Stridart

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Stridart (Stridart)

Composition:

Active substance: dutasteride;

1 capsule contains 0.5 mg of dutasteride;

Excipients: mono- and diglycerides, butylhydroxytoluene (E 321);

capsule shell: gelatin, glycerin, glycine; citric acid, anhydrous; titanium dioxide (E 171), yellow iron oxide (E 172), medium-chain triglycerides, Opacode WB Red ink, isopropyl alcohol.

Pharmaceutical form. Soft gelatin capsules.

Main physicochemical properties: soft, elongated gelatin capsules of yellow color, containing a clear oily liquid.

Pharmacotherapeutic group. Agents used in benign prostatic hyperplasia. Testosterone 5α-reductase inhibitors. Dutasteride. 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 the androgen primarily responsible for hyperplasia of prostate tissue. The maximum reduction in dihydrotestosterone during Stridec treatment is dose-dependent and occurs within the first 1–2 weeks. After 1 and 2 weeks of treatment with Stridec 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 the form of a solution in soft gelatin capsules. After a single 0.5 mg dose, peak plasma concentration is observed within 1–3 hours. The absolute bioavailability is 60% compared to a two-hour intravenous infusion. Bioavailability is not affected by food intake.

After single or multiple doses, dutasteride has a large volume of distribution (300 to 500 L). Protein binding exceeds 99.5%.

With daily dosing, approximately 60% of the steady-state plasma concentration of dutasteride is achieved within 1 month of treatment and about 90% within 3 months. A steady-state plasma concentration of approximately 40 ng/mL is reached after 6 months of treatment with a daily dose of 0.5 mg. Steady-state concentration of dutasteride 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.

In human plasma, according to mass spectrometry analysis, unchanged dutasteride, three major metabolites (4´-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride), and two minor metabolites (6,4´-dihydroxydutasteride and 15-hydroxydutasteride) are detected.

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

Only trace amounts of unchanged dutasteride are found in urine (less than 0.1% of the administered dose). The terminal elimination half-life of dutasteride is 3–6 weeks. Residual levels of dutasteride in blood plasma may be detected 4–6 months after discontinuation of treatment.

Based on pharmacokinetic and pharmacodynamic studies, dose adjustment of dutasteride according to patient age is not required.

The effect of renal impairment on the pharmacokinetics of dutasteride has not been studied. However, less than 0.1% of the dose is excreted in urine after administration of 0.5 mg dutasteride, so dose adjustment in patients with renal impairment is not necessary.

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

Safety and clinical studies.

Heart failure

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

In a placebo-controlled chemoprevention trial involving men aged 50 to 75 years with a prior negative prostate biopsy and baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL (men aged 50 to 60 years) or 3.0 ng/mL and 10.0 ng/mL (men over 60 years), the incidence of heart failure was higher in patients receiving dutasteride 0.5 mg once daily compared to those receiving placebo. In a post-hoc analysis conducted after this trial, a higher incidence of heart failure was observed in patients taking dutasteride and an alpha-blocker concurrently compared to subjects taking dutasteride without an alpha-blocker, placebo with an alpha-blocker, or placebo without an alpha-blocker. 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

A placebo-controlled trial involving 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 (men aged 50 to 60 years) or 3.0 ng/mL and 10.0 ng/mL (men over 60 years) was reported. Needle prostate biopsies were performed in subjects (mandated by the original protocol), and data were analyzed for Gleason score grading. Prostate cancer was diagnosed in patients 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 recorded in the dutasteride group compared to the placebo group. During the first and second years of the study, the number of patients diagnosed with Gleason score 8–10 prostate cancer was similar in both the dutasteride and placebo groups. During the third and fourth years, a greater number of Gleason score 8–10 prostate cancers were diagnosed in the dutasteride group compared to the placebo group. There are no data on the effect of dutasteride use beyond 4 years on the risk of developing prostate cancer. The percentage of patients diagnosed with Gleason score 8–10 prostate cancer remained constant over different periods of the study (first-second years, third-fourth years) in the dutasteride group, whereas in the placebo group, the percentage of patients with high-grade prostate cancer (Gleason score 8–10) was lower during the third and fourth years than during the first and second years (see section "Special precautions"). There was no difference in the incidence of prostate cancer with Gleason score 7–10.

In a study on the treatment of benign prostatic hyperplasia, where mandatory biopsy was not required by the protocol and all prostate cancer diagnoses were made based on indicated biopsies, the incidence of Gleason score 8–10 prostate cancer, and the relationship between dutasteride use and the development of high-grade prostate cancer remains unclear.

Breast cancer in men

According to healthcare database analyses of two case-control epidemiological studies conducted in the United States and the United Kingdom, no increased risk of male breast cancer was found with the use of 5α-reductase inhibitors. The results of the first study (in the United States) did not show a positive association with breast cancer. The second study (in the United Kingdom) assessed the relative risk of developing breast cancer associated with the use of 5α-reductase inhibitors compared to non-use.

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

Clinical characteristics.

Indications.

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

Contraindications.

Stridart is contraindicated in patients with hypersensitivity to dutasteride, other 5α-reductase inhibitors, soy, peanuts, or any other components of the drug.

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

Stridart is contraindicated in patients with severe hepatic impairment.

Interaction with other medicinal products and other forms of interaction.

Information on the reduction of serum PSA (prostate-specific antigen) levels during treatment with dutasteride, as well as recommendations regarding prostate cancer detection, 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 to 1.8 times higher in a small number of patients who were concurrently treated with verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) compared to other patients.

With long-term co-administration of dutasteride and 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, a reduction in the frequency of dutasteride dosing may be considered if adverse effects develop. It should be noted that in cases of enzyme inhibition over a prolonged period, 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 of cholestyramine one hour after a single 5 mg dose of dutasteride did not affect the pharmacokinetics of dutasteride.

Effect of dutasteride on the pharmacokinetics of other medicinal products.

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

In a small two-week study (N=24) involving healthy male subjects, dutasteride (0.5 mg daily) did not affect the pharmacokinetics of tamsulosin or terazosin. No evidence of pharmacodynamic interaction was observed in this study.

Special precautions for use.

Combined therapy may be prescribed only after careful assessment of benefit/ risk due to the potential increased risk of adverse reactions (including heart failure) and after consideration of alternative treatment options, including monotherapy (see section "Dosage and administration").

Dutasteride can be absorbed through the skin; therefore, women and children should avoid contact with damaged or leaking capsules (see section "Use during pregnancy or breastfeeding"). If capsule contents come into contact with the skin, the affected area should be washed immediately with soap and water.

The effect of hepatic impairment on the pharmacokinetics of dutasteride has not been studied. Since dutasteride is extensively metabolized and has a half-life of 3–5 weeks, the drug should be prescribed with caution in patients with mild to moderate hepatic impairment (see sections "Contraindications" and "Dosage and administration").

Use in combination with tamsulosin and heart failure.

Combined therapy may be prescribed only after careful assessment of benefit/ risk due to the potential increased risk of adverse reactions (including heart failure) and after consideration of alternative treatment options, including monotherapy.

An increased incidence of heart failure (a combined term for all reported events, predominantly heart failure and congestive heart failure) has been observed in subjects treated with a combination of dutasteride and an alpha-blocker, primarily tamsulosin, compared to subjects not receiving this combination. According to clinical trial data, the incidence of heart failure was low (≤1%) and variable across these studies. No imbalance in the incidence of cardiovascular adverse events has been observed in any of the trials. 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 "Pharmacological properties").

Effect on prostate-specific antigen (PSA) and detection of prostate cancer.

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

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

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

Use of Strident 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 Strident treatment. Therefore, if a physician decides to use the percentage of free PSA as a diagnostic tool for prostate cancer in a patient taking Strident, no doubling of the free PSA value is required.

Prior to initiating treatment with dutasteride and periodically during treatment, patients should undergo digital rectal examination and other prostate cancer screening procedures.

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

A study involving men aged 50 to 75 years with prior negative prostate biopsy results and baseline PSA levels between 2.5 ng/mL and 10.0 ng/mL has been reported. Prostate cancer was diagnosed in 1517 subjects. The incidence of high-grade prostate cancer (Gleason score 8–10) was higher in the group treated with dutasteride (29.09%) compared to the placebo group (19.06%). No increase in the incidence of Gleason score 5–6 or 7–10 prostate cancer was observed. A causal relationship between dutasteride use and higher-stage prostate cancer has not been established. The clinical significance of this numerical imbalance is unknown. Men receiving Strident should be regularly monitored for the risk of prostate cancer, including PSA testing.

Breast cancer

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

Leaking capsules

Dutasteride is absorbed through the skin; therefore, women and children should avoid contact with damaged or leaking capsules. If capsule contents come into contact with the skin, the affected 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 3–5 week half-life, treatment with dutasteride in patients with mild or moderate hepatic impairment should be undertaken with caution (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 interferes with the conversion of testosterone to dihydrotestosterone, which may impair the development of external genitalia in male fetuses. A small amount of dutasteride has been detected in the semen of subjects taking 0.5 mg of Strident daily. It is unknown whether dutasteride transferred to a woman's body via semen from a man being treated with dutasteride may affect a male fetus (this risk is highest during the first 16 weeks of pregnancy).

As with other 5α-reductase inhibitors, it is recommended that patients use condoms if their partner is pregnant or potentially could 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 dutasteride affecting 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 influence reaction speed when driving or operating machinery.

Given the pharmacokinetic and pharmacodynamic properties of dutasteride, it has no effect on the ability to drive a vehicle or operate machinery.

Method of Administration and Dosage

Stridart 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 Stridart is 1 capsule (0.5 mg) daily, taken orally. The capsule should be swallowed whole without opening or chewing, as contact with the capsule contents may cause irritation of the oral and pharyngeal mucosa.

Stridart may be taken independently of food intake.

Although symptom relief may be observed early during treatment, therapy should be continued for at least 6 months to allow an objective assessment of the drug's efficacy.

Renal impairment

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

Hepatic impairment

The pharmacokinetics of dutasteride in patients with hepatic impairment have not been studied; therefore, caution is advised when using the drug in patients with mild to moderate hepatic impairment. Stridart is contraindicated in patients with severe hepatic impairment.

Children

Use is contraindicated.

Overdose

According to clinical trial data, single doses of dutasteride up to 40 mg/day (80 times higher than therapeutic doses) administered for 7 days in volunteers did not raise safety concerns. During clinical trials, a dose of 5 mg/day of dutasteride administered for 6 months did not result in additional adverse reactions compared to the 0.5 mg/day dose.

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

Adverse Reactions

Monotherapy with Stridecor

Adverse reactions occurred in approximately 19% of 2167 patients treated with dutasteride during the first year of 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 two years in open-label extension studies, no changes in the adverse event profile were observed.

The following table lists adverse reactions identified during controlled clinical trials and in the post-marketing period. The adverse events observed during clinical trials, considered by investigators to be drug-related (occurring at a frequency ≥1%) and reported more frequently in patients receiving dutasteride compared to placebo during the first year of treatment, are listed below. Adverse events reported during the post-marketing period were identified from spontaneous post-marketing reports; therefore, their actual frequency is unknown.

Classification of frequency: very common (>1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to 1/100), rare (≥1/10,000 to 1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

* Adverse events related to the male reproductive system associated with dutasteride treatment (including monotherapy and combination with tamsulosin). The 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.

Strider in combination with the alpha-blocker tamsulosin.

Data from the 4-year CombAT study, which compared the administration of dutasteride 0.5 mg (n=1623) and tamsulosin 0.4 mg (n=1623) versus tamsulosin 0.4 mg (n=1611) once daily as monotherapies and in combination (n=1610), showed that the incidence of adverse events related to treatment during the first, second, third, and fourth years of therapy 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 events in the combination therapy group during the first year of treatment was due to a higher frequency of reproductive system disorders, particularly ejaculation disorders, observed in this group.

During the first year of treatment in the CombAT study, the adverse reactions listed below, considered by investigators to be related to drug exposure, occurred at a frequency ≥1%. The incidence of these reactions over the four years of treatment is presented 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, left ventricular failure, 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 sexual adverse reactions listed are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). The listed adverse reactions may persist after discontinuation of treatment. The role of dutasteride in this persistence is unknown.

d Includes breast tenderness and breast enlargement.

^ Includes decreased semen volume.

Other data.

The REDUCE trial revealed a higher incidence of Gleason score 8–10 prostate cancer in men receiving dutasteride compared with placebo.

It has not been established whether dutasteride affects prostate volume reduction or the investigation of other contributing factors that may have influenced the outcomes of this trial.

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging.

10 capsules in a blister pack.

30 or 90 capsules in a container.

1 blister pack or 1 container in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

STRIDES PHARMA SCIENCES LIMITED

Strides Pharma Science Limited

Manufacturer's address.

No. 36/7, Suragajakkanahalli, Indlavadi Cross, Anekal Taluk, Bengaluru, Karnataka 562106, India

No. 36/7, Suragajakkanahalli, Indlavadi Cross, Anekal Taluk, Bengaluru, Karnataka 562106, India

Marketing Authorization Holder.

Strides CIS Limited

Address of Marketing Authorization Holder.

Julia House, 3 Thermistocles Dervis Street, CY-1066, Nicosia, Cyprus

Julia House, 3 Thermistocles Dervis Street, CY-1066, Nicosia, Cyprus