Duodart capsules 0.5mg + 0.4mg №90 №1

Name:
Duodart caps. 0.5mg + 0.4mg per vial No. 90 per pack. No. 1
Description:
Oblong hard capsules with a brown body and an orange cap with the code “GS 7CZ” in black ink. The main active ingredient amsulosin + dutasteride Release form capsules Dosage 0.5 mg + 0.4 mg Pharmacological action Means for the treatment of benign prostatic hyperplasia. Antagonists of alpha-adrenergic receptors. ATX code: G04CA52. Pharmacodynamics Duodart™ is a combination of two pharmaceutical substances: dutasteride, a dual 5?-reductase inhibitor, and tamsulosin hydrochloride, an ?1a and ?1d adrenoceptor antagonist. These substances have a complementary mechanism of action that results in a rapid improvement in symptoms and urination, a reduction in the risk of acute urinary retention and the need for surgery for benign prostatic hyperplasia (BPH). Dutasteride inhibits the activity of isoenzymes 5a-reductase types 1 and 2, which are responsible for the conversion of testosterone to dihydrotestosterone. Dihydrotestosterone (DHT) is the main androgen responsible for prostate growth and the development of BPH. Tamsulosin inhibits the activity of ?1a and ?1d-adrenergic receptors in the smooth muscle of the stroma of the prostate and bladder neck. About 75% of ?1 receptors in the prostate are of the ?1a subtype. Use of dutasteride in combination with tamsulosin This leaflet includes the results of clinical studies of the free combination of dutasteride and tamsulosin. In a four-year, multicentre, international, randomized, double-blind, parallel-group clinical trial in men with moderate to severe symptoms of BPH with a prostate volume of ? 30 ml and a PSA concentration in the range of 1.5-10 ng / ml, the use of dutasteride 0.5 mg / day (n = 1623), tamsulosin 0.4 mg / day (n = 1611) and a combination of dutasteride 0.5 mg was studied plus tamsulosin 0.4 mg (n = 1610). Approximately 53% of patients had previously received therapy with 5-β-reductase inhibitors or si-adrenergic antagonists. The primary end point during the first 2 years of therapy was change in the International Prostatic Symptom Score (IPSS) score (an 8-item scale based on AUA-SI with an additional question on quality of life). Secondary endpoints assessed after 2 years of treatment included maximal urinary flow rate (Qmax) and prostate volume. Compared with the dutasteride group and the tamsulosin group, the results for IPSS obtained in the combination therapy group were significant from the time points of Month 3 and Month 9, respectively. The results for Qmax in the combination therapy group were significant from the time mark Month 6 compared to the dutasteride and tamsulosin groups. Combination therapy with dutasteride and tamsulosin leads to a more significant improvement in symptoms than the use of only one of these components. After two years of treatment, the combination therapy group experienced a statistically significant adjusted mean improvement in symptom scores of -6.2 points from baseline. The adjusted mean improvement in urinary flow rate from baseline was 2.4 ml/s in the combination therapy group; 1.9 ml/sec in the dutasteride group and 0.9 ml/sec in the tamsulosin group. The adjusted mean improvement in the BPH Impact Index (WI) from baseline was -2.1 points in the combination therapy group; -1.7 points in the dutasteride group and -1.5 points in the tamsulosin group. These improvements in urinary flow rate and BPH impact index were statistically significant in the combination therapy group compared to the monotherapy groups. The reduction in total prostate volume and transition zone volume after two years of treatment was statistically significant in the combination therapy group compared to the tamsulosin monotherapy group. The primary endpoint after 4 years of therapy was the time to the first episode of acute urinary retention (AUR) or surgery for BPH. After 4 years of therapy, the reduction in the risk of AUR or surgery for BPH in the combination therapy group was statistically significant (65.8% risk reduction at p < 0.001 95% CI 54.7% - 74.1%) compared with result in the tamsulosin monotherapy group. The 4-year rates of AUR and surgery for BPH in the combination group and tamsulosin group were 4.2% and 11.9%, respectively (p < 0.001). Compared with the dutasteride monotherapy group, the combination group had a 19.6% reduction in the risk of AUR and surgery for BPH (p = 0.18, 95% CI -10.9% - 41.7%). The 4-year rates of AUR and surgery for BPH in the dutasteride group were 5.2%. Secondary endpoints assessed after 4 years of therapy included time to clinical progression (a composite measure that included the following components: worsening, as evidenced by a change in IPSS score of ? 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 Symptoms Scale (IPSS), change in the maximum urination rate and prostate volume. The results of the study after 4 years of therapy are presented below. Parameter Time stamp Combination Dutasteride Tamsulosin AUR or surgery for BPH (%) Incidence at 48 months 4.2 5.2 11.9a Clinical progression* (%) 48 months 12.6 17.8b 21.5a IPSS (scores) ) Baseline48 months (change from baseline) 16.6 -6.3 16.4 -5.3b 16.4 -3.8a Qmax (ml/s) Baseline48 months (change from baseline) 10.92, 4 10.62.0 10.70.7a Prostate volume (ml) Baseline48 months (% change from baseline) 54.7 -27.3 54.6 -28.0 55.8 +4.6a Transition volume prostate zones (ml)# Baseline48 months (% change from baseline) 27.7 -17.9 30.3 -26.5 30.5 +18.2a BPH impact index (BII) (points) Baseline48 months (change from baseline) 5.3 -2.2 5.3 -1.8b 5.3 -1.2a IPSS question 8 (health assessment in the context of BPH) (points) Baseline48 months (change from baseline ) 3.6 -1.5 3.6 -1.3b 3.6 -1.1a equal - average values, values of changes from the initial level - adjusted average values. Clinical progression is a composite measure that included the following: worsening, as evidenced by a change in IPSS score of ? 4 points, cases of AUR associated with BPH, urinary incontinence, UTI and renal failure. evaluation was performed at selected study centers (13% of randomized patients). The results were significant in the combination therapy group (p < 0.001) compared with the tamsulosin group at 48 months. The results were significant in the combination therapy group (p < 0.001) compared with the dutasteride group at 48 months. Dutasteride Dutasteride 0.5 mg/day was compared with placebo in 4325 men with moderate to severe symptoms of BPH with a prostate volume >30 mL and a PSA level between 1.5 and 10 ng/mL over 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 period, with all patients remaining in the study continuing to receive the same dose of dutasteride 0.5 mg. After 4 years, of the initially randomized patients in the placebo group and in the dutasteride group, 37% and 40% of the subjects remained, respectively. Most (71%) of the 2340 men during the additional period of open therapy received treatment for 2 additional years. The most important clinical efficacy parameters were the American Urological Association Symptom Index (AUA-SI), maximum urinary flow rate (Qmax), incidence of acute urinary retention and surgery for BPH. The maximum value of the AUA-SI index, determined using the BPH Symptom Assessment Questionnaire of seven items, is 35 points. The initial average value of the index 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 dutasteride 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 seen during the first 2 years of double-blind therapy was maintained for another 2 years in the open-label extension study. Qmax (maximum urinary flow rate) The mean Qmax in clinical studies at baseline was about 10 ml/sec (normal Qmax ≥ 15 ml/sec). After one year and two years of therapy, urinary velocity increased in the placebo group by 0.8 and 0.9 ml/sec, respectively, and in the dutasteride group by 1.7 and 2.0 ml/sec, respectively. The difference between the two treatment groups over the time span from 1 to 24 months was statistically significant. The increase in maximum urinary flow rate observed during the first 2 years of double-blind therapy was maintained for another 2 years in extended open studies. Acute urinary retention (AUR) and surgery After two years of therapy, the incidence of AUR was 4.2% in the placebo group and 1.8% in the dutasteride group (57% risk reduction). This difference is statistically significant, meaning that in 42 (95% CI 30-73) patients, treatment with dutasteride for two years prevents one AUR. After two years of therapy, the incidence of surgery for BPH was 4.1% in the placebo group and 2.2% in the dutasteride group (48% risk reduction). This difference is statistically significant, meaning that in 51 patients (95% CI 33-109) treatment with dutasteride for two years avoided one surgical intervention. Hair Distribution The effect of dutasteride on hair distribution has not been formally studied as part of the Phase III clinical trial program; however, the use of 5-alpha 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 levels 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, and 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 concentration indicators were stable within the normal range and similar to placebo and dutasteride, these changes in TSH levels were regarded as clinically insignificant. The results of all clinical studies indicate the absence of a negative effect of dutasteride on thyroid function. Breast neoplasms In a two-year clinical study in which 3374 patients received dutasteride, as of the time of transition of participants to the 2-year extended (additional) open-label study, cases of breast cancer in men were noted in 2 patients in the dutasteride group and in 1 patient in the placebo group. In the 4-year CombAT and REDUCE clinical trials, no cases of breast cancer were reported in any treatment group, with 17,489 patient years of exposure to dutasteride and 5,027 patient years of exposure to the combination of tamsulosin and dutasteride. In two epidemiological case-control studies, one in the US (n = 339 breast cancers and n = 6780 controls) and the other in the UK Health Database (n = 398 breast cancers and n = 3930 control cases) has not been shown to increase the risk of developing breast cancer in men with the use of 5-alpha reductase inhibitors (see Precautions section). The results of the first study did not reveal an association with the development of breast cancer in men (relative risk for ? 1 year of use before diagnosis of breast cancer compared with < 1 year of use: 0.70: 95% CI 0.34; 1.45) . In the second study, the estimated odds ratio of developing breast cancer associated with the use of 5-alpha reductase inhibitors, compared with the group without use, was 1.08: 95% CI 0.62; 1.87). A causal relationship between the occurrence of breast cancer in men and long-term use of dutasteride has not been established. Effects 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 dustasteride group; n = 23 in the placebo group), for 52 weeks of therapy and 24 weeks of follow-up. After 52 weeks of treatment, the mean percent 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. Changes in the concentration and morphology of spermatozoa were not observed. 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 clinically significant change (30%), two patients in the dutasteride group after 52 weeks of therapy had a decrease in sperm count by more than 90% from baseline. levels, with a partial recovery noted at 24 weeks of follow-up. The possibility of reduced male fertility cannot be ruled out. Adverse events from the cardiovascular system In a 4-year study of BPH with dutasteride in combination with tamsulosin in 4844 men (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 both monotherapy groups: dutasteride - 4/1623, 0.2%, tamsulosin - 10/1611, 0.6%. In a separate four-year clinical trial (the REDUCE study) in 8231 patients aged 50 to 75 years with a previous negative biopsy for prostate cancer and a PSA concentration at baseline between 2.5 ng/mL and 10.0 ng / ml (in men aged 50 to 60 years) and 3 ng / ml - 10 ng / ml (in men over the age of 60 years) the frequency of cases described by the combined term "heart failure" in the dutasteride 0.5 mg group once daily (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 who received both dutasteride and a si-adrenergic antagonist (12/1152, 1.0%) was higher than in patients who received dutasteride no ?1-adrenoceptor antagonist (18/2953, 0.6%), placebo and ?1-adrenoceptor antagonist (1/1399, <0.1%), or placebo alone (15/2727, 0.6%). In a meta-analysis of 12 randomized clinical trials (n = 18802) with placebo control or comparator, which assessed the risks of developing cardiovascular adverse events with dutasteride (compared with control), no stable statistically significant increase in the risk of developing heart failure was found. 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). Prostate Cancer and High-Grade Tumors In a 4-year clinical trial of Duodart™ versus placebo (REDUCE study) in 8231 patients aged 50 to 75 years with previously negative prostate cancer biopsy results and PSA levels at baseline within 2.5 ng / ml - 10.0 ng / ml (in men aged 50 to 60 years) and 3 ng / ml - 10 ng / ml (in men over the age of 60 years) results of a puncture biopsy (initially mandatory according to the protocol) to determine the amount of points on the Gleason scale 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 dutasteride 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 rates of cancer cases with a Gleason score of 8-10 in the dutasteride group (n = 17, 0.5%) and in the placebo group (n = 18, 0.5%) were 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 dutasteride group (n = 12, 0.5%) was higher than in the placebo group (n = 1, <0.1%) (p = 0.0035). Data on the results of the use of dutasteride for more than 4 years in patients at risk of developing prostate cancer are not available. 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 dutasteride 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 time period Year 3 - Year 4 was lower than in the time period Year 1 - Year 2 (<0.1% and 0.5%, respectively) (See Precautions section). There were no differences in the incidence of cancer with a Gleason score of 7-10 (p = 0.81). An additional two-year follow-up study within the REDUCE study did not identify any new cases of prostate cancer with a Gleason score of 8-10. In a 4-year study in patients with BPH (the CombAT study), in which biopsy was not defined by the protocol and all prostate cancer diagnoses were based on biopsy according to indications, the incidence of cancer with a Gleason score of 8-10 was in groups dutasteride, tamsulosin and combination therapy 0.5% (n=8), 0.7% (n=11) and 0.3% (n=5), respectively. Four different epidemiological population studies (two of which were based on a total population of 174,895 people, one on a population of 13,892 people, and one on a population of 38,058 people) showed that the use of 5-alpha reductase inhibitors was not associated with the occurrence of high-grade prostate cancer. gradation, or prostate cancer, or with overall mortality. The relationship between dutasteride use and high-grade prostate cancer is not clear. Tamsulosin Tamsulosin increases the maximum rate of urination. It reduces obstruction by reducing the tone of the smooth muscles of the prostate and urethra, which leads to an improvement in emptying symptoms. It also improves filling symptoms, for which bladder instability plays an important role. This effect on emptying and filling symptoms persists during long-term therapy and significantly delays the need for surgery or catheterization. Antagonists of ?1-adrenergic receptors can reduce blood pressure by reducing the total peripheral vascular resistance. During clinical studies of tamsulosin, no clinically significant reduction in blood pressure was observed. Pharmacokinetics The bioequivalence of taking Duodart™ and co-administration of dutasteride and tamsulosin capsules has been demonstrated. A single dose bioequivalence study was conducted both on an empty stomach and after a meal. A 30% reduction in Cmax for tamsulosin in Duodart™ was observed when taken after a meal compared to fasting. Food intake had no effect on the AUC of tamsulosin. Absorption Dutasteride After taking a single dose of dutasteride 0.5 mg, the maximum concentration of the drug in serum is reached within 1-3 hours. Absolute bioavailability is about 60%. The bioavailability of dutasteride is independent of food intake. Tamsulosin Tamsulosin is absorbed from the intestine and has almost 100% bioavailability. The rate and degree of absorption of tamsulosin is reduced if the drug is taken within 30 minutes after a meal. The same level of absorption can be achieved if the patient always takes Duodart™ after the same meal. The plasma concentration of tamsulosin is dose proportional. After taking a single dose of tamsulosin after a meal, peak plasma concentrations are reached after approximately 6 hours. Steady-state concentration is reached on the 5th day of multiple dosing, with the mean steady-state concentration (Cmax) approximately two-thirds higher than the concentration after single dosing. Although this phenomenon has been observed in older patients, the same can be expected in younger patients. Distribution Dutasteride Dutasteride has a large volume of distribution (300 to 500 L) and a high degree of plasma protein binding (>99.5%). With daily intake, the concentration of dutasteride in serum reaches 65% of the concentration in the equilibrium state after 1 month and approximately 90% after 3 months. Steady-state serum dutasteride concentrations (Css) of approximately 40 ng/mL are achieved after 6 months of daily dosing of 0.5 mg of this drug. Approximately 11.5% of dutasteride enters semen from serum. Tamsulosin Tamsulosin is approximately 99% bound to plasma proteins. The volume of distribution is small (about 0.2 l/kg). Biotransformation Dutasteride Dutasteride is extensively metabolized in vivo. In vitro, dutasteride is metabolized by cytochrome P450 ZA4 and ZA5 to three monohydroxylated metabolites and one dihydroxylated metabolite. After ingestion of dutasteride at a dose of 0.5 mg / day until equilibrium concentrations of 1.0% -15.4% (mean value 5.4%) of the administered dose of dutasteride are excreted unchanged in the feces. The remainder is excreted in the feces as four major metabolites (39%, 21%, 7% and 7%) from drug-related substances and 6 secondary metabolites (less than 5% each). Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are found in human urine. Tamsulosin Enantiomeric bioconversion of tamsulosin |K(-) isomer to S(+) isomer does not occur in humans. Tamsulosin is extensively metabolized in the liver by enzymes of the cytochrome P450 system, and less than 10% of the dose is excreted unchanged by the kidneys. However, the pharmacokinetic profile of metabolites in humans has not been established. The results of in vitro studies indicate that CYP3A4 and CYP2D6 enzymes are involved in the metabolism of tamsulosin, and other CYP isoenzymes are also insignificantly involved. Inhibition of the activity of enzymes involved in hepatic metabolism can lead to an increase in the concentration of tamsulosin. Tamsulosin metabolites are actively conjugated with glucuronides or sulfates before being excreted by the kidneys. Excretion Dutasteride Excretion of dutasteride is dose dependent and can be described as two parallel elimination processes: one saturable at clinically relevant concentrations and one nonsaturable. At low serum concentrations (less than 3 ng/mL), dutasteride is rapidly eliminated by both elimination processes. After a single dose of 5 mg or less, dutasteride is rapidly eliminated from the body and has a short half-life of 3-9 days. At therapeutic concentrations, against the background of daily use of the drug at a dose of 0.5 mg / day, a slower, linear elimination prevails, the half-life is about 3-5 weeks. Tamsulosin Tamsulosin and its metabolites are mainly excreted by the kidneys, with about 9% of the drug excreted unchanged. After intravenous or oral administration of the immediate release dosage form, the plasma half-life of tamsulosin varies from 5 to 7 hours. Due to the controlled absorption rate in modified release capsules, the half-life of tamsulosin when taken after meals is about 10 hours, and at steady state about 13 hours. Elderly men Dutasteride The pharmacokinetics of dutasteride were studied in 36 healthy men aged 24 to 87 years following a single dose (5 mg) of dutasteride. There was no significant effect of age on dutasteride exposure, but the elimination half-life was shorter in men under 50 years of age. There were no statistically significant differences between the half-life in patients aged 50 to 69 years and in patients over the age of 70 years. Tamsulosin Cross-comparison of total exposure (AUC) and half-life of tamsulosin indicates that the pharmacokinetics of tamsulosin may be slightly prolonged in elderly men compared to young healthy volunteers. The intrinsic clearance does not depend on the binding of tamsulosin to alpha-1-acid glycoprotein, but decreases with age, resulting in a total exposure (AUC) of tamsulosin 40% higher in patients aged 55-75 years compared with those aged 20-75 years. 32 years old. Renal impairment Dutasteride The effect of renal impairment on the pharmacokinetics of dutasteride has not been studied. However, since less than 0.1% of the 0.5 mg dose of dutasteride at steady state is excreted in the urine, a clinically significant increase in the concentration of dutasteride in the blood plasma is not predicted (see section “Method of administration and doses”). Tamsulosin The pharmacokinetics of tamsulosin was compared in 6 patients with renal insufficiency of varying severity (creatinine clearance 10-29 and 30-69 ml / min / 1.73 m2) and in 6 healthy individuals (creatinine clearance > 90 ml / min / 1.73 m2 ). Despite the fact that there was a change in the total concentration of tamsulosin in plasma due to a change in binding to alpha-1-acid glycoprotein, the concentration of unbound (active) tamsulosin, as well as its own clearance, remained relatively stable. Thus, patients with renal insufficiency do not require dose adjustment of tamsulosin hydrochloride. However, studies of the use of tamsulosin in patients with end-stage renal disease (creatinine clearance < 10 ml / min / 1.73 m2) have not been conducted. Hepatic insufficiency Dutasteride The effect of hepatic insufficiency on the pharmacokinetics of dutasteride has not been studied (see section "Contraindications"). Since dutasteride is mainly excreted by metabolism, in patients with hepatic insufficiency, the concentration of dutasteride in plasma may increase and the half-life may increase (see sections "Method of application and Dose and Precautions section), Tamsulosin The pharmacokinetics of tamsulosin hydrochloride was compared in 8 patients with moderate hepatic impairment (Child-Pugh Class A and B) and in 8 subjects with normal hepatic function. Although there was a change in the total plasma concentration of tamsulosin due to a change in binding to alpha-1-acid glycoprotein, the concentration of unbound (active) tamsulosin did not change significantly, there was only a moderate (32%) change in the intrinsic clearance of unbound tamsulosin. Thus, patients with moderate hepatic impairment do not require dose adjustment of tamsulosin hydrochloride. No studies have been conducted on the use of tamsulosin hydrochloride in patients with severe hepatic impairment. Indications for use Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH). Reducing the risk of acute urinary retention and the need for surgical treatment in patients with moderate to severe symptoms of BPH. Dosage and administration Inside. Patients should be instructed to swallow the capsule whole approximately 30 minutes after the same meal. Capsules should not be opened or chewed. Contact with the contents of the dutasteride capsule inside the hard capsule may cause irritation of the mucous membranes of the mouth and throat. Dosage Adult men (including elderly men). The recommended dose of Duodart™ is one capsule (0.5 mg + 0.4 mg) once a day. When clinically appropriate, switching from tamsulosin or dutasteride monotherapy to Duodart™ can be considered, or Duodart™ can be substituted for co-administration of tamsulosin and dutasteride to simplify treatment. Patients with impaired renal function. The effect of impaired renal function on the pharmacokinetics of Duodart™ has not been studied. It is expected that dose adjustment in patients with impaired renal function is not required (see sections "Precautions" and "Pharmacokinetics"). Patients with impaired liver function. The effect of impaired liver function on the pharmacokinetics of Duodart™ has not been studied. Caution should be exercised when treating patients with mild to moderate hepatic impairment with Duodart™. Duodart™ is contraindicated in patients with severe hepatic insufficiency. Children Duodart™ is contraindicated in children and adolescents under the age of 18 (see section "Contraindications"). Use during pregnancy and lactation Duodart™ is contraindicated for use in women. Studies of the effect of the drug Duodart™ on pregnancy, breastfeeding and fertility have not been conducted. The information below is based on studies of the individual components of the formulation. Pregnancy Dutasteride As with other 5-alpha reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone and may inhibit the development of the vulva in the fetus when exposed to a woman carrying a male fetus. Small amounts of dutasteride have been detected in the seminal fluid of patients receiving dutasteride. It is not known whether dutasteride ingested by a woman with the sperm of a man treated with Duodart™ will have a negative effect on the male fetus (the risk is highest during the first 16 weeks of pregnancy). As with other 5-alpha reductase inhibitors, the use of a condom is recommended if the female partner is or may be pregnant. The administration of tamsulosin hydrochloride to pregnant female rats and rabbits did not reveal evidence of harmful effects on the fetus. Lactation There are no data on the excretion of dutasteride or tamsulosin in breast milk. Fertility There are reports of the effect of dutasteride on the characteristics of seminal fluid in healthy men (decrease in the number and motility of spermatozoa, a decrease in semen volume). The possibility of reduced male fertility cannot be ruled out. The effect of tamsulosin hydrochloride on sperm count and sperm function has not been evaluated. Precautions Combination therapy should be initiated after a careful risk-benefit analysis due to the potentially increased risk of adverse reactions (including heart failure), and after consideration of alternative therapeutic options, including monotherapy. Prostate Cancer and High-Grade Tumors The four-year, multicentre, randomized, double-blind, placebo-controlled REDUCE trial examined the effects of daily dutasteride 0.5 mg in patients at high risk of developing prostate cancer (including men aged 50 to 75 years with PSA concentrations of 2.5-10 ng/mL and a negative prostate biopsy 6 months prior to enrollment) versus placebo. The results of this study revealed a higher incidence of prostate cancer with a Gleason index of 8-10 in men taking dutasteride (n = 29, 0.9%) compared with placebo (n = 19, 0.6%). The relationship between the use of dutasteride and prostate cancer with a Gleason index of 8-10 is unclear. Thus, men taking Duodart™ should be regularly screened to assess for the presence of prostate cancer (see Pharmacodynamics section). Prostate Specific Antigen (PSA) The determination of serum PSA concentrations is an essential component of the screening process for prostate cancer. After 6 months of therapy, Duodart™ reduces serum PSA levels by approximately 50%. Patients taking Duodart™ should have a new baseline PSA level determined after 6 months of therapy, after which regular monitoring of PSA levels is recommended. Any confirmed increase in PSA levels from the trough of Duodart™ treatment may indicate the development of prostate cancer or non-compliance with Duodart™ therapy and should be carefully evaluated, even if these PSA levels remain within the normal range in patients not taking 5a inhibitors -reductases. When interpreting PSA values in patients taking dutasteride, previous PSA values should be used for comparison. Treatment with Duodart™ does not affect the use of PSA levels to diagnose prostate cancer once a new baseline has been established. The level of total PSA returns to its original value within 6 months after discontinuation of treatment. The ratio of free PSA to total remains constant even during therapy with Duodart™. If the doctor decides to use the percentage of free PSA to detect prostate cancer in men receiving Duodart™, no adjustment of this value is required. Before starting treatment with Duodart ™, and periodically during treatment, it is necessary to conduct a digital rectal examination, as well as use other research methods to detect prostate cancer or other diseases that can cause symptoms similar to those of benign prostatic hyperplasia. Adverse events from the cardiovascular system In two 4-year clinical studies, the incidence of heart failure (a complex term for events such as primary heart failure and congestive heart failure) was higher among patients taking the combination of dutasteride and an alpha-1-antagonist. adrenoreceptors, mainly tamsulosin, than among patients who did not take this combination. However, the incidence of heart failure in these studies was lower in all active treatment groups compared with the placebo group, and other data available for dutasteride and alpha1-adrenergic antagonists do not support the conclusion