Zoiprost

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

Composition:

Active substance: dutasteride;

1 soft capsule contains 0.5 mg of dutasteride;

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

Pharmaceutical form. Soft capsules.

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

Pharmacotherapeutic group. Drugs used in benign prostatic hyperplasia. Inhibitors of testosterone 5α-reductase. ATC code G04C B02.

Pharmacological Properties.

Pharmacodynamics.

Dutasteride is a dual inhibitor of 5α-reductase that inhibits 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. The maximum reduction of dihydrotestosterone during treatment with the medicinal product Zoiprost is dose-dependent and occurs within the first 1–2 weeks. After 1 and 2 weeks of treatment with Zoiprost at a daily dose of 0.5 mg, the mean concentration of dihydrotestosterone 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 as 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 (300–500 L). Protein binding exceeds 99.5%.

With a daily dose of 0.5 mg, 65% of the 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 mean concentration of dutasteride in semen is 3.4 ng/mL (range: 0.4–14 ng/mL). The distribution ratio of dutasteride from plasma to semen is approximately 11.5%.

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

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 found 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 treatment cessation.

According to pharmacokinetic and pharmacodynamic studies, dosage adjustment of dutasteride based on 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 a 0.5 mg dose of dutasteride; therefore, dosage 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 Warnings and Precautions for Use" and "Dosage and Administration").

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 receiving dutasteride (4/1623, 0.2%) or tamsulosin (10/1611, 0.6%).

In a separate four-year placebo-controlled clinical trial of dutasteride chemoprevention 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 50–60 years or between 3.0 ng/mL and 10.0 ng/mL in men aged ≥60 years (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 alpha-blocker concurrently (12/1152, 1.0%) compared to those taking 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 for Use").

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 50–60 years or between 3.0 ng/mL and 10.0 ng/mL in men aged ≥60 years (REDUCE study), 6706 patients underwent prostate needle biopsy (mandatory per the original protocol), and data from these biopsies were used for Gleason score grading. 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 on prostate cancer risk in men treated with dutasteride for more than 4 years. The percentage of patients diagnosed with Gleason score 8–10 prostate cancer remained constant across study periods (years 1–2 and 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% vs. 0.5%, respectively) (see section "Special Warnings and Precautions for Use"). There was no difference in the incidence of Gleason score 7–10 prostate cancer (p = 0.81).

In a four-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 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 cases of male breast cancer and n = 6780 controls) and another in the UK (n = 398 cases of male breast cancer and n = 3930 controls)—did not show an increased risk of male breast cancer associated with the use of 5α-reductase inhibitors. The first study found no association with breast cancer (relative risk for use ≥1 year before 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 male breast cancer cases 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.

The medicinal product Zoiprost is contraindicated in patients with hypersensitivity to dutasteride, other 5α-reductase inhibitors, soy, peanuts, or any other component 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 regarding the reduction in serum PSA (prostate-specific antigen) levels 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 primarily eliminated via metabolism. In vitro studies show that CYP3A4 and CYP3A5 are responsible for its metabolism. Formal interaction studies with potent CYP3A4 inhibitors have not been conducted. However, in a population pharmacokinetic study, serum dutasteride concentrations 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, combination of dutasteride with medicinal products that are potent inhibitors of CYP3A4 enzyme (e.g., ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally) may increase dutasteride serum concentrations. 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 enzyme inhibition, the long half-life of dutasteride 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 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 suggests 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 male subjects, 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 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 among patients treated with a combination of dutasteride and an alpha-blocker, mainly tamsulosin, compared to patients not receiving this combination. However, in these two studies, the incidence of heart failure was low (≤1%) and variable across the studies. No imbalance in the frequency of cardiovascular adverse reactions was observed in any of the studies. 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). 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 observed.

Effect on prostate-specific antigen (PSA)

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

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

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

The use of Zoiprost 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 unchanged during treatment with Zoiprost. Therefore, if a physician decides to use the percentage of free PSA as a diagnostic tool for prostate cancer in a patient taking Zoiprost, no adjustment of the value is necessary.

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

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

In a four-year clinical trial involving over 8,000 men aged 50 to 75 years with prior negative prostate biopsy and initial PSA levels between 2.5 ng/mL and 10.0 ng/mL (REDUCE study), prostate cancer was diagnosed in 1,517 men. The incidence of high-grade prostate cancer (Gleason score 8–10) was higher in the group receiving Zoiprost (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 the use of Zoiprost and high-grade prostate cancer has not been established. The clinical significance of this numerical imbalance is unknown. Men taking Zoiprost should undergo regular monitoring 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 long elimination half-life (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").

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 patients 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 to use condoms 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 human breast milk.

Fertility

Cases of altered semen parameters (reduced sperm count, ejaculate volume, and sperm motility) have been reported in healthy men taking dutasteride. A potential 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.

Dosage and Administration

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

Adult men (including elderly patients)

The recommended dose of Zoiprost is 1 capsule (0.5 mg) 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 pharynx.

Zoiprost can 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.

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 studies have shown 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 healthy volunteers. During clinical trials, administration of 5 mg of dutasteride daily for 6 months did not result in additional adverse reactions compared to 0.5 mg daily.

There is no specific antidote; therefore, in case 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. The majority of 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 new changes in the adverse reaction profile were observed.

Table 1 lists adverse reactions identified during controlled clinical trials. The adverse reactions listed below were those reported during clinical trials, considered by investigators to be drug-related (with an incidence ≥1%), and observed 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 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). These 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.

Zoiprost 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 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 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, cardiorespiratory failure, and congestive cardiomyopathy.

c The sexual 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 trial 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 trial 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").

Reporting of adverse reactions after drug registration is important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy to the Automated Information System for Pharmacovigilance 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 per blister; 3 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer. Olive Healthcare.

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