Dutasteride, tamsulosin hydrochloride.
Light Brown/Light Yellow Opaque Capsule filled with light yellow color coated pellets.
Each capsule contains: Tamsulosin Hydrochloride 400 mcg, Dutasteride 500 mcg.
Pharmacology: Pharmacodynamics: Mechanism of Action: Dutasteride + Tamsulosin HCl, is a combination of two drugs with complementary mechanism of actions to improve symptoms in patients with BPH: Dutasteride, a dual 5α-reductase inhibitor (5ARI) and Tamsulosin HCl, an antagonist of α1a-adrenoreceptors.
The pharmacodynamic effects of dutasteride-tamsulosin as a fixed combination would not be expected to be different from those of dutasteride and tamsulosin co-administered as separate components.
Dutasteride: Dutasteride is a dual inhibitor of 5 alpha-reductase. It inhibits both type 1 and type 2, 5 alpha-reductase isoenzymes, which are responsible for the conversion of testosterone to 5-alpha dihydrotestosterone (DHT).
Dihydrotestoterone is the androgen primarily responsible for hyperplasia of glandular prostatic tissue. It also lowers dihydrotestosterone levels, reduces prostate volume, improves lower urinary tract symptoms and urine flow and reduces and risk of AUR and BPH-related surgery.
The maximum effect of daily doses of dutasteride on the reduction of dihydrotestosterone is dose-dependent and is observed within one to two weeks. After one week and two weeks of daily dosing of dutasteride 500 mcg, median serum DHT concentrations were reduced by 85% and 90%, respectively.
In BPH patients treated with 500 mcg of dutasteride daily, the median decrease in dihydrotestosterone was 94% at one year and 93% at two years, and median increase in serum testosterone was 19% at both one and two years. This is an expected consequence of alpha-reductase inhibition and did not result in any known adverse events.
Tamsulosin: Tamsulosin inhibits α1a adrenergic receptors in the stromal prostatic smooth muscle and bladder neck. Approximately 75% of the α1-receptors in the prostate are of the α1a subtype. Tamsulosin rapidly (from one week) increases maximum urinary flow rate by reducing smooth muscle tension in the prostate and urethra, thereby relieving obstruction. It also improves the complex of irritative and obstructive symptoms in which bladder instability and tension of the smooth muscles of the lower urinary tract play an important role. Alpha-1 adrenergic blockers can reduce blood pressure by lowering peripheral resistance.
Dutasteride: The relation between long term use of Dutasteride and male breast cancer has not been established.
Pharmacokinetics: Bioequivalence was demonstrated between Dutasteride-Tamsulosin and concomitant dosing with separate Dutasteride and Tamsulosin capsules.
The single dose bioequivalence was performed in both fasted and fed states. A 30% reduction in Cmax was observed for Tamsulosin component of Dutasteride-Tamsulosin in the fed state compared to the fasted state. Food had no effect on AUC of Tamsulosin.
Absorption: Dutasteride: Administered orally in solution as a soft gelatin capsule. Following administration of a single 0.5 mg dose, peak serum concentrations of Dutasteride occur within 1 to 3 hours.
Absolute bioavailability in man is approximately 60% relative to a 2-hour intravenous infusion. The bioavailability of Dutasteride is not affected by food.
Tamsulosin: Tamsulosin HCl is absorbed from the intestine and is almost completely bioavailable.
Tamsulosin HCl exhibits linear kinetics, following single and multiple dosing, with achievement of steady state concentrations by the fifth day of once-a-day dosing. The rate of absorption of Tamsulosin HCl is reduced by recent meal. Uniformity of absorption can be promoted by the patient always taking Tamsulosin HCl approximately 30 minutes after the same time of meal each day.
Distribution: Dutasteride: Pharmacokinetic data following single and repeat oral doses show that dutasteride has large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma proteins (greater than 99.5%).
Following daily dosing, Dutasteride serum concentration achieve 65% steady state concentration after one month and approximately 90% after three months.
Steady state serum concentrations (Css) of approximately 40 nanograms/mL are achieved after six months of dosing 0.5 mg once a day. Similarly to serum, Dutasteride concentrations in semen achieved steady state at six months. After 52 weeks of therapy, semen Dutasteride concentrations averaged 3.4 nanograms/mL (range 0.4 to 14 nanograms/mL). Dutasteride partitioning from serum into semen averaged 11.5%.
Tamsulosin: The mean steady-state apparent volume of distribution of Tamsulosin HCl after intravenous administration to ten healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body.
Tamsulosin HCl is extensively bound to human plasma proteins (94% to 99%), primarily alpha-1 acid glycoprotein (AAG) with linear binding over a wide concentration range (20 to 600 nanograms/mL).
Biotransformation: Dutasteride: In vitro, Dutasteride is metabolised by the human cytochrome P450 isoenzyme CYP3A4 to two minor monohydroxylated metabolites, but it is not metabolised by the CYP1A2, CY2A6, CYP2E1, CYP2C8, CYP2C9, CYP2B6 or CYP2D6.
In human serum, following dosing to steady state, unchanged Dutasteride, three major metabolites (4'-hydroxydutasteride, 1,2-dihydrodutasteride and 6-hydroxydutasteride) and 2 minor metabolites (6, 4-dihydroxydutasteride and 15-hydroxydutasteride), as assessed by mass spectrometric response, have been detected.
Tamsulosin: Tamsulosin is no enantiomeric bioconversion from Tamsulosin HCl [R(-) isomer] to the S(+) isomer in humans. Tamsulosin HCl is extensively metabolised by cytochrome P450 enzymes in the liver and less than 10% of the dose is excreted in urine unchanged. However, the pharmacokinetic profile of the metabolites in humans has not been established. In vitro results indicate the CYP3A4 and CYP2D6 are involved in metabolism of Tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug metabolizing enzymes may lead to increase exposure to Tamsulosin. The metabolites of Tamsulosin HCl undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.
Elimination: Dutasteride: Dutasteride is extensively metabolised. Following oral dosing Dutasteride 500 mcg/day steady state in humans, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as Dutasteride in the faeces. The remainder is excreted in the faeces as four major metabolites comprising 39%, 21%, 7% each of drug-related material and six minor metabolites (less than 5% each).
Only trace amounts of unchanged Dutasteride (less than 0.1% of the dose) are detected on human urine.
At therapeutic concentrations, the terminal half-life of Dutasteride is 3 to 5 weeks.
Serum concentrations remain detectable (greater than 0.1 nanogram/mL) for up to 4 to 6 months after discontinuation of treatment.
At low serum concentrations (less than 3 nanograms/mL), Dutasteride is cleared rapidly by both the concentration-dependent and concentration-independent elimination pathways. Single doses 5 mg or less showed evidence of rapid clearance and a short half-life of 3 to 9 days.
At serum concentrations greater than 3 nanograms/mL, Dutasteride is cleared slowly (0.35 to 0.58 L/hr) primarily by linear, non-saturable elimination with terminal half-life of three to five weeks. At the therapeutic concentrations, the terminal half-life of Dutasteride is three to five weeks, and following repeat dosing of 500 mcg/day, the slower clearance dominates and the total clearance is linear and concentration-independent.
Tamsulosin: Tamsulosin half-life is 5 to 7 hours. Approximately 10% is excreted unchanged in urine.
Elderly: Dutasteride pharmacokinetics and pharmacodynamics were evaluated in 36 healthy male subjects between the ages of 24 and 87 years following administration of a single 5 mg dose of Dutasteride. Exposure of Dutasteride, represented by AUC and Cmax values, was not statistically different when comparing age groups. Half-life was not statistically different when comparing the 50 or 69 year old group with greater than 70 year old group, which encompasses the age of most men with BPH. No differences in drug effect as measured by DHT reduction were observed between age groups. Results indicated that no Dutasteride dose-adjustment based on age is necessary.
Renal Impairment: Dutasteride: The effect of renal impairment on Dutasteride pharmacokinetics has not been studied. However, less than 0.1% of steady-state 500 mcg dose of Dutasteride is recovered in human urine, so no adjustment in dosage is anticipated for patients with renal impairment.
Tamsulosin: The pharmacokinetics of Tamsulosin have been compared in 6 subjects with mild-moderate (30 ≤ CrCl < 70 mL/min/1.73 m2) or moderate-severe (10 ≤ CrCl < 30 mL/min/1.73 m2) renal impairment and 6 normal subjects (CrCl < 90 mL/min/1.73 m2). While a change in the overall plasma concentration of Tamsulosin was observed as the result of altered binding to AAG, the unbound active) concentration of Tamsulosin, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in Tamsulosin HCl capsules dosing.
Hepatic Impairment: Dutasteride: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized, exposure could be higher in hepatically impaired patients.
Tamsulosin: The pharmacokinetics of tamsulosin have been compared in 8 subjects with moderate hepatic impairment (Child-Pugh classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of tamsulosin was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin does not change significantly with only a modest (32%) change in intrinsic clearance of unbound tamsulosin. Therefore, patients with moderate hepatic impairment do not require an adjustment in tamsulosin dosage. Tamsulosin has not been studied in patients with severe hepatic impairment.
Dutasteride + Tamsulosin Hydrochloride (Tamulsin Plus) treats and prevents progression of benign prostatic hyperplasia (BPH) through alleviating symptoms, reducing prostate size (volume), improving urinary flow rate and reducing the risk of acute urinary retention (AUR) and the need for BPH-related surgery.
Adult males (including elderly): The recommended dosage of Dutasteride + Tamsulosin is one capsule (500 mcg/400 mcg) taken orally approximately 30 minutes after the same time of meal each day.
The capsules should be swallowed whole and not chewed or opened. Contact with the contents of the Dutasteride capsule contained with hard-shell capsule may result in irritation of the oropharyngeal mucosa.
Renal Impairment: The effect of renal impairment on Dutasteride + Tamsulosin HCl pharmacokinetics has not been studied. No adjustment in dosage is anticipated for patients with renal impairment.
Hepatic Impairment: The effect of hepatic impairment on Dutasteride + Tamsulosin HCl pharmacokinetics has not been studied so caution should be used in patients with mild to moderate hepatic impairment.
No data are available with regards to overdosage of Dutasteride + Tamsulosin HCl. The following statement reflect the information available on the individual components.
Dutasteride: No data available.
Tamsulosin: In case of acute hypotension occurring overdosage with Tamsulosin HCl cardiovascular support should be given. Restoration of blood pressure and normalization of heart rate may be accomplished by lying the patients down. If this is inadequate, administration of volume expanders and if necessary vasopressors should then be used and renal function should be monitored and supported as needed. Laboratory data indicate Tamsulosin HCl is 94% to 99% protein bound; therefore, dialysis is unlikely to be benefit in removing Tamsulosin from the body.
Dutasteride + Tamsulosin HCl is contraindicated in patients with known hypersensitivity to Dutasteride, other 5-alpha reductase inhibitors, Tamsulosin HCl or any component of the preparation.
Dutasteride + Tamsulosin HCl is contraindicated for use in women and children.
Prostate cancer: There was no increase incidence in Gleason 5-6 or 7-10 prostate cancers. No causal relationship between Dutasteride and high grade prostate cancer has been established. The clinical significance of the numerical imbalance is unknown. Men taking Dutasteride + Tamsulosin HCl should be regularly evaluated for prostate cancer risk including PSA testing.
Prostate specific antigen (PSA): PSA concentration is an important component of the screening to process to detect prostate cancer. Dutasteride + Tamsulosin HCl causes a decrease in mean serum PSA levels by approximately 50% after 6 months of treatment.
Pageants receiving Dutasteride + Tamsulosin HCl should have a new PSA baseline established after 6 months of treatment with Dutasteride + Tamsulosin HCl. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on Dutasteride + Tamsulosin HCl may signal the presence of prostate cancer or non-compliance to therapy with Dutasteride + Tamsulosin HCl and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5-ARI. In the interpretation of a PSA value for a patient taking Dutasteride + Tamsulosin HCl, previous PSA values should be sought for comparison. Treatment with Dutasteride + Tamsulosin HCl does not interfere with the use of PSA as a tool to assist in the diagnosis of prostate cancer after a new baseline has been established. Total serum PSA levels return to baseline within 6 months of discontinuing treatment. The ratio of free to total PSA remains constant even under the influence of Dutasteride + Tamsulosin HCl. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Dutasteride + Tamsulosin HCl therapy, no adjustment to its value appears necessary.
Digital rectal examination, as well as other evaluations for prostate cancer, should be performed on patients with BPH prior to initiating therapy with Dutasteride + Tamsulosin HCl and periodically thereafter.
Hypotension: As with other alpha-1 adrenergic blockers, orthostatic hypotension can occur in patients treated with Tamsulosin which in rare cases can result syncope.
Patients begging treatment with Dutasteride + Tamsulosin HCl should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness and vertigo) until the symptoms have resolved.
Caution is advised when alpha adrenergic blocking agents including tamsulosin are co-administered with PDE-5 inhibitors. Alpha adrenergic blockers and PDE-5 inhibitor are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially causes symptomatic hypotension.
Intraoperative Floppy Iris Syndrome: Intraoperative Floppy Iris Syndrome (IFIS, a variant of small pupil syndrome) has been observed during cataract surgery in some patients treated with alpha-1 adrenergic blockers after the operation.
During pre-operative assessment, cataract surgeons and ophthalmic teams should consider whether patients scheduled for cataract surgery are being or have been treated with Dutasteride + Tamsulosin HCl in order to ensure that appropriate measures will be in place to manage the IFIS during surgery.
Discontinuing Tamsulosin 1 to 2 weeks prior to cataract surgery is anecdotally considered helpful, but the benefit and duration of stopping therapy prior to cataract surgery has not yet been established.
Leaking capsules: Dutasteride is absorbed through the skin; therefore, women, children and adolescents must avoid contact with leaking capsules. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water.
Inhibitors of CYP3A4 and CYP2D6: Concurrent administration of tamsulosin hydrochloride with strong inhibitors of CYP3A4 (e.g. ketoconazole) or lesser extent, with strong inhibitors CYP2D6 (e.g. paroxitine) can increase tamsulosin exposure. Tamsulosin hydrochloride is therefore not recommended in patients taking a strong CYP3A4 inhibitor and should be used with caution in patients taking moderate CYP3A4 inhibitor (e.g. erythromycin), a strong or moderate CYP2D6 inhibitor, a combination of both CYP3A4 and CYP2D6 inhibitors, or in patients known to be poor metabolizers of CYP2D6.
Hepatic Impairment: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolised, and has half-life of three to five weeks, caution should be used in the administration of Dutasteride + Tamsulosin HCl to patients with liver disease.
Effects on Ability to Drive and Use Machines: There have been no studies to investigate the effect of Dutasteride + Tamsulosin HCl on the ability to perform tasks that require the judgement, motor or cognitive skills. However, patients should be informed about the possible occurrence of symptoms related to orthostatic hypotension such as dizziness when taking Dutasteride + Tamsulosin HCl.
There have been no studies to investigate the effect of Dutasteride + Tamsulosin HCl on pregnancy, lactation and fertility.
No data provided for fixed dose combination.
There have been no drug interaction studies for Dutasteride + Tamsulosin HCl.
The following statement reflect information available for the individual components.
Dutasteride: In contrast, no decrease in clearance was seen Amlodipine, another calcium channel antagonist, was co-administered with Dutasteride. A decrease in clearance and subsequent increase in exposure to Dutasteride, in the presence of CYP3A4 inhibitors, are unlikely to be clinically significant due to the wide margin of safety (up to 10-times the recommended dose has been given to patients for up to six months); therefore, no dose adjustment is necessary.
Store at temperatures not exceeding 30°C.
G04CA52 - tamsulosin and dutasteride ; Belongs to the class of alpha-adrenoreceptor antagonists. Used in the treatment of benign prostatic hypertrophy.
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