Dutamin

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

Composition:

Active substances: dutasteride, tamsulosin hydrochloride;

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

Excipients: glycerol monocaprylocaprate, butylhydroxytoluene (E 321), gelatin, glycerin, titanium dioxide (E 171), yellow iron oxide (E 172), medium-chain triglycerides, lecithin; microcrystalline cellulose, magnesium stearate, methacrylic acid copolymer dispersion, methacrylic copolymer (type A), sodium hydroxide, triacetin, talc;

Hard capsule shell: hypromellose, potassium chloride, carrageenan, titanium dioxide (E 171), sunset yellow FCF (E 110), red iron oxide.

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: elongated hard capsule with a brown body and an orange cap.

Each hard capsule contains pellets of tamsulosin hydrochloride with modified release and one soft gelatin capsule containing dutasteride.

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

Pharmacological properties.

Dutamin 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 complementary mechanisms of action, resulting in rapid relief of urinary symptoms, reduced risk of acute urinary retention (AUR), and decreased likelihood of needing surgical intervention due to 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 I and type II isoforms of 5α-reductase, the enzymes responsible for converting testosterone into dihydrotestosterone (DHT). DHT is the androgen primarily responsible for prostate growth and the development of benign prostatic hyperplasia.

Tamsulosin

Tamsulosin inhibits α1a and α1d adrenoceptors in the stromal smooth muscle of the prostate 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, clinically significant reductions in blood pressure were not observed in studies with tamsulosin.

Pharmacokinetics.

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

Bioequivalence studies of single doses were conducted both in the fasting state 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 administered within 30 minutes after food intake. Consistent absorption is ensured by taking Dutamin at the same time each day after a similar meal. Plasma tamsulosin concentration is proportional to the dose.

After administration of a single dose of tamsulosin following food intake, 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 single-dose administration 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%). After daily dosing, dutasteride serum concentration reaches 65% of steady-state concentration within 1 month and approximately 90% within 3 months.

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

Tamsulosin. In men, tamsulosin is approximately 99% bound to plasma proteins. The volume of distribution is small (approximately 0.2 L/kg).

Metabolism

Dutasteride. Dutasteride is actively metabolized in vivo. In vitro, dutasteride is metabolized by cytochrome P450 3A4 and 3A5, forming three monohydroxylated metabolites and one dihydroxylated metabolite.

After oral administration of 0.5 mg dutasteride daily 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 each drug-related substance, and six minor metabolites (each less than 5%). Only negligible amounts of unchanged dutasteride (<0.1% of dose) are found in human urine.

Tamsulosin. Enantiomeric bioconversion of tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer does not occur in humans. Tamsulosin hydrochloride is actively metabolized by hepatic cytochrome P450 enzymes, 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 elimination half-life ranging from 3 to 9 days.

At therapeutic concentrations following repeated 0.5 mg daily 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 elimination half-life of tamsulosin ranges from 5 to 7 hours. Due to absorption-rate-controlled pharmacokinetics, the true elimination half-life of tamsulosin from modified-release capsules taken after food is approximately 10 hours, and at steady state in patients, approximately 13 hours.

Elderly patients

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

Tamsulosin. Cross-study comparison of overall exposure to tamsulosin hydrochloride (AUC, area under the pharmacokinetic curve) and elimination half-life suggests 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 overall exposure being 40% higher (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 dutasteride dose is excreted 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. 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 concentration of tamsulosin hydrochloride 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, use in patients with end-stage renal disease (CLcr < 10 mL/min/1.73 m²) has 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, plasma dutasteride levels in these patients are expected to be elevated and elimination half-life prolonged (see sections "Dosage and administration" and "Special precautions").

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 concentration of tamsulosin hydrochloride 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.

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.

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

The drug 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.

The drug is contraindicated in patients with a history of orthostatic hypotension.

The drug is contraindicated in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

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

With long-term concomitant use of dutasteride and medicinal products that are potent inhibitors of the CYP3A4 enzyme (e.g., ritonavir, indinavir, nefazodone, itraconazole, orally administered ketoconazole), serum concentrations of dutasteride may increase. Further inhibition of 5α-reductase due to enhanced dutasteride activity is unlikely. However, dose reduction of dutasteride may be considered if adverse effects develop. It should be noted that in cases of enzyme activity 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 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 (N=24), two-week study involving 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 indicates that dutasteride does not inhibit or induce CYP2C9 enzyme activity or P-glycoprotein transporter activity. In vitro interaction studies suggest 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 α1-adrenoblockers, may theoretically result in an enhanced hypotensive effect. Dutamin should not be used in combination with other α1-adrenoblockers.

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

Concomitant use of tamsulosin hydrochloride and paroxetine (a potent CYP2D6 inhibitor) increases the Cmax and AUC of tamsulosin hydrochloride by 1.3 and 1.6 times, respectively. A similar increase is expected in patients who are poor metabolizers of CYP2D6 compared to extensive metabolizers when 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 significantly increase tamsulosin concentrations (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. Dutamin should be used with caution when combined with cimetidine.

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

No interactions were 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 (the cytochrome P450 enzyme system involved in 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 analysis 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.

Clinical trial data indicate 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 α-blocker, mainly tamsulosin, compared to those not receiving this combination. The incidence of heart failure was low (≤1%) and variable across these trials. No imbalance in the incidence of cardiovascular adverse events was observed 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").

When assessing the risk of cardiovascular adverse reactions associated with dutasteride use (compared to control groups), no consistent statistically significant increase in risk was observed for heart failure (RR 1.05; 95% CI 0.71, 1.57), acute myocardial infarction (RR 1.00; 95% CI 0.77, 1.30), or stroke (RR 1.20; 95% CI 0.88, 1.64).

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

Clinical studies involving >8000 men aged 50 to 75 years with a prior negative prostate biopsy and baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL (the REDUCE study) diagnosed prostate cancer in 1517 men. A higher incidence of Gleason score 8–10 prostate cancer was observed in the dutasteride group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%). A causal relationship between dutasteride use and the development of poorly differentiated prostate cancer has not been established. The clinical significance of this numerical imbalance is unclear.

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

In additional long-term follow-up of patients receiving dutasteride for chemoprevention (REDUCE study), a low incidence of new prostate cancer cases was observed (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 Dutamin should have a new baseline PSA level established 6 months after starting therapy. This level should then be monitored regularly. Any confirmed increase in PSA from the nadir level during Dutamin treatment may indicate the presence of prostate cancer or non-adherence to therapy 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 on Dutamin, previous PSA values should be used for comparison.

The use of PSA levels for diagnosing prostate cancer remains valid after establishing a new baseline during Dutamin therapy.

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 Dutamin treatment. If a physician decides to use the free PSA percentage to evaluate prostate cancer risk in a patient on Dutamin, no adjustment of the free PSA value is necessary.

Before initiating Dutamin therapy and periodically during treatment, men with benign prostatic hyperplasia should undergo digital rectal examination and other prostate cancer screening procedures.

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 α1-adrenoblockers, orthostatic hypotension may occur in patients treated with tamsulosin and, rarely, may lead to syncope.

Patients starting Dutamin therapy who experience initial signs of orthostatic hypotension (dizziness, weakness) should be placed in a sitting or lying position until symptoms resolve.

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

Intraoperative floppy iris syndrome (IFIS).

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

During preoperative evaluation, ophthalmic surgeons and their teams should determine whether a patient is currently or previously taking Dutamin. This information may help anticipate the potential occurrence of IFIS during surgery.

There have been isolated reports of a beneficial effect of discontinuing tamsulosin 1–2 weeks before 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 inhibitors of CYP3A4 (e.g., ketoconazole) or, to a lesser extent, 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. Caution is advised when using tamsulosin in patients receiving moderate CYP3A4 inhibitors (e.g., erythromycin), strong or moderate CYP2D6 inhibitors, combined 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 undertaken with caution (see sections "Posology and method of administration", "Contraindications", "Pharmacological properties").

Excipients.

Dutamin contains the colorant sunset yellow FCF (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 do not indicate an 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 lumps.

Use during pregnancy or breastfeeding.

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

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

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

Pregnancy. Like other 5α-reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone, which may impair the development of external genitalia in male fetuses. A small amount of dutasteride has been detected in semen during clinical studies. It is unknown whether dutasteride transferred via semen from a man treated with Dutamin 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 Dutamin, to prevent semen exposure.

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

Breastfeeding. 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 Dutamin 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 Dutamin therapy.

Dosage and Administration

Adults (including elderly patients)

The recommended dose of Dutamin 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, without opening or chewing, as contact with the capsule contents may cause irritation of the oral and pharyngeal mucosa.

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

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

Renal Impairment

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

Hepatic Impairment

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

Children

Use is contraindicated.

Overdose

There are no reported cases of Dutamin overdose. The following information refers to the use of each component separately.

Dutasteride

Clinical studies have shown 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 volunteers. In clinical trials, doses of dutasteride of 5 mg/day were administered for 6 months without an increase in adverse reactions compared to the 0.5 mg/day dose.

There is no specific antidote; therefore, in the event of a 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, if necessary, vasoconstrictors. Renal function should be monitored, and general supportive therapy provided. Dialysis may be ineffective because tamsulosin hydrochloride is almost completely protein-bound.

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

Adverse reactions

Data on the concomitant use of dutasteride and tamsulosin were obtained from the CombAT study, in which a combination of dutasteride 0.5 mg and tamsulosin 0.4 mg once daily over 4 years was compared to monotherapy with either agent.

Information on adverse reactions of each component separately (dutasteride and tamsulosin) is also provided below. Not all adverse reactions observed with individual components were reported during use of the combination product; therefore, information on adverse reactions associated with individual components 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% in the combination therapy group (dutasteride + tamsulosin); 15%, 6%, 3%, and 2% in the dutasteride monotherapy group; and 13%, 5%, 2%, and 2% in the tamsulosin monotherapy group. The higher percentage of adverse reactions in the combination therapy group during the first year of treatment was primarily due to a higher incidence of reproductive disorders, specifically ejaculation disorders observed in this group.

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

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

Frequency of adverse reactions identified in clinical studies: common (≥ 1/100 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.

System organ class	Adverse reactions	Dutasteride + tamsulosin a	Dutasteride	Tamsulosin c
Nervous system disorders	Syncope			Uncommon
	Dizziness	Common		Common
	Headache			Uncommon
Cardiac disorders	Heart failure (composite term1)	Uncommon	Uncommond
	Pounding heartbeat			Uncommon
Vascular disorders	Postural hypotension			Uncommon
Respiratory, thoracic and mediastinal disorders	Rhinitis			Uncommon
Gastrointestinal disorders	Constipation			Uncommon
	Diarrhea			Uncommon
	Nausea			Uncommon
	Vomiting			Uncommon
Skin and subcutaneous tissue disorders	Angioneurotic edema			Uncommon
	Stevens–Johnson syndrome			Very rare
	Urticaria			Uncommon
	Rash			Uncommon
	Pruritus			Uncommon
Reproductive system and breast disorders	Priapism	Common	Commonb
	Impotence3	Common	Commonb
	Libido disorders3 (decreased)	Common	Commonb
	Ejaculation disorders3^	Common	Commonb	Common
	Breast disorders2	Common	Commonb
General disorders	Asthenia			Uncommon

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

b From monotherapy studies of dutasteride in benign prostatic hyperplasia.

c From the European Union summary of product characteristics for tamsulosin.

d REDUCE study.

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

2 Including hyperesthesia and breast enlargement.

3 Adverse reactions related to sexual function are associated with dutasteride treatment (including 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 surveillance data

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

Dutasteride monotherapy

Immune system disorders

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

Psychiatric disorders

Unknown frequency: depression.

Skin and subcutaneous tissue disorders

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

Reproductive system and breast disorders

Unknown frequency: testicular pain and swelling.

Tamsulosin monotherapy

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

Additional cases reported during post-marketing use include atrial fibrillation, arrhythmia, tachycardia, dyspnea, epistaxis, visual disturbances (including decreased visual acuity), 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.

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

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging.

6 capsules in a blister; 5 blisters in a cardboard pack.

6 capsules in a blister; 15 blisters in a cardboard pack.

9 capsules in a blister; 10 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

SAG MANUFACTURING, S.L.U./

SAG MANUFACTURING, S.L.U.

Manufacturer's address and place of business.

Crta. N-I, Km 36, San Agustin de Guadalix, Madrid, 28750, Spain/

Ctra. N-I, Km 36, San Agustin de Guadalix, Madrid, 28750, Spain.

INSTRUCTION

for medical use of medicinal product

DUTAMIN

(DUTAMIN)

Composition:

Active substances: dutasteride, tamsulosin hydrochloride;

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

Excipients: glycerol monocaprylocaprate, butylhydroxytoluene (E 321), gelatin, glycerin, titanium dioxide (E 171), yellow iron oxide (E 172), medium-chain triglycerides, lecithin; microcrystalline cellulose, magnesium stearate, methacrylate copolymer dispersion, methacrylate copolymer (type A), sodium hydroxide, triacetin, talc;

Capsule shell: hypromellose, potassium chloride, carrageenan, titanium dioxide (E 171), orange-yellow S (E 110), red iron oxide.

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics: hard, elongated capsule with a brown body and an orange cap.

Each hard capsule contains pellets of tamsulosin hydrochloride with modified release and one soft gelatin capsule containing dutasteride.

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

Pharmacological Properties

Dutamin 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 complementary mechanisms of action, resulting in rapid relief of urinary symptoms, reduced risk of acute urinary retention (AUR), and decreased likelihood of requiring surgical intervention for benign prostatic hyperplasia (BPH).

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

Dutasteride

Dutasteride inhibits the activity of both type I and type II isoenzymes of 5α-reductase, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for prostate growth and the development of benign prostatic hyperplasia.

Tamsulosin

Tamsulosin inhibits α1a and α1d adrenoceptors in the stromal smooth muscles of the prostate 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 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 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 clinical studies, tamsulosin did not produce clinically significant reductions in blood pressure.

Pharmacokinetics

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

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 if administered within 30 minutes after a meal. Uniform absorption is ensured by taking Dutamin 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, 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 single-dose administration. 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%). 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 0.5 mg daily dosing. The mean transfer rate of dutasteride from serum into seminal fluid is 11.5%.

Tamsulosin. In men, tamsulosin is approximately 99% bound to plasma proteins. The volume of distribution is small (approximately 0.2 L/kg).

Metabolism

Dutasteride. Dutasteride is actively metabolized in vivo. In vitro, dutasteride is metabolized by cytochrome P450 3A4 and 3A5, forming three monohydroxylated metabolites and one dihydroxylated metabolite.

After oral administration of 0.5 mg/day dutasteride to steady-state, 1.0–15.4% (mean 5.4%) of the administered dose is excreted in feces unchanged. The remainder is excreted in feces as four major metabolites, accounting for 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 hepatic cytochrome P450 enzymes, 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 one 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 less, 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/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 formulations, the elimination half-life of tamsulosin in plasma ranges from 5 to 7 hours. Due to absorption-rate-limited pharmacokinetics, in the case of modified-release tamsulosin capsules, the apparent elimination half-life of tamsulosin taken after food is approximately 10 hours, and at steady-state in patients, approximately 13 hours.

Elderly Patients

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

Tamsulosin. Cross-comparative studies assessing the overall effect of tamsulosin hydrochloride (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 independent of tamsulosin hydrochloride binding to α1-acid glycoprotein but decreases with age, resulting in an overall 40% greater exposure (AUC) in patients aged 55–75 years compared to those aged 20–32 years.

Renal Impairment

Dutasteride. The effect of renal impairment on the pharmacokinetics of dutasteride has not been studied. However, less than 0.1% of a 0.5 mg dose of dutasteride is excreted in urine at steady-state; therefore, a clinically significant increase in plasma dutasteride concentration in patients with renal impairment is not expected (see section "Posology and Method of 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 concentration of tamsulosin hydrochloride 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, use in patients with end-stage renal disease (CLcr < 10 mL/min/1.73 m²) has not been studied.

Hepatic Impairment

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

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 hepatic function. Although changes in total plasma concentration of tamsulosin hydrochloride occurred due to variable binding to α1-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, 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.

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.

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

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

The drug is contraindicated in patients with a history of orthostatic hypotension.

The drug is contraindicated in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Studies on the interaction of Dutamin with other medicinal products have not been conducted. The following information refers to 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 dutasteride pharmacokinetics

Concomitant use with CYP3A4 and/or P-glycoprotein inhibitors

Dutasteride is primarily eliminated via metabolism. In vitro studies show that CYP3A4 and CYP3A5 are the main catalysts of 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 receiving 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 strong inhibitors of CYP3A4 enzyme (e.g., ritonavir, indinavir, nefazodone, itraconazole, oral ketoconazole), serum concentrations of dutasteride may increase. Further inhibition of 5α-reductase due to enhanced dutasteride effect is unlikely. However, dose reduction of dutasteride may be considered if adverse effects occur. It should be noted that, in case of enzyme inhibition over a prolonged period, the long elimination 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 α1-adrenoblockers, may theoretically lead to an enhanced hypotensive effect. Dutamin should not be used in combination with other α1-adrenoblockers.

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 CYP2D6 metabolizers compared to those with extensive metabolism when used concomitantly with strong 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 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 (area under the pharmacokinetic curve) of tamsulosin hydrochloride. Dutamin should be used with caution when combined with cimetidine.

A comprehensive study of the interaction between tamsulosin hydrochloride and warfarin has not been conducted. Results from limited in vitro and in vivo studies are insufficient. Concomitant 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, 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 hepatic 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 increased risk of adverse reactions (including heart failure), and after consideration of alternative treatment options, including monotherapy.

Cardiovascular adverse reactions.

Clinical trial data indicate 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 α-blocker, mainly tamsulosin, compared to those not receiving this combination. The incidence of heart failure was low (≤1%) and variable across these trials. No imbalance in the frequency of cardiovascular adverse events has been observed 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").

When assessing the risk of cardiovascular adverse reactions with dutasteride use (compared to the 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 (poorly differentiated) tumors according to Gleason score.

Clinical studies involving >8000 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 (REDUCE study) diagnosed prostate cancer in 1517 men. A higher incidence of Gleason score 8–10 prostate cancer was observed in the dutasteride group (n=29, 0.9%) compared to the placebo group (n=19, 0.6%). A causal relationship between dutasteride use and the development of poorly differentiated prostate cancer has not been established. The clinical significance of this numerical imbalance is unclear.

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

In an additional long-term follow-up of patients from the REDUCE study, where dutasteride was used for chemoprevention, a low incidence of new prostate cancer cases was observed (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 Dutamin should have a new baseline PSA level established 6 months after starting treatment. This level should then be monitored regularly. Any confirmed increase in PSA from the nadir level during Dutamin therapy may indicate the presence of prostate cancer or non-adherence to treatment and requires thorough evaluation, even if PSA levels remain within the normal range for men not treated with 5α-reductase inhibitors. When interpreting PSA levels in patients receiving Dutamin, previous PSA values should be considered for comparison.

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

The ratio of free to total PSA remains unchanged during Dutamin therapy. If a physician decides to use the percentage of free PSA to assess prostate cancer risk in a patient receiving Dutamin, no adjustment of the free PSA value is necessary.

Prior to initiating Dutamin therapy and periodically during treatment, patients with benign prostatic hyperplasia should undergo digital rectal examination and other prostate cancer screening procedures.

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 α1-adrenergic blockers, orthostatic hypotension may occur in patients treated with tamsulosin and, rarely, may lead to syncope.

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

Caution is advised when co-administering α-adrenergic blockers, including tamsulosin, with phosphodiesterase-5 inhibitors. Both drug classes 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 observed in some patients previously treated with tamsulosin. IFIS may increase the risk of ocular complications during or after surgery. Therefore, Dutamin is not recommended in patients scheduled for cataract surgery.

During preoperative evaluation, ophthalmic surgeons and their teams should determine whether the patient is currently or has previously been prescribed Dutamin to 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 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 should not be used in patients receiving strong CYP3A4 inhibitors. Caution is recommended 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), 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.

Dutamin contains the azo dye sunset yellow FCF (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 indicate no increased risk of male breast cancer with 5α-reductase inhibitor use. Physicians should inform patients to promptly report any changes in breast tissue, such as nipple discharge or swelling.

Use during pregnancy or breastfeeding.

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

Fertility. Dutasteride affects semen parameters (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 in clinical studies. It is unknown whether dutasteride transferred to a woman via semen from a man treated with Dutamin may affect a male fetus.

As with other 5α-reductase inhibitors, condom use during sexual intercourse is recommended when the female partner is pregnant and the male partner is being treated with Dutamin, to prevent semen exposure.

No evidence indicates 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 influence the speed of reactions when driving or operating machinery.

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

Dosage and Administration

Adults (including elderly patients)

The recommended dose of Dutamin 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 irritate the mucous membranes of the mouth and throat.

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

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

Renal Impairment

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

Hepatic Impairment

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

Children

Use is contraindicated.

Overdose

There are no data on cases of Dutamin overdose. Below is information regarding overdose with each individual component.

Dutasteride

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

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

Tamsulosin

There have been reports of acute overdose with tamsulosin hydrochloride at a dose of 5 mg, resulting in acute arterial hypotension (systolic blood pressure 70 mmHg), vomiting, and diarrhea. The patient improved on the same day after fluid infusion therapy. 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.

To prevent absorption in overdose, 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) should be administered.

Adverse Reactions

Information on the concomitant use of dutasteride and tamsulosin was obtained from the CombAT study, in which the combination of dutasteride 0.5 mg and tamsulosin 0.4 mg once daily for 4 years was compared with monotherapy using either agent alone.

Information on adverse reactions of each component separately (dutasteride and tamsulosin) is also provided below. Not all adverse reactions observed with individual components were reported during treatment with the combination product; therefore, information on adverse reactions associated with each individual component 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% in the combination therapy group (dutasteride + tamsulosin); 15%, 6%, 3%, and 2% in the dutasteride monotherapy group; and 13%, 5%, 2%, and 2% in the tamsulosin monotherapy group. The higher percentage of adverse reactions in the combination therapy group during the first year of treatment was primarily due to a higher incidence of reproductive system disorders, specifically ejaculation disorders observed in this group.

Adverse reactions occurring at a frequency ≥1% during the first year of treatment, based on data from the CombAT, REDUCE, and clinical studies of monotherapies with the individual components of the drug, are listed in the table.

Information on tamsulosin-related 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 (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000). Adverse reactions classified by system organ classes are listed in order of decreasing severity.

System organ class	Adverse reactions	Dutasteride + tamsulosin a	Dutasteride	Tamsulosin c
Nervous system disorders	Syncope			Uncommon
	Dizziness	Common		Common
	Headache			Uncommon
Cardiac disorders	Heart failure (composite term1)	Uncommon	Uncommond
	Palpitations			Uncommon
Vascular disorders	Postural hypotension			Uncommon
Respiratory, thoracic and mediastinal disorders	Rhinitis			Uncommon
Gastrointestinal disorders	Constipation			Uncommon
	Diarrhea			Uncommon
	Nausea			Uncommon
	Vomiting			Uncommon
Skin and subcutaneous tissue disorders	Angioedema			Uncommon
	Stevens-Johnson syndrome			Very rare
	Urticaria			Uncommon
	Rash			Uncommon
	Pruritus			Uncommon
Reproductive system and breast disorders	Priapism	Common	Commonb
	Impotence3	Common	Commonb
	Libido disorders3 (decreased)	Common	Commonb
	Ejaculation disorders3^	Common	Commonb	Common
	Breast disorders2	Common	Commonb
General disorders	Asthenia			Uncommon

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

b From monotherapy studies of dutasteride in benign prostatic hyperplasia.

c From the EU Summary of Product Characteristics for tamsulosin.

d The REDUCE study.

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

2 Including hyperesthesia and breast enlargement.

3 Adverse reactions related to sexual function disturbances 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 surveillance data

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

Dutasteride monotherapy

Immune system disorders

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

Psychiatric disorders

Frequency unknown: depression.

Skin and subcutaneous tissue disorders

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

Reproductive system and breast disorders

Frequency unknown: testicular pain and swelling.

Tamsulosin monotherapy

According to post-marketing surveillance, 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 "Special precautions").

During post-approval use, additional cases have been reported of atrial fibrillation, arrhythmia, tachycardia, dyspnea, epistaxis, visual disturbances including decreased visual acuity, erythema multiforme, exfoliative dermatitis, and dryness of the oral mucosa associated with tamsulosin use.

Other data

In a clinical trial (the REDUCE study), a higher incidence of high-grade prostate cancer (Gleason score 8–10) was observed in men treated with dutasteride compared to the placebo group (see sections "Special precautions" and "Pharmacological properties"). A causal relationship between dutasteride use and the development of high-grade prostate cancer according to Gleason 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. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging.

6 capsules in a blister; 5 blisters in a cardboard pack.

6 capsules in a blister; 15 blisters in a cardboard pack.

9 capsules in a blister; 10 blisters in a cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

GALENICUM HEALTH, S.L./
GALENICUM HEALTH, S.L.

Manufacturer's address and place of business.

Avda. Cornella 144, 7o-1a Edifico LEKLA, Esplugues de Llobregat, Barcelona, 08950, Spain/
Avda. Cornella 144, 7o-1a Edificio LEKLA, Esplugues de Llobregat, Barcelona, 08950, Spain.