Avodart® (Avodart®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceDutasterideDutasteride
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  • Avodart®
    capsules inwards 
    GlaxoSmithKline Trading, ZAO     Russia
  • Dutasteride Bacher
    capsules inwards 
    Bakter, OOO     Russia
    • Dosage form: & nbspcapsules
    Composition:Each capsule contains:

    Components

    Content in 1 capsule, mg

    Active substance:

    Dutasteride

    0,5

    Excipients:

    Mono-di-glycerides of caprylic / capric acid (MDC)

    349,5

    Butylhydroxytoluene

    0,035

    Weight of capsule contents

    350

    Components

    Content per 1 capsule, mg

    Capsule shell

    Gelatin

    144,8

    Glycerol (glycerol)

    70,8

    Titanium dioxide

    1,78

    Iron oxide yellow

    0,127

    Approximate weight of the capsule

    218

    Technological additives



    Triglycerides, medium chain (TSC)1

    qs

    Lecithin1

    qs

    Inks for printing



    Red ink for printing2

    qs


    1 - TCS and lecithin are used as lubricants in the manufacturing process. Total amount of lubricants per capsule does not exceed 1.5 mg. The concentration of lecithin in TCS is 0.1% w / w.

    2 - Red ink for printing is used in the production of the finished dosage form on the production site "Catalante France Bayneheim SA", France and are not used in the production of the finished dosage form at the production site of GlaxoSmithKline Pharmaceuticals SA, Poland.

    The amount of ink on each capsule is calculated in such a way that it was less than 0.28 mg.The materials remaining on the capsule are polyvinyl acetate phthalate (National Formulary), macrogol (polyethylene glycol) (Hebrew Pharmacopeia), propylene glycol (Hebrew Pharmacopeia), iron oxide red E172, CI77491.
    Description:

    Soft, oblong, opaque, yellow gelatin capsule, labeled1 code "GX CE2".

    1 - the application of the code "GX CE2" with red ink for printing is used in the manufacture of the finished dosage form at the production site "Catalante France Bayneheim SA", France.

    The application of the "GX CE2" code of gray color with the help of UV cold laser is used in the production of the finished dosage form on the production site of "GlaxoSmithKline Pharmaceuticals SA", Poland.
    Pharmacotherapeutic group:The double 5α-reductase inhibitor
    ATX: & nbsp

    G.04.C.B.02   Dutasteride

    Pharmacodynamics:

    Mechanism of action

    Dutasteride is a double inhibitor of 5α-reductase. It suppresses the activity of isoenzymes 5α-reductase 1 and 2 types, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). DHT is the main androgen responsible for hyperplasia of the glandular tissue of the prostate gland.

    Effect on the concentration of DHT and testosterone

    The maximum effect of dutasteride on the decrease in the concentration of DHT is dose-dependent and observed after 1 to 2 weeks after the start of treatment. After 1 and 2 weeks of taking dutasteride at a dose of 0.5 mg per day, the average values ​​of DHT concentrations in serum reduced by 85% and 90%, respectively.

    Pharmacokinetics:

    Suction

    After taking one dose (0.5 mg) of dutasteride, the maximum concentration of dutasteride in the serum is reached within 1-3 hours.

    Absolute bioavailability of dutasteride in men is about 60% with respect to a 2-hour intravenous infusion. Bioavailability of dutasteride does not depend on food intake.

    Distribution

    Pharmacokinetic data obtained after a single and multiple dutasteride administration indicate a large volume of its distribution (from 300 liters 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 stable level after 1 month and approximately 90% of the stable level after 3 months. Stable concentrations of serum dutasteride (Css) of about 40 ng / ml are achieved after 6 months of a single daily intake of 0.5 mg of this drug.In sperm, as in serum, stable concentrations of dutasteride are also reached after 6 months. After 52 weeks of treatment dutasteride in sperm concentration averaged 3.4 ng / ml (0.4 ng / ml to 14 ng / ml). From serum, about 11.5% of dutasteride enters the semen.

    Metabolism

    In vitro dutasteride metabolized by CYP3A4 isoenzyme of cytochrome P450 person to two small monohydroxylated metabolites; however, it does not apply isozymes CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 or CYP2D6 this system. After reaching a stable concentration of dutasteride in the serum using a mass spectrometric method, the unchanged dutasteride, 3 large metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride and 6-hydroxydutasteride) and 2 small metabolites (6,4'-dihydroxydutasteride and 15-hydroxydutasteride).

    Excretion

    In the human body dutasteride is subject to intensive metabolism. After ingestion of dutasteride in a daily dose of 0.5 mg to achieve a stable concentration of 1.0% to 15.4% (an average of 5.4%) the dose administered 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 accounting for less than 5%).

    Through the kidneys in humans excreted only trace amounts of unchanged dutasteride (less than 0.1% of the dose).

    When taking therapeutic doses of dutasteride, its final half-life is 3-5 weeks. Dutasteride is found in serum (in 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 saturable (i.e., depending on concentration) and one unsaturated (i.e., concentration-independent). At low concentrations in serum (less than 3 ng / ml) dutasteride It is quickly displayed with the help of both elimination processes. After a single dose of 5 mg or less in doses, dutasteride quickly eliminated from the body and has a short half-life, equal to 3-9 days.

    At serum levels above 3 ng / ml dutasteride is output more slowly (0.35-0.58 l / h), mainly through a linear unsaturated elimination process with a finite half-life of 3-5 weeks.

    With therapeutic concentrations, the final half-life is 3-5 weeks andagainst the background of daily intake of 0.5 mg, the slower clearance of dutasteride predominates; The overall clearance is linear and independent of concentration. The content of dutasteride in the serum (more than 0.1 ng / ml) is detected within 4-6 months after discontinuation of treatment.

    Older men

    The pharmacokinetics and pharmacodynamics of dutasteride were studied in 36 healthy volunteers aged 24 to 87 years after taking one dose (5 mg) of dutasteride. There were no statistically significant differences between the different age groups for pharmacokinetic parameters such as the area under the pharmacokinetic curve (AUC) and the maximum concentration in the blood plasma (Cmax). There were also no statistically significant differences in the half-life values ​​(T1 dutasteride between the age groups of men 50-69 years old and over 70 years of age, in which most men with benign prostatic hyperplasia (BPH) are included.

    Between different age groups, there were no significant differences in the degree of decrease in DHT levels. These results demonstrate that there is no need to reduce the dose of dutasteride depending on the age of the patients.
    Indications:

    Avodart® is administered to patients:

    - as a monotherapy for treatment and prevention of progression benignprostatic hyperplasia by reducing its size, alleviating symptoms, improving urination, reducing the risk of acute urinary retention, and the need for surgery;

    - as a combination therapy with αadrenoblockers for the treatment and prevention of the progression of benign prostatic hyperplasia by reducing its size, alleviating symptoms, improving the urineemitting, reducing the risk of acute urinary retention and the need for surgery. The combination of dutasteride and α1-adrenoblocker tamsulosin was mainly studied.

    Contraindications:

    Avodart® is contraindicated in patients with hypersensitivity to dutasteride or any component of the drug and other 5α-reductase inhibitors. The use of dutasteride is contraindicated in women and children.

    Carefully:Liver failure.
    Pregnancy and lactation:

    Fertility

    Effect of dutasteride in a daily dose of 0.5 mg on semen characteristics was studied in healthy volunteers aged 18-52 years. By the 52nd week of treatment in the group patients who received dutasteride, average values ​​of percentage decrease total number of spermatozoa, volume sperm and motor activity spermatozoa were 23%, 26%, and 18%, respectively, compared with initial level in the group of patients, who received a placebo. Concentration spermatozoa and their morphology is not changed.

    After 24 weeks of follow-up, the mean the percentage change in the total the number of spermatozoa in the group dutasteride remained 23% lower in compared with the original level. Average value for all sperm parameters in all time points remained in the limits and did not correspond criteria for clinically significant change (30%), at the 52nd week treatment in two volunteers in a group total amount of dutasteride spermatozoa decreased by more than 90% compared with the baseline, with partial recovery at week 24 observation.

    Thus, the clinical significance effects of dutasteride on sperm counts and on individual fertility patient is unknown.

    Pregnancy

    Dutasteride is contraindicated in women.

    Dutasteride has not been studied in women, since preclinical data suggest that suppression of DHT levels can to inhibit the development of outdoor genital organs in a male fetus.

    Lactation

    There is no data on the penetration of dutasteride into breast milk.
    Dosing and Administration:
    Avdard® can be used regardless of food intake.
    Capsules should be swallowed whole, not chewed, not opened, as the contents of the capsule can cause irritation of the mucous membrane of the oropharynx.

    BPH

    Adult men (including the elderly)

    The recommended dose of Avodart® is one capsule (0.5 mg) once a day orally. Capsules should be taken as a whole.

    Although the improvement in the background of the use of the drug occurs rather quickly, treatment should be continued for at least 6 months in order to objectively evaluate the therapeutic effect.

    For treatment of BPH, Avodart® can be given as a monotherapy or in combination with α1-adrenoblockers.

    Special patient groups

    Patients with impaired renal function

    When taking 0.5 mg of Avodart® daily, less than 0.1% of the dose is released through the kidneys, so there is no need to reduce the dose in patients with impaired renal function.

    Patients with hepatic impairment

    Currently, there is no data on the use of Avodart® in patients with impaired hepatic function. As dutasteride is subject to intensive metabolism, and its half-life is 3-5 weeks, care must be taken when Avodart® is treated with patients with hepatic impairment.

    Side effects:

    The undesirable phenomena presented below are listed according to the body systems and in accordance with the frequency of occurrence. Frequency of occurrence is defined as follows: very often (≥ 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), very rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of post-registration observation.

    Frequency of occurrence of undesirable phenomena formed on the basis of post-registration monitoring

    From the immune system

    Highly rarely: allergic reactions (rash, itching, hives, localized edema) and angioedema.

    From the skin and subcutaneous fat

    Rarely: alopecia (mainly loss of hair on the body) or hypertrichosis.

    Mental disturbance

    Highly rarely: a depressed state.

    From the side of the reproductive system and mammary glands

    Highly rarely: testicular pain, testicular edema.

    Frequency of occurrence of undesirable phenomena, formed on the basis of clinical research data (undesirable phenomena associated with the use of dutasteride as monotherapy)

    In the third phase of placebo-controlled studies with dutasteride compared with placebo, the researchers assessed the undesirable phenomena associated with the intake of dutasteride:

    1 - including soreness and enlargement of the mammary glands.

    2 - undesirable phenomena on the part of the reproductive system and mammary glands associated with the use of dutasteride (both in monotherapy and in combination with tamsulosin). These adverse events may persist after discontinuation of treatment and the effect of dutasteride on the preservation of these undesirable events is not known.

    Undesirable effects associated with the use of dutasteride in combination with tamsulosin

    The following adverse events were reported in the Comboth study (a comparison of dutasteride 0.5 mg and tamsulosin 0.4 mg once daily as monotherapy or as a combination for four years) and evaluated by researchers with a cumulative effect ≥ 1%).

    Unwantedaboute phenomenon

    The occurrence of an undesirable phenomenon during the period of tamsulosin in combination with dutasteride

    1st year

    2 nd year

    3 rd year

    4th year

    Combination1 (n)

    (n = 1610)

    (n = 1428)

    (n = 1283)

    (n = 1200)

    - Dutasteride

    (n = 1623)

    (n = 1464)

    (n = 1325)

    (n = 1200)

    - Tamsulosin

    (n = 1611)

    (n = 1468)

    (n = 1281)

    (n = 1112)

    erectile disfunction3


    - Combination

    6%

    2 %

    <1 %

    <1 %

    - Dutasteride

    5%

    2%

    <1 %

    <1 %

    - Tamsulosin

    3%

    1 %

    <1 %

    1 %

    Decreased libido3


    - Combination

    5%

    <1 %

    <1 %

    0%

    - Dutasteride

    4%

    1 %

    <1 %

    0%

    - Tamsulosin

    2%

    <1 %

    <1%

    <1 %

    Violation of ejaculationand3


    - Combination

    9 %

    1 %

    <1 %

    <1 %

    - Dutasteride

    1 %

    <1%

    <1 %

    <1 %

    - Tamsulosin

    3%

    <1%

    <1 %

    <1 %

    Violations from the mammary gland2


    - Combination

    2%

    <1 %

    <1 %

    <1 %

    - Dutasteride

    2%

    1 %

    <1 %

    <1 %

    - Tamsulosin

    <1 %

    <1 %

    <1 %

    0%

    Dizziness


    - Combination

    1 %

    <1 %

    <1 %

    <1 %

    - Dutasteride

    <1 %

    <1 %

    <1 %

    < 1 %

    - Tamsulosin

    1 %

    <1 %

    <1 %

    0%

























    1 - combination = dutasteride 0.5 mg once daily + tamsulosin 0.4 mg once a day;

    2 - including tenderness and enlargement of the mammary glands;

    3 - undesirable phenomena on the part of the reproductive system and mammary glands associated with the use of dutasteride (both in monotherapy and in combination with tamsulosin).These adverse events may persist after discontinuation of treatment. The effect of dutasteride on the preservation of these undesirable phenomena is unknown.

    Overdose:

    When appointing dutasteride to 40 mg / day, once (80 times higher than the therapeutic dose) for 7 days, no significant side effects were noted. During clinical trials, patients received dutasteride in a dose of 5 mg daily, while no additional side effects were observed to those observed with 0.5 mg of dutasteride. There is no specific antidote for dutasteride, so if you suspect an overdose, it is enough to carry out symptomatic and supportive treatment.

    Interaction:

    In vitro dutasteride metabolized by the isoenzyme CYP3A4 of the human cytochrome P450 system. Therefore, in the presence of inhibitors of CYP3A4, dutasteride concentrations in the blood can increase.

    With simultaneous application dutasteride with inhibitors of CYP3A4 verapamil and diltiazem decrease in clearance of dutasteride. At the same time, amlodipine, other calcium channel blockers when used simultaneously with dutasteride does not reduce the clearance of dutasteride.The decrease in clearance of dutasteride and the subsequent increase in its concentration in the blood in the presence of inhibitors of CYP3A4 is not clinically significant due to the wide range of dutasteride safety margins, so there is no need to adjust its dose.

    In vitro dutasteride is not metabolized by the following isoenzymes of the human cytochrome P450 system: CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 or CYP2D6. Dutasteride does not inhibit in vitro enzymes of the human cytochrome P450 system involved in the metabolism of drugs.

    In vitro dutasteride does not displace warfarin, acenocoumarol, fenprokumone, diazepam and phenytonin from the sites of their binding to plasma proteins, and these drugs, in turn, do not displace dutasteride.

    In studies of the interaction of dutasteride with tamsulosin, terazosin, warfarin, digoxin, and colestyramine, no clinically significant pharmacokinetic or pharmacodynamic interactions were observed in humans.

    When dutasteride is used simultaneously with lipid-lowering drugs, ACE inhibitors, beta-adrenoblockers, calcium channel blockers, corticosteroids, diuretics,non-steroidal anti-inflammatory drugs, type V phosphodiesterase inhibitors, and quinolone antibiotics, no significant undesirable drug interactions were observed.

    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, immediately wash the corresponding skin area with soap and water.

    Impaired liver function

    Currently, there is no data on the use of Avodart® in patients with impaired hepatic function. As dutasteride is subject to intensive metabolism, and its half-life is 3-5 weeks, care must be taken when Avodart® is treated with patients with hepatic impairment.

    Heart failure in combination dutasteride and tamsulosin

    In two 4-year clinical trials, the incidence of heart failure was higher in patients receiving a combination of dutasteride and α1-blocker, mainly tamsulosin, than in patients who did not receive a combination treatment.In these two studies, the incidence of heart failure remained low (<1%) with some variability between them. But in general, there were no discrepancies in the frequency of side effects from the cardiovascular system. The causal relationship between treatment with dutasteride (either as monotherapy or as a combination with α1-blocker) and the development of heart failure is not established.

    Effect on the detection of prostate-specific antigen (PSA) and prostate cancer (PCa)

    Patients should undergo digital rectal examination, and also use other methods of prostate gland testing, before starting treatment with dutasteride and periodically repeat them during treatment to exclude the development of PCa. Determination of serum PSA is an important component of screening aimed at detecting PCa. After a 6-month therapy with dutasteride, the average serum PSA level is reduced by approximately 50%. Patients receiving dutasteride, a new baseline PSA level should be determined after 6 months of therapy.In the future, it is recommended to regularly monitor the level of PSA. When interpreting the value of PSA 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 marker of PCa after the definition of a new baseline PSA level. Any confirmed increase in PSA relative to its lowest value in the treatment with dutasteride may indicate the development of PCa (particularly prostate cancer with a high degree of Gleason differentiation) or non-adherence to dutasteride therapy and should be carefully evaluated even if these PSA levels remain in the limits of normal values ​​for a given age group of patients not taking 5α-reductase inhibitors.

    The level of total PSA returns to the initial value within 6 months after the abolition of dutasteride.
    The ratio of free PSA to the total remains constant even against the background of dutasteride therapy. If the determination of the percentage of free PSA fraction is additionally used to detect PCa in men receiving dutasteride, correction of this value is not required.

    PCa and high grade tumors

    In a 4-year study (REDUCE), placebo versus dutasteride was compared in 8,231 volunteers aged 50 to 75 years with a negative biopsy result for PCa and a PSA level of 2.5 ng / ml to 10.0 ng / ml during 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 malignancy of the Gleason cancer was determined. 1517 patients were diagnosed with PCa during the study. In most cases, both in the dutasteride group and in the placebo group, a highly differentiated prostate cancer was diagnosed (the Gleason score was 5-6). Differences in the number of cases of PCa with an assessment of 7-10 points on the Gleason scale in the group. dutasteride and placebo group were absent (p = 0.81).

    After 4 years, there were more cases of PCa 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 assessing biopsy data in the 1-2 years, the number of patients diagnosed with PCa with an assessment of 8-10 points on the Gleason score was comparable in the dutasteride groups (n = 17, 0.5%) and placebo (n = 18, 0.5 %).When assessing biopsy data in the 3-4 years, more cases of PCa 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 PCa with an assessment of 8-10 points on the Gleason score was stable during all the time periods (during the 1-2 and 3-4 years) in the dutasteride group (0.5% in each period) , while in the placebo group, the percentage of patients diagnosed with PCa with a score of 8-10 points was lower during the 3-4 years than in the 1-2 years (<0.1% compared to 0.5 % respectively).

    In a 4-year study (SMBAT) of patients with BPH, in which prostate biopsy was not defined for all participants by the protocol, and all diagnoses of PCa were based on biopsy according to indications, PCa with a score of 8-10 Gleason score was diagnosed in 8 patients (<0.5%) with dutasteride in 11 patients (<0.7%) with tamsulosin and 5 patients (<0.3%) with combined therapy with dutasteride and tamsulosin:

    The causal relationship between the intake of dutasteride and the development of PCa of a high degree of gradation has not been established.

    Men taking dutasteride, should be held regularly a survey to assess the risk of developing PCa, including the PSA level.

    Breast cancer in men

    In clinical trials and during post-registration follow-up reported on the occurrence of breast cancer in men taking dutasteride. Patients should be warned that with any changes in the tissues of the mammary glands, such as the appearance of nodules or excretion from the nipples, it is necessary to immediately report this to your doctor.

    In clinical studies in which the effect of monotherapy with dutasteride (3,374 patient-years), 2 breast cancers were detected with dutasteride therapy (at 10 weeks and 11 months) and 1 in the patient who received the placebo. In subsequent clinical trials involving 8231 men aged 50 to 75 years with negative PCa biopsy and PSA levels ranging from 2.5 ng / mL to 10.0 ng / mL (17489 patient years), who received dutasteride and patients (5,027 patient-years) who received combination therapy with dutasteride and tamsulosin, no cases of breast cancer were detected in any of the comparison groups.

    At the moment, it is unclear whether there is a causal relationship between the occurrence of breast cancer in men and the long-term use of dutasteride.
    Effect on the ability to drive transp. cf. and fur:Dutasteride intake does not affect driving or working with machinery.
    Form release / dosage:Capsules 0.5 mg.
    Packaging:For 10 capsules in PVC / PVDC / Al blisters. For 3 or 9 blisters together with instructions for medical use in a pack of cardboard.
    Storage conditions:At a temperature of no higher than 30 ° C.

    Keep out of the reach of children.
    Shelf life:4 years.

    Do not use after expiration date
    Terms of leave from pharmacies:On prescription
    Registration number:LS-000052
    Date of registration:05.02.2010 / 07.03.2013
    Expiration Date:Unlimited
    The owner of the registration certificate:GlaxoSmithKline Trading, ZAO GlaxoSmithKline Trading, ZAO Russia
    Manufacturer: & nbsp
    Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO
    Information update date: & nbsp21.01.2017
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