2010/06/24

Avodart

Composition, structure and packing

Gelatine capsules, yellow, oblong, opaque, with markings in red ink "GX CE2" on one side. A capsule. dutasterid 500 mcg.

Excipients: mono-and diglycerides Caprylic / capric acid butilgidroksitoluol.

The composition of the shell capsules: gelatin, glycerol, titanium dioxide E171 (Cl77891), iron oxide yellow E172 (Cl77492).

Clinico-pharmacological group: Drug for treatment of benign prostatic hyperplasia. 5α-reductase inhibitor.

Pharmacological action

Drug for the treatment of benign prostatic hyperplasia.

Inhibits the activity of 5α-reductase isoenzymes type 1 and 2, which are responsible for the transformation of testosterone to 5α-dihydrotestosterone (DHT). Dihydrotestosterone is the main androgen responsible for hyperplasia of glandular tissue of the prostate gland. The maximum influence dutasterida reduce concentrations of dihydrotestosterone is a dose-dependent and is observed in 1-2 weeks. after starting treatment. After 1 and 2 weeks. Reception dutasterida a dose of 0.5 mg / day average concentrations of DHT in the serum is reduced by 85% and 90%. The drug reduces the size of the prostate, improves urination, and reduces the risk of acute urinary retention and the need for surgical treatment.

Pharmacokinetics

Absorption

After a single dose at a dose of 500 mg dutasterida Cmax in serum is achieved within 1-3 h. The 2-hour in / infusion absolute bioavailability is about 60%. Bioavailability dutasterida not depend on the meal.

Distribution

Plasma protein binding is high - more than 99.5%. Vd - 300-500 hp. With a daily intake of dutasterida concentration in serum reaches 65% of Css in 1 month and approximately 90% of this level 3 months later.

Css dutasterida in serum were approximately 40 ng / ml, achieved after 6 months of daily administration of the drug in a dose of 500 mcg. In sperm, as well as in serum, Css dutasterida also achieved in 6 months. Through 52 weeks. treatment dutasterida concentration in semen, on average 3.4 ng / ml (0.4-14 ng / ml). Of the serum in semen comes about 11.5% dutasterida.

Metabolism

In vitro dutasterid metabolized isoenzyme CYP3A4 with the formation of two secondary metabolites monogidroksilirovannyh, yet it does not apply isoenzymes CYP2C9, CYP2C19 and CYP2D6. After achieving Css dutasterida in serum by mass spectrometric method exhibit unaltered dutasterid, 3 major metabolite (4 'gidroksidutasterid, 1,2 - digidrodutasterid and 6 - gidroksidutasterid) and 2 secondary metabolite.

Withdrawal

Dutasterid subjected to intensive metabolism. After taking the drug orally at a dose of 500 mg / d to reach the equilibrium state of 1-15.4% (average 5.4%) of applied dose excreted in the faeces unchanged. The remainder of the dose was excreted in the form of 4 major metabolites, constituting 39%, 21%, 7% and 7% respectively, and 6 small metabolites (the share of each of which represents less than 5%). With urine in humans are derived trace amounts of unchanged dutasterida (less than 0.1% dose). When you receive dutasterida at therapeutic doses its final T1 / 2 is 3-5 weeks. Dutasterid detected in serum (at concentrations above 0.1 ng / ml) up to 4-6 months after the termination of his reception. Dutasterida pharmacokinetics can be described as a process of absorption and first order elimination of two parallel processes, one saturable (ie, dependent on the concentration) and one unsaturated (ie, not dependent on the concentration).

At low concentrations in serum (less than 3 ng / ml) dutasterid rapidly excreted by both processes of elimination. After receiving a single dose of 5 mg or less dutasterid rapidly excreted from the body and has a short T1 / 2, is 3-5 days. At concentrations in the serum of more than 3 ng / ml clearance dutasterida less - 0.35-0.58 L / h, with excretion occurs mainly through the unsaturated linear process with a finite T1 / 2 3-5 weeks. At therapeutic concentrations at the background of daily administration of the drug in a dose of 500 mcg prevails slower clearance dutasterida; total clearance is linear and not dependent on the concentration of character.

Pharmacokinetics in special clinical situations

Pharmacokinetics and pharmacodynamics dutasterida studied in 36 healthy men aged from 24 to 87 years after taking the drug in a single dose of 5 mg. Between age groups was not statistically significant differences in pharmacokinetic parameters such dutasterida as AUC and Cmax. There was also found statistically significant differences T1 / 2 dutasterida between the age group 50-69 years and age group over 70 years, which includes most of the men with benign prostate hyperplasia. Between age groups there was no significant difference in the degree of reduction of levels of DHT. These results indicate a lack of need to reduce the dose dutasterida elderly patients.

Statement
treatment of benign prostatic hyperplasia (to reduce the size of the prostate gland;
improve the current urine, to reduce the risk of acute urinary retention and the need of surgical treatment).

Dosage regimen

For men, including elderly patients, the recommended dose for ingestion of 500 mg (1 capsule.) 1 times / day. The capsules should be taken as a whole. The drug can be taken irrespective of food intake. The effect comes fairly quickly, but treatment should continue for at least 6 months in order to objectively evaluate the effect of the drug.

When violations of renal function reduce the dose of the drug is not required (because while taking the drug at a dose of 500 mg / day with urine is allocated less than 0.1% dose). Caution use the drug for patients with disorders of the liver, because dutasterid subjected to intensive metabolism in the liver, and its T1 / 2 is 3-5 weeks.

Side effect

On the part of the reproductive system: Erectile dysfunction, the change (decrease) libido, ejaculation disorder, gynecomastia (including pain and increased breast). Allergic reactions: in some cases - a rash, itching, urticaria, localized edema.

Contraindications
Hypersensitivity to dutasteridu and other components of the drug;
sensitivity to other inhibitors of 5α-reductases. Avodart is contraindicated in women and children.

Application for violations of liver function

Caution use the drug in patients with impaired liver function, t.k.dutasterid subjected to intensive metabolism in the liver, and its T1 / 2 is 3-5 weeks.

Application for violations of renal function

When violations of kidney function decline dose is not required (because while taking the drug at a dose of 500 mg / day with urine is allocated less than 0.1% dose).

Cautions

Dutasterid absorbed through the skin, so women and children should avoid contact with damaged capsules. In case of contact with damaged capsules should immediately wash the corresponding skin with soap and water.

In patients with benign prostate hyperplasia is necessary to finger rectal examination and other methods of investigating the prostate prior to treatment Avodartom and periodically repeat these studies in the treatment process to avoid the development of prostate cancer. The levels of prostate specific-antigen in serum is an important component of the complex studies aimed at identifying prostate cancer.

Usually a further survey carried out in patients with a concentration of prostate-specific antigen more than 4 ng / ml, in such cases can be shown biopsy of the prostate.

Baseline prostate-specific antigen less than 4 ng / ml in patients receiving dutasterid does not exclude the diagnosis of prostate cancer. After therapy Avodartom within 6 months a decrease in serum levels of prostate-specific antigen in patients with benign prostatic hyperplasia by approximately 50%, even in the presence of prostate cancer. Despite individual variability, the decline in prostate-specific antigen of approximately 50% observed in the whole range of initial concentrations of prostate-specific antigen (from 1.5 to 10 ng / ml). Therefore, when interpreting the level of prostate-specific antigen in men who received Avodart for 6 months or more, the measured level should be multiplied by 2, and then compare it to normal levels in men not receiving Avodart.

Effects on ability to drive vehicles and management mechanisms

Receiving Avodarta not affect the ability to drive a car and operate machinery.

Overdose

In case of overdose (receiving doses 80 times higher than therapeutic) side effects were noted. Dutasterida no specific antidote, and so if an overdose is suspected, enough to hold symptomatic and supportive treatment.

Drug Interactions

Since dutasterid metabolized isoenzyme CYP3A4, in the presence of inhibitors of CYP3A4 dutasterida concentration in the blood may increase. With simultaneous application dutasterida with CYP3A4 inhibitors verapamil and diltiazem have declined clearance. However, amlodipine, another calcium channel blockers does not reduce the clearance dutasterida.

With simultaneous application of inhibitors of CYP3A4 and Avodarta decrease dutasterida clearance and subsequent increase of its concentration in the blood is not significant due to wide therapeutic range with this drug, so there's no need to reduce the dose. In vitro CYP1A2, CYP2C9, CYP2C19 and CYP2D6 isoenzymes are not involved in the metabolism of dutasterida man; dutasterid not inhibit the enzyme cytochrome P450 in humans involved in the metabolism of drugs.

In applying dutasterida simultaneously with lipid-lowering drugs, ACE inhibitors, beta-blockers, calcium channel blockers, corticosteroids, diuretics, NSAIDs, inhibitors of PDE 5 and quinolone antibiotics derived, any significant drug interactions are not marked.

In the application within 2 weeks dutasterida simultaneously with tamsulosin or terazozinom not revealed any pharmacokinetic or pharmacodynamic interaction. With simultaneous application dutasterida and tamsulosin for 9 months demonstrated good tolerability of this combination.

Dutasterid does not displace warfarin, diazepam and phenytoin of the sites of their binding to plasma proteins, and these drugs, in turn, do not displace dutasterid. Warfarin, digoxin and kolestiramin not interact with dutasteridom.

Terms and Conditions of storage

The drug should be stored out of reach of children at or above 30 ° C.

Shelf life - 4 years.