Duodart capsules 0.5 mg + 0.4 mg 30 pcs
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Active ingredients
Dutasterid + Tamsulosin
Release form
Capsules
Composition
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), ferric oxide yellow (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, ferric oxide red (E 172), SW-9008 Black Ink (shellac, propylene glycol, ferrous oxide black (E172), potassium hydroxide).
Pharmacological effect
Duodart is a combination drug of dutasteride and tamsulosin with a complementary mechanism of action. Dutasteride, a dual inhibitor of 5α-reductase, inhibits the activity of type 1 and type 2α-reductase isoenzymes, which are responsible for the conversion of testosterone to 5α-dihydrotestosterone. Dihydrotestosterone (DHT) is the main androgen responsible for the hyperplasia of the glandular tissue of the prostate gland. Dutasteride reduces the level of DHT, reduces the size of the prostate gland, reduces the symptoms of the disease, leads to improved urination, reducing the risk of acute urinary retention and the need for surgical treatment. The maximum effect of dutasteride on a decrease in the concentration of DHT is dose-dependent and is observed 1–2 weeks after the start of treatment. After 1–2 weeks of dutasterid dosing at a dose of 0.5 mg / day, the median serum DHT concentrations are reduced by 85–90%, respectively. In patients with benign prostatic hyperplasia (BPH) while taking dutasteride at a dose of 0.5 mg / day, the average reduction in the level of DHT was 94% during the first year and 93% during the second year of therapy; average serum testosterone levels increased by 19% during the first and second years of treatment. This effect is 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 α1a-adrenoreceptors that are in the smooth muscles of the prostate gland, bladder neck and prostatic urethra. The blockade of α1a-adrenoreceptors leads to a decrease in the tone of the smooth muscles of the prostate gland, bladder neck and prostatic part of the urethra and improve urine flow.At the same time, both obstructive symptoms and irritative symptoms due to increased smooth muscle tone and detrusor hyperactivity in BPH are reduced.
Pharmacokinetics
AbsorptionAfter receiving a single dose of dutasteride, the maximum concentration of the drug in serum is reached within 1-3 hours. The absolute bioavailability is about 60% relative to a 2-hour intravenous infusion. The bioavailability of dutasteride does not depend on food intake. Tamsulosin hydrochloride is well absorbed in the intestine and has almost 100% bioavailability. Tamsulosin hydrochloride is characterized by linear kinetics, both in single and multiple dosage regimens. With a single dosing regimen, the equilibrium concentration of tamsulosin hydrochloride is reached by the 5th day. The absorption of tamsulosin hydrochloride slows down after a meal. The same level of absorption can be achieved if the patient takes tamsulosin hydrochloride daily, 30 minutes after the same meal. Distribution The pharmacokinetic data of single and repeated administration of dutasteride indicates a large volume of its distribution (from 300 to 500 l). Dutasteride has a high degree of plasma protein binding (> 99.5%). When taken daily, the concentration of dutasteride in serum reaches 65% of the stationary level after 1 month and approximately 90% of this level after 3 months. Stationary concentrations of dutasteride in serum (Css), equal to about 40 ng / ml, are achieved after 6 months of daily intake of 0.5 mg of this drug. In semen, as in serum, steady-state concentrations of dutasteride are also reached after 6 months. After 52 weeks of treatment, the concentration of dutasteride in semen averaged 3.4 ng / ml (from 0.4 to 14ng / ml). About 11.5% of dutasteride gets into semen from serum. Tamsulosin hydrochloride is mostly bound to plasma proteins (from 94 to 99%), mainly with alpha-1 acid glycoprotein.
Indications
treatment and prevention of progression of BPH by reducing its size, eliminating symptoms, increasing the speed of urination, reducing the risk of acute urinary retention and the need for surgical intervention.
Contraindications
- women; - children and teenagers under the age of 18; - severe degree of liver failure; - A history of orthostatic hypotension; - scheduled cataract surgery; - known hypersensitivity to tamsulosin hydrochloride, dutasteride, other 5α-reductase inhibitors, or any other ingredient of the drug.
Precautionary measures
The drug should be used with caution in mild and moderate liver failure.
Use during pregnancy and lactation
No studies have been conducted regarding the use of the drug Duodart during pregnancy, during breastfeeding and its effect on fertility. The data below reflects information available for individual components.
Dosage and administration
The drug is taken orally. Capsules should be taken whole without chewing or opening, drinking water. Contact with the contents of a soft gelatin capsule containing dutasteride, which is contained inside a hard capsule, with the oral mucosa may cause inflammation of the mucous membrane. In adult men (including elderly patients), the recommended dose of Duodart is 1 caps. 1 time / day, approximately 30 minutes after the same food intake. There is currently no data on the use of Duodart in patients with impaired renal function, but dose adjustment is not required when using Duodart. Now there is no data on the use drug Douodart in patients with impaired liver function.
Side effects
Adverse events caused by the use of tamsulosin hydrochloride in combination with dutasteride Very rarely (Disorders of the sexual sphere are associated with the use of a component of dutasteride and may persist after discontinuation of therapy. Undesirable effects caused by using dutasteride as monotherapy Rarely effects of tamsulosin hydrochloride as monotherapy Frequently (≥1 / 100 and Infrequently (≥1 / 1000 and Rarely (≥1 / 10 000 and Very rarely) (Postmarketing studies In traumatic atonic iris syndrome (IFIS, a type of small pupil syndrome) was observed during cataract surgery in some patients who received alpha1-blockers,including tamsulosin hydrochloride. Cases of atrial fibrillation, arrhythmia, tachycardia and dyspnea have been identified with tamsulosin. The frequency of adverse reactions and the relationship with taking tamsulosin has not been established.
Overdose
There is no data regarding overdose when taking a combination of dutasteride with tamsulosin hydrochloride. The data below reflects information available on individual components. Dutasteride Symptoms: When using dutasteride at a dose of up to 40 mg / day (80 times higher than the therapeutic dose) for 7 days, no adverse events were noted. In clinical studies with the appointment of 5 mg / day for 6 months, no adverse reactions other than those listed for the therapeutic dose (0.5 mg / day) were noted. Treatment: there is no specific antidote for dutasteride; therefore, if overdose is suspected, symptomatic and supportive treatment is sufficient. Tamsulosin hydrochloride Symptoms: An overdose of tamsulosin hydrochloride may develop acute hypotension. Treatment: symptomatic therapy. Blood pressure can recover when a person assumes a horizontal position. In the absence of effect, it is possible to apply agents that increase the bcc and, if necessary, vasoconstrictor agents. It is necessary to monitor the function of the kidneys. It is unlikely that dialysis will be effective, because tamsulosin hydrochloride is 94-99% bound to plasma proteins.
Interaction with other drugs
Studies on the interaction of the combination of dutasteride and tamsulosin with other drugs have not been conducted. The data below reflect the information available for individual components. DouasterideIn vitro metabolism studies have shown that dutasteride is metabolized by the CYP3A4 isoenzyme of the human cytochrome P450 enzyme system. Therefore, in the presence of CYP3A4 isoenzyme inhibitors, the concentration of dutasteride in the blood may increase. According to the results of a phase 2 study, while using dutasteride with CYP3A4 isoenzyme inhibitors verapamil and diltiazem, there is a decrease in dutasteride clearance by 37 and 44%, respectively. However, amlodipine, another calcium channel blocker, does not reduce the clearance of dutasteride. Reducing the clearance of dutasteride and the subsequent increase in its concentration in the blood while using this drug and CYP3A4 isoenzyme inhibitors is probably clinically insignificant due to the wide range of dutasteride safety limits (up to 10 -fold increase in the recommended dose for use up to 6 months),therefore, dose adjustment is not required. In vitro, dutasteride is not metabolized by the following human cytochrome P450 systems; In vitro studies have shown that dutasteride does not displace warfarin, acenocoumarol, fenprokumon, diazepam and phenytoin from their sites of binding to plasma proteins, and these drugs, in turn, do not displace dutasteride. Drugs that participated in research on the interaction - tamsulosin, terazosin, warfarin, digoxin and colestiramine. 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, quinolone inhibitors, type-5 and quinolone anti-viral inhibitors, IQTs, IQTs, IQTs, IQTs, IQTs, IQTs, IQTs, IQTs, IQTs, IQTs, IQTs, IQTs, IQTs, IQTs, IQTs, CI, calcium channel blockers, GCS, diuretics, NSAIDs, quinolone, 5% or pharmacodynamic drug interactions have been reported. TamsulosinThere is a theoretical risk of enhanced hypotensive effect and applying tamsulosin conjunction with drugs able to reduce blood pressure, including anesthetics, inhibitors of phosphodiesterase type 5 and other alpha 1-blockers. Doodart should not be used in combination with other alpha1-blockers. 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 factor 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 C max and AUC of tamsulosin with a factor 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 intense metabolism when used together with strong inhibitors of the CYP3A4 isoenzyme. The effect of co-administration of inhibitors of CYP3A4 and CYP2D6 isoenzymes with tamsulosia has not been clinically evaluated, however there is a potential for a significant increase in tamsulosin exposure. Simultaneous use of tamsulosin (400 μg) and cimetidine (400 mg every 6 hours for 6 days) resulted in a decrease in clearance ( 26%) and an increase in AUC (by 44%) of tamsulosin.Care must be taken when co-prescribing Douodart and cimetidine is used together. Exhaustive studies of the interactions between tamsulosin and warfarin have not been conducted. The results of limited in vitro and in vivo studies are not definitive. Caution should be exercised when co-prescribing warfarin and tamsulosin. In 3 studies in which tamsulosin (400 mcg for 7 days, then 800 mcg for the next 7 days) was taken together with atenolol, enalapril or nifedipine for 3 months, it was not revealed interdrug interaction, therefore, there is no need for dose adjustment when using these drugs together with the drug Duodart. Simultaneous administration of tamsulosin (400 µg / day for 2 days, then 800 µg / day for 5-8 days) and one-time about the / in the introduction of theophylline (5 mg / kg) did not lead to a change in the pharmacokinetics of theophylline, therefore, dose adjustment is not required. Simultaneous administration of tamsulosin (800 mcg / day) and a single dose of furosemide (20 mg) resulted in a decrease from 11% to 12% of Cmax and AMS of tamsulosin, however, it is assumed that these changes are clinically insignificant and dose adjustment is not required.
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, it is necessary to immediately wash the corresponding skin area with soap and water. The combined use of tamsulosin and strong inhibitors of CYP3A4 (ketoconazole), CYP2D6 (paroxetine), as well as their weaker inhibitors leads to an increase in the exposure of tamsulosin. Thus, the use of tamsulosin in combination with strong inhibitors of CYP3A4 is not recommended; The combination of CYP2D6 inhibitors and tamsulosin should be administered with caution. Since T1 / 2 dutasteride is 3-5 weeks and is mainly metabolized in the liver, Douodart should be used with caution in patients with liver disease. Combined therapy with tamsulosin hydrochloride and the development of heart failure In two 4-year clinical studies, the incidence of heart failure (a composite term for the occurring events, mainly heart failure and congestive heart failure) was higher in patients who received the combination of dutasteride and alpha 1 adrenergic blocker, mainly , tamsulosin hydrochloride than in patients not receiving the combined treatment.In two 4-year clinical studies, the incidence of heart failure remained low (≤ 1%) and varied between studies. But in general, there was no discrepancy in the incidence of side effects from the cardiovascular system. No causal link has been established between treatment with dutasteride (alone or in combination with an alpha1-blocker) and heart failure. Effect on the detection of PSA and prostate cancer In patients with BPH, a digital rectal examination and other methods of examining the prostate gland should be carried out before starting treatment with Douodart and periodically repeat these studies during treatment to rule out the development of prostate cancer. The determination of serum PSA concentrations is an important component of the screening process aimed at detecting prostate cancer. After 6 months of therapy, dutasteride reduces serum PSA levels in patients with BPH by about 50%. Patients taking the drug Duodart, should be determined new baseline PSA after 6 months of therapy. Any sustained increase in PSA levels at the lowest level when treated with Duodart may indicate development of prostate cancer (in particular, prostate cancer with a high degree of differentiation on the Gleason scale) or failure to comply with Duodart therapy and should be carefully evaluated, even if these levels are PSA remain within normal values in patients not taking 5α-reductase inhibitors. The overall PSA level returns to its original value within 6 months after dutasteride is discontinued. The ratio of free PSA to total remains constant even during therapy with dutasteride. When expressing this ratio in fractions to detect prostate cancer in men who receive dutasteride, correction of this value is not required. The risk of developing breast cancer In clinical studies during the treatment of BPH, 2 cases of breast cancer were identified in patients using dutasteride. The first case developed 10 weeks after the start of therapy, the second - 11 months; 1 case of breast cancer was also detected in a patient from the placebo group.The relationship between long-term dutasteride intake and the risk of developing breast cancer is unknown. Prostate Cancer In a clinical study of 4 years, 1,517 out of more than 8,000 men with preliminary negative biopsy results and a PSA level of 2.5–10 ng / ml were diagnosed with prostate cancer. A higher incidence of cancer was observed in patients from the dutasterid group (n = 29, 0.9%) compared with the placebo group (n = 19, 0.6%). There was no interaction between taking dutasteride and the degree of prostate cancer. Men taking dutasteride should be regularly screened for the risk of prostate cancer, including a PSA test. Arterial hypotension As with the use of any alpha1-adrenergic blockers, the use of tamsulosin hydrochloride can cause orthostatic hypotension, in rare cases leading to fainting. Patients starting treatment with Douodart should be warned to sit or lie down at the first sign of orthostatic hypotension (dizziness) until dizziness subsides. To avoid the development of symptomatic hypotension, caution should be exercised when co-prescribing alpha1-blockers and PDE5 inhibitors, since These drugs belong to the group of vasodilators and can lead to a decrease in blood pressure. Floppy iris syndrome Intraoperative atonic iris syndrome (IFIS, a type of small pupil syndrome) was observed during cataract surgery in some patients who received alpha1-adrenergic blockers, including tamsulosin hydrochloride. Syndrome atonic iris can lead to an increase in the number of complications during operations. During the preoperative examination, the ophthalmosurgeon should clarify whether the patient is taking a combination of dutasteride with tamsulosin hydrochloride to be able to prepare for the operation, and taking adequate measures when the iris atony occurs intraoperatively. Cancellation of tamsulosin hydrochloride 1-2 weeks before cataract surgery is considered favorable, but the benefits and the period of drug withdrawal before cataract surgery have not been established. Hepatic dysfunction There are currently no data on the use of the drug Douodart in patients with impaired liver function. SinceDutasteride undergoes intensive metabolism, and its T1 / 2 is 3-5 weeks. Care must be taken when treating Duodart with patients with impaired liver function. Impact on the ability to drive motor vehicles and control mechanisms There have been no studies that have studied the effect on driving and working with mechanisms. Patients should be informed about the possibility of symptoms associated with orthostatic hypotension, such as dizziness. Care must be taken when driving vehicles or potentially dangerous machinery.