Avodart

General characteristics. Structure:

Active ingredient: дутастерид 500 mkg

Excipients: mono - and diglycerides of caprylic/capric acid - 349.5 mg, butyl hydroxytoluene - 35 mkg.

Structure of a cover of the capsule: gelatin - 144.8 mg, глицерол - 70.8 mg, titanium dioxide - 1.78 mg, ferrous oxide yellow - 127 mkg, triglycerides srednetsepochechny - q.s., lecithin - q.s., red ink for the press ** - q.s.

* drawing the GX CE2 code red ink for the press is used by production of a ready dosage form on the production site of Catalent France Beinheim S.A. (France); drawing the GX CE2 code of gray color by means of UF of the cold laser is used by production of a ready dosage form on the production site of GlaxoSmithKline Pharmaceuticals S.A. (Poland).
** red ink for the press is used by production of a ready dosage form on the production site of Catalent France Beinheim S.A. (France) are also not used by production of a ready dosage form on the production site of GlaxoSmithKline Pharmaceuticals S.A. (Poland). The amount of ink on each capsule makes less than 0.28 mg; the materials remaining on the capsule are polyvinyl acetate phthalate, polyethyleneglycol, propylene glycol, ferrous oxide red (E172, CI77491).

Pharmacological properties:

Drug for treatment of a benign hyperplasia of a prostate. Dutasterid - double inhibitor 5α-reduktazy. Suppresses activity of isoenzymes of 5α-редуктазы 1 and 2 types which are responsible for transformation of testosterone in 5α-дигидротестостерон (DGT). Dihydrotestosterone is the main androgen responsible for a hyperplasia of ferruterous tissue of prostate gland.

The maximum influence of a dutasterid on decrease in concentration of DGT is dozozavisimy and is observed in 1-2 weeks after an initiation of treatment. In 1 and 2 weeks of reception of a dutasterid in a dose of 500 mkg / average values of concentration of dihydrotestosterone in serum decrease by 85% and 90%.

Pharmacokinetics. Absorption

After a single dose of drug in a dose of 500 mkg of Cmax of a dutasterid in serum it is reached during 1-3 h. Absolute bioavailability makes about 60% in relation to 2-hour in/in infusion. Bioavailability of a dutasterid does not depend on meal.

Distribution

The pharmacokinetic data obtained after single and multiple dose of a dutasterid confirms big Vd (from 300 to 500 l). Dutasterid possesses high extent of linkng with proteins of plasma (> 99.5%).

At daily reception concentration of a dutasterid in blood serum reaches 65% of stationary level in 1 month and about 90% of this level in 3 months. Stationary concentration of a dutasterid in blood serum (Css) equal to about 40 ng/ml are reached in 6 months of daily reception of 500 mkg of this drug. In sperm, as well as in blood serum, stationary concentration of a dutasterid are also reached in 6 months. In 52 weeks of treatment of concentration of a dutasterid in sperm averaged 3.4 ng/ml (from 0.4 to 14 ng/ml). From blood serum about 11.5% of a dutasterid get to sperm.

Metabolism

In vitro дутастерид is metabolized by CYP3A2 isoenzyme with formation of two small monohydroxylated metabolites; at the same time it is not affected by isoenzymes of CYP2C9, CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2B6, CYP2C19 and CYP2D6. After achievement of Css of a dutasterid, in serum by means of a mass and spectrometer method find not changed дутастерид, 3 large metabolites (4-gidroksidutasterid, 1,2-digidrodutasterid and 6-gidroksidutasterid) and 2 small metabolites.

Removal

In a human body дутастерид is exposed to intensive metabolism. After intake of a dutasterid in a daily dose of 500 mkg for achievement of Css from 1% to 15.4% (on average 5.4%) the accepted dose it is excreted through intestines in not changed look. Other part is excreted in the form of 4 large metabolites making 39%, 21%, 7% and 7% respectively and 6 small metabolites (less than 5% fall to the share of each of which).

Through kidneys at the person trace quantities of not changed dutasterid (less than 0.1% of a dose) are excreted.

At reception of therapeutic doses of a dutasterid its final T1/2 makes 3-5 weeks.

Dutasterid is found in blood serum (in concentration higher than 0.1 ng/ml) up to 4-6 months after the reception termination.

Linearity/nonlinearity

The pharmacokinetics of a dutasterid can be described as process of absorption of the first order and two parallel processes of elimination, one sated (i.e. depending on concentration) and one not saturable (i.e. not depending on concentration). At low concentration in blood serum (less than 3 ng/ml) дутастерид it is quickly removed by means of both processes of elimination. After a single dose in doses of 5 mg and less, дутастерид it eliminirutsya quickly from an organism and has the short elimination half-life equal to 3-9 days.

At concentration in blood serum higher than 3 ng/ml the clearance of a dutasterid occurs more slowly (0.35-0.58 l/h), is preferential by means of linear not saturable process of elimination since final T1/2 3-5 weeks. At therapeutic concentration against the background of daily reception of 500 mkg slower clearance of a dutasterid prevails; the general clearance carries the linear and not depending on concentration character.

Elderly men

The pharmacokinetics and pharmacodynamics of a dutasterid were studied at 36 healthy men aged from 24 up to 87 years after reception of one dose (5 mg) of this drug. Between different age groups there were no statistically significant distinctions in such pharmacokinetic parameters as AUC and Cmax. Also statistically significant distinctions on T1/2 values of a dutasterid between age groups of men of 50-69 years were not revealed and 70 years which include most of men with a benign hyperplasia of a prostate are more senior.

Between various age groups there were no significant differences in extent of decrease in the DGT levels. These results show lack of need of a dose decline of a dutasterid at elderly patients.

Indications to use:

— as monotherapy for treatment and prevention of progressing of a benign hyperplasia of a prostate by means of reduction of its sizes, relief of symptoms, improvement of an urination, decrease in risk of emergence of an acute ischuria and need of an operative measure;

— as a combination therapy with alfa1-adrenoblockers for treatment and prevention of progressing of a benign hyperplasia of a prostate by means of reduction of its sizes, relief of symptoms, improvement of an urination, decrease in risk of emergence of an acute ischuria and need of an operative measure. The combination of a dutasterid and alfa1-adrenoblocker of a tamsulozin was generally studied.

Route of administration and doses:

Drug can be accepted irrespective of meal.

Capsules should be swallowed entirely, not to chew and not to open as contents of the capsule can cause irritation of a mucous membrane of a stomatopharynx.

Benign Hyperplasia of a Prostate (BHP)

Adult men (including elderly) the recommended drug Avodart® dose - 1 capsule (500 mkg) of 1 time / Capsule it is necessary to accept entirely.

Though improvement against the background of use of drug occurs quickly enough, it is necessary to continue treatment not less than 6 months objectively to estimate therapeutic effect.

For treatment of DGPZh the drug Avodart® can be appointed as monotherapy or in a combination with alfa1-adrenoblockers.

Special groups of patients

At reception of 500 mkg / through kidneys less than 0.1% of a dose therefore there is no need to reduce a dose at patients with renal failures are allocated.

There are no data on use of the drug Avodart® for patients with abnormal liver functions now. As дутастерид is exposed to intensive metabolism, and its elimination half-life makes 3-5 weeks, it is necessary to be careful at treatment by the drug Avodart® of patients with abnormal liver functions.

Features of use:

Dutasterid is soaked up through skin therefore women and children have to avoid contact with the damaged capsules. In case of contact with the damaged capsules it is necessary to wash out the respective site of skin water with soap at once.

Abnormal liver function

There are no data on use of the drug Avodart® for patients with abnormal liver functions now. As дутастерид is exposed to intensive metabolism, and its elimination half-life makes 3–5 weeks, it is necessary to be careful at treatment by the drug Avodart® of patients with abnormal liver functions.

Heart failure at the combined use of a dutasterid and tamsulozin

In two 4 years' clinical trials the frequency of development of heart failure was higher at the patients receiving a combination of a dutasterid and alfa1-adrenoblocker, mainly a tamsulozina than at the patients who were not receiving the combined treatment. In these two researches the frequency of development of heart failure remained low (≤ 1%) with some variability between them. But in general discrepancies of indicators of frequency of side effects from cardiovascular system were not noted. To relationship of cause and effect between treatment dutasteridy (as monotherapy or in the form of a combination with alfa1-adrenoblocker) and development of heart failure it is not established.

Influence on identification of the prostates specific antigens (PSA) and prostate cancer (PC)

At patients it is necessary to conduct a manual rectal research, and also to use other methods of a research of a prostate, prior to treatment dutasteridy and to periodically repeat them in the course of treatment for an exception of development of RPZh.

Definition of concentration of the DOG in serum is an important component of the screening directed to identification of RPZh. After 6-month therapy dutasteridy the average DOG serumal level decreases approximately by 50%. To the patients accepting дутастерид the new basic level of the DOG after 6 months of therapy has to be defined. Further it is recommended to control the DOG level regularly.

Use of a dutasterid does not influence the diagnostic value of the DOG level as RPZh marker. Any confirmed increase in the DOG level concerning its smallest value at treatment dutasteridy can demonstrate development of RPZh (in particular, a prostate cancer with high degree of a differentiation on Gleason's scale) or non-compliance with the mode of therapy dutasteridy and has to be exposed to careful assessment even if these DOGS levels remain within normal values for this age category of the patients who are not accepting inhibitors 5α-reduktazy.

Level of the general DOG is returned to a reference value within 6 months after cancellation of a dutasterid.

The ratio of content of a free DOG to the general remains to constants even against the background of therapy dutasteridy. If determination of percent of maintenance of the DOG free fraction is in addition used for identification of RPZh from the men receiving дутастерид correction of this size is not required.

Influence of long reception of a dutasterid on development of cancer of chest glands in men

Influence of long reception of a dutasterid on development of cancer of chest glands in men is not revealed.

RPZh and tumors of high degree of gradation

In a 4-year research (REDUCE) comparison of use of placebo and a dutasterid at 8231 volunteers aged from 50 years up to 75 years, with a negative take of a biopsy on existence by RPZh and the level of DOG from 2.5 ng/ml to 10 ng/ml was carried out at primary inspection.

During the research to 6706 patients the puncture biopsy of a prostate was carried out and on the basis of the received results RPZh zlokachestvennost degree was determined by Gleason's scale. During the research the diagnosis of RPZh was made to 1517 patients. In most cases, both in group of a dutasterid, and in group of placebo, the high-differentiated RPZh was diagnosed (score on Gleason's scale 5-6). Distinctions in number of RPZh cases with assessment of 7-10 points on Gleason's scale in group of a dutasterid and group of placebo were absent (р = 0.81).

In 4 years more cases of RPZh with assessment of 8-10 points on Gleason's scale in group of a dutasterid were noted (n = 29; 0.9%) in comparison with group of placebo (n = 19; 0.6%) (р = 0.15). At assessment of data of a biopsy for 1-2 years the number of patients with the diagnosis of RPZh with assessment of 8-10 points on Gleason's scale was comparable in groups of a dutasterid (n = 17; 0.5%) and placebo (n = 18; 0.5%). At assessment of data of a biopsy for 3-4 year more cases of RPZh with assessment of 8-10 points on Gleason's scale in group of a dutasterid were diagnosed (n = 12; 0.5%) in comparison with group of placebo (n = 1; <0.1%) (р = 0.0035). The percentage ratio of patients with the diagnosis of RPZh with assessment of 8-10 points on Gleason's scale was stable during all temporary intervals (during 1-2 and 3-4 years) in group of a dutasterid (0.5% in every period) while in group of placebo the percent of patients with the diagnosis of RPZh with assessment of 8-10 points was lower for 3-4 years, than in 1-2 years (<0.1% in comparison with 0.5% respectively).

In a 4-year research (CombAT) of patients with DGPZh in which carrying out a biopsy of a prostate to all participants was not defined by the protocol and all diagnoses of RPZh were based on a biopsy according to indications, RPZh with assessment of 8-10 points on Gleason's scale was diagnosed for 8 patients (<0.5%) at reception of a dutasterid, for 11 patients (<0.7%) at reception of a tamsulozin and 5 patients (<0.3%) at a combination therapy dutasteridy and tamsuloziny.

To relationship of cause and effect between reception of a dutasterid and development of RPZh of high degree of gradation it is not established.

The men accepting дутастерид have to undergo regularly inspections concerning assessment of risk of development of RPZh, including the DOG level.

Influence on ability to driving of motor transport and to control of mechanisms

Reception of a dutasterid does not influence driving of the car or work with mechanisms.

Side effects:

The undesirable phenomena given below are listed depending on anatomo-physiological classification and frequency of occurrence. Frequency of occurrence is defined as follows: very often (≥1/10), it is frequent (≥1/100 and <1/10), infrequently (≥1/1000 and <1/100), is rare (≥ 1/10 000 and <1/1000), is very rare (<1/10 000, including separate cases). Categories of frequency were created on the basis of clinical trials of drug and post-registration observation.

The frequency of occurrence of the undesirable phenomena created on the basis of post-registration observation
                                                    From immune system
Very much
       seldom allergic reactions (including rash, an itch, urticaria, the localized hypostasis) and a Quincke's disease.
                                                From skin and a hypodermic fatty tissue
Seldom       alopecia (preferential loss of hair on a body) or hypertrichosis.
                          Disturbance of mentality
     The depression is very rare.
                                               From reproductive system
     Very seldom testicular pain, testicular hypostasis.

The frequency of occurrence of the undesirable phenomena created on the basis of these clinical trials (the undesirable phenomena connected by use of a dutasterid as monotherapy)

In the third phase of placebo - controlled researches using a dutasterid in comparison with placebo researchers estimated the undesirable phenomena connected with reception of a dutasterid:

Undesirable      Emergence undesirable     Emergence of undesirable
                  the phenomenon phenomenon in the 1st year of use        of the phenomenon in the 2nd year of use
                                                                        Platsebo Dutasterid Platsebo Dutasterid
                             (n = 2158)                (n = 2167)          (n = 1736)          (n = 1744)
Erectile
            disfunktsiya2 3%                              of 6%                   of 1%                       of 2%
Decrease
                    libido2 2%                              of 4%                  <1%                     <1%
Disturbance
eyakulyatsii2               <1%                             of 2%                 <1%                   <1%
Disturbances
from outside
chest zhelez1         <1%                             of 1%                   <1%                    of 1%

1 - including morbidity and increase in chest glands.

2 - the undesirable phenomena from reproductive system and chest glands connected using a dutasterid (both at monotherapy, and in a combination with tamsuloziny). These undesirable phenomena can remain after the termination of treatment and influence of a dutasterid on preservation of these undesirable phenomena is unknown.

The undesirable phenomena connected using a dutasterid in a combination with tamsuloziny

The undesirable phenomena given below were registered in the research CombAT (comparison of reception of a dutasterid of 500 mkg and a tamsulozin of 400 mkg of 1 times / as monotherapy or in the form of a combination within four years) and estimated by researchers with cumulative effect of ≥1%).

The undesirable phenomenon           Emergence of the undesirable phenomenon during the period
                                                      uses of a tamsulozin in a combination with dutasteridy
                                                    1st year                2nd year             3rd year             4th year
Kombinatsiya1 (n)                         (n = 1610)          (n = 1428)          (n = 1283)       (n = 1200)
Dutasterid                                (n = 1623)           (n = 1464)          (n = 1325)        (n = 1200)
Tamsulozin                                (n = 1611)            (n = 1468)          (n = 1281)        (n = 1112)
                                                          Erectile disfunktsiya3
Combination                                    of 6%                        of 2%                   <1%               <1%
Dutasterid                                      of 5%                        of 2%                    <1%                <1%
Tamsulozin                                     of 3%                        of 1%                    <1%                <1%
                                                               Decrease libido3
Combination                                    of 5%                      <1%                    <1%                   of 0%
Dutasterid                                      of 4%                         of 1%                     <1%                   of 0%
Tamsulozin                                     of 2%                       <1%                   <1%                <1%
                                                         Disturbance eyakulyatsii3
Combination                                    of 9%                          of 1%                   <1%                 <1%
Dutasterid                                     of 1%                        <1%                  <1%                  <1%
Tamsulozin                                     of 3%                        <1%                  <1%                 <1%
                                                Disturbances from chest zhelez2
Combination                                    of 2%                        <1%                  <1%                  <1%
Dutasterid                                     of 2%                           of 1%                   <1%                 <1%
Tamsulozin                                   <1%                      <1%                    <1%                   of 0%
                                                             Dizziness
Combination                                     of 1%                       <1%                   <1%                <1%
Dutasterid                                    <1%                      <1%                  <1%                 <1%
Tamsulozin                                       of 1%                       <1%                   <1%                    of 0%

1 – combination = дутастерид 500 mkg of 1 times / + тамсулозин 400 mkg of 1 times/;

2 – including morbidity and increase in mammary glands;

3 – the undesirable phenomena from reproductive system and chest glands connected using a dutasterid (both at monotherapy, and in a combination with tamsuloziny). These undesirable phenomena can remain after the treatment termination. Influence of a dutasterid on preservation of these undesirable phenomena is unknown.

Interaction with other medicines:

In vitro дутастерид is metabolized by an isoenzyme of CYP3A4 of fermental system of P450 cytochrome. In the presence of CYP3A4 inhibitors of concentration of a dutasterid can increase in blood.

At simultaneous use of a dutasterid with CYP3A4 inhibitors verapamil and diltiazem note decrease in clearance of a dutasterid. At the same time, амлодипин, other blocker of calcium channels, does not reduce clearance of a dutasterid. Reduction of clearance of a dutasterid and the subsequent increase in its concentration in blood at simultaneous use of this drug and CYP3A4 inhibitors is not significant owing to the broad range of safety limits of a dutasterid therefore there is no need to reduce its dose.

In vitro дутастерид is not metabolized by the following isoenzymes of system of P450 cytochrome of the person: CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19 and CYP2D6.

Dutasterid does not inhibit in vitro the enzymes of system of P450 cytochrome of the person participating in metabolism of medicines.

In vitro дутастерид does not force out warfarin, аценокумарол, фенпрокумон, diazepam and Phenytoinum from sites of their linkng with proteins of plasma, and these drugs, in turn, do not force out дутастерид.

When carrying out researches of interaction of a dutasterid with tamsuloziny, terazoziny, warfarin, digoxin and Colestyraminum at the person of any clinically significant pharmacokinetic or pharmakodinamichesky interactions did not note.

At use of a dutasterid along with hypolipidemic drugs, APF inhibitors, beta adrenoblockers, blockers of calcium channels, corticosteroids, diuretics, NPVP, inhibitors of phosphodiesterase of the 5th type and hinolonovy antibiotics of any significant undesirable medicinal interactions it was not observed.

Contraindications:

— hypersensitivity to a dutasterid and other components of drug;

— hypersensitivity to other inhibitors 5α-reduktazy.

Аводарт® it is contraindicated to women and children.

With care it is necessary to appoint drug at a liver failure.

Use of the drug AVODART® at pregnancy and feeding by a breast
Influence on fertility

Influence of a dutasterid in a daily dose of 500 mkg on characteristics of sperm was studied at healthy volunteers at the age of 18-52 years. By 52nd week of treatment average values of percentage decrease in total quantity of spermatozoa, volume of sperm and a physical activity of spermatozoa made 23%, 26% and 18% respectively in comparison with initial level. Concentration of spermatozoa and their morphological characteristics did not change.

In 24 weeks of observation average value of percentage change of total quantity of spermatozoa in group of a dutasterid remained 23% lower in comparison with initial level. Average value for all parameters of sperm in all temporary points remained within norm and did not correspond to the set criteria for clinically significant change (30%), on the 52nd week of treatment at two volunteers in group of a dutasterid total quantity of spermatozoa decreased more than by 90% in comparison with initial level, with partial recovery on the 24th week of observation.

Thus, clinical value of influence of a dutasterid on indicators of sperm and on individual fertility of the patient is unknown.

Pregnancy

Dutasterid is contraindicated to women. Dutasterid was not studied at women since preclinical data demonstrate that suppression of the DGT level can cause braking of development of external genitals in a fruit.

Lactation

There are no data on penetration of a dutasterid into breast milk.

Use at abnormal liver functions
It is necessary to use with care drug at patients with abnormal liver functions since дутастерид is exposed to intensive metabolism in a liver, and its T1/2 makes 3-5 weeks.

Use at renal failures
At renal failures the dose decline of drug is not required (since at administration of drug in a dose of 500 mkg / with urine less than 0.1% of a dose are allocated).

Use for elderly patients
Dose adjustment is not required.

Overdose:

At purpose of a dutasterid to 40 mg / once (is 80 times higher than a therapeutic dose) within 7 days of significant side effects it was not noted. At conduct of clinical trials patients within 6 months received дутастерид in a dose 5 mg daily, at the same time any additional side effects to those that were observed against the background of reception of 500 mkg of a dutasterid, it was revealed not.

There is no specific antidote of a dutasterid therefore at suspicion on overdose it is enough to carry out the symptomatic and supporting treatment.

Storage conditions:

Drug should be stored in the place, unavailable to children, at a temperature not above 30 °C. A period of validity - 4 years.

Issue conditions:

According to the recipe

Packaging:

10 - blisters (3) - packs cardboard.
10 - blisters (9) - packs cardboard.