Dutaphors

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:

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

Dutasteride, soft capsules 0.5 mg: glycerol monocaprylocaprate type I, butylated hydroxytoluene (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 physicochemical properties: hard capsules with an orange cap and brown body, containing white or almost white pellets and one yellow soft gelatin capsule with a yellowish oily liquid.

Pharmacotherapeutic group. Medicinal products used in benign prostatic hyperplasia. α1-adrenoreceptor antagonist. ATC code G04C A52.

Pharmacological Properties.

Pharmacodynamics.

Dutafors is a combination of two medicinal agents: dutasteride, a dual inhibitor of 5α-reductase (5ARI), and tamsulosin hydrochloride, an antagonist of α1a and α1d adrenergic receptors. These agents have complementary mechanisms of action, resulting in rapid relief of urinary symptoms, reduced risk of acute urinary retention (AUR), and decreased likelihood of surgical intervention for benign prostatic hyperplasia.

The pharmacodynamic effects of the fixed-dose combination of dutasteride and tamsulosin are not expected to differ from those observed with concomitant administration of dutasteride and tamsulosin as separate components.

Dutasteride

Dutasteride inhibits the activity of both type 1 and type 2 isoenzymes of 5α-reductase, which are responsible for converting testosterone into dihydrotestosterone (DHT). DHT is an androgen primarily responsible for prostate growth and the development of benign prostatic hyperplasia. Tamsulosin inhibits α1a and α1d adrenergic receptors in the smooth muscle of the prostate stroma and bladder neck. Approximately 75% of α1 receptors in the prostate are of the α1a subtype.

Tamsulosin

Tamsulosin increases the maximum urinary flow rate by reducing the tone of smooth muscles in the urethra and prostate, thereby alleviating obstruction. The drug also reduces the severity of irritative and obstructive symptoms, in which urinary incontinence and contraction of smooth muscles in the lower urinary tract play a significant role. This effect is achieved during long-term therapy. The need for surgical intervention or catheterization is significantly reduced.

α1-adrenergic receptor antagonists may reduce blood pressure by decreasing total peripheral resistance. However, during studies with tamsulosin, no clinically significant reduction in blood pressure was observed.

Pharmacokinetics.

Bioequivalence has been demonstrated between administration of the dutasteride-tamsulosin combination and simultaneous administration of separate capsules of dutasteride and tamsulosin.

Bioequivalence studies of single doses were conducted both under fasting conditions and after food intake. Compared to fasting, administration of the drug after food resulted in a 30% reduction in the maximum plasma concentration (Cmax) of tamsulosin in the dutasteride-tamsulosin combination. Food did not affect the area under the pharmacokinetic concentration-time curve (AUC) of tamsulosin.

Absorption

Dutasteride

After single oral administration of a 0.5 mg dose of dutasteride, the time to reach maximum serum concentration 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 reduced if taken within 30 minutes after a meal. Consistent absorption is ensured by taking Dutafors at the same time of day and after consuming a similar type of meal. Plasma tamsulosin concentration is dose-proportional.

After administration of a single dose of tamsulosin following a meal, Cmax is reached approximately 6 hours later. Steady-state concentration is achieved by day 5 of repeated dosing. The average steady-state concentration in patients is approximately two-thirds higher than after a single dose. Although this phenomenon was observed in elderly patients, similar results can be expected in younger patients.

Distribution

Dutasteride

Dutasteride has a large volume of distribution (300–500 L) and high plasma protein binding (>99.5%). After daily dosing, serum dutasteride concentration reaches 65% of steady-state levels within 1 month and approximately 90% within 3 months.

The steady-state serum concentration (Css), approximately 40 ng/mL, is achieved after 6 months of 0.5 mg daily dosing. The mean transfer rate of dutasteride from serum into seminal fluid is 11.5%.

Tamsulosin

In men, tamsulosin is approximately 99% bound to plasma proteins. The volume of distribution is small (approximately 0.2 L/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 0.5 mg dutasteride daily until steady-state is reached, 1.0–15.4% (mean 5.4%) of the administered dose is excreted unchanged in feces. The remainder is excreted in feces as four major metabolites (containing 39%, 21%, 7%, and 7% of drug-related substances, respectively) and six minor metabolites (each <5%). Only negligible amounts of unchanged dutasteride (<0.1% of dose) are found in human urine.

Tamsulosin

Enantiomeric bioconversion of tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer does not occur in humans. Tamsulosin hydrochloride is actively metabolized by hepatic cytochrome P450 enzymes, with less than 10% of the dose excreted unchanged in urine. However, the pharmacokinetic profile of metabolites in humans has not been established. In vitro studies indicate that CYP3A4 and CYP2D6 enzymes are involved in tamsulosin metabolism, with minor contributions from other CYP isoenzymes.

Inhibition of enzymes involved in hepatic metabolism may lead to enhanced tamsulosin effects. Before excretion in urine, tamsulosin hydrochloride metabolites undergo extensive conjugation with glucuronic acid or sulfate.

Elimination

Dutasteride

Dutasteride elimination is dose-dependent and should be described as occurring via two parallel pathways: one saturable at clinically relevant concentrations and the other nonsaturable. At low serum concentrations (<3 ng/mL), dutasteride is rapidly eliminated via both concentration-dependent and concentration-independent pathways. After single doses of 5 mg or lower, signs of rapid clearance were observed, with elimination half-life ranging from 3 to 9 days.

At therapeutic concentrations following repeated 0.5 mg daily dosing, the slower, linear elimination pathway predominates, with an elimination half-life of approximately 3–5 weeks.

Tamsulosin

Tamsulosin and its metabolites are primarily excreted in urine, with approximately 9% of the dose excreted as unchanged active substance.

After intravenous or oral administration in immediate-release formulations, the plasma elimination half-life of tamsulosin ranges from 5 to 7 hours. Due to absorption rate-limited pharmacokinetics with modified-release tamsulosin capsules, the true elimination half-life of tamsulosin taken after food is approximately 10 hours, and at steady-state in patients, approximately 13 hours.

Elderly Patients

Dutasteride

The pharmacokinetics of dutasteride were evaluated in 36 healthy male volunteers aged 24 to 87 years after a single 5 mg dose. No significant age-related effect on dutasteride was observed, although elimination half-life was shorter in men under 50 years of age. No statistically significant differences in half-life were observed when comparing the 50–69-year-old group with those aged 70 years and older.

Tamsulosin

Cross-comparative studies of overall tamsulosin hydrochloride exposure (AUC) and elimination half-life suggest that the pharmacokinetic effect of tamsulosin hydrochloride may be slightly prolonged in elderly patients compared to younger healthy male volunteers. Intrinsic clearance is independent of tamsulosin hydrochloride binding to α-1-acid glycoprotein but decreases with patient age, resulting in overall exposure being 40% greater (AUC) in patients aged 55–75 years compared to those aged 20–32 years.

Renal Impairment

Dutasteride

The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a 0.5 mg dose of dutasteride is excreted in urine at steady-state, so clinically significant increases in plasma dutasteride concentrations in patients with renal impairment are not expected (see section "Dosage and Administration").

Tamsulosin

Tamsulosin hydrochloride pharmacokinetics were compared in 6 patients with mild to moderate (30 ≤ CLcr < 70 mL/min/1.73 m²) or moderate to severe (10 ≤ CLcr < 30 mL/min/1.73 m²) renal impairment and 6 subjects with normal clearance (CLcr ≥ 90 mL/min/1.73 m²). Although changes in total plasma tamsulosin hydrochloride concentration occurred due to variable binding to α-1-acid glycoprotein, the concentration of unbound (active) tamsulosin hydrochloride and intrinsic clearance remained relatively stable. Therefore, dose adjustment of tamsulosin hydrochloride capsules is not required in patients with renal impairment. 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 dutasteride pharmacokinetics has not been studied (see section "Contraindications"). Since dutasteride is primarily eliminated via metabolism, increased plasma levels and prolonged elimination half-life are expected in these patients (see sections "Special Warnings" and "Dosage and Administration").

Tamsulosin

Tamsulosin hydrochloride pharmacokinetics were compared in 8 patients with moderate hepatic impairment (Child-Pugh classification: grades A and B) and 8 subjects with normal liver function. Although changes in total plasma tamsulosin hydrochloride concentration occurred due to variable binding to α-1-acid glycoprotein, the concentration of unbound (active) tamsulosin hydrochloride did not change significantly, with only a moderate (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, dose adjustment of tamsulosin hydrochloride is not required in patients with moderate hepatic impairment. The effect of tamsulosin hydrochloride has not been studied in patients with severe hepatic impairment.

Safety and Clinical Studies

Heart Failure

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

In a separate 4-year placebo-controlled trial of dutasteride chemoprevention involving 8231 men aged 50–75 years with prior negative prostate biopsy for prostate cancer and baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL in men aged 50–60 years or 3.0 ng/mL and 10.0 ng/mL in men aged 60 years and older (REDUCE study), the incidence of heart failure was higher in patients receiving dutasteride 0.5 mg once daily (30/4105, 0.7%) compared to placebo (16/4126, 0.4%). A retrospective analysis of this study showed a higher incidence of heart failure in patients receiving dutasteride and an α-blocker concurrently (12/1152, 1.0%) compared to those receiving dutasteride without an α-blocker (18/2953, 0.6%), placebo with an α-blocker (1/1399, <0.1%), or placebo without an α-blocker (15/2727, 0.6%). A causal relationship between dutasteride use (as monotherapy or in combination with α-blockers) and the occurrence of heart failure has not been established (see section "Special Warnings").

Prostate Cancer and High-Grade Tumors

In a 4-year study comparing dutasteride with placebo in 8231 men aged 50–75 years with prior negative prostate biopsy and baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL in men aged 50–60 years or 3.0 ng/mL and 10.0 ng/mL in men aged 60 years and older (REDUCE study), 6706 patients underwent prostate needle biopsy (mandated by the original protocol), with Gleason score data used for differentiation analysis. A total of 1517 patients were diagnosed with prostate cancer. Most prostate tumors (70%) detected by biopsy in both treatment groups were well-differentiated (Gleason score 5–6).

A higher incidence of high-grade prostate cancer (Gleason score 8–10) was observed in the dutasteride group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%) (p=0.15). During the first 2 years of the study, the number of patients with Gleason score 8–10 prostate cancer was similar in the dutasteride (n=17, 0.5%) and placebo (n=18, 0.5%) groups. From years 3 to 4, more cases of Gleason score 8–10 prostate cancer 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 effect on prostate cancer risk in men taking dutasteride for more than 4 years. The percentage of patients diagnosed with Gleason score 8–10 prostate cancer remained constant over different study periods (years 1–2, years 3–4) in the dutasteride group (0.5% in each period), whereas in the placebo group, the percentage of patients with high-grade prostate cancer (Gleason score 8–10) was lower in years 3–4 than in years 1–2 (<0.1% vs. 0.5%, respectively) (see section "Special Warnings"). There was no difference in the incidence of Gleason score 7–10 prostate cancer (p=0.81).

In a 4-year clinical trial of benign prostatic hyperplasia treatment (CombAT), where protocol-mandated biopsies were not required and all prostate cancer diagnoses were based on indicated biopsies, the incidence of Gleason score 8–10 prostate cancer was 0.5% (n=8) in the dutasteride group, 0.7% (n=11) in the tamsulosin group, and 0.3% (n=5) in the combination therapy group.

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

Male Breast Cancer

Two case-control epidemiological studies—one conducted in the USA (n=339 male breast cancer cases and n=6780 controls) and another in the UK (n=398 cases and n=3930 controls) using healthcare databases—did not show an increased risk of male breast cancer with 5α-reductase inhibitor use. The first study found no positive association with breast cancer (relative risk for ≥1 year of use before diagnosis vs. <1 year: 0.70; 95% CI 0.34, 1.45). The second study reported a relative risk of 1.08 (95% CI 0.62, 1.87) associated with 5α-reductase inhibitor use compared to non-use.

A causal relationship between male breast cancer and long-term dutasteride use has not been established.

Clinical characteristics.

Indications.

Treatment of moderate to severe symptoms of benign prostatic hyperplasia.

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

Contraindications.

Dutafors is not used for the treatment of women and children (see section "Use during pregnancy or breastfeeding").

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

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

Dutafors is contraindicated in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Studies on the interaction of the combined drug with other medicinal products have not been conducted. The following is available information on the individual components of the drug.

Dutasteride

For information on the reduction of serum prostate-specific antigen (PSA) levels during treatment with dutasteride and recommendations for the detection of prostate cancer, see section "Special instructions".

Effect of other medicinal products on the pharmacokinetics of dutasteride

Concomitant use with CYP3A4 and/or P-glycoprotein inhibitors

Dutasteride is primarily eliminated via metabolism. In vitro studies show that CYP3A4 and CYP3A5 are responsible for its metabolism. Formal interaction studies with potent CYP3A4 inhibitors have not been conducted. However, in a population pharmacokinetic study, serum concentrations of dutasteride were on average 1.6–1.8 times higher in a small number of patients who were concurrently treated with verapamil or diltiazem (moderate CYP3A4 inhibitors and P-glycoprotein inhibitors) compared to other patients.

With long-term concomitant use of dutasteride and medicinal products that are potent inhibitors of the CYP3A4 enzyme (e.g., ritonavir, indinavir, nefazodone, itraconazole, orally administered ketoconazole), serum concentrations of dutasteride may increase. Further inhibition of 5α-reductase due to enhanced dutasteride activity is unlikely. However, dose reduction of dutasteride may be considered if adverse effects occur. Due to enzyme inhibition, the long half-life of dutasteride may become even longer, and concomitant therapy may need to continue for more than 6 months before a new steady-state concentration is achieved.

Administration of 12 g cholestyramine one hour after a single 5 mg dose of dutasteride did not affect the pharmacokinetics of dutasteride.

Effect of dutasteride on the pharmacokinetics of other medicinal products

In a small two-week study (n=24) involving healthy male volunteers, dutasteride (0.5 mg daily) did not affect the pharmacokinetics of tamsulosin or terazosin. No evidence of pharmacodynamic interaction was observed in this study.

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

Tamsulosin

Concomitant use of tamsulosin hydrochloride with medicinal products that may lower blood pressure, including analgesics, phosphodiesterase-5 inhibitors, and other α-1-adrenergic blockers, may theoretically lead to an enhanced hypotensive effect. Therefore, Dutafors should not be used in combination with other α-1-adrenergic blockers.

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 who are poor CYP2D6 metabolizers compared to extensive metabolizers when tamsulosin is used concomitantly with potent CYP3A4 inhibitors.

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

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

A comprehensive study on 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, enalapril, nifedipine, or theophylline. Concomitant use of furosemide leads to a reduction in serum levels of tamsulosin, but since these levels remain within the normal range, dose adjustment is not required.

In vitro, neither diazepam, propranolol, trichlormethiazide, chloromadinone, amitriptyline, diclofenac, glibenclamide, nor simvastatin altered the free fraction of tamsulosin in human plasma. Tamsulosin also did not alter the free fractions of diazepam, propranolol, trichlormethiazide, and chloromadinone.

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

Special precautions for use.

Combination therapy should be prescribed only after careful analysis of the benefit-risk ratio due to the potential increased risk of adverse reactions (including heart failure) and evaluation of alternative treatment options, including monotherapy.

Cardiovascular adverse reactions

According to data from two 4-year clinical trials, the incidence of heart failure (a combined term for all reported events, primarily heart failure and congestive heart failure) was higher in individuals treated with a combination of dutasteride and an α-blocker, mainly tamsulosin, compared to those not receiving this combination. The incidence of heart failure was low (≤1%) and variable across these studies. There was no imbalance in the incidence of cardiovascular adverse events in any of the trials. A causal relationship between the use of dutasteride (alone or in combination with α-blockers) and the development of heart failure has not been established (see section "Pharmacological properties").

A meta-analysis of 12 randomized, placebo- or comparator-controlled clinical trials (n=18,802) was conducted to evaluate the risk of cardiovascular adverse reactions associated with dutasteride use (compared to the control group). No consistent 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) was observed.

Prostate cancer and high-grade Gleason tumors (poorly differentiated)

In a 4-year clinical trial involving over 8,000 men aged 50 to 75 years with prior negative prostate biopsy and baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL (the REDUCE study), prostate cancer was diagnosed in 1,517 men. A higher incidence of Gleason 8–10 prostate cancer was observed in the dutasteride group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%). A causal relationship between dutasteride use and the development of poorly differentiated prostate cancer has not been established. The clinical significance of this numerical imbalance is not clear.

Men taking Dutafors should undergo regular evaluations for the risk of developing prostate cancer, including prostate-specific antigen (PSA) testing.

In an additional 2-year follow-up study of the original REDUCE trial participants receiving dutasteride for chemoprevention, the incidence of new prostate cancer cases was low (dutasteride group [n=14, 1.2%] vs. placebo group [n=7, 0.7%]), with no new cases of Gleason 8–10 prostate cancer identified.

Long-term follow-up (up to 18 years) of patients from a clinical trial using another 5α-reductase inhibitor (finasteride) for chemoprevention showed no statistically significant difference between the finasteride and placebo groups in overall survival (HR 1.02, 95% CI 0.97–1.08) or survival after prostate cancer diagnosis (HR 1.01, 95% CI 0.85–1.20).

Effect on prostate-specific antigen (PSA)

Prostate-specific antigen (PSA) levels are an important component of screening for prostate cancer. Dutasteride can reduce serum prostate-specific antigen levels in patients by approximately 50% within 6 months of treatment.

Patients taking Dutafors should have a new baseline PSA level established 6 months after starting treatment with this medication. This level should then be monitored regularly. Any confirmed increase in PSA from the lowest level during Dutafors therapy may indicate the presence of prostate cancer or non-adherence to Dutafors treatment and requires careful evaluation, even if PSA levels remain within the normal range observed in men not treated with 5α-reductase inhibitors. When interpreting PSA levels in patients treated with Dutafors, previous PSA values should be considered for comparison.

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

The ratio of free PSA to total PSA remains unchanged even during Dutafors treatment. If a physician decides to use the percentage of free PSA to assess prostate cancer in a patient taking Dutafors, no adjustment of the free PSA value is necessary.

Before initiating Dutafors therapy and periodically during treatment, patients with benign prostatic hyperplasia should undergo digital rectal examination and other methods for detecting prostate cancer.

Renal impairment

Treatment of patients with severe renal impairment (creatinine clearance <10 mL/min) should be performed with caution, as the pharmacokinetics of dutasteride in such patients have not been studied.

Arterial hypotension

As with other α1-adrenergic blockers, orthostatic hypotension may occur in patients treated with tamsulosin and, in rare cases, may lead to syncope.

Patients who have recently started treatment with Dutafors and experience early signs of orthostatic hypotension (dizziness, weakness) should be advised to sit or lie down until symptoms resolve.

Caution is required when co-administering α-adrenergic blockers, including tamsulosin, with phosphodiesterase-5 inhibitors. Both α-adrenergic blockers and phosphodiesterase-5 inhibitors are vasodilators and may lower blood pressure. Concomitant use of these two drug classes may potentially cause symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").

Intraoperative floppy iris syndrome

During cataract and glaucoma surgery, intraoperative floppy iris syndrome (IFIS, a variant of small pupil syndrome) has been observed in some patients previously treated with tamsulosin. Intraoperative floppy iris syndrome may increase the risk of ocular complications during or after surgery. Therefore, the use of Dutafors is not recommended in patients scheduled for cataract surgery.

During preoperative evaluation, the ophthalmic surgeon and surgical team should determine whether the patient has previously or currently been prescribed Dutafors. This information will help anticipate the potential occurrence of intraoperative floppy iris syndrome during surgery.

There have been isolated reports of benefit from discontinuing tamsulosin 1–2 weeks prior to cataract or glaucoma surgery; however, the advantages and optimal timing for discontinuation before such surgery have not been established.

Leaking capsules

Dutasteride is absorbed through the skin; therefore, women and children should avoid contact with leaking capsules. If capsule contents come into contact with the skin, the area should be washed immediately with soap and water.

Inhibitors of CYP3A4 and CYP2D6

Concomitant use of tamsulosin hydrochloride with strong inhibitors of CYP3A4 (e.g., ketoconazole) or, to a lesser extent, with strong inhibitors of CYP2D6 (e.g., paroxetine) may increase tamsulosin concentrations (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, tamsulosin should not be used in patients receiving strong CYP3A4 inhibitors, and caution is recommended in patients receiving moderate CYP3A4 inhibitors (e.g., erythromycin), strong or moderate CYP2D6 inhibitors, a combination of both CYP3A4 and CYP2D6 inhibitors, or in patients who are poor metabolizers of CYP2D6.

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied. Due to the extensive metabolism of dutasteride and its long elimination half-life (3–5 weeks), treatment with dutasteride in patients with mild to moderate hepatic impairment should be performed with caution (see sections "Pharmacological properties", "Contraindications", and "Dosage and administration").

Excipients

The medicinal product contains the colorant sunset yellow (E 110), which may cause allergic reactions.

This medicinal product contains lecithin derived from soybean oil. It should not be used in patients with known allergy to peanuts or soy (see section "Contraindications").

Breast cancer in men

Rare cases of male breast cancer have been reported during clinical trials and in the post-marketing period. However, epidemiological studies indicate no increased risk of male breast cancer with the use of 5α-reductase inhibitors. Physicians should inform their patients about the need to report immediately any changes in breast tissue, such as nipple discharge or lumps.

Use during pregnancy or breastfeeding.

Dutafors is contraindicated for use in women. Studies evaluating the effects of the medicinal product on pregnancy, lactation, and fertility have not been conducted. The following information refers to the use of each component separately.

Fertility

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

No evaluation of the effect of tamsulosin hydrochloride on sperm count or function has been performed.

Pregnancy

Like other 5α-reductase inhibitors, dutasteride interferes with the conversion of testosterone to dihydrotestosterone, which may impair the development of external genitalia in male fetuses. A small amount of dutasteride has been detected in semen in studies. It is unknown whether dutasteride transferred to a woman via semen from a man treated with Dutafors may affect a male fetus.

As with other 5α-reductase inhibitors, it is recommended to use a condom during sexual intercourse if the female partner is pregnant and the male partner is taking Dutafors, to prevent semen exposure to the woman.

There is no evidence that administration of tamsulosin hydrochloride to pregnant rats and rabbits at doses exceeding therapeutic levels has adverse effects on the fetus.

Breastfeeding period

It is unknown whether dutasteride and tamsulosin pass into human breast milk.

Ability to influence reaction rate while driving or operating machinery.

No studies have been conducted on the effect of Dutafors on the ability to drive or operate machinery. However, patients should be informed about the possible occurrence of symptoms related to orthostatic hypotension, such as dizziness, during treatment with Dutafors.

Method of Administration and Dosage

Adults (including elderly patients)

The recommended dose of Dutafors is 1 capsule (0.5 mg/0.4 mg) once daily. The medication should be taken orally 30 minutes after food intake, at the same time each day. The capsule must be swallowed whole and should not be opened or chewed, as contact with the capsule contents may cause irritation of the oral and pharyngeal mucosa.

Dutafors can be used as a replacement for combination therapy with dutasteride and tamsulosin hydrochloride to facilitate treatment.

Switching from monotherapy with dutasteride or tamsulosin hydrochloride to Dutafors is possible if clinically justified.

Renal Impairment

The pharmacokinetics of the drug have not been studied in patients with renal impairment. Dose adjustment is not required for treating such patients (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Hepatic Impairment

The pharmacokinetics of the drug have not been studied in patients with hepatic impairment. Therefore, the drug should be used with caution in patients with mild to moderate hepatic impairment (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use"). Dutafors is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Children

Use in children under 18 years of age is contraindicated.

Overdose

There are no reported cases of Dutafors overdose. The following information refers to the individual components.

Dutasteride

Clinical studies have shown that single doses of dutasteride up to 40 mg daily (80 times higher than therapeutic doses) administered for 7 days did not raise safety concerns in healthy volunteers. In clinical trials, doses of dutasteride up to 5 mg daily for 6 months were administered without additional adverse reactions compared to 0.5 mg daily.

There is no specific antidote; therefore, symptomatic and supportive treatment should be administered in case of suspected overdose.

Tamsulosin

There have been reports of acute overdose with tamsulosin hydrochloride at a dose of 5 mg, resulting in acute arterial hypotension (systolic blood pressure 70 mmHg), vomiting, and diarrhea. These symptoms were managed with fluid infusion, and the patient recovered the same day. In cases of acute arterial hypotension following tamsulosin hydrochloride overdose, cardiovascular support should be provided. The patient should be placed in a supine position to restore blood pressure and normalize heart rate. If this is ineffective, plasma expanders should be administered, and, if necessary, vasoconstrictors. Renal function should be monitored, and general supportive therapy should be implemented. Dialysis may be ineffective, as tamsulosin hydrochloride is almost completely protein-bound in plasma.

To prevent absorption in overdose, vomiting should be induced. If large doses have been ingested, gastric lavage should be performed, followed by administration of activated charcoal and a laxative such as sodium sulfate.

Adverse reactions

Information on adverse reactions of each component separately (dutasteride and tamsulosin) is also provided below. Not all adverse reactions observed with each component used alone were reported during treatment with the combination of dutasteride + tamsulosin; therefore, information on adverse reactions associated with individual components of Dutafors is also included in this instruction.

According to the 4-year CombAT study, the percentage of adverse reactions identified by investigators during the first, second, third, and fourth years of treatment varied as follows: 22%, 6%, 4%, and 2% respectively in the combination therapy group (dutasteride + tamsulosin); 15%, 6%, 3%, and 2% in the dutasteride monotherapy group; and 13%, 5%, 2%, and 2% in the tamsulosin monotherapy group. The higher percentage of adverse reactions in the combination therapy group during the first year of treatment was primarily due to a higher incidence of reproductive disorders, specifically ejaculation disorders observed in this group.

Adverse reactions occurring at a frequency ≥1% during the first year of treatment, based on investigator-reported data from the CombAT and REDUCE studies, as well as clinical trials of monotherapies with components of Dutafors, are listed in the table.

Information regarding tamsulosin adverse reactions is based on data available from relevant medical resources. The frequency of these reactions may increase when dutasteride and tamsulosin are used concomitantly.

Frequency categories of adverse reactions observed in clinical studies: common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). Adverse reactions classified by system organ classes are presented in order of decreasing severity.

a Dutasteride + tamsulosin: in the CombAT study, the frequency of these adverse reactions decreases with each subsequent year from the 1st to the 4th.

b From monotherapy studies of benign prostatic hyperplasia with dutasteride.

c From the European Union Summary of Product Characteristics for tamsulosin.

d REDUCE study.

1 The preferred term "heart failure" includes congestive heart failure, heart failure, left ventricular failure, acute heart failure, cardiogenic shock, acute left ventricular failure, right ventricular failure, acute right ventricular failure, ventricular failure, cardiopulmonary failure, and congestive cardiomyopathy.

2 Including hyperesthesia and breast enlargement.

3 Adverse reactions related to sexual function are associated with dutasteride treatment (including both monotherapy and combination with tamsulosin). These adverse reactions may persist after discontinuation of treatment. The effect of dutasteride on their duration is unknown.

^ Including reduced semen volume.

Post-marketing data

In post-marketing surveillance, adverse reactions were reported based on spontaneous reports; therefore, the exact frequency of such reactions is unknown.

Dutasteride monotherapy

Immune system disorders

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

Psychiatric disorders

Frequency unknown: depression.

Skin and subcutaneous tissue disorders

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

Reproductive system and breast disorders

Frequency unknown: testicular pain and swelling.

Tamsulosin monotherapy

Post-marketing surveillance data indicate that during cataract and glaucoma surgery, some patients previously treated with α1-adrenergic blockers, including tamsulosin, experienced intraoperative floppy iris syndrome (IFIS, a variant of the small pupil syndrome) (see section "Special precautions").

During post-approval use, additional cases of atrial fibrillation, arrhythmia, tachycardia, dyspnea, epistaxis, visual disturbances (including decreased visual acuity), Stevens-Johnson syndrome, exfoliative dermatitis, and dryness of the oral mucosa have been reported in association with tamsulosin use.

Other data

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

Based on clinical trials and post-marketing experience, cases of male breast cancer have been reported (see section "Special precautions").

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 per blister, 5 blisters per pack. 9 hard capsules per blister, 10 blisters per pack.

Prescription status. Prescription only.

Manufacturer.

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

Manufacturer's address and location of operations.

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