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Drug for the treatment of benign prostatic hyperplasia. Dutasteride is a double inhibitor of 5α-reductase. Inhibits the activity of isoenzymes 5α-reductase 1 and 2 types, which are responsible for the conversion of testosterone to 5α-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 the reduction of DHT concentrations is dose-dependent and is observed 1-2 weeks after the start of treatment. After 1 and 2 weeks of dutasterid dosing at a dose of 500 µg / day, the mean values of serum dihydrotestosterone concentrations are reduced by 85% and 90%.
After a single dose of the drug in a dose of 500 µg Cmax of dutasteride in serum is reached within 1-3 hours. Absolute bioavailability is about 60% relative to a 2-hour w / in infusion. Bioavailability of dutasteride does not depend on food intake.
Pharmacokinetic data obtained after a single and repeated intake of dutasteride, indicates a large Vd (300 to 500 liters). 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 stationary level after 1 month and approximately 90% of this level after 3 months. Stationary concentrations of dutasteride in serum (Css), equal to about 40 ng / ml, are achieved after 6 months of daily intake of 500 μg of this drug. In semen, as in serum, steady-state concentrations of dutasteride are also reached after 6 months. After 52 weeks of treatment, the concentration of dutasteride in semen averaged 3.4 ng / ml (from 0.4 to 14 ng / ml). Approximately 11.5% of dutasteride gets into the semen from blood serum.
In vitro, dutasteride is metabolized by a CYP3A2 isoenzyme to form two small monohydroxylated metabolites; however, it is not affected by the isoenzymes CYP2C9, CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2B6, CYP2C19 and CYP2D6. After reaching Css dutasteride, unchanged dutasteride, 3 large metabolites (4′-hydroxydutasteride, 1,2-dihydrodutasteride and 6-hydroxydeasteride) and 2 small metabolites are detected in the serum using the mass spectrometric method.
In humans, dutasteride is extensively metabolized. After ingestion of dutasteride at a daily dose of 500 µg to achieve Css from 1% to 15.4% (on average 5.4%) of the dose taken is excreted through the intestine unchanged. The rest is excreted in the form of 4 large metabolites, constituting 39%, 21%, 7% and 7%, respectively, and 6 small metabolites (each of which accounts for less than 5%).
Traces of unchanged dutasteride (less than 0.1% of the dose) are excreted through the kidneys in humans.
When receiving therapeutic doses of dutasteride, its final T1 / 2 is 3-5 weeks.
Dutasteride is detected in the serum (at 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 saturated (that is, dependent on concentration) and one unsaturated (that is, not dependent on concentration). At low serum concentrations (less than 3 ng / ml), dutasteride is rapidly excreted through both elimination processes. After a single dose in doses of 5 mg or less, dutasteride is quickly eliminated from the body and has a short half-life of 3-9 days.
At serum concentrations above 3 ng / ml, the clearance of dutasteride occurs more slowly (0.35–0.58 l / h), mainly by means of a linear, unsaturated elimination process with a final T1 / 2 of 3-5 weeks. At therapeutic concentrations, with a daily intake of 500 µg, slower clearance of dutasteride prevails; total clearance is linear and not dependent on concentration.
The pharmacokinetics and pharmacodynamics of dutasteride were studied in 36 healthy men aged from 24 to 87 years after taking one dose (5 mg) of this drug. There were no statistically significant differences between different age groups in pharmacokinetic parameters such as AUC and Cmax. There were also no statistically significant differences in the dutasterid T1 / 2 values between the age groups of men 50-69 years and over 70 years, which include most men with benign prostatic hyperplasia.
Between different age groups there were no significant differences in the degree of reduction of DHT levels. These results demonstrate that there is no need to reduce the dose of dutasteride in elderly patients.
The drug can be taken regardless of the meal.
Capsules should be swallowed whole, not chewed and not opened, because the contents of the capsule can cause irritation of the mucous membrane of the oropharynx.
Benign prostatic hyperplasia (BPH)
Adult men (including the elderly) The recommended dose of Avodart is 1 capsule (500 µg) 1 time / day. Capsules should be taken whole.
Although improvement with the use of the drug comes fairly quickly, treatment should be continued for at least 6 months in order to objectively evaluate the therapeutic effect.
For the treatment of BPH, Avodart may be prescribed as monotherapy or in combination with alpha1-blockers.
⇝Special patient groups
When receiving 500 mg / day, the kidneys excrete less than 0.1% of the dose, so there is no need to reduce the dose in patients with impaired renal function.
Currently there are no data on the use of Avodart in patients with impaired liver function. Since dutasteride undergoes intensive metabolism, and its half-life is 3-5 weeks, care must be taken when treating Avodart with patients with impaired liver function.
When prescribing dutasteride up to 40 mg / day once (80 times higher than the therapeutic dose) for 7 days, no significant side effects were noted. When conducting clinical trials, patients received dutasteride at a dose of 5 mg daily for 6 months, while no additional side effects were found to those that were observed while receiving 500 μg of dutasteride.
There is no specific antidote for dutasteride; therefore, if an overdose is suspected, it is sufficient to conduct symptomatic and supportive treatment.
The adverse events presented below are listed depending on the anatomical and physiological classification and frequency of occurrence. The frequency of occurrence is determined 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 observation.
The frequency of occurrence of adverse events, formed on the basis of post-registration observation
⇝The immune system
– Allergic reactions (including rash, itching, urticaria, localized edema) and angioedema
⇝ From the skin and subcutaneous fat
– alopecia (mainly loss of body hair) or hypertrichosis
– depressed state
⇝From the reproductive system
– testicular pain, testicular edema
The frequency of occurrence of adverse events, formed on the basis of data from clinical studies (adverse events associated with the use of dutasteride as monotherapy)
– as monotherapy for the treatment and prevention of progression of benign prostatic hyperplasia by reducing its size, relieving symptoms, improving urination, reducing the risk of acute urinary retention and the need for surgery;
– as a combination therapy with alpha1-blockers for the treatment and prevention of progression of benign prostatic hyperplasia by reducing its size, relieving symptoms, improving urination, reducing the risk of acute urinary retention and the need for surgery. The combination of dutasteride and tamsulosin alpha1-blocker was mainly studied.
– hypersensitivity to dutasteride and other components of the drug;
– hypersensitivity to other 5α-reductase inhibitors;
– caution should be prescribed the drug for liver failure;
Avodart is contraindicated for women and children. Precautions should be prescribed the drug for liver failure.
Dutasteride is absorbed through the skin, so women and children should avoid contact with damaged capsules. In case of contact with damaged capsules, it is necessary to immediately wash the corresponding skin area with soap and water.
⇝Heart failure with combined use of dutasteride and tamsulosin
In two 4-year clinical studies, the incidence of heart failure was higher in patients who received the combination of dutasteride and alpha1-blocker, mainly 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 was no discrepancy in the incidence of side effects from the cardiovascular system. The causal connection between treatment with dutasteride (as monotherapy or in combination with an alpha1-blocker) and the development of heart failure has not been established.
Effect on the detection of prostate-specific antigen (PSA) and prostate cancer (PCa)
Patients need to conduct a digital rectal examination, as well as use other methods of research of the prostate gland, before starting treatment with dutasteride, and periodically repeat them during treatment to rule out the development of prostate cancer.
⇝The information can not be used to replace direct consultation with a doctor or make a decision on the use of medicines.