Avodart capsules 0.5mg, No. 90

• as monotherapy for the treatment and prevention of the progression of benign prostatic hyperplasia by reducing its size, relieving symptoms, improving urination, reducing the risk of acute urinary retention and the need for surgery;

• as a combination therapy with alpha1-blockers for the treatment and prevention of the progression of benign prostatic hyperplasia by reducing its size, relieving symptoms, improving urination, reducing the risk of acute urinary retention and the need for surgery. Basically, the combination of dutasteride and the alpha1-blocker tamsulosin has been studied.

The drug can be taken with or without food. The capsules should be swallowed whole, not chewed or opened, as the contents of the capsule may irritate the mucous membrane of the oropharynx.

Benign Prostatic Hyperplasia (BPH)

In adult men (including the elderly), the recommended dose of AvodartЃ is 1 caps. (500 mcg) 1 time / day.

Although the improvement with the use of the drug occurs rather quickly, the treatment should be continued for at least 6 months in order to objectively assess the therapeutic effect.

For the treatment of BPH, AvodartЃ can be prescribed as monotherapy or in combination with alpha1-blockers.

Special patient groups

When taking 500 mcg / day, less than 0.1% of the dose is excreted through the kidneys, so there is no need to reduce the dose in patients with impaired renal function.

Currently, there is no data on the use of AvodartЃ in patients with impaired liver function. Because dutasteride undergoes intensive metabolism, and its T1 / 2 is 3-5 weeks, care must be taken when treating patients with abnormal liver function with AvodartЃ.

Soft gelatin capsules, yellow, oblong, opaque, marked with the code 'GX CE2'.

1 caps.

dutasteride 500 mcg

Excipients: mono-di-glycerides of caprylic / capric acid (MDA) - 349.5 mg, butylhydroxytoluene - 0.035 mg.

• hypersensitivity to dutasteride and other components of the drug;

• hypersensitivity to other 5?-reductase inhibitors. AvodartЃ is contraindicated in women and children.

  The drug should be prescribed with caution in liver failure.

pharmachologic effect

Mechanism of action

Dutasteride is a dual 5?-reductase inhibitor. Suppresses the activity of 5?-reductase isoenzymes of types 1 and 2, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). Dihydrotestosterone is the main androgen responsible for hyperplasia of the glandular tissue of the prostate gland.

Pharmacodynamic properties

The maximum effect of daily doses of dutasteride on the decrease in DHT concentration is dose-dependent and is observed within 1-2 weeks. After 1 and 2 weeks of taking dutasteride at a dose of 500 ?g / day, the mean serum DHT concentrations decreased by 85% and 90%, respectively.

In patients with benign prostatic hyperplasia (BPH) who received dutasteride at a dose of 500 ?g / day, the average decrease in DHT concentration was 94% after 1 year and 93% after 2 years, the average increase in serum testosterone concentration was 19% as after 1 year, and after 2 years. This is the expected consequence of inhibition of 5?-reductase and does not lead to any of the known adverse events.

Pharmacokinetics

Suction

After taking a single dose of dutasteride (500 mcg), Cmax in serum is reached within 1-3 hours. The absolute bioavailability of dutasteride in men is about 60% relative to a 2-hour intravenous infusion. The bioavailability of dutasteride is independent of food intake.

Distribution

Pharmacokinetic data obtained after a single and repeated oral administration of dutasteride indicate a large Vd (from 300 to 500 liters). Dutasteride has a high degree of binding to blood plasma proteins (more than 99.5%).

With daily intake, the concentration of dutasteride in the blood serum reaches 65% of the equilibrium concentration after 1 month and approximately 90% of the equilibrium concentration after 3 months. The serum Css of dutasteride, approximately 40 ng / ml, is achieved after 6 months of a single daily intake of 500 mcg of dutasteride. In semen, as in blood serum, the Css of dutasteride is also reached after 6 months. After 52 weeks of treatment, dutasteride concentrations in semen averaged 3.4 ng / ml (0.4 to 14 ng / ml). From the blood serum, an average of 11.5% of dutasteride gets into the semen.

Metabolism

In vitro, dutasteride is metabolized by the CYP3A4 isoenzyme of the human cytochrome P450 system to two minor monohydroxylated metabolites; isoenzymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 or CYP2D6 are not involved in the metabolism of dutasteride.

After reaching Css of dutasteride in blood serum, unchanged dutasteride, 3 major metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride) and 2 minor metabolites (6,4'-dihydroxydutasteride and 15 -hydroxydutasteride). 5 dutasteride metabolites found in human serum were detected in rat serum, while the stereochemistry of hydroxyl groups at positions 6 and 15 of metabolites in humans and rats is unknown.

Withdrawal

Dutasteride is extensively metabolized. After oral administration of dutasteride in a daily dose of 500 mcg until an equilibrium concentration in humans is reached from 1% to 15.4% (on average 5.4%) of the dose taken, it is excreted through the intestine unchanged. The rest is excreted through the intestine in the form of 4 major metabolites, accounting for 39%, 21%, 7% and 7%, respectively, and 6 minor metabolites (each of which accounts for less than 5%).

Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are found in human urine. At low serum concentrations (less than 3 ng / ml), dutasteride is rapidly eliminated by both concentration-dependent and concentration-independent routes. With a single dose of dutasteride of 500 mcg or less, rapid clearance was observed with a short T1 / 2 of 3 to 9 days.

At a serum concentration of more than 3 ng / ml, dutasteride is excreted slowly (from 0.35 to 0.58 l / h), mostly linearly, regardless of concentration, with a final T1 / 2 from 3 to 5 weeks. When taking therapeutic doses of dutasteride, the final T1 / 2 is 3-5 weeks, after repeated administration at a dose of 500 ?g / day, a slower clearance dominates, and the total clearance is linear and independent of concentration. Dutasteride is detected in serum (at concentrations above 0.1 ng / ml) within 4-6 months after stopping treatment.

Pharmacokinetics in special patient groups

Elderly patients. The pharmacokinetics and pharmacodynamics of dutasteride were studied in 36 healthy male volunteers aged 24 to 87 years after taking a single dose (500 ?g) of dutasteride. There were no statistically significant differences between different age groups in terms of dutasteride exposure, represented by pharmacokinetic parameters such as AUC and Cmax. Also, there were no statistically significant differences for T1 / 2 values ??of dutasteride between the age groups of men 50-69 years old and over 70 years old, which include the majority of men with BPH. There were no differences in the effect of the drug, determined by the degree of decrease in DHT concentration, between different age groups. The presented results indicate that there is no need to adjust the dose of dutasteride depending on the age of the patients.

Patients with impaired renal function. The effect of renal impairment on the pharmacokinetics of dutasteride has not been studied. However, less than 0.1% of the equilibrium concentration of dutasteride (when taking a dose of 500 mcg of dutasteride) is excreted in humans by the kidneys, so there is no need for dose adjustment in case of impaired renal function.

Patients with impaired liver function. The effect of liver dysfunction on the pharmacokinetics of dutasteride has not been studied.

Application during pregnancy and lactation

Fertility

The effect of dutasteride at a daily dose of 0.5 mg on sperm characteristics was studied in healthy volunteers aged 18-52 years. By week 52 of treatment in the dutasteride group, the mean percent reductions in total sperm count, semen volume, and sperm motor activity were 23%, 26%, and 18%, respectively, compared with baseline in the placebo group. ... Sperm concentration and morphology did not change.

At 24 weeks follow-up, the mean percentage change in total sperm count in the dutasteride group remained 23% lower than baseline. The mean value for all sperm parameters at all time points remained within normal limits and did not meet the specified criteria for a clinically significant change (30%), at 52 weeks of treatment in two volunteers in the dutasteride group, the total sperm count decreased by more than 90%. compared with baseline, with partial recovery at 24 weeks of follow-up.

Thus, the clinical significance of the effect of dutasteride on sperm counts and on individual patient fertility is unknown.

Pregnancy

Dutasteride is contraindicated in women. Dutasteride has not been studied in women because preclinical evidence suggests that suppression of DHT levels can inhibit the development of the external genital organs in a male fetus.

Lactation period

There is no data on the penetration of dutasteride into breast milk.

Application for violations of liver function

The drug should be prescribed with caution in liver failure.

Application for impaired renal function

In case of impaired renal function, a decrease in the dose of the drug is not required.

Application in children

AvodartЃ is contraindicated in children.

special instructions

Prostate cancer (PCa)

The 4-year study involved more than 8000 men aged 50 to 75 years with a negative biopsy for PCa and a PSA concentration between 2.5 ng / ml and 10 ng / ml (REDUCE study) at the initial examination, while 1517 of they were diagnosed with prostate cancer. There were more cases of prostate cancer with a Gleason score of 8-10 in the dutasteride group (n = 29; 0.9%) compared with the placebo group (n = 19; 0.6%). There was no increase in the number of cases of prostate cancer with a score of 5-6 and 7-10 points on the Gleason scale. A causal relationship between dutasteride intake and the development of high grade PCa has not been established. The clinical significance of the quantitative imbalance is unknown. Men taking dutasteride should have regular screening to assess the risk of developing prostate cancer,including determination of PSA concentration.

In an additional 2-year follow-up study of patients from the REDUCE chemoprophylaxis study, new cases of prostate cancer were rarely diagnosed (dutasteride (n = 14, 1.2%) and placebo (n = 7, 0.7%)), new cases of prostate cancer were diagnosed as 8-10 points on the Gleason scale were absent.

Long-term follow-up (up to 18 years) in a study on chemoprophylaxis with another 5?-reductase inhibitor (finasteride) did not reveal a statistically significant difference in the use of finasteride and placebo in terms of overall survival (RR 1.02, 95% CI 0.97-1.08) or survival after confirmation of the diagnosis of prostate cancer (RR 1.01, 95% CI 0.85-1.20).

Prostate specific antigen (PSA)

Determination of the PSA concentration is an important component of screening aimed at detecting prostate cancer. After 6 months of dutasteride therapy, the mean serum PSA concentration decreases by about 50%.

For patients taking dutasteride, a new baseline PSA concentration should be established after 6 months of therapy. Thereafter, regular monitoring of the PSA concentration is recommended. Any confirmed increase in PSA concentration relative to its lowest value during treatment with dutasteride may indicate the development of prostate cancer or non-adherence to the drug therapy regimen and should be carefully evaluated, even if these PSA concentrations remain within the normal range for men not taking 5?-reductase inhibitors. When interpreting PSA concentration values ??in patients taking dutasteride, previous PSA concentration estimates should be used for comparison.

The use of dutasteride does not affect the diagnostic value of determining the PSA concentration as a marker of prostate cancer after a new baseline PSA concentration has been established.

The concentration of total PSA in serum returns to its original value within 6 months after discontinuation of dutasteride.

The ratio of the concentration of free PSA to total remains constant even during dutasteride therapy. If the determination of the percentage of free PSA fraction is additionally used to detect prostate cancer in men receiving dutasteride, this indicator does not need to be corrected.

In patients, it is necessary to carry out a digital rectal examination and use other methods for diagnosing prostate cancer before starting treatment with dutasteride, and also regularly repeat the examination of the patient during treatment.

Side effects from the cardiovascular system

In two 4-year clinical studies, the incidence of heart failure (a generalized term for the observed events, represented mainly by heart failure and congestive heart failure) was higher in patients receiving a combination of dutasteride and a ? 1-blocker, mainly tamsulosin, than in patients, not receiving combination treatment. In these two clinical studies, the incidence of heart failure remained low (<1%) and varied between studies. In general, there were no differences between the rates of cardiovascular side effects in both studies. A causal relationship between taking dutasteride (as monotherapy or in combination with a? 1-blocker) and heart failure has not been established.

In a meta-analysis of 12 randomized, placebo-controlled or comparative clinical trials (n = 18 802), the purpose of which was to assess the risk of cardiovascular side effects with the use of dutasteride (compared with the control group), there was no corresponding statistically significant increased risk of heart failure (RR 1.05, 95% CI 0.71, 1.57), acute myocardial infarction (RR 1.00, 95% CI 0.77, 1.30) or stroke (RR 1.20, 95% CI 0.88, 1.64).

Breast cancer

During clinical trials and in the post-registration period, there have been rare reports of the development of breast cancer in men taking dutasteride. However, data from epidemiological studies do not indicate an increased risk of developing breast cancer in men with the use of 5?-reductase inhibitors. Specialists should instruct patients to immediately report any changes in the breast, such as a lump in the gland or discharge from the nipple.

Leakage of capsule contents

Dutasteride is absorbed through the skin, therefore women and children should avoid contact with capsules that have leaked. In case of contact with such capsules, the affected area should be washed immediately with soap and water.

Liver dysfunction

The effect of liver dysfunction on the pharmacokinetics of dutasteride has not been studied. Since dutasteride is extensively metabolized and its T1 / 2 is 3 to 5 weeks, dutasteride should be used with caution in patients with impaired liver function.

Influence on the ability to drive vehicles and use mechanisms

Taking dutasteride does not affect driving a car or working with machinery.

Overdose

When dutasteride was prescribed up to 40 mg / day once (80 times higher than the therapeutic dose) for 7 days, no significant side effects were observed. In clinical studies, patients received dutasteride at a dose of 5 mg daily for 6 months, while no additional side effects to those observed while taking dutasteride at a dose of 500 mcg were not found.

Treatment: there is no specific antidote for dutasteride, therefore, if an overdose is suspected, it is sufficient to carry out symptomatic and supportive treatment.

Drug interactions

In vitro, dutasteride is metabolized by the CYP3A4 isoenzyme of the human cytochrome P450 enzyme system. Therefore, in the presence of CYP3A4 inhibitors, the concentration of dutasteride in the blood may increase.

With the simultaneous use of dutasteride with the CYP3A4 inhibitors verapamil and diltiazem, there is a decrease in the clearance of dutasteride. At the same time, amlodipine and other calcium channel blockers, when used simultaneously with dutasteride, do not reduce the clearance of dutasteride. A decrease in the clearance of dutasteride and a subsequent increase in its concentration in the blood in the presence of CYP3A4 inhibitors is not clinically significant due to the wide range of dutasteride safety boundaries, so there is no need to adjust its dose.

In vitro, dutasteride is not metabolized by the following isoenzymes of the human cytochrome P450 system: CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 or CYP2D6.

Dutasteride does not inhibit in vitro human cytochrome P450 enzymes involved in drug metabolism.

In vitro, dutasteride does not displace warfarin, acenocoumarol, phenprocoumon, diazepam and phenytoin from their plasma protein binding sites, and these drugs, in turn, do not displace dutasteride.

When conducting studies of the interaction of dutasteride with tamsulosin, terazosin, warfarin, digoxin and cholestyramine in humans, no clinically significant pharmacokinetic or pharmacodynamic interactions were observed.

When using dutasteride simultaneously with lipid-lowering drugs, ACE inhibitors, beta-blockers, calcium channel blockers, corticosteroids, diuretics, NSAIDs, phosphodiesterase type 5 inhibitors and quinolone antibiotics, no significant undesirable drug interactions were observed.