Avodart

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AVODART (AVODART)

Composition:

Active substance: dutasteride;

1 capsule contains 0.5 mg of dutasteride;

Excipients: mono- and diglycerides of caprylic/capric acids, butylated hydroxytoluene (E 321);

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

Pharmaceutical form. Soft gelatin capsules.

Main physicochemical properties: pale yellow, opaque, elongated soft gelatin capsules with imprint GX CE2.

Pharmacotherapeutic group. Drugs used in benign prostatic hyperplasia. Inhibitors of testosterone 5α-reductase. ATC code G04C B02.

Pharmacological Properties.

Pharmacodynamics. Dutasteride is a dual inhibitor of 5α-reductase, inhibiting both type 1 and type 2 isoenzymes of 5α-reductase responsible for the conversion of testosterone into 5α-dihydrotestosterone. Dihydrotestosterone is an androgen primarily responsible for prostate tissue hyperplasia. The maximum reduction of dihydrotestosterone with Avodart treatment is dose-dependent and occurs within the first 1–2 weeks. After the 1st and 2nd week of Avodart administration at a daily dose of 0.5 mg, the average dihydrotestosterone concentration decreases by 85% and 90%, respectively.

In patients with benign prostatic hyperplasia receiving 0.5 mg of dutasteride daily, the average reduction in dihydrotestosterone levels was 94% after 1 year and 93% after 2 years of treatment. The average testosterone level increased by 19% after both 1 and 2 years.

Pharmacokinetics. Dutasteride is administered orally 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 to 500 L). Protein binding exceeds 99.5%.

With a daily dose of 0.5 mg, 65% of the steady-state plasma concentration of dutasteride is achieved after 1 month of treatment and approximately 90% after 3 months. A steady-state concentration of approximately 40 ng/mL in plasma is reached after 6 months of daily 0.5 mg dosing. As in plasma, steady-state concentration in semen is achieved after 6 months. After 52 weeks of treatment, the average concentration of dutasteride in semen is 3.4 ng/mL (range: 0.4–14 ng/mL). The distribution ratio of dutasteride from plasma to semen is approximately 11.5%.

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

Mass spectrometry analysis in human plasma detects 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, 1 to 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 detected in urine. The terminal half-life of dutasteride is 3–5 weeks. Residual levels of dutasteride in plasma may be detected up to 4–6 months after discontinuation of treatment.

According to pharmacokinetic and pharmacodynamic studies, dose adjustment of dutasteride based on 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 dutasteride; therefore, dose adjustment in patients with renal impairment is not required.

The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied (see sections "Dosage and Administration" and "Special Precautions").

Safety and Clinical Studies.

Heart Failure

In a 4-year clinical trial evaluating dutasteride in combination with tamsulosin for the treatment of benign prostatic hyperplasia in 4844 men (CombAT study), the incidence of heart failure (a composite term) was higher in the combination therapy group (14/1610, 0.9%) than in either monotherapy group receiving dutasteride (4/1623, 0.2%) or tamsulosin (10/1611, 0.6%).

In a separate 4-year placebo-controlled chemoprevention trial involving 8231 men aged 50 to 75 years with prior negative prostate biopsy for prostate cancer and baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL in men aged 50 to 60 years or between 3.0 ng/mL and 10.0 ng/mL in men aged 60 years and older (REDUCE study), the incidence of heart failure was higher in patients receiving dutasteride 0.5 mg once daily (30/4105, 0.7%) compared to those receiving placebo (16/4126, 0.4%). In a retrospective analysis of this study, a higher incidence of heart failure was observed in patients receiving dutasteride and an alpha-blocker concurrently (12/1152, 1.0%) compared to those receiving dutasteride without an alpha-blocker (18/2953, 0.6%), placebo with an alpha-blocker (1/1399, < 0.1%), or placebo without an alpha-blocker (15/2727, 0.6%). A causal relationship between dutasteride use (alone or in combination with alpha-blockers) and the development of heart failure has not been established (see section "Special Precautions").

Prostate Cancer and High-Grade Tumors

In a 4-year placebo-controlled trial involving 8231 men aged 50 to 75 years with prior negative prostate biopsy for prostate cancer and baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL in men aged 50 to 60 years or between 3.0 ng/mL and 10.0 ng/mL in men aged 60 years and older (REDUCE study), 6706 subjects underwent prostate needle biopsy (mandated by the original protocol), and biopsy results were used for Gleason score grading. A total of 1517 patients were diagnosed with prostate cancer in the study. Most prostate tumors (70%) detected by biopsy in both treatment groups were well-differentiated (Gleason score 5–6).

A higher incidence of high-grade prostate cancer (Gleason score 8–10) was observed in the dutasteride group (n = 29, 0.9%) compared to the placebo group (n = 19, 0.6%) (p = 0.15). During years 1–2 of the study, the number of patients diagnosed with Gleason score 8–10 prostate cancer was similar in the dutasteride group (n = 17, 0.5%) and the placebo group (n = 18, 0.5%). During years 3–4, more cases of Gleason score 8–10 prostate cancer were diagnosed in the dutasteride group (n = 12, 0.5%) compared to the placebo group (n = 1, < 0.1%) (p = 0.0035). There are no data on the effect 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 high-grade 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 Precautions"). There was no difference in the incidence of Gleason score 7–10 prostate cancer (p = 0.81).

In a 4-year clinical trial of benign prostatic hyperplasia treatment (CombAT), where mandatory biopsy was not required by the original protocol and all prostate cancer diagnoses were biopsy-confirmed based on clinical indications, 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 USA (n = 339 breast cancer cases and n = 6780 controls) and another in the UK (n = 398 breast cancer cases and n = 3930 controls)—did not show an increased risk of male breast cancer with 5α-reductase inhibitor use. The first study found no association with breast cancer (relative risk with ≥1 year of use before diagnosis vs. <1 year: 0.70; 95% CI 0.34, 1.45). In the second study, the relative risk of breast cancer associated with 5α-reductase inhibitor use compared to non-use was 1.08; 95% CI 0.62, 1.87.

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

Clinical characteristics.

Indications.

Treatment of symptoms of moderate to severe benign prostatic hyperplasia (BPH); reduction of the risk of acute urinary retention and the need for surgical intervention in patients with symptoms of moderate to severe benign prostatic hyperplasia.

Contraindications.

Avodart is contraindicated in patients with hypersensitivity to dutasteride, other 5α-reductase inhibitors, soy, peanuts, or any component of the product.

Avodart is not indicated for use in women and children (see section "Use in pregnancy and breastfeeding").

Avodart is contraindicated in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Information regarding decreased levels of PSA (prostate-specific antigen) in blood serum during treatment with dutasteride, as well as information on detection of prostate cancer, see section "Special precautions for use".

Effect of other medicinal products on the pharmacokinetics of dutasteride

Concomitant use with CYP3A4 and/or P-glycoprotein inhibitors:

Dutasteride is primarily eliminated via metabolism. In vitro studies 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 treated with verapamil or diltiazem (moderate CYP3A4 inhibitors and P-glycoprotein inhibitors) compared to other patients.

With long-term use of dutasteride in combination with medicinal products that are potent inhibitors of the CYP3A4 enzyme (e.g., ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally), serum concentrations of dutasteride may increase. Further inhibition of 5α-reductase due to prolonged action of dutasteride is unlikely. However, dose reduction of dutasteride may be considered if adverse effects develop. It should be noted that in case of prolonged enzyme inhibition, the long half-life 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 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 P-glycoprotein transporter. In vitro interaction studies indicate that dutasteride does not inhibit the enzymes CYP1A2, CYP2D6, CYP2C9, CYP2C19, or CYP3A4.

In a small study (N=24) of two weeks' duration 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 for increased risk of adverse reactions (including heart failure) and after consideration of alternative treatment options, including monotherapy (see section "Dosage and administration").

Cardiovascular adverse reactions

Based on data from two 4-year clinical trials, the incidence of heart failure (a collective term for all reported events, primarily primary heart failure and congestive heart failure) was higher in patients treated with a combination of Avodart and an alpha-blocker, mainly tamsulosin, compared to patients not receiving this combination. However, in these two trials, the overall incidence of heart failure was low (≤1%) and variable across the studies. No imbalance in the incidence of cardiovascular adverse events was observed in any of the trials. A causal relationship between dutasteride use (alone or in combination with alpha-blockers) and the occurrence of heart failure has not been established (see section "Pharmacological properties").

A meta-analysis of 12 randomized, placebo-controlled or comparative clinical trials (n = 18,802) was conducted to evaluate the risk of cardiovascular adverse reactions with dutasteride compared to control groups. No consistent statistically significant increase in risk was found for 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)

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

Avodart reduces serum PSA levels by approximately 50% on average within 6 months of treatment.

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

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

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

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

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

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

In a 4-year clinical trial involving over 8,000 men aged 50 to 75 years with prior negative prostate biopsy and baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL (the REDUCE study), prostate cancer was diagnosed in 1,517 patients. The incidence of high-grade prostate cancer (Gleason score 8–10) was higher in the group treated with Avodart (n = 29.09%) compared to the placebo group (n = 19.06%). No increase in the incidence of prostate cancer with Gleason scores 5–6 or 7–10 was observed. A causal relationship between Avodart use and high-grade prostate cancer has not been established. The clinical significance of this numerical imbalance is unknown. Men receiving Avodart should be regularly monitored for the risk of prostate cancer, including PSA testing.

In an additional 2-year follow-up study of patients from the REDUCE trial, the incidence of new prostate cancer cases was low (dutasteride group [n=14, 1.2%] vs. placebo group [n=7, 0.7%]), with no new cases of Gleason score 8–10 prostate cancer identified.

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

Breast cancer

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

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied. Due to the extensive metabolism of dutasteride and its long elimination half-life (3–5 weeks), caution is advised when treating patients with mild to moderate hepatic impairment (see sections "Dosage and administration", "Contraindications", "Pharmacological properties").

Use during pregnancy or breastfeeding.

Dutasteride is contraindicated for use in women.

Use during pregnancy

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

Use during breastfeeding

It is unknown whether dutasteride passes into 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.

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

Method of Administration and Dosage

Avodart 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 Avodart 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 oral and pharyngeal mucosa.

Avodart may be taken regardless of food intake.

Although symptom relief 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, Avodart should be used with caution in 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 the drug in patients with mild to moderate hepatic impairment. Avodart is contraindicated in patients with severe hepatic impairment.

Children

Use is contraindicated.

Overdose

Clinical studies have shown that single doses of dutasteride up to 40 mg/day (80 times higher than the therapeutic dose) administered for 7 days did not raise safety concerns in healthy volunteers. In clinical trials, dutasteride was administered at a dose of 5 mg/day for 6 months without an increase in adverse reactions compared to the 0.5 mg/day dose.

There is no specific antidote. In the event of suspected overdose, symptomatic and supportive treatment should be administered.

Adverse Reactions

Avodart Monotherapy

Adverse reactions occurred in approximately 19% of 2167 patients treated with dutasteride during the first year of treatment in two-year, placebo-controlled Phase III studies. Most of the observed adverse events were mild to moderate in severity and involved the reproductive system. During the subsequent 2 years of open-label extension studies, no changes in the adverse event profile were observed.

Table 1 lists adverse reactions identified during controlled clinical trials and in the post-marketing period. The adverse reactions listed below, observed during clinical trials and considered by investigators to be drug-related (with a frequency ≥1%), occurred more frequently in patients receiving dutasteride compared to placebo during the first year of treatment. Adverse reactions reported in the post-marketing period were identified from spontaneous post-marketing reports, and thus 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 not known (cannot be estimated from available data).

Table 1

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

^ Includes decreased semen volume.

• Includes breast tenderness and enlargement.

Avodart in combination with the alpha-blocker tamsulosin

Data from the 4-year CombAT study, which compared daily administration of dutasteride 0.5 mg (n = 1,623) and tamsulosin 0.4 mg (n = 1,611) alone 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 the combination therapy with dutasteride/tamsulosin; 15%, 6%, 3%, and 2% for dutasteride monotherapy; and 13%, 5%, 2%, and 2% for tamsulosin monotherapy. The higher incidence of adverse reactions in the combination therapy group during the first year of treatment was due to a higher frequency of reproductive system disorders, particularly ejaculation disorders, observed in this group.

During the first year of treatment in the CombAT study, the adverse reactions listed below, considered by investigators to be related to drug administration, were reported at an incidence of ≥1%; the incidence of these reactions over the four years of treatment is presented in Table 2.

Table 2

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

b The general term "Heart failure" includes congestive heart failure, heart failure, left ventricular dysfunction, acute heart failure, cardiogenic shock, acute left ventricular failure, right ventricular failure, acute right ventricular failure, ventricular dysfunction, cardiopulmonary failure, and congestive cardiomyopathy.

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

d Includes breast tenderness and breast enlargement.

^ Includes decreased semen volume.

Other data

The REDUCE study revealed a higher incidence of prostate cancer with Gleason score 8–10 in men receiving dutasteride compared to placebo. It is unknown whether the results of this study were influenced by prostate volume reduction or other factors related to dutasteride use.

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

Shelf life.

4 years.

Storage conditions.

Store at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging. 10 capsules in a blister pack made of polyvinyl chloride/aluminum foil, with 3 or 9 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer. Delpharm Poznan S.A., Poland.

Manufacturer's address and location of operations.

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