Pharmacological properties of the drug Penester
The development of benign prostatic hyperplasia (BPH) is caused by the transformation of the hormone testosterone into its more active analogue - dihydrotestosterone, which stimulates prostatic hyperplasia. Finasteride selectively inhibits one of the intracellular enzymes (5 α-reductase), which transforms testosterone into dihydrotestosterone. Thus, finasteride reduces the level of dihydrotestosterone in the blood. As a result, the growth of prostate tissue slows down. In patients, the volume of the prostate gland decreases and urination is normalized. After oral administration, finasteride is absorbed relatively slowly. Its peak concentration in blood plasma is reached 2 hours after administration. The bioavailability of finasteride after oral administration is 63%. Approximately 93% of the drug binds to plasma proteins. The half-life is 6 hours, although with age (in patients over 70 years of age) it can increase to 8 hours. Finasteride is metabolized in the liver, and its metabolites are excreted in urine and feces. Plasma clearance is approximately 165 ml/min, volume of distribution is 76 l.
Penester, 30 pcs., 5 mg, film-coated tablets
Adverse reactions to the drug are divided into system-organ classes in accordance with the classification of the Medical Dictionary of Regulatory Activities (MedDRA)
. The frequency of adverse reactions was determined according to the following gradation (WHO classification): very often - >1/10; often - from >1/100 to <1/10; uncommon - from >1/1000 to <1/100; rarely - from >1/10000 to <1/1000; very rarely - from <1/10000, including individual reports; unknown frequency (frequency cannot be determined, since the information was obtained based on post-marketing experience with the drug).
The most common symptoms experienced by patients were impotence and decreased libido, although the incidence of these side effects gradually decreased during treatment.
From the immune system:
unknown frequency - hypersensitivity reactions, incl. angioedema (including swelling of the lips, face and larynx).
Mental disorders:
often - decreased libido; unknown frequency - depression, decreased libido, which persists after cessation of therapy.
From the heart:
unknown frequency - feeling of heartbeat.
From the liver and biliary tract:
unknown frequency - increased activity of liver transaminases.
For the skin and subcutaneous tissues:
uncommon - rash; unknown frequency - urticaria, itching.
From the genital organs and mammary glands:
often - erectile dysfunction; infrequently - impaired ejaculation, enlargement and tenderness of the mammary glands; unknown frequency - testicular pain, erectile dysfunction that persists after cessation of therapy; male infertility and/or decreased quality of seminal fluid.
As part of the MTOPS
compared finasteride 5 mg/day (n=768), doxazosin 4 mg/day or 8 mg/day (n=756), combination therapy with finasteride 5 mg/day and doxazosin 4 or 8 mg /day (n = 786), and placebo (n = 737). According to the results of this study, the safety and tolerability profile of the combination therapy was generally consistent with the profile of its individual components. The incidence of ejaculation disorders in patients receiving combination therapy was comparable to the sum of the incidence of this adverse event during the two types of monotherapy.
A 7-year placebo-controlled study was conducted in 18,882 healthy men. Analyzable prostate biopsy data were available for 9060 subjects, with prostate cancer detected in 803 (18.4%) men treated with finasteride 5 mg and 1147 (24.4%) men treated with finasteride 5 mg. those receiving placebo. According to the results of needle biopsy, prostate cancer with a Gleason score of 7–10 was diagnosed in 280 (6.4%) men in the group receiving finasteride at a dose of 5 mg, while in the placebo group cancer with this degree of differentiation was diagnosed in 237 (5.1%) patients. Additional analyzes suggested that the increase in the prevalence of low-grade prostate cancer observed in the finasteride 5 mg group may be attributable to outcome bias related to the effect of finasteride 5 mg treatment on prostate volume. Of the total number of prostate cancer cases diagnosed in this study, approximately 98% of cases were classified as localized cancer (clinical stage T1 or T2) at the time of diagnosis. The clinical significance of data on a tumor process with a differentiation grade of 7–10 points on the Gleason scale is unknown.
Laboratory indicators.
When assessing the results of laboratory tests, it is necessary to take into account that in patients receiving treatment with finasteride, the PSA content in the blood plasma decreases.
Most patients experience a rapid decline in PSA during the first months of therapy, followed by stabilization. The initial PSA value established after finasteride therapy is approximately half the corresponding value observed before the start of treatment. Therefore, in patients treated with finasteride for 6 months or more, the PSA value should be doubled compared with normal values in untreated men.
There were no other differences in the values of standard laboratory parameters between the groups of patients receiving finasteride and placebo.
Special instructions for the use of the drug Penester
In case of renal failure (creatinine clearance ≤0.9 ml/min), there is no need to adjust the dose of the drug. In case of liver failure, the drug is prescribed with caution, since finasteride is metabolized in the liver. Patients with a large volume of residual urine or severe urinary retention require careful monitoring, since they are particularly at risk for obstructive uropathy. Small amounts of finasteride have been detected in semen. Therefore, women of childbearing potential should not come into direct contact with sperm from patients taking finasteride. Finasteride does not affect patients' ability to drive vehicles or operate potentially dangerous machinery. Effect on serum prostate-specific antigen (PSA) levels: In controlled clinical trials in patients with BPH and elevated PSA levels, the rate of BPH progression to malignancy over the long term was not statistically different between the 2 alternative groups (one treated with finasteride, others given placebo) . Before starting treatment with finasteride and in the future, patients with BPH are recommended to periodically undergo a digital rectal examination of the prostate gland and other diagnostic tests to exclude the possible development of cancer. Effect on laboratory tests: Serum PSA concentration depends on the size of the prostate gland and increases with age. In patients taking finasteride, PSA concentrations usually decrease. In most cases, a rapid decrease in PSA is noted during the 1st month of therapy, but then its level stabilizes. After a 6-month course of treatment, the PSA concentration in patients with BPH is only half its initial level.
Penester
Finasteride is a synthetic 4-azasteroid compound. It is a specific competitive inhibitor of type II 5-alpha reductase, an intracellular enzyme that converts testosterone into the active androgen - dihydrotestosterone (DHT). In benign prostatic hyperplasia (BPH), its enlargement depends on the conversion of testosterone to DHT in the prostate. Finasteride is highly effective in reducing the concentration of DHT both in blood plasma and in prostate tissue. Suppression of DHT formation is accompanied by a decrease in the size of the prostate gland, an increase in maximum urinary flow rate and a decrease in the severity of symptoms associated with prostatic hyperplasia.
Finasteride has no affinity for androgen receptors.
According to the results of a clinical trial (PLESS), which included patients with moderate to severe symptoms of BPH and prostate enlargement, finasteride reduced the incidence of acute urinary retention from 7/100 to 3/100 over a 4-year period, and the frequency of the need for surgical intervention (transurethral resection of the prostate (TURP) or prostatectomy) - from 10/100 to 5/100. These changes were also associated with improvements in BPH symptoms (2-point reduction on the quasi-AUA symptom scale), a sustained reduction in prostate volume of approximately 20%, and a sustained increase in urinary flow rate.
The MTOPS (Medical Therapy Of Prostate Symptoms) study lasted 4 to 6 years, in which 3,047 men with symptoms of BPH were randomized to receive: finasteride 5 mg/day; doxazosin at a dose of 4 mg/day or 8 mg/day; a combination of finasteride at a dose of 5 mg/day and doxazosin at a dose of 4 mg/day or 8 mg/day; or placebo. Treatment led to a significant reduction in the risk of clinical progression of BPH, which was 34% (p=0.002) with finasteride, 39% (p<0.001) with doxazosin, and 67% (p<0.001) with combination therapy compared to placebo. In most cases, progression of BPH (274 of 351) was manifested by a worsening of BPH symptoms by > 4 points on the International Prostate Symptom Score, while among patients receiving finasteride, the risk of worsening symptoms assessed by the score was reduced by 30% (95 % CI: 6-48%), among those receiving doxazosin - by 46% (95% CI: 25-60%), and among those receiving combination therapy - by 64% (95% CI: 48-75 %) relative to the placebo group. Among patients receiving finasteride, the risk of acute urinary retention was reduced by 67% (p = 0.011), in the group receiving doxazosin - by 31% (p = 0.296), and in the group receiving combination therapy - by 79% (p = 0.001). ) relative to the placebo group.
A significant difference from placebo was observed only in the groups of patients receiving finasteride and combination therapy.
Pharmacokinetics
Suction
Cmax of finasteride in blood plasma is achieved approximately 2 hours after oral administration. Absorption of finasteride from the gastrointestinal tract is completed 6-8 hours after oral administration. The bioavailability of finasteride when administered orally is approximately 80% of the intravenous reference dose and is independent of food intake.
Distribution
Plasma protein binding is approximately 93%. Plasma clearance is about 165 ml/min, Vd is 76 l.
With long-term therapy, a slow accumulation of finasteride in small quantities is observed. When finasteride is taken orally daily at a dose of 5 mg, its minimum equilibrium concentration in blood plasma reaches 8-10 ng/ml and remains stable over time.
In patients receiving the drug for 7-10 days, finasteride was detected in the cerebrospinal fluid. When taking the drug at a dose of 5 mg/day, finasteride is found in small quantities in the seminal fluid.
Metabolism and excretion
T1/2 of finasteride averages 6 hours. In men, after a single oral dose of 14C-labeled finasteride, 39% of the dose taken is excreted by the kidneys in the form of metabolites (unchanged finasteride is practically not excreted by the kidneys); 57% - through the intestines. This study identified 2 metabolites of finasteride that have negligible 5-alpha reductase inhibitory effects compared to finasteride.
Pharmacokinetics in special clinical situations
In old age, the rate of elimination of finasteride decreases slightly. With age, T1/2 increases: in men 18-60 years old, the average T1/2 is 6 hours, and in men over 70 years old - 8 hours. These changes do not have clinical significance, and, therefore, there is no need to reduce the dose of the drug in elderly men required.
In patients with chronic renal failure (creatinine clearance from 9 to 55 ml/min), the distribution of 14C-labeled finasteride when taking a single dose did not differ from that in healthy volunteers. The binding of finasteride to plasma proteins also did not differ in patients with impaired renal function.
In case of renal failure, part of the metabolites of finasteride, which is normally excreted by the kidneys, is excreted through the intestines. This is manifested by an increase in the amount of finasteride metabolites in feces with a corresponding decrease in their concentration in urine. In patients with renal failure who do not require hemodialysis, no dose adjustment of finasteride is required.
Penester®
Adverse reactions identified during clinical trials (PLESS study).
Adverse reactions are divided into system-organ classes in accordance with the Medical Dictionary of Regulatory Activities (MedDRA) classification.
The frequency of adverse reactions was determined according to the following gradation (classification of the World Health Organization):
- very often - more than 1/10;
- often - from more than 1/100 to less than 1/10;
- infrequently - from more than 1/1000 to less than 1/100;
- rarely - from more than 1/10000 to less than 1/1000;
- very rarely - from less than 1/10000, including individual messages.
Mental disorders:
often - decreased libido.
Disorders of the skin and subcutaneous tissues:
infrequently - skin rash.
Genital and breast disorders
: often - sexual dysfunction; uncommon - impaired ejaculation, decreased ejaculate volume, enlarged mammary glands, pain in the mammary glands.
The MTOPS trial compared finasteride 5 mg daily (n = 768), doxazosin 4 mg daily or 8 mg daily (n = 756), and combination therapy of finasteride 5 mg daily and doxazosin 4 or 8 mg per day (n = 786), and placebo (n = 737). According to the results of this study, the safety and tolerability profile of combination therapy was generally consistent with the profile of its individual components. The incidence of ejaculation disorders in patients receiving combination therapy was comparable to the sum of the incidence of this adverse event during the two types of monotherapy.
A 7-year placebo-controlled RSRT study was conducted in 18,882 healthy men. Analyzable prostate biopsy data were available for 9,060 subjects, with prostate cancer detected in 803 (18.4%) men receiving finasteride 5 mg daily and 1,147 (24.4%) ) men receiving placebo. According to the results of needle biopsy, prostate cancer with a Gleason score of 7-10 was diagnosed in 280 (6.4%) men in the group receiving finasteride at a daily dose of 5 mg, while in the placebo group, cancer with this degree of differentiation was diagnosed in 237 (5.1%) patients.
Additional analyzes suggested that the increase in the prevalence of low-grade prostate cancer observed in the group of patients receiving finasteride at a dose of 5 mg per day may be explained by bias in the assessment of the results associated with the effect of treatment with finasteride at a dose of 5 mg once daily. on the volume of the prostate gland. Of the total number of prostate cancer cases diagnosed in this study, approximately 98% of cases were classified as localized cancer (clinical stage T1 or T2) at the time of diagnosis. The clinical significance of data on a tumor process with a degree of differentiation of 7-10 points on the Gleason scale is unknown.
Information obtained on the basis of post-registration experience with the drug
The frequency of adverse reactions is unknown because it is not always possible to establish frequency and a causal relationship with the effects of finasteride based on the data obtained, since these reactions were reported voluntarily from a population of unknown size.
Immune system disorders:
frequency unknown - hypersensitivity reactions, including itching, urticaria, angioedema (including swelling of the lips, face and larynx).
Disorders of the liver and biliary tract:
frequency unknown - increased activity of “liver” transaminases.
Cardiac disorders:
frequency unknown - feeling of heartbeat.
Mental disorders:
frequency unknown - depression, decreased libido, which persists after cessation of therapy.
Disorders of the genital organs and breast:
frequency unknown - sexual dysfunction (erectile dysfunction and ejaculation disorders) that persists after cessation of treatment, testicular tenderness, male infertility and/or decreased quality of seminal fluid. After discontinuation of finasteride, the quality of seminal fluid returned to normal or improved.
Laboratory indicators
When assessing the results of laboratory tests, it is necessary to take into account that in patients receiving treatment with finasteride, the content of prostate-specific antigen (PSA) in the blood plasma decreases. Most patients experience a rapid decline in PSA during the first months of therapy, followed by stabilization. The initial PSA value established after finasteride therapy is approximately half the corresponding value observed before the start of treatment. Therefore, in patients treated with finasteride for 6 months or more, the PSA value should be doubled compared with normal values in untreated men.
There were no other differences in the values of standard laboratory parameters between the groups of patients receiving finasteride and placebo.
Penester tablets po 5mg bl N10x3 Zentiva a.s.
Finasteride, a synthetic 4-azasteroid compound, is a specific inhibitor of type II 5-alpha reductase, an intracellular enzyme that converts testosterone into the more active androgen, dihydrotestosterone (DHT). In benign prostatic hyperplasia (BPH), its enlargement depends on the conversion of testosterone to DHT in the prostate gland. Finasteride is highly effective in reducing the concentration of DHT in both the blood and prostate tissue. Suppression of DHT formation is accompanied by a decrease in the size of the prostate gland, an increase in maximum urinary flow rate and a decrease in the severity of symptoms associated with prostatic hyperplasia. Finasteride has no affinity for the androgen receptor. The drug does not have a significant effect on the lipid profile (i.e. total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides) and bone mineral density. Finasteride has no effect on blood levels of cortisol, estradiol, prolactin, thyroid-stimulating hormone and thyroxine compared to placebo. A single dose of finasteride at a dose of 5 mg leads to a rapid decrease in the concentration of DHT in the blood serum, with the maximum effect achieved after 8 hours. Although the concentration of finasteride in the blood plasma fluctuates over 24 hours, the concentration of DHT remains constant. This means that the plasma concentration of finasteride is not directly related to the plasma concentration of DHT. In patients with DHT treated with finasteride 5 mg daily for 4 years, there was an approximately 70% reduction in blood DHT concentrations, which was associated with an approximately 20% reduction in prostate volume. In addition, the concentration of prostate-specific antigen (PSA) decreased by approximately 50% compared to its initial concentration, which suggests a decrease in the growth of prostate epithelial cells. The decrease in DHT concentration and decrease in the severity of prostatic hyperplasia, accompanied by a decrease in PSA concentration, persisted in studies for up to 4 years. In these studies, testosterone levels in the blood increased by approximately 10-20%, remaining within physiological values. When finasteride was used for 7-10 days in patients referred for prostatectomy, there was a decrease in the concentration of DHT in prostate tissue by approximately 80% and an increase in the concentration of testosterone in prostate tissue by 10 times compared with the concentration before treatment. It was found that long-term (more than 4 years) use of finasteride in patients with BPH and moderate or severe symptoms of the disease reduced the risk of all urological complications (surgical interventions: transurethral resection of the prostate or prostatectomy; acute urinary retention requiring catheterization) by 51% and was accompanied by a pronounced and persistent decrease in prostate volume, as well as a persistent increase in maximum urinary flow rate and improvement in symptoms (PLESS study). In patients who took finasteride for 3 months and achieved a reduction in prostate volume of approximately 20%, when treatment was stopped, prostate volume returned to its previous size after 3 months. Thus, treatment with finasteride helps reduce the size of an enlarged prostate gland, increases urinary flow rate and reduces symptoms associated with BPH.
