Tamduet

Tamduet

dutasteride + tamsulosin

Manufacturer:

Ajanta Pharma Phil

Distributor:

Ajanta Pharma Phil
Full Prescribing Info
Contents
Dutasteride, tamsulosin hydrochloride.
Description
Each capsule contains: Dutasteride 500 mcg, Tamsulosin hydrochloride 400 mcg.
Action
Pharmacology: Pharmacodynamics: Mechanism of Action: Dutasteride + Tamsulosin HCl is a combination of two drugs with complementary mechanisms of action to improve symptoms in patients with BPH: Dutasteride, a dual 5a-reductase inhibitor (5 ARI) and Tamsulosin HCl, an antagonist of α1a-adrenoreceptors.
The pharmacodynamic effects of dutasteride-tamsulosin as a fixed dose 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).
Dihydrotestosterone 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 the risk of AUR and BPH-related surgery.
The maximum effect of daily doses of dutasteride on the reduction on 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 the median increase in serum testosterone was 19% at both one and two years. This is an expected consequence of 5 alpha-reductase inhibition and did not result in any known adverse events.
The relationship between long-term use of Dutasteride and male breast cancer has not been established.
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 a 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 relationship 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 the fasted and fed states. A 30% reduction in Cmax was observed for the 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 men 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 a recent meal. Uniformity of absorption can be promoted by the patient always taking Tamsulosin HCl approximately 30 minutes after the same meal each day.
Distribution: Dutasteride: Pharmacokinetic data following single and repeat oral doses show that Dutasteride has a large volume of distribution (300 to 500 L). Dutasteride is highly bound to plasma proteins (greater than 99.5%).
Following daily dosing, Dutasteride serum concentrations achieve 65% of 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 metabolized by the human cytochrome P450 isoenzyme CYP3A4 to two minor monohydroxylated metabolites, but it is not metabolized by CYP1A2, CY2A6, CYP2E1, CYP2C8, CYP2C9, CYP2C19, 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: There is no enantiomeric bioconversion from Tamsulosin HCl [R(-) isomer] to the S(+) isomer in humans. Tamsulosin HCl is extensively metabolized 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 that 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 increased exposure to Tamsulosin. The metabolites of Tamsulosin HCl undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.
Elimination: Dutasteride: Dutasteride is extensively metabolized. Following oral dosing of Dutasteride 500 mcg/day to steady state in humans, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as Dutasteride in the feces. The remainder is excreted in the feces as four major metabolites comprising 39%, 21%, 7%, and 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 in human urine.
At therapeutic concentrations, the terminal half-life of dutasteride is 3 to 5 weeks.
Serum concentrations remain detectable (greater than 0.1 nanograms/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 of 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 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 to 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 to 69-year-old group to the greater than 70 years 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 a 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 has been compared in 6 subjects with mild-moderate (30 s CrCl < 70 mL/min/1.73 m2) or moderate-severe (10 s 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.
Tamsulosin: The pharmacokinetics of Tamsulosin HCl have been compared in 8 subjects with moderate hepatic dysfunction (Child-Pugh's classification: Grades A and B) and 8 normal subjects. While a change in the overall plasma concentration of Tamsulosin HCl was observed as the result of altered binding to AAG, the unbound (active) concentration of Tamsulosin HCl does not change significantly with only a modest (32%) change in intrinsic clearance of unbound Tamsulosin HCl. Therefore, patients with moderate hepatic dysfunction do not require an adjustment in Tamsulosin HCl dosage. Tamsulosin HCl has not been studied in patients with severe hepatic dysfunction.
Indications/Uses
Dutasteride + Tamsulosin HCl treats and prevents progression of benign prostatic hyperplasia (BPH) by 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.
Dosage/Direction for Use
Adult males (including elderly): The recommended dose of Dutasteride + Tamsulosin is one capsule (500 mcg/400 mcg) taken orally approximately 30 minutes after the same time of meal each day.
Capsules should be swallowed whole and not chewed or opened. Contact with the contents of Dutasteride + Tamsulosin capsule contained within the hard-shell capsule may result in irritation of the oropharyngeal mucosa.
Renal Impairment: The effect of renal impairment on Dutasteride + Tamsulosin HCl pharmacokinetics has been studied. However, 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.
Overdosage
No data are available with regard to overdosage of Dutasteride + Tamsulosin HCl. The following statements reflect the information available on the individual components.
Dutasteride: No data available.
Tamsulosin: In case of acute hypotension occurring after overdosage with Tamsulosin HCl cardiovascular support should be given. Restoration of blood pressure and normalization of heart rate may be accomplished by lying the patient 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 that Tamsulosin HCl is 94% to 99% protein bound; therefore, dialysis is unlikely to be of benefit in removing Tamsulosin from the body.
Contraindications
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 (see Use in Pregnancy & Lactation).
Special Precautions
Prostate cancer: There was no increased 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 process to detect prostate cancer. Dutasteride + Tamsulosin HCl causes a decrease in mean serum PSA levels by approximately 50% after 6 months of treatment.
Patients 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 is 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 in syncope.
Patients beginning 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 PDE5 inhibitors. Alpha adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause 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, including tamsulosin. IFIS may lead increase in the risk of eye complications during and 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 IFIS if it occurs 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 have not yet been established.
Leaking capsules: Dutasteride is absorbed through the skin; therefore, women and children 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: Concomitant administration of tamsulosin hydrochloride with strong inhibitors of CYP3A4 (e.g. ketoconazole), or to a lesser extent, with strong inhibitors of CYP2D6 (e.g. paroxetine) 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 a 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.
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 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.
Hepatic impairment: The effect of hepatic impairment on dutasteride pharmacokinetics has not been studied. Because dutasteride is extensively metabolized and has a half-life of three to five weeks, caution should be used in the administration of Dutasteride + Tamsulosin HCl to patients with liver disease.
Use In Pregnancy & Lactation
There have been no studies to investigate the effect of Dutasteride + Tamsulosin HCl on pregnancy, lactation and fertility.
Adverse Reactions
No data provided for fixed dose combination.
Drug Interactions
There have been no drug interaction studies for Dutasteride + Tamsulosin Hydrochloride. The following statements reflect the information available on the individual components.
Dutasteride: In contrast, no decrease in clearance was seen when 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.
Storage
Store at temperatures not exceeding 30°C.
MIMS Class
Drugs for Bladder & Prostate Disorders
ATC Classification
G04CA52 - tamsulosin and dutasteride ; Belongs to the class of alpha-adrenoreceptor antagonists. Used in the treatment of benign prostatic hypertrophy.
Presentation/Packing
Form
Tamduet cap
Packing/Price
100's (P45/cap);30's (P45/cap)
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