Duostad

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DUOSTAD (DUOSTAD)

Composition:

Active substances: dutasteride, tamsulosin hydrochloride;

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

Excipients:

soft gelatin capsule: propylene glycol monocaprylate, type II; butylhydroxytoluene (E 321); gelatin (gelling type B, 150 Bloom); glycerin; titanium dioxide (E 171); medium-chain triglycerides; lecithin;

modified-release pellets: methacrylic acid – ethyl acrylate copolymer (1:1), dispersion 30% (sodium lauryl sulfate – 0.7%, polysorbate 80 – 2.3%); microcrystalline cellulose; dibutyl sebacate; polysorbate 80; colloidal silicon dioxide aqueous; calcium stearate;

hard gelatin capsule: iron oxide black (E 172); iron oxide red (E 172); titanium dioxide (E 171); iron oxide yellow (E 172); gelatin (gelling type B, 150 Bloom);

black ink: shellac (E 904); iron oxide black (E 172); propylene glycol (E 1520); concentrated ammonia solution (E 527); potassium hydroxide (E 525).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: elongated hard gelatin capsules of size №0EL, approximately 24.2 × 7.7 mm, with a brown body and a beige cap, marked with "C001" in black ink on the cap. The content of the hard gelatin capsule: a soft gelatin capsule of elongated shape (approximately 16.5 × 6.5 mm), light yellow in color, filled with a clear liquid and white or almost white granules of tamsulosin.

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

Pharmacological properties.

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

No differences in pharmacodynamic effects are expected between the fixed-dose combination of dutasteride and tamsulosin and 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 gland growth and the development of benign prostatic hyperplasia.

Tamsulosin.

Tamsulosin inhibits α1a and α1d adrenoceptors in the stromal smooth muscle of the prostate gland and bladder neck. Approximately 75% of α1 receptors in the prostate are of the α1a subtype.

Tamsulosin increases the maximum urinary flow rate by reducing smooth muscle tone in the urethra and prostate, thereby relieving obstruction. The drug also reduces the severity of irritative and obstructive symptoms, in which urinary urgency 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 combination of dutasteride + tamsulosin and the simultaneous administration of dutasteride and tamsulosin as separate capsules.

Bioequivalence studies of single doses were conducted both fasting and after food intake. Compared to fasting conditions, a 30% reduction in Cmax (maximum concentration) of tamsulosin was observed when administered after food intake in the dutasteride + tamsulosin combination. Food intake did not affect the AUC (area under the pharmacokinetic curve) of tamsulosin.

Absorption.

Dutasteride. After oral administration of a single 0.5 mg dose of dutasteride, the time to reach peak 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 gastrointestinal tract 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 Duostad at the same time of day after consuming a similar type of meal. Plasma tamsulosin concentration is dose-proportional.

After a single dose of tamsulosin taken after food, peak plasma concentration is reached approximately 6 hours later. Steady-state concentration is achieved by day 5 of treatment. The average steady-state concentration (Cmax) in patients is approximately two-thirds higher than after a single dose of tamsulosin. 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, dutasteride serum concentration reaches 65% of steady-state levels within 1 month and approximately 90% within 3 months.

Steady-state serum concentration (Css), approximately 40 ng/mL, is achieved after 6 months of daily 0.5 mg dosing. The mean transfer rate of dutasteride from serum into semen 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 substances, respectively, and six minor metabolites (each <5%). Only negligible amounts of unchanged dutasteride (<0.1% of dose) are detected in human urine.

Tamsulosin. Enantiomeric bioconversion of tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer does not occur in humans. Tamsulosin hydrochloride is extensively 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 glucuronide 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/day 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, where approximately 9% of the dose is present as unchanged active substance.

After intravenous or oral administration in immediate-release formulation, the elimination half-life of tamsulosin in plasma ranges from 5 to 7 hours. Due to controlled absorption rate, the apparent elimination half-life of tamsulosin from modified-release capsules, taken once after food, is approximately 10 hours, and approximately 13 hours at steady-state concentration.

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. No statistical differences in half-life were observed when comparing the 50–69-year-old group with those over 70 years.

Tamsulosin. Cross-comparative studies of overall tamsulosin hydrochloride exposure (AUC [area under the pharmacokinetic curve]) 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 α1-acid glycoprotein but decreases with patient age, resulting in a 40% higher 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 dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a 0.5 mg dose of dutasteride at steady-state is excreted in urine, 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). Although changes in total plasma tamsulosin hydrochloride concentration occurred due to variable binding to α1-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, studies have not been conducted in patients with end-stage renal disease (CLcr < 10 mL/min/1.73 m²).

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, plasma dutasteride levels in these patients are expected to be elevated, and elimination half-life prolonged (see sections "Dosage and administration" and "Special warnings and precautions for use").

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. Although changes in total plasma tamsulosin hydrochloride concentration occurred due to variable binding to α1-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, patients with moderate hepatic impairment do not require dose adjustment of tamsulosin hydrochloride. 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 study 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 dutasteride monotherapy (4/1623, 0.2%) or tamsulosin monotherapy (10/1611, 0.6%).

In a separate 4-year placebo-controlled clinical trial of dutasteride for chemoprevention 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 over 60 years (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 taking dutasteride and an α-blocker concurrently (12/1152, 1.0%) compared to those taking 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%). No causal relationship between dutasteride use (alone or in combination with α-blockers) and the occurrence of heart failure has been established (see section "Special warnings and precautions for use").

Prostate cancer and high-grade tumors.

In a 4-year study evaluating dutasteride versus 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 over 60 years (REDUCE study), prostate needle biopsy (mandatory per primary protocol) was performed in 6706 subjects, with Gleason grading used for tumor 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 placebo (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 3–4, more cases of Gleason score 8–10 prostate cancer were diagnosed in the dutasteride group (n = 12, 0.5%) compared to placebo (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 time in the dutasteride group (0.5% in each period), whereas in the placebo group, the percentage of patients with high-grade 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 study of benign prostatic hyperplasia treatment (CombAT), where mandatory biopsy was not required by 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 (first group: 339 patients with male breast cancer, second group: 6780 control patients) and another in the UK (first group: 398 patients with male breast cancer, second group: 930 control patients) 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 breast cancer 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) for male breast cancer associated with 5α-reductase inhibitor use compared to non-use.

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

Clinical characteristics.

Indications.

For the treatment of moderate to severe symptoms of benign prostatic hyperplasia.

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

Contraindications.

Duodart is contraindicated:

• in women and children (see section "Use during pregnancy or breastfeeding");
• 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;
• in patients with a history of orthostatic hypotension;
• in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Studies on the interaction of Duodart with other medicinal products have not been conducted. The information below refers to its individual components.

Dutasteride.

For information on the reduction of serum prostate-specific antigen (PSA) levels during treatment with dutasteride and recommendations regarding the detection of prostate cancer, 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 (such as 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 frequency reduction of dutasteride may be considered if adverse effects occur. It should be noted that due to enzyme inhibition over a prolonged period, 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 of 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 subjects, 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 CYP2C9 enzyme activity or P-glycoprotein transporter activity. 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, 5-phosphodiesterase inhibitors, and other α1-adrenoblockers, may theoretically enhance hypotensive effects. Duodart should not be used in combination with other α1-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 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 it 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% reduction in clearance and a 44% increase in AUC (area under the pharmacokinetic curve) of tamsulosin hydrochloride. Duodart should be used with caution when combined with cimetidine.

A comprehensive investigation of the interaction between tamsulosin hydrochloride and warfarin has not been conducted. Results from 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 reduced serum levels of tamsulosin; however, since these levels remain within the normal range, dose adjustment is not required.

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

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

Special precautions for use.

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

Cardiovascular adverse reactions

In 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 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 studies. 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 "Pharmacological properties").

A meta-analysis of 12 randomized, placebo- or active-controlled clinical trials (n = 18,802) evaluated the risk of cardiovascular adverse reactions with dutasteride use (compared to control groups). 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 (poorly differentiated) tumors according to Gleason score.

In a 4-year clinical study involving over 8,000 men aged 50 to 75 years with a prior negative prostate cancer 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 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 unclear.

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

In an additional 2-year follow-up of the original REDUCE study participants, 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 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) 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).

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

Patients taking Duostad should have a new baseline PSA level established 6 months after initiating treatment with this medication. This level should then be monitored regularly. Any confirmed increase in PSA from the nadir level during Duostad therapy may indicate the presence of prostate cancer or non-adherence to Duostad 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 receiving Duostad, previous PSA values should be considered for comparison.

The use of Duostad 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 baseline within 6 months after discontinuation of treatment.

The ratio of free to total PSA remains constant during Duostad therapy. If a physician decides to use the percentage of free PSA to evaluate for prostate cancer in a patient receiving Duostad, no adjustment of the free PSA value is necessary.

Prior to initiating Duostad therapy and periodically during treatment, patients with benign prostatic hyperplasia should undergo digital rectal examination and other methods for detecting 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 α1-adrenergic blockers, therapy with tamsulosin may lead to orthostatic hypotension, which in rare cases may result in syncope.

Patients initiating Duostad therapy who experience symptoms of orthostatic hypotension (e.g., dizziness, weakness) should be advised to sit or lie down until symptoms resolve.

Caution should be exercised when co-administering α-adrenergic blockers, including tamsulosin, with phosphodiesterase-5 (PDE-5) inhibitors. Both α-blockers and PDE-5 inhibitors are vasodilators and may lower blood pressure. Concomitant use of these two drug classes 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, some patients previously treated with tamsulosin have experienced intraoperative floppy iris syndrome (IFIS), a variant of the small pupil syndrome. IFIS may increase the risk of ocular complications during or after surgery. Therefore, Duostad is not recommended in patients scheduled for cataract surgery.

During preoperative evaluation, the ophthalmic surgeon and surgical team should determine whether the patient is currently or has previously been treated with Duostad. This information will help anticipate the possible occurrence of IFIS 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 of discontinuation before 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 CYP3A4 inhibitors (e.g., ketoconazole) or, 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 is not recommended in patients receiving strong CYP3A4 inhibitors. Caution is advised when administering tamsulosin to 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), caution is advised when treating patients with mild or moderate hepatic impairment (see sections "Dosage and administration", "Contraindications", "Pharmacological properties").

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 their patients to promptly report any changes in breast tissue, such as nipple discharge or lumps.

Use during pregnancy or breastfeeding.

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

Fertility.

Dutasteride affects semen parameters (reduced sperm count, semen volume, and sperm motility). A potential 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 inhibits the conversion of testosterone to dihydrotestosterone, which may impair the development of external genitalia in male fetuses. Small amounts of dutasteride have been detected in semen. It is unknown whether dutasteride transferred via semen from a man treated with Duostad to a pregnant woman may 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 Duostad, to prevent semen exposure.

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

Breastfeeding.

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

Ability to influence the ability to drive and use machines.

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

Method of Administration and Dosage

Adults (including elderly patients).

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

If necessary, Duostad may be used as a replacement for combination therapy with dutasteride and tamsulosin hydrochloride to simplify treatment.

Duostad may replace monotherapy with dutasteride or monotherapy with tamsulosin hydrochloride if clinically justified.

Renal Impairment.

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

Hepatic Impairment.

The pharmacokinetics of Duostad 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 "Special Precautions" and "Pharmacokinetics"). Duostad is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Children.

Use is contraindicated.

Overdose.

There are no reported cases of Duostad overdose. Below is information regarding overdose of each component separately.

Dutasteride.

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

There is no specific antidote; therefore, in the event of possible 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 mmHg), vomiting, and diarrhea. These were managed with infusion therapy, after which the patient rapidly improved. 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 provided. Dialysis may be ineffective, as tamsulosin hydrochloride is almost completely bound to plasma proteins.

In overdose, to prevent absorption, vomiting should be induced. If large doses have been ingested, gastric lavage, activated charcoal, and laxatives (e.g., sodium sulfate) should be administered.

Adverse Reactions

Clinical studies with Duostad have not been conducted; however, bioequivalence of Duostad to the combination of dutasteride and tamsulosin has been demonstrated. Information on concomitant use was obtained from the CombAT study (combination of Avodart and tamsulosin), in which combination therapy with dutasteride 0.5 mg and tamsulosin 0.4 mg once daily for 4 years was compared to 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 Duostad; therefore, information on adverse reactions associated with the individual components of Duostad is 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 higher rates 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 the individual components of Duostad, 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 with concomitant use of dutasteride and tamsulosin.

Frequency categories for adverse reactions observed in clinical studies are defined as follows:
Frequent (≥ 1/100 to < 1/10),
Uncommon (≥ 1/1,000 to < 1/100),
Rare (≥ 1/10,000 to < 1/1,000),
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 umbrella 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 insufficiency, and congestive cardiomyopathy.

2 Including hyperesthesia and breast enlargement.

3 Adverse reactions related to sexual dysfunction are associated with dutasteride treatment (including monotherapy and 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.

Data from post-marketing studies.

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

Frequency not known: allergic reactions, including rash, pruritus, urticaria, localized edema, and angioedema.

Psychiatric disorders

Frequency not known: depression.

Skin and subcutaneous tissue disorders

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

Reproductive system and breast disorders

Frequency not known: testicular pain and swelling.

Tamsulosin monotherapy.

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

Additional cases reported during post-approval use include atrial fibrillation, arrhythmia, tachycardia, dyspnea, epistaxis, visual disturbances including decreased visual acuity, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, and dryness of the oral mucosa associated 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 "Special precautions" and "Pharmacological properties"). A causal relationship between dutasteride use and the development of high-grade Gleason prostate cancer has not been established.

Clinical trials and post-marketing surveillance have reported cases of male breast cancer (see section "Special precautions").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals, as well as patients or their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

After first opening of the bottle, use within 90 days.

Storage conditions.

No special storage conditions required.

Keep out of the reach of children.

Packaging.

30 or 90 capsules in a bottle; 1 bottle per cardboard box.

Prescription status. By prescription only.

Manufacturer.

STADA Arzneimittel AG, Germany /
STADA Arzneimittel AG, Germany.

LABORATORIOS LEON FARMA, S.A., Spain /
LABORATORIOS LEON FARMA, S.A., Spain.

Manufacturer's address and location of operations.

Stadastrasse 2-18, 61118 Bad Vilbel, Germany /
Stadastrasse 2-18, 61118 Bad Vilbel, Germany.

Calle La Vallina S/N, Poligono Industrial Navatejera, Villaquilambre, 24193, Spain /
Calle La Vallina S/N, Poligono Industrial Navatejera, Villaquilambre, 24193, Spain.