Instructions Dutasteride T 0.5mg/0.4mg capsules No. 30
Composition
active ingredients: dutasteride, tamsulosin hydrochloride;
1 hard capsule contains 0.5 mg dutasteride, 0.4 mg tamsulosin hydrochloride, equivalent to 0.367 mg tamsulosin; excipients: soft gelatin capsule containing: propylene glycol monocaprylate type II, butylhydroxytoluene (E 321), gelatin (gelling agent type B, 150 Bloom), glycerol, titanium dioxide (E 171), medium chain triglycerides, soy lecithin;
modified-release granules: methacrylic acid - ethyl acrylate copolymer (1:1), dispersion 30% (sodium lauryl sulfate 0.7%, polysorbate 80 2.3%), microcrystalline cellulose, dibutyl sebacate, polysorbate 80, colloidal silicon dioxide, calcium stearate;
hard gelatin capsule: black iron oxide (E 172), red iron oxide (E 172), titanium dioxide (E 171), yellow iron oxide (E 172), gelatin;
composition of ink (for inscription) black, containing: shellac (E 904), black iron oxide (E 172), propylene glycol (E 1520), concentrated ammonium solution (E 527), potassium hydroxide (E 525).
Dosage form
The capsules are hard.
Main physical and chemical properties: oblong hard gelatin capsule No. 0EL measuring approximately 24.2 × 7.7 mm, brown capsule body, beige cap with the inscription С001 in black ink. Capsule contents: oblong soft gelatin capsule (approximately 16.5 × 6.5 mm) light yellow in color, filled with a clear liquid; tamsulosin granules from white to almost white in color.
Pharmacotherapeutic group
Drugs used in benign prostatic hyperplasia. α1-adrenoceptor antagonist. ATC code G04C A52.
Pharmacological properties
Pharmacodynamics.
Dutasteride T is a combination of two drugs: dutasteride, a dual 5α-reductase inhibitor, 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, reduces the risk of acute urinary retention, and reduces the need for surgery for benign prostatic hyperplasia.
Dutasteride
Dutasteride inhibits the activity of both type 1 and type 2 5α-reductase isoenzymes, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). DHT is an androgen primarily responsible for prostate growth and the development of benign prostatic hyperplasia.
Tamsulosin
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 binds selectively and competitively to postsynaptic α1 receptors, in particular to the α1a and α1d subtypes. This causes relaxation of the smooth muscle of the prostate and urethra.
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.
Dutasteride in combination with tamsulosin
Clinical studies indicate better efficacy of combination therapy based on the 5α-reductase inhibitor dutasteride and the α1-adrenoblocker tamsulosin, compared to the use of each drug separately.
Pharmacokinetics.
The use of the combination of dutasteride-tamsulosin and simultaneous administration of appropriate doses of dutasteride and tamsulosin capsules separately demonstrated their bioequivalence.
Single-dose bioequivalence studies were conducted under both fasting and fed conditions. Compared to fasting conditions, a 30% decrease in the maximum concentration (Cmax) of tamsulosin as a component of the dutasteride-tamsulosin combination was observed when administered after food. Food had no effect on the area under the pharmacokinetic curve (AUC) of tamsulosin.
Absorption
Dutasteride
Following a single oral dose of 0.5 mg dutasteride, the time to peak serum concentrations of dutasteride was 1–3 hours. Absolute bioavailability was approximately 60%. Food intake did not affect the bioequivalence of dutasteride.
Tamsulosin
After a single dose of tamsulosin after a meal, peak plasma concentrations are reached after approximately 6 hours. Steady-state concentrations are reached on the 5th day of multiple dosing. The mean steady-state concentrations in patients are approximately two-thirds higher than those after a single dose of tamsulosin. Although this phenomenon has been 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 is highly bound to plasma proteins (>99.5%). Following daily dosing, serum concentrations of dutasteride reach 65% of steady-state concentrations after 1 month and approximately 90% after 3 months.
Steady-state serum concentrations of approximately 40 ng/mL are achieved after 6 months of dosing with 0.5 mg/day. The mean serum to seminal transfer 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 concentrations, 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, containing 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/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 present as unchanged active substance.
After intravenous or oral administration of the immediate-release formulation, the plasma half-life of tamsulosin ranges from 5 to 7 hours. Due to absorption-rate-controlled pharmacokinetics, the true half-life of tamsulosin administered after meals is approximately 10 hours with tamsulosin modified-release capsules and approximately 13 hours at steady-state in patients.
Elderly patients
Dutasteride
The pharmacokinetics of dutasteride were evaluated in 36 healthy men aged 24 to 87 years after a single 5 mg dose. There was no significant age-related effect of dutasteride, 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 study group with the 70 year old study 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 α1-acid glycoprotein, but decreases with age, resulting in a 40% higher total exposure (AUC) in patients aged 55 to 75 years compared to patients aged 20 to 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).
The pharmacokinetics of tamsulosin hydrochloride were compared in 6 patients with mild to moderate (30 ≤ creatinine clearance (CC) < 70 ml/min/1.73 m2) or moderate to severe (10 ≤ CC < 30 ml/min/l.73 m2) renal impairment and in 6 subjects with normal clearance (CC < 90 ml/min/1.73 m2). While the total plasma concentration of tamsulosin hydrochloride varied as a result of variable binding to α1-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 failure (creatinine clearance < 10 mL/min/1.73 m2) were not studied.
Liver failure
Dutasteride
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 plasma levels of dutasteride will be increased in these patients and the half-life of dutasteride will be prolonged (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 total plasma concentration of tamsulosin hydrochloride varied as a result of variable binding to α1-acid glycoprotein, the concentration of unbound (active) tamsulosin hydrochloride did not change significantly, and only a moderate (32%) change in the intrinsic clearance of unbound tamsulosin hydrochloride was observed. Therefore, patients with moderate hepatic impairment do not require dose adjustment of tamsulosin hydrochloride. 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 Avodart Combination Study (CombAT), the incidence of heart failure (combined event) in the combination therapy group (14/1,610, 0.9%) was higher 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 level 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 over 60 years (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 alpha-blocker concomitantly (12/1152, 1.0%) compared to subjects receiving dutasteride without an alpha-blocker (18/2953, 0.6%), placebo and an alpha-blocker (1/1399, <0.1%), or placebo without an alpha-blocker (15/2727, 0.6%). A causal relationship between the use of dutasteride (alone or in combination with alpha-blockers) and the occurrence of heart failure has not been established (see section 4.4).
Prostate cancer and poorly differentiated tumors
A higher incidence (n=29, 0.9%) of poorly differentiated prostate cancer (Gleason score 8–10) was observed in the dutasteride group compared with 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 with the placebo group (n=1, <0.1%) (p=0.0035). There is 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% in each time period), 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 confirmed by 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.
Breast cancer in men
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 the development of breast cancer in men and long-term use of dutasteride has not been established.
Indication
The drug is prescribed to patients for whom taking its individual components - tamsulosin and dutasteride - in appropriate doses was effective in treating moderate to severe symptoms of benign prostatic hyperplasia.
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
The drug is contraindicated:
for the treatment of women and children (see section "Use during pregnancy or breastfeeding");
patients with hypersensitivity to dutasteride, other 5a-reductase inhibitors, tamsulosin (including tamsulosin-induced angioedema), other components of the drug or to soy and peanut;
patients with a history of orthostatic hypotension;
patients with severe liver failure.
Interaction with other medicinal products and other types of interactions
Available information on interactions of the active substances of the drug is presented separately.
Dutasteride
For information on the reduction in serum prostate-specific antigen (PSA) levels during treatment with dutasteride and recommendations regarding 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
When dutasteride is co-administered with drugs that are potent inhibitors of the CYP3A4 enzyme (such as ritonavir, indinavir, nefazodone, itraconazole, ketoconazole, administered orally), serum concentrations of dutasteride may increase. Further inhibition of 5α-reductase with enhanced dutasteride action is unlikely. However, the frequency of dutasteride dosing may be reduced if side effects are observed. It should be noted that the long half-life may be further prolonged with enzyme inhibition, and concomitant therapy may then require more than 6 months before a new steady-state concentration is reached.
Administration of 12 g of cholestyramine one 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 subjects, 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 alpha-1-adrenoblockers, may theoretically lead to an increased hypotensive effect. Dutasteride T should not be used in combination with other alpha-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.
Concomitant use of tamsulosin hydrochloride and paroxetine (a strong CYP2D6 inhibitor) increases 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 metabolisers compared to extensive metabolisers when co-administered with strong CYP3A4 inhibitors.
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 (area under the pharmacokinetic curve) (44%) of tamsulosin hydrochloride. Dutasteride T 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) using 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
A meta-analysis of 12 randomized, placebo- or comparator-controlled clinical trials (n=18,802) evaluating the risk of cardiovascular adverse events with dutasteride (compared to control) found 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 biopsy for prostate cancer 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 the drug should undergo regular examinations to determine the risk of developing prostate cancer, including a prostate-specific antigen test.
In an additional 2-year follow-up of the original patients receiving dutasteride as 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) as chemoprophylaxis showed no statistically significant difference between the finasteride and placebo groups in terms of 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
Before starting Dutasteride T, the patient should be examined to exclude other possible conditions that may cause the same symptoms as benign prostatic hyperplasia. A digital rectal examination should be performed before starting treatment and periodically during treatment, as well as a prostate-specific antigen (PSA) test as needed.
Serum PSA concentration is an important component of the screening process for prostate cancer. Dutasteride T is able to reduce serum PSA levels in patients by approximately 50% after 6 months of treatment.
Patients taking Dutasteride T should have a new baseline PSA level determined 6 months after starting 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 T may be indicative of prostate cancer or non-adherence to the drug regimen and should be investigated carefully, even if PSA values are within the normal range in men not treated with 5α-reductase inhibitors (see section "Pharmacological properties"). When interpreting PSA values in patients treated with Dutasteride T, previous PSA values should be taken into account for comparison.
The use of Dutasteride T does not affect the use of PSA levels for the diagnosis of prostate cancer after establishing a new baseline antigen level (see section "Pharmacological properties").
Total serum PSA levels return to baseline within 6 months of discontinuation of treatment. The ratio of free PSA to total PSA remains stable even during Dutasteride T therapy. If the physician decides to use the percentage of free PSA to screen for prostate cancer in a patient treated with Dutasteride T, no adjustment for free PSA is necessary.
Heart failure
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 alpha-blocker, primarily tamsulosin, compared to subjects not treated with such a combination. The incidence of heart failure was lower in the drug-treated group compared to placebo. Other available data on the use of dutasteride do not support an effect on the risk of cardiovascular disease (see section 5.1).
Kidney failure
Treatment of patients with severe renal insufficiency (CC < 10 ml/min) should be carried out with caution, since the pharmacokinetics of dutasteride in such patients have not been studied.
Arterial hypotension
At the first signs of orthostatic hypotension (dizziness, weakness), patients who have started treatment with the drug should be seated in a chair or placed in bed until the symptoms subside.
Caution should be exercised when α-adrenergic blockers, including tamsulosin, are used concomitantly with phosphodiesterase-5 inhibitors. α-adrenergic 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
Intraoperative atonic iris syndrome (IAAS, a variant of narrow pupil syndrome) has been reported in some patients undergoing cataract and glaucoma surgery who have previously received tamsulosin. IAS may increase the risk of ocular complications during or after surgery. Therefore, treatment with the drug 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 or currently been prescribed tamsulosin, which will allow predicting the possible occurrence of intraoperative atonic iris syndrome during surgery.
Therefore, tamsulosin treatment is not recommended for patients scheduled for cataract surgery. During the preoperative examination, the ophthalmologist and his team should determine whether the patient has previously or currently been prescribed tamsulosin. This will allow predicting the possible occurrence of intraoperative atonic iris syndrome during surgery.
There have been isolated reports of a positive 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 CYP2D6 metabolisers.
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 or moderate hepatic impairment (see sections 5.1, 5.2, and 4.3).
Breast cancer in men
Rare cases of breast cancer have been reported in men 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.
Cases of allergic reactions to tamsulosin have been reported in patients with a history of allergy to sulfonamides. Caution should be exercised when administering tamsulosin hydrochloride to patients with a history of allergy to sulfonamides.
Use during pregnancy or breastfeeding
The drug is contraindicated for the treatment of women. Studies of the effect of the drug on pregnancy, lactation and fertility have not been conducted. Information on the use of each component separately is provided below.
Fertility.
Ejaculation disorders were observed in short- and long-term clinical trials of tamsulosin. Cases of ejaculation disorders, retrograde ejaculation and insufficient ejaculation have been reported in the post-marketing period. Dutasteride affects the characteristics of the ejaculate (reduction in sperm count, ejaculate volume and sperm motility). The risk of reduced male fertility cannot be excluded.
The effect of tamsulosin hydrochloride on sperm count or sperm 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 in studies. It is not known whether dutasteride administered to women with male fertility affects the
