Avodart capsules 0.5 mg 90 pcs
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Active ingredients
Dutasteride
Release form
Capsules
Composition
Dutasteride 500 mcg. Adjuvants: caprylic / capric mono-di-glycerides (MDC) - 349.5 mg, butyl hydroxytoluene - 0.035 mg. Capsule shell weight - 350 mg. Capsule composition: gelatin - 144.8 mg, glycerol (glycerol) - 70.8 mg titanium dioxide - 1.78 mg, iron oxide yellow - 0.127 mg; technological additives - medium chain triglycerides (TSC) - q.s., lecithin - q.s .; red ink for printing - q.s.
Pharmacological effect
Drug for the treatment of benign prostatic hyperplasia. Dutasteride is a double inhibitor of 5α-reductase. Suppresses the activity of isoenzymes 5α-reductase 1 and 2 types, which are responsible for the conversion of 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 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 mcg / day, the mean values of serum dihydrotestosterone concentrations are reduced by 85% and 90%, respectively.
Pharmacokinetics
Absorption After a single dose of the drug in a dose of 500 mcg Cmax of dutasteride in serum is achieved within 1-3 hours. Absolute bioavailability is about 60% relative to a 2-hour w / in infusion. The bioavailability of dutasteride does not depend on food intake. Distribution The pharmacokinetic data obtained after a single and repeated administration of dutasteride indicates a large Vd (300 to 500 l). Dutasteride has a high degree of binding to plasma proteins (> 99.5%). When taken daily, the concentration of dutasteride in serum reaches 65% of the stable level after 1 month and approximately 90% of the stable level after 3 months. Stable serum dutasteride concentrations (Css), equal to about 40 ng / ml, are achieved after 6 months of a single daily dose of 500 μg of this drug. In semen, as in the serum, stable concentrations of dutasteride are also achieved 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. Metabolism In vitro, dutasteride is metabolized by the human cytochrome P450 cytoprotein cytochrome P450 isoenzyme to form two small monohydroxylated metabolites; however, it is not affected by isozymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19 or CYP2D6.After reaching Css dutasteride in the serum using the mass spectrometry method, unchanged dutasteride, 3 large metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride and 6-hydroxydutasteride) and 2 small metabolites (6,4'-dihydroxydutasteride and 15-hydroxydasteride) are detected ). Intake In human body, dutasteride is extensively metabolized. After ingestion of dutasteride at a daily dose of 500 mcg 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 through the intestine in the form of 4 large metabolites, comprising 39%, 21%, 7% and 7%, respectively, and 6 small metabolites (each of which accounts for less than 5%). Only trace amounts of unchanged dutasteride (less than 0.1% of the dose). When receiving therapeutic doses of dutasteride, its final T1 / 2 is 3-5 weeks. Douasteride is detected in serum (at concentrations above 0.1 ng / ml) up to 4-6 months after discontinuation. Linearity / nonlinearity Pharmacokinetics dutasterid we It 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 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), mainly through a linear unsaturated elimination process with a final T1 / 2 3-5 weeks. At therapeutic concentrations, the final T1 / 2 against the background of daily intake of 500 μg is dominated by a slower clearance of dutasteride; total clearance is linear and not dependent on concentration. The serum dutasteride content (more than 0.1 ng / ml) is detected within 4-6 months after cessation of treatment. Pharmacokinetics in special patient groups The pharmacokinetics and pharmacodynamics of dutasteride were studied in 36 healthy volunteers aged from 24 to 87 years after a single dose (5 mg ) dutasteride. Between different age groups there were no statistically significant differences in pharmacokinetic parameters such as AUC and Cmax in plasma.There were also no statistically significant differences in dutasteride T1 / 2 values between the age groups of men 50-69 years and over 70 years, which include most men with benign prostatic hyperplasia. There were no significant differences between the different age groups in the levels of DHT . These results demonstrate that there is no need to reduce the dose of dutasteride depending on the age of the patients.
Indications
- 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-adrenergic blockers for treating and preventing the progression of benign prostatic hyperplasia by reducing its size, relieving symptoms, improving urine emission, reducing the risk of acute urinary retention and the need for surgical intervention. The combination of dutasteride and tamsulosin alpha1-blocker was mainly studied.
Contraindications
- hypersensitivity to dutasteride and other components of the drug; - hypersensitivity to other 5α-reductase inhibitors. Avodart is contraindicated in women and children. The drug should be prescribed with caution in case of hepatic insufficiency.
Precautionary measures
Application for violations of the liver functionWith caution, you should prescribe the drug for liver failure. Application for violations of the kidney function In case of violations of the kidney function, a lower dose of the drug is not required (because if you take the drug at a dose of 500 mcg / day with urine less than 0.1% of the dose is excreted). in children Avodart is contraindicated in children. Use in elderly patients Dose adjustment is not required.
Use during pregnancy and lactation
Effect on fertility The effect of dutasteride at a daily dose of 500 mcg on sperm characteristics was studied in healthy volunteers aged 18–52 years. By the 52nd week of treatment in the group of patients who received dutasteride, the average values of the percentage reduction in the total number of spermatozoa, sperm volume and motor activity of spermatozoa were 23%, 26% and 18%, respectively, compared with the initial level in the group of patients receiving placebo.The concentration of spermatozoa and their morphological characteristics did not change. After 24 weeks of observation, the average value of the percentage change in the total number of spermatozoa in the dutasteride group remained 23% lower than the initial level. The average 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 number of spermatozoa decreased by more than 90% compared with baseline, with partial recovery on the 24th week of observation. Thus, the clinical significance of the effect of dutasteride on sperm indices and on the patient’s individual fertility is unknown. Pregnancy Dutasteride otivopokazan women. Dutasteride has not been studied in women, because preclinical data suggest that suppression of DHT may cause inhibition of the development of the external genital organs in the male fetus. Lactation There is no data on the penetration of dutasteride into breast milk.
Dosage and administration
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) In adult men (including elderly), the recommended dose of Avodart is 1 caps. (500 mcg) 1 time / day. Although improvement occurs with the use of the drug 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 prescribed as monotherapy or in combination with alpha1-blockers. When taking 500 mcg / 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 function liver function. Since Dutasteride is subjected to intensive metabolism, and its T1 / 2 is 3-5 weeks. Care must be taken when treating Avodart with patients with impaired liver function.
Side effects
On the part of the immune system: very rarely - allergic reactions (including rash, itching, urticaria, localized edema) and angioedema. On the side of the skin and subcutaneous fat: rarely - alopecia (mainly body hair loss) or hypertrichosis. Mental disorder: very rarely - depressed. For the reproductive system: very rarely - testicular pain, testicular edema.
Overdose
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 studies, patients received dutasteride at a dose of 5 mg daily for 6 months, while no additional side effects were observed for those that were observed while receiving dutasteride at a dose of 500 μg, it was not found. The treatment: there is no specific dutasteride antidote, therefore, in cases of suspected overdose, symptomatic and supportive treatment is sufficient.
Interaction with other drugs
In vitro, dutasteride is metabolized by the CYP3A4 isoenzyme of the human cytochrome P450 enzyme system. Consequently, in the presence of CYP3A4 inhibitors, the concentration of dutasteride in the blood may increase. With the simultaneous use of dutasteride with CYP3A4 inhibitors, verapamil and diltiazem, there is a decrease in the clearance of dutasteride. At the same time, amlodipine and other calcium channel blockers, when used simultaneously with dutasteride, do not reduce the clearance of dutasteride. The reduction of dutasteride clearance and the subsequent increase in its concentration in the blood 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. CYP2C8, CYP2C9, CYP2C19, CYP2B6 or CYP2D6. Dutasteride does not inhibit in vitro human cytochrome P450 enzymes involved in drug metabolism. In vitro, dutasteride is not displaced It contains warfarin, acenocoumarol, fenprocumone, diazepam, and phenytoin from their plasma protein binding sites, and these drugs, in turn, do not displace dutasteri. When conducting research on the interaction of dutasteride with tamsulosin, terazosin, warfarin,digoxin and colestyramine in humans any clinically significant pharmacokinetic or pharmacodynamic interactions not otmechalos.Pri application dutasteride simultaneously with lipid-lowering drugs, ACE inhibitors, beta-blockers, calcium channel blockers, corticosteroids, diuretics, NSAIDs, inhibitors of phosphodiesterase type 5 and quinolone no significant drug interaction was observed with antibiotics.
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, it is necessary to immediately wash the corresponding area of the skin with soap and water. Liver function impairment Currently there are no data on the use of Avodart in patients with impaired liver function. Since Dutasteride undergoes intensive metabolism, and its T1 / 2 is 3-5 weeks. Care must be taken when treating Avodart with patients with impaired liver function. Heart failure with combined use of dutasteride and tamsulosin 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. No causal relationship between treatment with dutasteride (as monotherapy or in combination with alpha1-blocker) and the development of heart failure has not been established. The effect on prostate-specific antigen (PSA) and prostate cancer (PCa) is detected study, as well as use other methods of research of the prostate gland, before starting treatment with dutasteride and periodically repeat them in the treatment process to rule out the development of prostate cancer. Ntratsii PSA in serum is an important component of the screening aimed at identifying prostate cancer.After 6 months of dutasteride therapy, the average serum PSA level is reduced by about 50%. Patients taking dutasteride should have a new baseline PSA level determined after 6 months of therapy. In the future, it is recommended to regularly monitor the level of PSA. When interpreting the PSA value in 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 prostate cancer marker after determining a new baseline PSA level. Any confirmed increase in the PSA level with respect to its lowest value in the treatment with dutasteride may indicate the development of prostate cancer (in particular, prostate cancer with a high degree of differentiation on the Gleason scale) or failure to comply with dutasteride therapy and should be carefully evaluated, even if these PSA levels remain at limits of normal values for this age group of patients not taking 5α-reductase inhibitors. The overall PSA level returns to its initial value within 6 months after the cancellation of dutasteride. The ratio of the content of free PSA to the total remains constant even during therapy with dutasteride. If the determination of the percentage of free PSA is additionally used to detect prostate cancer in men receiving dutasteride, no correction is required. RAP and high-grade tumors A 4-year study (REDUCE) compared the use of placebo and dutasteride in 8231 volunteers aged 50 years up to 75 years, with a negative biopsy for the presence of prostate cancer and PSA level from 2.5 ng / ml to 10 ng / ml during the initial examination. During the study, 6706 patients underwent prostate biopsy PS and on the basis of the results determined by the degree of malignancy of prostate cancer Gleason score. In the course of the study, 1517 patients were diagnosed with PCa. In most cases, both in the dutasterid group and in the placebo group, a highly differentiated prostate cancer was diagnosed (Gleason score 5-6). There were no differences in the number of cases of prostate cancer with a score of 7–10 on the Gleason score in the dutasteride group and the placebo group (p = 0.81). Over 4 years, there were more cases of prostate cancer with a score of 8–10 on the Gleason score 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 diagnosed with prostate cancer with an estimate of 8–10 on the Gleason score was comparable in the dutasteride groups (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 score of 8–10 on the Gleason score 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 score of 8-10 on the Gleason score was stable for all time periods (for the period of the 1-2nd and 3-4th years) in the dutasteride group (0.5% in each period), While in the placebo group, the percentage of patients diagnosed with prostate cancer with an estimate of 8–10 points was lower for 3–4 years than in 1–2 years (<0.1% compared to 0.5%, respectively). 4 -year-old study (CombAT) of patients with BPH, in which all participants were not determined by the protocol of the prostate gland biopsy, and all diagnoses of prostate cancer warped for biopsy according to indications, prostate cancer with an estimated 8–10 points on the Gleason score was diagnosed in 8 patients (<0.5%) while taking dutasteride, 11 patients (<0.7%) while taking tamsulosin and 5 patients (<0.3%) with combination therapy with dutasteride and tamsulosin. There is no causal connection between dutasteride and the development of prostate cancer. A high degree of gradation has not been established. Men who take dutasteride should be regularly examined for the assessment of the risk of developing prostate cancer, including the level of PSA. research and observation during the post-marketing reports of occurrence of breast cancer in men taking dutasteride. Patients should be warned that when any changes in the tissues of the mammary glands, such as nodules or nipples, should be reported, the physician should be informed immediately. In clinical studies that investigated the effects of BPH monotherapy with dutasteride 2 cases of breast cancer were detected during dutasteride therapy (after 10 weeks and 11 months) and 1 case in a patient who received placebo. In subsequent clinical trials in which 8231 men aged 50 to 75 years took part with a negative biopsy for prostate cancer and PSA levels in the range of 2.5 ng / ml to 10 ng / ml (17489 patient-years), which received dutasteride, and patients (5027 patient-years),who received combined therapy with dutasteride and tamsulosin, there were no cases of breast cancer found in any of the comparison groups. At the moment, it is not clear whether there is a causal relationship between the occurrence of breast cancer in men and the long-term use of dutasteride. Impact on driving ability motor transport and machinery management Reception of dutasteride does not affect driving a car or working with machinery.