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Pharmacological action of Avodart
Mechanism of action
Dutasteride is a dual 5α-reductase inhibitor. Suppresses the activity of 5α-reductase isoenzymes of types 1 and 2, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). Dihydrotestosterone is the main androgen responsible for hyperplasia of the glandular tissue of the prostate.
The maximum effect of daily doses of dutasteride on the decrease in DHT concentration is dose-dependent and is observed within 1-2 weeks. After 1 and 2 weeks of taking dutasteride at a dose of 500 μg / day, the mean serum DHT concentrations decreased by 85% and 90%, respectively.
In patients with benign prostatic hyperplasia (BPH) who received dutasteride at a dose of 500 μg / day, the average decrease in DHT concentration was 94% after 1 year and 93% after 2 years, the average increase in serum testosterone concentration was 19% as after 1 year, and after 2 years. This is the expected consequence of 5α-reductase inhibition and does not lead to any of the known adverse events.
Pharmacokinetics of Avodart
After taking a single dose of dutasteride (500 μg) Cmax in serum is reached within 1-3 hours. The absolute bioavailability of dutasteride in men is about 60% relative to a 2-hour intravenous infusion. The bioavailability of dutasteride is independent of food intake.
Pharmacokinetic data obtained after single and repeated oral administration of dutasteride indicate a large Vd (from 300 to 500 liters). Dutasteride has a high degree of binding to blood plasma proteins (more than 99.5%).
When taken daily, the serum concentration of dutasteride reaches 65% of the equilibrium concentration after 1 month and approximately 90% of the equilibrium concentration after 3 months.Css of Serumdutasteride, approximately 40 ng / ml, are achieved after 6 months of a single daily intake of 500 mcg of dutasteride. In semen, as in blood serum, Css of dutasteride are also reached after 6 months. After 52 weeks of treatment, semen concentrations of dutasteride averaged 3.4 ng / ml (0.4 to 14 ng / ml). From the blood serum, an average of 11.5% of dutasteride enters the semen.
In vitro dutasteride is metabolized by the CYP3A4 isoenzyme of the human cytochrome P450 system to two minor monohydroxylated metabolites; isoenzymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 or CYP2D6 are not involved in the metabolism of dutasteride.
After reaching Css dutasteride in blood serum, unchanged dutasteride, 3 major metabolites (4'-hydroxydutasteride, 1,2-dihydroductasteride, and 6-hydroxydutasteride) and 2 minor metabolites (6,4'-dihydroxydutasteride and 15-hydroxydutasteride). Five dutasteride metabolites found in human serum were detected in rat serum, while the stereochemistry of hydroxyl groups at positions 6 and 15 of metabolites in humans and rats is unknown.
Dutasteride undergoes intensive metabolism. After oral administration of dutasteride in a daily dose of 500 mcg until an equilibrium concentration in humans is reached from 1% to 15.4% (on average 5.4%) of the dose taken, it is excreted through the intestine unchanged. The rest is excreted through the intestine in the form of 4 major metabolites, constituting 39%, 21%, 7% and 7%, respectively, and 6 minor metabolites (each of which accounts for less than 5%).
Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are found in human urine. At low serum concentrations (less than 3 ng / ml), dutasteride is rapidly eliminated by both concentration-dependent and concentration-independent routes. With a single dose of dutasteride of 500 mcg or less, a rapid clearance was observed with a short T1/2 of 3 to 9 days.
At a serum concentration of more than 3 ng / ml, dutasteride is excreted slowly (from 0.35 to 0.58 l / h), mostly linearly, regardless of concentration, with a final T1/2 from 3 to 5 weeks. When taking therapeutic doses of dutasteride, the final T1/2 is 3-5 weeks, after repeated administration at a dose of 500 μg / day, a slower clearance dominates, and the total clearance is linear and independent of concentration. Dutasteride is found in serum (at concentrations above 0.1 ng / ml) within 4-6 months after stopping treatment.
Pharmacokinetics in special groups of patients
Elderly patients. The pharmacokinetics and pharmacodynamics of dutasteride were studied in 36 healthy male volunteers aged 24 to 87 years after taking a single dose (500 μg) of dutasteride. There were no statistically significant differences in dutasteride exposure, represented by pharmacokinetic parameters such as AUC and Cbetween different age groupsmax,. Also, statistically significant differences for Tvalues ofnot been established1/2 dutasteride havebetween the age groups of men 50-69 years old and over 70 years old, which include the majority of men with BPH. There were no differences in the effect of the drug, determined by the degree of decrease in DHT concentration, between different age groups. The presented results indicate that there is no need to adjust the dose of dutasteride depending on the age of the patients.
Patients with impaired renal function. The effect of renal dysfunction on the pharmacokinetics of dutasteride has not been studied. However, less than 0.1% of the equilibrium concentration of dutasteride (when taking a dose of 500 mcg of dutasteride) is excreted by the kidneys in humans, so there is no need for dose adjustment in case of impaired renal function.
Patients with impaired liver function. The effect of impaired liver function on the pharmacokinetics of dutasteride has not been studied.
Indications Avodart formulation®
- as monotherapy for the treatment and prevention of the progression of benign prostatic hyperplasia by reducing its size, alleviation of symptoms, improvement of urination, decrease the risk of acute urinary retention and the need for surgical intervention;
- as a combination therapy with alpha-adrenergic1blockers for the treatment and prevention of the 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 the alphawas mainly studied1-adrenergic blocker tamsulosin.
Dosage regimen of Avodart
The drug can be taken with or without food. The capsules should be swallowed whole, not chewed or opened, as the contents of the capsule may irritate 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 with the use of the drug occurs rather quickly, the treatment should be continued for at least 6 months in order to objectively assess the therapeutic effect.
For the treatment of BPH Avodartformulation® may be designated as a monotherapy or in combination with an alpha1adrenoblokatorami.
Special groups of patients
When taking 500 mcg / day, less than 0.1% of the dose is excreted through the kidneys, 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 liver function. Because dutasteride undergoes extensive metabolism and its T1/2 is 3-5 weeks, care must be taken in the treatment of drug Avodart® patients with impaired liver function.
- hypersensitivity to dutasteride or any other component of the drug and other 5α-reductase inhibitors;
- women and children.
- With caution: liver failure.
Pregnancy and lactation
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 the percentage reduction in total sperm count, semen volume and sperm motor activity were 23, 26 and 18%, respectively, compared with the baseline level in the group of patients receiving placebo. Sperm concentration and morphology did not change.
At 24 weeks follow-up, the mean percentage change in total sperm count in the dutasteride group remained 23% lower than baseline. The mean value for all sperm parameters at all time points remained within the normal range and did not meet the specified criteria for a clinically significant change (30%); at the 52nd week of treatment in two volunteers in the dutasteride group, the total sperm count decreased by more than 90%. compared with the baseline, with partial recovery at the 24th week of observation.
Thus, the clinical significance of the effect of dutasteride on sperm counts and on individual patient fertility is unknown.
Dutasteride is contraindicated in women. Dutasteride has not been studied in women because preclinical evidence suggests that suppression of DHT levels can inhibit the development of the external genital organs in a male fetus.
There is no data on the penetration of dutasteride into breast milk.
When dutasteride was prescribed up to 40 mg / day once (80 times higher than the therapeutic dose) for 7 days, no significant side effects were observed. In clinical trials, patients received dutasteride at a dose of 5 mg daily for 6 months, while no additional side effects to those observed with 0.5 mg of dutasteride were found.
Treatment: symptomatic and supportive. there is no specific antidote for dutasteride.
Dutasteride is absorbed through the skin, and therefore 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.
Liver dysfunction. Currently, there is no data on the use of Avodart® in patients with impaired liver function. Due to the fact that dutasteride undergoes extensive metabolism and its T1/2 is 3-5 weeks, care must be taken in the treatment Avodart drug® patients with impaired liver function.
Heart failure with the combined use of dutasteride and tamsulosin. In two 4-year clinical studies, the incidence of heart failure was higher in patients who received a combination of dutasteride and an α1-blocker, mainly tamsulosin, than in patients who did not receive the combination treatment. In these two studies, the incidence of heart failure remained low (≤1%) with some variability between the two. But in general, there were no discrepancies in the rates of side effects from CVS. A causal relationship between dutasteride treatment (as monotherapy or in combination with an α1-blocker) and the development of heart failure has not been established.
Influence on the detection of prostate-specific antigen (PSA) and prostate cancer (PCa). In patients, it is necessary to carry out a digital rectal examination, as well as use other methods of examining the prostate gland before starting treatment with dutasteride and periodically repeat them during treatment to exclude the development of prostate cancer.
Determination of serum PSA concentration is an important component of PCa screening. After 6 months of dutasteride therapy, the mean serum PSA level is reduced by about 50%. Patients taking dutasteride should have a new baseline PSA level after 6 months of therapy. In the future, it is recommended to regularly monitor the PSA level.
The use of dutasteride does not affect the diagnostic value of PSA levels as a marker of prostate cancer. Any confirmed increase in PSA levels relative to their lowest value during dutasteride treatment may indicate the development of PCa (in particular PCa with a high degree of Gleason differentiation) or non-adherence to the dutasteride therapy regimen and should be carefully evaluated, even if these PSA levels remain within the normal range. for this age group of patients not taking 5α-reductase inhibitors.
The total PSA level returns to its original value within 6 months after discontinuation of dutasteride.
The ratio of the content of free PSA to total remains constant even during dutasteride therapy. If the determination of the percentage of free PSA fraction is additionally used to detect prostate cancer in men receiving dutasteride, this value does not need to be corrected.
The effect of long-term administration of dutasteride on the development of breast cancer in men. The effect of long-term administration of dutasteride on the development of breast cancer in men was not found.
PCa and high grade tumors. A 4-year study (REDUCE) compared placebo versus dutasteride in 8,231 volunteers aged 50 to 75 years with a negative biopsy for PCa and PSA levels of 2.5 to 10 ng / ml at the initial examination.
In the course of the study, 6706 patients underwent puncture biopsy of the prostate gland and, based on the results obtained, the degree of prostate cancer was determined according to the Gleason scale. During the study, 1517 patients were diagnosed with prostate cancer. In most cases, both in the dutasteride group and in the placebo group, highly differentiated prostate cancer was diagnosed (the sum of points on the Gleason scale is 5-6). There were no differences in the number of cases of prostate cancer with a Gleason score of 7-10 in the dutasteride group and the placebo group (p = 0.81).
After 4 years, there were more cases of prostate cancer 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 evaluating biopsy data for 1–2 years, the number of patients with prostate cancer with an 8–10 Gleason score was comparable in the groups of dutasteride (n = 17; 0.5%) and placebo (n = 18; 0.5 %). When evaluating biopsy data for 3-4 years, more cases of prostate cancer were diagnosed with a Gleason score of 8-10 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 prostate cancer with a Gleason score of 8-10 was stable over all time intervals (for a period of 1-2 and 3-4 years) in the dutasteride group (0.5% in each period), while as in the placebo group, the percentage of patients diagnosed with prostate cancer with a score of 8-10 points was lower during 3-4 years than in 1-2 years (<0.1% versus 0.5%, respectively).
In a 4-year study (CombAT) of patients with BPH, in which prostate biopsy was not specified for all participants by protocol and all PCa diagnoses were based on an indicative biopsy, PCa 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 combination therapy with dutasteride and tamsulosin. A causal relationship between dutasteride intake and the development of high grade PCa has not been established. Men taking dutasteride should be screened regularly to assess the risk of PCa, including PSA levels.
Influence on the ability to drive vehicles and work with mechanisms. Taking dutasteride does not affect driving a car or working with machinery.
The adverse events presented below are listed by body system and in accordance with the 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 / 10000 and <1/1000; very rare - <1/10000, including isolated cases. Frequency categories were formed on the basis of post-registration observation.
The frequency of occurrence of adverse events, formed on the basis of post-registration observation
On the part of the immune system: very rarely - allergic reactions (including rash, itching, urticaria, localized edema) and angioedema.
On the part of the skin and subcutaneous fat: rarely - alopecia (mainly loss of body hair) or hypertrichosis.
Mental disorder: very rarely - a depressive state.
From the reproductive system and mammary glands: very rarely - testicular pain, testicular edema.
Clinical Trials (Adverse Events Associated with Dutasteride Monotherapy)
In the third phase of placebo-controlled studies using dutasteride versus placebo, researchers evaluated adverse events associated with dutasteride.