Trade name Avoprost
INN Dutasteride
Chemical name (5α, 17(β)-N-{2,5-bis(trifluoromethyl)-phenyl}-3-oxo-4-
Azaadrost-1-en-17-carboxamide
Dosage form capsules
Composition one capsule contains Dutasteride 0.5 mg
Excipients mono- and diglycerides of caprylic/capric acid, butyl hydroxytoluene
Capsule shell composition: Gelatine, Glycerol, Titanium dioxide E-171, Purifier Water, Iron Oxide E-172, Lecithin, medium chain triglycerides.
Description Soft Gelatine Capsules of oval shape with a seal, opaque, light-yellow color.
Pharmacological group Agent for cure of urologic diseases, agent for cure of benign prostate hyperplasia.
ATC code G04CB02

INN Dutasteride
Chemical name (5α, 17(β)-N-{2,5-bis(trifluoromethyl)-phenyl}-3-oxo-4-
Azaadrost-1-en-17-carboxamide
Dosage form capsules
Composition one capsule contains Dutasteride 0.5 mg
Excipients mono- and diglycerides of caprylic/capric acid, butyl hydroxytoluene
Capsule shell composition: Gelatine, Glycerol, Titanium dioxide E-171, Purifier Water, Iron Oxide E-172, Lecithin, medium chain triglycerides.
Description Soft Gelatine Capsules of oval shape with a seal, opaque, light-yellow color.
Pharmacological group Agent for cure of urologic diseases, agent for cure of benign prostate hyperplasia.
ATC code G04CB02

Indications for usage
_treatment of moderate and severe symptoms of benign prostate hyperplasia (BPH);
_reduced risk of acute ischuria and need of intervention in patients with moderate and severe symptoms of BPH.
Rout of administration and dose
Avoprost is intended for oral usage. Swallow an integral capsule with a glass of water. Do not open the capsules and/or masticate as the capsule content can cause irritation of tunica mucosa of oropharyngeal surface.
Intake of Avoprost is not subject to food taking.
Avoprost can be administered as monotherapy and also in combination with α1-adrenoceptor antagonist Tamsulosin (0.4 mg) (see «Safety measures» and «Side effects»).

Adult men (including elderly)
Recommended dose of the drug Avoprost is an oral intake of one capsule (0.5 mg) 1 time daily.
Symptom improvement can be observed at early stages of treatment still it could be required 6 months to reach the response to therapy.
Dose correction for elderly patients has not been studied.

Patients with renal insufficiency
Renal insufficiency effect on Dutasteride pharmacokinetics has not been studied.
Dose correction for patients with renal insufficiency is not intended.
Patients with compromised liver function
Compromised liver function effect on Dutasteride pharmacokinetics has not been studied, hence administer with caution to patients with slight to moderate compromised liver function (see section «Safety measures»). Dutasteride is contraindicated to patients with severe hepatic failure (see section «Contraindications»).

Safety measures
Combined therapy shall be indicated only after careful risk/benefit analysis due to elevated probability side effect occurrence (including heart failure) and also after study of alternative treatment variants including monotherapy (see section «Rout of administration and dose»).
Prostate tumor and neoplasms of low differentiation degree
The effect of Dutasteride, 0.5 mg daily, on patients with higher risk of tumor of prostate development was evaluated in a four-year multicenter randomized double blind placebo controlled clinical study REDUCE (including men from 50 to 75 years old with the level of prostate-specific antigen within 2.5-10 ng/ml and negative biopsy result prior to be recruited in the study) as compared to placebo. The results of said study found out an elevated rate of tumor cases of prostate (8-10 by Glisson’s scale) in men administered Dutasteride (n=29, 0.9%) in comparison with men administered placebo (n=19, 0.9%). The relation between Dutasteride intake and prostate tumor (8-10 by Glisson’s scale) is unclear. It is necessary to examine regularly men administered Dutasteride for the development of prostate tumor.

Prostate-specific antigen (PSA)
The level of PSA in blood serum is an important constituent of the process to detect prostate tumor. 6 months after treatment with Dutasteride the mean concentration of PSA in serum decreases by 50% approx.
After 6 months of Dutasteride therapy it is needed to determine in patients a new initial parameter of PSA concentration. Further it is recommended to monitor regularly the concentration of PSA. Any verification of PSA level increase from a minimum value can demonstrate the presence of prostate tumor or the absence of a patient’s compliance to Dutasteride therapy and should be thoroughly studied even if estimated parameters are within standard values for men not administered the inhibitor of 5-α-reductase. When interpreting the parameter of PSA level in patients administered Dutasteride, this parameter shall be compared with a previous level of PSA.
Dutasteride intake does not prevent the use of such a marker as PSA level in the process of prostate tumor diagnostics after determination of a new initial level.
PSA concentration parameter in serum returns to the initial value within 6 months after therapy termination. The ratio of unbounded PSA to total PSA is maintained constant even in case of Dutasteride administration. If clinicians apply a percentage content of unbound PSA in prostate tumor diagnostics in men administered Dutasteride, dose correction based on its value is not needed. It is necessary to perform a digital rectal investigation and other examinations to eliminate prostate tumor prior to Dutasteride therapy and then further periodically.

Disorder of cardiovascular system
In the course of four-year clinical study of cardiac insufficiency frequency rate (compound term for a number of reported cases, mainly cardiac decompensation and congestive heart failure) was a little higher in patients administered the combination of Dutasteride and α-adrenoceptor antagonists, mainly Tamsulosin, if compared with patients administered monotherapy. However, these studies reported that the frequency rate of cardiac insufficiency was lower in all the groups administered an active therapy compared to placebo group. Other data obtained for Dutasteride or α-adrenoceptor antagonists do not evidence higher risk of cardiovascular system diseases.

Breast cancer
In the course of clinical studies and post-marketing observation the development of mammary gland tumor was rarely reported in men administered Dutasteride. However, in epidemiological studies no reports evidenced risk increase of mammary gland development in men administered inhibitors of 5-α-reductase. Doctors shall instruct the patients about obligatory immediate communications of any alterations in mammary gland tissues (like for example nodes or discharge from nipples).

Hepatic failure
Use of Dutasteride in patients with hepatic failure has not been studied. Hence, administer Dutasteride with care to patients with hepatic failure of slight to a moderate degree.

Capsule damage
Dutasteride is absorbed through skin, therefore women, children and adolescents shall avoid contact with damaged capsules. In case of a contact with damaged capsules, wash immediately the site with water and soap.

Interaction with other drugs
Data on the reduction of PSA level in blood serum during Dutasteride therapy and on recommendations to detect prostate tumor are presented in section «Precaution measures».
Influence of other drugs on Dutasteride pharmacokinetics
Concurrent use of inhibitors CYP3A4 and/or P-glycoprotein.
Dutasteride is mainly removed from the body as metabolites. In vitro metabolism of Dutasteride is catalyzed by isoenzymes CYP3A4 and CYP3A5. Official studies of interaction with strong inhibitors were not carried out. At the same time the results of pharmacokinetic study of a population demonstrate that Dutasteride concentrations in blood serum of a small number of patients administered concurrent Verapamil or Diltiazem (moderate inhibitor CYP3A4 or inhibitor P-glycoprotein), were in the mean 1.6-1.8 time higher than in other patients).
The course duration of combined use of Dutasteride and strong inhibitors of isoenzyme CYP3A4 (Ritonavir, Indinavir, Nefazodone, Itraconazole, Ketoconazole administered perorally) can provoke Dutasteride serum concentration rise. Extra inhibition of 5-α-reductase under Dutasteride higher exposition is unlikely. At the same time if side effect arises, consider the possible decrease of Dutasteride frequency intake. It is worth noting that enzyme inhibiting can cause even more extended half-life period resulting in over 6 months for reaching a new equilibrium state.
Cholestyramine, 12 g intake 1 hour after a single dose of Dutasteride, 5 mg, does not affect Dutasteride pharmacokinetics.
Dutasteride influence on pharmacokinetics of other drugs
Dutasteride does not influence on Warfarin or Digoxin pharmacokinetics. It demonstrates that Dutasteride does not inhibit/induce either isoenzyme CYP2C9 or transport protein Р-glycoprotein. In vitro Dutasteride does not inhibit enzymes like CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4.
In a small clinical study (n=24) of a two-week duration with the participation of healthy men the use of Dutasteride (0.5 mg daily) did not affect Tamsulosin and Terazosin pharmacokinetics. The results to prove pharmacodynamics interaction were not obtained in said study.
Administration during pregnancy and lactation
Influence on fertility
Dutasteride is contraindicated to women.

Pregnancy
Like other inhibitors of 5-α-reductase Dutasteride prevents testosterone conversion in dihydrotestosterone; Dutasteride effect on the organism of a pregnant woman bearing the fetus of a male sex can negatively affect the development of external genitals of the fetus (see section «Precautions measures»). Low quantities of Dutasteride were found in sperm of tested subjects treated with daily dose 0.5 mg. It is unknown if mother’s contact with sperm of a patient administered Dutasteride affects negatively the fetus of a male sex (the highest risk of a contact is during the first 16 weeks of pregnancy).
Like in case of all inhibitors of 5-α-reductase, to eliminate a pregnant or supposed to be pregnant woman’s contact with sperm of a man administered the drug by using a condom.

Lactation
It is unknown if Dutasteride discharges with breast milk.

Fertility
It was reported that Dutasteride altered sperm features (lower number of spermatozoids, sperm volume and spermatozoid motility) in healthy men. Possible decrease of male fertility cannot be excluded.

Side effects
Dutasteride use in monotherapy
Side effects developed in the course of the first year of therapy in about 19% of 2617 patients who were administered Dutasteride in the course of two-year placebo controlled clinical study phase III. The majority of side effects were slightly or moderately apparent and related to reproductive system. In the course of a further two-year open extended study, side effect profile alterations were not found.
Table below presents the description of side effects in controlled clinical studies and in post-marketing observations. Side effects listed below in the judgement of the researcher are associated with drug intake (ratio score NLT 1%) in the course of the first year of therapy mainly in patients from Dutasteride group than in Placebo group. Spontaneous reports of side effects in post-marketing studies did not permitted to establish the frequency rate of the reactions.
The assessment of undesirable effects is based on the data below on frequency occurrence: very often 1/10 administrations (> 10%); often  1/100 administrations (> 1% and < 10%); not often  1/1000 administrations (> 0.1% and < 1%); rare  1/10000 administrations (> 0.01% and< 0.1%); very rare  1/10000 administrations (< 0.01%) and frequency rate is unknown (cannot be evaluated based on the available data).


1 Said side effects for reproduction system are associated with Dutasteride use (in monotherapy mode and in combination with Tamsulosin). They can resist after termination of therapy. Dutasteride role in the resistance of these side effects has not been ascertained.
2 sperm volume decrease

Combined therapy with the drug Avoprost and
α-adrenoceptor antagonist Tamsulosin.
Data of four-year study CombAT in the course of which Dutasterid 0.5 mg monotherapy (n = 1623) 1 time daily was compared with Tamsulosin monotherapy 0.4 mg (n = 1611) 1 time daily and combined therapy (n = 1610) manifested the frequency rate of side effects associated with therapy in the opinion of the researcher, in the first, the second, the third and the fourth year of therapy were 22%, 6%, 4% and 2% respectively for combined therapy with Dutasteride/Tamsulosin; 15%, 6%, 3% and 2% for Dutasteride monotherapy, and 13%, 5%, 2% and 2% for Tamsulosin therapy. Hi9gher frequency of side effect occurrence in the first year of treatment in combined therapy group was associated with higher frequency of genital system disorders in particular disorders of ejaculation observed in said group. Side effects are described below, with reported frequency NLT 1% in the first year of study CombAT.

Other data
The data obtained in clinical study REDUCE demonstrated higher prostate tumor frequency rate ascertained as 8-10 points by Glisson’s scale in Dutasteride group than in Placebo group. What exactly, Dutasteride feature to decreases prostate gland volume or factors associated with the study performed, affected the results of said study, was not ascertained.
Further phenomenon was noted in clinical studies and in post-marketing period: mammary gland tumor in men (see section «Precaution measures»).
Please, send the data on side effects to InfoBase dedicated to undesirable reactions (effects) of the drug including reports on lack of efficacy of the drug discovered in The Republic of Belarus (“Center for expertise and trials in healthcare” Unitary Venture under Ministry of health of The republic of Belarus http:www.rceth.by). Communicating undesirable reactions you will help to obtain more data about drug safety.

Overdose
In the course of clinical trials of Dutasteride with the participation of healthy volunteers, single daily doses of Dutasteride up to 40 mg/day (80 therapeutic does) were administered for 7 days without significant safety problems. In clinical studies doses 5 mg/day were administered for 6 months without the development of undesirable reactions other than those observed in use of therapeutic dose 0.5 mg.
Specific antidote in case of Dutasteride overdose is absent, thus if overdose is suspected adequate symptomatic and supporting therapy shall be administered.

Contraindications
Dutasteride is contraindicated to:
- Women, children and adolescents (see section «Pregnancy and lactation. Influence on fertility»);
- Patients with hypersensitivity to Dutasteride, other inhibitors of 5-α- reductase or any ingredient of this drug;
- Patients with severe hepatic insufficiency
Influence on driving ability and operating mechanisms
In terms of pharmacodynamics properties of Dutasteride, it is not supposed that Dutasteride intake shall influence driving ability and operating mechanisms.

Dosage form
Soft Gelatine Capsules, 10 capsules per blister made of opaque polyvinyl chloride/polyvinyl dichloride film and printed lacquered aluminum foil, 3 or 6 blisters per pack with leaflet.
Storage conditions
Store at temperature not exceeding 25 С.
Store away from children.
Shelf life
2 years. Do not use after the expiration date indicated on the pack.
Sale conditions
Prescribed drug