Duodart® [Dutasteride, Tamsulosin]

Pharmacological properties

duodart is a combination of two drugs: dutasteride, a dual 5α-reductase inhibitor (5 api), and tamsulosin hydrochloride, an adrenergic antagonist of α1a and α1d. these drugs have a complementary mechanism of action, due to which there is rapid relief of urination, the risk of acute urinary retention and the likelihood of surgery for benign prostatic hyperplasia are reduced.

It is not expected that the pharmacodynamic effects of a fixed dosage combination of dutasteride + tamsulosin differ from those obtained with the simultaneous use of dutasteride and tamsulosin as separate components.

Dutasteride. Dutasteride inhibits the activity of both the 1st and 2nd type of 5α-reductase isoenzymes, which are responsible for the conversion of testosterone to dihydrotestosterone. Dihydrotestosterone is an androgen, which is primarily responsible for the growth of the prostate gland and the development of benign prostatic hyperplasia. Tamsulosin inhibits α adrenoreceptor activity_1a and α_1d in the stromal smooth muscles of the prostate gland and the neck of the bladder. About 75% of α receptors₁ in the prostate are α subtype receptors_1a.

Tamsulosin. Tamsulosin increases the maximum speed of urine flow by reducing the tone of the smooth muscles of the urethra and prostate gland, eliminates obstruction. The drug also reduces the severity of symptoms of irritation and obstruction, in the development of which an important role is played by urinary incontinence and contraction of the smooth muscles of the lower urinary tract. This effect is achieved with prolonged therapy. The need for surgery or catheterization is greatly reduced.

Antagonists α₁β-adrenoreceptors can lower blood pressure by lowering total peripheral resistance. During the study, the effects of tamsulosin did not show a clinically significant decrease in blood pressure.

Pharmacokinetics Between the introduction of the combination of dutasteride + tamsulosin and the simultaneous administration of doses of dutasteride and tamsulosin in capsules, bioequivalence was separately demonstrated.

Single dose bioequivalence studies have been performed both on an empty stomach and after a meal. Compared to fasting, a 30% decrease in C was noted after eating_max tamsulosin in the combination of dutasteride + tamsulosin. Food did not affect tamsulosin AUC.

Suction

Dutasteride. Following oral administration of a single 0.5 mg dose of dutasteride, time to reach C_max plasma dutasteride was 1-3 hours. The absolute bioavailability was about 60%. Eating does not affect the bioequivalence of dutasteride.

Tamsulosin. Tamsulosin is absorbed from the intestine and is almost completely bioavailable. Both the rate and degree of absorption of tamsulosin are reduced if it is taken within 30 minutes after eating. The uniformity of absorption is ensured by taking Duodart at the same time of the day after ingestion of similar food. The concentration of tamsulosin in blood plasma is proportional to the dose.

After taking a single dose of tamsulosin after eating C_max in blood plasma is reached after 6 hours. Equilibrium concentration is achieved on the 5th day of repeated administration. The average equilibrium concentration in patients is approximately ⅔ higher than the concentration after a single injection 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 high binding to plasma proteins (99.5%). After daily doses, the concentration of dutasteride in the blood plasma is 65% of the equilibrium concentration after 1 month and about 90% after 3 months.

An equilibrium plasma concentration of about 40 ng / ml is reached after 6 months of administration at a dose of 0.5 mg / day.The average value of dutasteride from plasma to seminal fluid is 11.5%.

Tamsulosin. In men, tamsulosin binds to plasma proteins by approximately 99%. The volume of distribution is small (about 0.21 / kg body weight).

Metabolism

Dutasteride. Dutasteride is extensively 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 dutasteride at a dose of 0.5 mg / day until an equilibrium concentration of 1.0-15.4% (average value of 5.4%) is reached, the administered dose of dutasteride is excreted unchanged with feces. The remaining amount is excreted in the feces in the form of 4 main metabolites containing 39; 21; 7 and 7% of each drug-related material; and 6 minor metabolites (5% each). In human urine, only a small amount of unchanged dutasteride was detected (0.1% of the dose).

Tamsulosin. Enantiomeric bioconversion from tamsulosin hydrochloride [R (-) isomer] to S (+) isomer does not occur in humans. Tamsulosin hydrochloride is actively metabolized by cytochrome P450 enzymes in the liver, less than 10% of the dose excreted unchanged in the urine. But the pharmacokinetic profile of metabolites in humans has not been established. In vitro studies indicate that the enzymes CYP 3A4 and CYP 2D6 are involved in the metabolism of tamsulosin, and the participation of other CYP isoenzymes is insignificant.

Inhibition of the activity of enzymes involved in hepatic metabolism can lead to an increased effect of tamsulosin. Before excretion with urine, the metabolites of tamsulosin hydrochloride undergo widespread binding to glucuronide or sulfate.

Breeding

Dutasteride. Dutasteride excretion is dose-dependent and is characterized by two parallel elimination processes, one saturated (concentration-dependent) and one unsaturated (independent of it). At low plasma concentrations (3 ng / ml), dutasteride is rapidly excreted in both a dependent and a concentration-independent manner. When using single doses of ≤5 mg, signs of rapid clearance were detected and T was established_½which lasts from 3 to 9 days.

At therapeutic concentrations, after repeated administration of a dose of 0.5 mg / day, a slow, linear route of excretion dominates, and T_½ is about 3-5 weeks.

Tamsulosin. Tamsulosin and its metabolites are excreted mainly in urine, in which about 9% of the dose is present as an unchanged active substance.

Following iv or oral administration of an immediate release dosage form T_½ tamsulosin contained in blood plasma ranges from 5-7 hours. Due to pharmacokinetics controlled by the rate of absorption, in the case of tamsulosin in modified-release capsules, this T_½ Tamsulosin, taken after meals, is about 10 hours, and in equilibrium concentration in patients is about 13 hours.

Elderly patients

Dutasteride. The pharmacokinetics of dutasteride was evaluated in 36 healthy men aged 24–87 years after administration of a single dose of 5 mg. A significant dependence of the action of dutasteride on age was not detected, but T_½ was shorter in men under the age of 50 years. Statistical Differences in T_½ not observed when comparing a group of 50–69-year-old subjects with a group of subjects over the age of 70 years.

Tamsulosin. Cross-sectional comparative study of the overall effect of tamsulosin hydrochloride (AUC) and T_½ indicates that the pharmacokinetic effect of tamsulosin hydrochloride may be slightly longer in elderly patients compared with young healthy male volunteers. The intrinsic clearance is independent of the binding of tamsulosin hydrochloride to α₁-acid glycoprotein, but decreases with age, as a result of which the overall effect is 40% stronger (AUC) in patients aged 55–75 years compared with action in patients aged 20–32 years.

Renal failure

Dutasteride. The effect of renal failure on the pharmacokinetics of dutasteride has not been studied. But in human urine there is a 0.1% dose of dutasteride (0.5 mg) in equilibrium concentration, therefore, a clinically significant increase in the concentration of dutasteride in blood plasma in patients with renal failure should not be expected (see APPLICATION).

Tamsulosin. The pharmacokinetics of tamsulosin hydrochloride was compared in 6 patients with mild to moderate renal failure (30≤CL_cr70 ml / min / 1.73 m²) or moderate to severe (10≤CL_cr 30 ml / min / 1.73 m²) degrees and in 6 subjects with normal clearance (CL_cr90 ml / min / 1.73 m²) While in the total concentration of tamsulosin hydrochloride in blood plasma, a change was observed as a result of variable binding to α₁-acid glycoprotein, the concentration of unbound (active) tamsulosin hydrochloride, as well as its own clearance remained relatively stable. Therefore, patients with renal failure do not require dose adjustment of tamsulosin hydrochloride in capsules. But patients with end-stage renal failure (CL_cr10 ml / min / 1.73 m²) have not been investigated.

Liver failure

Dutasteride. The effect of liver failure on the pharmacokinetics of dutasteride has not been studied (see CONTRAINDICATIONS). Since dutasteride is excreted primarily through metabolism, plasma levels of dutasteride in these patients are expected to be elevated, and T_½ Dutasteride will be prolonged (see APPLICATION and SPECIAL INSTRUCTIONS).

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 study participants with normal liver function. While a change in the total plasma concentration of tamsulosin hydrochloride was observed as a result of alternating binding to α₁-acid glycoprotein, the concentration of unbound (active) tamsulosin hydrochloride did not undergo significant changes, only a moderate (32%) change in the intrinsic clearance of unbound tamsulosin hydrochloride was detected. Therefore, patients with moderate impaired liver function do not require dose adjustment of tamsulosin hydrochloride. The effects of tamsulosin hydrochloride have not been studied in patients with severely impaired liver function.

Safety and clinical research

Heart failure. In a 4-year clinical study of the use of dutasteride in combination with tamsulosin for the treatment of benign prostatic hyperplasia in 4844 men (CombAT study), the incidence of heart failure (collective concept) in the combination therapy group (14/1610; 0.9%) was higher. than in any monotherapy group with dutasteride (4/1623; 0.2%) or tamsulosin (10/1611; 0.6%).

In a separate 4-year clinical study involving 8231 men aged 50–75 years with preliminary negative biopsy for prostate cancer and baseline prostate-specific antigen (PSA) 2.5–10.0 ng / ml in men aged 50 –60 years or 3.0–10.0 ng / ml in men over 60 (REDUCE studies) found that the incidence of heart failure in patients taking dutasteride 0.5 mg once a day (30/4105; 0, 7%), higher compared with patients receiving placebo (16/4126; 0.4%). A retrospective analysis of this study showed a higher heart failure rate in patients taking dutasteride and an α-adrenergic blocker at the same time (12/1152; 1.0%), compared with subjects who received dutasteride without an α-adrenergic blocking agent (18/2953; 0.6%), a placebo and an α-adrenergic receptor blocker (1/1399; 0.1%) or a placebo without an α-adrenergic receptor blocker (15/2727; 0.6%). 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 SPECIAL INSTRUCTIONS).

Prostate cancer and low-grade tumors.In a 4-year study that examined the effects of dutasteride versus placebo, 8,231 men aged 50–75 years with preliminary negative biopsy data for prostate cancer and baseline PSA levels of 2.5–10.0 ng / ml in men aged 50-60 years or 3.0-10.0 ng / ml for men over 60 years of age (REDUCE studies) 6706 subjects underwent needle biopsy of the prostate gland (mandatory according to the primary protocol), the data of which were used to analyze differentiation according to Gleason scale. The study identified 1,517 patients diagnosed with prostate cancer. Most prostate tumors (70%) detected by biopsy in both treatment groups had a high level of differentiation (5-6 points on the Gleason score).

In the dutasteride group, a higher frequency (n = 29; 0.9%) of low-grade prostate cancer (8-10 points on the Gleason score) was recorded compared with the placebo group (n = 19; 0.6%) (p = 0, fifteen). In the first 2 years of the study, the number of patients with prostate cancer with an indicator of 8-10 points on the Gleason score was the same in the dutasteride group (n = 17; 0.5%) and in the placebo group (n = 18; 0.5%). During the 3-4 years of the study, a greater number of cases of prostate cancer with an indicator of 8-10 points on the Gleason score were recorded 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 effect on prostate cancer risk in men taking dutasteride for more than 4 years. The percentage of patients diagnosed with prostate cancer with an indicator of 8-10 points on the Gleason score remained constant at different periods of the study (1-2 years, 3-4 years) in the dutasteride group (0.5% in each period), while in the placebo group, the percentage of patients with low-grade prostate cancer (8-10 points on the Gleason score) was lower in 3-4 years than in 1-2 years (0.1 and 0.5% respectively) (see SPECIAL INSTRUCTIONS). 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 for the treatment of benign prostatic hyperplasia (CombAT), where a mandatory biopsy was not provided by the primary protocol and all diagnoses of prostate cancer were established on the basis of indications of a biopsy, the incidence of prostate cancer was 8–10 on the Gleason score it 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 low-grade prostate cancer remains unclear.

Breast cancer in men. 2 controlled epidemiological studies, one in the United States (n = 339 cases of breast cancer and n = 6780 in the control group), and the other in the UK (n = 398 cases of breast cancer and n = 3930 in the control group) in health databases , showed no increase in the risk of developing breast cancer in men with the use of 5α-reductase inhibitors. The results of the first study did not reveal a positive relationship with breast cancer (relative risk for ≥1 year of use before diagnosis of breast cancer compared with 1 year of use: 0.70: 95% CI 0.34, 1.45). In a second study, the estimated relative risk of breast cancer associated with the use of 5α-reductase inhibitors compared with the lack of use was 1.08: 95% CI 0.62, 1.87).

A causal relationship between cases of breast cancer in men and prolonged use of dutasteride has not been established.

Indications

Treatment of moderate to severe symptoms of benign prostatic hyperplasia. reduced risk of acute urinary retention and the need for surgical intervention in patients with moderate and severe symptoms of benign prostatic hyperplasia.

Application

Adults (including elderly patients). the recommended dose of duodart is 1 capsule (0.5 mg / 0.4 mg) per day. the drug is taken orally 30 minutes after a meal and at the same time.the capsule should be swallowed whole without opening or chewing, since contact with the contents of the capsule may irritate the mucous membrane of the mouth and pharynx.

Duodart can be used to replace combination therapy with dutasteride and tamsulosin hydrochloride in order to facilitate treatment.

Replacing with duodart dutasteride or tamsulosin hydrochloride during monotherapy is possible, if it is clinically justified.

Renal failure. The pharmacokinetics of dutasteride-tamsulosin in patients with renal failure have not been studied. Changing the dose of the drug to treat such patients is not required (see SPECIAL INSTRUCTIONS and Pharmacokinetics).

Liver failure. The pharmacokinetics of dutasteride + tamsulosin have not been studied in patients with hepatic insufficiency, therefore, the drug should be used with caution in mild to moderate hepatic insufficiency (see SPECIAL INSTRUCTIONS and Pharmacokinetics). In patients with severe hepatic insufficiency, the drug is contraindicated (see CONTRAINDICATIONS).

Children. The use is contraindicated.

Contraindications

The drug is not used to treat women and children (see use during pregnancy and lactation). 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.

Side effects

Clinical studies of the use of duodart have not been conducted, but the bioequivalence of duodart and the combined use of dutasteride and tamsulosin have been demonstrated. information on the simultaneous use was obtained from a combat study (a combination of avodart and tamsulosin), which compared combinations of dutasteride at a dose of 0.5 mg and tamsulosin 0.4 mg once a day for 4 years or monotherapy with these drugs.

Information about the side effects for each component separately (dutasteride and tamsulosin) is given below. Not all adverse reactions that were noted when using each component separately were reported when taking Duodart, and therefore information about adverse reactions when using individual components of Duodart is also included in this instruction.

According to the 4-year CombAT study, the proportion of adverse reactions identified by researchers during the 1st, 2nd, 3rd and 4th year of treatment changed, respectively: 22; 6; 4 and 2% in combination therapy with dutasteride + tamsulosin; fifteen; 6; 3 and 2% - with monotherapy with dutasteride; thirteen; 5; 2 and 2% - with monotherapy with tamsulosin. A higher percentage of adverse reactions in the group receiving combination therapy during the 1st year of treatment is due to high rates of reproductive disorders, namely, ejaculation disorders identified in the group.

Adverse reactions that occurred with a frequency of ≥1% during the first year of use, according to research data from CombAT, REDUCE, as well as from clinical studies of monotherapy with Duodart components, are given in the table.

Information on adverse reactions to tamsulosin is based on data available from the relevant medical resources. The frequency of their occurrence may increase with the simultaneous use of dutasteride and tamsulosin.

The frequency of adverse reactions identified in clinical trials: often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000, 1/1000), very rarely ( 1/10 000). Adverse reactions classified by classes of organ systems are presented in decreasing order of severity.

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

^bFrom studies of monotherapy for benign prostatic hyperplasia with dutasteride.

^cFrom basic information on tamsulosin safety for EU countries.

^dREDUCE study.

¹The collective term “heart failure” includes congestive heart failure, heart failure, left ventricular failure, acute heart failure, cardiogenic shock, acute left ventricular failure, right ventricular failure, acute right ventricular failure, ventricular failure, cardiopulmonary failure, congestive cardiopathy.

²Including hyperesthesia and breast enlargement.

³Adverse reactions associated with impaired sexual function are associated with treatment with dutasteride (including monotherapy and a combination with tamsulosin). These adverse reactions may continue after treatment is discontinued. The role of dutasteride in their duration is unknown.

Post-marketing research data. In post-marketing observation, adverse reactions were recorded from spontaneous messages, so the exact frequency of such reactions is unknown.

Dutasteride Monotherapy

Immune system disorders: frequency unknown - allergic reactions, including rash, itching, urticaria, localized edema, and angioedema.

Mental disorders: frequency unknown - depression.

Disorders from the skin and subcutaneous tissue: rarely - alopecia (mainly hair loss on the body), hypertrichosis.

Disorders from the reproductive system and mammary glands: frequency is unknown - testicular pain and swelling.

Tamsulosin monotherapy. According to post-marketing surveillance during surgery for cataracts and glaucoma in some patients previously treated with α blockers₁-adrenoreceptors, including tamsulosin, intraoperative syndrome of atonic iris (ICAP, a variant of the narrow pupil syndrome) was noted (see SPECIAL INSTRUCTIONS).

During post-registration use, there were additional reports of cases of atrial fibrillation, arrhythmias, tachycardia, dyspnea, nosebleeds, visual impairment, including in the form of a decrease in its severity, polymorphic erythema, exfoliative dermatitis and dry mouth, associated with tamsulosin.

Other data. In a clinical trial