Dutasteride

Pharmacological properties

dutasteride, a double 5α-reductase inhibitor, inhibits both type 1 and type 2 isoenzymes of 5α-reductase, which are responsible for the conversion of testosterone to 5α-dihydrotestosterone. dihydrotestosterone is an androgen that is primarily responsible for prostatic tissue hyperplasia. the maximum decrease in the level of dihydrotestosterone while taking avodart depends on the dose and is observed in the first 1-2 weeks. after the 1st and 2nd week of using Avodart in a daily dose of 0.5 mg, the average concentration of dihydrotestosterone decreases by 85 and 90%, respectively.

In patients with benign prostatic hyperplasia who received 0.5 mg of dutasteride per day, the average decrease in the level of dihydrotestosterone was 94% after 1 year and 93% after 2 years of treatment, the average level of testosterone increased by 19% after 1 and 2 years.

Pharmacokinetics Dutasteride is administered orally in the form of a solution in soft gelatin capsules. After a single dose of 0.5 mg C_max the drug in blood plasma is reached after 1-3 hours. Absolute bioavailability is 60% if applied by 2-hour iv infusion. Bioavailability is independent of food intake.

Dutasteride after a single or multiple doses has a large volume of distribution (300-500 l). The percentage of protein binding is more than 99.5%.

When used in a daily dose of 0.5 mg, 65% of a constant stable concentration of dutasteride in blood plasma is achieved after 1 month of treatment and about 90% after 3 months. A stable constant concentration of dutasteride of about 40 ng / ml in blood plasma is achieved after 6 months of treatment in a daily dose of 0.5 mg. As in blood plasma, a stable concentration of dutasteride in seminal fluid is reached after 6 months. After 52 weeks of treatment, the average concentration of dutasteride in seminal fluid is 3.4 ng / ml (in the range of 0.4-14 ng / ml). The percentage of distribution of dutasteride from blood plasma to seminal fluid is about 11.5%.

In vitro, dutasteride is metabolized by human cytochrome P450 CYP 3A4 enzymes to two monohydroxyl metabolites.

According to spectrometric analysis in human blood plasma, unchanged dutasteride, 3 major metabolites (4′-hydroxidutasteride, 1,2-dihydrodutasteride and 6-hydroxidutasteride) and 2 small metabolites (6,4′-dihydroxidutasteride and 15-hydroxidutasteride) are detected.

Dutasteride is extensively metabolized. After oral administration of dutasteride at a dose of 0.5 mg / day, 1-15.4% (on average 5.4%) of the dose taken is excreted in the feces in the form of unchanged dutasteride. The remainder of the applied dose is excreted as metabolites.

In the urine, only traces of unchanged dutasteride are detected (0.1% of the dose taken). Final t_½ dutasteride is 3-5 weeks. Plasma dutasteride residues can be detected 4-6 months after the end of treatment.

According to the study of pharmacokinetics and pharmacodynamics, it is not necessary to change the dose of dutasteride in accordance with the age of the patient.

The effect of renal failure on the pharmacokinetics of dutasteride has not been studied. However, when taking 0.5 mg of dutasteride with urine in a person, less than 0.1% of the dose is excreted, so changing the dose for patients with renal failure is not required.

The effect of hepatic insufficiency on the pharmacokinetics of dutasteride has not been studied (see APPLICATION and SPECIAL INSTRUCTIONS).

Safety and clinical research

Heart failure. In a 4-year clinical study of the use of dutasteride in combination with tamsulosin for the treatment of benign prostatic hyperplasia in 4844 men (CombAT study), the incidence of heart failure (collective concept) in the combination therapy group (14/1610; 0.9%) was higher. than in any monotherapy group with dutasteride (4/1623; 0.2%) or tamsulosin (10/1611; 0.6%).

In a separate 4-year clinical comparative study of placebo with dutasteride chemoprophylaxis involving 8231 people aged 50 to 75 years with a preliminary negative biopsy result for prostate cancer and an initial prostate-specific antigen (PSA) of 2.5-10.0 ng / ml in men 50-60 years old or 3.0-10.0 ng / ml in men over 60 years old (REDUCE studies), it was found that the incidence of heart failure in patients taking 0.5 mg dutasteride once a day (30 / 4105; 0.7%), higher than p patients receiving placebo (16/4126; 0.4%).A retrospective analysis of this study showed a higher heart failure rate in patients taking dutasteride and an α-adrenergic blocker at the same time (12/1152; 1.0%), compared with subjects who received dutasteride without an α-adrenergic blocking agent (18/2953; 0.6%), a placebo and an α-adrenergic receptor blocker (1/1399; 0.1%) or a placebo without an α-adrenergic receptor blocker (15/2727; 0.6%). A causal relationship between the use of dutasteride (alone or in combination with α-adrenergic blockers) and the occurrence of heart failure has not been established (see SPECIAL INSTRUCTIONS).

Prostate cancer and low-grade tumors. In a 4-year comparative study of placebo and dutasteride in 8,231 people aged 50 to 75 years with a preliminary negative biopsy of prostate cancer and baseline PSA levels of 2.5-10.0 ng / ml in men aged 50-60 years or 3.0-10.0 ng / ml in men over the age of 60 (REDUCE studies) 6706 subjects underwent needle biopsy of the prostate (mandatory according to the primary protocol), the data of which were used to analyze differentiation on the Gleason scale. The study identified 1,517 patients diagnosed with prostate cancer. Most prostate tumors (70%) detected by biopsy in both treatment groups had a high level of differentiation (5-6 points on the Gleason score).

In the dutasteride group, a higher frequency (n = 29; 0.9%) of low-grade prostate cancer (8-10 points on the Gleason score) was recorded compared with the placebo group (n = 19; 0.6%) (p = 0, fifteen). In the 1st – 2nd years of the study, the number of patients with prostate cancer with differentiation of 8–10 points on the Gleason score was the same in the dutasteride group (n = 17; 0.5%) and in the placebo group (n = 18; 0.5 %). In the 3-4 years of the study, a greater number of cases of prostate cancer with differentiation of 8-10 points on the Gleason score were diagnosed in the dutasteride group (n = 12; 0.5%) compared with the placebo group (n = 1; 0.1 %) (p = 0.0035). There is no data on the effect on prostate cancer risk in men taking dutasteride for more than 4 years. The percentage of patients diagnosed with prostate cancer with a differentiation of 8-10 points on the Gleason score remained constant at different periods of the study (1-2 years, 3-4 years) in the dutasteride group (0.5% in each period), while in the placebo group, the percentage of patients with low-grade prostate cancer (8-10 points on the Gleason score) was lower in 3-4 years than in 1-2 years (0.1 and 0.5% respectively) (see SPECIAL INSTRUCTIONS). There was no difference in the incidence of prostate cancer with a differentiation of 7–10 on the Gleason score (p = 0.81).

In a 4-year clinical study of the treatment of benign prostatic hyperplasia (CombAT), where the primary protocol did not require a biopsy, and all diagnoses of prostate cancer were established on the basis of a biopsy according to indications, the frequency of prostate cancer with differentiation of 8-10 points on the Gleason score amounted to 0.5% (n = 8) in the dutasteride group, 0.7% (n = 11) in the tamsulosin group and 0.3% (n = 5) in the combination therapy group.

The relationship between the use of dutasteride and the occurrence of low-grade prostate cancer remains unclear.

Breast cancer in men. Two controlled epidemiological studies: one in the United States (339 cases of breast cancer and 6,780 participants in the control group) and the other in the UK (398 cases of breast cancer and 3,930 participants in the control group) showed no increased risk of cancer breast cancer in men with 5α-reductase inhibitors. The results of the first study did not reveal a relationship with breast cancer (relative risk (HR) when applied for ≥1 years before a diagnosis of breast cancer compared with 1 year: 0.70: 95% confidence interval (CI) 0.34–1 , 45). In a second study, the relative risk of developing breast cancer associated with the use of 5α-reductase inhibitors compared with the lack of use was 1.08: 95% CI 0.62–1.87).

A causal relationship between cases of breast cancer in men and prolonged use of dutasteride has not been established.

Indications

Treatment of symptoms of moderate to severe benign prostatic hyperplasia; reducing the risk of acute urinary retention and, if necessary, surgical intervention in patients with symptoms of moderate to severe benign prostatic hyperplasia.

Application

Avodart can be prescribed alone or in combination with an α-adrenergic blocker tamsulosin (0.4 mg).

Adult men (including elderly patients). The recommended dose of Avodart is 1 capsule (0.5 mg) per day for oral administration. The capsule should be swallowed whole without opening or chewing, since contact with the contents of the capsule may irritate the mucous membrane of the mouth and pharynx.

Avodart can be taken without regard to meals.

Despite the fact that relief from taking the drug is noted at an early stage, for an objective assessment of the effectiveness of the drug, treatment should be continued for at least 6 months.

Renal failure. The pharmacokinetics of dutasteride in patients with renal failure has not been studied, therefore, it should be used with caution in patients with severe renal failure.

Liver failure. The pharmacokinetics of dutasteride in patients with liver failure has not been studied, therefore, caution should be used in patients with mild to moderate liver failure. In patients with severe hepatic insufficiency, dutasteride is contraindicated.

Children. The use is contraindicated.

Contraindications

Hypersensitivity to dutasteride, other 5α-reductase inhibitors, soy, peanuts or other components of the drug.

The drug is not used to treat women and children (see. Use during pregnancy and lactation). Dutasteride is contraindicated in patients with severe hepatic impairment.

Side effects

Monotherapy with Avodart. according to 3 placebo-controlled clinical trials of phase III with dutasteride compared with placebo, the following adverse reactions were noted, which, according to the researchers, were associated with the use of the drug (with a frequency of occurrence of ≥1%).

* Adverse reactions associated with impaired sexual function associated with treatment with dutasteride (including monotherapy and combination with tamsulosin). These adverse reactions may continue after treatment is discontinued. The effect of dutasteride on their duration is unknown.

** Including breast tenderness and its hypertrophy.

According to the following 2-year open clinical trials, the profile of side effects of the drug has not changed.

Combination therapy (Avodart + tamsulosin). According to a clinical trial CombAT (combination of Avodart with tamsulosin) compared with the combination of Avodart 0.5 mg and tamsulosin 0.4 mg once a day and monotherapy for 4 years, adverse reactions were identified that, according to the researchers, were associated with the use of the drug (with a cumulative occurrence rate of ≥1%).

^aThe combination is dutasteride 0.5 mg 1 time per day plus tamsulosin 0.4 mg 1 time per day.

^bAdverse reactions associated with impaired sexual function are associated with treatment with dutasteride (including monotherapy and a combination with tamsulosin). These adverse reactions may continue after treatment is discontinued. The effect of dutasteride on their duration is unknown.

^cIncluding breast tenderness and its hypertrophy.

^dThe term "heart failure" includes congestive heart failure, left ventricular failure, acute left ventricular failure, cardiogenic shock, acute heart failure, right ventricular failure, acute right ventricular failure, congestive cardiomyopathy, cardiopulmonary failure, ventricular.

Post-Marketing Research Data

Immune system: very rarely - allergic reactions, including rash, itching, urticaria, localized edema and angioedema.

Mental disorders: very rarely - depressed mood.

Skin and subcutaneous tissue: rarely - alopecia (mainly hair loss on the body), hypertrichosis.

Reproductive system and disorders of the breast: very rarely - testicular pain and swelling.

Cases of breast cancer in men have been reported in clinical and post-marketing studies (see SPECIAL INSTRUCTIONS).

special instructions

Dutasteride can be absorbed through the skin, so women and children should avoid contact with leaking capsules (see Application