Dustarin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DUSTARIN® (DUSTARIN)

Composition:

Active substance: dutasteride;

1 capsule contains 0.5 mg of dutasteride;

Excipients: butylhydroxytoluene (E 321); glycerol monocaprylocaprate (type I);

Capsule shell: gelatin; glycerin; titanium dioxide (E 171); yellow iron oxide (E 172); purified water.

Pharmaceutical form. Soft capsules.

Main physicochemical properties: soft gelatin capsules of elongated shape, light yellow in color, size 7.

Pharmacotherapeutic group. Agents 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, 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 during dutasteride treatment is dose-dependent and occurs within the first 1–2 weeks. After the 1st and 2nd week of dutasteride 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 dutasteridе 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 a solution in 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 dosing, dutasteride has a large volume of distribution (300–500 L). Plasma protein binding exceeds 99.5%.

With a daily dose of 0.5 mg, 65% of steady-state plasma concentration of dutasteride is achieved within 1 month of treatment and approximately 90% within 3 months. A steady-state plasma concentration of approximately 40 ng/mL is reached after 6 months of treatment at 0.5 mg daily. As in plasma, steady-state concentration in semen is also 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 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 of human plasma has detected 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 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 levels of dutasteride in plasma may be detected up to 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 urine after administration of 0.5 mg of dutasteride in humans; therefore, 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 "Special Warnings and Precautions for Use" and "Dosage and Administration").

Safety and Clinical Studies.

Heart Failure

Reports exist of a study evaluating the use of dutasteride in combination with tamsulosin for the treatment of benign prostatic hyperplasia. The incidence of heart failure (a composite term) was higher in the combination therapy group than in either monotherapy group receiving dutasteride or tamsulosin alone.

In a placebo-controlled chemoprevention trial involving 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 ng/mL and 10 ng/mL in men aged 60 years and older, a higher incidence of heart failure was observed in patients receiving dutasteride 0.5 mg once daily compared to those receiving placebo. A retrospective analysis of this study showed a higher incidence of heart failure in patients who received dutasteride and an alpha-blocker concurrently compared to subjects who received dutasteride without an alpha-blocker, placebo with an alpha-blocker, or placebo without an alpha-blocker. 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 "Special Warnings and Precautions for Use").

Prostate Cancer and High-Grade Tumors

A placebo-controlled trial comparing dutasteride in men aged 50 to 75 years with prior negative prostate biopsy for prostate cancer and baseline PSA levels between 2.5 ng/mL and 10 ng/mL in men aged 50 to 60 years or between 3 ng/mL and 10 ng/mL in men aged 60 years and older has been reported. Mandatory core prostate biopsies were performed in study subjects according to the initial protocol, and histopathological data were analyzed using the Gleason scoring system. Patients diagnosed with prostate cancer were identified during the study. Most prostate tumors (70%) detected by biopsy in both treatment groups were well-differentiated (Gleason score 5–6).

A higher incidence of poorly differentiated 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, a greater number of 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 across 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 poorly differentiated prostate cancer (Gleason score 8–10) was lower during years 3–4 than during 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 (p = 0.81).

In a study of benign prostatic hyperplasia treatment where mandatory biopsy was not required by the primary protocol and all prostate cancer diagnoses were established by biopsy on clinical indication, the incidence of Gleason score 8–10 prostate cancer 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 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 another in the United Kingdom (n = 398 cases of 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% CI: 0.34, 1.45). The second study reported a relative risk of breast cancer associated with 5α-reductase inhibitor use compared to non-use of 1.08 (95% CI: 0.62, 1.87).

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

Clinical characteristics.

Indications.

Treatment of symptoms of moderate to severe benign prostatic hyperplasia; reduction of the risk of developing 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, or to any component of the formulation.

Dutasteride must not be used for treatment of women and children (see sections «Use during pregnancy or breastfeeding», «Pediatric use»).

Dutasteride is contraindicated in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Information regarding 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.

Concomitant use with CYP3A4 and/or P-glycoprotein inhibitors

Dutasteride is primarily eliminated by 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 concentrations of dutasteride were on average 1.6–1.8 times higher in a small number of patients who were concurrently receiving verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) 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, orally administered ketoconazole), 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 in case of adverse effects. It should be noted that 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 of cholestyramine one hour after a single 5 mg dose of dutasteride did not affect the pharmacokinetics of dutasteride.

Effect of dutasteride on the pharmacokinetics of other medicinal products.

Dutasteride does not affect the pharmacokinetics of warfarin or digoxin. This indicates that dutasteride does not inhibit or induce the activity of the CYP2C9 enzyme or the P-glycoprotein transporter. In vitro interaction studies data indicate that dutasteride does not inhibit the enzymes CYP1A2, CYP2D6, CYP2C9, CYP2C19, or CYP3A4.

In a small two-week study (N=24) involving healthy males, 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 considering alternative treatment options, including monotherapy (see section "Dosage and administration").

Cardiovascular adverse reactions

An increased incidence of heart failure (a collective term for all reported events, primarily primary heart failure and congestive heart failure) has been observed in patients treated with a combination of dutasteride and an alpha-blocker, mainly tamsulosin, compared to patients not receiving this combination. According to study data, the incidence of heart failure was low (≤1%) and variable across these studies. No imbalance in the incidence of cardiovascular adverse events has been 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.

Effect on prostate-specific antigen (PSA)

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

Dustarin® is capable of reducing serum PSA levels by approximately 50% on average within 6 months of treatment.

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

The use of the drug does not affect the utility of PSA levels for diagnosing prostate cancer once a new baseline level has been established.

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

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

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

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

A study involving 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 has been reported. Prostate cancer was diagnosed in 1517 patients. The incidence of prostate cancer with Gleason scores of 8–10 was higher in the group treated with dutasteride (n = 29.09%) compared to the placebo group (n = 19.06%). No increase in the incidence of Gleason score 5–6 or 7–10 prostate cancer was observed. A causal relationship between dutasteride use and high-grade prostate cancer has not been established. The clinical significance of this numerical imbalance is unknown. Men receiving Dustarin® should be regularly monitored for the risk of prostate cancer, including PSA testing.

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 the use of 5α-reductase inhibitors. Patients should promptly report any changes in breast tissue, such as nipple discharge or lumps.

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 immediately washed 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, caution should be exercised when treating patients with mild to moderate hepatic impairment (see sections "Pharmacological properties", "Contraindications", "Dosage and administration").

Use during pregnancy or breastfeeding.

Dutasteride is contraindicated for use in women.

Pregnancy. Like other 5α-reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone, which may impair the development of external genitalia in male fetuses. Small amounts of dutasteride have been detected in the semen of subjects taking 0.5 mg dutasteride daily. It is unknown whether dutasteride transferred to a woman via semen from a man being treated with dutasteride 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 may potentially become pregnant, to prevent semen exposure to the woman.

Breastfeeding. It is unknown whether dutasteride is excreted in human 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 affect reaction speed when driving or operating machinery.

Given the pharmacokinetic and pharmacodynamic properties, dutasteride does not affect the ability to drive or operate machinery.

Method of Administration and Dosage

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

Adult men (including elderly patients)

The recommended dose of Dustrarin® is 1 capsule (0.5 mg) daily, taken orally. The capsule should be swallowed whole and not opened or chewed, as contact with the capsule contents may cause irritation of the mucous membranes of the mouth and throat.

Dustrarin® can be taken independently of food intake.

Although symptom improvement may be observed early in 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 is advised 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 using in patients with mild to moderate hepatic impairment.

Dustrarin® is contraindicated in patients with severe hepatic impairment.

Children.

Use is contraindicated.

Overdose.

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. Administration of dutasteride 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; therefore, in the event of suspected overdose, symptomatic and supportive therapy should be administered.

Adverse Reactions

Dustarim® Monotherapy

Available data indicate that approximately 19% of 2167 patients receiving dutasteride in two-year studies experienced adverse reactions during the first year of treatment. Most of the observed adverse events were mild or moderate in severity and involved the reproductive system. No changes in the adverse event profile were observed during the subsequent two years in open-label extension studies.

The following table lists adverse reactions identified during clinical trials and in the post-marketing period. The adverse reactions observed during clinical trials, which in the opinion of investigators were related to drug administration (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 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

* Adverse events related to the male 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 volume of semen.

• Includes breast tenderness and enlargement.

Duodart® in combination with the alpha-blocker tamsulosin

Data from a 4-year study comparing daily administration of dutasteride 0.5 mg (n = 1,623) and tamsulosin 0.4 mg (n = 1,611) as monotherapy and in combination (n = 1,610) showed that the incidence of drug-related adverse events 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 events 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 study, the adverse reactions listed below, considered by investigators to be related to drug exposure, were reported at an incidence of ≥1%. The incidence of these reactions over four years of treatment is summarized in the table below:

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

A study showed a higher incidence of prostate cancer with Gleason score 8–10 in men receiving dutasteride compared to placebo. It is unknown whether reduced prostate volume or other factors related to dutasteride use influenced the study outcomes.

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

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 pack.

Prescription status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT" (manufactured from bulk product produced by HAP S.A., Greece).

Manufacturer's address and location of its business activity.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua