EZETREKS

INSTRUCTIONS for medical use of the medicinal product DUTAFORCE (DUTAFORCE)

Composition:

active substances: dutasteride, tamsulosin hydrochloride;

1 capsule contains 0.5 mg of dutasteride and 0.4 mg of tamsulosin hydrochloride;

excipients:

hard capsule shell: hypromellose, carrageenan (E 407), potassium chloride, titanium dioxide (E 171), yellow "sunset" (E 110), iron oxide red (E 172);

dutasteride, soft capsules 0.5 mg: glycerol monocaprylocaprate type I, butylhydroxytoluene (E 321), gelatin, glycerin, titanium dioxide (E 171), iron oxide yellow (E 172), medium-chain triglycerides, lecithin (E 322);

tamsulosin hydrochloride, pellets 0.4 mg: microcrystalline cellulose, magnesium stearate, methacrylic acid - ethyl acrylate copolymer (1:1) dispersion 30%, methacrylic acid - ethyl acrylate copolymer (1:1), sodium hydroxide, triacetin, talc, titanium dioxide (E 171).

Pharmaceutical form.

Hard capsules.

Main physical and chemical properties:

hard capsules with an orange cap and a brown body, containing white or off-white pellets and one yellow soft gelatin capsule with a oily yellowish liquid.

Pharmacotherapeutic group.

Drugs used in benign prostatic hyperplasia. Alpha-1 adrenoreceptor antagonist. ATC code G04C A52.

Pharmacological properties.

Pharmacodynamics.

Dutafors is a combination of two medicinal products: dutasteride, a dual 5-alpha-reductase inhibitor (5ARI), and tamsulosin hydrochloride, an alpha-1a and alpha-1d adrenoreceptor antagonist. These medicinal products have a complementary mechanism of action, resulting in rapid relief of urination, reduced risk of acute urinary retention (AUR), and reduced likelihood of needing surgical intervention for benign prostatic hyperplasia.

It is not expected that the pharmacodynamic effects of the fixed-dose combination of dutasteride and tamsulosin will differ from those obtained with concomitant administration of dutasteride and tamsulosin as separate components.

Dutasteride

Dutasteride inhibits the activity of both type 1 and type 2 isoforms of 5-alpha-reductase, which are responsible for converting testosterone to dihydrotestosterone (DHT). DHT is an androgen that is primarily responsible for the growth of the prostate and the development of benign prostatic hyperplasia. Tamsulosin inhibits the activity of alpha-1a and alpha-1d adrenoreceptors in the stromal smooth muscle of the prostate and the neck of the urinary bladder. Approximately 75% of alpha-1 receptors in the prostate are alpha-1a subtype receptors.

Tamsulosin

Tamsulosin increases the maximum flow rate of urine by reducing the tone of the smooth muscles of the urethra and prostate, eliminating obstruction. The drug also reduces the severity of symptoms of irritation and obstruction, in the development of which a significant role is played by urinary incontinence and contraction of the smooth muscles of the lower urinary tract. Such an effect is achieved during long-term therapy. The need for surgical intervention or catheterization is significantly reduced.

Alpha-1 adrenoreceptor antagonists may decrease blood pressure by reducing total peripheral resistance. During the study of the effect of tamsulosin, no clinically significant decrease in blood pressure was observed.

Pharmacokinetics.

A bioequivalence study between the combination of dutasteride and tamsulosin and concomitant administration of dutasteride and tamsulosin in separate capsules has been demonstrated.

A bioequivalence study of single doses was conducted both in the fasting state and after food intake. Compared to the fasting state, when the drug was administered after food intake, a 30% decrease in the maximum concentration (Cmax) of tamsulosin in the combination of dutasteride and tamsulosin was observed. Food did not affect the area under the pharmacokinetic curve "concentration-time" (AUC) of tamsulosin.

Absorption

Dutasteride

After oral administration of a single dose of 0.5 mg of dutasteride, the time to reach its maximum concentration in serum was 1-3 hours. Absolute bioavailability was approximately 60%. Food intake did not affect the bioavailability of dutasteride.

Tamsulosin

Tamsulosin is absorbed from the intestine and is almost completely bioavailable. Both the rate and extent of tamsulosin absorption are decreased if it is taken within 30 minutes after eating. Uniform absorption is ensured by taking the medicinal product Dutafors at the same time of day after eating the same type of food. The concentration of tamsulosin in plasma is proportional to the dose.

After administration of a single dose of tamsulosin after food, Cmax is reached approximately 6 hours later. Steady-state concentration is reached on the 5th day of multiple administration. The mean steady-state concentration in patients is approximately two-thirds higher than the concentration after a single dose of tamsulosin. Although this phenomenon was observed in elderly patients, the same result can be expected in younger patients.

Distribution

Dutasteride

Dutasteride has a large volume of distribution (300-500 liters) and high binding to plasma proteins (>99.5%). After daily administration of doses, the concentration of dutasteride in serum reaches 65% of the steady-state concentration after 1 month and approximately 90% after 3 months.

The steady-state concentration in serum (Css), which is approximately 40 ng/ml, is reached after 6 months of administration of a dose of 0.5 mg per day. The mean transfer of dutasteride from serum to seminal fluid is 11.5%.

Tamsulosin

In men, tamsulosin is bound to plasma proteins by approximately 99%. The volume of distribution is small (approximately 0.21/kg).

Metabolism

Dutasteride

Dutasteride is actively metabolized in vivo. In vitro, dutasteride is metabolized by cytochrome P450 3A4 and 3A5, forming three monohydroxylated metabolites and one dihydroxylated metabolite.

After oral administration of dutasteride at a dose of 0.5 mg per day to reach steady-state concentration, 1.0-15.4% (mean 5.4%) of the administered dose of dutasteride is excreted in the feces in unchanged form. The rest is excreted in the feces in the form of 4 main metabolites, which contain 39%, 21%, 7%, and 7% of each substance related to the medicinal product, and 6 secondary metabolites (less than 5% each). Only insignificant amounts of unchanged dutasteride (less than 0.1% of the dose) are found in human urine.

Tamsulosin

Enantiomeric bioconversion of tamsulosin hydrochloride [(R)-isomer] to (S)-isomer does not occur in humans. Tamsulosin hydrochloride is actively metabolized by cytochrome P450 enzymes in the liver, and less than 10% of the dose is excreted in the urine in unchanged form. 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, as well as the minor involvement of other CYP isoenzymes.

Inhibition of the activity of enzymes involved in liver metabolism may lead to enhanced action of tamsulosin. Before excretion in the urine, tamsulosin hydrochloride metabolites undergo extensive binding to glucuronide or sulfate.

Excretion

Dutasteride

The excretion of dutasteride depends on the dose, and this process should be described as occurring through two parallel pathways: one is saturated at clinically significant concentrations, and the other is non-saturated. At low concentrations in serum (less than 3 ng/ml), dutasteride is rapidly excreted by both concentration-dependent and concentration-independent pathways. When using single doses of 5 mg or less, signs of rapid clearance and a half-life of 3-9 days were found.

At therapeutic concentrations, after repeated administration of a dose of 0.5 mg per day, the slower, linear pathway of excretion predominates, and the half-life is approximately 3-5 weeks.

Tamsulosin

Tamsulosin and its metabolites are excreted mainly in the urine, in which approximately 9% of the dose is in the form of unchanged active substance.

After intravenous or oral administration in an immediate-release formulation, the half-life of tamsulosin in plasma ranges from 5 to 7 hours. Due to pharmacokinetics regulated by the rate of absorption in the case of tamsulosin in capsules with modified release, the true half-life of tamsulosin taken after food is approximately 10 hours, and in steady-state concentration in patients, it is approximately 13 hours.

Elderly patients

Dutasteride

The pharmacokinetics of dutasteride was evaluated in 36 healthy male volunteers aged 24 to 87 years after administration of a single dose of 5 mg. No significant effect of dutasteride on age was observed, but the half-life was shorter in men under 50 years of age. There were no statistical differences in half-life when comparing the group of 50-69-year-old subjects with the group of subjects over 70 years old.

Tamsulosin

A crossover study comparing the overall effect of tamsulosin hydrochloride (AUC) and half-life indicates that the pharmacokinetic effect of tamsulosin hydrochloride may be slightly longer in elderly patients compared to young healthy male volunteers. The intrinsic clearance does not depend on the binding of tamsulosin hydrochloride to alpha-1 acid glycoprotein, but decreases with age, resulting in a 40% stronger effect (AUC) in patients aged 55-75 years compared to patients aged 20-32 years.

Renal impairment

Dutasteride

The effect of renal impairment on the pharmacokinetics of dutasteride has not been studied. However, less than 0.1% of the dose of dutasteride 0.5 mg at steady-state concentration is found in human urine, so a clinically significant increase in dutasteride concentration in plasma is not expected in patients with renal impairment (see "Method of administration and dosage").

Tamsulosin

The pharmacokinetics of tamsulosin hydrochloride was compared in 6 patients with renal impairment from mild to moderate (30 ≤ CLcr <70 ml/min/1.73 m2) or from moderate to severe (10 ≤ CLcr <30 ml/min/1.73 m2) and in 6 subjects with normal creatinine clearance (CLcr <90 ml/min/1.73 m2). While there was a change in the total concentration of tamsulosin hydrochloride in plasma due to variable binding to alpha-1 acid glycoprotein, the concentration of unbound (active) tamsulosin hydrochloride and its intrinsic clearance remained relatively stable. Therefore, patients with renal impairment do not require dose adjustment of tamsulosin hydrochloride. However, patients with end-stage renal disease (CLcr <10 ml/min/1.73 m2) were not studied.

Hepatic impairment

Dutasteride

The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied (see "Contraindications"). Since dutasteride is excreted mainly by metabolism, it is expected that the level of dutasteride in the plasma of these patients will be increased, and the half-life will be longer (see "Special instructions" and "Method of administration and dosage").

Tamsulosin

The pharmacokinetics of tamsulosin hydrochloride was compared in 8 patients with moderate liver function impairment (Child-Pugh: grades A and B) and in 8 subjects with normal liver function. While there was a change in the total concentration of tamsulosin hydrochloride in plasma due to variable binding to alpha-1 acid glycoprotein, the concentration of unbound (active) tamsulosin hydrochloride did not change significantly, with only a moderate (32%) change in the intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, patients with moderate liver function impairment do not require dose adjustment of tamsulosin hydrochloride. The effect of tamsulosin hydrochloride has not been studied in patients with severe liver function impairment.

Safety and clinical studies

Heart failure

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

In a separate 4-year clinical comparative study of placebo with chemical prevention using dutasteride in 8231 men aged 50 to 75 years with previous negative prostate biopsy results and an initial PSA level between 2.5 ng/ml and 10.0 ng/ml in men aged 50 to 60 years or 3 ng/ml and 10.0 ng/ml in men aged 60 years (REDUCE study), it was found that the frequency of heart failure in patients taking dutasteride 0.5 mg once daily (30/4105, 0.7%) was higher compared to patients taking placebo (16/4126, 0.4%). A retrospective analysis of this study showed a higher frequency of heart failure in patients taking dutasteride and an alpha-blocker simultaneously (12/1152, 1.0%) compared to patients taking dutasteride without an alpha-blocker (18/2953, 0.6%), placebo and an alpha-blocker (1/1399, <0.1%), or placebo without an alpha-blocker (15/2727, 0.6%). A causal relationship between the use of dutasteride (as monotherapy or in combination with alpha-blockers) and the development of heart failure has not been established (see "Special instructions").

Prostate cancer and high-grade tumors

In a 4-year study in which the effect of dutasteride was compared with placebo in 8231 men aged 50 to 75 years with previous negative prostate biopsy results and an initial PSA level between 2.5 ng/ml and 10.0 ng/ml in men aged 50 to 60 years or 3 ng/ml and 10.0 ng/ml in men aged 60 years (REDUCE study), 6706 patients underwent needle biopsy of the prostate (mandatory according to the primary protocol), the data of which were used to analyze the differentiation according to the Gleason scale. In the study, 1517 patients were diagnosed with prostate cancer. Most of the prostate tumors (70%) found through biopsy in both treatment groups had a high level of differentiation (5-6 points on the Gleason scale).

In the dutasteride group, a higher frequency of low-differentiated prostate cancer (n = 29, 0.9%) was registered compared to the placebo group (n = 19, 0.6%) (p = 0.15). In the first 2 years of the study, the number of patients with prostate cancer with a score of 8-10 on the Gleason scale was the same in the dutasteride group (n = 17, 0.5%) and in the placebo group (n = 18, 0.5%). During the 3-4 years of the study, a larger number of cases of prostate cancer with a score of 8-10 on the Gleason scale were diagnosed in the dutasteride group (n = 12, 0.5%) compared to the placebo group (n = 1, <0.1%) (p = 0.0035). There are no data on the impact on the risk of developing prostate cancer in men who took dutasteride for more than 4 years. The percentage of patients diagnosed with prostate cancer with a score of 8-10 on the Gleason scale remained constant during different periods of the study (1-2 years, 3-4 years) in the dutasteride group (0.5% in each period), while in the placebo group, the percentage of patients with low-differentiated prostate cancer (8-10 on the Gleason scale) was lower in the 3-4 years than in the 1-2 years (<0.1% and 0.5%, respectively) (see "Special instructions"). No difference was found in the frequency of cases of prostate cancer with a score of 7-10 on the Gleason scale (p = 0.81).

Breast cancer in men

Two case-control epidemiological studies, one conducted in the United States (n = 339 cases of breast cancer and n = 6780 in the control group) and the other in the United Kingdom (n = 398 cases of breast cancer and n = 3930 in the control group) in health care databases, did not show any increased risk of breast cancer in men taking 5-alpha-reductase inhibitors. The results of the first study did not find a positive association with breast cancer (relative risk for ≥1 year of use before diagnosis of breast cancer compared to <1 year of use: 0.70; 95% CI 0.34, 1.45). In the second study, the estimated relative risk of breast cancer associated with the use of 5-alpha-reductase inhibitors compared to non-use was 1.08 (95% CI 0.62, 1.87).

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

Clinical characteristics

Indications

Treatment of moderate and severe symptoms of benign prostatic hyperplasia.

Reducing the risk of acute urinary retention and the need for surgical intervention in patients with moderate and severe symptoms of benign prostatic hyperplasia.

Contraindications

Dutafors is not used to treat women and children (see "Use during pregnancy or breastfeeding").

Dutafors is contraindicated in patients with hypersensitivity to dutasteride, other 5-alpha-reductase inhibitors, tamsulosin (including tamsulosin-induced angioneurotic edema), other components of the medicinal product, or to soy and peanuts.

Dutafors is contraindicated in patients with a history of orthostatic arterial hypotension.

Dutafors is contraindicated in patients with severe liver impairment.

Interactions with other medicinal products and other types of interactions

Studies of the interaction of the combination medicinal product with other medicinal products have not been conducted. The available information on individual components of the medicinal product is provided below.

Dutasteride

For information on the decrease in prostate-specific antigen (PSA) levels in serum during treatment with dutasteride and recommendations for detecting prostate cancer, see "Special instructions".

Influence of other medicinal products on the pharmacokinetics of dutasteride

Concomitant use with CYP3A4 and/or P-glycoprotein inhibitors

Dutasteride is excreted mainly by metabolism. In vitro studies show that the catalysts of metabolism are CYP3A4 and CYP3A5. Official interaction studies with potent CYP3A4 inhibitors have not been conducted. However, in a population pharmacokinetic study, dutasteride concentrations in serum were on average 1.6-1.8 times higher in a small number of patients who were concomitantly treated with verapamil or diltiazem (moderate CYP3A4 and P-glycoprotein inhibitors) compared to other patients.

During long-term concomitant use of dutasteride with medicinal products that are potent inhibitors of the CYP3A4 enzyme (e.g., ritonavir, indinavir, nefazodone, itraconazole, ketoconazole, taken orally), the concentration of dutasteride in serum may increase. Further inhibition of 5-alpha-reductase with enhanced dutasteride activity is unlikely. However, a possible reduction in the frequency of dutasteride administration may be necessary in the event of adverse reactions. In the event of enzyme inhibition, the long half-life may become even longer, and concomitant therapy may last more than 6 months before a new steady-state concentration is reached.

Concomitant use of 12 g of cholestyramine 1 hour after administration of a single dose of 5 mg of dutasteride did not affect the pharmacokinetics of dutasteride.

Influence of dutasteride on the pharmacokinetics of other medicinal products

In a small study (n = 24) lasting 2 weeks in healthy male volunteers, dutasteride (0.5 mg per day) did not affect the pharmacokinetics of tamsulosin or terazosin. In this study, there were also no signs of pharmacodynamic interaction.

Dutasteride does not affect the pharmacokinetics of warfarin or digoxin. This indicates that dutasteride does not inhibit/induce the activity of the CYP2C9 enzyme or the P-glycoprotein transporter. Data from in vitro interaction studies indicate that dutasteride does not inhibit the CYP1A2, CYP2D6, CYP2C9, CYP2C19, or CYP3A4 enzymes.

Tamsulosin

Concomitant use of tamsulosin hydrochloride with medicinal products that can lower blood pressure, including analgesics, phosphodiesterase inhibitors, and other alpha-1 adrenoblockers, may theoretically lead to enhanced hypotensive action. Therefore, Dutafors should not be used in combination with other alpha-1 adrenoblockers.

Concomitant use of tamsulosin hydrochloride and ketoconazole (a potent CYP3A4 inhibitor) increases the Cmax and AUC of tamsulosin hydrochloride by 2.2 and 2.8 times, respectively.

Concomitant use of tamsulosin hydrochloride and paroxetine (a potent CYP2D6 inhibitor) increases the Cmax and AUC of tamsulosin hydrochloride by 1.3 and 1.6 times, respectively. A similar increase is expected in patients with poor CYP2D6 metabolism compared to those with extensive metabolism when concomitantly used with potent CYP3A4 inhibitors.

The effect of concomitant use of both CYP3A4 and CYP2D6 inhibitors with tamsulosin has not been clinically studied, but it may potentially significantly increase the concentration of tamsulosin (see "Special instructions").

Concomitant use of tamsulosin hydrochloride (0.4 mg) and cimetidine (400 mg every 6 hours for 6 days) resulted in a decrease in clearance (26%) and an increase in AUC (44%) of tamsulosin hydrochloride. The medicinal product Dutafors should be used with caution in combination with cimetidine.

A comprehensive study of the interaction between tamsulosin hydrochloride and warfarin has not been conducted. The results of limited in vitro and in vivo studies are insufficient. Concomitant treatment with warfarin and tamsulosin hydrochloride should be carried out with caution.

No interaction was observed when tamsulosin hydrochloride was administered concomitantly with atenolol or enalapril, or nifedipine, or theophylline. Concomitant use of furosemide results in a decrease in the level of tamsulosin in serum, but since these levels remain within the normal range, dose adjustment is not required.

In vitro, neither diazepam, nor propranolol, nor trichlormethiazide, nor chlormadinone, nor amitriptyline, nor diclofenac, nor glibenclamide, nor simvastatin changes the free fraction of tamsulosin in human plasma. Tamsulosin also does not change the free fractions of diazepam, propranolol, trichlormethiazide, and chlormadinone.

No interaction at the level of liver metabolism was observed during in vitro studies with microsomal fractions of the liver (the cytochrome P450 system, which metabolizes medicinal products) using amitriptyline, salbutamol, and glibenclamide. However, diclofenac may increase the rate of elimination of tamsulosin.

Special instructions

Combination therapy is prescribed after careful analysis of the benefit/risk ratio due to the potential increase in the risk of adverse reactions (including heart failure) and the study of alternative treatment options, including monotherapy.

Cardiovascular adverse reactions

According to two 4-year clinical studies, the frequency of heart failure (a collective term for all reports, mainly heart failure and congestive heart failure) was higher in individuals treated with a combination of dutasteride and an alpha-blocker, mainly tamsulosin, compared to those not treated with such a combination. The frequency of heart failure was low (≤1%) and variable within these studies. There are no imbalances in the frequency of cardiovascular adverse events in any of the studies. A causal relationship between the use of dutasteride (alone or in combination with alpha-blockers) and the development of heart failure has not been established (see "Pharmacological properties").

A meta-analysis of 12 randomized, placebo- or comparator-controlled clinical studies (n = 18,802) evaluating the risk of cardiovascular adverse events with dutasteride (compared to the control group) did not establish a sustained statistically significant increase in the risk of heart failure (RR 1.05; 95% CI 0.71, 1.57), acute myocardial infarction (RR 1.00; 95% CI 0.77, 1.30), or stroke (RR 1.20; 95% CI 0.88, 1.64).

Prostate cancer and high-grade tumors

In the course of a 4-year clinical study involving more than 8,000 men aged 50 to 75 years with previous negative prostate biopsy results and an initial PSA level between 2.5 ng/ml and 10.0 ng/ml (REDUCE study), a higher frequency of prostate cancer with a differentiation of 8-10 on the Gleason scale was observed in the dutasteride group (n = 29, 0.9%) compared to the placebo group (n = 19, 0.6%). A causal relationship between the use of dutasteride and the development of low-differentiated prostate cancer has not been established. The clinical significance of this numerical imbalance is unknown.

Men using Dutafors should undergo regular examinations to determine the risk of developing prostate cancer, including a prostate-specific antigen test.

In an additional consecutive 2-year follow-up of the original patients using dutasteride for chemical prevention (REDUCE study), a low frequency of new cases of prostate cancer (dutasteride group [n = 14, 1.2%]) and placebo group [n = 7, 0.7%]) was established, with no new cases of prostate cancer with a differentiation of 8-10 on the Gleason scale identified.

Long-term consecutive (up to 18 years) follow-up of patients from a clinical study using another 5-alpha-reductase inhibitor (finasteride) for chemical prevention did not show a statistically significant difference between the finasteride and placebo groups in terms of overall survival (HR 1.02; 95% CI 0.97, 1.08) or survival after diagnosis of prostate cancer (HR 1.01; 95% CI 0.85, 1.20).

Influence on prostate-specific antigen (PSA)

The concentration of prostate-specific antigen (PSA) is an important component of the screening process for detecting prostate cancer. Dutasteride can decrease the level of serum PSA in patients by approximately 50% after 6 months of treatment.

Patients taking Dutafors should have a new baseline PSA level established after 6 months of treatment with this medicinal product. This level is then recommended to be checked regularly. Any confirmed increase in PSA level from the lowest level during treatment with Dutafors may be a sign of prostate cancer or non-compliance with the treatment regimen and requires careful examination, even if PSA levels are within the normal range for men not treated with 5-alpha-reductase inhibitors. When interpreting PSA levels in patients treated with Dutafors, previous PSA levels should be taken into account for comparison.

The overall level of serum PSA returns to the initial level within 6 months after stopping treatment.

The ratio of free PSA to total PSA remains constant even during treatment with Dutafors. If the doctor decides to use the percentage of free PSA to detect prostate cancer in a patient taking Dutafors, no correction of the free PSA level is required.

Excipients

The medicinal product contains the dye yellow "sunset" (E 110), which can cause allergic reactions.

This medicinal product contains lecithin derived from soybean oil. In case of established allergy to peanuts or soy, this medicinal product should not be used (see "Contraindications").

Breast cancer in men

Rare cases of breast cancer in men have been reported during clinical studies and in the post-marketing period. However, epidemiological studies indicate that there is no increased risk of breast cancer in men taking 5-alpha-reductase inhibitors. Doctors should inform their patients about the need to immediately report any changes in breast tissue, such as nipple discharge or swelling.

Use during pregnancy or breastfeeding

Dutafors is contraindicated for the treatment of women. Studies on the effect of the medicinal product on pregnancy, lactation, and fertility have not been conducted. The information on the use of each component separately is provided below.

Fertility

Dutasteride affects the characteristics of ejaculate (reduced sperm count, ejaculate volume, and sperm motility). The risk of decreased male fertility cannot be excluded.

The effect of tamsulosin hydrochloride on sperm count or function has not been evaluated.

Pregnancy

Like other 5-alpha-reductase inhibitors, dutasteride prevents the conversion of testosterone to dihydrotestosterone, which may slow the development of external genitalia in a male fetus. A small amount of dutasteride has been detected in the ejaculate during a study. It is unknown whether dutasteride, which enters the body of a woman through semen, affects a male fetus.

As with the use of other 5-alpha-reductase inhibitors, it is recommended to use a condom during sexual intercourse if the woman is pregnant and the man is taking the medicinal product Dutafors to prevent semen from entering the woman's body.

Breastfeeding

It is unknown whether dutasteride and tamsulosin are excreted in human breast milk.

Ability to affect the speed of reaction when driving vehicles or operating machinery

Studies on the effect of the medicinal product Dutafors on the ability to drive vehicles or operate machinery have not been conducted. However, patients should be informed about the possible development of symptoms associated with orthostatic arterial hypotension, such as dizziness, when using Dutafors.

Method of administration and dosage

Adults (including elderly patients)

The recommended dose of Dutafors is 1 capsule (0.5 mg/0.4 mg) per day. The medicinal product is taken orally 30 minutes after food intake at the same time of day. The capsule should be swallowed whole, without opening or chewing, as contact with the contents of the capsule can cause irritation of the mucous membranes of the mouth and throat.

Dutafors can be used to replace combination therapy with dutasteride and tamsulosin hydrochloride to facilitate treatment.

Replacing dutasteride or tamsulosin hydrochloride with monotherapy is possible if it is clinically justified.

Renal impairment

The pharmacokinetics of the medicinal product in patients with renal impairment has not been studied. It is not necessary to adjust the dose of the medicinal product for the treatment of such patients (see "Pharmacokinetics" and "Special instructions").

Hepatic impairment

The pharmacokinetics of the medicinal product in patients with hepatic impairment has not been studied, so the medicinal product should be used with caution in patients with mild and moderate hepatic impairment (see "Pharmacokinetics" and "Special instructions"). Patients with severe hepatic impairment are contraindicated (see "Contraindications").

Children

Use is contraindicated in children under 18 years of age.

Overdose

There are no data on cases of overdose with Dutafors. The information on the use of each component separately is provided below.

Dutasteride

According to clinical studies, single doses of dutasteride up to 40 mg per day (80 times higher than therapeutic) for 7 days did not cause concerns about safety. During clinical studies, doses of dutasteride of 5 mg per day for 6 months were used without the appearance of additional adverse reactions compared to the use of dutasteride at a dose of 0.5 mg per day.

There is no specific antidote, so in case of possible overdose, symptomatic and supportive therapy is performed.

Tamsulosin

Reports of acute overdose of tamsulosin hydrochloride at a dose of 5 mg have been received, resulting in acute arterial hypotension (systolic blood pressure 70 mmHg), vomiting, and diarrhea, which were treated with fluid infusion, after which the patient felt relief on the same day. In case of acute arterial hypotension that occurs after an overdose of tamsulosin hydrochloride, support of cardiovascular activity should be ensured. The patient should be placed in a horizontal position to restore blood pressure and normalize heart rate. If this does not help, plasma substitutes and, if necessary, vasoconstrictors should be prescribed. It is necessary to monitor kidney function and provide general supportive therapy. Dialysis may be ineffective, as tamsulosin hydrochloride is almost completely bound to plasma proteins.

In case of overdose, to prevent absorption, the patient should induce vomiting. If large doses of the medicinal product are taken, gastric lavage, activated charcoal, and a laxative, such as sodium sulfate, should be administered.

Adverse reactions

Information on adverse reactions for each component separately (dutasteride and tamsulosin) is also provided below. Not all adverse reactions reported with the use of each component separately have been reported with the use of the combination of dutasteride and tamsulosin, so information on adverse reactions with the use of individual components of Dutafors is also included in this instruction.

According to the 4-year CombAT study, the percentage of adverse reactions identified by researchers during the first, second, third, and fourth years of treatment changed: respectively, 22%, 6%, 4%, and 2% with combination therapy with dutasteride and tamsulosin; 15%, 6%, 3%, and 2% with monotherapy with dutasteride; 13%, 5%, 2%, and 2% with monotherapy with tamsulosin. A higher percentage of adverse reactions in the combination therapy group during the first year of treatment is due to higher rates of reproductive disorders, namely ejaculation disorders, which were observed in the combination group.

Adverse reactions that occurred with a frequency of ≥1% during the first year of application, according to the researchers' analysis of the CombAT, REDUCE studies, and clinical studies of monotherapy with the components of Dutafors, are presented in the table.

Information on adverse reactions of tamsulosin is based on available data. The frequency of their occurrence may increase with concomitant use of dutasteride and tamsulosin.

The frequency of adverse reactions that occurred, according to clinical studies and post-marketing surveillance, is presented in the table.

Post-marketing study data

Adverse reactions were reported from spontaneous reports, so the exact frequency of such reactions is unknown.

Monotherapy with dutasteride

Immune system disorders

Frequency unknown: allergic reactions, including rash, pruritus, urticaria, localized edema, and angioneurotic edema.

Psychiatric disorders

Frequency unknown: depression.

Skin and subcutaneous tissue disorders

Rare: alopecia (mainly body hair loss), hirsutism.

Reproductive system and breast disorders

Frequency unknown: testicular pain and swelling.

Monotherapy with tamsulosin

According to post-marketing surveillance, during cataract surgery and glaucoma surgery in some patients who had previously taken alpha-1 adrenoblockers, including tamsulosin, an intraoperative floppy iris syndrome (IFIS, a variant of the small pupil syndrome) was noted (see "Special instructions").

During post-marketing use, additional reports of cases of atrial fibrillation, arrhythmia, tachycardia, dyspnea, nosebleeds, vision disorders, including decreased visual acuity, multiform erythema, exfoliative dermatitis, and dry mouth have been associated with the use of tamsulosin.

Other data

In the course of a clinical study (REDUCE study), men treated with dutasteride had a higher frequency of prostate cancer (Gleason score 8-10) compared to the placebo group (see "Pharmacological properties" and "Special instructions"). A causal relationship between the use of dutasteride and the development of high-grade prostate cancer has not been established.

According to clinical studies and post-marketing surveillance, reports of cases of breast cancer in men have been received (see "Special instructions").

Shelf life

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of the reach of children.

Packaging

6 hard capsules in a blister pack, 5 blister packs in a carton. 9 hard capsules in a blister pack, 10 blister packs in a carton.

Release category

Prescription only.

Manufacturer

SAG MANUFACTURING, S.L.U., Spain.

Manufacturer's location and address

Carretera Nacional 1 Km 36, San Agustin del Guadalix, 28750 Madrid, Spain.