Instructions for Dutafors hard capsules 0.5 mg + 0.4 mg blister No. 30
Composition
active ingredients: dutasteride, tamsulosin hydrochloride;
1 capsule contains dutasteride 0.5 mg and tamsulosin hydrochloride 0.4 mg;
excipients:
hard capsule shell: hypromellose, carrageenan (E 407), potassium chloride, titanium dioxide (E 171), sunset yellow (E 110), iron oxide red (E 172);
dutasteride, soft capsules 0.5 mg: glycerol monocaprylocaprate type I, butylhydroxytoluene (E 321), gelatin, glycerin, titanium dioxide (E 171), iron oxide yellow (E 172), medium chain triglycerides, lecithin (E 322);
tamsulosin hydrochloride, pellets 0.4 mg: microcrystalline cellulose, magnesium stearate, methacrylic acid - ethyl acrylate copolymer (1:1) dispersion 30%, methacrylic acid - ethyl acrylate copolymer (1:1), sodium hydroxide, triacetin, talc, titanium dioxide (E 171).
Dosage form
The capsules are hard.
Main physicochemical properties: hard capsules with an orange cap and a brown body, containing white or whitish pellets and one yellow soft gelatin capsule with an oily yellowish liquid.
Pharmacotherapeutic group
Drugs used in benign prostatic hyperplasia. α1-adrenoceptor antagonist. ATC code G04C A52.
Pharmacological properties
Pharmacodynamics
Dutafors is a combination of two drugs: dutasteride, a dual 5α-reductase inhibitor (5-ARI), and tamsulosin hydrochloride, an α1a and α1d adrenoceptor antagonist. These drugs have a complementary mechanism of action, which results in rapid reduction of urinary output, reduced risk of acute urinary retention (AUR), and reduced likelihood of needing surgery for benign prostatic hyperplasia.
The pharmacodynamic effects of the fixed-dose combination of dutasteride and tamsulosin are not expected to differ from those obtained with the concomitant administration of dutasteride and tamsulosin as separate components.
Dutasteride
Dutasteride inhibits the activity of both type 1 and type 2 isoenzymes of 5-α-reductase, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). DHT is an androgen that is primarily responsible for prostate growth and the development of benign prostatic hyperplasia. Tamsulosin inhibits the activity of α1a and α1d adrenoceptors in the stromal smooth muscle of the prostate and bladder neck. Approximately 75% of the α1 receptors in the prostate are receptors of the α1a subtype.
Tamsulosin
Tamsulosin increases the maximum urine flow rate by reducing the tone of the smooth muscles of the urethra and prostate gland, which eliminates obstruction. The drug also reduces the severity of symptoms of irritation and obstruction, in the development of which urinary incontinence and contraction of the smooth muscles of 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.
Alpha-1 adrenoceptor antagonists may reduce blood pressure by reducing total peripheral resistance. No clinically significant reduction in blood pressure was observed in a study of tamsulosin.
Pharmacokinetics
Bioequivalence has been demonstrated between the administration of the dutasteride-tamsulosin combination and the simultaneous administration of doses of dutasteride and tamsulosin capsules separately.
Single-dose bioequivalence studies were conducted under both fasting and fed conditions. Compared to the fasting state, a 30% decrease in maximum concentration (Cmax) of tamsulosin in the dutasteride-tamsulosin combination was observed when the drug was administered under fed conditions. Food had no effect on the area under the pharmacokinetic curve (AUC) of tamsulosin.
Absorption
Dutasteride
After oral administration of a single 0.5 mg dose of dutasteride, the time to reach maximum serum concentrations was 1 to 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 absorption of tamsulosin are reduced if it is taken within 30 minutes after a meal. Uniform absorption is ensured by taking Dutafors at the same time of day after eating the same type of food. The concentration of tamsulosin in the blood plasma is proportional to the dose.
After a single dose of tamsulosin after a meal, Cmax is reached after about 6 hours. Steady-state concentrations are reached on the 5th day of multiple administration. The average steady-state concentration in patients is approximately two-thirds higher than the concentration after a single dose of tamsulosin. Although this phenomenon was observed in elderly patients, the same result can be expected in younger patients.
Distribution
Dutasteride
Steady-state serum concentrations (Css) of approximately 40 ng/ml are achieved after 6 months of dosing with 0.5 mg/day. The mean serum to seminal fraction of dutasteride is 11.5%.
Tamsulosin
In men, tamsulosin is approximately 99% bound to plasma proteins. The volume of distribution is small (approximately 0.21/kg).
Metabolism
Dutasteride
Dutasteride is extensively metabolized in vivo. In vitro, dutasteride is metabolized by cytochrome P450 3A4 and 3A5 to form three monohydroxylated metabolites and one dihydroxylated metabolite.
Following oral administration of dutasteride at a dose of 0.5 mg/day to steady-state, 1.0–15.4% (mean 5.4%) of the administered dose of dutasteride is excreted unchanged in the feces. The remainder is excreted in the feces as 4 major metabolites, accounting for 39%, 21%, 7%, and 7% of each of the drug-related substances, and 6 minor metabolites (less than 5% each). Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) have been detected in human urine.
Tamsulosin
Enantiomeric bioconversion from tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer does not occur in humans. Tamsulosin hydrochloride is extensively metabolized by cytochrome P450 enzymes in the liver, and less than 10% of the dose is excreted unchanged in the urine. However, the pharmacokinetic profile of the metabolites in humans has not been established. In vitro studies indicate that CYP3A4 and CYP2D6 are involved in the metabolism of tamsulosin, with minor involvement of other CYP isoenzymes.
Inhibition of the activity of enzymes involved in hepatic metabolism may lead to enhanced effects of tamsulosin. Tamsulosin hydrochloride metabolites undergo extensive conjugation with glucuronide or sulfate before excretion in the urine.
Breeding
Dutasteride
The elimination of dutasteride is dose-dependent and can be described as occurring via two parallel pathways: one saturable at clinically relevant concentrations and the other non-saturable. At low serum concentrations (less than 3 ng/mL), dutasteride is rapidly eliminated by both concentration-dependent and concentration-independent pathways. Single doses of 5 mg or less have been shown to exhibit rapid clearance and a half-life of 3 to 9 days.
At therapeutic concentrations, after repeated administration of a dose of 0.5 mg per day, a slower, linear elimination pathway dominates, with a half-life of approximately 3–5 weeks.
Tamsulosin
Tamsulosin and its metabolites are excreted mainly in the urine, in which approximately 9% of the dose is in the form of unchanged active substance.
After intravenous or oral administration of immediate-release formulations, the plasma half-life of tamsulosin ranges from 5 to 7 hours. Due to the absorption-rate-controlled pharmacokinetics of tamsulosin modified-release capsules, the true half-life of tamsulosin administered after meals is approximately 10 hours and at steady-state in patients is approximately 13 hours.
Elderly patients
Dutasteride
The pharmacokinetics of dutasteride were evaluated in 36 healthy male volunteers aged 24 to 87 years after administration of a single 5 mg dose. There was no significant age-related effect of dutasteride exposure, but the half-life was shorter in men aged <50 years. There was no statistical difference in half-life when comparing the 50–69 year old group with the 70 year old group.
Tamsulosin
A cross-sectional comparative study of the total exposure (AUC) and half-life of tamsulosin hydrochloride indicates that the pharmacokinetics of tamsulosin hydrochloride may be slightly longer in elderly patients compared to young healthy male volunteers. Intrinsic clearance is independent of the binding of tamsulosin hydrochloride to α-1-acid glycoprotein, but decreases with age, resulting in a 40% higher total exposure (AUC) in patients aged 55–75 years compared to patients aged 20–32 years.
Kidney failure
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 recovered in human urine at steady state, and therefore no clinically significant increase in dutasteride plasma concentrations is expected in patients with renal impairment (see 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 in 6 subjects with normal clearance (CLcr < 90 mL/min/1.73 m2). While the total plasma concentration of tamsulosin hydrochloride varied as a result of variable binding to α-1-acid glycoprotein, the concentration of unbound (active) tamsulosin hydrochloride and its intrinsic clearance remained relatively stable. Therefore, no dose adjustment of tamsulosin hydrochloride capsules is required in patients with renal impairment. However, patients with end-stage renal disease (CLcr <10 mL/min/1.73 m2) were not studied.
Liver failure
The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied (see section 4.3). Since dutasteride is eliminated primarily by metabolism, it is expected that dutasteride plasma levels will be increased and the elimination half-life will be prolonged in these patients (see sections 4.4 and 4.8).
Tamsulosin
The pharmacokinetics of tamsulosin hydrochloride were compared in 8 patients with moderate hepatic impairment (Child-Pugh classification: grades A and B) and in 8 subjects with normal hepatic function. While the change in total plasma concentrations of tamsulosin hydrochloride was observed as a result of variable binding to α-1-acid glycoprotein, the concentration of unbound (active) tamsulosin hydrochloride did not change significantly, only a moderate (32%) change in the intrinsic clearance of unbound tamsulosin hydrochloride was noted. Therefore, patients with moderate hepatic impairment do not require dose adjustment of tamsulosin hydrochloride. The effect of tamsulosin hydrochloride has not been studied in patients with severe hepatic impairment.
Safety and clinical studies
Heart failure
In a 4-year clinical trial of dutasteride in combination with tamsulosin for the treatment of benign prostatic hyperplasia in 4,844 men (the CombAT study), the incidence of heart failure (combined event) in the combination therapy group was higher (14/1,610, 0.9%) than in either dutasteride (4/1,623, 0.2%) or tamsulosin (10/1,611, 0.6%) monotherapy group.
In a separate 4-year clinical trial comparing placebo with dutasteride chemoprophylaxis in 8231 men aged 50 to 75 years with a previous negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL in men aged 50 to 60 years or 3 ng/mL and 10.0 ng/mL in men aged 60 years or older (the REDUCE study), the incidence of heart failure was higher in patients receiving dutasteride 0.5 mg once daily (30/4105, 0.7%) compared to patients receiving placebo (16/4126, 0.4%). A retrospective analysis of this study showed a higher incidence of heart failure in patients receiving dutasteride and an α-blocker concomitantly (12/1152, 1.0%) compared to patients receiving dutasteride without an α-blocker (18/2953, 0.6%), placebo and an α-blocker (1/1399, <0.1%), or placebo without an α-blocker (15/2727, 0.6%). A causal relationship between the use of dutasteride (as monotherapy or in combination with α-blockers) and the occurrence of heart failure has not been established (see section 4.4).
Prostate cancer and poorly differentiated tumors
In a 4-year study comparing dutasteride with placebo, 8231 men aged 50 to 75 years with a previous negative biopsy for prostate cancer and a baseline PSA between 2.5 ng/mL and 10.0 ng/mL in men aged 50 to 60 years or 3 ng/mL and 10.0 ng/mL in men aged 60 years or older (REDUCE study), 6706 patients underwent a core needle biopsy of the prostate (mandatory under the original protocol) and the data were used for Gleason grade analysis. The study identified 1517 patients with a diagnosis of prostate cancer. The majority of prostate tumors (70%) detected by biopsy in both treatment groups were highly differentiated (Gleason grade 5–6).
A higher incidence (n=29, 0.9%) of poorly differentiated prostate cancer (Gleason score 8–10) was observed in the dutasteride group 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 prostate cancer with a Gleason score of 8–10 was similar in the dutasteride group (n=17, 0.5%) and the placebo group (n=18, 0.5%). During the 3rd and 4th years of the study, a higher number of prostate cancer with a Gleason score of 8–10 was diagnosed in the dutasteride group (n=12, 0.5%) compared to the placebo group (n=1, <0.1%) (p=0.0035). There are no data on the risk of developing prostate cancer in men taking dutasteride for more than 4 years. The percentage of patients diagnosed with prostate cancer with a Gleason score of 8-10 remained constant across the different study periods (years 1-2, years 3-4) in the dutasteride group (0.5% at each time point), while in the placebo group the percentage of patients with poorly differentiated 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 4.4). There was no difference in the incidence of prostate cancer with a Gleason score of 7-10 (p=0.81).
In a 4-year clinical trial of benign prostatic hyperplasia (Combat), where the primary protocol did not require biopsy and all prostate cancer diagnoses were made on biopsy as indicated, the incidence of prostate cancer with a Gleason score of 8–10 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 the use of dutasteride and the occurrence of poorly differentiated prostate cancer remains unclear.
Two case-control epidemiological studies, one conducted in the USA (n=339 breast cancer cases and n=6780 controls) and the other in the UK (n=398 breast cancer cases and n=3930 controls) in health databases, did not show any increased risk of breast cancer in men with the use of 5α-reductase inhibitors. The results of the first study did not show a positive association with breast cancer (relative risk for ≥1 year of use before breast cancer diagnosis compared with <1 year of use: 0.70: 95% CI 0.34, 1.45). In the second study, the estimated relative risk of breast cancer associated with the use of 5α-reductase inhibitors compared with no use was 1.08: 95% CI 0.62, 1.87.
A causal relationship between cases of male breast cancer and long-term use of dutasteride has not been established.
Indication
Treatment of moderate to severe symptoms of benign prostatic hyperplasia.
Reducing the risk of acute urinary retention and the need for surgery in patients with moderate to severe symptoms of benign prostatic hyperplasia.
Contraindication
Dutafors is not used to treat women and children (see section “Use during pregnancy or breastfeeding”).
Dutafors is contraindicated in patients with hypersensitivity to dutasteride, other 5a-reductase inhibitors, tamsulosin (including tamsulosin-induced angioedema), other components of the drug, or to soy and peanut.
Dutafors is contraindicated in patients with a history of orthostatic hypotension.
Dutafors is contraindicated in patients with severe hepatic insufficiency.
Interaction with other medicinal products and other types of interactions
No interaction studies have been conducted with the combination product. The available information on the individual components of the drug is given below. Dutasteride
For information on the reduction in serum prostate-specific antigen (PSA) levels during treatment with dutasteride and recommendations for prostate cancer screening, see section 4.4.
Effect of other medicinal products on the pharmacokinetics of dutasteride
Use with CYP3A4 and/or P-glycoprotein inhibitors
Dutasteride is eliminated primarily by metabolism. In vitro studies indicate that CYP3A4 and CYP3A5 are the catalyzers of metabolism. Formal interaction studies with potent CYP3A4 inhibitors have not been conducted. However, in a population pharmacokinetic study, dutasteride serum concentrations were on average 1.6-1.8-fold higher in a small number of patients who were concomitantly treated with verapamil or diltiazem (moderate CYP3A4 inhibitors and P-glycoprotein inhibitors) than in other patients.
With long-term use of dutasteride in combination with drugs that are potent inhibitors of the CYP3A4 enzyme (e.g. ritonavir, indinavir, nefazodone, itraconazole, ketoconazole, administered orally), the concentration of dutasteride in the blood serum may increase. Further inhibition of 5α-reductase with increased dutasteride action is unlikely. However, a reduction in the frequency of dutasteride doses may be necessary in the event of side effects. In the event of inhibition of enzyme activity, the long half-life may become even longer and concomitant therapy may in this case last more than 6 months before a new equilibrium concentration is reached.
Administration of 12 g of cholestyramine 1 hour after a single dose of 5 mg dutasteride had no effect on the pharmacokinetics of dutasteride.
Effect of dutasteride on the pharmacokinetics of other drugs
In a small two-week study (n=24) in healthy male volunteers, dutasteride (0.5 mg daily) had no effect on the pharmacokinetics of tamsulosin or terazosin. This study also showed no evidence of a pharmacodynamic interaction.
Dutasteride does not affect the pharmacokinetics of warfarin or digoxin. This indicates that dutasteride does not inhibit/induce the activity of the CYP2C9 enzyme or the P-glycoprotein transporter. In vitro interaction studies indicate that dutasteride does not inhibit CYP1A2, CYP2D6, CYP2C9, CYP2C19, or CYP3A4.
Tamsulosin
Concomitant use of tamsulosin hydrochloride with drugs that can lower blood pressure, including analgesics, phosphodiesterase 5 inhibitors and other α-1-adrenoblockers, may theoretically lead to an increased hypotensive effect. Therefore, Dutafors should not be used in combination with other α-1-adrenoblockers.
Concomitant use of tamsulosin hydrochloride and ketoconazole (a strong CYP3A4 inhibitor) increases Cmax and AUC of tamsulosin hydrochloride by 2.2 and 2.8 times, respectively.
The effect of co-administration of both CYP3A4 inhibitors and CYP2D6 inhibitors with tamsulosin has not been clinically studied, but there is a potential for significant increases in tamsulosin concentrations (see section 4.4).
Concomitant use of tamsulosin hydrochloride (0.4 mg) and cimetidine (400 mg every 6 hours for 6 days) resulted in a decrease in clearance (26%) and an increase in AUC (44%) of tamsulosin hydrochloride. Dutafors should be used with caution in combination with cimetidine.
A comprehensive interaction study of tamsulosin hydrochloride and warfarin has not been conducted. The results of limited in vitro and in vivo studies are insufficient. Caution should be exercised when warfarin and tamsulosin hydrochloride are co-administered.
No interaction was observed when tamsulosin hydrochloride was administered concomitantly with atenolol or enalapril, or nifedipine, or theophylline. Concomitant use of furosemide results in a decrease in serum tamsulosin levels, but since these levels remain within the normal range, dose adjustment is not required.
In vitro, neither diazepam, propranolol, trichlormethiazide, chlormadinone, amitriptyline, diclofenac, glibenclamide, nor simvastatin alter the free fraction of tamsulosin in human plasma. Tamsulosin also does not alter the free fractions of diazepam, propranolol, trichlormethiazide, and chlormadinone.
No interaction at the level of hepatic metabolism was observed in in vitro studies with liver microsomal fractions (representing the cytochrome P450 drug-metabolizing enzyme system) with amitriptyline, salbutamol and glibenclamide. However, diclofenac may increase the rate of elimination of tamsulosin.
Application features
Combination therapy is prescribed after a careful analysis of the benefit/risk ratio due to the potential increased risk of adverse reactions (including heart failure) and the study of alternative treatment options, including monotherapy.
Cardiovascular adverse reactions
In two 4-year clinical trials, the incidence of heart failure (a composite term for all reports, primarily heart failure and congestive heart failure) was higher in subjects treated with the combination of dutasteride and an α-blocker, primarily tamsulosin, compared to subjects not treated with such a combination. The incidence of heart failure was low (≤1%) and variable within these trials. There was no disparity in the incidence of cardiovascular adverse events in any of the trials. A causal relationship between the use of dutasteride (alone or in combination with α-blockers) and the occurrence of heart failure has not been established (see section 5.1).
A meta-analysis of 12 randomized, placebo- or comparator-controlled clinical trials (n=18,802) was conducted to assess the risk of adverse reactions from
Cardiovascular system with dutasteride (compared to the control group). There was no consistent statistically significant increase in the risk of heart failure (RR 1.05; 95% CI 0.71, 1.57), acute myocardial infarction (RR 1.00; 95% CI 0.77, 1.30) or stroke (RR 1.20; 95% CI 0.88, 1.64).
Prostate cancer and high-grade Gleason tumors (poorly differentiated)
In a 4-year clinical trial of >8000 men aged 50 to 75 years with a previous negative prostate cancer biopsy and a baseline PSA level between 2.5 ng/mL and 10.0 ng/mL (REDUCE study), 1517 men were diagnosed with prostate cancer. There was a higher incidence of prostate cancer with a Gleason score of 8-10 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 occurrence of low-grade prostate cancer has not been established. The clinical significance of the digital imbalance has not been established.
Men using Dutasteride should have regular screening to determine their risk of developing prostate cancer, including a prostate-specific antigen test.
In an additional 2-year follow-up of the original patients receiving dutasteride for chemoprophylaxis (REDUCE study), a low incidence of new prostate cancer cases (dutasteride group [n=14, 1.2%]) and placebo group [n=7, 0.7%]) was observed, with no new cases of prostate cancer with Gleason score 8–10 identified.
Long-term follow-up (up to 18 years) of patients from a clinical trial using another 5α-reductase inhibitor (finasteride) for chemoprophylaxis 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 diagnosis of prostate cancer (HR 1.01, 95% CI 0.85–1.20).
Effect on prostate-specific antigen (PSA)
Patients taking Dutasteride should have a new baseline PSA level determined 6 months after treatment with this drug. It is recommended that this level be checked regularly thereafter. Any confirmed increase in PSA from the nadir during use of Dutasteride may be indicative of prostate cancer or non-adherence to Dutasteride therapy and should be investigated carefully, even if PSA values are within normal limits in men not treated with 5α-reductase inhibitors. When interpreting PSA values in patients treated with Dutasteride, previous PSA values should be taken into account for comparison.
The use of Dutafors does not affect the use of prostate-specific antigen levels for the diagnosis of prostate cancer after establishing a new baseline level.
Total serum prostate-specific antigen levels return to baseline within 6 months after discontinuation of treatment.
The ratio of free prostate-specific antigen to total PSA remains stable even during Dutafors treatment. If the physician decides to use the percentage of free PSA in a patient taking Dutafors to diagnose prostate cancer, no adjustment of the free PSA level is necessary.
Before starting treatment with Dutafors and periodically during treatment, patients with benign prostatic hyperplasia should undergo a digital rectal examination, as well as other methods of detecting prostate cancer.
Kidney failure
Treatment of patients with severe renal impairment (creatinine clearance <10 ml/min) should be carried out 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 in rare cases may lead to syncope.
At the first signs of orthostatic hypotension (dizziness, weakness), patients who have started treatment with Dutafors should be moved to a sitting or lying position until the symptoms subside.
Caution should be exercised when α-blockers, including tamsulosin, are used concomitantly with phosphodiesterase-5 inhibitors. α-blockers and phosphodiesterase-5 inhibitors are vasodilators and may reduce blood pressure. Concomitant use of these two classes of drugs has the potential to cause symptomatic hypotension (see section 4.5).
Intraoperative atonic iris syndrome
During cataract and glaucoma surgery, intraoperative atonic iris syndrome (ISAR, a variant of narrow pupil syndrome) has been reported in some patients previously treated with tamsulosin. Intraoperative atonic iris syndrome may lead to an increased risk of ocular complications during or after surgery. Therefore, the use of Dutafors is not recommended in patients scheduled for cataract surgery.
During the preoperative examination, the ophthalmologist and his team should determine whether the patient has previously been or is currently being prescribed Dutafors. This will allow predicting the possible occurrence of intraoperative atonic iris syndrome during surgery.
There have been isolated reports of a beneficial effect of stopping tamsulosin 1–2 weeks before cataract and glaucoma surgery, but the benefits and timing of stopping treatment before cataract and glaucoma surgery have not been established.
Leaky capsules
Dutasteride is absorbed through the skin, so women and children should avoid contact with unsealed capsules. If the capsule liquid comes into contact with the skin, it should be washed off immediately with soap and water.
CYP3A4 and CYP2D6 inhibitors
Concomitant use of tamsulosin hydrochloride with strong CYP3A4 inhibitors (e.g. ketoconazole) or, to a lesser extent, with strong CYP2D6 inhibitors (e.g. paroxetine) may increase tamsulosin concentrations (see section 4.5). Therefore, tamsulosin is not recommended in patients treated with strong CYP3A4 inhibitors and caution is advised in patients treated with 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 metabolisers of CYP2D6.
Liver failure
The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied. Due to the extensive metabolism of dutasteride and its 3-5 week half-life, dutasteride should be used with caution in patients with mild to moderate hepatic impairment (see sections 5.1, 5.2 and 5.2).
Excipients
The medicine contains sunset yellow dye (E 110), which may cause allergic reactions.
Breast cancer in men
Rare cases of breast cancer in men have been reported during clinical trials and in the post-marketing period. However, epidemiological studies indicate no increased risk of breast cancer in men with the use of 5α-reductase inhibitors. Physicians should advise their patients to promptly report any changes in breast tissue, such as nipple discharge or swelling.
Use during pregnancy or breastfeeding
Dutafors is contraindicated for the treatment of women. Studies on the effects of the drug on pregnancy, lactation and fertility have not been conducted. Information on the use of each component separately is provided below.
Fertility
Dutasteride affects ejaculate characteristics (reduction in sperm count, ejaculate volume, and sperm motility). The risk of reduced male fertility cannot be ruled out.
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 inhibit the development of external genitalia in male fetuses. Small amounts of dutasteride have been detected in ejaculate during a study. It is not known whether dutasteride administered to a woman with a male fetus treated with Dutafors will affect the male fetus.
As with other 5α-reductase inhibitors, it is recommended to use a condom during sexual intercourse if the woman is pregnant and the man is using Dutafors, in order to prevent sperm from entering the woman's body.
There is no evidence that administration of tamsulosin hydrochloride to pregnant rats and rabbits at doses exceeding therapeutic doses adversely affects the fetus.
Breastfeeding period
It is not known whether dutasteride and tamsulosin pass into human breast milk.
Ability to influence reaction speed when driving vehicles or other mechanisms
No studies have been conducted to study the effects of Dutafor on the ability to drive or use machines. However, patients should be informed of the possible occurrence of symptoms associated with orthostatic hypotension, including dizziness, when using Dutafor.
Method of administration and doses
Adults (including elderly patients)
The recommended dose of Dutafors is 1 capsule (0.5 mg/0.4 mg) per day. The drug is taken orally 30 minutes after eating at the same time. The capsule should be swallowed whole, not opened or chewed, as contact with the contents of the capsule may cause irritation of the mucous membrane of the mouth and pharynx.
Dutafors can be used to replace combination therapy with dutasteride and tamsulosin hydrochloride in order to facilitate treatment.
Replacement of dutasteride or tamsulosin hydrochloride with Dutafors in monotherapy is possible if clinically justified.
Kidney failure
The pharmacokinetics of the drug in patients with renal insufficiency have not been studied. Dose adjustment is not required for the treatment of such patients (see sections "Pharmacokinetics" and "Special warnings and precautions for use").
