Dustera combo

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DUSTERA COMBO (DusteraCombo)

Composition:

Active substances: dutasteride, tamsulosin hydrochloride;

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

Excipients:

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

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

hard gelatin capsule: iron oxide black (E172), iron oxide red (E172), titanium dioxide (E171), iron oxide yellow (E172), gelatin;

ink composition: shellac, iron oxide black (E172), propylene glycol, ammonia solution concentrated, potassium hydroxide.

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard gelatin capsule of elongated shape, with a brown body and a beige cap marked with "C001" in black ink on the cap. The capsule contents: an oblong soft gelatin capsule (approximately 16.5 mm x 6.5 mm) of light yellow color, filled with a clear liquid and white or almost white tamsulosin pellets.

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

Pharmacological Properties.

Pharmacodynamics.

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

No differences in pharmacodynamic effects are expected between the fixed-dose combination of dutasteride and tamsulosin and those observed when dutasteride and tamsulosin are administered concomitantly as separate components.

Dutasteride

Dutasteride inhibits the activity of both type 1 and type 2 isoenzymes of 5-alpha-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 arterial 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 simultaneous administration of separate capsules containing dutasteride and tamsulosin.

Bioequivalence studies of single doses were conducted both in the fasting state and after food intake. Compared to fasting conditions, administration after food intake 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 oral administration of a single 0.5 mg dose of dutasteride, the time to reach Cmax in serum was 1–3 hours. Absolute bioavailability was approximately 60%. Food intake did not affect the bioavailability of dutasteride.

Tamsulosin

Tamsulosin is absorbed from the intestine and is almost completely bioavailable. Both the rate and extent of tamsulosin absorption are reduced when administered within 30 minutes after a meal. Consistent absorption is ensured by taking Dustera Combo at the same time each day after consuming a similar type of meal. Plasma tamsulosin concentration is dose-proportional.

After administration of a single dose of tamsulosin following food intake, Cmax in plasma is reached approximately 6 hours later. Steady-state concentration is achieved by day 5 of multiple dosing. 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, 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%). With daily dosing, dutasteride concentration in serum reaches 65% of steady-state concentration 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 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 dutasteride daily to steady-state, 1–15.4% (mean 5.4%) of the administered dose is excreted unchanged in feces. The remainder is excreted in feces as four major metabolites (39%, 21%, 7%, and 7% of each drug-related substance) 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 cytochrome P450 enzymes in the liver, and less than 10% of the dose is 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 an 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 a 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 formulations, the plasma half-life of tamsulosin ranges from 5 to 7 hours. Due to absorption rate-limited pharmacokinetics, the apparent half-life of tamsulosin in modified-release capsules taken after food is approximately 10 hours, and at steady-state in patients, approximately 13 hours.

Elderly Patients

Dutasteride

Dutasteride pharmacokinetics 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 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 total exposure (AUC) and half-life of tamsulosin hydrochloride suggest that the pharmacokinetic effect of tamsulosin hydrochloride may be slightly prolonged in elderly patients compared to younger healthy male volunteers. Intrinsic clearance does not depend 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 dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a 0.5 mg dose of dutasteride is found in urine at steady-state; therefore, a clinically significant increase in plasma dutasteride concentration in patients with renal impairment is 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 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. However, patients with end-stage renal disease (CLcr < 10 mL/min/1.73 m²) have not been 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 Precautions" and "Dosage and Administration").

Tamsulosin

Tamsulosin hydrochloride pharmacokinetics were compared in 8 patients with mild to moderate hepatic impairment (Child-Pugh classes A and B) and 8 subjects with normal liver function. Although changes in total plasma tamsulosin hydrochloride concentration occurred due to variable binding to alpha-1-acid glycoprotein, the concentration of unbound (active) tamsulosin hydrochloride did not change significantly, and only a moderate (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride was observed. Therefore, dose adjustment of tamsulosin hydrochloride is not required in patients with mild to 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 evaluating 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 group (4/1623, 0.2%) or tamsulosin monotherapy group (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 Precautions").

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 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), 6706 patients underwent prostate needle biopsy (mandated by the original protocol), with data used for Gleason score 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. However, during years 3–4, 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 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 time 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 Precautions"). 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 required by the original protocol 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.

Breast Cancer in Men

Two case-control epidemiological studies—one conducted in the USA (n = 339 breast cancer cases and n = 6780 controls) and another in the UK (n = 398 breast cancer cases and n = 3930 controls) using healthcare databases—showed no 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 breast cancer associated with 5α-reductase inhibitor use versus non-use of 1.08; 95% CI 0.62, 1.87.

A causal relationship between male breast cancer cases 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.

Dustera Combo medicinal product is not used for treatment of women and children (see section "Use during pregnancy or breastfeeding").

Dustera Combo is contraindicated in patients with hypersensitivity to dutasteride, other 5α-reductase inhibitors, tamsulosin (including tamsulosin-induced angioedema), other components of the product, or to soy and peanuts.

Dustera Combo is contraindicated in patients with a history of orthostatic hypotension.

This medicinal product is also contraindicated in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

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

Dutasteride

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

Effect of other medicinal products on the pharmacokinetics of dutasteride

Concomitant use with CYP3A4 inhibitors 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.

Long-term concomitant use of dutasteride with medicinal products that are potent inhibitors of the CYP3A4 enzyme (e.g., ritonavir, indinavir, nefazodone, itraconazole, orally administered ketoconazole) may increase serum concentrations of dutasteride. Further inhibition of 5α-reductase due to enhanced dutasteride activity is unlikely. However, dose reduction of dutasteride may be considered if adverse reactions occur. In cases of prolonged enzyme inhibition, the long half-life 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 (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 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, phosphodiesterase-5 inhibitors, and other alpha-1-adrenergic blockers, may theoretically lead to an enhanced hypotensive effect. Dustera Combo should not be used in combination with other alpha-1-adrenergic blockers.

Concomitant administration of tamsulosin hydrochloride and ketoconazole (a strong 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 strong 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 strong 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% decrease in clearance and a 44% increase in AUC of tamsulosin hydrochloride. Dustera Combo should be used with caution in combination with cimetidine.

A comprehensive study on the interaction between tamsulosin hydrochloride and warfarin has not been conducted. Limited in vitro and in vivo data are insufficient. Concomitant treatment with warfarin and tamsulosin hydrochloride should be performed 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 tamsulosin serum 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 during in vitro studies using liver microsomal fractions (indicative of 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.

Combination 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 consideration of alternative treatment options, including monotherapy.

Cardiovascular adverse reactions

Data from two 4-year clinical trials showed a higher incidence of heart failure (a combined term for all reported events, primarily heart failure and congestive heart failure) in individuals treated with a combination of dutasteride and an alpha-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 frequency of cardiovascular adverse events in any of the trials. A causal relationship between the use of dutasteride (alone or in combination with alpha-blockers) and the development of heart failure has not been established (see section "Pharmacological properties").

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

In a 4-year clinical study involving >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 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 remains unclear.

Men taking the medicinal product Duster Combo should undergo regular evaluations for prostate cancer risk, 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 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 prostate cancer screening. Dutasteride reduces serum PSA levels by approximately 50% within 6 months of treatment.

Patients taking Duster Combo 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 Duster Combo therapy may indicate 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 treated with Duster Combo, previous PSA values should be considered for comparison.

The use of Duster Combo 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 Duster Combo treatment. If a physician decides to use the percent free PSA to evaluate prostate cancer risk in a patient on Duster Combo, no adjustment of the free PSA value is required.

Before initiating Duster Combo 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 undertaken with caution, as the pharmacokinetics of dutasteride have not been studied in such patients.

Arterial hypotension

As with other alpha-1-adreoblockers, orthostatic hypotension may occur in patients treated with tamsulosin and, rarely, may lead to syncope.

Patients starting Duster Combo who experience initial signs of orthostatic hypotension (dizziness, weakness) should immediately sit or lie down until symptoms resolve.

Caution is advised when co-administering alpha-adrenoblockers, including tamsulosin, with phosphodiesterase-5 inhibitors. 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 and glaucoma surgery, intraoperative floppy iris syndrome (IFIS, a variant of small pupil syndrome) has been reported in some patients previously treated with tamsulosin. IFIS may increase the risk of ocular complications during or after surgery. Therefore, the use of Duster Combo 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 previously taking Duster Combo to anticipate the possible occurrence of IFIS during surgery.

There have been isolated reports of a beneficial effect of discontinuing tamsulosin 1–2 weeks prior to cataract or glaucoma surgery; however, the benefits 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, and caution is advised in patients receiving moderate CYP3A4 inhibitors (e.g., erythromycin), strong or moderate CYP2D6 inhibitors, dual 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 to moderate hepatic impairment (see sections "Pharmacological properties", "Contraindications", and "Dosage and administration").

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 5α-reductase inhibitors. Physicians should inform patients to promptly report any changes in breast tissue, such as nipple discharge or swelling.

Use during pregnancy or breastfeeding.

Duster Combo is contraindicated for use in women. Studies on the effects of Duster Combo on pregnancy, lactation, and fertility have not been conducted. The following information refers to the individual components.

Fertility

Dutasteride affects semen characteristics (reduced sperm count, ejaculate volume, and sperm motility). A 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. Small amounts of dutasteride have been detected in semen. It is unknown whether dutasteride transferred to a woman via semen from a man taking Duster Combo affects a male fetus.

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

There is no evidence that administration of tamsulosin hydrochloride to pregnant rats and rabbits at doses exceeding the therapeutic dose has a negative effect on the fetus.

Breastfeeding period

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

Ability to influence reaction speed when driving or operating machinery.

No studies have been conducted on the effect of Duster Combo 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 Duster Combo.

Method of Administration and Dosage

Adults (including elderly patients)

The recommended dose of Duster Combo 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 should be swallowed whole and must not be opened or chewed, as contact with the capsule contents may cause irritation of the oral and pharyngeal mucosa.

Duster Combo may be used as a replacement for combination therapy with dutasteride and tamsulosin hydrochloride to facilitate treatment.

Substitution of monotherapy with dutasteride or tamsulosin hydrochloride by Duster Combo is possible if clinically justified.

Renal Impairment

The pharmacokinetics of Duster Combo in patients with renal impairment have not been studied. Dose adjustment is not required for this patient population (see sections "Pharmacokinetics" and "Special Warnings and Precautions for Use").

Hepatic Impairment

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

Children

Use is contraindicated.

Overdose

There are no reported cases of overdose with Duster Combo. The following information refers to the administration of each component separately.

Dutasteride

Clinical trial data indicate 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 clinical studies, doses of dutasteride 5 mg daily were administered for 6 months without additional adverse reactions compared to 0.5 mg daily.

There is no specific antidote; therefore, in the event of suspected overdose, symptomatic and supportive treatment 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 restore blood pressure and normalize heart rate. If this is ineffective, plasma expanders should be administered, and vasopressors added if necessary. Renal function should be monitored, and general supportive therapy initiated. Dialysis may be ineffective, as tamsulosin hydrochloride is almost completely protein-bound.

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

Adverse Reactions

Clinical studies with Duster Combo have not been conducted; however, bioequivalence of Duster Combo has been demonstrated when dutasteride and tamsulosin are used concomitantly. Information on concomitant use was obtained from the CombAT study (combination of Avodart and tamsulosin), in which a combination of 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 during use of Duster Combo. Therefore, information on adverse reactions associated with individual components of Duster Combo 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 higher rates 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, REDUCE, and clinical monotherapy studies of the individual components of Duster Combo, 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 for adverse reactions observed in clinical studies are defined as: common (≥ 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), and frequency not known (cannot be estimated from available data).

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 decreased with each subsequent year from the 1st to the 4th.

b. From clinical studies of monotherapy of BPH with dutasteride.

c. From the European Union summary of safety data for tamsulosin.

d. REDUCE study (see section "Pharmacodynamics").

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 failure, and congestive cardiomyopathy.
2. Including breast tenderness and enlargement.
3. Adverse reactions related to the reproductive system 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 reduced 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

Frequency unknown: allergic reactions, including rash, pruritus, urticaria, localized swelling, 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 has reported that during cataract and glaucoma surgery, some patients previously treated with alpha1-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 have been reported of atrial fibrillation, arrhythmia, tachycardia, dyspnea, epistaxis, visual disturbances including decreased visual acuity, Stevens-Johnson syndrome, exfoliative dermatitis, and dryness of the oral mucosa associated with tamsulosin use.

Other data

In a clinical study (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 prostate cancer (Gleason score 8–10) has not been established.

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

Reporting suspected adverse reactions after the medicine is authorized is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

7 hard capsules, 30 hard capsules, or 90 hard capsules in a high-density polyethylene bottle with a polypropylene cap, child-resistant closure, and silica gel desiccant.

One bottle with the package leaflet for medical use is placed in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

LABORATORIOS LEON FARMA, S.A. (manufacturing of the intermediate product (soft capsules of dutasteride 0.5 mg), final medicinal product, primary and secondary packaging, quality control, and batch release).

Manufacturer's address.

C/La Vallina s/n, Poligono Industrial Navatejera, Villaquilambre, León, 24193, Spain.