Duodart, 0.5 mg+0.4 mg 30 pcs

Duodart^® is a combination drug of dutasteride and tamsulosin with a complementary mechanism of action.

Dutasteride is a dual 5α-reductase inhibitor and inhibits the activity of type 1 and type 2 5α-reductase isoenzymes, which are responsible for converting testosterone to 5α-dihydrotestosterone.

Dihydrotestosterone (DHT) is the main androgen responsible for glandular hyperplasia of the prostate. Dutasteride reduces DHT levels, decreases the size of the prostate gland, reduces symptoms, leads to improved urination, and decreases the risk of acute urinary retention and the need for surgical treatment.

The maximum effect of dutasteride on reducing DHT concentrations is dose-dependent and is seen 1 to 2 weeks after the start of treatment. After 1-2 weeks of dutasteride at a dose of 0.5 mg/day median serum DHT concentrations are reduced by 85-90%, respectively.

In patients with benign prostatic hyperplasia (BPH) receiving dutasteride at a dose of 0.5 mg/day, median levels of DHT decreased 94% during the first year and 93% during the second year of therapy; median serum testosterone levels increased by 19% during the first and second years of treatment.

This effect is due to a decrease in 5α-reductase levels and does not lead to any known adverse reactions.

Tamsulosin hydrochloride is a blocker of postsynaptic α_1a-adrenoreceptors located in the smooth muscle of the prostate, bladder neck and prostatic urethra. Blockade of α_1a-adrenoreceptors leads to decrease of tone of the smooth muscles of the prostate, bladder neck and prostatic part of the urethra and improves the outflow of urine.

At the same time both obstructive symptoms and irritative symptoms caused by increased tone of smooth muscles and detrusor hyperactivity in BPH are reduced.

Indications

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

Composition

the active ingredient:

dutasteride,

tamsulosin hydrochloride

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),

iron oxide yellow (E172),

medium chain triglycerides and lecithin;

microcrystalline cellulose,

methacrylate copolymer dispersion,

talc,

triethylcitrate;

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),

The SW-9008 Black Ink (shellac, propylene glycol, black iron oxide (E172), potassium hydroxide).

How to take, the dosage

Adult males (including elderly) are prescribed 1 capsule (0.5 mg/0.4 mg) orally, once daily, 30 minutes after the same meal, with water.

The capsules should be taken whole without opening or chewing, because contact of the capsule contents with the oral mucosa may cause mucosal inflammation.

There are currently no data on the use of Duodart® in patients with impaired renal function.

There is no need for dose adjustment in this patient cohort.

There are currently no data on the use of Duodart ® in patients with hepatic impairment.

The drug should be used with caution in patients with mild to moderate hepatic impairment. Duodart ® is contraindicated in patients with severe hepatic impairment.

Interaction

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

Dutasteride

Dutasteride is metabolized by the CYP3A4 isoenzyme of the cytochrome P450 enzyme system. Blood concentrations of dutasteride may increase in the presence of CYP3A4 inhibitors.

In concomitant use of dutasteride with CYP3A4 inhibitors verapamil and diltiazem, there is a decrease in clearance of dutasteride by 37% and 44%, respectively. However, amlodipine, another calcium channel blocker, does not decrease the clearance of dutasteride.

The decrease in clearance of dutasteride and the subsequent increase in its blood concentrations with concomitant use of this drug and CYP3A4 inhibitors is not significant due to the wide range of safety limits 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 P450 system: CYP1A2, CYP2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, CYP2B6 and CYP2D6.

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

Dutasteride does not displace warfarin, acenocoumarol, phenprocoumon, diazepam and phenytoin from their binding sites to plasma proteins, and these drugs, in turn, do not displace dutasteride.

There have been no observed effects on the pharmacokinetics and pharmacodynamics of co-administration of dutasteride with tamsulosin, terazosin, warfarin, digoxin and cholisteramine.

When using dutasteride concomitantly with hypolipidemic drugs, ACE inhibitors, beta-adrenoblockers, calcium channel blockers, corticosteroids, diuretics, NSAIDs, FDE5 inhibitors and quinolone antibiotics no significant drug interaction has been noted.

Tamsulosin hydrochloride

There is a theoretical risk of increased hypotensive effect when using tamsulosin hydrochloride with drugs that can decrease BP, including anesthetics, alpha1-adrenoblockers and FDE5 inhibitors. Do not use Duodart® in combination with other alpha1-adreno-blockers.

The co-administration of tamsulosin and ketoconazole (a strong CYP3A4 inhibitor) leads to an increase in the Cmax and AUC of tamsulosin hydrochloride to 2.2 and 2.8 respectively. Co-administration of tamsulosin and paroxetine (a strong CYP2D6 inhibitor) increases the Cmax and AUC of tamsulosin hydrochloride to 1.3 and 1.6, respectively. Co-administration of CYP2D6 and CYP3A4 inhibitors with tamsulosin has not been studied, but a significant increase in tamsulosin exposure is expected with this combination.

The simultaneous use of tamsulosin hydrochloride (0.4 mg) and cimetidine (400 mg every 6 hours) for 6 days resulted in decreased clearance (by 26%) and increased AUC of tamsulosin hydrochloride (by 44%). Caution is required when co-administering Duodart® and cimetidine.

Total studies of drug interactions between tamsulosin hydrochloride and warfarin have not been conducted. Caution should be exercised when using warfarin and tamsulosin hydrochloride concomitantly.

In three studies in which tamsulosin hydrochloride (0.4 mg for 7 days, then 0.8 mg for the next 7 days) was taken together with atenolol, enalapril or nifedipine for 3 months, no interaction was found; therefore, no dose adjustment is necessary when using these drugs together with Duodart ®.

The concomitant use of tamsulosin hydrochloride (0.4 mg/day for 2 days, then 0.8 mg/day for 5-8 days) and a single IV infusion of theophylline (5 mg/kg) did not result in changes in the pharmacokinetics of theophylline, hence no dose adjustment is required.

The concomitant use of tamsulosin hydrochloride (0.8 mg/day) and a single IV dose of furosemide (20 mg) resulted in an 11 to 12% decrease in Cmax and AUC of tamsulosin hydrochloride, but these changes are not expected to be clinically significant and no dose adjustment is required.

The combined use of dutasteride and tamsulosin hydrochloride

In two 4-year clinical trials, the incidence of heart failure (a composite term of events noted, mainly heart failure and congestive heart failure) was higher in patients who received the combination of dutasteride and alpha1 adrenoblocker, mainly tamsulosin hydrochloride, than patients who did not receive the combination treatment. In two 4-year clinical trials, the incidence of heart failure remained low (≤1%) and varied between studies. But overall, there were no differences in the incidence of cardiovascular adverse events. No causal relationship was found between treatment with dutasteride (alone or in combination with an alpha1-adrenoblocker) and heart failure.

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, the area concerned should be washed immediately with soap and water.

The combined use of tamsulosin and strong inhibitors of CYP3A4 (ketoconazole), CYP2D6 (paroxetine), and their weaker inhibitors leads to increased exposure of tamsulosin. Thus, the use of tamsulosin in combination with strong CYP3A4 inhibitors is not recommended; the combination of CYP2D6 inhibitors and tamsulosin should be prescribed with caution.

Because the T1/2 of dutasteride is 3-5 weeks and is metabolized primarily in the liver, Duodart® should be used with caution in patients with liver disease.

Tamsulosin hydrochloride combination therapy and the development of heart failure

In two 4-year clinical trials, the incidence of heart failure (a composite term of events noted, mainly heart failure and congestive heart failure) was higher in patients who received the combination of dutasteride and alpha1 adrenoblocker, mainly tamsulosin hydrochloride, than patients who did not receive the combination treatment. In two 4-year clinical trials, the incidence of heart failure remained low (≤1%) and varied between studies. But overall, there were no differences in the incidence of cardiovascular adverse events. No causal relationship was found between treatment with dutasteride (alone or in combination with an alpha1-adrenoblocker) and heart failure.

Impact on detection of PSA and prostate cancer

In patients with BPH, a finger rectal examination and other prostate examinations should be performed before starting treatment with Duodart ® and periodically repeated during treatment to rule out the development of prostate cancer.

The determination of serum PSA concentrations is an important component of the screening process for prostate cancer.

After 6 months of therapy, dutasteride reduces serum PSA levels in patients with BPH by approximately 50%.

Patients taking Duodart® should have a new baseline PSA level determined after 6 months of therapy.

Any sustained elevation of PSA levels relative to the lowest level during treatment with Duodart® may indicate the development of prostate cancer (particularly high Gleason grade prostate cancer) or non-compliance with Duodart® therapy.sup>® and should be carefully evaluated even if these PSA levels remain within normal limits in patients not taking 5α-reductase inhibitors.

Total PSA levels return to baseline within 6 months of dutasteride withdrawal.

The ratio of free to total PSA remains constant even with dutasteride therapy. When this ratio is expressed as a fraction to detect prostate cancer in men receiving dutasteride, no correction of this value is necessary.

The risk of developing breast cancer

In clinical trials during treatment of BPH, 2 cases of breast cancer were identified in patients treated with dutasteride. The first case developed 10 weeks after starting therapy, the second after 11 months; there was also 1 case of breast cancer in a patient in the placebo group. The correlation between long-term dutasteride administration and the risk of developing breast cancer is unknown.

Prostate cancer

In a 4-year clinical trial, 1,517 of more than 8,000 men with preliminary negative biopsies and PSA levels of 2.5-10 ng/mL were diagnosed with prostate cancer. A higher incidence of cancer was observed in patients in the dutasteride group (n=29, 0.9%) compared to the group receiving placebo (n=19, 0.6%). No interaction was found between dutasteride intake and the extent of prostate cancer. Men taking dutasteride should be screened regularly for prostate cancer risk, including a PSA test.

Arterial hypotension

As with any alpha1-adrenoblocker, orthostatic hypotension may occur with tamsulosin hydrochloride, rarely leading to fainting.

Patients starting treatment with Duodart® should be warned to sit or lie down at the first sign of orthostatic hypotension (dizziness) until the dizziness subsides.

In order to avoid the development of symptomatic hypotension, caution should be exercised when co-administering alpha1-adreno-blockers and PDE5 inhibitors, as these drugs are vasodilators and may decrease BP.

Floppy iris syndrome

Intraoperative atonic iris syndrome (IFIS, a type of small pupil syndrome) has been seen during cataract surgery in some patients receiving alpha1-adrenoblockers including tamsulosin hydrochloride. Atonic iris syndrome may lead to increased surgical complications.

The ophthalmic surgeon should clarify during the preoperative evaluation whether the patient is taking a combination of dutasteride and tamsulosin hydrochloride to enable preparation for surgery, and to take adequate measures if iris atony occurs intraoperatively.

The withdrawal of tamsulosin hydrochloride 1-2 weeks before cataract surgery is considered favorable, but the benefit and time period of withdrawal before cataract surgery have not been established.

Hepatic impairment

There are currently no data on the use of Duodart ® in patients with hepatic impairment. Because dutasteride is extensively metabolized and its T1/2 is 3-5 weeks, caution should be exercised when treating with Duodart® in patients with liver dysfunction.

The effect on driving and operating machinery

There have been no studies investigating the effect on driving and operating machinery.

Patients should be advised of the possibility of symptoms associated with orthostatic hypotension, such as dizziness. Caution should be exercised when driving motor vehicles or operating potentially dangerous machinery.

Contraindications

– women;

– children and adolescents under 18 years of age;

– severe hepatic impairment;

– history of orthostatic hypotension;

– planned cataract surgery;

– known hypersensitivity to tamsulosin hydrochloride, dutasteride, other 5α-reductase inhibitors, or any other ingredient of the drug.

Side effects

Adverse events due to the use of tamsulosin hydrochloride in combination with dutasteride

Very rare (

Sexual dysfunction is associated with the use of dutasteride and may persist after discontinuation of therapy.

Unwanted phenomena due to the use of dutasteride as monotherapy

Rare (≥1/10,000 and

Very rare (

Adverse events due to the use of tamsulosin hydrochloride as monotherapy

Frequent (≥1/100 and

Infrequent (≥1/1000 and

Rare (≥1/10,000 and

Very rare (

Post-marketing studies

Intraoperative atonic iris syndrome (IFIS, a type of small pupil syndrome) has been observed during cataract surgery in some patients receiving alpha1-adrenoblockers, including tamsulosin hydrochloride.

Cases of atrial fibrillation, arrhythmias, tachycardia and dyspnea have been reported with tamsulosin. The frequency of adverse reactions and the association with tamsulosin administration have not been established.

Overdose

There are no data on overdose when taking a combination of dutasteride and tamsulosin hydrochloride. The following data reflect the information available about the individual components.

Dutasteride

Symptoms: No adverse events have been reported when dutasteride is administered at doses up to 40 mg/day (80 times the therapeutic dose) for 7 days. No adverse reactions beyond those listed for the therapeutic dose (0.5 mg/day) have been reported in clinical studies when administered 5 mg/day for 6 months.

Treatment: There is no specific antidote for dutasteride, so symptomatic and supportive treatment is sufficient if overdose is suspected.

Tamsulosin hydrochloride

Symptoms: an overdose of tamsulosin hydrochloride may result in acute hypotension.

Treatment: symptomatic therapy. BP may be restored when the person takes a horizontal position. If there is no effect, means increasing the blood pressure and, if necessary, vasoconstrictors may be used. Renal function should be monitored. It is unlikely that dialysis will be effective, as tamsulosin hydrochloride is 94-99% bound to plasma proteins.