Avodart capsules 0.5 mg №30

Release form, composition and packaging

Capsules gelatinous, yellow, oblong, opaque, marked with red ink "GX CE2" on one side.

Excipients: mono- and diglycerides of caprylic / capric acid, butylhydroxytoluene.

The composition of the shell of the capsule: gelatin, glycerol (glycerin), titanium dioxide E171 (Cl77891), iron oxide yellow E172 (Cl77492).

Clinico-pharmacological group

Drug for the treatment of benign prostatic hyperplasia. 5α-reductase inhibitor

Pharmacology

Drug for the treatment of benign prostatic hyperplasia. Suppresses the activity of isoenzymes 5α-reductase 1 and type 2, which are responsible for the conversion of testosterone to 5α-dihydrotestosterone (DHT). Dihydrotestosterone is the main androgen responsible for the hyperplasia of the glandular tissue of the prostate gland.

The maximum effect of dutasteride on the reduction of dihydrotestosterone concentrations is dose-dependent and is observed 1-2 weeks after the start of treatment. After 1 and 2 weeks of dutasterid intake at a dose of 0.5 mg / day, the average concentration of dihydrotestosterone in serum is reduced by 85% and 90%.

The drug reduces the size of the prostate gland, improves urination and reduces the risk of acute urinary retention and the need for surgical treatment.

Pharmacokinetics

Suction

After a single dose of 500 mcg C_max dutasteride in serum is achieved within 1-3 hours. With a 2-hour IV infusion, the absolute bioavailability is about 60%. Bioavailability of dutasteride does not depend on food intake.

Distribution

Plasma protein binding is high - more than 99.5%. V_d - 300-500 l.

With daily intake, the concentration of dutasteride in serum reaches 65% of C_ss in 1 month and approximately 90% of this level in 3 months.

C_ss Dutasteride in serum, approximately 40 ng / ml, is achieved after 6 months of daily administration of the drug in a dose of 500 μg. In semen, as in serum, C_ss Dutasteride is also achieved after 6 months. After 52 weeks of treatment, the concentrations of dutasteride in semen are on average 3.4 ng / ml (0.4-14 ng / ml). Approximately 11.5% of dutasteride is supplied to semen from serum.

Metabolism

In vitro, dutasteride is metabolized by CYP3A4 isoenzyme to form two small monohydroxylated metabolites; however, it is not affected by isozymes CYP2C9, CYP2C19 and CYP2D6. After reaching C_ss dutasteride, in the serum using the mass spectrometry method, unchanged dutasteride, 3 large metabolites (4 'hydroxydutasteride, 1,2 - dihydrodutasteride and 6 - hydroxideduasteride) and 2 small metabolites are detected.

Removal

Dutasteride undergoes intensive metabolism. After the drug is taken orally at a dose of 500 mcg / day until an equilibrium state is reached, 1–15.4% (5.4% on average) of the dose taken are excreted in the feces unchanged. The rest of the dose is excreted in the form of 4 large metabolites, constituting 39%, 21%, 7% and 7%, respectively, and 6 small metabolites (each of which accounts for less than 5%).

Traces of unchanged dutasteride (less than 0.1% of the dose) are excreted in human urine.

When taking dutasteride at therapeutic doses, its final T_1/2 is 3-5 weeks.

Dutasteride is detected in serum (in concentrations of more than 0.1 ng / ml) up to 4-6 months after discontinuation.

The pharmacokinetics of dutasteride can be described as a first-order absorption process and two parallel elimination processes, one saturated (ie, dependent on concentration) and one unsaturated (that is, not dependent on concentration).

At low serum concentrations (less than 3 ng / ml), dutasteride is rapidly excreted due to both elimination processes. After a single dose in doses of 5 mg or less, dutasteride is rapidly excreted from the body and has a short T_1/23-5 days.

At concentrations in serum more than 3 ng / ml, the clearance of dutasteride is less — 0.35–0.58 l / h, while excretion is carried out mainly by means of a linear unsaturated process with a final T_1/2 3-5 weeks At therapeutic concentrations on the background of daily intake of the drug at a dose of 500 μg, a slower clearance of dutasteride prevails; total clearance is linear and not dependent on concentration.

Older men

Pharmacokinetics and pharmacodynamics of dutasteride were studied in 36 healthy men aged from 24 to 87 years after taking the drug in a single dose of 5 mg. Between different age groups there were no statistically significant differences in such pharmacokinetic parameters of dutasteride as AUC and C_max. No statistically significant differences of T were found._1/2 dutasteride between the age group of 50-69 years and the age group over 70 years, which includes the majority of men with benign prostatic hyperplasia.

There were no significant differences between the age groups in the degree of reduction in DHT levels. These results indicate that there is no need to reduce the dose of dutasteride in elderly patients.

Indications for use of the drug

- treatment and prevention of progression of benign prostatic hyperplasia (in order to reduce the size of the prostate gland, relieve symptoms, improve urination and reduce the risk of acute urinary retention and the need for surgical treatment);

- combination therapy with alpha₁-adrenergic blockers for the treatment and prevention of progression of benign prostatic hyperplasia (to reduce the size of the prostate gland, relieve symptoms, improve urination). The combination of dutasteride and Tamsulosin (alpha₁-block blocker) has been studied.

Dosing regimen

Dutasteride can be used as monotherapy, as well as in combination with alpha₁-blockers.

The drug can be taken regardless of the meal.

The effect comes pretty quickly, but treatment should continue for at least 6 months in order to objectively evaluate the effect of the drug.

For adult males, including elderly patients, The recommended oral dose is 500 mcg (1 capsule) 1 time per day.Capsules should be swallowed whole, not chewed and not opened, because the contents of the capsule can cause irritation of the mucous membrane of the oropharynx.

At renal dysfunction dose adjustment of the drug is not required (because when taking the drug in a dose of 500 mg / day with the urine less than 0.1% of the dose is excreted).

It is necessary to carefully use the drug in patients with impaired liver functionbecause Dutasteride is extensively metabolized in the liver, and its T_1/2 is 3-5 weeks.

Adverse Effects

Clinical research data

Monotherapy Dutasteride: impotence, change (decrease) in libido, impaired ejaculation, gynecomastia (includes soreness and enlargement of the mammary glands).

Combination therapy Dutasteride and tamsulosin: impotence, change (decrease) in libido, impaired ejaculation, gynecomastia (includes soreness and enlargement of the mammary glands), dizziness.

Observations in clinical practice: very rarely - allergic reactions (rash, itching, urticaria, limited edema, angioedema).

Contraindications to the use of the drug

- hypersensitivity to dutasteride and other components of the drug;

- hypersensitivity to other inhibitors of 5α-reductase.

Avodart is contraindicated for women and children.

Use of the drug during pregnancy and lactation

Impact on fertility

The effect of dutasteride at a daily dose of 500 mcg on sperm characteristics was studied in healthy volunteers aged 18–52 years.By the 52nd week of treatment, the average values ​​of the percentage reduction in the total sperm count, sperm volume, and sperm motility were 23%, 26%, and 18%, respectively, compared to baseline. Sperm concentration and morphological characteristics did not change. A 30% reduction is considered clinically significant, thus the clinical significance of the effect of dutasteride on individual fertility is unknown.

Application for violations of the liver

It is necessary to use the drug with caution in patients with impaired liver functionbecause Dutasteride is extensively metabolized in the liver, and its T_1/2 is 3-5 weeks.

Application for violations of kidney function

At renal dysfunction a dose reduction of the drug is not required (as when taking the drug in a dose of 500 mcg / day, less than 0.1% of the dose is excreted in the urine).

special instructions

Dutasteride is absorbed through the skin, so women and children should avoid contact with damaged capsules. In case of contact with damaged capsules, it is necessary to immediately wash the corresponding skin area with soap and water.

Effect on the detection of prostate-specific antigen and prostate cancer

In patients with benign prostatic hyperplasia, digital rectal examination and other methods of examining the prostate gland should be carried out before starting Avodart and periodically repeated these studies during treatment to rule out the development of prostate cancer.

Determination of serum concentrations of prostate-specific antigen is an important component of a complex of research aimed at detecting prostate cancer. Usually an additional examination is carried out in patients with a prostate-specific antigen concentration of more than 4 ng / ml; in such cases, a prostate biopsy may be indicated. An initial prostate-specific antigen level of less than 4 ng / ml in patients receiving dutasteride does not preclude the diagnosis of prostate cancer.

After treatment with Avodart for 6 months, there is a decrease in the serum level of prostate-specific antigen in patients with benign prostatic hyperplasia by about 50%, even in the presence of prostate cancer. Despite individual differences, a decrease in the level of prostate-specific antigen by about 50% is observed over the entire range of initial concentrations of prostate-specific antigen (from 1.5 to 10 ng / ml). Thus, when interpreting the level of a prostate-specific antigen in a man who receives Avodart for 6 months or more, the measured level must be multiplied by 2 and only then compared with the normal level without dutasteride therapy. This calculation of the content of prostate-specific antigen allows you to save the specificity and reliability of the analysis, as well as the ability to detect prostate cancer.

Any stable increase in prostate-specific antigen levels with dutasteride therapy should be carefully assessed, including the possibility of non-compliance with dutasteride therapy.

The level of total prostate-specific antigen returns to its original level within 6 months after the withdrawal of dutasteride.

The ratio of free prostate-specific antigen to the total remains constant even during therapy with dutasteride. When expressing this ratio in fractions to detect prostate cancer in men who receive dutasteride, correction of this value is not required.

Combination therapy with tamsulosin

In two clinical trials lasting 4 years, the frequency of occurrence of heart failure (collective term, as mainly heart failure or congestive heart failure was reported) in patients treated with dutasteride and alpha adrenoblocker, mainly tamsulosin, was higher than in patients not taking this combination. In both studies, the incidence of heart failure was low (≤ 1%) and variable in various studies. The overall disproportion in the incidence of cardiovascular disorders was not observed in any of the studies. The causal relationship between treatment with dutasteride as monotherapy or in combination with alpha-blocker and the development of heart failure has not been established.

Influence on ability to drive motor transport and control mechanisms

Receiving Avodarta does not affect the ability to drive a car and work with mechanisms.

Overdose

With an overdose (receiving the dose 80 times higher than therapeutic) side effects were noted.

There is no specific antidote for dutasteride, and therefore, if overdose is suspected, symptomatic and supportive treatment is sufficient.

Drug interaction

Since dutasteride is metabolized by a CYP3A4 isoenzyme, in the presence of CYP3A4 inhibitors, concentrations of dutasteride in the blood may increase.

With the simultaneous use of dutasteride with CYP3A4 inhibitors Verapamil and diltiazem, a decrease in the clearance of dutasteride is noted. However, Amlodipine , another Calcium channel blocker, does not reduce the clearance of dutasteride.

With simultaneous use of Avodarta and inhibitors of CYP3A4, a decrease in the clearance of dutasteride and the subsequent increase in its concentration in the blood is not clinically significant due to the wide therapeutic index of this drug, therefore, dose adjustment is not required.

In vitro CYP1A2, CYP2C9, CYP2C19 and CYP2D6 isoenzymes are not involved in the metabolism of dutasteride in humans; Dutasteride does not inhibit cytochrome P450 isoenzymes involved in drug metabolism.

Dutasteride does not displace Warfarin , diazepam, and phenytoin from their association with plasma proteins , and these drugs, in turn, do not displace dutasteride.

When using dutasteride simultaneously with lipid-lowering drugs, ACE inhibitors, beta-blockers, calcium channel blockers, corticosteroids, diuretics, NSAIDs , PDE5 inhibitors and quinolone antibiotics, no significant drug interaction is noted.

No clinically significant interaction of dutasteride with tamsulosin, terazosin, warfarin, Digoxin and colestiramine was detected.

Pharmacy sales terms

The drug is available on prescription.

Terms and conditions of storage

The drug should be stored out of the reach of children at a temperature not higher than 30 ° C.