Dutapro

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

Composition:

Active substance: dutasteride;

1 soft capsule contains 0.5 mg of dutasteride;

Excipients: glycerol monocaprylocaprate Imwitor 742, butylhydroxytoluene (E 321), gelatin, glycerin, titanium dioxide (E 171), yellow iron oxide (E 172), purified water, Opacode Black Printing Ink NS-78-17821, caprylic/capric acid triglyceride Miglyol 812N.

Pharmaceutical form. Soft capsules.

Main physicochemical properties: opaque, dull yellow, elongated soft gelatin capsules containing a clear liquid, marked with «DUTA05» in black edible ink.

Pharmacotherapeutic group. Agents used in benign prostatic hyperplasia. Testosterone 5α-reductase inhibitors. ATC code G04C B02.

Pharmacological properties.

Pharmacodynamics.

Dutasteride is a dual inhibitor of 5α-reductase, inhibiting both type 1 and type 2 isoenzymes of 5α-reductase, which are responsible for the conversion of testosterone into 5α-dihydrotestosterone. Dihydrotestosterone is an androgen primarily responsible for prostate tissue hyperplasia. The maximum reduction in dihydrotestosterone levels during treatment with Dutapro depends on the dose and occurs within the first 1–2 weeks. After 1 and 2 weeks of treatment with Dutapro at a daily dose of 0.5 mg, the mean dihydrotestosterone concentration decreases by 85% and 90%, respectively.

In patients with benign prostatic hyperplasia treated with 0.5 mg of dutasteride daily, the mean reduction in dihydrotestosterone levels was 94% after 1 year and 93% after 2 years of treatment. The mean testosterone level increased by 19% after both 1 and 2 years of treatment.

Pharmacokinetics.

Dutasteride should be administered orally in the form of a solution in soft gelatin capsules. After a single 0.5 mg dose, maximum plasma concentration is observed within 1–3 hours. Absolute bioavailability is 60%. Bioavailability is not affected by food intake.

After single or multiple doses, dutasteride has a large volume of distribution (ranging from 300 L to 500 L). The extent of protein binding exceeds 99.5%.

When administered at a daily dose of 0.5 mg, 65% of the steady-state concentration of dutasteride in plasma is achieved after 1 month of treatment and approximately 90% after 3 months. A steady-state concentration of approximately 40 ng/mL in plasma is reached after 6 months of treatment at a daily dose of 0.5 mg. As in plasma, steady-state concentrations of dutasteride in semen are achieved after 6 months. After 52 weeks of treatment, the mean concentration of dutasteride in semen is 3.4 ng/mL (range: 0.4–14 ng/mL). The extent of dutasteride distribution from plasma to semen is approximately 11.5%.

In vitro, dutasteride is metabolized by the CYP3A4 enzymes of human cytochrome P450 to two monohydroxylated metabolites.

Spectrometric analysis in human plasma reveals unchanged dutasteride, three major metabolites (4´-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and two minor metabolites (6,4´-dihydroxydutasteride and 15-hydroxydutasteride).

Dutasteride is extensively metabolized. After oral administration of 0.5 mg dutasteride daily, 1% to 15.4% (mean 5.4%) of the administered dose is excreted in feces as unchanged dutasteride. The remainder of the dose is excreted as metabolites.

Only trace amounts of unchanged dutasteride (<0.1% of the administered dose) are detected in urine. The terminal elimination half-life of dutasteride is 3–5 weeks. Residual amounts of dutasteride in plasma may be detected up to 4–6 months after discontinuation of treatment.

Based on pharmacokinetic and pharmacodynamic studies, dose adjustment according to patient age is not required.

The effect of renal impairment on the pharmacokinetics of dutasteride has not been studied. However, less than 0.1% of the dose is excreted in human urine after administration of 0.5 mg dutasteride; therefore, dose adjustment in patients with renal impairment is not necessary.

The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied (see sections "Special precautions" and "Dosage and administration").

Safety and clinical studies.

Heart failure

In a four-year clinical trial evaluating dutasteride in combination with tamsulosin for the treatment of benign prostatic hyperplasia in 4844 men (CombAT study), the incidence of heart failure (composite term) was higher in the combination therapy group (14/1610, 0.9%) than in either monotherapy group receiving dutasteride (4/1623, 0.2%) or tamsulosin (10/1611, 0.6%).

In a separate four-year placebo-controlled clinical trial involving 8231 men aged 50 to 75 years with a prior negative prostate biopsy for prostate cancer and initial PSA levels between 2.5 ng/mL and 10.0 ng/mL in men aged 50 to 60 years or between 3 ng/mL and 10.0 ng/mL in men aged 60 years and older (REDUCE study), the incidence of heart failure was higher in patients receiving dutasteride 0.5 mg once daily (30/4105, 0.7%) compared to those receiving placebo (16/4126, 0.4%). In a retrospective analysis of this study, a higher incidence of heart failure was observed in patients receiving dutasteride and an alpha-blocker concurrently (12/1152, 1.0%) compared to those receiving dutasteride without an alpha-blocker (18/2953, 0.6%), placebo with an alpha-blocker (1/1399, <0.1%), or placebo without an alpha-blocker (15/2727, 0.6%). A causal relationship between the use of dutasteride (alone or in combination with alpha-blockers) and the occurrence of heart failure has not been established (see section "Special precautions").

Prostate cancer and high-grade tumors

In a four-year placebo-controlled trial involving 8231 men aged 50 to 75 years with a prior negative prostate biopsy for prostate cancer and initial PSA levels between 2.5 ng/mL and 10.0 ng/mL in men aged 50 to 60 years or between 3 ng/mL and 10.0 ng/mL in men aged 60 years and older (REDUCE study), 6706 patients underwent prostate needle biopsy (mandated by the original protocol), and data from these biopsies were used for Gleason score analysis. A total of 1517 patients were diagnosed with prostate cancer in the study. The majority of prostate tumors (70%) detected by biopsy in both treatment groups were well-differentiated (Gleason score 5–6).

A higher incidence of high-grade prostate cancer (Gleason score 8–10) was observed in the dutasteride group (n = 29, 0.9%) compared to the placebo group (n = 19, 0.6%) (p = 0.15). During years 1–2 of the study, the number of patients diagnosed with Gleason score 8–10 prostate cancer was similar in the dutasteride group (n = 17, 0.5%) and the placebo group (n = 18, 0.5%). During years 3–4, more cases of Gleason score 8–10 prostate cancer were 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 effect of dutasteride use beyond 4 years on the risk of developing prostate cancer. The percentage of patients diagnosed with Gleason score 8–10 prostate cancer remained constant over different periods of the study (years 1–2, years 3–4) in the dutasteride group (0.5% in each period), whereas in the placebo group, the percentage of patients with high-grade prostate cancer (Gleason score 8–10) was lower during years 3–4 than during years 1–2 (<0.1% vs. 0.5%, respectively) (see section "Special precautions"). There was no difference in the incidence of prostate cancer with Gleason score 7–10 (p = 0.81).

In a four-year clinical trial of benign prostatic hyperplasia treatment (CombAT study), in which mandatory biopsy was not required by the original protocol and all prostate cancer diagnoses were based on biopsy for clinical indications, the incidence of Gleason score 8–10 prostate cancer was n = 8, 0.5% in the dutasteride group, n = 11, 0.7% in the tamsulosin group, and n = 5, 0.3% in the combination therapy group.

The relationship between dutasteride use and the development of high-grade prostate cancer remains unclear.

Breast cancer in men

Two case-control epidemiological studies—one conducted in the United States (n = 339 breast cancer cases and n = 6780 controls) and the other in the United Kingdom (n = 398 breast cancer cases and n = 3930 controls)—did not show an increased risk of male breast cancer associated with the use of 5α-reductase inhibitors. The results of the first study showed no association with breast cancer (relative risk for use ≥1 year before breast cancer diagnosis compared to use <1 year: 0.70; 95% confidence interval (CI) 0.34; 1.45). In the second study, the relative risk of breast cancer associated with 5α-reductase inhibitor use compared to non-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.

Clinical characteristics.

Indications.

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

Contraindications.

The medicinal product Dutapro is contraindicated in patients with hypersensitivity to dutasteride, other 5α-reductase inhibitors, soy, peanuts, or any other components of the product.

Do not use for treatment of women and children (see section "Use during pregnancy or breastfeeding").

Contraindicated in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Information on the reduction of PSA (prostate-specific antigen) levels in blood serum during treatment with dutasteride, as well as information on the detection of prostate cancer, 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 eliminated primarily via metabolism. In vitro studies indicate that CYP3A4 and CYP3A5 are responsible for its metabolism. Formal interaction studies with strong 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 use of dutasteride in combination with medicinal products that are potent inhibitors of the CYP3A4 enzyme (e.g., ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally), serum concentrations of dutasteride may increase. Further inhibition of 5α-reductase due to prolonged action of dutasteride is unlikely. However, dose reduction of dutasteride may be considered if adverse reactions occur. In case of prolonged enzyme inhibition, the half-life may become even longer, and concomitant therapy may thus 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

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 P-glycoprotein transporter. In vitro interaction studies indicate that dutasteride does not inhibit the enzymes CYP1A2, CYP2D6, CYP2C9, CYP2C19, or CYP3A4.

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.

Special precautions for use.

Combined therapy may be prescribed only after careful assessment of benefit/risk due to the potential increased risk of adverse reactions (including heart failure) and after considering alternative treatment options, including monotherapy (see section "Dosage and administration").

Cardiovascular adverse reactions

According to data from four-year clinical trials, the incidence of heart failure (a collective term for all reported events, primarily primary heart failure and congestive heart failure) was higher in patients treated with a combination of dutasteride and an alpha-blocker, mainly tamsulosin, compared to patients not receiving this combination. In these two trials, the incidence of heart failure was low (≤1%) and variable across the studies. There was no imbalance in the incidence of cardiovascular adverse reactions in any of the trials. A causal relationship between the use of dutasteride (alone or in combination with alpha-blockers) and the development of heart failure has not been established (see section "Pharmacological properties").

A meta-analysis of 12 randomized, placebo-controlled or comparative clinical trials (n = 18,802) was conducted to evaluate the risk of cardiovascular adverse reactions with dutasteride use (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).

Effect on prostate-specific antigen (PSA)

PSA level is an important component of the screening process for detecting prostate cancer.

The medicinal product Dutapro is capable of reducing serum PSA levels in patients by approximately 50% on average within 6 months of treatment.

Patients taking the medicinal product Dutapro should have a new baseline PSA level established 6 months after initiating treatment. This level should then be monitored regularly. Any confirmed increase in PSA from the lowest level during treatment with Dutapro may indicate the presence of prostate cancer or non-compliance with the treatment regimen and requires careful evaluation, even if PSA values remain within the normal range for men not treated with 5α-reductase inhibitors. When interpreting PSA values in patients taking Dutapro, previous PSA values should be considered for comparison.

The use of Dutapro does not affect the utility of PSA levels for diagnosing prostate cancer once a new baseline has been established.

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

The ratio of free PSA to total PSA remains constant even during treatment with Dutapro. Therefore, if a physician decides to use the percentage of free PSA as a marker for prostate cancer detection in a patient taking Dutapro, no adjustment of the value is necessary.

Digital rectal examination, as well as other methods for detecting prostate cancer, should be performed before initiating dutasteride therapy and periodically during treatment.

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

In a four-year clinical trial involving >8000 men aged 50 to 75 years with prior negative prostate biopsy results and baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL (the REDUCE study), prostate cancer was diagnosed in 1517 men. The incidence of prostate cancer with Gleason scores of 8–10 was higher in the group receiving Dutapro (n = 29, 09%) compared to the placebo group (n = 19, 06%). No increase in the incidence of prostate cancer with Gleason scores of 5–6 or 7–10 was observed. A causal relationship between the use of Dutapro and high-grade prostate cancer has not been established. The clinical significance of the numerical imbalance is unknown. Men taking Dutapro should be regularly monitored for the risk of prostate cancer, including PSA testing.

In an additional sequential two-year follow-up study of patients from the dutasteride chemoprevention trial (REDUCE study), the incidence of new prostate cancer cases was low (dutasteride group [n = 14, 1.2%] vs. placebo group [n = 7, 0.7%]), with no new cases of Gleason 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 diagnosis of prostate cancer (HR 1.01, 95% CI 0.8–1.20).

Breast cancer

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 the use of 5α-reductase inhibitors. Patients should promptly report any changes in breast tissue, such as nipple discharge or swelling.

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.

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 of 3–5 weeks, caution should be exercised when treating patients with mild to moderate hepatic impairment (see sections "Pharmacological properties", "Contraindications", and "Dosage and administration").

Mood changes and depression

In patients receiving another oral 5-alpha-reductase inhibitor, mood changes including depressed mood, depression, and, less frequently, suicidal ideation have been reported. Patients experiencing any of these symptoms should be advised to consult their physician.

Use during pregnancy or breastfeeding.

Dutasteride is contraindicated for use in women.

Use during 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 the semen of patients taking 0.5 mg dutasteride daily. It is unknown whether dutasteride transferred to a woman via semen from a treated male partner may affect a male fetus (this risk is highest during the first 16 weeks of pregnancy).

As with other 5α-reductase inhibitors, the use of condoms is recommended if the patient's partner is pregnant or potentially could become pregnant, to prevent exposure of the woman to semen.

Use during breastfeeding

It is unknown whether dutasteride passes into breast milk.

Fertility

Cases of effects of dutasteride on ejaculate characteristics (reduced sperm count, ejaculate volume, and sperm motility) have been reported in healthy men. A potential risk of reduced male fertility cannot be excluded.

Ability to influence the speed of reactions when driving or operating machinery.

Due to the pharmacokinetic and pharmacodynamic properties of dutasteride, it does not affect the ability to drive or operate machinery.

Dosage and Administration

The medicinal product Dutapro can be prescribed alone or in combination with the alpha-blocker tamsulosin (0.4 mg).

Adults (including elderly patients)

The recommended dose of the medicinal product Dutapro is 1 capsule (0.5 mg) once daily for oral administration. 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.

Dutapro can be taken independently of food intake.

Although symptom improvement may be observed early in treatment, treatment should be continued for at least 6 months to allow an objective assessment of the drug's efficacy.

Renal impairment

The pharmacokinetics of dutasteride in patients with renal impairment have not been studied; therefore, caution should be exercised when prescribing the drug to patients with severe renal impairment.

Hepatic impairment

The pharmacokinetics of dutasteride in patients with hepatic impairment have not been studied. Therefore, dutasteride should be used with caution in patients with mild to moderate hepatic impairment. The drug is contraindicated in patients with severe hepatic impairment.

Children

Use is contraindicated.

Overdose

Clinical trial data indicate that single doses of dutasteride up to 40 mg daily (80 times higher than therapeutic doses) administered for 7 days did not raise safety concerns in volunteers. During clinical trials, doses of dutasteride up to 5 mg daily administered for 6 months did not result in additional adverse reactions compared to 0.5 mg daily.

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

Adverse reactions

Dutasteride monotherapy

Adverse reactions occurred in approximately 19% of the 2167 patients treated with dutasteride in two-year, placebo-controlled Phase III studies during the first year of treatment. Most of the observed adverse reactions were mild or moderate in severity and involved the reproductive system. In subsequent 2-year open-label extension studies, no changes in the adverse reaction profile were observed.

Table 1 lists adverse reactions identified during controlled clinical trials. The adverse reactions listed below, observed during clinical trials and considered by investigators to be drug-related (with an incidence ≥1%), occurred more frequently in patients treated with dutasteride compared to placebo during the first year of treatment.

Frequency classification: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Table 1

*The adverse reactions related to the reproductive system listed below are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). The adverse reactions listed below may persist after discontinuation of treatment. The role of dutasteride in this persistence is unknown.

^ Includes decreased semen volume.

• Includes breast tenderness and enlargement.

The medicinal product Dutapro in combination with the alpha-blocker tamsulosin

Data from the four-year CombAT study, which compared the administration of dutasteride 0.5 mg (n = 1,623) and tamsulosin 0.4 mg (n = 1,611) once daily as monotherapies and in combination (n = 1,610), showed that the incidence of drug-related adverse reactions during the first, second, third, and fourth years of treatment was 22%, 6%, 4%, and 2%, respectively, for combination therapy with dutasteride/tamsulosin, 15%, 6%, 3%, and 2% for dutasteride monotherapy, and 13%, 5%, 2%, and 2% for tamsulosin monotherapy. The higher incidence of adverse reactions in the combination therapy group during the first year of treatment was due to a higher frequency of reproductive system disorders, particularly ejaculation disorders, observed in this group.

During the first year of treatment in the CombAT study, the adverse reactions listed below, considered by investigators to be related to drug administration, were reported at a frequency of ≥1%. The incidence of these reactions over four years of treatment is presented in Table 2.

Table 2

a Combination: dutasteride 0.5 mg once daily plus tamsulosin 0.4 mg once daily.

b The general 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.

c The adverse reactions related to the reproductive system listed below are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). The listed adverse reactions may persist after discontinuation of treatment. The role of dutasteride in this persistence is unknown.

d Includes breast tenderness and breast enlargement.

^ Includes decreased semen volume.

Other data

The REDUCE study revealed a higher incidence of prostate cancer with Gleason score 8–10 in men receiving dutasteride compared to placebo. It is unknown whether prostate volume reduction or other factors related to dutasteride use influenced the outcomes of this study. Cases of male breast cancer have been reported (see section "Special precautions").

Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy to the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of reach of children.

Packaging. 10 capsules in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Olive Pharmaceuticals Limited.

Manufacturer's address and location of business operations.
Unit-II, Plot No. 163/2, Mahatma Gandhi Udhyog Nagar, Dabhel Village, Nani Daman, Daman - 396 210, India.