Restad

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

Composition:

Active substance: dutasteride;

1 soft capsule contains 0.5 mg of dutasteride;

Excipients: butylhydroxytoluene (E 321), propylene glycol monolaurate;

Capsule shell: gelatin, glycerin, titanium dioxide (E 171), quinoline yellow (E 104), yellow sunset FCF (E 110).

Pharmaceutical form. Soft capsules.

Main physicochemical characteristics: soft gelatin capsules, oval-shaped, opaque, yellowish to yellow in color, containing a clear colorless solution.

Pharmacotherapeutic group.

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

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

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 with dutasteride is dose-dependent and occurs within the first 1–2 weeks. After the 1st and 2nd week of treatment with dutasteride 0.5 mg daily, the mean dihydrotestosterone concentration decreases by 85% and 90%, respectively.

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

Clinical efficacy and safety.

Heart failure.

In a 4-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 (composite term) was higher in the combination therapy group (14/1610, 0.9%) than in either monotherapy group with dutasteride (4/1623, 0.2%) or tamsulosin (10/1611, 0.6%).

In a separate 4-year placebo-controlled comparative study of dutasteride chemoprevention involving 8231 men aged 50 to 75 years with a previously negative prostate biopsy for prostate cancer 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 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 subjects 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 low-differentiated tumors.

In a 4-year placebo-controlled comparative study involving 8231 men aged 50 to 75 years with a previously negative prostate biopsy for prostate cancer and baseline 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), prostate needle biopsy (mandated by the original protocol) was performed in 6706 subjects, and data from these biopsies were used for Gleason score differentiation analysis. A total of 1517 patients were diagnosed with prostate cancer. The majority of prostate tumors (70%) detected by biopsy in both treatment groups were highly differentiated (Gleason score 5–6).

A higher incidence of low-differentiated prostate cancer (Gleason score 8–10) was recorded 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 with prostate cancer with Gleason score 8–10 was similar in the dutasteride group (n = 17, 0.5%) and the placebo group (n = 18, 0.5%). During years 3–4, a greater number of cases of prostate cancer with Gleason score 8–10 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 on the risk of developing prostate cancer in men taking dutasteride for more than 4 years. The percentage of patients diagnosed with low-differentiated prostate cancer (Gleason score 8–10) remained constant across different study periods (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 low-differentiated prostate cancer (Gleason score 8–10) was lower during years 3–4 than during years 1–2 (< 0.1% and 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 4-year clinical study of benign prostatic hyperplasia treatment (CombAT), where mandatory biopsy was not required by the original protocol and all prostate cancer diagnoses were established by indication-based biopsy, the incidence of prostate cancer with Gleason score 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 dutasteride use and the occurrence of low-differentiated prostate cancer remains unclear.

Male breast cancer.

Two case-control epidemiological studies—one conducted in the USA (n = 339 male breast cancer cases and n = 6780 in the control group) and another in the UK (n = 398 male breast cancer cases and n = 3930 in the control group)—did not show an increased risk of male breast cancer with the use of 5α-reductase inhibitors. Results from the first study showed no association with breast cancer (relative risk with ≥1 year of use prior to diagnosis of breast cancer compared to <1 year of use: 0.70; 95% CI 0.34, 1.45). In the second study, the relative risk of breast cancer associated with the use of 5α-reductase inhibitors compared to non-use was 1.08; 95% CI 0.62, 1.87.

A causal relationship between the occurrence of male breast cancer and long-term use of dutasteride has not been established.

Pharmacokinetics.

Absorption.

Following oral administration of 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.

Distribution.

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

With daily dosing of 0.5 mg, 65% of steady-state plasma concentration 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 daily 0.5 mg dosing. As in plasma, steady-state concentration in semen is 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 distribution percentage of dutasteride from plasma to semen is approximately 11.5%.

Metabolism.

Dutasteride is extensively metabolized. In vitro, dutasteride is metabolized by human cytochrome P450 CYP3A4 enzymes into two monohydroxylated metabolites. Spectrometric analysis in human plasma detects unchanged dutasteride, three major metabolites (4´-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and two minor metabolites (6,4´-dihydroxydutasteride and 15-hydroxydutasteride).

Elimination.

Following oral administration of 0.5 mg/day dutasteride, 1–15.4% (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 levels of dutasteride in plasma may be detected up to 4–6 months after discontinuation of treatment.

Special patient populations.

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 as unchanged dutasteride after administration of 0.5 mg, so 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 sections "Special precautions" and "Dosage and administration").

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to dutasteride, other 5α-reductase inhibitors, soy, peanuts, and/or any of the excipients of the medicinal product.
• Severe hepatic impairment.
• Use in women (see section "Use during pregnancy and breastfeeding").
• Use in children.

Interaction with other medicinal products and other forms of interaction.

Information regarding decreased levels of PSA in blood plasma during dutasteride use, as well as information on detection of prostate cancer, see section "Special precautions for use".

Effect of other medicinal products on the pharmacokinetics of dutasteride.

Agents that are 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 potent 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 who were concurrently treated with verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) compared to other patients.

With long-term co-administration of dutasteride and agents that are strong 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 if adverse reactions occur. It should be noted that in case of enzyme inhibition, the long half-life may become even longer, and concomitant therapy may need to continue for more than 6 months before a new steady-state concentration is achieved.

Cholestyramine.

Administration of 12 g 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.

Warfarin, digoxin.

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.

Tamsulosin, terazosin.

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 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 two 4-year clinical studies, the incidence of heart failure (a collective term for all reports, 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 who did not receive this combination. In these two studies, the incidence of heart failure was low (≤1%) and variable across the studies. There was no disproportionality in the incidence of cardiovascular adverse reactions in any of the studies. 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 ("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 concentration is an important component of the screening process for detecting prostate cancer.

Dutasteride can reduce plasma PSA levels in patients by approximately 50% on average after 6 months of treatment.

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

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

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

The ratio of free PSA to total PSA remains constant even during dutasteride treatment. Therefore, if a physician decides to use the percentage of free PSA as a diagnostic tool for prostate cancer in a patient taking this medication, no adjustment of the value is necessary.

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

Risk of prostate cancer and high-grade tumors (poorly differentiated) according to the Gleason score.

In a 4-year clinical study involving >8,000 men aged 50 to 75 years with prior negative prostate cancer biopsy results and baseline 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 prostate cancer with Gleason scores of 8–10 in the group treated with dutasteride (n = 29.09%) was higher compared to the placebo group (n = 19.06%). No increase in the incidence of prostate cancer with Gleason scores 5–6 and 7–10 was observed. A causal relationship between dutasteride use and high-grade prostate cancer has not been established. The clinical significance of the numerical disproportionality is unknown. Men taking this medication should be regularly monitored for the risk of prostate cancer, including PSA testing.

In an additional 2-year follow-up study of patients who participated in the dutasteride chemoprevention trial (the 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 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).

Risk of 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 immediately report any changes in breast tissue, such as nipple discharge or swelling, while taking this medication.

Damaged capsules.

Dutasteride is absorbed through the skin; therefore, women and children should avoid contact with damaged capsules. If the liquid from the capsule comes into contact with the skin, it should be immediately washed off 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 active metabolism of dutasteride and its 3- to 5-week elimination half-life, caution should be exercised when administering the drug to patients with mild or moderate hepatic impairment (see sections "Dosage and administration", "Contraindications", "Pharmacological properties").

Warnings regarding excipients.

The medication contains Yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

The medication is contraindicated for use in women.

Pregnancy.

Like other 5α-reductase inhibitors, dutasteride interferes with 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 subjects taking a daily dose of 0.5 mg. It is unknown whether dutasteride transferred to a woman's body via semen from a treated male partner affects a male fetus (this risk is highest during the first 16 weeks of pregnancy).

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

Breastfeeding period.

It is unknown whether dutasteride passes into breast milk.

Fertility.

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

Ability to influence reaction speed when driving vehicles or operating machinery.

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

Dosage and Administration

The medicinal product is intended for oral administration.

The capsule should be swallowed whole and must not be opened or chewed, as contact with the capsule contents may cause irritation of the mucous membranes of the mouth and pharynx. The drug can be taken regardless of food intake.

The medicinal product can be used as monotherapy or in combination with the alpha-blocker tamsulosin (0.4 mg).

Adult men (including elderly patients).

The recommended dose is 0.5 mg (1 capsule) once daily.

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

Patients with renal impairment.

The pharmacokinetics of dutasteride in patients with renal impairment have not been studied. Therefore, the medicinal product should be used with caution in patients with severe renal impairment.

Patients with hepatic impairment.

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

Children.

The medicinal product is contraindicated in children.

Overdose.

Clinical trial data indicate that single doses of dutasteride up to 40 mg/day (80 times higher than the therapeutic dose) administered for 7 days did not cause safety concerns in healthy volunteers. In clinical studies, dutasteride administered at a dose of 5 mg/day for 6 months did not result in additional adverse reactions compared to the 0.5 mg/day dose.

There is no specific antidote. In the event of suspected overdose, symptomatic and supportive therapy should be administered.

Adverse reactions.

Monotherapy with dutasteride.

Adverse reactions occurred in approximately 19% of patients receiving dutasteride during the first year of treatment in two-year, placebo-controlled Phase III studies. Most of the adverse reactions observed were mild to 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 listed below, observed during clinical trials and considered by investigators to be drug-related (with a frequency ≥1%), 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 (≥ 1/10,000 to 1/1,000), 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 listed adverse reactions may persist after discontinuation of treatment. The role of dutasteride in this persistence is unknown.

^ Includes decreased semen volume.

• Includes breast tenderness and enlargement.

Combination therapy with the alpha-blocker tamsulosin.

Data from the 4-year CombAT study, which compared the administration of dutasteride 0.5 mg and tamsulosin 0.4 mg once daily as monotherapies and in combination, 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 following adverse reactions considered by investigators to be drug-related were reported at an incidence ≥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 the results of this study were influenced by reduced prostate volume or other factors related to dutasteride use.

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

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

3 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

10 capsules in a blister; 3 blisters in a cardboard box, or 30 capsules in a bottle; 1 bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

UORLД MEDICIN ILAC SAN. VE TIC. A.S. /
WORLD MEDICINE ILAC SAN. VE TIC. A.S.

Manufacturer's address and location of operations.

15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine.