Dutris

INSTRUCTIONS for medical use of the medicinal product Dutrys (Dutrys)

Composition:

Active substance: dutasteride;

1 capsule contains 0.5 mg of dutasteride;

Excipients: propylene glycol monocaprylate, type II; butylhydroxytoluene (E 321);

Capsule shell: gelatin, glycerin, titanium dioxide (E 171).

Pharmaceutical form. Soft capsules.

Main physicochemical properties: light-yellow, oblong (approximately 16.5 x 6.5 mm) soft gelatin capsules filled with a clear liquid.

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 to 5α-dihydrotestosterone. Dihydrotestosterone is an androgen primarily responsible for prostate tissue hyperplasia. The maximum reduction in dihydrotestosterone during Dutrace treatment is dose-dependent and occurs within the first 1–2 weeks. After the 1st and 2nd weeks of taking Dutrace at a daily dose of 0.5 mg, the average concentration of dihydrotestosterone decreases by 85% and 90%, respectively.

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

Heart failure.

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

In a separate four-year placebo-controlled clinical trial of dutasteride for chemoprevention involving 8231 men aged 50 to 75 years with a prior negative prostate cancer biopsy and baseline prostate-specific antigen (PSA) levels between 2.5 ng/mL and 10.0 ng/mL in men aged 50 to 60 years or 3.0 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 taking dutasteride and an α-blocker concurrently (12/1152, 1.0%) compared to those taking dutasteride without an α-blocker (18/2953, 0.6%), placebo with 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 (alone or in combination with alpha-blockers) and the occurrence of heart failure has not been established (see section «Special precautions for use»).

Breast cancer in men.

Two case-control epidemiological studies, one conducted in the USA (n = 339 breast cancer cases and n = 6780 in the control group) and another in the UK (n = 398 breast cancer cases and n = 3930 in the control group), showed no increased risk of developing breast cancer in men using 5α-reductase inhibitors. The results of the first study showed no association with breast cancer (relative risk with ≥1 year of use before breast cancer diagnosis compared to <1 year: 0.70; 95% 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 the development of male breast cancer and long-term use of dutasteride has not been established.

Pharmacokinetics.

Absorption

After a single 0.5 mg dose, peak plasma concentration is observed within 1–3 hours. Absolute bioavailability is 60% following a two-hour intravenous infusion. Bioavailability is unaffected by food intake.

Distribution

Dutasteride has a large volume of distribution (300–500 L) after single or multiple doses. Plasma protein binding exceeds 99.5%.

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

Biological transformation

In vitro, dutasteride is metabolized by human cytochrome P450 CYP3A4 enzymes into 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).

Elimination

Dutasteride is extensively metabolized. After oral administration of 0.5 mg/day, 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 found in urine. The terminal elimination half-life of dutasteride is 3–5 weeks. Residual levels of dutasteride in plasma may be detected 4–6 months after discontinuation of treatment.

Elderly patients

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

Patients with renal impairment

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 urine after administration of 0.5 mg of dutasteride; therefore, dosage adjustment in patients with renal impairment is not required.

Patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied (see section «Special precautions for use» and «Method of administration and dosage»).

Preclinical safety data

Current studies on general toxicity, genotoxicity, and carcinogenicity have not shown significant risk to humans.

Reproductive toxicity studies in male rats showed decreased prostate and seminal vesicle weight, reduced sex gland secretion, and impaired fertility parameters (due to the pharmacological effect of dutasteride). The clinical significance of these findings is unknown.

As with other 5α-reductase enzyme inhibitors, administration of dutasteride during pregnancy resulted in feminization of male fetuses in rats and rabbits. Dutasteride was detected in the blood of female rats after mating with male rats receiving dutasteride. When dutasteride was administered to primates during pregnancy, no feminization of male fetuses was observed at exposure levels significantly exceeding those likely to occur via human sperm transmission. It is unlikely that transmission of dutasteride via semen would adversely affect a male fetus.

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.

Dutras is contraindicated:

• in patients with hypersensitivity to dutasteride, other 5α-reductase inhibitors, soy, peanuts, or any other component of the drug.
• for treatment of women and children (see sections "Use during pregnancy and breastfeeding", "Pediatric use").
• in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Information on the reduction of plasma PSA levels during dutasteride use, 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.

Inhibitors of CYP3A4 and/or P-glycoprotein.

Dutasteride is primarily eliminated via metabolism. In vitro studies show that CYP3A4 and CYP3A5 are responsible for its metabolism. Formal interaction studies with strong inhibitors of CYP3A4 have not been conducted. However, in a population pharmacokinetic study, plasma concentrations of dutasteride were on average 1.6–1.8 times higher in a small number of patients concomitantly treated with verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) compared to other patients.

With long-term use of dutasteride together with agents that are potent inhibitors of the CYP3A4 enzyme (e.g., ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally), plasma 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 in case of adverse reactions. It should be noted that enzyme inhibition may further prolong the already long half-life, and concomitant therapy may thus need to continue for more than 6 months before a new steady-state concentration is achieved.

Long-term administration of dutasteride with drugs that are strong inhibitors of the CYP3A4 enzyme (such as ritonavir, indinavir, nefazodone, itraconazole, oral ketoconazole) may lead to increased dutasteride concentrations. Further inhibition of 5α-reductase due to prolonged action of dutasteride is unlikely. However, dose reduction of dutasteride may be considered in case of adverse reactions. It should be noted that enzyme inhibition may further prolong the already long half-life, 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 or 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 2-week study (N=24) involving healthy men, dutasteride (0.5 mg daily) did not affect the pharmacokinetics of tamsulosin or terazosin. No evidence of pharmacodynamic interaction was observed in this study.

Special precautions for use

Combination 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").

Effect on the cardiovascular system

According to data from four-year clinical studies, the incidence of heart failure (a combined term for all reported events, predominantly heart failure and congestive heart failure) was slightly higher among patients treated with a combination of Dutris and an α-blocker, mainly tamsulosin, compared to patients who did not receive such combination therapy. However, the incidence of heart failure was lower in all groups receiving dutasteride treatment compared to the placebo group. Other available data for dutasteride or α-blockers do not confirm a conclusion about increased cardiovascular risk (see section "Pharmacodynamics").

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). 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) was established.

Effect on prostate-specific antigen (PSA) and detection of prostate cancer

Serum prostate-specific antigen (PSA) concentration is an important component of the screening process for detecting prostate cancer.

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

Patients taking Dutris should have a new baseline PSA level established 6 months after starting treatment with this medication. This level should then be monitored regularly. Any confirmed increase in PSA from the lowest level during Dutris treatment may indicate the presence of prostate cancer (particularly high-grade cancer) or non-compliance with Dutris therapy and requires thorough evaluation, even if PSA levels remain within the normal range observed in men not treated with 5α-reductase inhibitors. When interpreting PSA levels in patients treated with Dutris, previous PSA values should be considered for comparison.

The use of Dutris does not affect the utility of PSA levels for diagnosing prostate cancer after establishing a new baseline level.

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

The ratio of free PSA to total PSA remains constant during Dutris treatment. Therefore, if a physician decides to use free PSA measurement to detect prostate cancer in a patient taking Dutris, no adjustment of the free PSA value is required.

Prior to initiating treatment with dutasteride and periodically during treatment, patients should undergo digital rectal examination and other prostate cancer screening procedures.

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

In a four-year clinical study involving 8,000 men aged 50 to 75 years with prior negative prostate biopsy results and initial PSA levels between 2.5 ng/mL and 10.0 ng/mL (the REDUCE study), prostate cancer was diagnosed in 1,517 patients. The incidence of high-grade prostate cancer (Gleason score 8–10) was higher in the group treated with Dutris (29.09%) compared to the placebo group (19.06%). No increase in the incidence of prostate cancer with Gleason scores 5–6 or 7–10 was observed. A causal relationship between Dutris use and high-grade prostate cancer has not been established. The clinical significance of this numerical imbalance is unknown. Men treated with Dutris should be regularly monitored for the risk of prostate cancer, including PSA testing.

In an additional two-year follow-up study of patients from the dutasteride chemoprevention trial (REDUCE study), a low incidence of new prostate cancer cases was observed (dutasteride group [n=14, 1.2%] vs. placebo group [n=7, 0.7%]), with no new cases of Gleason score 8–10 prostate cancer identified.

Long-term follow-up (up to 18 years) of patients from a clinical trial using another 5α-reductase inhibitor (finasteride) for chemoprevention showed no statistically significant difference between the finasteride and placebo groups in overall survival (HR 1.02, 95% CI 0.97–1.08) or survival after prostate cancer diagnosis (HR 1.01, 95% CI 0.85–1.20).

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 5α-reductase inhibitors. Patients should be advised to promptly report any changes in breast tissue, such as nipple discharge or breast swelling, during treatment.

Leaking capsules

Dutasteride is absorbed through the skin; therefore, women and children should avoid contact with leaking capsules (see section "Use during pregnancy or breastfeeding"). If capsule contents come into contact with the skin, the affected area should be washed immediately with soap and water.

Patients with hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied. Due to the extensive metabolism of dutasteride and its long elimination half-life (3–5 weeks), caution should be exercised when administering the drug to patients with mild to moderate hepatic impairment (see sections "Pharmacological properties" and "Dosage and administration").

Use during pregnancy or breastfeeding

Dutasteride is contraindicated in women.

Pregnancy

Like other 5α-reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone, which may impair the development of external genitalia in male fetuses. Small amounts of dutasteride have been detected in the semen of subjects taking 0.5 mg daily. It is unknown whether dutasteride transferred to a woman via semen from a treated male partner may affect a male fetus (the risk is highest during the first 16 weeks of pregnancy).

As with other 5α-reductase inhibitors, it is recommended that patients use condoms if their partner is pregnant or potentially could become pregnant, to prevent semen exposure to the woman.

Breastfeeding

It is unknown whether dutasteride is excreted in human breast milk.

Fertility

Cases of dutasteride affecting sperm characteristics (reduced sperm count, semen volume, and sperm motility) have been reported in healthy men (see section "Pharmacodynamics"). A risk of reduced male fertility cannot be excluded.

Ability to influence reaction speed 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.

Method of Administration and Dosage

Dutris can be prescribed alone or in combination with the α-blocker tamsulosin (0.4 mg).

Adult men (including elderly patients)

The recommended dose of Dutris is 1 capsule (0.5 mg) once daily for oral administration. The capsules should be swallowed whole and must not be opened or chewed, as contact with the capsule contents may cause irritation of the oral and pharyngeal mucosa.

Dutris may be taken independently of food intake.

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

Patients with 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.

Patients with hepatic impairment

The pharmacokinetics of dutasteride in patients with hepatic impairment have not been studied; therefore, caution is advised when administering the drug to patients with mild to moderate hepatic impairment. Dutris is contraindicated in patients with severe hepatic impairment.

Children

Use is contraindicated.

Overdose

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

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

Adverse reactions

Dutasteride monotherapy

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

Table 1 lists adverse reactions identified during controlled clinical trials and in the post-marketing period. The adverse reactions observed during clinical trials were considered by investigators to be drug-related (with a frequency ≥1%) and occurred more frequently in patients receiving dutasteride compared to placebo during the first year of treatment. Adverse reactions reported during the post-marketing period were identified from spontaneous post-marketing reports; therefore, their actual frequency is unknown.

Frequency classification: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon ((≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (<1/10000), frequency not known (cannot be estimated from available data).

Table 1

*Adverse reactions related to sexual function disturbances are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after discontinuation of treatment. The effect of dutasteride on their duration is unknown.

^Includes decreased semen volume.

+Includes breast tenderness and enlargement.

Combination therapy with the α-blocker tamsulosin

Data from the four-year CombAT study, which compared daily administration of dutasteride 0.5 mg (n=1623) and tamsulosin 0.4 mg (n=1611) as monotherapies and in combination (n=1610), showed that the incidence of adverse reactions related to drug use during the first, second, third, and fourth year 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 following adverse reactions related to drug administration, as assessed by investigators, occurred at a frequency of ≥1%; the incidence of these reactions over 4 years of treatment is presented in Table 2.

Table 2

aCombination – dutasteride 0.5 mg once daily plus tamsulosin 0.4 mg once daily.

bThe 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 insufficiency, congestive cardiomyopathy.

cAdverse reactions related to sexual function disorders are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after discontinuation of treatment. The effect of dutasteride on their duration is unknown.

dIncludes 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 the results of this study were influenced by prostate volume reduction or other factors related to dutasteride use.

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

Reporting suspected adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging to protect from light. Keep out of reach of children.

Packaging.

10 capsules in a blister, 3 or 9 blisters in a cardboard box; 15 capsules in a blister; 2 or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia/KRKA, d.d., Novo mesto, Slovenia.

Laboratorios Leon Farma, S.A., Spain.

Manufacturer's address and location of its business operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

Poligono Industrial Navatejera, C/La Villina s/n, Villaquilambre, 24193 Leon, Spain.