Prostaar

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

Composition:

Active substance: dutasteride;

1 soft capsule contains dutasteride 0.5 mg;

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

Pharmaceutical form. Soft capsules.

Main physico-chemical 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, inhibiting both type 1 and type 2 isoenzymes of 5α-reductase responsible for the conversion of testosterone into 5α-dihydrotestosterone. Dihydrotestosterone is an androgen primarily responsible for the hyperplasia of prostate tissue. The maximum reduction in dihydrotestosterone levels during treatment with the medicinal product ProstAAR is dose-dependent and occurs within the first 1–2 weeks. After 1 and 2 weeks of treatment with ProstAAR 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.

Pharmacokinetics.

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

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

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

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

Spectrometric analysis of 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 unchanged in feces. 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 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.

Based on pharmacokinetic and pharmacodynamic studies, dosage 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, since less than 0.1% of the dose is excreted in human urine after administration of 0.5 mg dutasteride, 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 trial evaluating 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 involving 8231 men aged 50 to 75 years with a prior negative prostate cancer biopsy 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 receiving dutasteride and an alpha-blocker concurrently (12/1152, 1.0%) compared to those receiving dutasteride without an alpha-blocker (18/2953, 0.6%), placebo with an alpha-blocker (1/1399, <0.1%), or placebo without an alpha-blocker (15/2727, 0.6%). A causal relationship between dutasteride use (alone or in combination with alpha-blockers) and the development 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 cancer biopsy 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 (mandated by the original protocol), and data were analyzed using the Gleason scoring system. A total of 1517 patients were diagnosed with prostate cancer during the study. The majority of prostate tumors detected by biopsy in both treatment groups were well-differentiated (70%, 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%). However, during years 3–4, more cases of Gleason score 8–10 prostate cancer were diagnosed in the dutasteride group (n = 12, 0.5%) compared to the placebo group (n = 1, <0.1%) (p = 0.0035). There are no data on the effect of dutasteride use beyond 4 years on the risk of developing prostate cancer. The percentage of patients diagnosed with Gleason score 8–10 prostate cancer remained constant over time in the dutasteride group (0.5% in both periods), whereas in the placebo group, the percentage of patients with high-grade prostate cancer (Gleason score 8–10) was lower in years 3–4 compared to 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 prostate cancer with Gleason score 7–10 between groups (p = 0.81).

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

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

Breast Cancer in Men

Two case-control epidemiological studies—one conducted in the United States (n = 339 cases of male breast cancer and n = 6780 controls) and the other in the United Kingdom (n = 398 cases 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 in the risk of acute urinary retention and the need for surgical intervention in patients with symptoms of moderate to severe benign prostatic hyperplasia.

Contraindications.

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

It must not be used 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 prostate-specific antigen (PSA) 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

Concomitant use with CYP3A4 and/or P-glycoprotein inhibitors

Dutasteride is primarily eliminated via metabolism. In vitro studies indicate 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 of dutasteride in combination with medicinal products that are potent inhibitors of the CYP3A4 enzyme (e.g., ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally), serum concentrations of dutasteride may increase. Further inhibition of 5α-reductase due to prolonged action of dutasteride is unlikely. However, dose reduction of dutasteride may be considered if adverse reactions occur. In case of prolonged enzyme inhibition, the 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 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 suggests that dutasteride does not inhibit or induce the activity of the CYP2C9 enzyme or the P-glycoprotein transporter. In vitro interaction studies indicate that dutasteride does not inhibit the CYP1A2, CYP2D6, CYP2C9, CYP2C19, or CYP3A4 enzymes.

In a small (n = 24), two-week study in healthy men, dutasteride (0.5 mg daily) did not affect the pharmacokinetics of tamsulosin or terazosin. No evidence of pharmacodynamic interaction was observed in this study.

Special precautions for use.

Combination therapy may be prescribed 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 among 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 (see section "Pharmacological properties").

A meta-analysis of 12 randomized, placebo-controlled or comparative clinical trials (n = 18,802) was conducted to evaluate the risk of cardiovascular adverse reactions with dutasteride use (compared to the control group). There was no consistent statistically significant increase in the risk of heart failure (RR 1.05; 95% CI 0.71–1.57), acute myocardial infarction (RR 1.00; 95% CI 0.77–1.30), or stroke (RR 1.20; 95% CI 0.88–1.64).

Effect on prostate-specific antigen (PSA)

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

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

Patients taking the medicinal product ProstAAР should have a new baseline PSA level established 6 months after starting this medicinal product. This level should then be monitored regularly. Any confirmed increase in PSA level from the lowest level during treatment with ProstAAР may indicate the presence of prostate cancer or non-adherence to the ProstAAР regimen 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 taking ProstAAР, previous PSA values should be considered for comparison.

The use of ProstAAР 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 even during treatment with ProstAAР. Therefore, if a physician decides to use the percentage of free PSA as an indicator for prostate cancer in a patient taking ProstAAР, no adjustment of the value is required.

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

Prostate cancer and high-grade Gleason 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 baseline 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 prostate cancer with Gleason scores 8–10 was higher in the group receiving ProstAAР (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 ProstAAР and higher-grade prostate cancer has not been established. The clinical significance of the numerical disproportionality is unknown. Men taking ProstAAР should be regularly monitored for the risk of prostate cancer, including PSA testing.

In an additional two-year follow-up study of patients who participated in 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 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 0.8–1.20).

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 3–5 week elimination half-life, dutasteride treatment in patients with mild or moderate hepatic impairment should be used with caution (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 dutasteride daily. It is unknown whether dutasteride transferred to a woman via semen from a treated man affects a male fetus (this risk is highest during the first 16 weeks of pregnancy).

As with other 5α-reductase inhibitors, the use of condoms is recommended if the patient's partner is pregnant or potentially could become pregnant, to prevent 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 parameters (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 affect 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 ProstAAR can be prescribed alone or in combination with the alpha-blocker tamsulosin (0.4 mg).

Adult men (including elderly patients)

The recommended dose of the medicinal product ProstAAR is 1 capsule (0.5 mg) daily for oral administration. The capsule should be swallowed whole and not opened or chewed, as contact with the capsule contents may irritate the mucous membranes of the mouth and pharynx.

The medicinal product ProstAAR can be taken independently of food intake.

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

Renal impairment

The pharmacokinetics of dutasteride in patients with renal impairment have not been studied; therefore, ProstAAR should be prescribed with caution in patients with severe renal impairment.

Hepatic impairment

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

Children

Use is contraindicated.

Overdose

According to clinical trial data, 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. In clinical trials, doses of dutasteride up to 5 mg daily administered for 6 months did not result in additional adverse reactions compared to 0.5 mg daily.

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

Adverse Reactions

Dutasteride monotherapy

Adverse reactions occurred in approximately 19% of 2167 patients treated with dutasteride during the first year of two-year, placebo-controlled Phase III 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. The adverse reactions listed were those identified during clinical trials considered by investigators to be drug-related (with a frequency ≥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

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

^ Includes decreased volume of semen.

• Includes breast tenderness and enlargement.

The medicinal product ProstAAr 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 separately and in combination (n = 1,610), showed that the incidence of drug-related adverse reactions 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 adverse reactions listed below, considered by investigators to be related to drug administration, were reported at an incidence of ≥1%; the incidence of these reactions over four years of treatment is presented in Table 2.

Table 2

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

b The general term "Heart failure" includes congestive heart failure, heart failure, left ventricular failure, acute heart failure, cardiogenic shock, acute left ventricular failure, right ventricular failure, acute right ventricular failure, ventricular failure, cardiopulmonary insufficiency, 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 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 reductions in prostate volume or other factors related to dutasteride use. Cases of male breast cancer have been reported (see section "Special precautions for use").

Reporting of adverse reactions following marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all suspected adverse reactions and lack of efficacy to the Automated Information System for Pharmacovigilance via the 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 and sight of children.

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

Prescription status. Prescription only.

Manufacturer. Olive Healthcare.

Manufacturer's address and location of operations.

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