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Michael P. Brooklyn

AVODART (DUTASTERIDE) 0.5 mg. #30 tablets

AVODART (DUTASTERIDE) 0.5 mg. #30 tablets

Brand: GlaxoSmithKline
Product Code: avodart
Availability: In Stock
Price: $88.00
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DELIVERY WITHIN 9-11 DAYS.
PHARMACOLOGICAL PROPERTIES
 
Dutasteride, a double inhibitor of 5α-reductase inhibits both Type 1 and Type 2 isoenzymes of 5α-reductase, responsible for converting testosterone to 5α-dihydrotestosterone. Dihydrotestosterone is an androgen, which is primarily responsible for prostatic hyperplasia of the prostate. The maximum decrease in the level of dihydrotestosterone against the background of Avodart's intake depends on the dose and is noted in the first 1-2 weeks. After the 1st and 2nd week of using Avodart in a daily dose of 0.5 mg, the average concentration of dihydrotestosterone decreases by 85 and 90%, respectively.
 
In patients with benign prostatic hyperplasia receiving 0.5 mg of dutasteride per day, the average reduction in dihydrotestosterone level was 94% at 1 year and 93% at 2 years of treatment, the average testosterone level was increased by 19% at 1 and 2 years.
 
Pharmacokinetics. Dutasteride is administered orally in the form of p-ra in soft gelatin capsules. After taking a single dose of 0.5 mg Cmax drug in blood plasma is achieved after 1-3 hours. Absolute bioavailability is 60% in case of application by 2-hour IV infusion. Bioavailability does not depend on food intake.
 
Dutasteride after a single or multiple administration has a large volume of distribution (300-500 liters). The percentage of binding with proteins is more than 99.5%.
 
When used in a daily dose of 0.5 mg, 65% of the constant steady concentration of dutasteride in the blood plasma is achieved after 1 month of treatment and about 90% - after 3 months. A stable constant concentration of dutasteride of about 40 ng / ml in blood plasma is achieved after 6 months of treatment at a daily dose of 0.5 mg. As in blood plasma, a steady concentration of dutasteride in the semen is achieved after 6 months. After 52 weeks of treatment, the average concentration of dutasteride in the seminal fluid is 3.4 ng / ml (within 0.4-14 ng / ml). The percentage of distribution of dutasteride from blood plasma to seminal fluid is about 11.5%.
 
In vitro, dutasteride is metabolized by human CYP 3A4 cytochrome P450 enzymes to two monohydroxy metabolites.
 
According to spectrometric analysis, unchanged dutasteride, 3 main metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride and 6-hydroxydutasteride) and 2 small metabolites (6,4'-dihydroxydutasteride and 15-hydroxydutasteride) are detected in human blood plasma.
 
Dutasteride is extensively metabolized. After oral administration of dutasteride at a dose of 0.5 mg / day 1-15.4% (an average of 5.4%), the accepted dose is excreted with feces in the form of unchanged dutasteride. The rest of the applied dose is excreted in the form of metabolites.
 
In the urine, only traces of unchanged dutasteride are detected (<0.1% of the dose taken). The final T½ dutasteride is 3-5 weeks. Remains of dutasteride in the blood plasma can be detected after 4-6 months after the end of treatment.
 
According to the study of pharmacokinetics and pharmacodynamics, a dose of dutasteride according to the age of the patient is not required to change.
 
The effect of renal failure on the pharmacokinetics of dutasteride has not been studied. However, when taking 0.5 mg of dutasteride in the urine, less than 0.1% of the dose is excreted in a person, so it is not necessary to change the dose for patients with renal insufficiency.
 
The effect of hepatic insufficiency on the pharmacokinetics of dutasteride has not been studied (see APPLICATION and SPECIFIC INDICATIONS).
 
Safety and clinical research
 
Heart failure. In a 4-year clinical trial using dutasteride in combination with tamsulosin to treat benign prostatic hyperplasia in 4844 men (the CombAT study), the incidence of heart failure (collective concept) in the combination therapy group (14/1610, 0.9%) was higher, than in any group of monotherapy with dutasteride (4/1623, 0.2%) or tamsulosin (10/1611, 0.6%).
 
In a separate 4-year clinical comparative study of placebo with chemoprevention of dutasteride involving 8231 people aged 50 to 75 years with a preliminary negative biopsy result in prostate cancer and a baseline level of prostate-specific antigen (PSA) of 2.5-10.0 ng / ml in men 50-60 years old or 3.0-10.0 ng / ml in men aged 60 years (REDUCE) found that the incidence of heart failure in patients taking dutasteride 0.5 mg once daily (30 / 4105; 0.7%), higher compared with n patients receiving placebo (16/4126, 0.4%). A retrospective analysis of this study showed a higher incidence of heart failure in patients taking dutasteride and an α-adrenergic blocker at the same time (12/1152, 1.0%), compared with subjects receiving dutasteride without an α-adrenergic blocker (18/2953; 0.6%), placebo and α-adrenoreceptor blocker (1/1399, <0.1%) or placebo without α-adrenoreceptor blocker (15/2727, 0.6%). The causal relationship between the use of dutasteride (alone or in combination with α-adrenoreceptor blockers) and the occurrence of heart failure is not established (see SPECIAL INSTRUCTIONS).
 
Prostate cancer and low-grade tumors. In a 4-year comparative study of placebo and dutasteride involving 8231 people aged 50 to 75 years with a preliminary negative biopsy result in prostate cancer and a baseline PSA level of 2.5-10.0 ng / ml in men aged 50-60 years or 3.0-10.0 ng / ml in men aged 60 years (REDUCE studies), 6706 subjects underwent a needle biopsy of the prostate (mandatory according to the primary protocol), the data of which were used to analyze Gleason differentiation. The study identified 1517 patients diagnosed with prostate cancer. The majority of prostate tumors (70%) detected by biopsy in both treatment groups had a high level of differentiation (5-6 points on the Gleason scale).
 
In the dutasteride group, a higher incidence (n = 29; 0.9%) of the low-grade prostate cancer (8-10 on the Gleason score) was recorded compared with the placebo group (n = 19, 0.6%) (p = 0, 15). In the 1-2 years of the study, the number of patients with prostate cancer with differentiation of 8-10 points on the Gleason score was the same in the dutasteride group (n = 17, 0.5%) and in the placebo group (n = 18, 0.5 %). In the 3-4 years of the study, more cases of prostate cancer with differentiation of 8-10 points on the Gleason score were diagnosed in the dutasteride group (n = 12, 0.5%) compared with the placebo group (n = 1, <0, 1%) (p = 0.0035). There is no evidence of an effect on the risk of developing prostate cancer in men taking dutasteride for more than 4 years. The percentage of patients diagnosed with prostate cancer with differentiation of 8-10 points on the Gleason scale remained constant at different periods of the study (1-2 years, 3-4 years) in the dutasteride group (0.5% in each period), while in the placebo group, the percentage of patients with low-grade prostate cancer (8-10 points on the Gleason score) was lower in the 3-4 years than in the 1-2 years (<0.1 and 0.5 %, respectively) (see SPECIAL INSTRUCTIONS). There was no difference in the incidence of prostate cancer with a Gleason score of 7-10 (p = 0.81).
 
In a 4-year clinical trial of treatment of benign prostatic hyperplasia (CombAT), where the primary protocol did not provide mandatory biopsies, and all diagnoses of prostate cancer were established on the basis of biopsy according to indications, the incidence of prostate cancer with differentiation of 8-10 points on the Gleason scale was 0.5% (n = 8) in the dutasteride group, 0.7% (n = 11) in the tamsulosin group and 0.3% (n = 5) in the combination therapy group.
 
The relationship between the use of dutasteride and the occurrence of low-grade prostate cancer remains unclear.
 
Breast cancer in men. Two controlled epidemiological studies: one conducted in the United States (339 cases of breast cancer and 6,780 participants in the control group) and the other in the UK (398 breast cancers and 3,930 control subjects) showed no increased risk of developing cancer Breast cancer in men with 5α-reductase inhibitors. The results of the first study showed no association with breast cancer (relative risk (HR)
 
INDICATIONS
 
treatment of symptoms of moderate to severe benign prostatic hyperplasia; reduction of the risk of acute urinary retention and, if necessary, surgical intervention in patients with symptoms of moderate to severe benign prostatic hyperplasia.
 
APPLICATION
 
The avodart can be administered alone or in combination with an α-adrenergic blocker tamsulosin (0.4 mg).
 
Adult men (including elderly patients). The recommended dose of Avodart is 1 capsule (0.5 mg) per day for oral administration. The capsule should be swallowed whole, without opening and not chewing, because when contacting the contents of the capsule, irritation of the mucous membrane of the mouth and pharynx is possible.
 
Avodart can be taken regardless of food intake.
 
Despite the fact that relief from taking the drug is noted at an early stage, for an objective assessment of the effectiveness of the drug, treatment should be continued for at least 6 months.
 
Renal failure. The pharmacokinetics of dutasteride in patients with renal insufficiency has not been studied, so caution should be given to patients with severe renal insufficiency.
 
Liver failure. The pharmacokinetics of dutasteride in patients with hepatic insufficiency has not been studied, so with caution should be applied to the drug with mild and moderate hepatic insufficiency. Patients with severe hepatic insufficiency dutasteride is contraindicated.
 
Children. The use is contraindicated.
 
CONTRAINDICATIONS
 
hypersensitivity to dutasteride, other 5α-reductase inhibitors, soy, peanuts or other components of the drug.
 
The drug is not used to treat women and children (see Application during pregnancy and lactation). Dutasteride is contraindicated in patients with severe hepatic insufficiency.
 
SIDE EFFECTS
 
monotherapy with Avodart. According to 3 placebo-controlled clinical trials of Phase III with dutasteride compared with placebo, the following adverse reactions were noted, which, according to the researchers' definition, were associated with drug use (at a rate of ≥1%).
 
Post-marketing research data
 
Immune system: very rarely - allergic reactions, including rash, itching, hives, localized edema and angioedema.
 
Disorders of the psyche: very rarely - a depressive mood.
 
Skin and subcutaneous tissue: rarely - alopecia (mainly loss of hair on the body), hypertrichosis.
 
Reproductive system and breaches from the breast: very rarely - testicular pain and swelling.
 
Cases of breast cancer in men have been reported in clinical and post-marketing studies (see SPECIAL INSTRUCTIONS).
 
SPECIAL INSTRUCTIONS
 
dutasteride can be absorbed through the skin, so women and children should avoid contact with leaking capsules (see Application during pregnancy and lactation). If the liquid from the capsule has got on the skin, it should be washed off immediately with soap and water.
 
The effect of hepatic insufficiency on the pharmacokinetics of dutasteride has not been studied. Since dutasteride is extensively metabolized and its T½ is 3-5 weeks, the drug should be administered with caution to patients with mild to moderate hepatic impairment (see APPLICATION and PHARMACOLOGICAL PROPERTIES).
 
Adverse reactions from the cardiovascular system. Combination therapy can be given after a thorough assessment of the benefit / risk due to a potential increase in the risk of adverse reactions (including heart failure) and after considering alternative treatment options, including monotherapy.
 
According to 4-year clinical studies, the incidence of heart failure (the combined term for all reports, predominantly heart failure and congestive heart failure) was higher among patients receiving Avodart's combination with an α-adrenergic blocker, mainly tamsulosin, not using this combination. According to these two studies, the incidence of heart failure was low (≤1%) and variable within these studies. There is no imbalance in the incidence of cardiovascular side effects in any of the studies. The causal relationship between the use of Avodart (alone or in combination with α-adrenoreceptor blockers) and the onset of heart failure has not been established (see PHARMACOLOGICAL PROPERTIES).
 
Effect on the PSA. The concentration of PSA is an important component of the screening process for detecting prostate cancer.
 
The avodart is able to reduce the level of plasma PSA in patients by an average of 50% after 6 months of treatment.
 
In patients taking Avodart, it is necessary to determine a new baseline level of PSA 6 months after treatment with this drug. Subsequently, this level is recommended to be checked regularly. Any confirmed increase in PSA from the lowest value with Avodart can be evidence of prostate cancer or failure to adhere to the Avodart treatment regimen and requires careful study, even if the PSA is within normal limits in men who have not been treated with 5α-reductase inhibitors. When interpreting PSA in patients taking Avodart, the previous PSA measures should be taken into account for comparison.
 
The use of Avodart does not affect the use of the PSA level for the diagnosis of prostate cancer after the establishment of its new baseline value.
 
The total plasma PSA level returns to baseline within 6 months after discontinuation of treatment.
 
The ratio of free PSA to total PSA remains constant even with Avodart. Therefore, if the patient, who is taking Avodart, chooses a percentage of free PSA to determine prostate cancer, correction of its significance is not required.
 
Before the start of the course of treatment with dutasteride and periodically during therapy, it is necessary to perform a digital rectal examination of the patient, as well as to use other methods for detecting prostate cancer.
 
Prostate cancer and tumors of high degree of graduation according to Gleason (low-grade). In a 4-year clinical trial involving> 8000 men aged 50-75 years with preliminary negative biopsy data for prostate cancer and a baseline PSA level of 2.5-10.0 ng / ml (REDUCE) in 1517 is diagnosed with prostate cancer. The incidence of prostate cancer (8-10 points on the Gleason score) was higher in the group treated with Avodart (n = 29, 0.9%) than in the placebo group (n = 19, 0.6%). An increase in the incidence of prostate cancer in the Gleason score of 5-6 and 7-10 was not observed. The causal relationship between the use of Avodart and the high stages of prostate cancer has not been established. The clinical significance of the numerical imbalance is unknown. Men taking Avodart should be checked regularly for the risk of prostate cancer, including the definition of PSA.
 
In an additional sequential 2-year study involving patients who participated in the dutasteride-as-chemoprevention (REDUCE) study, a low incidence of new prostate cancer cases (dutasteride group [n = 14, 1.2%] and placebo group [n = 7, 0.7%]) with the absence of new identified cases of prostate cancer with differentiation of 8-10 points on the Gleason scale.
 
Long-term follow-up (up to 18 years) of patients from a clinical trial using another 5α-reductase inhibitor (finasteride) as a chemoprophylaxis did not show a statistically significant difference between the finasteride and placebo groups in the overall survival rate (HR 1.02, 95% CI 0, 97-1.08) or survival after diagnosis of prostate cancer (HR 1.01, 95% CI 0.85-1.20).
 
Breast cancer. There have been reports of rare cases of breast cancer in men during clinical trials and in the postmarketing period. At the same time, epidemiological studies indicate a lack of an increased risk of developing breast cancer in men with 5α-reductase inhibitors. Patients should immediately report any changes in breast tissue, for example, discharge from the nipple or swelling.
 
Unsealed capsules. Dutasteride is absorbed through the skin, so women and children should avoid contact with unsealed capsules. If the liquid from the capsule has got on the skin, it should be washed off immediately with soap and water.
 
Liver failure. The effect of hepatic insufficiency on the pharmacokinetics of dutasteride has not been studied. Due to the active metabolism of dutasteride and 3-5 weeks of T½, treatment with dutasteride in patients with mild or moderate hepatic insufficiency should be conducted with caution (see APPLICATION, CONTRAINDICATIONS, PHARMACOLOGICAL PROPERTIES).
 
Use during pregnancy and lactation
 
Fertility. A study of the effect of dutasteride at a dose of 0.5 mg / day on the characteristics of ejaculate in 27 healthy volunteers aged 18-52 years (n = 27 in the dutasteride group, n = 23 in the placebo group) for 52 weeks and 24 weeks after observations showed a decrease in the total number of spermatozoa, ejaculate volume and motility of spermatozoa by 23; 26 and 18% compared with changes in the placebo group. The concentration of sperm and its morphology remained unchanged. After 24 weeks of follow-up, the average percentage of changes in total sperm count in the dutasteride group remained 23% below baseline. While the mean values ​​for all the sperm parameters remained within the normal range and did not meet certain criteria for clinically significant changes (30%), in two patients of the dutasteride group there was a decrease in the number of spermatozoa by more than 90% compared with the baseline 52nd week of treatment and with a partial restoration of their number after 24 weeks of follow-up. The clinical significance of the effect of dutasteride on sperm characteristics for individual patient fertility is unknown.
 
Pregnancy. Dutasteride is contraindicated for the treatment of women. The use of dutasteride for the treatment of women was not studied, because, according to the preclinical study, it was suggested that suppression of the level of circulating dihydrotestosterone may inhibit the development of the external genitalia in the male fetus that the female is bearing.
 
Lactation. It is not known whether dutasteride penetrates the breast milk of a woman.
 
The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Given the pharmacokinetic and pharmacodynamic properties of dutasteride does not affect the ability to drive and other mechanisms.
 
INTERACTIONS
 
since dutasteride is metabolized by the CYP 3A4 isoenzyme, the plasma dutasteride concentration may increase with CYP 3A4 inhibitors. Prolonged administration of dutasteride with preparations that are potent inhibitors of the CYP 3A4 enzyme (such as ritonavir, indinavir, nefazodone, itraconazole, ketoconazole orally) may increase dutasteride concentration. According to the study, the clearance of dutasteride decreases with simultaneous application with inhibitors of CYP 3A4 verapamil (37%) and diltiazem (44%). However, the clearance of dutasteride does not decrease when used with amlodipine, another antagonist of calcium channels.
 
The decrease in clearance and the corresponding increase in the effect of dutasteride in the presence of inhibitors of CYP 3A4 is not of great clinical significance due to the wide spectrum of drug safety.
 
In vitro, dutasteride is not metabolized by CYP 1A2, CYP 2A6, CYP 2E1, CYP 2C8, CYP 2C9, CYP 2C19, CYP 2B6 and CYP 2D6 - isoenzymes of the cytochrome P450 system in humans.
 
Dutasteride does not inhibit the isoenzymes of the cytochrome P450 system in humans in vitro and does not induce isoenzymes of CYP 1A, CYP 2B and CYP 3A rats and dogs in vivo.
 
In vitro studies have shown that dutasteride does not displace warfarin, acenocoumarol, fenprocumone, diazepam or phenytoin from the association with blood plasma proteins, as these components do not replace dutasteride. The interaction of dutasteride with tamsulosin, terazocine, warfarin, digoxin, and colestyramine was studied. Clinically significant interaction was not revealed.
 
Although no specific studies were conducted on the interaction with other drugs, about 90% of all patients received other drugs during the clinical trials of dutasteride. Clinically significant adverse reactions were not observed with the simultaneous use of dutasteride with antihyperlipidemic drugs, ACE inhibitors, β-adrenoreceptor blockers, calcium channel blockers, GCS, diuretics, NSAIDs, PDE type V inhibitors and quinoline antibiotics.
 
OVERDOSE
 
According to clinical studies, in volunteers, single dutasteride doses up to 40 mg / day (80 times higher than therapeutic) for 7 days did not cause concern in terms of safety of their use. During clinical trials, dutasteride doses of 5 mg / day for 6 months without additional side effects compared with dutasteride at a dose of 0.5 mg / day.
 
There is no specific antidote, therefore, in case of a possible overdose, symptomatic and supportive therapy is performed.
 
STORAGE CONDITIONS
 
at a temperature not exceeding 30 ° C.