Dutasteride-Vista capsules No. 90

Instructions for Dutasteride-Vista capsules No. 90

Composition

active ingredient: dutasteride;

1 capsule contains dutasteride 0.5 mg;

excipients: glycerol monocaprylocaprate Type 1, butylhydroxytoluene (E 321); capsule shell: gelatin, glycerol, purified water, titanium dioxide (E 171), yellow iron oxide (E 172), medium chain triglycerides, soy lecithin (E 322).

Dosage form

Soft capsules.

Main physicochemical properties: elongated opaque yellow soft gelatin capsules containing an oily yellowish liquid.

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 week 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 within 1-3 hours. Absolute bioavailability is 60% when administered by a two-hour intravenous infusion. 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 constant steady-state concentration of dutasteride of approximately 40 ng/ml in the blood serum is achieved after 6 months of treatment in a daily dose of 0.5 mg. As in the blood serum, a constant 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 humans after a 0.5 mg dose of dutasteride, 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 “Method of administration and dosage” and “Special warnings and precautions for use”).

Safety and clinical studies.

Heart failure

In a separate 4-year clinical trial comparing placebo with dutasteride chemoprophylaxis in 8231 patients 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 in men aged 50 to 60 years or 3 ng/mL and 10.0 ng/mL in men aged 60 years or older (the 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%). A retrospective analysis of this study showed a higher incidence of heart failure in patients receiving dutasteride and an alpha-blocker concomitantly (12/1152, 1.0%) compared to subjects receiving dutasteride without an alpha-blocker (18/2953, 0.6%), placebo and 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 4.4).

Prostate cancer and poorly differentiated tumors

In a 4-year comparative study of placebo and dutasteride in 8231 patients 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 in men aged 50 to 60 years or 3 ng/mL and 10.0 ng/mL in men aged 60 years or older (REDUCE study), 6706 subjects underwent a core needle biopsy of the prostate (mandatory according to the original protocol) and the data were used for the analysis of Gleason grade. The study identified 1517 patients with a diagnosis of prostate cancer. The majority of prostate tumors (70%) detected by biopsy in both treatment groups were highly differentiated (Gleason grade 5–6).

A higher incidence (n = 29, 0.9%) of poorly differentiated prostate cancer (Gleason score 8–10) was reported in the dutasteride group compared to the placebo group (n = 19, 0.6%) (p = 0.15). In 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%). In years 3–4 of the study, a higher number of prostate cancer cases with Gleason score 8–10 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 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 8-10 points on the Gleason scale remained constant across the different study periods (years 1-2, years 3-4) in the dutasteride group (0.5% in each time period), while in the placebo group the percentage of patients with poorly differentiated prostate cancer (8-10 points on the Gleason scale) was lower in years 3-4 than in years 1-2 (< 0.1% and 0.5%, respectively) (see section "Special instructions for use"). There was no difference in the incidence of prostate cancer with a differentiation of 7-10 points on the Gleason scale (p = 0.81).

In a 4-year clinical trial of the treatment of benign prostatic hyperplasia (Combat), 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 (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 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 cases of male breast cancer 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, if necessary, surgical intervention in patients with symptoms of moderate to severe benign prostatic hyperplasia.

Contraindication

DUTASTERIDE-VISTA is contraindicated in patients with hypersensitivity to dutasteride, other 5a-reductase inhibitors, soy, peanut, or other components of the drug.

DUTASTERIDE-VISTA should not be used to treat women and children (see section “Use during pregnancy or breastfeeding”).

DUTASTERIDE-VISTA 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

Use with CYP3A4 and/or P-glycoprotein inhibitors.

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 times higher in a small number of patients who were concomitantly treated with verapamil or diltiazem (moderate CYP3A4 inhibitors and P-glycoprotein inhibitors) than in other patients.

A study showed that dutasteride clearance was reduced when co-administered with the CYP3A4 inhibitors verapamil (37%) and diltiazem (44%). However, dutasteride clearance was not reduced when co-administered with amlodipine, another calcium channel antagonist.

Since dutasteride is metabolized by CYP3A4, serum concentrations of dutasteride may increase in the presence of CYP3A4 inhibitors. Long-term administration of DUTASTERIDE-VISTA with drugs that are strong inhibitors of the CYP3A4 enzyme (such as ritonavir, indinavir, nefezadone, itraconazole, ketoconazole, administered orally) may result in increased concentrations of dutasteride. 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 necessary if side effects develop. It should be noted that the long half-life may be further prolonged in the presence of enzyme inhibition and concomitant therapy may require more than 6 months before a new steady-state concentration is reached.

In vitro, dutasteride is not metabolized by CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6, and CYP2D6 isoenzymes of the cytochrome P450 system in humans.

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 2-week study (N=24) in healthy male subjects, 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.

In vitro studies have shown that dutasteride does not displace warfarin, acenocoumarol, phenprocoumon, diazepam or phenytoin from plasma protein binding, nor do these components displace dutasteride. The interaction of dutasteride with tamsulosin, terazosin, warfarin, digoxin and cholestyramine has been studied. No clinically significant interactions have been identified. Administration of 12 g of cholestyramine 1 hour after a single dose of 5 mg dutasteride had no effect on the pharmacokinetics of dutasteride.

Although specific drug interaction studies have not been conducted, approximately 90% of all patients in clinical trials of dutasteride were receiving other medications. No clinically significant adverse reactions were observed when dutasteride was administered concomitantly with antihyperlipidemic agents, angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, corticosteroids, diuretics, nonsteroidal anti-inflammatory drugs, phosphodiesterase type V inhibitors, and quinoline antibiotics.

Application features

Cardiovascular adverse reactions

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).

In 4-year clinical trials, the incidence of heart failure (a composite term for all reports, primarily primary heart failure and congestive heart failure) was higher in patients treated with the combination of dutasteride and an alpha-blocker, primarily tamsulosin, compared to patients not receiving such a combination. In these two studies, the incidence of heart failure was low (≤ 1%) and variable within the studies. There was no disparity in the incidence of cardiovascular adverse events in either study. A causal relationship between the use of dutasteride (alone or in combination with alpha-blockers) and the occurrence of heart failure has not been established ("Pharmacological properties").

A meta-analysis of 12 randomized, placebo-controlled, or comparative clinical trials (n = 18,802) evaluating the risk of cardiovascular adverse events with dutasteride (compared to control) found 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).

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

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

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

The use of the drug DUTASTERIDE-VISTA does not affect the use of PSA levels for the diagnosis of 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 DUTASTERIDE-VISTA. Therefore, if the physician decides to use the percentage of free PSA as a definition of prostate cancer for a patient taking DUTASTERIDE-VISTA, no adjustment is necessary.

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

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

In a 4-year clinical trial involving >8000 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 (REDUCE study), 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 Dutasteride-Vista should be regularly screened for prostate cancer, including PSA testing.

In an additional consecutive two-year study of patients enrolled in a study of dutasteride as chemoprophylaxis (REDUCE study), a low incidence of new cases of prostate cancer (dutasteride group [n=14, 1.2%]) and placebo group [n=7, 0.7%]) was observed, with no new cases of prostate cancer with a Gleason score of 8-10 identified.

Long-term consecutive follow-up (up to 18 years) of patients from a clinical trial using another 5α-reductase inhibitor (finasteride) as chemoprophylaxis showed no statistically significant difference between the finasteride and placebo groups in overall survival rates (HR 1.02, 95% CI 0.97-1.08) or survival after diagnosis of prostate cancer (HR 1.01, 95% CI 0.85-1.20).

Breast cancer

Rare cases of breast cancer in men have been reported during clinical trials and in the post-marketing period. However, epidemiological studies suggest no increased risk of breast cancer in men with the use of 5α-reductase inhibitors. Patients should promptly 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 or moderate hepatic impairment (see sections 4.2, 4.3, and 4.8).

Use during pregnancy or breastfeeding

Fertility.

Cases of dutasteride affecting ejaculate characteristics (reduction in sperm count, ejaculate volume and sperm motility) have been reported in healthy men. A risk of reduced male fertility cannot be excluded.

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.

Breast-feeding.

It is not known whether dutasteride passes into human breast milk.

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.

Method of administration and doses

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

Adult males (including elderly patients)

The recommended dose of Dutasteride-Vista is 1 capsule (0.5 mg) per day for oral administration. The capsule should be swallowed whole, not opened or chewed, as contact with the capsule contents may cause irritation of the mucous membrane of the mouth and pharynx.

Dutasteride-Vista 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, caution should be exercised in patients with mild to moderate hepatic impairment. The drug is contraindicated in patients with severe hepatic impairment.

Children.

Use is contraindicated.

Overdose

In clinical studies, single doses of dutasteride up to 40 mg/day (80 times the therapeutic dose) for 7 days in human volunteers did not raise safety concerns. In clinical studies, doses of dutasteride 5 mg/day were administered for 6 months without additional adverse reactions compared to dutasteride 0.5 mg/day.

There is no specific antidote, therefore, in case of possible overdose, symptomatic and supportive therapy is performed.

Side effects

Dutasteride monotherapy

Approximately 19% of 2167 patients treated with dutasteride in two-year, placebo-controlled phase III studies experienced adverse reactions during the first year of treatment. The majority of adverse events observed were mild to moderate in severity and involved the reproductive system. No changes in the adverse event profile were observed in the subsequent 2-year open-label extension studies.

Table 1 lists adverse reactions identified during controlled 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 reported at a higher incidence 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).

Table 1

* Adverse reactions related to sexual dysfunction have been associated with treatment with dutasteride (including monotherapy and combination with tamsulosin). These adverse reactions may persist after discontinuation of treatment. The effect of dutasteride on their duration is unknown.

^ Includes decreased sperm volume.

Combination therapy (dutasteride + tamsulosin)

Data from the 4-year CombAT study, which compared dutasteride 0.5 mg (n = 1,623) and tamsulosin 0.4 mg (n = 1,611) once daily alone and in combination (n = 1,610), showed that the incidence of drug-related adverse events during the first, second, third, and fourth years of treatment was 22%, 6%, 4%, and 2% 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, including ejaculation disorders, observed in this group.

During the first year of treatment in the CombAT study, the following adverse reactions considered by the investigators to be drug-related were reported at a frequency of greater than or equal to 1%; the incidence of these reactions over 4 years of treatment is shown in Table 2.

Table 2

a combination – dutasteride 0.5 mg once daily plus tamsulosin 0.4 mg once daily.

b Adverse reactions related to sexual dysfunction have been associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse reactions may persist after discontinuation of treatment. The effect of dutasteride on their duration is unknown.

c Including breast tenderness and enlargement.

d The term heart failure includes congestive heart failure, heart failure, left ventricular failure, acute left ventricular failure, cardiogenic shock, acute heart failure, right ventricular failure, acute right ventricular failure, congestive cardiomyopathy, cardiopulmonary failure, ventricular failure, cardiopulmonary failure, congestive cardiomyopathy.

^ Includes decreased sperm volume.

Research data

The REDUCE trial 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 reduction in prostate volume or other factors related to dutasteride use influenced the results of this study.

On the part of the immune system

Very rare: allergic reactions including rash, itching, urticaria, localised oedema and angioedema.

From the psyche

Very rare: depressed mood.

Skin and subcutaneous tissue disorders

Rare: alopecia (mainly body hair loss), hypertrichosis.

Reproductive system and breast disorders

Very rare: testicular pain and swelling.

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

Expiration date

4 years.

Storage conditions

Store in the original packaging to protect from moisture at a temperature not exceeding 30 ° C. Keep out of the reach of children.

Packaging

10 capsules in a blister, 3 or 9 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Galenicum Hales, S.L.

CINDEA PHARMA, S.L.

Address

Ave. Cornella 144, 70-1a LECLA Building, Esplugues de Llobregat, Barcelona, 08950, Spain.

Poligono Industrial Emiliano Revilla Sanz, Avenida de Agreda, 31, Olvega, Soria, 42110, Spain.