's disease and small tortoiseshell *).
 
Disturbances of mentality: often: decrease in sexual desire (libido), depression.
 
Disturbances from a nervous system: very often: dizziness **; often: drowsiness, headache *, paresthesias *, sleeplessness *, тревожность*.
 
Disturbances from vessels: very often: heat "inflows" **; often: arterial гипертензия*.
 
Disturbances from heart: often: a myocardial infarction (it was reported about cases with a lethal outcome) *; infrequently: heart failure.
 
Disturbances from digestive tract: very often: abdominal pain **, lock **, nausea **, diarrhea *; often: dyspepsia, meteorism, рвота*.
 
Disturbances from respiratory system, bodies of a thorax and a mediastinum: very often: asthma; often: strengthening of cough *, pharyngitis *, bronchitis *, pneumonia *, rhinitis *; infrequently: intersticial pulmonary diseases (it was reported about cases with a lethal outcome) (post-marketing experience).

Disturbances from a liver and biliary tract: often: tranzitorny changes from a liver (hepatotoxic), including increase in activity of "hepatic" transaminases, jaundice, increase in activity of an alkaline phosphatase * (the described changes of function of a liver seldom were estimated as serious, often had tranzitorny character, completely disappeared or decreased after drug withdrawal); seldom: a liver failure (relationship of cause and effect is authentically not established with reception of a bikalutamid) (post-marketing experience).
 
Disturbances from skin and hypodermic fabrics: very often: rash ***; often: an alopecia, a hirsutism/growth recovery of hair, the xeroderma, a skin itch raised потливость*.
 
Disturbances from skeletal and muscular and connecting fabric: often: ostealgias *, myasthenia *, arthralgia *, arthritis *, dorsodynia *, pathological переломы*.

Disturbances from kidneys and urinary tract: very often: a hamaturia **, night desires on an urination *; often: an infection of urinary tract *, the speeded-up urination *, an ischuria *, disturbance of an urination *, an incontience мочи*.
 
Disturbances from generative organs and a mammary gland: very often: a gynecomastia (can remain even after the therapy termination, especially in case of administration of drug for a long time) and morbidity of mammary glands; often: impotence / erectile dysfunction.
 
Disturbances from endocrine system: often: hyperglycemia *; frequency is unknown: decrease in tolerance to glucose (post-marketing experience) *.

Disturbances from a metabolism and food: very often: adynamy; often: anorexia, increase in body weight, degrowth тела*.
 
The general frustration and disturbances in an injection site: very often: a stethalgia **, peripheral hypostases **, pains *, pains in a small pelvis *, infections *; often: grippopodobny синдром*.
 
* These side effects were observed only at a concomitant use of a bikalutamid (on 50 mg once a day) with GNRG analogs.
 
** These side effects were observed at use of a bikalutamid on 150 mg once a day met often, and is not really frequent.
 
*** These side effects were observed at a concomitant use of a bikalutamid (on 50 mg once a day) with analogs of GNRG frequent, and is not really frequent.

Interaction with other medicines:

Proofs pharmakodinamichesky or pharmacokinetic interaction between bikalutamidy and analogs of GNRG are not received.
 
In the researches in vitro it is shown that (R) - the enantiomer of a bikalutamid is CYP3A4 isoenzyme inhibitor, to a lesser extent influencing activity of isoenzymes of CYP 2C9, CYP 2C19 and CYP 2D6. In clinical trials with use of phenazone as a marker of activity of P450 (CYP) cytochrome potential ability of a bikalutamid to interaction with other medicines is not revealed, however, at use of a bikalutamid within 28 days against the background of midazolam reception, the area under a curve "concentration time" (AUC) of midazolam increased by 80%.
 
Contraindicated simultaneous use of a bikalutamid with such drugs as терфенадин, астемизол and цизаприд.

It is necessary to be careful at purpose of a bikalutamid along with cyclosporine or blockers of "slow" calcium channels. Perhaps, the dose decline of these drugs, especially in case of development of by-effects will be required. After the beginning of use or cancellation of a bikalutamid recommend to carry out careful monitoring of concentration of cyclosporine in a blood plasma and a clinical condition of the patient.
 
It is necessary to show care at the co-administration of a bikalutamid and drugs oppressing microsomal enzymes of a liver, for example, with Cimetidinum or ketokonazoly as their simultaneous use can lead to increase in concentration of a bikalutamid in a blood plasma and, perhaps, to increase in frequency of emergence of side effects.
 
Bikalutamid strengthens effect of indirect anticoagulants of a coumarinic row, including, warfarin since competes with them for linkng with proteins. It is regularly recommended to control a prothrombin time at purpose of a bikalutamid to the patients receiving indirect anticoagulants of a coumarinic row.

Contraindications:

- Hypersensitivity to a bikalutamid or other components of drug;
- a concomitant use with terfenadiny, astemizoly and tsizapridy;
- бикалутамид it should not be appointed to children and women.

With care:
- Abnormal liver function;
- lactose intolerance;
- deficit of lactase and glyukozo-galaktozny malabsorption.

Overdose:

Overdose cases at the person are not described. The specific antidote does not exist.

Symptomatic treatment. Carrying out dialysis is not effective as бикалутамид strongly contacts proteins of a blood plasma and is not removed by kidneys in not changed look. The general maintenance therapy and monitoring of the vital functions of an organism is shown.

Storage conditions:

To store in the dry, protected from light place, at a temperature not above 30 °C. To store in the place, unavailable to children. A period of validity - 4 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 14 tablets in a blister strip packaging from aluminum foil and a film of PVC. On 2 blister strip packagings together with the application instruction in a cardboard pack. On 10 tablets in a blister strip packaging from aluminum foil and a film of PVC. On 3 blister strip packagings together with the application instruction in a cardboard pack.