Avodart capsules 0.5mg №10×3

Name:
Avodart caps 0.5 mg in blister pack No. 10×3
Description:
oblong, opaque, yellow gelatin capsule, marked with the code “GX CE2”. The main active ingredient is Dutasteride Release form 10 capsules in PVC / PVDC / AI blisters. On 3 or 9 blisters together with the application instruction in a cardboard box. Dosage 0.5 mg Pharmacological action Means for the treatment of urological diseases. Agents for the treatment of benign prostatic hyperplasia. CodeATC: G04CB02 Pharmacodynamics Dutasteride reduces circulating levels of dihydrotestosterone (DHT) by inhibiting the activity of 5-β-reductase type 1 and type 2 isoenzymes, which are responsible for the conversion of testosterone to DHT. In monotherapy mode Effect on the concentration of dihydrotestosterone (DHT) / testosterone The effect of daily intake of the drug Avodart™ on the reduction of DHT levels is dose-dependent and is observed after 1-2 weeks (decrease by 85 and 90%, respectively). In patients with benign prostatic hyperplasia (BPH) who received dutasteride at a dose of 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 is detected as early as one month after the start of treatment and continues until the 24th month (p < 0.001). At 12 months of treatment, Avodart resulted in a mean reduction in prostate volume of 23.6% (from 54.9 ml at baseline to 42.1 ml), while in the placebo group the mean volume reduction was 0 .5% (from 54.0 ml to 53.7 ml). Significant (p < 0.001) reduction also occurred in the transitional zone of the prostate after one month of therapy, it continued until 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 increase in volume by an average of 7 .9% (from 26.8 ml to 27.5 ml). The reduction in prostate volume observed during the first two years of double-blind therapy was maintained for an additional two years of therapy in expanded open studies. Reducing the size of the prostate gland leads to symptomatic relief and a reduced risk of acute urinary retention (AUR) and surgery for BPH. Clinical efficacy and safety Avodart™ 0.5 mg/day was compared with placebo in 4325 male subjects with BPH with moderate to severe symptoms, a prostate volume of ?30 ml, and a PSA level of range of 1.5-10 ng/mL in three 2-year, multicenter, international, placebo-controlled, double-blind, primary efficacy studies. These clinical studies were extended to four years with an additional open-label 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 in the placebo group and in the dutasteride group, 37 and 40% of the subjects remained, respectively. The majority (71%) of the 2340 open-label extensions received treatment for two 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 Avodart™ drug group 3.2, 3.8 and 4.5 points respectively. Differences between treatment groups were statistically significant. The improvement in AUA-SI observed during the first two years of double-blind therapy was maintained for another two years in the expanded open studies. 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, the rate of urination 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 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 two years of double-blind therapy was maintained for another two years in extended open 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 1.8% (57% risk reduction). This difference is statistically significant, meaning that treatment of 42 (95% CI 30-73) patients with Avodart™ for two years prevented one case of AUR. After two 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 51 patients (95% CI 33-109) treated with Avodart™ 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-β-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 - 5/6 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 2-year clinical study with a duration of 3374 patient-years of dutasteride, at the time of transition of participants to a 2-year extended (additional) open-label study, cases of breast cancer in men were observed in 2 patients in the dutasteride group and in 1 patient in the dutasteride group. placebo group. In the 4-year CombAT and REDUCE clinical trials, no cases of breast cancer were reported in either 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-β-reductase inhibitors (see section "Precautions"). The results of the first study did not reveal a positive association between 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 for breast cancer associated with the use of 5-β-reductase inhibitors compared with no use was 1.08: 95% CI 0.62; 1.87. The relationship between long-term use of dutasteride and breast cancer in men 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 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. In combination with the alpha-adrenergic blocker tamsulosin In a multicenter, international, randomized, double-blind, parallel-group clinical trial (the CombAT study) in patients with moderate to severe symptoms of BPH, with a prostate volume of ?30 mL and a PSA level of 1 .5-10 ng/mL, the following drugs were studied: 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 5-?-reductase inhibitors or ?-adrenergic blockers. 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 Avodart™ drug 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 point of Month 6 compared to the Avodart™ and tamsulosin groups. The primary endpoint after 4 years of therapy was the time to the first occurrence of 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 Avodart monotherapy group, the combined therapy group reduced the risk of AUR and surgery for BPH by 19.6% (p = 0.18, 95% CI 10.9% - 41.7%). The incidence rates of AUR and surgery due to 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 measure of deterioration as evidenced by a >4 point change in IPSS score, 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 Avodart™ Tamsulosin combination AUR and surgery for BPH (%) 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 (07 baseline change) 54.7-27.3 54.6-28.0 55.8+4.6a Transition zone volume prostate (ml)# Baseline48 months (change from baseline) 27.7-17.9 30.3-26.5 30.518.2a 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 th from baseline – adjusted mean values. * Clinical progression is a composite measure that included: worsening as evidenced by a >4 change in IPSS score, BPH-related AUR, urinary incontinence, UTI, and renal failure, # assessed at individual study centers (13% randomized patients). a. The results were significant in the combination therapy group (p < 0.001) compared with the tamsulosin group at 48 months. b. The results were significant in the combination therapy group (p < 0.001) compared with the Avodart™ group after 48 months. Adverse events from the cardiovascular system In a 4-year study of BPH with 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 both monotherapy groups: Avodart™ -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 and 10.0 ng/mL ( in men aged 50 to 60 years) and 3 - 10 ng / ml (in men over the age of 60 years) the frequency of cases described by the combined term "heart failure" in the Avodart 0.5 mg once a day group (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 both Avodart™ and a ?-adrenergic blocker (12/1152, 1.0%) was higher than in patients treated with Avodart™ alone (18/2953, 0.6%), placebo and β-blocker (1/1399, <0.1%) or placebo alone (15/2727, 0.6%) (see .section "Precautions"). In a meta-analysis of 12 randomized clinical trials with placebo or comparator clinical trials (n = 18802) assessing the risks of developing cardiovascular adverse events with Avodart (compared with control), no stable statistically significant increase was found risk of developing heart failure (RR (relative risk) 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 prostate cancer In a four-year clinical study of Avodart™ versus placebo (REDUCE study) in 8231 patients aged 50 to 75 years with a previously negative biopsy result for prostate cancer and with a concentration PSA at baseline within 2.5 - 10.0 ng / ml (in men aged 50 to 60 years) and 3 - 10 ng / ml (in men over 60 years of age) results of a needle biopsy (initially mandatory for 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 was higher in the Avodart™ group (n = 29, 0.9%) than in the placebo group (n = 19, 0.6%) (p = 0.15). During the first two years of therapy, cancer rates with a Gleason score of 8-10 in the Avodart™ (n = 17, 0.5%) and placebo (n = 17, 0.5%) groups 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 Avodart™ drug 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 with diagnosed prostate cancer with a Gleason score of 8-10 was stable throughout all study periods (years 1-2, years 3-4) in the Avodart™ drug 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). In an additional 2-year follow-up study after the end of the REDUCE study, there were no 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 protocol-driven and all prostate cancer diagnoses were based on biopsy by indication, the incidence of cancer with a Gleason score of 8-10 was as follows: drug group Avodart™ - n = 8, 0.5%; the tamsulosin group, n = 11, 0.7%; and the combination therapy group, n = 5, 0.3%. The results of 4 different epidemiological population studies (2 of which included a total population of 174,895 people, one of 13,892 people and one of 38,058 people) showed that the use of 5-β-reductase inhibitors was not accompanied by an increase in the incidence of high-grade prostate cancer. malignancy, no prostate cancer, and no overall mortality. The relationship between the use of Avodart™ and high-grade prostate cancer is not clear. Effects on Sexual Function The effect of dutasteride-tamsulosin fixed combination on sexual function was evaluated in a double-blind, placebo-controlled study in sexually active men with BPH (n=243 dutasteride-tamsulosin combination, n=246 placebo). At 12 months, there was a statistically significant (p < 0.001) greater decrease (worsening) in the Men's Sexual Health Assessment Questionnaire (MSHQ) scores in the combination therapy group. The decline in scores was predominantly due to deterioration in ejaculation and overall satisfaction, rather than erection score. These changes did not affect study participants' attitudes toward the combination drug, which was rated as statistically significantly higher than placebo satisfaction throughout the study (p < 0.05). In this study, sexual adverse events occurred within 12 months of therapy and resolved in about half of the cases within 6 months of therapy. The dutasteride-tamsulosin combination and dutasteride monotherapy are known to cause undesirable effects on the part of sexual function (see section "Side Effects"). As noted in other clinical studies, including CombAT and REDUCE, the incidence of adverse events on the part of sexual function decreases over time with continued therapy. PharmacokineticsAbsorption After taking a single dose of 0.5 mg orally, the maximum concentration of dutasteride in serum is reached within 1-3 hours. Absolute bioavailability is about 60%. The bioavailability of dutasteride is independent of food intake. Distribution 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 equilibrium concentrations after 1 month. and approximately 90% of this level after 3 months. The equilibrium concentration of dutasteride in serum (Css), equal to approximately 40 ng / ml, is reached after 6 months. daily intake of 0.5 mg once a day. Approximately 11.5% of dutasteride enters semen from serum. Biotransformation Dutasteride is extensively metabolized in vivo. In vitro, dutasteride is metabolized by the CYP3A4 and CYP3A5 isoenzymes of the P450 system to form three monohydroxylated metabolites and one dihydroxylated metabolite. After ingestion of dutasteride at a dose of 0.5 mg per day and reaching an equilibrium state in serum, from 1.0 to 15.4% (on average 5.4%) of the dose taken is excreted unchanged in the feces. The rest of the dose is excreted as 4 major metabolites accounting for 39%, 21%, 7% and 7%, respectively, and 6 minor metabolites (less than 5% each). In human urine, only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are found. Elimination Excretion of dutasteride is dose-dependent. The elimination process can be described as two parallel elimination processes, one saturable at clinically relevant concentrations and one non-saturable. At low serum concentrations (less than 3 ng/mL), dutasteride is rapidly eliminated by both concentration-dependent and concentration-independent 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. Elderly men The pharmacokinetics of dutasteride was studied in a study in 36 healthy male volunteers aged 24 to 87 years after a single dose of 5 mg. 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. Renal insufficiency The effect of renal insufficiency 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 in patients with renal insufficiency. Hepatic insufficiency The effect of hepatic insufficiency on the pharmacokinetics of dutasteride has not been studied (see section “Contraindications”), Since dutasteride is predominantly 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 dosage” and “Precautions”). 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. Information on the effect of treatment and patient populations studied in clinical studies is presented in the Pharmacodynamics section. Dosage and administration Avodart™ can be used as monotherapy, as well as in combination with ?-blocker tamsulosin (0.4 mg) (see sections “Precautions”, “Side Effects”, “Pharmacodynamics”). Adult men (including the elderly) The recommended dose of Avodart™ is one capsule (0.5 mg) once daily by mouth. Capsules should be swallowed whole, not chewed, not opened, since the contents of the capsule may cause irritation of the oropharyngeal mucosa. The capsules can be taken with or without food. Improvement in symptoms may be seen early in treatment, but it may take up to 6 months to achieve a response to therapy. Dose adjustment when used in elderly patients is not required. Patients with impaired renal function The effect of renal insufficiency on the pharmacokinetics of dutasteride has not been studied. In patients with renal insufficiency, dose adjustment is not expected (see section “Pharmacokinetics”). Patients with impaired liver function The effect of hepatic insufficiency on the pharmacokinetics of dutasteride has not been studied, therefore, caution should be exercised when used in patients with mild to moderate hepatic insufficiency (see sections “Precautions” and “Pharmacokinetics”). Dutasteride is contraindicated for use in patients with severe hepatic impairment (see section “Contraindications”). Use during pregnancy and lactation Avodart™ is contraindicated for use in women. Pregnancy Like other 5-β-reductase inhibitors, dutasteride prevents the conversion of testosterone to dihydrotestosterone; the effect of dutasteride on the body of a pregnant woman carrying a male fetus may adversely affect the development of the external genitalia of the fetus (see section “Precautions”). Small amounts of dutasteride were detected in the semen of subjects treated with Avodart™ at a daily dose of 0.5 mg. It is not known whether the mother’s exposure to the sperm of a patient receiving dutasteride has a negative effect on the male fetus (the greatest risk of exposure occurs during the first 16 weeks of pregnancy). As with all 5-β-reductase inhibitors, if pregnancy occurs or if pregnancy is suspected, contact of the woman with the sperm of the receiving man should be avoided using a condom. Lactation It is not known whether dutasteride is excreted in breast milk. Fertility It has been reported that dutasteride has an effect on sperm properties (decrease in sperm count, sperm volume and sperm motility) in healthy men (see Pharmacodynamics section). The possibility of a decrease in male fertility cannot be ruled out. Precautions Combination therapy should be prescribed only after a thorough assessment of the benefits and risks due to the increased likelihood of adverse reactions (including heart failure), as well as after consideration of alternative treatment options, including monotherapy (see section “Method of application and dosage”). Prostate Cancer and Low-grade Tumors The four-year, multicenter, randomized, double-blind, placebo-controlled REDUCE clinical trial examined the effects of dutasteride 0.5 mg daily in patients at high risk of developing prostate cancer (including men aged 50 to 75 years with a PSA level in the range of 2.5-10 ng / ml and a negative biopsy result 6 months before enrollment in the study) compared with placebo. The results of this study revealed an increase in the incidence of prostate cancer (8-10 on the Gleason score) in men treated with dutasteride (n = 29, 0.9%) compared with the placebo group (n = 19, 0.9%) . The relationship between dutasteride and prostate cancer (8-10 on the Gleason scale) is not clear. Men taking dutasteride should be regularly screened for the development of prostate cancer. Prostate-specific antigen (PSA) The serum prostate-specific antigen (PSA) concentration is an important part of the prostate cancer detection process. After 6 months of using Avodart™, mean serum PSA concentrations are reduced by approximately 50%. After 6 months of therapy with Avodart™, patients should have a new baseline PSA concentration determined. Subsequently, it is recommended to regularly monitor the concentration of PSA. Any confirmed increase in PSA levels from the minimum value during treatment with Avodart ™ may indicate the presence of prostate cancer or lack of compliance with Avodart ™ drug therapy and should be carefully studied, even if the assessed indicators are not outside the normal range for men, do not receiving an inhibitor of 5-β-reductase (see the section “Pharmacodynamics”). When interpreting a PSA reading in a patient receiving Avodart™, this reading should be compared with previous PSA readings. The use of the drug Avodart™ does not preclude the use of a PSA marker in the process of diagnosing prostate cancer after a new baseline has been determined. Serum total PSA concentrations return to baseline within 6 months after discontinuation of therapy. The ratio of unbound PSA to total PSA remains constant even with Avodart™. If clinicians use the percentage of unbound PSA when diagnosing prostate cancer in men receiving Avodart™, dose adjustment based on its value does not appear to be necessary. A digital rectal examination and other examinations to rule out prostate cancer should be performed prior to initiating Avodart™ treatment and periodically thereafter. Cardiovascular disorders In two four-year clinical studies, the incidence of heart failure (a composite term for a number of reported events, mainly heart failure and congestive heart failure) was slightly higher in patients taking the combination of Avodart™ and β-blockers , predominantly tamsulosin, compared with patients on monotherapy. However, in these studies, the incidence of heart failure was lower in all active treatment groups compared with the placebo group. Other data obtained for dutasteride or alpha-blockers do not indicate an increased risk of diseases of the cardiovascular system (see the Pharmacodynamics section). Breast cancer There have been rare reports of breast cancer in men taking dutasteride during clinical trials and post-marketing surveillance. However, epidemiological studies have not shown an increase in the risk of developing breast cancer in men with the use of 5-β-reductase inhibitors. Physicians should instruct patients to report any changes in breast tissue (eg, nodules or nipple discharge) immediately. Damaged capsules Dutasteride is absorbed through the skin, so women, children and adolescents should avoid contact with damaged capsules. In case of contact with damaged capsules, immediately wash the affected skin area with soap and water. Hepatic impairment Dutasteride has not been studied in patients with hepatic impairment. Therefore, dutasteride should be used with caution in patients with mild to moderate hepatic impairment. Interaction with other drugs Information on the decrease in serum PSA levels during dutasteride therapy and recommendations for the detection of prostate cancer are presented in the Precautions section. Effect of other medicinal products on the pharmacokinetics of dutasteride Co-administration with CYP3A4 inhibitors and/or P-glycoprotein inhibitors Dutasteride is predominantly eliminated by metabolism. In vitro metabolism of dutasteride is catalyzed by CYP3A4 and CYP3A5 isoenzymes. Formal interaction studies with potent inhibitors of CYP3A4 have not been conducted. At the same time, the results of one population pharmacokinetic study indicated that the concentrations of dutasteride in the blood serum in a small number of patients who received both verapamil or diltiazem (a moderate inhibitor of CYP3A4 and a P-glycoprotein inhibitor) were on average 1.6- 1.8 times higher than other patients. Long-term combined use of dutasteride and potent inhibitors of the CYP3A4 isoenzyme (ritonavir, indinavir, nefazodone, itraconazole, ketoconazole when administered orally) can cause an increase in the concentration of dutasteride in serum. Additional inhibition of 5-β-reductase with increasing exposure to dutasteride is unlikely. However, if side effects occur, consider reducing the frequency of taking dutasteride. It should also be noted that in the case of inhibition of the action of the enzyme, the long half-life may be further increased, as a result of which it may take more than 6 months to reach a new equilibrium state. The use of cholestyramine at a dose of 12 g one hour after a single dose of dutasteride 5 mg did not affect the pharmacokinetics of dutasteride. Effects of dutasteride on the pharmacokinetics of other medicinal products Dutasteride does not affect the pharmacokinetics of warfarin or digoxin. This suggests that dutasteride does not inhibit/induce either the CYP2C9 isoenzyme or the P-glycoprotein transport protein. In vitro, dutasteride does not inhibit isoenzymes such as CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. In a small clinical study (N = 24) lasting two weeks in healthy men, the use of dutasteride (0.5 mg per day) did not affect the pharmacokinetics of tamsulosin and tetrazosin. Results indicative of a pharmacodynamic interaction were not obtained in this study. Contraindications Avodart™ is contraindicated in: women, children and adolescents (see section “Effects on fertility, pregnancy and lactation); patients with hypersensitivity to dutasteride, other 5-β-reductase inhibitors, soy, peanuts, or any