Universal reference book for medicines
Product name: AVODART ® (AVODART ® )

Active substance: dutasteride

Type: The drug for the treatment of benign prostatic hyperplasia.
Inhibitor of 5? -reductase
Manufacturer: GlaxoSmithKline Trading (Russia) manufactured by Catalent France Beinheim (France)
Composition, form of production and packaging
Capsules
soft gelatinous, yellow, oblong, opaque, marked * with code "GX CE2".

1 caps.

dutasteride 500 μg

Excipients: caprylic / capric acid mono di-glycerides (MDC) - 349.5 mg, butylhydroxytoluene - 0.035 mg.

The weight of the contents of the capsule is 350 mg.

The composition of the capsule shell: gelatin - 144.8 mg, glycerol (glycerin) - 70.8 mg, titanium dioxide - 1.78 mg, iron oxide yellow - 0.127 mg;
technological additives - medium chain triglycerides (TSC) ** - qs, lecithin ** - qs; red ink for printing *** - qs
10 pieces.
- blisters (3) - packs of cardboard.
10 pieces.
- blisters (9) - packs of cardboard.
* The application of the "GX CE2" code with red ink for printing is used in the manufacture of the finished dosage form at the production site of Catalent France Beinheim SA (France).
The application of the "GX CE2" code in gray with a UV cold laser is used in the production of the finished dosage form at the production site of GlaxoSmithKline Pharmaceuticals SA (Poland).
** TCS and lecithin are used as lubricants in the manufacturing process.
The total amount of lubricants per capsule does not exceed 1.5 mg. The concentration of lecithin in the TSC 0.1% IV.
*** Red ink for printing is used in the manufacture of the finished dosage form on the production site of Catalent France Beinheim SA (France) and is not used in the production of the finished dosage form at the production site of GlaxoSmithKline Pharmaceuticals SA (Poland).
The amount of ink on each capsule is calculated in such a way that it is less than 0.28 mg. The materials remaining on the capsule are polyvinyl acetate phthalate (National Formulary), macrogol (polyethylene glycol) (Hebrew Pharmacopeia), propylene glycol (Hebrew Pharmacopeia), iron oxide red (E172, CI77491).
INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2017.

PHARMACHOLOGIC EFFECT

The drug for the treatment of benign prostatic hyperplasia.
Dutasteride is a double inhibitor of 5? -reductase. Suppresses the activity of isoenzymes of 5-reductase 1 and 2 types, which are responsible for converting testosterone to dihydrotestosterone (DHT). Dihydrotestosterone is the main androgen responsible for the hyperplasia of the glandular tissue of the prostate gland.
The maximum effect of dutasteride on decreasing concentrations of DHT is dose-dependent and observed 1-2 weeks after the start of treatment.
After 1 and 2 weeks of taking dutasteride at a dose of 500 μg / day, the average serum concentrations of dihydrotestosterone decrease by 85% and 90%, respectively.
PHARMACOKINETICS

Suction

After a single dose of 500 μg C max, dutasteride in the serum is reached within 1-3 hours. Absolute bioavailability is about 60% with respect to a 2-hour IV infusion.Bioavailability of dutasteride does not depend on food intake.

Distribution

The pharmacokinetic data obtained after a single and multiple dutasteride administration indicates a large V d (from 300 to 500 L).
Dutasteride has a high degree of binding to plasma proteins (> 99.5%).
With daily intake, the concentration of dutasteride in the serum reaches 65% of the stable level after 1 month and approximately 90% of the stable level after 3 months.
Stable concentrations of serum dutasteride (C ss ), approximately 40 ng / ml, are achieved after 6 months of a single daily intake of 500 μg of this drug. In sperm, as in serum, stable concentrations of dutasteride are also reached after 6 months. After 52 weeks of treatment, the concentrations of dutasteride in the sperm averaged 3.4 ng / ml (0.4 to 14 ng / ml). From serum, about 11.5% of dutasteride enters the semen.
Metabolism

In vitro, dutasteride is metabolized by the CYP3A4 isoenzyme of the human cytochrome P450 system to form two small monohydroxylated metabolites;
At the same time, isoenzymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19 or CYP2D6 do not act on it. After reaching C ss of dutasteride in the serum using a mass spectrometric method, unchanged dutasteride, 3 large metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride and 6-hydroxydutasteride) and 2 small metabolites (6,4'-dihydroxydutasteride and 15- hydroxydutasteride).
Excretion

In the human body, dutasteride undergoes intensive metabolism.
After ingestion of dutasteride in a daily dose of 500 mcg to achieve C ss from 1% to 15.4% (an average of 5.4%) of the accepted dose is excreted through the intestine in unchanged form. The rest is excreted through the intestine in the form of 4 large metabolites, accounting for 39%, 21%, 7% and 7%, respectively, and 6 small metabolites (each accounting for less than 5%).
Through the kidney in humans only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are excreted.

When taking therapeutic doses of dutasteride, its final T 1/2 is 3-5 weeks.

Dutasteride is found 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., depending on concentration) and one unsaturated (i.e., concentration-independent).
At low serum concentrations (less than 3 ng / ml), dutasteride is rapidly excreted by both elimination processes. After a single dose of 5 mg or less, dutasteride is rapidly eliminated from the body and has a short T 1/2 , equal to 3-9 days.
At concentrations in the serum above 3 ng / ml, dutasteride is excreted more slowly (0.35-0.58 l / h), mainly through a linear unsaturated elimination process with a finite T 1/2 of 3-5 weeks.
At therapeutic concentrations, the final T 1/2 with a daily intake of 500 μg is dominated by a slower clearance of dutasteride; The overall clearance is linear and independent of concentration. The content of dutasteride in the blood serum (more than 0.1 ng / ml) is detected within 4-6 months after discontinuation of treatment.
Pharmacokinetics in specific patient groups

The pharmacokinetics and pharmacodynamics of dutasteride were studied in 36 healthy volunteers aged 24 to 87 years after receiving a single dose (5 mg) of dutasteride.There were no statistically significant differences between the different age groups for such pharmacokinetic parameters as AUC and C max in blood plasma.
There were also no statistically significant differences in T 1/2 dutasteride values ​​between the age groups of men 50-69 years old and over 70 years of age, which include the majority of men with benign prostatic hyperplasia.
Between different age groups, there were no significant differences in the degree of decrease in DHT levels.
These results demonstrate that there is no need to reduce the dose of dutasteride depending on the age of the patients.
INDICATIONS

- as a monotherapy for the treatment and prevention of the progression of benign prostatic hyperplasia by reducing its size, alleviating symptoms, improving urination, reducing the risk of acute urinary retention and the need for surgery;

- as a combined therapy with alpha 1- adrenoblockers to treat and prevent the progression of benign prostatic hyperplasia by reducing its size, alleviating symptoms, improving urination, reducing the risk of acute urinary retention, and the need for surgery.
The combination of dutasteride and alpha 1- adrenoblocker tamsulosin was mainly studied.
DOSING MODE

The drug can be taken regardless of food intake.
Capsules should be swallowed whole, not chewed and not opened, as the contents of the capsule can cause irritation of the mucous membrane of the oropharynx.
Benign prostatic hyperplasia (BPH)

In adult men (including the elderly), the recommended dose of Avodart® is 1 caps.
(500 mcg) 1 time / day.
Although the improvement in the background of the use of the drug occurs rather quickly, treatment should be continued for at least 6 months in order to objectively evaluate the therapeutic effect.

For the treatment of BPH, Avodart® can be given as monotherapy or in combination with alpha 1- adrenoblockers.

When taking 500 μg / day through the kidneys, less than 0.1% of the dose is released, so there is no need to reduce the dose in patients with impaired renal function.

Currently, there is no data on the use of Avodart ® in patients with impaired hepatic function .
Because Dutasteride is subject to intensive metabolism, and its T 1/2 is 3-5 weeks, care must be taken when treating Avodart® patients with impaired liver function.
SIDE EFFECT

The adverse events presented below are listed by systems and according to frequency of occurrence.
Frequency of occurrence is defined as follows: very often (? 1/10), often (? 1/100 and <1/10), infrequently (? 1/1000 and <1/100), rarely (? 1/10 000 and < 1/1000), very rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.
Frequency of occurrence of undesirable phenomena, formed on the basis of post-registration observation

From the immune system

Very rarely allergic reactions (including rash, itching, hives, localized edema) and angioedema

From the skin and subcutaneous fat

Rarely, alopecia (mainly hair loss on the body) or hypertrichosis

Mental disturbance

Very rarely depressed

From the side of the reproductive system and mammary glands

Very rarely testicular pain, testicular edema

Frequency of occurrence of undesirable phenomena, formed on the basis of clinical research data (undesirable phenomena associated with the use of dutasteride as monotherapy)

In the third phase of placebo-controlled trials with dutasteride compared with placebo, the researchers assessed the undesirable effects associated with dutasteride:

Adverse event The occurrence of an undesirable phenomenon in the first year of use The occurrence of an undesirable phenomenon in the 2 nd year of use

Placebo (n = 2158) Dutasteride (n = 2167) Placebo (n = 1736) Dutasteride (n = 1744)

Erectile dysfunction 2 3% 6% 1% 2%

Reduction of libido 2 2% 4% <1% <1%

Violation of ejaculation 2 <1% 2% <1% <1%

Breast disorders 1 <1% 1% <1% 1%

1 - including tenderness and enlargement of the mammary glands.

2 - undesirable phenomena on the part of the reproductive system and mammary glands associated with the use of dutasteride (both in monotherapy and in combination with tamsulosin).
These adverse events may persist after discontinuation of treatment and the effect of dutasteride on the preservation of these undesirable events is not known.
Undesirable effects associated with the use of dutasteride in combination with tamsulosin

The following adverse events were reported in the CombAT study (comparison of dutasteride 500 μg and tamsulosin 400 μg 1 time / day as monotherapy or as a combination for 4 years) and evaluated by researchers with a cumulative effect of 1%).

Adverse event The occurrence of an undesirable phenomenon during the period of tamsulosin in combination with dutasteride

Year 1 Year 2 Year 3 Year 4 Year

Combination 1 (n) (n = 1610) (n = 1428) (n = 1283) (n = 1200)

Dutasteride (n = 1623) (n = 1464) (n = 1325) (n = 1200)

Tamsulosin (n = 1611) (n = 1468) (n = 1281) (n = 1112)

Erectile dysfunction 3

The combination of 6% 2% <1% <1%

Dutasteride 5% 2% <1% <1%

Tamsulosin 3% 1% <1% <1%

Decreased libido 3

The combination of 5% <1% <1% 0%

Dutasteride 4% 1% <1% 0%

Tamsulosin 2% <1% <1% <1%

Violation of ejaculation 3

Combination 9% 1% <1% <1%

Dutasteride 1% <1% <1% <1%

Tamsulosin 3% <1% <1% <1%

Breast problems 2

The combination of 2% <1% <1% <1%

Dutasteride 2% 1% <1% <1%

Tamsulosin <1% <1% <1% 0%

Dizziness

The combination of 1% <1% <1% <1%

Dutasteride <1% <1% <1% <1%

Tamsulosin 1% <1% <1% 0%

1 - combination = dutasteride 500 mcg 1 time / day + tamsulosin 400 mcg 1 time / day;

2 - including tenderness and enlargement of the mammary glands;

3 - undesirable phenomena on the part of the reproductive system and mammary glands associated with the use of dutasteride (both in monotherapy and in combination with tamsulosin).
These adverse events may persist after discontinuation of treatment. The effect of dutasteride on the preservation of these undesirable phenomena is unknown.
CONTRAINDICATIONS

- hypersensitivity to dutasteride and other components of the drug;

- Hypersensitivity to other inhibitors of 5? -reductase.

Avodart® is contraindicated in women and children.

With caution should prescribe the drug for liver failure.

PREGNANCY AND LACTATION

Impact on fertility

The effect of dutasteride in a daily dose of 500 μg on the characteristics of sperm was studied in healthy volunteers aged 18-52 years.
By the 52nd week of treatment, in the group of patients receiving dutasteride, the mean percentages of the total sperm count, sperm volume and motor activity of spermatozoa were 23%, 26%, and 18%, respectively, compared to baseline in the placebo group. The concentration of spermatozoa and their morphological characteristics did not change.
After 24 weeks of follow-up, the mean percentage change in the total number of spermatozoa in the dutasteride group remained 23% lower compared to baseline.
The mean value for all sperm parameters at all time points remained within the norm and did not meet the criteria for a clinically significant change (30%), at the 52nd week of treatment in two volunteers in the dutasteride group, the total number of spermatozoa decreased by more than 90% compared with the baseline, with partial recovery at the 24th week of follow-up.
Thus, the clinical significance of the effect of dutasteride on sperm counts and individual patient fertility is unknown.

Pregnancy

Dutasteride is contraindicated in women.
Dutasteride was not studied in women; preclinical data suggest that suppressing the level of DHT can cause inhibition of the development of external genital organs in a male fetus.
Lactation

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

APPLICATION FOR FUNCTIONS OF THE LIVER

In case of violations of kidney function, a dose reduction is not required (as when taking the drug at a dose of 500 mcg / day with urine, less than 0.1% of the dose is released).

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

With caution should prescribe the drug for liver failure.

APPLICATION FOR CHILDREN

Avodart ® is contraindicated in children.

APPLICATION IN ELDERLY PATIENTS

Correction of the dose is not required.

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, immediately wash the corresponding skin area with soap and water.
Impaired liver function

Currently, there is no data on the use of Avodart ® in patients with impaired hepatic function.
Because Dutasteride is subject to intensive metabolism, and its T 1/2 is 3-5 weeks, care must be taken when treating Avodart® patients with impaired liver function.
Heart failure with 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 alpha 1- adrenoblocker, mainly tamsulosin, than patients who did not receive combination treatment.
In these two studies, the incidence of heart failure remained low (? 1%) with some variability between them. But in general, there were no discrepancies in the frequency of side effects from the cardiovascular system. The causal relationship between treatment with dutasteride (as monotherapy or as a combination with alpha 1- adrenoblocker) and the development of heart failure is not established.
Effect on the detection of prostate-specific antigen (PSA) and prostate cancer (PCa)

Patients should undergo digital rectal examination, and also use other methods of prostate gland testing, before starting treatment with dutasteride and periodically repeat them during treatment to exclude the development of PCa.

Determination of serum PSA is an important component of screening aimed at detecting PCa.
After a 6-month therapy with dutasteride, the average serum PSA level is reduced by approximately 50%. Patients taking dutasteride should be given a new baseline PSA level after 6 months of therapy. In the future, it is recommended to regularly monitor the level of PSA. When interpreting the PSA value of a patient taking dutasteride, the previous PSA value should be used for comparison.
The use of dutasteride does not affect the diagnostic value of PSA as a marker of PCa after the definition of a new baseline PSA level.
Any confirmed increase in PSA level relative to the least of its value in the treatment of dutasteride may indicate the development of prostate cancer (particularly prostate cancer with a high degree of differentiation by Gleason score), or treatment non-compliance with dutasteride should be carefully evaluated, even if the levels of PSA remain within the normal range for this age category of patients not taking inhibitors of 5? -reductase.
Total PSA level returns to baseline within 6 months after discontinuation of dutasteride.
The ratio of free PSA to total content remains constant even compared with dutasteride therapy. If the determination of percent free PSA content fraction is further used to detect prostate cancer in men receiving dutasteride, this correction value is required.
Prostate cancer and tumors high gradation
at the 4-year study (REDUCE) were compared applying a placebo and dutasteride at 8231 volunteer aged 50 years to 75 years with negative biopsies for the presence of prostate cancer, and PSA level of 2.5 ng / ml to 10 ng / ml at the initial examination.
In the study, 6706 patients underwent needle biopsy of the prostate gland and on the basis of the results determined by the degree of malignancy of prostate cancer Gleason score. 1517 patients in the study were diagnosed with prostate cancer. In most cases, both the dutasteride group and in the placebo group, a highly differentiated prostate cancer (score Gleason score 5-6) was diagnosed. Differences in the number of cases of prostate cancer with the assessment of 7-10 points on the Gleason score in the dutasteride group and the placebo group were absent (p = 0.81).
more cases of prostate cancer was observed after 4 years with an estimate 8-10 Gleason dutasteride group (n = 29; 0.9%) compared with the placebo group (n = 19; 0.6%) (p = 0.15). When evaluating biopsy for 1-2 minutes years the number of patients diagnosed with prostate cancer with an estimate 8-10 Gleason grade was comparable in groups dutasteride (n = 17; 0.5%) or placebo (n = 18; 0.5%). When evaluating biopsy for 3-4th years was diagnosed more cases of prostate cancer with the assessment of 8-10 points Gleason dutasteride group (n = 12; 0.5%) compared with the placebo group (n = 1, <0.1%) (p = 0.0035). The percentage of patients diagnosed with prostate cancer with an estimate 8-10 Gleason was stable for all time intervals (period of 1-2 minutes and 3-4 minutes years) dutasteride group (0.5% in each period)while in the placebo group, the percentage of patients with a diagnosis of prostate cancer with the assessment of 8-10 points was lower during a 3-4 second period than in the 1-2 th years (<0.1% compared to 0.5% respectively).
The 4-year study (CombAT) patients with BPH, in which a biopsy of the prostate all participants was not defined protocol, and all diagnoses of prostate cancer based on biopsy if indicated, prostate cancer with an estimate of 8-10 Gleason was diagnosed in 8 patients (<0.5%) when receiving dutasteride, 11 patients (<0.7%) with tamsulosin and 5 patients (<0.3%) in the combination therapy with tamsulosin and dutasteride.
The causal connection between the reception and the development of prostate cancer dutasteride high gradation is not established.
Men taking dutasteride, should be regularly monitored for assessing the risk of developing prostate cancer, including a PSA level.
Breast cancer in men
In clinical studies and post-marketing surveillance during the reported occurrence of breast cancer in men taking dutasteride. Patients should be warned that the appearance of any changes in the tissues of the breast, such as the appearance of nodules or discharge from the nipple, should immediately report it to your doctor.
In clinical studies, which were conducted to study the effect of monotherapy with dutasteride for BPH (3374 patient-years), 2 cases of breast cancer associated with dutasteride treatment (10 weeks and 11 months) and 1 case in a patient receiving placebo. In subsequent clinical trials, which involved 8231 men aged 50 to 75 years with negative biopsies for prostate cancer, and PSA level in the range of 2.5 ng / ml to 10 ng / ml (17,489 patient-years) who received dutasteride and patients (5027 patient-years) who received komibinirovannuyu therapy with dutasteride and tamsulosin, there was no evidence of cases of breast cancer in any of the comparison groups.
At the moment, it is unclear whether there is a causal relationship between the occurrence of breast cancer in men and the long-term use of dutasteride.
Impact on the ability to drive vehicles and manage mechanisms

Admission dutasteride does not affect driving or using machinery.
OVERDOSE

When assigning dutasteride to 40 mg / day one (80 times higher than the therapeutic dose) for 7 days, significant side effects were noted. In clinical studies, patients within 6 months dutasteride received a dose of 5 mg daily, with any additional adverse effects to those observed in patients receiving dutasteride dose of 500 ug, was not detected.
Treatment: the specific antidote dutasteride is not, so if you suspect an overdose enough to spend symptomatic and supportive treatment.
DRUG INTERACTION

In vitro dutasteride metabolized by CYP3A4 isoenzyme of cytochrome P450 enzyme systems of man. Consequently, in the presence of inhibitors in the blood concentration of CYP3A4 may increase dutasteride.
With simultaneous application of dutasteride CYP3A4 inhibitors verapamil and diltiazem marked reduction in clearance of dutasteride. However, amlodipine, other calcium channel blockers, while the use of dutasteride not reduce the ground clearance of dutasteride. Decreasing clearance dutasteride and the subsequent increase in its concentration in the blood in the presence of CYP3A4 inhibitors is not clinically significant because of the wide range of dutasteride security boundaries, so there is no need to adjust the dose.
In vitro dutasteride not metabolized following isozymes of cytochrome P450 Human: CYP1A2, CYP2A6, CYP2E1, CYP2C8 , CYP2C9, CYP2C19, CYP2B6 or CYP2D6.
Dutasteride does not inhibit the enzyme in vitro system of human cytochrome P450 involved in the metabolism of drugs.
In vitro dutasteride does not displace warfarin, acenocoumarol, phenprocoumon, diazepam and phenytoin of the sites of their binding to plasma proteins, and these drugs are, in turn, do not displace dutasteride.
In carrying out studies of the interaction of dutasteride with tamsulosin, terazosin, warfarin, digoxin and kolestiraminom a person of any clinically significant pharmacokinetic or pharmacodynamic interactions were observed.
When applied simultaneously with dutasteride hypolipidemic drugs, ACE inhibitors, beta-blockers, calcium channel blockers, corticosteroids, diuretics, NSAIDs, inhibitors of phosphodiesterase type 5 and quinolone antibiotics any significant undesirable drug interaction was observed.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be kept out of reach of children at a temperature not higher than 30 ° C.
Shelf life - 4 years.

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