Avodart, 0.5 mg capsules 90 pcs

Pharmacological action Pharmacological action – antiandrogenic.

Pharmacodynamics

Dutasteride is a double inhibitor of 5α-reductase. Inhibits the activity of 5α-reductase type 1 and 2 isoenzymes, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). DHT is the main androgen responsible for glandular hyperplasia in the prostate gland.

The effect on DHT and testosterone concentrations. The maximum effect of dutasteride on reduction of DHT concentration is dose-dependent and is observed 1-2 weeks after the start of treatment. After 1 and 2 weeks of dutasteride at a dose of 0.5 mg/day, the average values of serum DHT concentrations are reduced by 85 and 90%, respectively.

Pharmacokinetics

Intake

After a single dose of 0.5 mg, the Tmax of dutasteride in serum is 1-3 hrs.

The absolute bioavailability of dutasteride in males is approximately 60% relative to a 2-hour IV infusion. The bioavailability of dutasteride is independent of food intake.

Distribution

Pharmacokinetic data obtained after single and multiple doses of dutasteride indicate a large Vd (300 to 500 L). Dutasteride has a high degree of binding to plasma proteins (>99.5%).

When taken daily, the serum concentration of dutasteride reaches 65% of the stable level after 1 month and approximately 90% of that level after 3 months. Stable serum concentrations of dutasteride (ss) of approximately 40 ng/mL are achieved after 6 months of daily administration of 0.5 mg of the drug. In sperm, as well as in serum, stable concentrations of dutasteride are also achieved after 6 months. After 52 weeks of treatment, dutasteride concentrations in sperm averaged 3.4 ng/ml (0.4 to 14 ng/ml). Approximately 11.5% of dutasteride was transferred from serum to sperm.

Metabolism

In vitro, dutasteride is metabolized by the human cytochrome P450 system CYP3A4 isoenzyme to two small monohydroxylated metabolites; However, it is not affected by the CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 or CYP2D6 isoenzymes of this system. After achieving stable serum concentrations of dutasteride, 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 by mass spectrometric method.

Dutasteride undergoes intensive metabolism in the human body. After oral administration of dutasteride at a dose of 0.5 mg/day until a stable concentration is reached, 1 to 15.4% (5.4% on average) of the dose taken is excreted through the intestine unchanged. The remainder is excreted through the intestine as 4 major metabolites, accounting for 39, 21, 7, and 7%, respectively, and 6 minor metabolites (each accounting for less than 5%).

Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are excreted through the kidneys in humans.

Therapeutic doses of dutasteride have a final T1/2 of 3-5 weeks.

Dutasteride is detectable in serum (in concentrations above 0.1 ng/ml) up to 4-6 months after discontinuation.

Linearity/nonlinearity

The pharmacokinetics of dutasteride can be described as a first-order absorption process and two parallel elimination processes, one saturable (i.e., concentration-dependent) and one unsaturated (i.e., concentration-independent). At low serum concentrations (less than 3 ng/ml), dutasteride is rapidly eliminated by both elimination processes. After a single dose of 5 mg or less, dutasteride is rapidly eliminated from the body and has a short T1/2 of 3-9 days.

At serum concentrations above 3 ng/ml, dutasteride is eliminated more slowly (0.35-0.58 L/h), primarily via a linear, unsaturated elimination process, with a final T1/2 of 3-5 weeks. At therapeutic concentrations, the final T1/2 is 3-5 weeks, and a slower clearance of dutasteride predominates with daily administration of 0.5 mg; overall clearance is linear and concentration-independent. Serum levels of dutasteride (greater than 0.1 ng/mL) are detectable for 4-6 months after discontinuation of treatment.

Elderly men

The pharmacokinetics and pharmacodynamics of dutasteride were studied in 36 healthy men aged 24 to 87 years after a single dose (5 mg) of the drug. There were no statistically significant differences between the different age groups in such pharmacokinetic parameters as AUC and Cmax. There were also no statistically significant differences in T1/2 values of dutasteride between the age groups of men 50-69 years old and over 70 years old, which include most men with BPH.

There were no significant differences between the different age groups in the degree of reduction of DHT levels. These results demonstrate that there is no need to reduce the dose of dutasteride depending on the age of patients.

Indications

Prostatic hyperplasia

As monotherapy:

Treatment and prevention of progression of benign prostatic hyperplasia by reducing the size of the prostate, improving urination, reducing the risk of acute urinary retention and the need for surgical intervention.

As combined therapy with α1-adrenoblockers:

Treatment and prevention of the progression of benign prostatic hyperplasia by reducing prostate size, improving urination, and reducing the risk of acute urinary retention and the need for surgical intervention. The combination of dutasteride and the α1-adrenoblocker tamsulosin has been primarily studied.

Active ingredient

Dutasteride

Composition

1 capsule contains:

The active ingredient:

Dutasteride – 500 mcg.

The excipients:

Mono- and diglycerides of caprylic/capric acid – 349.5 mg;
Butylhydroxytoluene – 35 µg.

The composition of the capsule shell:

Gelatin – 144.8 mg;
Glycerol – 70.8 mg;
Titanium dioxide – 1.78 mg;
Iron oxide yellow – 127 µg;
Medium-chain triglycerides – q.s;
Lecithin – q.s;
Red Printing Ink** – q.s.

How to take, the dosage

Orally, regardless of meals, swallowed whole without chewing or opening the capsule because the contents of the capsule may cause irritation of the oropharyngeal mucosa.

Adult men (including elderly adults)

The recommended dose of Avodart® is 1 capsule (0.5 mg) once daily.

While improvement with Avodart® is rapid, treatment should be continued for at least 6 months to give an objective assessment of the therapeutic effect. For treatment of BPH, Avodart® may be prescribed as monotherapy or in combination with α1-adrenoblockers.

Patients with impaired renal function: At 0.5 mg of Avodart® per day, less than 0.1% of the dose is renal excretion, so there is no need to decrease the dose in patients with impaired renal function.

Patients with hepatic impairment: Currently, there are no data on the use of Avodart® in patients with hepatic impairment. Since dutasteride is extensively metabolized and its T1/2 is 3-5 weeks, during the treatment with Avodart® patients with hepatic impairment one should be cautious.

Interaction

In vitro dutasteride is metabolized by the CYP3A4 isoenzyme of the human cytochrome P450 system. Therefore, in the presence of CYP3A4 inhibitors, blood concentrations of dutasteride may increase.

In concomitant use of dutasteride with CYP3A4 inhibitors verapamil and diltiazem, there is a decrease in clearance of dutasteride. At the same time, amlodipine, other BCCs when used concomitantly with dutasteride do not decrease the clearance of dutasteride. The decrease in clearance of dutasteride and subsequent increase in its blood concentration in the presence of CYP3A4 inhibitors is not clinically significant due to the wide range of safety limits of dutasteride, so there is no need to adjust its dose.

In vitro, dutasteride is not metabolized by the following isoenzymes of the human cytochrome P450 system: CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 or CYP2D6.

Dutasteride does not inhibit in vitro human cytochrome P450 system enzymes involved in drug metabolism.

In vitro dutasteride does not displace warfarin, acenocoumarol, phenprocoumon, diazepam and phenytoin from their binding sites to plasma proteins, and these drugs in turn do not displace dutasteride.

In studies of interactions of dutasteride with tamsulosin, terazosin, warfarin, digoxin and colestiramine in humans, no clinically significant pharmacokinetic or pharmacodynamic interactions have been observed.

When using dutasteride concomitantly with hypolipidemic drugs, ACE inhibitors, β-adrenoblockers, BCCs, corticosteroids, diuretics, NSAIDs, FDE-5 inhibitors and quinolone antibiotics no significant adverse drug interactions were observed.

Special Instructions

Dutasteride is absorbed through the skin, so women and children should avoid contact with damaged capsules. In case of contact with damaged capsules, the area of skin should be washed immediately with soap and water.

Hepatic impairment

There are currently no data on the use of Avodart® in patients with hepatic impairment. Because dutasteride is extensively metabolized and its half-life is 3-5 weeks, caution should be exercised when using Avodart® in patients with hepatic impairment.

Heart failure with the combined use of dutasteride and tamsulosin

In two 4-year clinical trials, the incidence of heart failure was higher in patients who received a combination of dutasteride and an alpha1-adrenoblocker, primarily tamsulosin, than in patients who did not receive the combined treatment. In these two studies, the incidence of heart failure remained low (≤ 1%) with some variability between them. But in general, there were no differences in the incidence of cardiovascular adverse events. No causal relationship between treatment with dutasteride (as monotherapy or in combination with an alpha1-adrenoblocker) and the development of heart failure was found.

The effect on the detection of prostate-specific antigen (PSA) and prostate cancer (PCa)

Patients should have a finger rectal examination, as well as other prostate examinations, before starting treatment with dutasteride and repeated periodically during treatment to rule out the development of PCa.

Serum PSA concentration determination is an important component of screening to detect PCa. After 6 months of therapy with dutasteride, average serum PSA levels decrease by about 50%. Patients taking dutasteride should have a new baseline PSA level determined after 6 months of therapy. Thereafter, regular monitoring of PSA levels is recommended.

The use of dutasteride has no effect on the diagnostic value of PSA levels as a marker of BPH. Any confirmed increase in PSA levels relative to the lowest PSA level during treatment with dutasteride may indicate the development of PCa (particularly high Gleason grade prostate cancer) or non-compliance with dutasteride therapy and should be carefully evaluated even if these PSA levels remain within normal limits for this age group of patients not taking 5α-reductase inhibitors.

Total PSA levels return to baseline within 6 months of dutasteride withdrawal.

The ratio of free PSA to total PSA remains constant even with dutasteride therapy. If the PSA free fraction percentage is additionally used to detect BPH in men receiving dutasteride, no correction of this value is necessary.

The effect of long-term dutasteride administration on the development of breast cancer in men

There has been no effect of long-term dutasteride administration on the development of breast cancer in men.

Breast cancer and high-grade tumors

The 4-year study (REDUCE) compared the use of placebo and dutasteride in 8,231 volunteers aged 50 to 75 years, with a negative biopsy result for PCa and PSA levels of 2.5 ng/mL to 10 ng/mL at baseline examination.

In the study, 6706 patients underwent a puncture biopsy of the prostate and the results were used to determine the degree of PCa malignancy according to the Gleason score. 1,517 patients were diagnosed with BC during the study. The majority of cases in both the dutasteride and placebo groups were diagnosed with highly differentiated PCa (Gleason score of 5-6). There were no differences in the number of cases of BC with a Gleason score of 7-10 in the dutasteride group and the placebo group (p = 0.81).

Four years later, there were more cases of BC with a Gleason score of 8-10 in the dutasteride group (n = 29; 0.9%) compared with the placebo group (n = 19; 0.6%) (p = 0.15%). When biopsy data were evaluated over 1-2 years, the number of patients with a Gleason score of 8-10 were comparable in the dutasteride (n = 17; 0.5%) and placebo groups (n = 18; 0.5%). When biopsy data were evaluated at 3 to 4 years, more cases of BC with a Gleason score of 8-10 were diagnosed in the dutasteride group (n = 12; 0.5%) compared with the placebo group (n = 1; < 0.1%) (p = 0.0035). The percentage of patients diagnosed with 8 to 10 Gleason score PCD was stable over all time periods (over years 1-2 and 3-4) in the dutasteride group (0.5% in each period), whereas the percentage of patients diagnosed with 8-10 score PCD was lower over years 3-4 than in years 1-2 (< 0.1% vs. 0.5%, respectively) in the placebo group.

In a 4-year study (CombAT) of patients with BPH in which performing a prostate biopsy on all participants was not defined by protocol and all diagnoses of BPH were based on biopsy by indication, BPH with a Gleason score of 8-10 was diagnosed in 8 patients ( < 0.5%) with dutasteride, 11 patients ( < 0.7%) with tamsulosin, and 5 patients ( < 0.3%) with dutasteride/tamsulosin combination therapy.

There was no causal relationship between dutasteride administration and the development of high-grade PCa.

Men taking dutasteride should have regular assessments of their risk of developing high-grade PCa, including PSA levels.

Impact on driving and operating machinery

The administration of dutasteride does not affect driving or operating machinery.

Contraindications

– hypersensitivity to dutasteride or any other component of the drug and other 5α-reductase inhibitors;

– women and children.

With caution: hepatic insufficiency.

Side effects

The undesired phenomena presented below are listed by body system and according to frequency of occurrence. The frequency of occurrence is defined as follows: very frequently, ?1/10; frequently, ?1/100 and < 1/10; infrequently, ?1/1000 and < 1/100; rarely, ?1/10000 and < 1/1000; very rarely, < 1/10000, including individual cases. Frequency categories were formed based on post-registration follow-up.

Frequency of adverse events formed on the basis of post-registration observation

Immune system disorders: very rare – allergic reactions (including rash, pruritus, urticaria, localized edema) and angioedema.

Skin and subcutaneous fatty tissue: rarely – alopecia (mostly loss of body hair) or hypertrichosis.

Mental disorders: very rare – depression.

Reproductive system and breast disorders: very rare – testicular pain, testicular edema.

The incidence of adverse events formed from data from clinical trials (adverse events associated with the use of dutasteride as monotherapy)

In phase 3 placebo-controlled trials with dutasteride compared to placebo, investigators evaluated adverse events associated with taking dutasteride.

Overdose

When dutasteride was administered up to 40 mg/day once (80 times the therapeutic dose) for 7 days, no significant side effects were observed. In a clinical study, patients received dutasteride at a dose of 5 mg daily for 6 months, with no additional side effects to those observed with 0.5 mg dutasteride.

Treatment: symptomatic and supportive, as there is no specific antidote for dutasteride.

Pregnancy use

Fertility. The effect of dutasteride at a daily dose of 0.5 mg on sperm characteristics was studied in healthy volunteers aged 18-52 years. By the 52nd week of treatment in the group of patients receiving dutasteride, the mean values of percentage reductions in total sperm count, sperm volume and sperm motility were 23, 26 and 18%, respectively, compared with baseline in the group of patients receiving placebo. Sperm concentration and morphology were unchanged.

After 24 weeks of follow-up, the mean percentage change in total sperm count in the dutasteride group remained 23% lower compared to baseline. The mean value for all semen parameters at all time points remained within the normal range and did not meet the set criteria for a clinically significant change (30%), at 52 weeks of treatment in two volunteers in the dutasteride group, total sperm count decreased by more than 90% from baseline, with a partial recovery at 24 weeks of follow-up.

Thus, the clinical significance of the effect of dutasteride on sperm counts and on a patient’s individual fertility is unknown.

Dutasteride is contraindicated in women. Dutasteride has not been studied in women because preclinical data suggest that suppression of DHT levels may cause inhibition of male fetal external genital development.

There are no data on the penetration of dutasteride into breast milk.

Similarities

Dutasteride