Avodart soft gelatin capsules 0.5 mg No. 90

Instructions for Avodart soft gelatin capsules 0.5 mg No. 90

Composition

active ingredient: dutasteride;

1 capsule contains dutasteride 0.5 mg;

excipients: caprylic/capric acid monodiglycerides, butylhydroxytoluene (E 321);

capsule shell: gelatin, glycerin, titanium dioxide (E 171), iron oxide yellow (E 172), medium chain triglycerides and lecithin.

Dosage form

Soft gelatin capsules.

Main physicochemical properties: pale yellow opaque oblong soft gelatin capsules marked GX CE2.

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 while taking Avodart is dose-dependent and occurs in the first 1–2 weeks. After the 1st and 2nd weeks of taking Avodart 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 achieved within 1–3 hours. 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. Protein binding 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 serum is achieved after 6 months of use in a daily dose of 0.5 mg. As in the 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 serum to 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 “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 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 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 patients 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 (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 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 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 low-grade prostate cancer (Gleason score 8–10) was observed in the dutasteride group compared with 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 number of prostate cancer with Gleason score 8–10 was diagnosed in the dutasteride group (n = 12, 0.5%) compared with the placebo group (n = 1, < 0.1%) (p = 0.0035). There is 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 during years 3-4 than during 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 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

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

Avodart is not used to treat women and children (see section “Use during pregnancy and breastfeeding”).

Avodart 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-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 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.

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

In two 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 Avodart with an alpha-blocker, primarily tamsulosin, compared to patients not receiving such a combination. In these two trials, the incidence of heart failure was low (≤ 1%) and variable within the trials. There was no disparity in the incidence of cardiovascular adverse events in either trial. A causal relationship between dutasteride (alone or in combination with alpha-blockers) and 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 increased 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)

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

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

Patients taking Avodart 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 while taking Avodart may indicate the presence of prostate cancer or non-adherence to Avodart therapy and should be investigated carefully, even if PSA values are within the normal range for men not treated with 5α-reductase inhibitors. When interpreting PSA values in patients treated with Avodart, previous PSA values should be taken into account for comparison.

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

The ratio of free PSA to total PSA remains stable even during treatment with Avodart. Therefore, if a physician decides to use the free PSA percentage as a marker of prostate cancer in a patient taking Avodart, 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.

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 Avodart-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 Avodart and advanced prostate cancer has not been established. The clinical significance of the numerical disparity is unknown. Men treated with Avodart should have regular screening for prostate cancer, including PSA testing.

In an additional 2-year follow-up study of patients enrolled in the dutasteride chemoprophylaxis trial (REDUCE trial), a low incidence of new prostate cancer cases (dutasteride group [n=14, 1.2%] and placebo group [n=7, 0.7%]) was observed, with no new cases of prostate cancer with Gleason score 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 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 4.2, 4.3, and 5.1).

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.

Use during 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 Avodart 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.

Use during 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

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

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

Kidney failure

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

Liver failure

The pharmacokinetics of dutasteride in patients with hepatic impairment have not been studied, 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 any safety concerns. In clinical studies, dutasteride was administered at a dose of 5 mg/day for 6 months without additional adverse reactions compared to dutasteride at a dose of 0.5 mg/day.

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

Adverse reactions

Avodart Monotherapy

Approximately 19% of 2,167 patients treated with dutasteride in 2-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 affected 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 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).

Table 1

* The following are adverse reactions from the reproductive system 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.

^ Includes decreased semen volume.

+ Includes breast sensitivity and enlargement.

Avodart in combination with the alpha-blocker 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, particularly 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 four years of treatment is shown in Table 2.

Table 2

(n=1610)

(n=1623)

(n=1611)

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 sperm volume.

Other 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.

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

Expiration date

4 years.

Storage conditions

Store at a temperature not exceeding 30 ° C. Keep out of the reach of children.

Packaging

10 capsules in a polyvinyl chloride/aluminum foil blister, 9 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

GlaxoSmithKline Pharmaceuticals SA, Poland.

Location of the manufacturer and its business address

189, Grunwaldzka Street, 60-322 Poznan, Poland./189, Grunwaldzka Street, 60-322 Poznan, Poland.