Kombodart instructions for use. Duodart: instructions for use

Duodart: instructions for use and reviews

Solid capsules of hypromellose, oblong, size No. 00; with a brown body and an orange cap with the code "GS 7CZ" in black ink; the contents of the capsules are a soft gelatin capsule containing dutasteride and pellets containing tamsulosin hydrochloride.

Capsules are soft gelatinous, oblong, opaque, dull yellow.

One capsule contains: dutasteride - 50 mcg.

Excipients: mono-di-glycerides of caprylic / capric acid (MDA) - 299.47 mg, butylhydroxytoluene (BHT) - 0.03 mg.

The total mass of the contents is 300 mg.

The composition of the capsule shell: gelatin - 116.11 mg, glycerol - 66.32 mg, titanium dioxide - 1.29 mg, iron dye yellow oxide - 0.13 mg.

The total weight of the capsule shell is 184 mg.

Technological additives: medium chain triglycerides (MCTs) - q.s., lecithin - q.s.

The total weight is 484 mg.

Pellets from white to almost white.

One capsule contains: tamsulosin hydrochloride - 400 mcg.

Excipients: microcrystalline cellulose - 138.25 mg, methacrylic acid copolymer: ethyl acrylate (1: 1) 30% dispersion * - 8.25 mg, talc - 8.25 mg, triethyl citrate - 0.825 mg.

The mass of the pellet core is 156 mg.

Pellet shell composition: methacrylic acid copolymer: ethyl acrylate (1: 1) 30% dispersion * - 10.4 mg, talc - 4.16 mg, triethyl citrate - 1.04 mg.

The weight of the pellet shell is 15.6 mg.

The total weight is 172 mg.

The composition of the brown body of a hard capsule made of hypromellose: carrageenan - 0-1.3 mg, potassium chloride - 0-0.8 mg, titanium dioxide ~ 1 mg, iron dye red oxide ~ 5 mg, purified water ~ 5 mg, hypromellose-2910 - up to 100 mg ...

The composition of the orange cap of the hard capsule of hypromellose: carrageenan - 0-1.3 mg, potassium chloride - 0-0.8 mg, titanium dioxide ~ 6 mg, sunset yellow dye ** ~ 0.1 mg, purified water ~ 5 mg, hypromellose-2910 - up to 100 mg, black ink ~ 0.05 mg.

Technological additives: carnauba wax - q.s., corn starch - q.s.

The composition of black ink SW-9010: shellac - 24-27% w / w, propylene glycol - 3-7% w / w, iron dye black oxide - 24-28% w / w.

The composition of black ink SW-9008: shellac - 24-27% w / w, propylene glycol - 3-7% w / w, iron dye black oxide - 24-28% w / w, potassium hydroxide - 0.05-0.1%.

The theoretical total weight per capsule is 0.05 mg.

30 pcs. - bottles made of high density polyethylene (1) - cardboard packs.

90 pcs. - bottles made of high density polyethylene (1) - cardboard packs.

* a mixture of a copolymer of methacrylic acid: ethyl acrylate also contains the excipients polysorbate 80 and sodium lauryl sulfate as emulsifiers.

** in the manufacturer's dossier called "FD&C yellow dye 6".

Pharmacokinetics

Bioequivalence has been demonstrated between Duodart and the simultaneous administration of separate capsules of dutasteride and tamsulosin.

A bioequivalence study has been conducted single dose in patients both on an empty stomach and after meals. At the same time, there was a decrease in the Cmax of tamsulosin in the blood serum by 30% after meals compared to taking a combination of dutasteride and tamsulosin on an empty stomach. Food intake had no effect on tamsulosin AUC.

Pharmacodynamics

It is expected that the pharmacodynamic properties of dutasteride and tamsulosin in the form of a combined preparation will not differ from the properties of dutasteride and tamsulosin used simultaneously in the form of separate components.

Dutasteride

Dutasteride lowers DHT levels, reduces the size of the prostate gland, helps eliminate symptoms of lower urinary tract diseases and increases urinary flow, and also reduces the risk of acute urinary retention and the need for surgery.

The maximum effect of daily doses of dutasteride on the decrease in DHT concentrations is dose-dependent and is observed within 1-2 weeks. After 1 and 2 weeks of taking dutasteride at a dose of 500 μg / day, the mean serum DHT concentrations decreased by 85% and 90%, respectively.

In patients with BPH who received 500 μg of dutasteride per day, the average decrease in DHT levels was 94% after 1 year and 93% after 2 years, the average increase in serum testosterone levels was 19% both after 1 year and after 2 years. This is the expected consequence of 5α-reductase inhibition and does not lead to any of the known adverse events.

Tamsulosin

Tamsulosin increases maximum speed urination by reducing the tone of smooth muscles of the prostate and urethra and, therefore, reduces obstruction. Tamsulosin also reduces the complex of symptoms of filling and emptying, in the development of which bladder instability and smooth muscle tone of the lower urinary tract play a significant role. Alpha1-blockers can lower blood pressure by lowering peripheral resistance.

Clinical pharmacology

A drug for the treatment and control of symptoms of benign prostatic hyperplasia. Combination of a 5α-reductase inhibitor with an alpha1-blocker.

The drug Duodart is a combination of two components with complementary mechanisms of action that contribute to the elimination of symptoms in patients with benign prostatic hyperplasia (BPH): a dual 5α-reductase inhibitor - dutasteride and a blocker of α1a-adrenergic receptors - tamsulosin.

Dutasteride inhibits the activity of 5α-reductase isoenzymes of the 1st and 2nd types, under the action of which testosterone is converted into 5α-dihydrotestosterone (DHT), the main androgen responsible for hyperplasia of the glandular tissue of the prostate gland.

Tamsulosin inhibits α1a-adrenergic receptors in the smooth muscles of the stroma of the prostate gland and the bladder neck. Approximately 75% of the α1-adrenergic receptors in the prostate gland are receptors of the α1a subtype.

Indications for use Duodart

Treatment and prevention of the progression of BPH by reducing its size, eliminating symptoms, increasing the rate of urination, reducing the risk of acute urinary retention and the need for surgery.

Contraindications to the use of Duodart

• hypersensitivity to dutasteride, other 5α-reductase inhibitors, tamsulosin or any other component of the drug;
• orthostatic hypotension (including history);
• severe liver failure;
• age under 18;
• the use of the drug is contraindicated in women and children.

The drug should be prescribed with caution in chronic renal failure(CC below 10 ml / min), arterial hypotension, planned cataract surgery, combined use with powerful or moderately active inhibitors of the CYP3A4 isoenzyme (ketoconazole, variconazole and others).

Duodart Use during pregnancy and children

The use of the drug is contraindicated in children.

There have been no studies on the use of the drug Duodart during pregnancy, during the period breastfeeding and its effects on fertility. The data below reflects the information available for the individual components.

Fertility

Dutasteride

The effect of dutasteride intake at a dose of 500 μg / day on sperm characteristics was evaluated in healthy volunteers aged 18 to 52 years during 52 weeks of treatment and 24 weeks of follow-up after completion of treatment. At 52 weeks, the mean deviations from baseline for total sperm count, semen volume and sperm motility in the dutasteride group were 23%, 26% and 18%, respectively, when taking into account the deviations from baseline in the placebo group. Sperm concentration and morphology did not change. After 24 weeks of follow-up, the mean deviation in total sperm count in the dutasteride group was 23% lower than baseline. While the mean values ​​for all sperm parameters at all time points remained within the normal range and did not meet the predetermined criteria for clinically significant changes(30%), in two patients in the dutasteride group, sperm count after 52 weeks decreased by more than 90% from baseline values ​​with partial recovery after 24 weeks of observation. The clinical significance of the effect of dutasteride on sperm fertility rates in individual patients is unknown.

Tamsulosin

The effect of tamsulosin on sperm count and sperm performance has not been evaluated.

Pregnancy and the period of breastfeeding

The drug Duodart is contraindicated for use in women.

There is no data on the excretion of dutasteride or tamsulosin in breast milk.

Dutasteride

The use of dutasteride has not been studied in women, because data from preclinical studies have shown that suppression of circulating DHT levels can slow or suppress the formation of the external genitalia in male fetuses if a woman received dutasteride during pregnancy.

Tamsulosin

Administration of tamsulosin to pregnant female rats and rabbits at doses higher than therapeutic doses did not show any signs of fetal damage.

Duodart Side effects

Clinical studies of the drug Duodart have not been conducted, however, information on the use of the combination is available as a result of the CombAT clinical study (comparison of dutasteride 500 mcg and tamsulosin 400 mcg 1 time / day for 4 years in combination or as monotherapy).

Information on the profiles of adverse reactions to individual components (dutasteride and tamsulosin) is also provided.

Drug interactions

Studies on the interaction of the combination of dutasteride and tamsulosin with other drugs have not been conducted. The data below reflects the information available for the individual components.

Dutasteride

In vitro metabolic studies have shown that dutasteride is metabolized by the CYP3A4 isoenzyme of the human cytochrome P450 enzyme system. Therefore, in the presence of inhibitors of the isoenzyme CYP3A4, the concentration of dutasteride in the blood may increase.

According to the results of a phase 2 study, with the simultaneous use of dutasteride with inhibitors of the CYP3A4 isoenzyme verapamil and diltiazem, there is a decrease in the clearance of dutasteride by 37 and 44%, respectively. However, amlodipine, another calcium channel blocker, does not decrease dutasteride clearance.

A decrease in the clearance of dutasteride and a subsequent increase in its concentration in the blood with the simultaneous use of this drug and inhibitors of the isoenzyme CYP3A4 is probably clinically insignificant due to the wide range of dutasteride safety boundaries (up to a 10-fold increase in the recommended dose when used for up to 6 months), therefore dose adjustment not required.

In vitro, dutasteride is not metabolized by the following isoenzymes of the human cytochrome P450 system: CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 and CYP2D6.

Dutasteride does not inhibit in vitro human cytochrome P450 enzymes involved in drug metabolism.

In vitro studies have shown that dutasteride does not displace warfarin, acenocoumarol, phenprocoumon, diazepam and phenytoin from the sites of their binding to blood plasma proteins, and these drugs, in turn, do not displace dutasteride. Medications who participated in interaction studies - tamsulosin, terazosin, warfarin, digoxin and cholestyramine. At the same time, no clinically significant pharmacokinetic or pharmacodynamic interaction was observed.

When using dutasteride simultaneously with lipid-lowering drugs, ACE inhibitors, beta-blockers, calcium channel blockers, GCS, diuretics, NSAIDs, phosphodiesterase type 5 inhibitors and quinolone antibiotics of any significant pharmacokinetic or pharmacodynamic drug interactions was not noted.

Tamsulosin

There is a theoretical risk of increased hypotensive effect when using tamsulosin in conjunction with drugs that can lower blood pressure, including anesthetics, phosphodiesterase type 5 inhibitors and other alpha1-blockers. Do not use Duodart in combination with other alpha1-blockers.

The simultaneous use of tamsulosin and ketoconazole (a strong inhibitor of the isoenzyme CYP3A4) leads to an increase in Cmax and AUC of tamsulosin with a coefficient of 2.2 and 2.8, respectively. The simultaneous use of tamsulosin and paroxetine (a strong inhibitor of the isoenzyme CYP2D6) leads to an increase in Cmax and AUC of tamsulosin with a coefficient of 1.3 and 1.6, respectively. A similar increase in exposure is expected in patients with a slow metabolism of the CYP2D6 isoenzyme compared with patients with an intensive metabolism when used together with strong inhibitors of the CYP3A4 isoenzyme. The effect of co-administration of inhibitors of isoenzymes CYP3A4 and CYP2D6 with tamsulosia has not been clinically evaluated, but there is a potential for a significant increase in tamsulosin exposure.

The simultaneous use of tamsulosin (400 μg) and cimetidine (400 mg every 6 hours for 6 days) led to a decrease in clearance (by 26%) and an increase in AUC (by 44%) of tamsulosin. Care must be taken when prescribing Duodart and cimetidine together.

Exhaustive studies of drug-drug interactions between tamsulosin and warfarin have not been conducted. The results of the limited in vitro and in vivo studies are inconclusive. Caution should be exercised with the simultaneous administration of warfarin and tamsulosin.

In 3 studies in which tamsulosin (400 mcg for 7 days, then 800 mcg for the next 7 days) was co-administered with atenolol, enalapril or nifedipine for 3 months, no drug-drug interactions were found, therefore, there is no need for dose adjustment when using these drugs together with Duodart.

The simultaneous administration of tamsulosin (400 μg / day for 2 days, then 800 μg / day for 5-8 days) and a single intravenous administration of theophylline (5 mg / kg) did not lead to a change in the theophylline pharmacokinetics, therefore, dose adjustment did not required.

The simultaneous administration of tamsulosin (800 μg / day) and a single intravenous injection of furosemide (20 mg) led to a decrease from 11% to 12% in the Cmax and AUC of tamsulosin, but it is assumed that these changes are clinically insignificant and dose adjustment is not required.

Dosage Duodart

The drug is taken orally. The capsules should be taken whole, without chewing or opening, with water. Contact of the contents of the soft gelatin capsule containing dutasteride, which is contained within the hard capsule, with the oral mucosa may cause mucosal inflammation.

In adult men (including elderly patients), the recommended dose of Duodart is 1 caps. 1 time / day, approximately 30 minutes after the same meal.

Currently, there is no data on the use of the drug Duodart in patients with impaired renal function, however, when using the drug Duodart, dose adjustment is not required.

Currently, there is no data on the use of the drug Duodart in patients with impaired liver function.

Overdose

There are no data on overdose when taking a combination of dutasteride and tamsulosin. The data below reflects information on the individual components.

Dutasteride

Symptoms

When using dutasteride at a dose of up to 40 mg / day (80 times higher therapeutic dose) no significant adverse reactions were observed within 7 days. IN clinical research when dutasteride was prescribed at a dose of 5 mg / day for 6 months, no adverse reactions other than those listed for the therapeutic dose (500 μg / day) were noted.

There is no specific antidote for dutasteride, therefore, if an overdose is suspected, symptomatic and supportive treatment should be carried out.

Tamsulosin

Symptoms: with an overdose of tamsulosin, acute arterial hypotension may develop.

Treatment: in case of development of arterial hypotension, symptomatic therapy is necessary. BP can be restored when the patient assumes a horizontal position. If there is no effect, you can use drugs that increase the BCC, and, if necessary, vasoconstrictor... Kidney function should be monitored and, if necessary, maintained. Dialysis is unlikely to be effective because tamsulosin is associated with blood plasma proteins by 94-99%.

Active ingredients

Compound

1 capsule contains dutasteride 0.5 mg and tamsulosin hydrochloride 0.4 mg. excipients: caprylic acid monodiglycerides, butylhydroxytoluene (E 321), gelatin, glycerin, titanium dioxide (E171), yellow iron oxide (E172), medium chain triglycerides and lecithin. microcrystalline cellulose, methacrylate copolymer dispersion, talc, triethyl citrate. hard capsule shell: carrageenan (E 407), potassium chloride, titanium dioxide (E 171), FD & C Yellow 6 (E 110), hypromellose, carnauba wax, corn starch, red iron oxide (E 172), SW-9008 Black Ink (shellac, propylene glycol, black iron oxide (E172), potassium hydroxide).

Pharmacological effect

Duodart is a combined preparation of dutasteride and tamsulosin with a complementary mechanism of action. Dutasteride is a dual inhibitor of 5α-reductase, inhibits the activity of 5α-reductase isoenzymes of the 1st and 2nd types, which are responsible for the conversion of testosterone into 5α-dihydrotestosterone. Dihydrotestosterone (DHT) is the main androgen responsible for hyperplasia of the glandular tissue of the prostate. Dutasteride reduces DHT levels, reduces the size of the prostate gland, reduces symptoms of the disease, leads to improved urination, a decrease in the risk of acute urinary retention and the need for surgical treatment... The maximum effect of dutasteride on the decrease in DHT concentration is dose-dependent and is observed 1-2 weeks after the start of treatment. After 1–2 weeks of taking dutasteride at a dose of 0.5 mg / day, the median serum DHT concentrations decrease by 85–90%, respectively. In patients with benign prostatic hyperplasia (BPH), when taking dutasteride at a dose of 0.5 mg / day, the average decrease in DHT levels was 94% during the first year and 93% during the second year of therapy. mean serum testosterone levels increased 19% during the first and second years of treatment. This effect due to a decrease in the level of 5α. -reductase and does not lead to the development of any known adverse reactions. Tamsulosin hydrochloride is a blocker of postsynaptic α .1a-adrenergic receptors located in the smooth muscles of the prostate gland, bladder neck and prostatic urethra. Blockade of α .1a-adrenergic receptors leads to a decrease in the tone of smooth muscles of the prostate gland, bladder neck and prostatic urethra and an improvement in urine outflow. At the same time, both obstructive symptoms and irritative symptoms due to increased smooth muscle tone and detrusor hyperactivity in BPH decrease.

Indications

Treatment and prevention of the progression of BPH by reducing its size, eliminating symptoms, increasing the rate of urination, reducing the risk of acute urinary retention and the need for surgery.

Contraindications

Increased sensitivity to dutasteride, other 5α.-reductase inhibitors, tamsulosin or any other component of the drug. - orthostatic hypotension (including history). - severe liver failure. - age up to 18 years. - the use of the drug is contraindicated in women and children.

Side effects

special instructions

Adverse events associated with the use of tamsulosin hydrochloride in combination with dutasteride: Very rare (less than 1/10 000): allergic reactions (rash, pruritus, urticaria, localized edema and angioedema), priapism, loss of consciousness Rarely (≥ .1 / 10 000 and less than 1/1000): alopecia, hypertrichosis Uncommon (≥ .1 / 1000 or less than 1/100): impaired ejaculation, retrograde ejaculation Often (≥. 1/100 or less than 1/10): gynecomastia, decreased libido, erectile dysfunction, dizziness Adverse events due to the use of tamsulosin hydrochloride as monotherapy Very rarely (less than 1/10 000): priapism Rare (≥ .1 / 10,000 and less than 1/1000): loss of consciousness, angioedema Uncommon (≥ .1 / 1,000 or less than 1/100): rapid heartbeat, constipation, diarrhea, vomiting, abnormal ejaculation rhinitis, rash, pruritus, urticaria postural hypotension Often (≥. 1/100 or less than 1/10): dizziness, orthostatic hypotension

Trade name of the drug: Duodart

International non-proprietary name:

Dutasteride + Tamsulosin (Dutasteridum + Tamsulosinum)

Dosage form: modified release capsules

Active substance: dutasteride + tamsulosin

Pharmacotherapeutic group:

drugs for the treatment of benign prostatic hypertrophy

Pharmacological properties:

Duodart contains two components: a double 5alpha-reductase inhibitor - dutasteride and an alpha1a-adrenergic receptor blocker - tamsulosin, which complement each other in terms of the mechanism of action. Dutasteride lowers dihydrotestosterone levels, shrinks the size of the prostate gland, relieves symptoms of lower urinary tract diseases and increases urinary flow, and also reduces the risk of acute urinary retention and the need for surgery.

Tamsulosin increases the maximum urinary flow rate by decreasing the smooth muscle tone of the prostate and urethra and therefore reduces the obstruction and irritation symptoms associated with benign prostatic hyperplasia. Tamsulosin also eliminates the complex of symptoms of accumulation and emptying, in the development of which detrusor overactivity plays a significant role, alpha1-blockers can lower blood pressure by reducing peripheral resistance.

Indications for use:

Treatment and prevention of the progression of benign prostatic hyperplasia (reducing its size, reducing symptoms of the disease, improving urination, reducing the risk of acute urinary retention and the need for surgical treatment).

Contraindications:

Known hypersensitivity to tamsulosin, dutasteride, other 5-alpha reductase inhibitors, or any other ingredient in the drug; women; children and adolescents under 18; severe degree liver failure; history of orthostatic hypotension; planned cataract surgery.

Method of administration and dosage:

Adult men (including the elderly) are prescribed 1 capsule (0.5 mg / 0.4 mg) orally, 1 time / day, 30 minutes after the same meal with water. The capsules should be taken whole, without opening or chewing, since the contact of the capsule contents with the oral mucosa can cause inflammation from the mucous membrane.

Side effect:

Adverse events due to the use of tamsulosin hydrochloride in combination with dutasteride: very rare (<1/10 000) - импотенция, снижение либидо, нарушение эякуляции, гинекомастия, болезненность грудных желез, головокружение.

Disorders of the sexual sphere are associated with the use of the dutasteride component and can persist after discontinuation of therapy.

Adverse events due to the use of dutasteride as monotherapy. Rarely (≥1 / 10,000 and<1/1 000) - алопеция (преимущественно выпадение волос на теле), гипертрихоз. Очень редко (<1/10 000) – депрессия, боль и отек в области яичек. Нежелательные явления, обусловленные применением тамсулозина гидрохлорида в качестве монотерапии. Часто (≥1/100 и <1/10): головокружение, нарушение эякуляции. Нечасто (≥1/1 000 и <1/100): учащенное сердцебиение, запор, диарея, рвота, астения, ринит, сыпь, зуд, крапивница, постуральная гипотензия. Редко (≥1/10 000 и <1/1 000): потеря сознания, ангионевротический отек. Очень редко (<1/10 000): приапизм, синдром Стивенса-Джонсона. Постмаркетинговые исследования. Интраоперационный синдром атоничной радужки (IFIS, вид синдрома маленького зрачка) наблюдался при операциях по поводу катаракты у некоторых пациентов, получавших α1-адреноблокаторы, включая тамсулозина гидрохлорид. Были выявлены случаи развития фибрилляции предсердий, аритмии, тахикардии и одышки на фоне приема тамсулозина. Частота побочных реакций и связь с приемом тамсулозина не установлена.

Interaction with other medicinal products:

There have been no studies investigating drug-drug interactions for the combination of dutasteride with tamsulosin hydrochloride. The data below reflects the information available on the individual components.

Dutasteride. Dutasteride is metabolized by the CYP3A4 isoenzyme of the cytochrome P-450 enzyme system. In the presence of CYP3A4 inhibitors, the concentration of dutasteride in the blood may increase. With the simultaneous use of dutasteride with the CYP3A4 inhibitors verapamil and diltiazem, there is a decrease in the clearance of dutasteride by 37% and 44%, respectively. However, amlodipine, another calcium channel blocker, does not decrease dutasteride clearance. A decrease in the clearance of dutasteride and a subsequent increase in its concentration in the blood with the simultaneous use of this drug and CYP3A4 inhibitors is not significant due to the wide range of safety boundaries of this drug, so there is no need to reduce its dose. In vitro, dutasteride is not metabolized by the following isoenzymes of the human cytochrome P-450 system: CYP1A2, CY2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 and CYP2D6. Dutasteride does not inhibit in vitro human cytochrome P-450 enzymes involved in drug metabolism. Dutasteride does not displace warfarin, acenomorol, fenprocomon, diazepam and phenytoin from their plasma protein binding sites, and these drugs, in turn, do not displace dutasteride. There was no effect on the pharmacokinetics and pharmacodynamics of the combined use of dutasteride in combination with tamsulosin, terazosin, warfarin, digoxin and cholysteramine. When dutasteride is used simultaneously with lipid-lowering drugs, ACE inhibitors, beta-blockers, calcium channel blockers, corticosteroids, diuretics, nonsteroidal anti-inflammatory drugs, phosphodiesterase type V inhibitors and quinolone antibiotics, no significant drug interactions have been observed.

Tamsulosin hydrochloride. There is a theoretical risk of increased hypotensive effect when tamsulosin hydrochloride is used in conjunction with drugs that can lower blood pressure, including anesthetics, α1-blockers and PDE5 inhibitors. Do not use Duodart in combination with other α1-blockers. The combined use of tamsulosin and ketoconazole (a strong inhibitor of CYP3A4) leads to an increase in the Cmax and AUC of tamsulosin hydrochloride to 2.2 and 2.8, respectively. The combined administration of tamsulosin and paroxetine (a strong inhibitor of CYP2D6) leads to an increase in the Cmax and AUC of tamsulosin hydrochloride to 1.3 and 1.6, respectively. The concomitant use of CYP2D6 and CYP3A4 inhibitors with tamsulosin has not been studied, but with this combination a significant increase in tamsulosin exposure is expected. The simultaneous use of tamsulosin hydrochloride (0.4 mg) and cimetidine (400 mg every six hours) for six days led to a decrease in clearance (by 26%) and an increase in the AUC of tamsulosin hydrochloride (by 44%). Care must be taken when using Duodart and cimetidine together. Exhaustive studies of drug-drug interactions between tamsulosin hydrochloride and warfarin have not been conducted. Caution should be exercised with the simultaneous use of warfarin and tamsulosin hydrochloride. In three studies in which tamsulosin hydrochloride (0.4 mg for seven days, then 0.8 mg for the next seven days) was taken with atenolol, enalapril, or nifedipine for three months, no interaction was found, therefore, no the need for dose adjustment when using these drugs together with Duodart. The simultaneous use of tamsulosin hydrochloride (0.4 mg / day for two days, then 0.8 mg / day for 5 to 8 days) and a single intravenous administration of theophylline (5 mg / kg) did not change the pharmacokinetics of theophylline, therefore, no dose adjustment is required. The simultaneous use of tamsulosin hydrochloride (0.8 mg / day) and a single intravenous dose of furosemide (20 mg) resulted in a decrease of 11 to 12% in the Cmax and AUC of tamsulosin hydrochloride, however, these changes are expected to be clinically insignificant and dose adjustment will not be required ...

Combined use of dutasteride and tamsulosin hydrochloride. In two 4-year clinical studies, the incidence of heart failure (a composite term of observed events, mainly heart failure and congestive heart failure) was higher in patients treated with a combination of dutasteride and an α1-blocker, mainly tamsulosin hydrochloride, than in patients. not receiving combination treatment. In two 4-year clinical studies, the incidence of heart failure remained low (≤ 1%) and varied between studies. But in general, there were no discrepancies in the rates of side effects from the cardiovascular system. No causal relationship has been established between dutasteride treatment (alone or in combination with an α1-blocker) and heart failure.

Shelf life: 2 years

Terms of dispensing from pharmacies: on prescription

Manufacturer:

Catalent Germany Schorndorf GmbH, Germany.

Compound

Active substances: dutasteride 0.5 mg, tamsulosin hydrochloride 0.4 mg.

Indications for use Duodart

Treatment and prevention of the progression of benign prostatic hyperplasia (reducing its size, reducing symptoms of the disease, improving urination, reducing the risk of acute urinary retention and the need for surgical treatment).

Contraindications to the use of Duodart

• Hypersensitivity to dutasteride, other 5-a reductase inhibitors, tamsulosin or any other component of the drug.
• Orthostatic hypotension (including history).
• Severe liver failure.
• Age under 18.
• The use of the drug is contraindicated in women and children.

Adult men (including the elderly) 1 capsule (0.5 mg / 0.4 mg) orally, once a day, 30 minutes after the same meal with water.

The capsules should be taken whole, without opening or chewing, since the contact of the capsule contents with the oral mucosa can cause inflammation from the mucous membrane.

Patients with impaired renal function Currently, there is no data on the use of the drug Duodart in patients with impaired renal function.

Patients with impaired liver function Currently, there is no data on the use of the drug Duodart in patients with impaired liver function. Since dutasteride undergoes intensive metabolism, and its half-life is 3 to 5 weeks, care must be taken when treating patients with impaired liver function with Duodart.

pharmachologic effect

Duodart is a combination of two drugs: dutasteride, a dual inhibitor of 5α-reductase (API 5), and tamsulosin hydrochloride, an antagonist of adrenergic receptors 1a and 1d. These drugs have a complementary mechanism of action, due to which there is a rapid relief of urination, the risk of acute urinary retention (AUR) is reduced and the likelihood of the need for surgery for benign prostatic hyperplasia decreases.

Dutasteride inhibits the activity of both type 1 and type 2 isoenzymes of 5α-reductase, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). DHT is an androgen primarily responsible for the growth of the prostate gland and the development of benign prostatic hyperplasia. Tamsulosin inhibits the activity of adrenergic receptors α1a and β1d in the stromal smooth muscles of the prostate gland and the bladder neck. About 75% of the β 1 receptors in the prostate gland are β 1a receptors.

Tamsulosin increases the maximum urine flow rate by reducing the tone of the smooth muscles of the urethra and prostate gland, eliminates obstruction. The drug also reduces the severity of symptoms of irritation and obstruction, in the development of which urinary incontinence and contraction of the smooth muscles of the lower urinary tract play a significant role. This effect is achieved with prolonged therapy. The need for surgery or catheterization is greatly reduced.

Antagonists of α 1-adrenergic receptors can lower blood pressure by reducing the total peripheral resistance. During the study of the effect of tamsulosin, no clinically significant decrease in blood pressure was noted.

Pharmacokinetics

Bioequivalence has been demonstrated between the administration of the dutasteride-tamsulosin combination and the simultaneous administration of doses of dutasteride and tamsulosin capsules separately.

Single dose bioequivalence studies were conducted both on an empty stomach and after a meal. Compared with the fasting state, a 30% decrease in the Cmax of the tamsulosin ingredient of the dutasteride-tamsulosin combination was noted after a meal. Food did not affect the AUC of tamsulosin.

Suction

Dutasteride. After oral administration of a single 0.5 mg dose of dutasteride, the time to reach Cmax of dutasteride in blood plasma was 1-3 hours. The absolute bioavailability was about 60%. Food intake does not affect the bioequivalence of dutasteride.

Tamsulosin. Tamsulosin is absorbed in the intestine and is almost completely bioavailable. Both the rate and degree of absorption of tamsulosin are reduced if it is taken within 30 minutes after a meal. The uniformity of absorption is ensured by taking Duodart at the same time of the day after taking similar food. The concentration of tamsulosin in blood plasma is proportional to the dose.

After taking a single dose of tamsulosin after meals, Cmax in blood plasma is reached after 6 hours. Equilibrium concentration is reached on the 5th day of repeated administration. The average equilibrium concentration in patients is approximately? higher concentration after a single administration of tamsulosin. Although this phenomenon has been observed in elderly patients, the same result can be expected in younger patients.

Distribution

Dutasteride. Dutasteride has a large volume of distribution (300-500 L) and high binding to blood plasma proteins (> 99.5%). After daily administration of doses, the concentration of dutasteride in the blood plasma is 65% of the equilibrium concentration after 1 month and about 90% after 3 months.

The equilibrium concentration in blood plasma, which is about 40 ng / ml, is reached after 6 months of administration at a dose of 0.5 mg / day. The average value of dutasteride intake from blood plasma into seminal fluid is 11.5%.

Tamsulosin. In men, tamsulosin binds to blood plasma proteins by about 99%. The volume of distribution is small (about 0.21 / kg body weight).

Metabolism

Dutasteride. Dutasteride is extensively metabolized in vivo. In vitro, dutasteride is metabolized by cytochrome P450 3A4 and 3A5, forming three monohydroxylated metabolites and one dihydroxylated metabolite.

After oral administration of dutasteride at a dose of 0.5 mg / day until an equilibrium concentration is reached, 1.0-15.4% (average value - 5.4%) of the administered dose of dutasteride is excreted unchanged in the feces. The rest are excreted in the feces in the form of 4 main metabolites, containing 39; 21; 7% and 7% of each of the drug-related materials and 6 minor metabolites (<5% каждый). В моче человека выявлено лишь незначительное количество неизмененного дутастерида (<0,1% дозы).

Tamsulosin. Enantiomeric bioconversion from tamsulosin hydrochloride to the S (+) isomer does not occur in humans. Tamsulosin hydrochloride is actively metabolized by cytochrome P450 enzymes in the liver, less than 10% of the dose is excreted in the urine unchanged. But the pharmacokinetic profile of metabolites in humans has not been established. The results of in vitro studies indicate that the enzymes CYP 3A4 and CYP 2D6 are involved in the metabolism of tamsulosin, and the participation of other CYP isoenzymes is also insignificant.

Inhibition of the activity of enzymes involved in hepatic metabolism can lead to an increased effect of tamsulosin. Before excretion in the urine, the metabolites of tamsulosin hydrochloride are extensively bound to glucuronide or sulfate.

Withdrawal

Dutasteride. The elimination of dutasteride is dose-dependent and is characterized by two parallel elimination processes, one saturable (concentration-dependent) and one unsaturated (concentration-independent). At low plasma concentrations (<3 нг/мл) дутастерид быстро выводится как зависящим, так и не зависящим от концентрации путем. При применении однократных доз?5 мг выявлены признаки быстрого клиренса и установлен T?, который длится от 3 до 9 дней.

At therapeutic concentrations after repeated administration of a dose of 0.5 mg / day, a slow, linear excretion pathway dominates, and T? is about 3-5 weeks.

Tamsulosin. Tamsulosin and its metabolites are excreted mainly in the urine, in which about 9% of the dose is present as an unchanged active substance.

After i.v. or oral administration of an immediate-release dosage form, T? tamsulosin contained in blood plasma fluctuates in the range of 5-7 hours. Due to the pharmacokinetics controlled by the rate of absorption, in the case of tamsulosin in modified release capsules, the real T? tamsulosin, taken after meals, is about 10 hours, and at an equilibrium concentration in patients - about 13 hours.

Elderly patients

Dutasteride. The pharmacokinetics of dutasteride was evaluated in 36 healthy men aged 24-87 years after administration of a single dose of 5 mg. No significant dependence of the action of dutasteride on age was revealed, but T? was shorter in men under the age of 50. Statistical differences in T? not noted when comparing a group of 50-69-year-old subjects with a group of subjects over the age of 70 years.

Tamsulosin. Cross-sectional comparative study of the total effect of tamsulosin hydrochloride (AUC) and T? indicates that the pharmacokinetic effect of tamsulosin hydrochloride may be slightly longer in elderly patients compared with young healthy male volunteers. The intrinsic clearance does not depend on the binding of tamsulosin hydrochloride to α 1-acid glycoprotein, but decreases with age, resulting in a 40% stronger overall effect (AUC) in patients aged 55-75 years compared to the effect in patients aged 20- 32 years.

Renal failure

Dutasteride. The effect of renal failure on the pharmacokinetics of dutasteride has not been studied. But in human urine it turns out<0,1% дозы дутастерида (0,5 мг) в равновесной концентрации, поэтому клинически значимого повышения концентрации дутастерида в плазме крови у пациентов с почечной недостаточностью ожидать не следует (см. ПРИМЕНЕНИЕ).

Tamsulosin. The pharmacokinetics of tamsulosin hydrochloride were compared in 6 patients with mild to moderate renal insufficiency (30 × CLcr<70 мл/мин/1,73 м2) или от умеренной до тяжелой (10?CLcr <30 мл/мин/1,73 м2) степени и у 6 исследуемых с нормальным клиренсом (CLcr<90 мл/мин/1,73 м2). В то время как в общей концентрации тамсулозина гидрохлорида в плазме крови отмечали изменение в результате переменного связывания с?1-кислым гликопротеином, концентрация несвязанного (активного) тамсулозина гидрохлорида, а также собственный клиренс, оставались относительно стабильными. Поэтому пациентам с почечной недостаточностью не требуется коррекции дозы тамсулозина гидрохлорида в капсулах. Но пациентов с терминальной стадией почечной недостаточности (CLcr<10 мл/мин/1,73 м2) не исследовали.

Liver failure

Dutasteride. The effect of hepatic failure on the pharmacokinetics of dutasteride has not been studied (see CONTRAINDICATIONS). Since dutasteride is excreted predominantly by metabolism, it is expected that the plasma levels of dutasteride in these patients will be elevated, and T? dutasteride will be long-lasting (see APPLICATION and SPECIAL INSTRUCTIONS).

Tamsulosin. The pharmacokinetics of tamsulosin hydrochloride were compared in 8 patients with moderate hepatic impairment (Child-Pugh classification: grades A and B) and in 8 study participants with normal liver function. While a change in the total concentration of tamsulosin hydrochloride in blood plasma was noted as a result of variable binding to β 1-acid glycoprotein, the concentration of unbound (active) tamsulosin hydrochloride did not undergo significant changes, only a moderate (32%) change in the intrinsic clearance of unbound tamsulosin hydrochloride was revealed. ... Therefore, patients with moderate hepatic impairment do not require dose adjustment of tamsulosin hydrochloride. The effect of tamsulosin hydrochloride has not been studied in patients with severe hepatic dysfunction.

Side effects Duodart

Erectile dysfunction, decreased libido, impaired ejaculation, gynecomastia, allergic reactions (including rash, itching, urticaria, localized edema), dizziness and angioedema.

Application during pregnancy and lactation: The drug Duodart is contraindicated for use in women. There is no data on the excretion of dutasteride or tamsulosin in breast milk.

Overdose

There are no data on overdose when taking a combination of dutasteride with tamsulosin hydrochloride. The data below reflects the information available on the individual components.

Dutasteride

Symptoms: when using dutasteride at a dose of up to 40 mg / day (80 times higher than the therapeutic dose), no adverse events were observed for 7 days. In clinical studies, with the appointment of 5 mg per day for 6 months, there were no adverse reactions other than those listed for the therapeutic dose (0.5 mg per day).

Treatment: there is no specific antidote for dutasteride, therefore, if an overdose is suspected, it is sufficient to carry out symptomatic and supportive treatment.

Tamsulosin hydrochloride

Symptoms: with an overdose of tamsulosin hydrochloride, acute hypotension may develop.

Treatment: symptomatic therapy. Blood pressure can be restored when a person takes a horizontal position. If there is no effect, you can use agents that increase the volume of circulating blood and, if necessary, vasoconstrictor agents. It is necessary to monitor kidney function. Dialysis is unlikely to be effective because tamsulosin hydrochloride is 94-99% bound to plasma proteins.

Drug interactions

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

Tamsulosin: There is a theoretical risk of increased hypotensive effect when using tamsulosin in conjunction with drugs that can lower blood pressure, including anesthetics, phosphodiesterase type 5 inhibitors and other a1 adrenergic blockers. Do not use Duodart in combination with other A1 blockers.

Storage conditions

At a temperature not higher than 30 ° C. Keep out of the reach of children!
Shelf life 2 years Do not use after the expiration date.