Dustarin capsules 0.5 mg No. 30

Instructions for Dustarin capsules 0.5 mg No. 30

Composition

active ingredient: dutasteride;

1 capsule contains dutasteride 0.5 mg;

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

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

Dosage form

Soft capsules.

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

Pharmacotherapeutic group

Drugs used in benign prostatic hyperplasia. Testosterone-5a-reductase inhibitors. ATC code G04C B02.

Pharmacological properties

Pharmacodynamics

Dutasteride is a dual 5α-reductase inhibitor that inhibits both type 1 and type 2 5α-reductase isoenzymes, which are responsible for the conversion of testosterone to 5α-dihydrotestosterone. Dihydrotestosterone is an androgen that is primarily responsible for prostatic hyperplasia. The maximum reduction in dihydrotestosterone with dutasteride is dose-dependent and occurs in the first 1–2 weeks. After the 1st and 2nd weeks of dutasteride at a daily dose of 0.5 mg, the average concentration of dihydrotestosterone decreases by 85 and 90%, respectively.

In patients with benign prostatic hyperplasia who received 0.5 mg of dutasteride per day, the average decrease in dihydrotestosterone levels was 94% after 1 year and 93% after 2 years of treatment, and the average testosterone level increased by 19% after 1 and 2 years.

Pharmacokinetics

Dutasteride is administered orally as a solution in soft gelatin capsules. After a single dose of 0.5 mg, peak serum concentrations are observed 1–3 hours later. Absolute bioavailability is 60%. Bioavailability is independent of food intake.

Dutasteride has a large volume of distribution (300 to 500 L) after single or multiple doses. The percentage of binding to blood proteins is over 99.5%.

When used in a daily dose of 0.5 mg, 65% of the constant steady-state concentration of dutasteride in the blood serum is achieved after 1 month of treatment and approximately 90% - after 3 months. A stable concentration of dutasteride of approximately 40 ng/ml in the blood serum is achieved after 6 months of use in a daily dose of 0.5 mg. As in the blood serum, a steady-state concentration of dutasteride in the seminal fluid is achieved after 6 months. After 52 weeks of treatment, the average concentration of dutasteride in the seminal fluid is 3.4 ng/ml (range 0.4-14 ng/ml). The percentage of distribution of dutasteride from the blood serum to the seminal fluid is approximately 11.5%.

In vitro, dutasteride is metabolized by human cytochrome P450 enzymes CYP3A4 to two monohydroxyl metabolites.

According to spectrometric analysis, unchanged dutasteride, 3 major metabolites (4´-hydroxydutasteride, 1,2-dihydrodutasteride and 6-hydroxydutasteride) and 2 minor metabolites (6,4´-dihydroxydutasteride and 15-hydroxydutasteride) are detected in human serum.

Dutasteride is extensively metabolized. After oral administration of dutasteride at a dose of 0.5 mg/day, 1 to 15.4% (average 5.4%) of the administered dose is excreted in the feces as unchanged dutasteride. The remainder of the administered dose is excreted as metabolites.

Only traces of unchanged dutasteride are found in the urine (less than 0.1% of the administered dose). The terminal half-life of dutasteride is 3–5 weeks. Residues of dutasteride can be detected in the serum 4–6 months after the end of treatment.

Based on pharmacokinetic and pharmacodynamic studies, it is not necessary to adjust the dose of dutasteride based on the patient's age.

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 the urine of a 0.5 mg dose of dutasteride in humans, and therefore no dose adjustment is necessary in patients with renal impairment.

The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied (see sections 4.4 and 4.2).

Safety and clinical studies

Heart failure

A study of dutasteride in combination with tamsulosin for the treatment of benign prostatic hyperplasia has been reported. The incidence of heart failure (combined event) in the combination therapy group was higher than in either dutasteride or tamsulosin monotherapy group.

3 ng/mL and 10 ng/mL in men aged 60 years and older, the incidence of heart failure was found to be higher in patients taking dutasteride 0.5 mg once daily compared to patients taking placebo. A retrospective analysis of this study showed a higher incidence of heart failure in patients taking dutasteride and an alpha-blocker concomitantly compared to subjects taking dutasteride without an alpha-blocker, placebo and 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 occurrence of heart failure has not been established (see section "Special instructions").

Prostate cancer and poorly differentiated tumors

A study comparing placebo and dutasteride was reported in men aged 50 to 75 years with a previous negative biopsy result for prostate cancer and a baseline PSA between 2.5 ng/mL and 10 ng/mL in men aged 50 to 60 years or 3 ng/mL and 10 ng/mL in men aged 60 years or older. Subjects underwent a core needle biopsy of the prostate (mandatory in the original protocol) and the data were used to analyze the Gleason score. The study identified patients with a diagnosis of prostate cancer. The majority of prostate tumors (70%) detected by biopsy in both treatment groups were highly differentiated (Gleason score 5–6).

A higher incidence (n = 29, 0.9%) of poorly differentiated prostate cancer (Gleason score 8–10) was observed in the dutasteride group compared to the placebo group (n = 19, 0.6%) (p = 0.15). During years 1–2 of the study, the number of patients with prostate cancer with Gleason score 8–10 was similar in the dutasteride group (n = 17, 0.5%) and the placebo group (n = 18, 0.5%). During years 3–4 of the study, a higher incidence of prostate cancer with Gleason score 8–10 was observed in the dutasteride group (n = 17, 0.5%).

Gleason score 8-10 was diagnosed in the dutasteride group (n = 12, 0.5%) compared to the placebo group (n = 1, < 0.1%) (p = 0.0035). There is no evidence of an effect on the risk of developing prostate cancer in men taking dutasteride for more than 4 years. The percentage of patients diagnosed with prostate cancer with a differentiation of Gleason score 8-10 remained constant across the different study periods (years 1-2, years 3-4) in the dutasteride group (0.5% in each time 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% and 0.5%, respectively) (see section 4.4). There was no difference in the incidence of prostate cancer with a differentiation of 7–10 points on the Gleason scale (p = 0.81).

As found in the study of the treatment of benign prostatic hyperplasia, where the primary protocol did not require mandatory biopsy and all prostate cancer diagnoses were established on biopsy as indicated, the incidence of prostate cancer with a differentiation of Gleason score 8–10 was 0.5% (n = 8) in the dutasteride group, 0.7% (n = 11) in the tamsulosin group, and 0.3% (n = 5) in the combination therapy group.

The relationship between the use of dutasteride and the occurrence of poorly differentiated 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 any increased risk of breast cancer in men with the use of 5α-reductase inhibitors. The results of the first study showed no association with breast cancer (relative risk for use ≥ 1 year before breast cancer diagnosis compared with use < 1 year: 0.70: 95% CI 0.34, 1.45). In the second study, the relative risk of breast cancer associated with the use of 5α-reductase inhibitors compared with no use was 1.08: 95% CI 0.62, 1.87.

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

Indication

Treatment of symptoms of moderate to severe benign prostatic hyperplasia; reduction of the risk of acute urinary retention and the need for surgery in patients with symptoms of moderate to severe benign prostatic hyperplasia.

Contraindication

Dutasteride is contraindicated in patients with hypersensitivity to dutasteride, other 5a-reductase inhibitors, or to any of the other components of the drug.

Dutasteride should not be used to treat women and children (see sections “Use during pregnancy or breastfeeding”, “Children”).

Dutasteride is contraindicated in patients with severe hepatic impairment.

Interaction with other medicinal products and other types of interactions

For information on the reduction in serum PSA (Prostate-Specific Antigen) levels during treatment with dutasteride, as well as information on the detection of prostate cancer, see the section "Special Instructions for Use".

Effect of other medicinal products on the pharmacokinetics of dutasteride

Dutasteride is primarily eliminated by metabolism. In vitro studies indicate that CYP3A4 and CYP3A5 are the catalyzers of metabolism. Formal interaction studies with potent CYP3A4 inhibitors have not been conducted. However, in a population pharmacokinetic study, dutasteride serum concentrations were on average 1.6-1.8-fold higher in a small number of patients concomitantly treated with verapamil or diltiazem (moderate CYP3A4 inhibitors and P-glycoprotein inhibitors) than in other patients.

With prolonged use of dutasteride in combination with drugs that are potent inhibitors of the CYP3A4 enzyme (e.g. ritonavir, indinavir, nefazodone, itraconazole, ketoconazole, administered orally), the concentration of dutasteride in the blood serum may increase. Further inhibition of 5α-reductase with an increase in the duration of action of dutasteride is unlikely. However, a reduction in the frequency of dutasteride doses may be possible in the event of side effects. It should be noted that in the case of inhibition of enzyme activity, the long half-life may become even longer and concomitant therapy may in this case last more than 6 months before a new equilibrium concentration is reached.

Administration of 12 g of cholestyramine 1 hour after a single dose of 5 mg dutasteride had no effect on the pharmacokinetics of dutasteride.

Effect of dutasteride on the pharmacokinetics of other drugs

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 the P-glycoprotein transporter. In vitro interaction studies indicate that dutasteride does not inhibit CYP1A2, CYP2D6, CYP2C9, CYP2C19, or CYP3A4.

In a small two-week study (N=24) in healthy men, dutasteride (0.5 mg daily) had no effect on the pharmacokinetics of tamsulosin or terazosin. This study also showed no evidence of a pharmacodynamic interaction.

Application features

Combination therapy should be considered after careful benefit/risk assessment due to the potential increased risk of adverse reactions (including heart failure) and after consideration of alternative treatment options, including monotherapy (see section 4.2).

Cardiovascular adverse reactions

The incidence of heart failure (a composite term for all reports, primarily primary heart failure and congestive heart failure) was found to be higher in patients treated with the combination of dutasteride with an alpha-blocker, primarily tamsulosin, compared to patients not receiving such a combination. The incidence of heart failure was low (≤ 1%) and variable across studies. There was no disparity 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.

Effect on prostate-specific antigen (PSA)

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

Dustarin® is able to reduce serum PSA levels in patients by an average of approximately 50% after 6 months of treatment.

Patients taking Dustarin® should have a new baseline PSA level determined 6 months after treatment with this drug. Thereafter, it is recommended that this level be checked regularly. Any confirmed increase in PSA levels from the nadir during treatment may indicate the presence of prostate cancer or non-adherence to Dustarin® treatment and should be investigated carefully, even if PSA levels are within the normal range for men not treated with 5a-reductase inhibitors. When interpreting PSA levels in patients treated with Dustarin®, previous PSA levels should be taken into account for comparison.

The use of the drug does not affect the use of PSA levels for diagnosing prostate cancer after its new baseline level is established.

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

The ratio of free PSA to total PSA remains stable even during treatment with Dustarin®. Therefore, if the physician decides to use the percentage of free PSA as a definition of prostate cancer for a patient taking Dustarin®, no adjustment is necessary.

Before starting treatment with dutasteride and periodically during treatment, a digital rectal examination of the patient should be performed, as well as other methods of detecting prostate cancer should be used.

A study was reported in men aged 50 to 75 years with a previous negative biopsy result for prostate cancer and a baseline PSA level between 2.5 ng/mL and 10.0 ng/mL. 1517 were diagnosed with prostate cancer. The incidence of prostate cancer (Gleason 8–10) in the dutasteride-treated group (n = 29.09%) was higher than in the placebo-treated group (n = 19.06%). There was no increase in the incidence of prostate cancer with Gleason 5–6 and 7–10. A causal relationship between dutasteride use and advanced prostate cancer has not been established. The clinical significance of the numerical disparity is unknown. Men treated with Dustarin® should be regularly screened for prostate cancer risk, including PSA testing.

Breast cancer

Rare cases of breast cancer in men have been reported during clinical trials and in the post-marketing period. However, epidemiological studies indicate no increased risk of breast cancer in men with the use of 5α-reductase inhibitors. Patients should immediately report any changes in breast tissue, such as nipple discharge or swelling.

Leaky capsules

Dutasteride is absorbed through the skin, so women and children should avoid contact with unsealed capsules. If the capsule liquid comes into contact with the skin, it should be washed off immediately with soap and water.

Liver failure

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 half-life, dutasteride should be used with caution in patients with mild to moderate hepatic impairment (see sections 5.1, 5.3, and 4.8).

Ability to influence reaction speed when driving vehicles or other mechanisms

Given its pharmacokinetic and pharmacodynamic properties, dutasteride does not affect the ability to drive or use machines.

Use during pregnancy or breastfeeding

Dutasteride is contraindicated for the treatment of women.

Pregnancy. Like other 5α-reductase inhibitors, dutasteride inhibits the conversion of testosterone to dihydrotestosterone, which may inhibit the development of external genitalia in male fetuses. Small amounts of dutasteride have been detected in the ejaculate of subjects taking 0.5 mg of dutasteride daily. It is not known whether dutasteride ingested by a woman who is pregnant with a man taking dutasteride will affect the male fetus (the 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 pregnant to prevent sperm from entering the woman's body.

Breastfeeding: It is not known whether dutasteride passes into breast milk.

Fertility: Dutasteride has been reported to affect ejaculate characteristics (reduced sperm count, ejaculate volume, and sperm motility) in healthy men. A risk of reduced male fertility cannot be excluded.

Method of administration and doses

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

Adult males (including elderly patients)

The recommended dose of Dustarin® is 1 capsule (0.5 mg) per day orally. The capsule should be swallowed whole, not opened or chewed, as contact with the capsule contents may cause irritation of the oral and pharyngeal mucosa.

The drug Dustarin® can be taken regardless of meals.

Despite the fact that relief from taking the drug may be observed at an early stage, to objectively assess the effectiveness of the drug, treatment should be continued for at least 6 months.

Kidney failure

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

Liver failure

The pharmacokinetics of dutasteride have not been studied in patients with hepatic impairment, therefore, it should be used with caution in mild to moderate hepatic impairment.

The drug is contraindicated in patients with severe hepatic impairment.

Children

Contraindicated use.

Overdose

Single doses of dutasteride up to 40 mg/day (80 times the therapeutic dose) for 7 days did not raise any safety concerns. Dutasteride 5 mg/day for 6 months did not result in additional adverse reactions compared to dutasteride 0.5 mg/day.

There is no specific antidote, therefore, in case of suspected overdose, symptomatic and supportive therapy should be provided.

Adverse reactions

It is reported that approximately 19% of 2167 patients treated with dutasteride in two-year studies experienced adverse reactions during the first year of treatment. The majority of adverse events observed were mild or moderate in severity and affected the reproductive system. No changes in the adverse event profile were observed in the subsequent two-year open-label extension studies.

The following table lists adverse reactions identified during clinical trials and during post-marketing use. Adverse events identified during clinical trials that were considered by the investigators to be drug-related (incidence ≥ 1%) were observed at a higher frequency in patients receiving dutasteride than in patients receiving placebo during the first year of treatment. Adverse events identified during post-marketing use were identified from spontaneous post-marketing reports, so their true frequency is unknown.

Frequency classification: very common (> 1/10), common (≥ 1/100 to <1/10), uncommon (1/1000 to 1/100), rare (1/10,000 to 1/1,000)), very rare (<1/10,000), frequency unknown (cannot be estimated from the available data).

* The following are adverse reactions from the reproductive system 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 sperm volume.

+ Includes breast sensitivity and enlargement.

Dustarin® in combination with the alpha-blocker tamsulosin

In a 4-year study comparing dutasteride 0.5 mg (n = 1,623) and tamsulosin 0.4 mg (n = 1,611) once daily alone and in combination (n = 1,610), the incidence of drug-related adverse events during the first, second, third, and fourth years of treatment was 22%, 6%, 4%, and 2% for the dutasteride/tamsulosin combination therapy, 15%, 6%, 3%, and 2% for dutasteride monotherapy, and 13%, 5%, 2%, and 2% for tamsulosin monotherapy, respectively. The higher incidence of adverse reactions in the combination therapy group during the first year of treatment was due to the higher incidence of reproductive disorders, particularly ejaculation disorders, observed in this group.

During the first year of treatment in the study, the following adverse reactions, which the investigators considered to be drug-related, were reported with a frequency greater than or equal to 1%; the incidence of these reactions over four years of treatment is shown 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, congestive cardiomyopathy.

c The following adverse reactions from the reproductive system are associated with treatment with dutasteride (including monotherapy and combination with tamsulosin). These adverse reactions may persist after discontinuation of treatment. The role of dutasteride in this persistence is unknown.

d Includes breast tenderness and enlargement.

^ Includes decreased semen volume.

Other data

The study found a higher incidence of prostate cancer with a Gleason score of 8–10 in men taking dutasteride compared to placebo. It is not known whether the results of this study were influenced by the reduction in prostate volume or other factors related to dutasteride use.

Cases of breast cancer in men have been reported during clinical trials and during the post-marketing period (see section 4.4).

Expiration date

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 pack.

Vacation category

According to the recipe.

Producer

JSC "KYIV VITAMIN FACTORY" (production from bulk products of "GAP SA", Greece).

Location of the manufacturer and its business address

04073, Ukraine, Kyiv, Kopylivska St., 38.