Omlus duo

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OMLOS Duo OMLOS®Duo

Composition:

Active substances: dutasteride, tamsulosin hydrochloride;

1 capsule contains 0.5 mg of dutasteride and 0.4 mg of tamsulosin hydrochloride (equivalent to 0.367 mg of tamsulosin);

Excipients:

Dutasteride soft capsule contains: propylene glycol monocaprylate, type II; butylhydroxytoluene (E 321); soft capsule shell (gelatin, glycerin, titanium dioxide (E 171), medium-chain triglycerides, soy lecithin).

Tamsulosin pellets contain: methacrylic acid copolymer dispersion 30%, microcrystalline cellulose, dibutyl sebacate, polysorbate 80, colloidal aqueous silicon dioxide, calcium stearate.

Hard capsule shell contains: black iron oxide (E 172), red iron oxide (E 172), titanium dioxide (E 171), yellow iron oxide (E 172), gelatin.

Black Ink composition: shellac (E 904), black iron oxide (E 172), propylene glycol (E 1520), concentrated ammonia solution, potassium hydroxide.

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: elongated, hard capsules, size 0EL, approximately 24.2 mm x 7.7 mm, with a brown-colored capsule body and a beige-colored cap, marked with black ink «С001».

Each hard capsule contains modified-release tamsulosin hydrochloride pellets, white to almost white in color, and an elongated soft gelatin capsule (approximately 16.5×6.5 mm) containing dutasteride, light yellow in color, filled with a clear liquid.

Pharmacotherapeutic group. Agents used in benign prostatic hyperplasia. α1-adrenoreceptor antagonist. ATC code G04CA52.

Pharmacological Properties

Pharmacodynamics

Dutasteride/tamsulosin is a combination of two medicinal agents: dutasteride, a dual 5α-reductase inhibitor (5ARI), and tamsulosin hydrochloride, an α1a and α1d adrenoceptor antagonist. 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 requiring surgical intervention for benign prostatic hyperplasia (BPH).

The pharmacodynamic effects of the fixed-dose combination of dutasteride and tamsulosin are not expected to differ from those observed with the 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 the conversion of testosterone to dihydrotestosterone (DHT). DHT is an androgen primarily responsible for prostate growth and the development of benign prostatic hyperplasia. Tamsulosin inhibits α1a and α1d adrenoceptor activity in the smooth muscle stroma of the prostate 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-adrenoceptor antagonists may reduce blood pressure by decreasing total peripheral resistance. However, in studies evaluating the effect of tamsulosin, no clinically significant reduction in blood pressure was observed.

Pharmacokinetics

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

Single-dose bioequivalence studies were conducted both in the fasting state and after food intake. Compared to the fasting state, administration 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 plasma concentration-time curve (AUC) of tamsulosin.

Absorption

Dutasteride

After a single oral dose of 0.5 mg dutasteride, the time to reach Cmax 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 administered within 30 minutes after a meal. Consistent absorption is ensured by taking dutasteride/tamsulosin at the same time each day after consuming a similar type of meal. Plasma concentrations of tamsulosin are dose-proportional.

After a single dose of tamsulosin taken after a meal, Cmax is reached approximately 6 hours later. Steady-state concentrations are achieved by day 5 of repeated dosing. The average Cmax in patients is approximately two-thirds higher than the concentration observed after a single dose of tamsulosin. Although this phenomenon has been observed in elderly patients, the same result 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 concentrations of dutasteride reach 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 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/day dutasteride to steady-state, 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 (accounting for 39%, 21%, 7%, and 7% of drug-related material, respectively) and six minor metabolites (each <5%). Only negligible amounts of unchanged dutasteride (<0.1% of dose) are excreted 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. 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 glucuronide or sulfate.

Elimination

Dutasteride

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

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

Tamsulosin

Tamsulosin and its metabolites are primarily excreted in urine, with approximately 9% of the dose present 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, the true elimination half-life of tamsulosin from modified-release capsules 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 men aged 24 to 87 years after a single 5 mg dose. No significant age-related effect on dutasteride was observed, although the elimination half-life was shorter in men under 50 years of age. There were no statistically significant differences in half-life when comparing subjects aged 50–69 years with those aged 70 years and older.

Tamsulosin

Cross-comparative studies of the overall effect of tamsulosin hydrochloride (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 not dependent on tamsulosin hydrochloride binding to alpha-1-acid glycoprotein but decreases with age, resulting in a 40% greater overall exposure (AUC) in patients aged 55–75 years compared to those 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 a 0.5 mg dose of dutasteride is excreted in urine at steady-state, so a clinically significant increase in plasma dutasteride concentration in patients with renal impairment is not expected (see section "Dosage and Administration").

Tamsulosin

The pharmacokinetics of tamsulosin hydrochloride 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). While changes in total plasma concentration of tamsulosin hydrochloride were observed due to variable binding to alpha-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. 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 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 Precautions for Use" and "Dosage and Administration").

Tamsulosin

The pharmacokinetics of tamsulosin hydrochloride were compared in 8 patients with moderate hepatic impairment (Child-Pugh classification: grades A and B) and 8 subjects with normal liver function. While changes in total plasma concentration of tamsulosin hydrochloride were observed 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 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 in combination with tamsulosin for the treatment of benign prostatic hyperplasia in 4844 men (CombAT study), the incidence of heart failure (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 chemoprevention trial with dutasteride 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 alpha-blocker concurrently (12/1152; 1.0%) compared to those receiving dutasteride without an alpha-blocker (18/2953; 0.6%), placebo with an alpha-blocker (1/1399; <0.1%), or placebo without an alpha-blocker (15/2727; 0.6%). A causal relationship between dutasteride use (alone or in combination with alpha-blockers) and the occurrence of heart failure has not been established (see section "Special Warnings and Precautions for Use").

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 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), prostate needle biopsy (mandated by the original protocol) was performed in 6706 patients, and data were used for Gleason score differentiation analysis. Prostate cancer was diagnosed in 1517 patients. 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 group (n = 17; 0.5%) and the placebo group (n = 18; 0.5%). 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 of dutasteride use beyond 4 years on prostate cancer risk. The percentage of patients 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 and Precautions for Use"). 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 mandatory biopsy was not part of the original protocol and all prostate cancer diagnoses were biopsy-confirmed based on clinical indications, 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 breast cancer cases and n = 6780 controls], the other in the UK [n = 398 breast cancer 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). In the second study, the relative risk of male breast cancer associated with 5α-reductase inhibitor use compared to non-use was 1.08; 95% CI 0.62; 1.87.

A causal relationship between male breast cancer and long-term use of dutasteride 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.

Dutasteride/tamsulosin is not indicated for use in women and children (see section "Use in pregnancy or breastfeeding").

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

Dutasteride/tamsulosin is contraindicated in patients with a history of orthostatic hypotension.

Dutasteride/tamsulosin is contraindicated in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Studies on the interaction of dutasteride/tamsulosin with other medicinal products have not been conducted. The following information is based on data for the individual components of the product.

Dutasteride

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

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 indicate 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, ketoconazole administered orally), 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. In cases of enzyme inhibition, the long half-life of dutasteride may be further prolonged, 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 (N = 24), two-week study in healthy men, 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 the 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 alpha-1-adrenergic blockers, may theoretically result in an enhanced hypotensive effect. Dutasteride/tamsulosin should not be used in combination with other alpha-1-adrenergic blockers.

Concomitant administration 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 metabolizers of CYP2D6 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 may potentially lead to a significant increase in tamsulosin concentration (see section "Special precautions for use").

Concomitant administration 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. Dutasteride/tamsulosin should be used with caution in combination with cimetidine.

A comprehensive study of the interaction between tamsulosin hydrochloride and warfarin has not been conducted. Results from limited in vitro and in vivo studies are insufficient. Concomitant use of warfarin and tamsulosin hydrochloride should be performed with caution.

No interaction was observed when tamsulosin hydrochloride was administered simultaneously with atenolol, enalapril, nifedipine, or theophylline. Concomitant use of furosemide leads to a reduction in serum tamsulosin levels; however, since these levels remain within the normal range, dose adjustment is not required.

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

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

Special precautions for use.

Combined therapy should be prescribed only after careful assessment of the benefit-risk ratio due to the potential increase in risk of adverse reactions (including heart failure), and after consideration of alternative treatment options, including monotherapy.

Cardiovascular adverse reactions

According to data from two 4-year clinical studies, 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 alpha-blocker, primarily tamsulosin, compared to those not treated with this combination. The incidence of heart failure was low (≤1%) and variable across these studies. There was no imbalance 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 occurrence of heart failure has not been established (see section "Pharmacological properties").

A meta-analysis of 12 randomized, placebo- or active-controlled clinical trials (n = 18,802) was conducted to evaluate the risk of cardiovascular adverse reactions associated with dutasteride use (compared to control groups). No consistent statistically significant increase in risk was observed for 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 (Gleason score 8–10) tumors

In a 4-year clinical study involving over 8000 men aged 50 to 75 years with a 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 1517 men. A higher incidence of Gleason score 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 established.

Men taking dutasteride/tamsulosin should undergo regular screening for prostate cancer risk, including prostate-specific antigen (PSA) testing.

In an additional 2-year follow-up study of the original REDUCE trial participants, the incidence of new prostate cancer cases was low in both the dutasteride group (n = 14; 1.2%) and the placebo group (n = 7; 0.7%), with no new cases of Gleason score 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) as 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)

Serum prostate-specific antigen (PSA) concentration is an important component of prostate cancer screening. Dutasteride/tamsulosin reduces serum PSA levels by approximately 50% within 6 months of treatment initiation.

Patients taking dutasteride/tamsulosin should have a new baseline PSA level established 6 months after starting treatment. This level should then be monitored regularly. Any confirmed increase in PSA from the nadir level during dutasteride/tamsulosin therapy may indicate the presence of prostate cancer or non-adherence to treatment and requires thorough 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 receiving dutasteride/tamsulosin, previous PSA values should be used for comparison.

The use of dutasteride/tamsulosin does not affect the utility of PSA levels for diagnosing prostate cancer once a new baseline has been established.

Total serum PSA levels return to pretreatment levels within 6 months after discontinuation of therapy.

The ratio of free to total PSA remains unchanged during treatment with dutasteride/tamsulosin. If a physician decides to use the free PSA percentage to evaluate prostate cancer risk in a patient on dutasteride/tamsulosin, no adjustment of the free PSA value is necessary.

Prior to initiating treatment with dutasteride/tamsulosin and periodically during therapy, patients with benign prostatic hyperplasia should undergo digital rectal examination and other screening methods for prostate cancer.

Renal impairment

Caution is advised when treating patients with severe renal impairment (creatinine clearance <10 mL/min), as the pharmacokinetics of dutasteride have not been studied in such patients.

Arterial hypotension

As with other alpha1-adrenergic blockers, orthostatic hypotension may occur in patients treated with tamsulosin and, rarely, may lead to syncope.

Patients starting dutasteride/tamsulosin therapy who experience early signs of orthostatic hypotension (dizziness, weakness) should immediately sit or lie down until symptoms resolve.

Caution should be exercised when co-administering alpha-adrenergic blockers, including tamsulosin, with phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil). Both classes of drugs are vasodilators and may lower blood pressure. Concomitant use may potentially lead to symptomatic hypotension (see section "Interaction with other medicinal products and other forms of interaction").

Intraoperative floppy iris syndrome (IFIS)

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

Prior to surgery, the ophthalmic surgeon and surgical team should inquire about current or past use of dutasteride/tamsulosin to anticipate the potential occurrence of IFIS during surgery.

Isolated reports suggest a potential benefit from discontinuing tamsulosin 1–2 weeks before cataract or glaucoma surgery; however, the benefits and optimal timing for discontinuation 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.

CYP3A4 and CYP2D6 inhibitors

Concomitant use of tamsulosin hydrochloride with strong CYP3A4 inhibitors (e.g., ketoconazole) and, to a lesser extent, strong CYP2D6 inhibitors (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. Caution is recommended when using tamsulosin 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 CYP2D6 metabolizers.

Hepatic impairment

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

Excipients

Omlus Duo contains soy lecithin and propylene glycol.

This medicinal product contains soy lecithin, which may contain soybean oil. The product should not be used in patients with peanut or soy allergy.

Each capsule contains approximately 103 mg of propylene glycol.

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 have not shown an increased risk of male breast cancer with 5α-reductase inhibitors. Physicians should inform patients about the need to promptly report any changes in breast tissue, such as nipple discharge or lumps.

Use during pregnancy or breastfeeding.

Dutasteride/tamsulosin is contraindicated for use in women. Studies on the effects of dutasteride/tamsulosin on pregnancy, lactation, and fertility have not been conducted. The following information refers to the use of each component separately.

Fertility

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

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

Pregnancy

Like other 5α-reductase inhibitors, dutasteride inhibits 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.

It is unknown whether dutasteride transferred via semen from a male partner treated with dutasteride/tamsulosin can affect a male fetus.

As with other 5α-reductase inhibitors, condom use is recommended during sexual intercourse if the female partner is pregnant and the male partner is being treated with dutasteride/tamsulosin, to prevent exposure of the fetus to the drug.

No adverse effects on the fetus were observed in pregnant rats and rabbits administered tamsulosin hydrochloride at doses exceeding the therapeutic range.

Breastfeeding

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

Ability to affect reaction speed when driving or operating machinery.

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

Administration and Dosage

Adults (including elderly patients)

The recommended dose of dutasteride/tamsulosin is 1 capsule (0.5 mg/0.4 mg) once daily. The medication should be taken orally 30 minutes after eating, at the same time each day. The capsule should be swallowed whole and not opened or chewed, as contact with the capsule contents may irritate the mucous membranes of the mouth and throat.

Dutasteride/tamsulosin may be used to replace combination therapy with dutasteride and tamsulosin hydrochloride to facilitate treatment.

Switching from Omlos Duo, dutasteride, or tamsulosin hydrochloride monotherapy is possible if clinically justified.

Renal Impairment

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

Hepatic Impairment

The pharmacokinetics of dutasteride/tamsulosin in patients with hepatic impairment have not been studied; 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"). The drug is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Children

Use is contraindicated.

Overdose

There are no reported cases of overdose with dutasteride/tamsulosin. The following information refers to the use of each component separately.

Dutasteride

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

There is no specific antidote; therefore, in the event of suspected overdose, symptomatic and supportive therapy should be administered.

Tamsulosin

Cases of acute overdose with tamsulosin hydrochloride at a dose of 5 mg have been reported, resulting in acute arterial hypotension (systolic blood pressure 70 mm Hg), vomiting, and diarrhea. These symptoms were managed with fluid infusion, after which the patient improved 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 help 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 instituted. Dialysis may be ineffective because tamsulosin hydrochloride is almost completely bound to plasma proteins.

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

Adverse Reactions

Clinical studies with dutasteride/tamsulosin combination have not been conducted; however, bioequivalence of dutasteride/tamsulosin has been demonstrated when dutasteride and tamsulosin are coadministered. Data on concomitant use are derived from the CombAT study (Combination of Dutasteride and Tamsulosin), which compared combination therapy with dutasteride 0.5 mg and tamsulosin 0.4 mg once daily for 4 years versus monotherapy with either agent.

Information on adverse reactions for each component separately (dutasteride and tamsulosin) is also provided below. Not all adverse reactions observed with individual components have been reported with dutasteride/tamsulosin combination; therefore, adverse reaction data from individual components of dutasteride/tamsulosin are included in this instruction.

In the 4-year CombAT study, the percentage of adverse reactions identified by investigators during the 1st, 2nd, 3rd, and 4th years of treatment was: 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 system 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, REDUCE, and monotherapy clinical trials of dutasteride/tamsulosin components, are listed in the table.

Information on 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 of adverse reactions identified in clinical studies: common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000). Adverse reactions classified by system organ classes are listed in descending order of 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 EU Summary of Product Characteristics for tamsulosin.

d The 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 disorders are associated with the use of dutasteride (both as monotherapy and in combination with tamsulosin). These adverse reactions may persist after discontinuation of treatment. The effect of dutasteride on their duration is unknown.

^ Including decreased semen volume.

Post-marketing data

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

Dutasteride monotherapy

Immune system disorders

Unknown frequency: allergic reactions, including rash, pruritus, urticaria, localized edema, and angioedema.

Psychiatric disorders

Unknown frequency: depression.

Skin and subcutaneous tissue disorders

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

Reproductive system and breast disorders

Unknown frequency: testicular pain and swelling.

Tamsulosin monotherapy

Based on post-marketing surveillance, during cataract and glaucoma surgery, some patients previously treated with alpha-1 adrenergic blockers, including tamsulosin, experienced intraoperative floppy iris syndrome (a variant of the small pupil syndrome) (see section "Special warnings and precautions for use").

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 warnings and precautions for use"). 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 surveillance, cases of male breast cancer have been reported (see section "Special warnings and precautions for use").

Shelf life.

2 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 30 °C. The medication should be used within 90 days after opening.

Keep out of the reach of children.

Packaging.

Capsules in a polyethylene bottle with a cap containing a silica gel desiccant.

One bottle containing 30 capsules, together with the package leaflet, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ALKALOID AD Skopje.

ALKALOID AD Skopje.

Manufacturer's address and place of business.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.

Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.