Dutasteride + Tamsulosin Pharmasyntez (Capsules) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

G04CA52 (Tamsulosin and Dutasteride)

Active Substances

Dutasteride (Rec.INN registered by WHO)

Tamsulosin (Rec.INN registered by WHO)

Dosage Form

Dutasteride + Tamsulosin Pharmasintez

Modified-release capsules 0.5 mg+0.4 mg: 10, 30, 60, or 90 pcs.

Dosage Form, Packaging, and Composition

Modified-release capsules are hard gelatin capsules with an orange to red-orange body and a red-brown to dark brown cap; capsule contents: white or almost white spherical pellets and a soft gelatin opaque oval-shaped light yellow capsule with a seam; soft gelatin capsule contents: a clear colorless or slightly yellowish liquid.

Excipients: mono- and diglycerides of capric/caprylic acids, butylated hydroxytoluene (BHT) (E321), gelatin, glycerol (glycerin), titanium dioxide (E171), iron oxide yellow (E172), sugar spheres (ASTM 18#20), hypromellose E5, sodium lauryl sulfate, talc, colloidal silicon dioxide, ethylcellulose (7Cps), diethyl phthalate, methacrylic acid copolymer dispersion (L-30D) 30%, titanium dioxide, polysorbate 80, sodium hydroxide.

Capsule body composition: titanium dioxide, Ponceau 4R (E124), Sunset Yellow FCF (E110), gelatin.
Capsule cap composition: indigo carmine (E132), Ponceau 4R (E124), titanium dioxide, gelatin.

10 pcs. – blister packs (1) – cardboard packs.
10 pcs. – blister packs (3) – cardboard packs.
10 pcs. – blister packs (6) – cardboard packs.
10 pcs. – blister packs (9) – cardboard packs.
10 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
60 pcs. – polymer jars (1) – cardboard packs.
90 pcs. – polymer jars (1) – cardboard packs.

Clinical-Pharmacological Group

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

Pharmacotherapeutic Group

Drugs used in urology; drugs for the treatment of benign prostatic hyperplasia; alpha-adrenergic blockers

Pharmacological Action

A combined drug. It is a combination of two components with complementary mechanisms of action that help relieve symptoms in patients with benign prostatic hyperplasia (BPH): the dual 5α-reductase inhibitor dutasteride and the α_1a-adrenergic receptor blocker tamsulosin.

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

Dutasteride reduces DHT levels, decreases the size of the prostate gland, helps relieve symptoms of lower urinary tract diseases and increase the urinary flow rate, and also reduces the risk of acute urinary retention and the need for surgical intervention.

The maximum effect of daily doses of dutasteride on reducing 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 mcg/day, the mean serum DHT concentrations decreased by 85% and 90%, respectively.

In patients with BPH receiving Dutasteride at a dose of 500 mcg/day, the mean reduction in DHT level was 94% after 1 year and 93% after 2 years, the mean increase in serum testosterone level was 19% both after 1 year and after 2 years. This is an expected consequence of 5α-reductase inhibition and does not lead to any known adverse events.

Tamsulosin inhibits α_1a-adrenergic receptors in the smooth muscles of the prostate stroma and bladder neck. Approximately 75% of α₁-adrenergic receptors in the prostate are of the α_1a subtype.

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

Pharmacokinetics

After a single oral dose of dutasteride (500 mcg), C_max in serum is reached within 1-3 hours. The absolute bioavailability of dutasteride in men is about 60% relative to a 2-hour intravenous infusion. The bioavailability of dutasteride is not affected by food intake.

Pharmacokinetic data obtained after single and multiple oral administration of dutasteride indicate a large V_d (from 300 L to 500 L). Dutasteride is characterized by a high degree of binding to plasma proteins (>99.5%). With daily intake, the serum concentration of dutasteride reaches 65% of the steady-state concentration after 1 month and approximately 90% of the steady-state concentration level after 3 months. Steady-state serum concentrations of dutasteride, approximately 40 ng/ml, are achieved after 6 months of single daily administration of dutasteride at a dose of 500 mcg. In semen, as in serum, steady-state concentrations of dutasteride are also achieved after 6 months. After 52 weeks of treatment, concentrations of dutasteride in semen averaged 3.4 ng/ml (from 0.4 to 14 ng/ml). Approximately 11.5% of dutasteride passes from serum into semen.

In vitro, Dutasteride is metabolized by the human CYP3A4 isoenzyme to two minor monohydroxylated metabolites.

After reaching steady-state serum concentrations of dutasteride, unchanged Dutasteride, 3 major metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride, and 6-hydroxydutasteride) and 2 minor metabolites (6,4'-dihydroxydutasteride and 15-hydroxydutasteride) were detected using mass spectrometry. The 5 metabolites of dutasteride found in human serum were determined in rat serum, with the stereochemistry of the hydroxyl groups at positions 6 and 15 of the metabolites in humans and rats being unknown.

In the human body, Dutasteride undergoes extensive metabolism. To achieve steady-state concentrations after oral administration of dutasteride at a daily dose of 500 mcg, from 1% to 15.4% (on average 5.4%) of the administered dose is excreted through the intestine unchanged. The remainder is excreted through the intestine as 4 major metabolites, accounting for 39%, 21%, 7%, and 7%, respectively, and 6 minor metabolites (each accounting for less than 5%). Only trace amounts of unchanged dutasteride (less than 0.1% of the dose) are found in human urine.

At low serum concentrations (less than 3 ng/ml), Dutasteride is rapidly eliminated by both concentration-dependent and concentration-independent pathways. After a single dose of dutasteride of 5 mg or less, rapid clearance with a short T_1/2 of 3 to 9 days was observed.

At serum concentrations above 3 ng/ml, Dutasteride is eliminated slowly (from 0.35 to 0.58 L/h), mainly linearly, with a T_1/2 of 3 to 5 weeks. When dutasteride is taken at therapeutic doses, its terminal T_1/2 is 3-5 weeks and after repeated administration at a dose of 500 mcg/day, the slower clearance dominates and the total clearance is linear and independent of concentration. Dutasteride is detected in serum (at concentrations above 0.1 ng/ml) up to 4-6 months after discontinuation of its use.

Tamsulosin is absorbed in the intestine and has almost 100% bioavailability. Tamsulosin hydrochloride is characterized by linear pharmacokinetics after single and multiple doses, with steady-state concentrations reached on day 5 when taken once daily. The absorption rate of tamsulosin hydrochloride is slowed after food intake. The same level of absorption can be achieved if the patient takes Tamsulosin daily, approximately 30 minutes after the same meal.

The mean equilibrium apparent V_d of tamsulosin after intravenous administration of 1 mg was 16 L. Plasma protein binding is 94-99%, mainly to α₁-acid glycoprotein, and binding is linear over a wide concentration range (20-600 ng/ml).

No enantiomeric bioconversion of tamsulosin from the R(-) isomer to the S(+) isomer was observed in humans. Tamsulosin is extensively metabolized by human cytochrome P450 system isoenzymes in the liver, and less than 10% of the administered dose is excreted unchanged by the kidneys. Results obtained in vitro show that CYP3A4 and CYP2D6 isoenzymes are involved in the metabolism of tamsulosin, with minor involvement of other cytochrome P450 isoenzymes. Inhibition of liver enzymes involved in the metabolism of tamsulosin may lead to an increase in its exposure. Tamsulosin metabolites undergo extensive conjugation with glucuronides or sulfates before renal excretion.

The T_1/2 of tamsulosin is 5-7 hours. About 10% of tamsulosin is excreted unchanged by the kidneys.

Indications

Treatment and prevention of the progression of BPH by reducing its size, relieving symptoms, increasing the urinary flow rate, reducing the risk of acute urinary retention and the need for surgical intervention.

ICD codes

Dosage Regimen

Take one capsule orally once a day.

Swallow the capsule whole; do not chew or crush the capsule or its pellets.

Take the capsule approximately 30 minutes after the same meal each day to ensure consistent absorption.

Adhere to a daily dosing schedule for optimal therapeutic effect; do not skip doses.

If a dose is missed, take it as soon as remembered unless it is almost time for the next dose; in that case, skip the missed dose and resume the regular schedule.

Do not take a double dose to make up for a forgotten one.

The therapeutic effect on symptoms and urinary flow may develop over several weeks to months of continuous treatment.

Continue treatment as long as prescribed by a physician; this is a long-term therapy for benign prostatic hyperplasia.

Do not discontinue use without consulting your doctor, as symptoms may return.

Adverse Reactions

From the reproductive system and breast ≥1% – erectile dysfunction, decreased libido, ejaculation disorder, breast changes; very rarely – testicular pain, testicular swelling, priapism.

From the nervous system ≥1% – dizziness; very rarely – mood deterioration; rarely – fainting.

From the immune system very rarely – allergic reactions (including rash, itching, urticaria, localized edema and angioedema).

From the skin and subcutaneous tissue rarely – alopecia (mainly body hair loss), hypertrichosis; very rarely – Stevens-Johnson syndrome.

From the cardiovascular system: infrequently – palpitations, postural hypotension.

From the digestive system: infrequently – constipation, diarrhea, vomiting.

From the organ of vision during post-registration observations, cases of intraoperative floppy iris syndrome as a variant of intraoperative floppy iris syndrome during cataract surgery were identified, which was associated with the use of α_1a-adrenergic blockers, including tamsulosin.

During the use of tamsulosin, the following adverse reactions were also recorded atrial fibrillation, arrhythmia, tachycardia, dyspnea, epistaxis, blurred vision, visual impairment, erythema multiforme, exfoliative dermatitis and dry mouth.

Contraindications

Orthostatic hypotension (including history); severe hepatic impairment; age under 18 years; use is contraindicated in women and children; hypersensitivity to dutasteride, other 5α-reductase inhibitors, tamsulosin.

With caution

Chronic renal failure (CrCl<10 ml/min), arterial hypotension, planned cataract surgery, when used concomitantly with potent or moderately active inhibitors of the CYP3A4 isoenzyme (including ketoconazole, voriconazole).

Use in Pregnancy and Lactation

Drugs containing the combination Dutasteride + Tamsulosin are contraindicated for use in women.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

Use in Renal Impairment

Should be used with caution in chronic renal failure (CrCl<10 ml/min).

Pediatric Use

The use of the drug is contraindicated in children.

Geriatric Use

The drug is approved for use in elderly patients.

Special Precautions

Men taking Dutasteride should undergo regular examinations to assess the risk of developing prostate cancer, including determining the PSA level.

Determination of the PSA level is an important component of screening aimed at detecting prostate cancer. After 6 months of therapy with dutasteride, the mean serum PSA level decreases by approximately 50%.

Patients should undergo digital rectal examination and use other methods for diagnosing prostate cancer before starting treatment with this combination, and also regularly repeat the patient examination during treatment.

During clinical trials and in the post-registration period, rare reports of the development of breast cancer in men taking Dutasteride have been registered. However, epidemiological study data do not indicate an increased risk of breast cancer in men when using 5α-reductase inhibitors. Specialists should instruct patients to immediately report any changes in the breasts, such as lumps in the breast or nipple discharge.

As with the use of any alpha-adrenergic blockers, orthostatic hypotension may occur when taking tamsulosin, in rare cases leading to fainting.

Intraoperative floppy iris syndrome (IFIS, a variant of intraoperative floppy iris syndrome) was observed during cataract surgery in some patients receiving alpha₁-adrenergic blockers, including Tamsulosin. IFIS can lead to an increased risk of complications during and after surgery.

Since Dutasteride is extensively metabolized and its T_1/2 is from 3 to 5 weeks, this combination should be used with caution in patients with impaired liver function.

Effect on the ability to drive vehicles and operate machinery

The possibility of symptoms associated with orthostatic hypotension, such as dizziness, when using drugs containing this combination should be taken into account.

Drug Interactions

Dutasteride

In 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, blood concentrations of dutasteride may increase.

According to the results of phase 2 studies, with the simultaneous use of dutasteride with the CYP3A4 isoenzyme inhibitors verapamil and diltiazem, a decrease in the clearance of dutasteride by 37% and 44%, respectively, was noted.

Tamsulosin

There is a theoretical risk of enhanced hypotensive effect when using tamsulosin concomitantly with drugs that can lower blood pressure, including anesthetics, PDE5 inhibitors and other alpha₁-adrenergic blockers. This combination should not be used in combination with other alpha₁-adrenergic blockers.

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

Concomitant use of tamsulosin (400 mcg) 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. Caution is required when used concomitantly.

Caution should be exercised when co-administering warfarin and tamsulosin.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.