Expiration date: 10/2022
The composition and form of issue:
Capsules. 1 caps. contains:
dutasteride 0.5 mg
excipients: butylhydroxytoluene — 0,035 mg mono-di-glycerides of Caprylic/capric acid (MDC) — 349,5 mg
capsule shell: gelatin — 157,4 mg glycerine (glycerol) with 89.9 mg titanium dioxide E171 (CI77891) — 1.7 mg iron oxide yellow E172 (CI77492) — 0,2 mg red ink print — q.s.
blistere in 10 PCs. in cardboard pack 3 or 9 blisters.
Description pharmaceutical form:
Capsules: oblong, opaque, yellow gelatin, with printed text "GX CE2" in red ink on one side.
Absorption. After a single dose of 0.5 mg dutasteride Cmax in serum is reached within 1-3 h. the Absolute bioavailability is about 60% relative to 2-hour in/infusion. Bioavailability dutasteride not depend on food intake.
Distribution. Single and multiple dutasteride is characterized by a large Vd (300 to 500 l). Dutasteride has a high degree of binding to plasma proteins (>99.5 percent). With a daily intake of dutasteride concentration in the serum reaches 65% of the stationary level after 1 month and approximately 90% of this level in 3 months. Dutasteride steady concentration in the serum (CSS), equal to about 40 ng/ml are achieved after 6 months of daily administration of 0.5 mg of the drug. In sperm, as in serum, the stationary concentration dutasteride also are achieved after 6 months. After 52 weeks of treatment the concentration dutasteride in semen averaged 3.4 ng/ml (0.4 to 14 ng/ml). Of serum in the sperm enters approximately 11.5% dutasteride.
Biotransformation. In vitro, dutasteride is metabolized by the enzyme CYP3A4 of cytochrome P450 to two metabolites secondary monohydroxylated however, it does not apply the enzymes of this system CYP2C9, and CYP2D6 CYP2C19. After reaching Css dutasteride in the serum using mass spectrometry technique detects unchanged dutasteride, 3 major metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride and 6-hydroxydutasteride) and 2 secondary metabolite.
Elimination. Dutasteride is subjected to intensive metabolism. Once inside dutasteride at a dose of 0.5 mg/day to achieve steady state in humans, 1.0 to 15.4% (mean of 5.4%) of the dose excreted in the faeces unchanged. The remainder of the dose excreted as 4 major metabolites, constituting 39%, 21%, 7% and 7%, respectively, and 6 minor metabolites (each share of which accounts for less than 5%).
With urine in humans, trace amounts are excreted unchanged dutasteride (less than 0.1% of the dose).
When you receive dutasteride therapeutic doses its final T1/2 is 3-5 weeks. Dutasteride is found in serum (at concentrations above 0.1 ng/ml) up to 4-6 months after you stop taking it.
Linearity/non-linearity. Pharmacokinetics dutasteride can be described as the absorption process is first order and two of the parallel process of elimination, one saturable (i.e. concentration-independent) and an unsaturated (i.e. independent of concentration). At low concentrations in serum (less than 3 ng/ml), dutasteride is rapidly excreted through both processes of elimination. After receiving a single dose of 5 mg and dutasteride less quickly eliminated from the body and has a short T1/2 equal to 3-5 days. At concentrations in serum above 3 ng/ml clearance dutasterida is slower (0,35–0,58 l/h) primarily by linear of an unsaturated process of elimination with the final T1/2 is 3-5 weeks. At therapeutic concentrations, on the background of daily administration of 0.5 mg, is dominated by a slower clearance dutasterida total clearance is linear and concentration-independent in nature.
Older men. The pharmacokinetics and pharmacodynamics dutasteride was studied in 36 healthy men aged 24 to 87 years after a single dose (5 mg) of the drug. Between different age groups was not statistically significant differences in such pharmacokinetic parameters dutasteride as AUC and Cmax. It was not revealed statistically significant differences in T1/2 dutasteride between the age group 50-69 years age group older than 70 years, which includes most men with BPH. Between age groups there were no significant differences in the degree of decrease in the levels of dihydrotestosterone. These results demonstrate the lack of necessary to reduce the dose dutasteride in elderly patients.
Description pharmacological action:
Dutasteride — bivalent inhibitor 5&alpha-reductase. Inhibits the activity of isozymes 5&alpha-reductase of 1st and 2nd types, which are responsible for the conversion of testosterone to 5&alpha-dihydrotestosterone (DHT). Dihydrotestosterone is the primary androgen responsible for hyperplasia of the glandular tissue of the prostate.
Effect on concentration of dihydrotestosterone and testosterone. Dutasteride maximum impact on reducing concentrations of DHT is dose dependent and is observed within 1-2 weeks after the start of treatment. After 1 and 2 weeks of admission dutasteride at a dose of 0.5 mg/day median values of concentrations of DHT in serum is reduced by 85% and 90%, respectively.
- treatment and prevention of progression of BPH (a decrease in the size of the prostate gland, to improve urination and reduce the risk of acute urinary retention and need for surgical treatment)
- treatment and prevention of progression of BPH (a decrease in the size of the prostate gland, relief of symptoms, including improvement in urination) in combination with &alpha1-blockers (studied combination dutasteride and alpha1-blocker — tamsulosin).
Hypersensitivity to dutasteride, other inhibitors 5&alpha-reductase inhibitor or to any ingredient of the drug.
Dutasteride is contraindicated in women and children.
These clinical studies
Monotherapy with dutasteride: impotence, change (reduction) libido, violation of ejaculation, gynecomastia (includes pain and breast increase).
Combination therapy with dutasteride and tamsulosin: impotence, change (reduction) libido, violation of ejaculation, gynecomastia (includes pain and breast increase), dizziness.
Monitoring data in routine clinical practice
Very rarely, allergic reactions such as rash, itching, hives, limited swelling, angioneurotic edema.
Dutasteride is metabolized by the CYP3A4 enzyme system cytochrome P450. In the presence of inhibitors of CYP3A4 dutasteride concentration in the blood may increase.
While the use of dutasteride with the CYP3A4 inhibitors verapamil and diltiazem, there is a decrease in clearance dutasterida. However, amlodipine, another CCB, does not reduce ground clearance dutasterida. Dutasteride reduction in clearance and subsequent increase of its concentration in the blood, while the use of this drug and inhibitors of CYP3A4, is not clinically significant due to the wide therapeutic index of this drug, therefore, dose adjustment is not required.
In vitro, dutasteride is not metabolized by the following isoenzymes of cytochrome P450 humans: CYP1A2, CYP2C9, CYP2C19 and СYP2D6.
Dutasteride does not inhibit in vitro the enzymes of cytochrome P450 involved in the metabolism of drugs.
Dutasteride does not displace warfarin, diazepam and phenytoin from their binding to plasma proteins, and these drugs, in turn, do not displace dutasteride.
When applying dutasteride simultaneously with lipid lowering drugs, ACE inhibitors, &beta-blockers, CCB, corticosteroids, diuretics, NSAIDs, phosphodiesterase type 5 inhibitors and quinoline antibiotics of any significant drug interactions were observed.
Not detected clinically significant drug interactions with dutasteride tamsulosin, terazosin, warfarin, digoxin and kolestiraminom.
Method of application and dose:
Inside, regardless of meals, swallowing whole without chewing and without opening the capsule, as the capsule contents can cause irritation of the mucous membrane of the oropharynx.
Dutasteride can be used in monotherapy and also in combination with &alpha1-blockers. The effect occurs quite quickly, but treatment should continue for at least 6 months in order to objectively evaluate the effect of the drug.
Adult males (including elderly)
Dutasteride the recommended dose is 1 capsule. (0.5 mg) 1 every day.
Patients with impaired renal function
When receiving 0.5 mg dutasteride a day with urine it is allocated less than 0.1% of the dose, therefore dose adjustment in patients with renal impairment is not required.
Patients with impaired liver function
Dutasteride is subjected to intensive metabolism, and T1/2 is 3-5 weeks, so care must be taken when treating patients with impaired liver function.
In case of overdose (receiving a dose 80 times higher than therapeutic doses) side effects were noted.
Treatment: if you suspect an overdose, enough to spend symptomatic and supportive treatment. Specific antidote dutasterida no.
Dutasteride is absorbed through the skin and therefore women and children should avoid contact with damaged capsules. In case of contact with damaged capsules should immediately wash the relevant skin area with soap and water.
Impact on detection of prostate specific antigen and prostate cancer. In patients with BPH are necessary to carry out a digital rectal examination and other methods of examination of the prostate before treatment dutasteride and periodically repeat these studies in the treatment process to prevent the development of prostate cancer. The determination of the concentration of prostate specific antigen in serum is an important component of the screening process aimed at identifying prostate cancer. Usually an additional examination carried out in patients with prostate specific antigen concentrations above 4 ng/ml in such cases, it may be shown prostate biopsy. Baseline prostate specific antigen less than 4 ng/ml in patients receiving dutasteride does not exclude a diagnosis of prostate cancer.
After 6 months of dutasteride therapy reduces serum levels of prostate specific antigen in patients with BPH is about 50% even in the presence of prostate cancer. Despite individual differences, the decrease in the level of prostatic specific antigen by approximately 50% observed in the whole range of initial values of concentrations of prostate specific antigen (from 1.5 to 10 ng/ml). Thus, when interpreting the level of prostate specific antigen in men, which gets dutasteride for 6 months or longer, the measured level should be multiplied by two, and then compare it to the normal level without treatment dutasterida. This calculation of the content of the prostate specific antigen allows to preserve the specificity and reliability of the analysis, and the ability of the test to detect prostate cancer.
Any steady increase in the level of prostate specific antigen during therapy with dutasteride should undergo careful evaluation, including the possibility of non-compliance with mode of therapy dutasterida. The level of total prostate specific antigen returns to the original value within 6 months after the cancellation dutasteride. The ratio of the content of free prostatic specific antigen to the total remains constant even during therapy with dutasteride. When expressing this ratio in fractions for the detection of prostate cancer in men receiving dutasteride, correction of this magnitude is not required.
Combination therapy with tamsulosin. When conducting two clinical trials with a duration of 4 years the incidence of heart failure (a collective term, mainly because it was reported heart failure or congestive heart failure) in patients treated with dutasteride and &alpha-a blocker, mainly tamsulosin was higher than in patients not taking such a combination. In both studies, the incidence of cardiac failure was low (&le1%) and variable in different studies.
Causal relationship between treatment with dutasteride as monotherapy or in combination with the &alpha-a blocker and the development of heart failure is not established.
The impact on fertility. Influence dutasterida in a daily dose of 0.5 mg on the characteristics of sperm were studied in healthy volunteers aged 18-52 years. To 52 weeks of treatment the average values of the percentage reduction in total sperm count, semen volume and motor activity of sperms was 23%, 26% and 18%, respectively, compared to baseline. The sperm concentration and morphology did not change. Is considered a clinically significant 30% reduction, thus, the clinical value of dutasteride influence on individual fertility of the patient is unknown.
Effects on ability to drive and moving mechanisms. Welcome dutasteride no effect on driving and operating machinery.