Prostid

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

Composition:

Active substance: dutasteride;

1 soft capsule contains 0.5 mg of dutasteride;

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

Pharmaceutical form. Soft capsules.

Main physicochemical characteristics: 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 G04CB02.

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 the hyperplasia of prostate tissue. Maximal reduction of dihydrotestosterone during Prostide treatment is dose-dependent and occurs within the first 1–2 weeks. After the first and second weeks of Prostide administration at a daily dose of 0.5 mg, 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.

Pharmacokinetics

Dutasteride is administered orally in the form of soft gelatin capsules. After a single 0.5 mg dose, peak 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 (300–500 L). The extent of plasma protein binding exceeds 99.5%.

When administered at a daily dose of 0.5 mg, 65% of the steady-state concentration of dutasteride in blood serum is achieved within 1 month of treatment and approximately 90% within 3 months. A steady-state concentration of approximately 40 ng/mL in blood serum is reached after 6 months of treatment at a daily dose of 0.5 mg. As in blood serum, steady-state concentration of dutasteride 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 percentage distribution of dutasteride from blood serum 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 of human serum 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/day, between 1% and 15.4% (mean 5.4%) of the administered dose is excreted in feces as unchanged dutasteride. The remainder of the administered dose is excreted as metabolites.

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

Based on pharmacokinetic and pharmacodynamic studies, dose adjustment of dutasteride 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, so 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 "Dosage and Administration" and "Special Warnings and Precautions").

Safety and Clinical Studies

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) 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 four-year placebo-controlled clinical trial of dutasteride for chemoprevention in 8231 men aged 50 to 75 years with a prior 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 3.0 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 who received dutasteride and an alpha-blocker concurrently (12/1152, 1.0%) compared to subjects who received 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 Warnings and 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 baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL in men aged 50 to 60 years or between 3.0 ng/mL and 10.0 ng/mL in men aged 60 years and older (REDUCE study), 6706 subjects underwent prostate needle biopsy (mandatory per 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. Most prostate tumors (70%) detected by biopsy in both treatment groups were well-differentiated (Gleason score 5–6).

The dutasteride group showed a higher incidence (n=29, 0.9%) of high-grade prostate cancer (Gleason score 8–10) 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 on prostate cancer risk in men taking dutasteride for more than 4 years. The percentage of patients diagnosed with Gleason score 8–10 prostate cancer remained constant over 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 high-grade prostate cancer (Gleason score 8–10) was lower in years 3–4 than in years 1–2 (<0.1% and 0.5%, respectively) (see section "Special Warnings and Precautions"). There was no difference in the incidence of prostate cancer with Gleason score 7–10 (p=0.81).

In a four-year clinical study of benign prostatic hyperplasia treatment (CombAT study), in which mandatory biopsy was not required by the original protocol and all prostate cancer diagnoses were biopsy-confirmed based on 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 USA (n=339 breast cancer cases and n=6780 controls) and the other in the UK (n=398 breast cancer cases and n=3930 controls)—did not show an increased risk of male breast cancer with the use of 5α-reductase inhibitors. The first study found no association with breast cancer (relative risk for use ≥1 year before breast cancer diagnosis compared to use <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 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 of the risk of acute urinary retention and the need for surgical intervention in patients with symptoms of moderate to severe benign prostatic hyperplasia.

Contraindications.

Dutasteride is contraindicated in patients with hypersensitivity to dutasteride, other 5α-reductase inhibitors, soy, peanuts, or any component of the product.

Dutasteride should not be used for treatment of women and children (see section "Use in pregnancy or lactation").

Dutasteride is contraindicated in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Information on the reduction of serum PSA (prostate-specific antigen) levels during treatment with dutasteride, 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

Use in combination with CYP3A4 and/or P-glycoprotein inhibitors

Dutasteride is primarily eliminated by metabolism. *In vitro* studies show that metabolism is catalyzed by CYP3A4 and CYP3A5. Formal interaction studies with potent 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, oral itraconazole, ketoconazole), serum concentrations of dutasteride may increase. Further inhibition of 5α-reductase due to prolonged action of dutasteride is unlikely. However, reduction in the frequency of dutasteride dosing may be considered if adverse effects develop. It should be noted that if enzyme activity is suppressed for a prolonged period, 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.

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* study data 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) had no effect on 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 for increased risk of adverse reactions (including heart failure) and after consideration of alternative treatment options, including monotherapy (see section "Dosage and administration").

Cardiovascular adverse reactions

According to data from four-year clinical studies, 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 studies, the incidence of heart failure was low (≤1%) and variable across the studies. There was no imbalance in the incidence of cardiovascular adverse events 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 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)

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

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

Patients taking dutasteride 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 dutasteride treatment may indicate the presence of prostate cancer or non-compliance with dutasteride therapy and requires careful evaluation, even if PSA levels are within the normal range for men not treated with 5α-reductase inhibitors. When interpreting PSA levels in patients treated with dutasteride, previous PSA values should be considered for comparison.

Serum total PSA levels return to baseline within 6 months after discontinuation of treatment.

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

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

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

In a four-year clinical study involving >8000 men aged 50 to 75 years with prior negative prostate biopsy results for prostate cancer and initial PSA levels between 2.5 ng/mL and 10.0 ng/mL (REDUCE study), prostate cancer was diagnosed in 1517 patients. The incidence of high-grade prostate cancer (Gleason score 8–10) was higher in the group treated with dutasteride (n=29, 0.9%) compared to the placebo group (n=19, 0.6%). No increase in the incidence of prostate cancer with Gleason scores 5–6 or 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 imbalance is unknown. Men receiving dutasteride 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), 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 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 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 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 3- to 5-week elimination half-life, dutasteride treatment in patients with mild to moderate hepatic impairment should be used with caution (see sections "Dosage and administration", "Contraindications", "Pharmacological properties").

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. Small amounts of dutasteride have been detected in the semen of subjects taking 0.5 mg dutasteride daily. It is unknown whether dutasteride transferred to a woman 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.

Use during breastfeeding

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 rate when driving or operating machinery.

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

Method of Administration and Dosage

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

Adults (including elderly patients)

The recommended dose of Prostid is 1 capsule (0.5 mg) daily for oral administration. The capsule should be swallowed whole, without opening or chewing, as contact with the capsule contents may cause irritation of the mucous membranes of the mouth and throat.

Prostid can be taken regardless 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.

Renal Impairment

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

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. Prostid is contraindicated in patients with severe hepatic impairment.

Children

Use is contraindicated.

Overdose

According to clinical study data, single doses of dutasteride up to 40 mg/day (80 times higher than therapeutic doses) administered for 7 days did not raise safety concerns in healthy volunteers. During clinical trials, doses of dutasteride up to 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; therefore, in the event of a possible 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 during the first year of the two-year, placebo-controlled Phase III studies. Most of the observed adverse events 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 event profile were observed.

Table 1 lists adverse reactions identified during controlled clinical trials. The adverse events listed were those identified during clinical trials that, in the opinion of the investigators, were related to drug exposure (with a frequency ≥1%) and occurred more frequently in patients receiving 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 the available data).

Table 1

*Adverse events related to the reproductive system 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.

Prostate in combination with the alpha-blocker tamsulosin

Data from the four-year CombAT study, which compared 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 events during the first, second, third, and fourth years of treatment was 22%, 6%, 4%, and 2%, respectively, in the combination therapy group (dutasteride/tamsulosin); 15%, 6%, 3%, and 2% in the dutasteride monotherapy group; and 13%, 5%, 2%, and 2% in the tamsulosin monotherapy group. 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 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 sexual system adverse reactions listed 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 prostate volume reduction or other factors related to dutasteride use. Cases of male breast cancer have been reported (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through 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 category. Prescription only.

Manufacturer. Olive Healthcare.

Manufacturer's address and location of operations.

Unit-II, Plot No. 163/2, Mahatma Gandhi Udhyog Nagar, Dabhil Village, Nani Daman, Daman - 396 210, India.