On the safety of using Avodart (dutasteride) in patients with benign prostatic hyperplasia (BPH)

Pharmacological properties of the drug Avodart

Pharmacodynamics . Dutasteride is a 5-α-reductase inhibitor that inhibits both type 1 and type 2 5-α-reductase isoenzymes, which are responsible for the conversion of testosterone to 5-α-dihydrotestosterone. Dihydrotestosterone is an androgen primarily responsible for hyperplasia of prostate tissue. The maximum decrease in dihydrotestosterone while taking Avodart depends on the dose and is observed in the first 1–2 weeks. After the 1st and 2nd weeks of treatment with Avodart at a daily dose of 0.5 mg, the average concentration of dihydrotestosterone decreases by 85 and 90%, respectively. In patients with benign prostatic hyperplasia receiving 0.5 mg dutasteride per day, the average decrease in dihydrotestosterone levels was 94% after 1 year and 93% after 2 years of treatment, the average testosterone level increased by 19% after 1 and 2 years. This is an expected consequence of 5-α-reductase inhibition and does not result in the various known side effects. According to multicenter, placebo-controlled, double-blind clinical studies involving 4,325 men with prostatic hyperplasia (30 cm3), the use of Avodart at a dose of 0.5 mg/day led to the prevention of disease progression both by reducing the risk of acute urinary retention and the need for surgical intervention, and a statistically significant improvement in the condition of the lower urinary tract, an increase in urination rate and a decrease in prostate volume compared to placebo. All of the above changes were noted over a period of 24 months. Pharmacokinetics . Dutasteride is used orally in the form of a solution in soft gelatin capsules. After taking a single dose of 0.5 mg, the maximum concentration of the drug in the blood plasma is observed after 1–3 hours. Absolute bioavailability is 60% and does not depend on food intake. Dutasteride after a single or multiple dose has a large volume of distribution (300–500 l). Binding to blood plasma proteins is 99.5%. When used in a daily dose of 60%, a constant equilibrium concentration of dutasteride in the blood plasma is achieved after 1 month of treatment and about 90% after 3 months. A constant equilibrium concentration of dutasteride of approximately 40 ng/ml in blood plasma is achieved after 6 months of administration at a daily dose of 0.5 mg. Similarly with blood plasma, a constant equilibrium concentration of dutasteride in seminal fluid is achieved after 6 months. After 52 weeks of treatment, the average concentration of dutasteride in seminal fluid is 3.4 ng/ml (range 0.4–14 ng/ml). The distribution ratio of dutasteride from blood plasma to seminal fluid is about 11.5%. In vitro, dutasteride is metabolized by human cytochrome P450 CYP3A4 enzymes to two monohydroxyl metabolites. In blood plasma, according to spectrometric analysis, unchanged dutasteride, 3 major metabolites (4-hydroxydutasteride, 1,2-dihydrodutasteride and 6-hydroxydutasteride) and 2 minor metabolites (6,4-dihydroxydutasteride and 15-hydroxydutasteride) 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%) is excreted in the feces in the form of unchanged dutasteride, the rest in the form of metabolites. Traces of unchanged dutasteride (≤0.1%) are determined in urine. The final half-life of dutasteride is 3–6 weeks. Traces of dutasteride in blood plasma can be detected 4–6 months after the end of treatment.

Avodart

Use during pregnancy and breastfeeding

Effect 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 week 52 of treatment, the mean percentage reductions in total sperm count, semen volume, and sperm motility were 23%, 26%, and 18%, respectively, from baseline. The concentration of sperm and their morphological characteristics did not change.

At 24 weeks of 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 the normal range and did not meet the specified criteria for a clinically significant change (30%), at week 52 of treatment, two volunteers in the dutasteride group had a more than 90% reduction in total sperm count compared with baseline, with partial recovery at 24 weeks of observation.

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

Pregnancy

Dutasteride is contraindicated in women. Dutasteride has not been studied in women because Preclinical data suggest that suppression of DHT levels may inhibit the development of the external genitalia in the fetus.

Lactation

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

Use for liver dysfunction

The drug should be used with caution in patients with impaired liver function, because dutasteride undergoes intensive metabolism in the liver, and its T1/2 is 3-5 weeks.

The drug should be prescribed with caution in case of liver failure.

Use for renal impairment

In case of impaired renal function, a reduction in the dose of the drug is not required (since when taking the drug at a dose of 500 mcg/day, less than 0.1% of the dose is excreted in the urine).

Use in children

Avodart® is contraindicated in children.

Use in elderly patients

No dose adjustment is required.

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, immediately wash the affected area of ​​skin with soap and water.

Liver dysfunction

There are currently no data on the use of Avodart® in patients with impaired liver function. Since dutasteride is extensively metabolized and its half-life is 3-5 weeks, caution must be exercised when treating patients with impaired liver function with Avodart®.

Heart failure with combined use of dutasteride and tamsulosin

In two 4-year clinical studies, the incidence of heart failure was higher in patients receiving the combination of dutasteride and an alpha1-blocker, primarily tamsulosin, than in patients not receiving the combination treatment. In these two studies, the incidence of heart failure remained low (≤ 1%) with some variability between them. But in general, there were no differences in the incidence of side effects from the cardiovascular system. A cause-and-effect relationship between treatment with dutasteride (as monotherapy or in combination with an alpha1-blocker) and the development of heart failure has not been established.

Impact on the detection of prostate-specific antigen (PSA) and prostate cancer (PCa)

Patients should undergo a digital rectal examination, as well as other methods of examining the prostate gland, before starting treatment with dutasteride and periodically repeat them during treatment to exclude the development of prostate cancer.

Determination of serum PSA concentration is an important component of screening for PCa. After 6 months of dutasteride therapy, the mean serum PSA level decreases by approximately 50%. Patients taking dutasteride should have a new baseline PSA level determined after 6 months of therapy. In the future, it is recommended to regularly monitor PSA levels.

The use of dutasteride does not affect the diagnostic value of PSA level as a marker of prostate cancer. Any confirmed increase in PSA levels relative to the nadir during dutasteride treatment may indicate the development of prostate cancer (particularly high-grade Gleason prostate cancer) or non-adherence to dutasteride therapy and should be carefully assessed, even if these PSA levels remain unchanged. within normal values ​​for this age category of patients not taking 5α-reductase inhibitors.

Total PSA levels return to baseline within 6 months after discontinuation of dutasteride.

The ratio 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, no correction of this value is required.

The effect of long-term use of dutasteride on the development of breast cancer in men

There was no effect of long-term use of dutasteride on the development of breast cancer in men.

PCa and high-grade tumors

The 4-year study (REDUCE) compared placebo and dutasteride in 8231 volunteers aged 50 to 75 years with a negative biopsy for prostate cancer and a PSA level of 2.5 ng/ml to 10 ng/ml at initial examination. .

During the study, 6,706 patients underwent a puncture biopsy of the prostate gland and, based on the results obtained, the degree of malignancy of prostate cancer was determined according to the Gleason score. 1517 patients were diagnosed with prostate cancer during the study. In the majority of cases, both in the dutasteride group and in the placebo group, well-differentiated prostate cancer was diagnosed (Gleason score 5-6). There was no difference in the number of cases of PCa with a Gleason score of 7-10 in the dutasteride group and the placebo group (p = 0.81).

After 4 years, there were more cases of PCa with a Gleason score of 8-10 in the dutasteride group (n = 29; 0.9%) compared with the placebo group (n = 19; 0.6%) (p = 0.15). When assessing biopsy data over 1-2 years, the number of patients diagnosed with PCa with a Gleason score of 8-10 was comparable in the dutasteride (n = 17; 0.5%) and placebo (n = 18; 0.5%) groups. When assessing biopsy data at 3-4 years, more cases of PCa with a Gleason score of 8-10 were diagnosed in the dutasteride group (n = 12; 0.5%) compared with the placebo group (n = 1; < 0.1%) (p = 0.0035). The percentage of patients diagnosed with PCa with a Gleason score of 8-10 was stable over all time periods (1-2 and 3-4 years) in the dutasteride group (0.5% in each period), while in In the placebo group, the percentage of patients diagnosed with PCa with a score of 8-10 was lower in years 3-4 than in years 1-2 (<0.1% compared with 0.5%, respectively).

In a 4-year study (CombAT) of patients with BPH, in which prostate biopsy was not mandated for all participants and all PCa diagnoses were based on indicated biopsy, PCa with a Gleason score of 8–10 was diagnosed in 8 patients (<0.5%) when taking dutasteride, 11 patients (<0.7%) when taking tamsulosin and 5 patients (<0.3%) when taking combination therapy with dutasteride and tamsulosin.

A cause-and-effect relationship between taking dutasteride and the development of high-grade prostate cancer has not been established.

Men taking dutasteride should undergo regular screening to assess their risk of developing prostate cancer, including PSA levels.

Impact on the ability to drive vehicles and operate machinery

Taking dutasteride does not affect driving or operating machinery.

Indications for use of the drug Avodart

Treatment and prevention of progression of benign prostatic hyperplasia by reducing the size of the prostate gland, reducing the severity of symptoms of the disease, improving urine flow, reducing the risk of acute urinary retention and, if necessary, surgical intervention. In combination with tamsulosin, it treats and prevents the progression of benign prostatic hyperplasia by reducing the size of the prostate gland, reducing the severity of symptoms of the disease and improving urine flow.

Use of the drug Avodart

Avodart can be prescribed as monotherapy or in combination with the α-receptor blocker tamsulosin (0.4 mg). Adult men (including elderly patients) The recommended dose of Avodart is 1 capsule (0.5 mg) per day orally. The capsule is swallowed whole, do not open or chew, since contact with the contents of the capsule may irritate the mucous membrane of the oral cavity and pharynx. Avodart can be taken with or without food. Despite the fact that a decrease in the severity of symptoms of the disease may be noted a short time after taking the drug, to objectively assess the effectiveness of the drug, treatment should be continued for at least 6 months. Renal failure For patients with renal failure, no dose adjustment is necessary. Hepatic impairment The pharmacokinetics of dutasteride have not been studied in patients with hepatic impairment.

Instructions for use AVODART™ (AVODART)

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

Avodart™ in monotherapy mode

Effect on dihydrotestosterone (DHT)/testosterone concentrations

The effect of daily intake of Avodart™ on reducing DHT levels is dose-dependent and is observed after 1-2 weeks (reduction by 85% and 90%, respectively).

In patients with benign prostatic hyperplasia (BPH) receiving dutasteride 0.5 mg/day, the median decrease in serum DHT concentration was 94% after 1 year of therapy and 93% after 2 years of therapy, and the median increase in serum testosterone concentration was 19 % after 1 and 2 years of therapy.

Effect on prostate volume

A significant decrease in prostate volume was detected within 1 month after the start of treatment and continued until the 24th month (p <0.001). At the 12th month of treatment, the use of Avodart™ led to an average reduction in prostate volume by 23.6% (from 54.9 ml at baseline to 42.1 ml); in the placebo group, the average reduction in volume was 0.5% (from 54.0 ml to 53.7 ml). A significant (p <0.001) decrease also occurred in the transition zone of the prostate gland after one month of therapy, and it continued through the 24th month; After 12 months, the average reduction in the volume of the transition zone of the prostate in the Avodart™ treatment group was 17.8% (from 26.8 ml at baseline to 21.4 ml), while in the placebo group there was an average increase in volume of 7.9% (from 26.8 ml to 27.5 ml). The reduction in prostate volume observed during the first 2 years of double-blind therapy was maintained for an additional 2 years of therapy in the open-label extension studies. Reducing the size of the prostate gland leads to relief of symptoms and a reduced risk of acute urinary retention (AUR) and surgery for BPH.

Clinical researches

Avodart™ at a dose of 0.5 mg/day was studied in comparison with placebo in 4325 male subjects with BPH with moderate to severe symptoms, prostate volume ≥30 ml and PSA concentration in the range of 1.5-10 ng/ ml in three two-year, multicenter, international, placebo-controlled, double-blind, primary efficacy studies. These clinical studies were extended to 4 years with an additional open-label treatment period, with all patients remaining in the study continuing to receive the same 0.5 mg dose. After 4 years, of the initially randomized patients, 37% and 40% of subjects remained in the placebo group and in the dutasteride group, respectively. The majority (71%) of the 2340 subjects in the open-label extension periods received treatment for 2 additional years.

The most important parameters of clinical effectiveness were:

• American Urological Association Symptom Index (AUA-SI), maximum urinary flow rate (Qmax), incidence of acute urinary retention and surgery for BPH.

The maximum AUA-SI score, determined using the seven-item BPH Symptom Questionnaire, is 35 points. The initial average index value was approximately 17 points. After six months, one year and two years of therapy, the improvement in the index in the placebo group was 2.5, 2.5 and 2.3 points, respectively, and in the Avodart™ group – 3.2, 3.8 and 4.5 points, respectively. The differences between the two treatment groups were statistically significant. The improvement in AUA-SI observed during the first two years of double-blind therapy was maintained for an additional two years in the open-label extension study.

Qmax (maximum voiding rate)

The mean Qmax in clinical studies at baseline was approximately 10 mL/sec (normal Qmax ≥15 mL/sec). After one year and two years of therapy, urinary flow rate increased in the placebo group by 0.8 and 0.9 ml/sec, respectively, and in the Avodart™ drug group by 1.7 and 2.0 ml/sec, respectively. The differences between the two treatment groups in the period from 1st to 24th month were statistically significant. The increase in peak urinary flow rate observed during the first 2 years of double-blind therapy was maintained for an additional 2 years in open-label extension studies.

Acute urinary retention and surgery

After two years of therapy, the incidence of AUR in the placebo group was 4.2%, and in the Avodart™ group it was 1.8% (57% risk reduction). This difference is statistically significant; it means that treatment of 42 (95% CI 30-73) patients with Avodart™ for two years prevented 1 case of AUR.

After 2 years of therapy, the incidence of surgery for BPH was 4.1% in the placebo group and 2.2% in the Avodart™ group (48% risk reduction). This difference is statistically significant, meaning that treatment of 51 patients (95% CI 33-109) with Avodart™ for two years avoided one surgical procedure.

Hair distribution

The effect of dutasteride on hair distribution has not been formally studied in the Phase III clinical trial program; However, the use of 5α-reductase inhibitors may reduce hair loss and promote hair growth in patients with male pattern baldness (male androgenetic alopecia).

Thyroid function

The effect on thyroid function was studied in a one-year clinical study in healthy men. After one year of dutasteride therapy, the level of unbound thyroxine did not change, while at the same time, compared with placebo, the level of thyroid-stimulating hormone (TSH) increased slightly (by 0.4 µIU/ml). However, since the TSH levels varied, the range of median TSH levels (1.4-1.9 µIU/ml) was within the normal range (0.5-4.0 µIU/ml), and the thyroxine concentrations were stable within normal limits and similar when used placebo and dutasteride, these changes in TSH levels were regarded as not clinically significant. The results of all clinical studies indicate the absence of a negative effect of dutasteride on thyroid function.

Breast neoplasms

In a 2-year clinical trial in which 3374 patients received dutasteride, breast cancer was reported in 2 patients in the dutasteride group and 1 patient in the placebo group at the time of entry into the 2-year open-label extension study. In the CombAT and REDUCE clinical trials, which were conducted over 4 years, there were no breast cancer cases in either treatment group, with dutasteride exposure of 17,489 patient-years and tamsulosin plus dutasteride exposure of 5,027 patient-years. As of now, it has not been established whether there is a cause-and-effect relationship between long-term use of dutasteride and the development of breast cancer in men.

Effect on male fertility

The effect of dutasteride at a dose of 0.5 mg/day on sperm properties was studied in a study involving healthy volunteers aged 18 to 52 years (n=27 in the dutasteride group; n=23 in the placebo group), during 52 weeks of therapy and 24 weeks of follow-up observations. After 52 weeks of treatment, the mean percentage reductions in total sperm count, semen volume, and sperm motility adjusted for change from baseline in the placebo group were 23%, 26%, and 18%, respectively. No changes in sperm concentration or morphology were noted. At 24 weeks of follow-up, the mean percentage change in total sperm count in the dutasteride group remained 23% below baseline. While the mean values ​​of all parameters at all time points remained within the normal range and did not meet the predefined criteria for a clinically significant change (30%), two patients in the dutasteride group had a decrease in sperm count of more than 90% from baseline after 52 weeks of therapy , with partial recovery noted at 24 weeks of follow-up. The possibility of decreased male fertility cannot be ruled out.

Avodart™ in combination with the alpha-blocker tamsulosin

A multicenter, international, randomized, double-blind, parallel-group clinical trial (CombAT study) enrolled patients with moderate to severe BPH symptoms, prostate volume ≥30 mL, and PSA concentrations between 1.5 and 10 ng/mL. use of the following drugs:

• Avodart™ 0.5 mg/day (n=1623), tamsulosin 0.4 mg/day (n=1611) and the combination of Avodart™ 0.5 mg plus tamsulosin 0.4 mg (n=1610). Approximately 53% of patients had previously received therapy with 5α-reductase inhibitors or α-adrenergic blockers. The primary endpoint during the first 2 years of therapy was change in International Prostatic Symptom Scale (IPSS) score (an 8-item scale based on the AUA-SI with an additional question on quality of life). Secondary endpoints assessed after 2 years of treatment included maximum urinary flow rate (Qmax) and prostate volume. Compared with the Avodart™ group and the tamsulosin group, the IPSS results obtained in the combination therapy group were significant starting at the Month 3 and Month 9 time points, respectively. Results for Qmax in the combination therapy group were significant from the Month 6 time point compared with the Avodart™ and tamsulosin groups.

The primary endpoint after 4 years of therapy was the time to the first episode of AUR or surgery for BPH. After 4 years of therapy, the reduction in the risk of AUR or surgery due to BPH in the combination therapy group was statistically significant (65.8% risk reduction with p value <0.001 [95% CI 54.7-74.1%]) compared with the result in the tamsulosin monotherapy group . The incidence rates of AUR and surgery for BPH over 4 years in the combination therapy group and in the tamsulosin group were 4.2% and 11.9%, respectively (p < 0.001). Compared with the Avodart monotherapy group, the combination therapy group reduced the risk of AUR and surgery due to BPH by 19.6% (p=0.18 [95% CI 10.9-41.7%]). The incidence rates of AUR and surgery for BPH over 4 years in the combination therapy group and in the Avodart™ drug group were 4.2% and 5.2%, respectively.

Secondary endpoints assessed after 4 years of therapy included time to clinical progression (a composite indicator that included the following components:

• deterioration confirmed by a change in IPSS score ≥4 points, cases of AUR associated with BPH, urinary incontinence, urinary tract infection (UTI) and renal failure);
• change in the score on the International Prostatic Symptom Score (IPSS), change in maximum urinary flow rate and prostate volume. The results of the study after 4 years of therapy are presented below.

The values ​​of the indicators at the initial level are averages, the values ​​of changes from the initial level are adjusted averages.

* Clinical progression is a composite measure that includes the following components: deterioration confirmed by a change in IPSS score of ≥4 points, cases of AUR associated with BPH, urinary incontinence, UTI, and renal failure.

# The assessment was conducted at individual study sites (13% of randomized patients).

a Results were significant in the combination therapy group (p < 0.001) compared with the tamsulosin group at 48 months.

b Results were significant in the combination therapy group (p < 0.001) compared with the Avodart™ group at 48 months.

Heart failure

In a 4-year study of BPH using Avodart™ in combination with tamsulosin in 4844 patients (CombAT study), the incidence of cases described by the combined term "heart failure" in the combination therapy group (14/1610, 0.9%) was higher than in the combination therapy group (14/1610, 0.9%). both monotherapy groups:

• Avodart™ – 4/1623, 0.2%, tamsulosin – 10/1611, 0.6%.

In a separate clinical trial (the REDUCE study) involving 8231 patients aged 50 to 75 years with a previously negative biopsy for prostate cancer and a baseline PSA concentration of 2.5-10.0 ng/ml (in men aged 50 to 60 years old) and 3-10 ng/ml (in men over 60 years old) the frequency of cases described by the combined term “heart failure” in the group of Avodart™ 0.5 mg 1 time / day (30/4105, 0.7% ) was higher than in the placebo group (16/4126, 0.4%). A retrospective analysis of the results of this study indicated that the incidence of cases described by the combined term “heart failure” in patients receiving Avodart™ and an α-adrenergic blocker simultaneously (12/1152, 1.0%) was higher than in patients receiving Avodart™ monotherapy (18/2953, 0.6%), placebo and α-adrenergic blocker (1/1399, <0.1%) or placebo alone (15/2727, 0.6%) (see section "Special Instructions").

Prostate cancer and high-grade prostate cancer

In a clinical trial of Avodart™ compared with placebo (the REDUCE study) involving 8231 patients aged 50 to 75 years with a previously negative biopsy for prostate cancer and with a PSA concentration at baseline in the range of 2.5-10.0 ng/ml (in men aged 50 to 60 years) and 3-10 ng/ml (in men aged over 60 years), core biopsy results (initially required by protocol) to determine the Gleason score were available for 6706 patients. Prostate cancer was diagnosed in 1517 patients in this study. The majority of biopsy-detected prostate cancers in both treatment groups were low-grade tumors (Gleason score 5-6, 70%).

The incidence of prostate cancer with a Gleason score of 8-10 in the Avodart™ group (n=29, 0.9%) was higher than in the placebo group (n=19, 0.6%) (p=0.15). During the first two years of therapy, the incidence of cancer with a Gleason score of 8-10 in the Avodart™ group (n=17, 0.5%) and in the placebo group (n=17, 0.5%) was similar. Over the next two years (year 3-year 4), the incidence of diagnosed prostate cancer with a Gleason score of 8-10 in the Avodart™ group (n=12, 0.5%) was higher than in the placebo group (n= 1, <0.1%) (p=0.0035). There are no data on the results of using Avodart™ for more than 4 years in patients at risk of developing prostate cancer. The percentage of patients diagnosed with prostate cancer with a Gleason score of 8-10 was stable throughout all study periods (years 1-2, years 3-4) in the Avodart™ group (0.5% in each period); however, in the placebo group, the percentage of patients diagnosed with prostate cancer with a Gleason score of 8-10 in the Year 3-Year 4 time period was lower than in the Year 1-Year 2 time period (<0.1% and 0.5% respectively) (see section “Special instructions”). There was no difference in the incidence of cancer with Gleason score 7-10 (p=0.81).

In a 4-year study of patients with BPH (the CombAT study), in which biopsy was not protocol-defined and all prostate cancer diagnoses were based on indicated biopsy, the incidence of Gleason score 8–10 cancers was as follows:

• Avodart™ group - n=8, 0.5%, tamsulosin group - n=11, 0.7% and combination therapy group - n=5, 0.3%.

The association between Avodart™ use and high-grade prostate cancer does not appear to be clear.

Side effects of Avodart

According to clinical studies Monotherapy with Avodart When used, the following adverse reactions were observed according to clinical studies with an incidence of 1% compared to placebo

* including soreness and hypertrophy of the mammary glands.

According to subsequent two-year clinical studies, the side effect profile of the drug did not change. Combination therapy (Avodart + tamsulosin) The following adverse reactions were noted in clinical studies with an incidence of 1% when comparing the combination of Avodart and tamsulosin and monotherapy with these drugs

* including soreness and hypertrophy of the mammary glands.

Data from post-marketing studies. From the immune system: very rarely - allergic reactions, including rash, itching, urticaria, localized edema and angioedema.

Medical Internet conferences

For a long time, BPH was considered a surgical pathology, and only starting in the 90s, drug therapy became part of the generally accepted standards of treatment [1]. Of the modern drugs used in the conservative treatment of patients with prostate hyperplasia, only 5-alpha reductase inhibitors are able to prevent the progression of the disease [2,3]. However, the rate of reduction in clinical manifestations of BPH under the influence of avodart, as well as the accompanying morphological changes in prostate tissue, have not been fully studied.

Target. Clinical study of the picture and morphological substrate of BPH under the influence of avodart during short periods of treatment.

Material and methods. We studied material obtained from 51 patients diagnosed with BPH who were treated with Avodart for 1 to 2 months in the urology clinic of the Clinical Hospital named after. S.R. Peacemakers SSMU. Depending on the clinical effectiveness of Avodart, patients were divided into 2 groups: the first group – patients who noted subjective improvement – ​​20 people (39%); the second group - patients who did not notice improvement - 31 people (61%). The therapeutic effect was assessed based on a study of PSA levels; TRUS of the prostate with determination of the size of the gland, residual urine (RUR) before and after conservative treatment; uroflowmetric control; morphological verification using polyfocal biopsy of the prostate under transrectal ultrasound control (according to indications) and surgical material obtained before and after conservative treatment.

Results. According to TRUS data, in patients of the first group after 1-2 months of treatment with avodart, the average volume of the prostate gland was 56 cm3, which is 9 cm3 (13%) less than before the start of treatment, while in the second group the volume of the gland did not change in dynamics and remained 65cm. The amount of OM in the first group decreased from 84 ml to 49 ml, that is, by 42%, while in the second group it decreased by only 6 ml (6%). During control uroflowmetry and assessment of the maximum urine flow rate (Qmax) in patients of the first group, the average Qmax was 10.1 ml/sec, increased by 1.6 ml/sec (16%), in the second group – by 0.1 ml/ sec (1%). When assessing the average urine flow rate (Qav), a similar trend was noted: the increase in Qav in the first group was 1.1 ml/sec (26%), in the second it increased by 0.8 ml/sec and amounted to 19%. When analyzing PSA levels in these groups, a decrease in total PSA was found by 53% and 2%, respectively. The values ​​of PSA density over time had a similar trend, and in the first group the average level was 0.16 ng/ml/cm3, in the second group it was already 0.2 ng/ml/cm3, and its decrease compared to the values ​​before treatment was 36% and 9 % respectively.

Analysis of biopsy material from 51 patients in the group before treatment revealed that most often signs of proliferation and hyperplasia were detected from the glandular component, which made it possible to diagnose the simple glandular form in 48% of cases. In 45.6% of cases, the glandular-fibrotic variant was diagnosed, and only in 6.4% of cases the stromal variant of BPH was found.

Of the 51 patients who underwent treatment with Avodart for 1-2 months, before treatment the diagnosis of PIN was made in 29 cases, with PINS in 14 patients and PINNS in 15. 1-2 months after treatment, the dynamics of morphological changes were diverse. In the first group, no significant morphological changes occurred in 13 patients, and the patients retained the morphological type of PIN that was diagnosed before treatment. In 3 cases, patients with PINNS were diagnosed with PINNS, and one patient with a simple glandular form developed PINNS. And in 3 patients an obvious therapeutic pathomorphosis was noted: in 2 PINNS and in 1 PINNS, diagnosed before treatment, did not appear after the course. It is worth noting that these patients also showed clear improvements in the results of laboratory and instrumental examination. In the second group, no significant morphological changes were observed in 14 patients. However, in 13 cases, negative dynamics were noted: in 5 cases, PINNS was diagnosed in patients with PINNS, in 4 cases, PIN appeared in patients with a simple form of glandular hyperplasia, and 4 patients who were diagnosed with prostate cancer deserved special attention, and in 2 cases well-differentiated and 2-moderately differentiated adenocarcinoma. And only in 4 cases was a positive therapeutic pathomorphosis observed: in 2 cases of PINNS and in one case PINNS, diagnosed before treatment, did not appear after, and in one case PINNS turned into PINNS. Noteworthy was the decrease in the severity of inflammatory infiltration in the first group, which may explain the positive clinical result, while in the second it was significantly pronounced.

Conclusions. Thus, a comparative analysis of the morphological picture of the prostate in patients after a short course of treatment with Avodart made it possible to establish: patients with more pronounced positive clinical dynamics, as well as significant positive laboratory and instrumental changes, are an objective reflection of the therapeutic pathomorphosis of PIN in patients with benign prostatic hyperplasia. In this regard, this group of patients can be recommended to continue conservative therapy for a longer period under clinical and laboratory control. This will allow you to delay surgical treatment or avoid it.

For patients with no obvious positive or negative clinical, laboratory and instrumental dynamics, it is advisable to undergo surgical treatment or perform a repeat biopsy in the early stages due to the risk of developing prostate cancer.

Special instructions for the use of Avodart

Dutasteride can be absorbed through the skin, so women and children should avoid contact with leaking capsules. If liquid from the capsule gets on your skin, it should be washed off immediately with soap and water. The effect of liver failure on the pharmacokinetics of dutasteride has not been studied. Since dutasteride is extensively metabolized and its half-life is 3–5 weeks, the drug is used with caution in liver diseases. Effect on prostate specific antigen (PSA) and prostate cancer detection. Before starting a course of treatment with dutasteride and periodically during treatment, a digital rectal examination of the patient and other tests should be performed to detect prostate cancer. PSA concentration is an important component of the screening method for detecting prostate cancer. Typically, a plasma PSA concentration of 4 ng/mL (Hybritech) requires further evaluation and a prostate biopsy. It should also be taken into account that a baseline PSA level of ≤4 ng/ml in patients receiving dutasteride does not exclude the possibility of diagnosing prostate cancer. Treatment with Avodart can reduce plasma PSA levels in benign prostatic hyperplasia by approximately 50% after 6 months, even in the presence of prostate cancer. Although there may be individual variations, a reduction in PSA of approximately 50% is predicted as it was observed across the entire range of baseline PSA values ​​(1.5 to 10 ng/mL). In order to interpret the PSA value in men who have taken Avodart for 6 months or more, the PSA value should be doubled for comparison with the normal PSA ranges in men who have not been treated. This correction maintains the sensitivity and specificity of the PSA test and allows this test to detect prostate cancer. Any persistent increase in PSA levels during treatment with Avodart requires careful consideration, including a decision regarding the inappropriateness of treatment with Avodart. Total serum PSA levels return to baseline within 6 months after cessation of treatment. The ratio of free PSA to total PSA remains constant even during treatment with Avodart. Therefore, when using the percentage of free PSA in a patient taking Avodart to diagnose prostate cancer, doubling the free PSA value should not be used. Fertility A study of the effect of dutasteride at a dose of 0.5 mg / day on the characteristics of the ejaculate in 27 healthy volunteers over 52 weeks of treatment and 24 weeks of follow-up revealed a decrease in total sperm count, ejaculate volume and sperm motility by 23; 26 and 18% compared with changes in the placebo group. Sperm concentration and morphology remained unchanged. At 24 weeks of follow-up, the mean percentage change in total sperm count in the dutasteride group remained 23% below baseline. While the mean values ​​for all semen parameters at all periods remained within the normal range and did not meet certain criteria for clinically significant changes (30%), 2 patients in the dutasteride group had a decrease in sperm count of more than 90% compared to baseline level at the 52nd week of treatment and a partial restoration of their number after 24 weeks of follow-up. The clinical significance of the effect of dutasteride on sperm characteristics for individual patient fertility is not known. During pregnancy and breastfeeding . Dutasteride is contraindicated for use in women. The use of dutasteride for the treatment of women has not been studied, since preclinical studies suggest that a decrease in the level of circulating dihydrotestosterone may lead to impaired development of the external genitalia in the male fetus. Children . Use is contraindicated. Considering the pharmacokinetic and pharmacodynamic properties, dutasteride does not affect the reaction rate when driving vehicles or working with machinery .

Avodart, 90 pcs., 0.5 mg, capsules

Dutasteride is absorbed through the skin and therefore women and children should avoid contact with damaged capsules. In case of contact with damaged capsules, immediately wash the affected area of ​​skin with soap and water.

Liver dysfunction.

There are currently no data on the use of Avodart® in patients with impaired liver function. Due to the fact that dutasteride undergoes intensive metabolism, and its T1/2 is 3-5 weeks, caution must be exercised when treating patients with impaired liver function with Avodart®.

Heart failure with the combined use of dutasteride and tamsulosin.

In two 4-year clinical studies, the incidence of heart failure was higher in patients receiving the combination of dutasteride and an α1-blocker, primarily tamsulosin, than in patients not receiving the combination treatment. In these two studies, the incidence of heart failure remained low (≤1%) with some variability between them. But in general, there were no discrepancies in the incidence of cardiovascular side effects. A cause-and-effect relationship between treatment with dutasteride (as monotherapy or in combination with an α1-blocker) and the development of heart failure has not been established.

Impact on the detection of prostate-specific antigen (PSA) and prostate cancer (PCa).

Patients should undergo a digital rectal examination, as well as other methods of examining the prostate gland before starting treatment with dutasteride and periodically repeat them during treatment to exclude the development of prostate cancer.

Determination of serum PSA concentration is an important component of screening for PCa. After 6 months of dutasteride therapy, the mean serum PSA level decreases by approximately 50%. Patients taking dutasteride should have a new baseline PSA level determined after 6 months of therapy. In the future, it is recommended to regularly monitor PSA levels.

The use of dutasteride does not affect the diagnostic value of PSA level as a marker of prostate cancer. Any confirmed increase in PSA levels relative to the nadir during dutasteride treatment may indicate the development of PCa (particularly high-Gleason grade PCa) or non-adherence to dutasteride therapy and should be carefully evaluated, even if these PSA levels remain within the normal range. for this age category of patients not taking 5α-reductase inhibitors.

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

The ratio 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, correction of this value is not required.

The effect of long-term use of dutasteride on the development of breast cancer in men.

No effect of long-term use of dutasteride on the development of breast cancer in men was found.

PCa and high-grade tumors.

The 4-year study (
REDUCE
) compared placebo and dutasteride in 8231 volunteers aged 50 to 75 years with a negative biopsy for PCa and a PSA level of 2.5 to 10 ng/mL at baseline.

During the study, 6,706 patients underwent a puncture biopsy of the prostate gland and, based on the results obtained, the degree of malignancy of prostate cancer was determined according to the Gleason score. 1517 patients were diagnosed with prostate cancer during the study. In the majority of cases, both in the dutasteride group and in the placebo group, well-differentiated prostate cancer was diagnosed (Gleason score 5–6). There was no difference in the number of cases of PCa with a Gleason score of 7–10 between the dutasteride group and the placebo group (p=0.81).

After 4 years, there were more cases of PCa with a Gleason score of 8–10 in the dutasteride group (n=29; 0.9%) compared with placebo (n=19; 0.6%; p=0.15 ). When assessing biopsy data for 1-2 years, the number of patients diagnosed with PCa with a Gleason score of 8-10 was comparable in the dutasteride (n = 17; 0.5%) and placebo (n = 18; 0.5) groups. %). When assessing biopsy data at 3–4 years, more cases of PCa with a Gleason score of 8–10 were diagnosed in the dutasteride group (n=12; 0.5%) compared with the placebo group (n=1; <0). .1%; p=0.0035). The percentage of patients diagnosed with PCa with a Gleason score of 8–10 was stable across all time periods (1–2 and 3–4 years) in the dutasteride group (0.5% in each period), while In the placebo group, the percentage of patients diagnosed with PCa with a score of 8–10 was lower in years 3–4 than in years 1–2 (<0.1% versus 0.5%, respectively).

In a 4-year study ( CombAT

) patients with BPH, in which prostate biopsy was not mandated for all participants by protocol and all PCa diagnoses were based on indicated biopsy, PCa with a Gleason score of 8–10 was diagnosed in 8 patients (<0.5%) at taking dutasteride, in 11 patients (<0.7%) when taking tamsulosin and 5 patients (<0.3%) with combination therapy with dutasteride and tamsulosin. A cause-and-effect relationship between taking dutasteride and the development of high-grade prostate cancer has not been established. Men taking dutasteride should undergo regular screening to assess their risk of developing prostate cancer, including PSA levels.

Impact on the ability to drive vehicles and operate machinery.

Taking dutasteride does not affect driving or operating machinery.

Avodart drug interactions

Since dutasteride is metabolized by the CYP3A4 isoenzyme, plasma concentrations of dutasteride may be increased in the presence of CYP3A4 inhibitors, and the clearance of dutasteride is decreased when administered concomitantly with the CYP3A4 inhibitors verapamil (37%) and diltiazem (44%). However, the clearance of dutasteride is not reduced when used with another calcium channel antagonist, amlodipine. The decrease in clearance and corresponding increase in the effect of dutasteride in the presence of CYP3A4 inhibitors is not of great clinical significance due to the wide range of safety of the drug. In vitro, the isoenzymes CYP 1A2, CYP 2C9, CYP2 C19 and CYP 2D6 do not take part in the metabolism of dutasteride in humans; dutasteride does not inhibit enzymes of the cytochrome P450 system in humans involved in the metabolism of drugs. In vitro studies have shown that dutasteride does not displace warfarin, diazepam or phenytoin from binding to plasma proteins, nor do these components replace dutasteride. The interaction of dutasteride with tamsulosin, terazocin, warfarin, digoxin and cholestyramine was studied. No clinically significant interaction was identified. Although specific drug interaction studies have not been conducted, approximately 90% of all patients in clinical trials of dutasteride received other concomitant therapy. No clinically significant adverse reactions were observed with the simultaneous use of dutasteride with antihyperlipidemic drugs, ACE inhibitors, β-adrenergic receptor blockers, calcium channel blockers, corticosteroids, diuretics, NSAIDs, phosphodiesterase type V inhibitors and quinolone antibiotics. According to a study examining the interaction of tamsulosin or terazocin in combination with Avodart for 2 weeks, no signs of pharmacokinetic or pharmacodynamic interaction were identified.

Avodart overdose, symptoms and treatment

According to clinical studies, in volunteers a single dose of dutasteride up to 40 mg/day (80 times higher than the therapeutic dose) for 7 days did not cause undesirable manifestations, taking into account the safety of their use. In clinical studies, a dose of dutasteride was used at a dose of 5 mg/day for 6 months without the occurrence of additional adverse reactions compared to the use of dutasteride at a dose of 0.5 mg/day. There is no specific antidote, so in case of possible overdose, symptomatic therapy is carried out.