Duodart

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DUODART™ (DUODART)

Composition:

Active substances: dutasteride, tamsulosin hydrochloride;

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

Excipients: monodiglycerides of caprylic acid, butylhydroxytoluene (E 321), gelatin, glycerin, titanium dioxide (E 171), yellow iron oxide (E 172), medium-chain triglycerides and lecithin; microcrystalline cellulose, methacrylic acid copolymer dispersion, talc, triethyl citrate;

Capsule shell: carrageenan (E 407), potassium chloride, titanium dioxide (E 171), FD&C Yellow No. 6 (E 110), hypromellose, carnauba wax, corn starch, red iron oxide (E 172), SW-9008 Black Ink (shellac, propylene glycol, black iron oxide (E 172), potassium hydroxide).

Pharmaceutical form. Hard capsules.

Main physicochemical properties: hard capsule of elongated shape with a brown body and an orange cap marked with "GS" in black ink. 7CZ

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

Pharmacological Properties.

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

No differences in pharmacodynamic effects are expected between the fixed-dose combination of dutasteride and tamsulosin compared to the co-administration of dutasteride and tamsulosin 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 into dihydrotestosterone (DHT). DHT is an androgen primarily responsible for prostate growth and the development of benign prostatic hyperplasia. Tamsulosin inhibits α1a and α1d adrenergic receptors in the smooth muscle 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 relieving obstruction. The drug also reduces the severity of irritative and obstructive symptoms, in which urinary incontinence and contraction of smooth muscles in the lower urinary tract play a significant role. This effect is achieved during long-term therapy. The need for surgical intervention or catheterization is significantly reduced.

α1-adrenergic receptor antagonists may reduce blood pressure by decreasing total peripheral resistance. However, during studies on 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 doses of dutasteride and tamsulosin in capsule form.

Bioequivalence studies of single doses were conducted both under fasting conditions and after food intake. Compared to fasting, administration after food resulted in a 30% reduction in Cmax (maximum concentration) of tamsulosin in the dutasteride-tamsulosin combination. Food 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 intestine and is almost completely bioavailable. Both the rate and extent of tamsulosin absorption are reduced when taken within 30 minutes after a meal. Consistent absorption is ensured by taking Duodart at the same time of day and after a similar type of meal. Plasma tamsulosin concentration is dose-proportional.

After administration of a single dose of tamsulosin following a meal, peak plasma concentration is reached approximately 6 hours later. Steady-state concentration is achieved by day 5 of repeated 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, 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%). With daily dosing, serum dutasteride 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 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/day dutasteride until steady-state is reached, 1.0–15.4% (mean 5.4%) of the administered dose is excreted unchanged in feces. The remainder is excreted in feces as four major metabolites, accounting for 39%, 21%, 7%, and 7% of drug-related substances, 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 actively metabolized by cytochrome P450 enzymes in the liver, 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 effects of tamsulosin. Before excretion in urine, tamsulosin hydrochloride metabolites undergo extensive conjugation with glucuronic acid or sulfate.

Excretion

Dutasteride

Dutasteride excretion is dose-dependent, and the process should be described as occurring via two parallel pathways: one saturable at clinically relevant concentrations and the other non-saturable. 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 a half-life ranging from 3 to 9 days.

At therapeutic concentrations following repeated 0.5 mg/day dosing, the slower, linear elimination pathway dominates, 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 formulation, the plasma half-life of tamsulosin ranges from 5 to 7 hours. Due to absorption-rate-limited pharmacokinetics, with modified-release tamsulosin capsules, the apparent half-life of tamsulosin 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 half-life was shorter in men under 50 years. 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 on the overall effect of tamsulosin hydrochloride (AUC [area under the pharmacokinetic curve]) and 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 does not depend on tamsulosin hydrochloride binding to alpha-1-acid glycoprotein but decreases with patient age, resulting in an overall effect that is 40% stronger (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 human urine, so clinically significant increases in plasma dutasteride concentration in patients with renal impairment are not expected (see section "Dosage and Administration").

Tamsulosin

Tamsulosin hydrochloride pharmacokinetics were compared in 6 patients with mild to moderate (30 ≤ CLcr < 70 mL/min/1.73 m²) or moderate to severe (10 ≤ CLcr < 30 mL/min/1.73 m²) renal impairment and 6 subjects with normal clearance (CLcr < 90 mL/min/1.73 m²). While changes in total plasma concentration of tamsulosin hydrochloride 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) were not studied.

Hepatic Impairment

Dutasteride

The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied (see section "Contraindications"). Since dutasteride is primarily eliminated via metabolism, increased plasma levels and prolonged half-life are expected in these patients (see sections "Dosage and Administration" and "Special Warnings").

Tamsulosin

Tamsulosin hydrochloride pharmacokinetics were compared in 8 patients with moderate hepatic impairment (Child-Pugh classification: grades A and B) and 8 subjects with normal liver function. While changes in total plasma concentration of tamsulosin hydrochloride occurred 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 study of dutasteride combined 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 chemoprevention involving 8231 men aged 50–75 years with prior negative prostate biopsy for prostate cancer and baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL in men aged 50–60 years or 3.0 ng/mL and 10.0 ng/mL in men 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 who received dutasteride and an alpha-blocker concurrently (12/1152, 1.0%) compared to those who received 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 heart failure has not been established (see section "Special Warnings").

Prostate Cancer and High-Grade Tumors

In a 4-year study comparing dutasteride with placebo in 8231 men aged 50–75 years with prior negative prostate biopsy 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 subjects underwent prostate needle biopsy (mandatory per primary protocol), and data were used for Gleason score analysis. A total of 1517 patients were diagnosed with prostate cancer. The majority of 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 recorded 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 placebo group (n = 18, 0.5%). 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 on prostate cancer risk in men taking dutasteride for more than 4 years. The percentage of patients diagnosed with Gleason score 8–10 prostate cancer remained constant across 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% and 0.5%, respectively) (see section "Special Warnings"). There was no difference in the incidence of Gleason score 7–10 prostate cancer (p = 0.81).

In a 4-year clinical study of benign prostatic hyperplasia treatment (CombAT), where mandatory biopsy was not required by 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.

Male Breast Cancer

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—did not show any 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 male 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 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.

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

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

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

Duodart is contraindicated 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 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 regarding 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. It should be noted that if enzyme activity is suppressed for 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 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 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, 5-phosphodiesterase inhibitors, and other alpha-1-adrenergic blockers, may theoretically lead to an enhanced hypotensive effect. Duodart should not be used in combination with other alpha-1-adrenergic blockers.

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

Concomitant use of tamsulosin hydrochloride and paroxetine (a potent CYP2D6 inhibitor) increases the Cmax and AUC of tamsulosin hydrochloride by 1.3 and 1.6 times, respectively. A similar increase is expected in patients who are poor 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 clinically studied, but may potentially lead to a substantial 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 (area under the pharmacokinetic curve) of tamsulosin hydrochloride. Duodart should be used with caution in combination 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 use of 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 reduced serum levels of tamsulosin, but 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.

Combined therapy should be prescribed only after careful analysis 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 trials, the incidence of heart failure (a combined term for all reported events, primarily heart failure and congestive heart failure) was higher in individuals treated with a combination of dutasteride and an alpha-blocker, mainly tamsulosin, compared to those not receiving this combination. The incidence of heart failure was low (≤1%) and variable across these studies. No imbalance in the incidence of cardiovascular adverse events was observed 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 "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 tumors (poorly differentiated)

In a 4-year clinical trial involving over 8,000 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 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 Duodart 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 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)

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

Patients taking Duodart 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 lowest level achieved during Duodart therapy may indicate the presence of prostate cancer or non-adherence to Duodart 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 values in patients receiving Duodart, previous PSA values should be used for comparison.

The use of Duodart 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 Duodart therapy. If a physician decides to use the percentage of free PSA to evaluate for prostate cancer in a patient taking Duodart, no adjustment of the free PSA value is necessary.

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

Renal impairment

Treatment of patients with severe renal impairment (creatinine clearance <10 mL/min) should be performed with caution, as the pharmacokinetics of dutasteride 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, in rare cases, may lead to syncope.

Patients who experience initial signs of orthostatic hypotension (dizziness, weakness) after starting Duodart should be advised to sit or lie down until symptoms resolve.

Caution should be exercised when co-administering alpha-adrenergic blockers, including tamsulosin, with phosphodiesterase-5 (PDE-5) inhibitors. Both alpha-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, intraoperative floppy iris syndrome (IFIS, a variant of the 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, Duodart 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 Duodart. This information may help anticipate the potential 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 benefits and optimal timing for 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 inhibitors of CYP3A4 (e.g., ketoconazole) or, to a lesser extent, with strong inhibitors of CYP2D6 (e.g., paroxetine) may increase tamsulosin concentrations (see section "Interaction with other medicinal products and other forms of interaction"). Therefore, tamsulosin 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, a combination of both CYP3A4 and CYP2D6 inhibitors, or in patients who are poor metabolizers of CYP2D6.

Hepatic impairment

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

Excipients

Duodart contains the dye FD&C Yellow No. 6 (E 110), which may cause allergic reactions.

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 the use of 5α-reductase inhibitors. Physicians should inform their patients about the need to promptly report any changes in breast tissue, such as nipple discharge or lumps.

Use during pregnancy or breastfeeding.

Duodart is contraindicated for use in women. Studies evaluating the effects of Duodart 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 risk of reduced male fertility cannot be excluded.

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

Pregnancy.

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

Ability to affect reaction speed when driving or operating machinery.

No studies have been conducted to evaluate the effect of Duodart 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 Duodart treatment.

Method of Administration and Dosage

Adults (including elderly patients)

The recommended dose of Duodart is 1 capsule (0.5 mg/0.4 mg) once daily. The medication should be taken orally 30 minutes after food intake, at approximately 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.

Duodart may be used to replace combination therapy with dutasteride and tamsulosin hydrochloride for treatment simplification.

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

Renal Impairment

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

Hepatic Impairment

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

Children

Use is contraindicated.

Overdose

There are no reported cases of Duodart overdose. Below is information regarding overdose 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 the therapeutic dose) administered for 7 days did not raise safety concerns. In clinical trials, doses of dutasteride up to 5 mg/day were administered for 6 months without additional adverse reactions compared to the standard dose of 0.5 mg/day.

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

Tamsulosin

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

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

Adverse Reactions

Clinical trials specifically evaluating the use of Duodart have not been conducted; however, bioequivalence of Duodart has been demonstrated when dutasteride and tamsulosin are co-administered. Information on concomitant use is derived from the CombAT study (combination of Avodart 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 associated with each component individually (dutasteride and tamsulosin) is also provided below. Not all adverse reactions observed with individual components have been reported during treatment with Duodart; therefore, information on adverse reactions associated with individual components of Duodart 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 disorders, specifically ejaculation disorders, observed in this group.

Adverse reactions occurring at a frequency of ≥1% during the first year of treatment, based on data from the CombAT, REDUCE, and individual component monotherapy clinical trials, are listed in the table below.

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 follows:
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).

Adverse reactions classified by system organ class 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 EU Summary of Product Characteristics for tamsulosin.

d REDUCE study.

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

2 Including hyperesthesia and breast enlargement.

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

^ Including decreased semen volume.

Post-marketing data

In post-marketing surveillance, adverse reactions were reported from 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 data indicate that during cataract and glaucoma surgery, some patients previously treated with alpha1-adrenoblockers, including tamsulosin, experienced intraoperative floppy iris syndrome (IFIS, a variant of the small pupil syndrome) (see "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, 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 "Special precautions" and "Pharmacological properties"). A causal relationship between dutasteride use and the development of high-grade (Gleason 8–10) 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 precautions").

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

Opaque high-density polyethylene bottles, white in color, with child-resistant polypropylene caps, containing 30 or 90 capsules per bottle; 1 bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Catalent Germany Schorndorf GmbH, Germany /
Catalent Germany Schorndorf GmbH, Germany.

Manufacturer's location and address of the manufacturing site.

Steinbeisstr. 1 und 2, Schorndorf, Baden-Wuerttemberg, 73614, Germany /
Steinbeisstr. 1 und 2, Schorndorf, Baden-Wuerttemberg, 73614, Germany.