Tamduet

Hard gelatin capsule with blue coloured opaque cap and red opaque body, non-brittle size "1" containing white to off white & yellow coloured spherical pellets.
Each hard gelatin capsule contains: Dutasteride, EP 500 mcg (as immediate-release pellets), Tamsulosin hydrochloride, USP 400 mcg (as sustained-release pellets).

Pharmacotherapeutic Group: Alpha-adrenoreceptor antagonist.
Pharmacology: Pharmacological Action: Dutasteride + Tamsulosin HCl is a combination of two drugs: Dutasteride, a dual 5α-reductase inhibitor (5 ARI), and Tamsulosin hydrochloride, an antagonist of α_1a and α_1d adrenoreceptors. These drugs have complementary mechanisms of action that rapidly improve symptoms, and urinary flow and reduce the risk of acute urinary retention (AUR) and the need for BPH-related surgery.
Dutasteride inhibits both type 1 and type 2, 5 alpha-reductase isoenzymes, which are responsible for the conversion of testosterone to dihydrotestosterone (DHT). DHT is the androgen primarily responsible for prostate growth and BPH development. Tamsulosin inhibits α_1a and α_1d adrenergic receptors in the stromal prostatic smooth muscle and bladder neck. Approximately 75% of the α₁-receptors in the prostate are of the α_1a subtype.
The combination of Dutasteride and Tamsulosin improves symptoms more than either component alone. After 2 years of treatment, co-administration therapy showed a statistically significant adjusted mean improvement in symptom scores from baseline of -6.2 units.
Pharmacokinetics: Absorption: Dutasteride: Following oral administration of a single 500 mcg Dutasteride dose, the time to peak serum concentrations of Dutasteride is 1 to 3 hours. The absolute bioavailability is approximately 60%. The bioavailability of Dutasteride is not affected by food.
Tamsulosin: Tamsulosin is absorbed from the intestine and is almost completely bioavailable. Both the rate and extent of absorption of Tamsulosin are reduced when taken within 30 minutes of a meal. Uniformity of absorption can be promoted by the patient always taking Dutasteride + Tamsulosin HCl after the same meal. Tamsulosin shows dose-proportional plasma exposure. After a single dose of Tamsulosin in the fed state, plasma concentrations of Tamsulosin peak at around 6 hours and, in the steady state, which is reached by day 5 of multiple dosing, the mean steady-state C_max in patients is about two-thirds higher than that reached after a single dose. Although this was observed in elderly patients, the same finding would also be expected in younger patients.
Distribution: Dutasteride: Dutasteride has a large volume of distribution (300 to 500 L) and is highly bound to plasma proteins (>99.5%). Following daily dosing, Dutasteride serum concentrations achieve 65% of steady-state concentration after 1 month and approximately 90% after 3 months.
Steady-state serum concentrations (C_ss) of approximately 40 ng/mL are achieved after 6 months of dosing 0.5 mg once a day. Dutasteride partitioning from serum into semen averaged 11.5%.
Tamsulosin: In man, Tamsulosin is about 99% bound to plasma proteins. The volume of distribution is small (about 0.2 L/kg).
Biotransformation: Dutasteride: Dutasteride is extensively metabolized in vivo. In vitro, Dutasteride is metabolized by the cytochrome P450 3A4 and 3A5 to three monohydroxylated metabolites and one dihydroxylated metabolite. Following oral dosing of Dutasteride 500 mcg/day to steady state, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as unchanged Dutasteride in the feces. The remainder is excreted in the feces as 4 major metabolites comprising 39%, 21%, 7%, and 7% each of drug-related material and 6 minor metabolites (less than 5% each). Only trace amounts of unchanged Dutasteride (less than 0.1% of the dose) are detected in human urine.
Tamsulosin: There is no enantiomeric bioconversion from Tamsulosin hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride 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 the 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 hydrochloride undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.
Elimination: Dutasteride: The elimination of dutasteride is dose-dependent. The process appears to be described by two parallel elimination pathways: one that is saturable at clinically relevant concentrations and one that is non-saturable. At low serum concentrations (less than 3 ng/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.
Following repeat dosing of 500 mcg/day at therapeutic concentrations, the slower, linear elimination pathway is dominating and the half-life is approximately 3-5 weeks.
Tamsulosin: Tamsulosin and its metabolites are mainly excreted in the urine with about 9% of a dose being present in the form of an unchanged active substance. Following intravenous or oral administration of an immediate-release formulation, the elimination half-life of Tamsulosin in plasma ranges from 5 to 7 hours. Due to the absorption rate-controlled pharmacokinetics with Tamsulosin-modified release capsules, the apparent elimination half-life of Tamsulosin in the fed state is approximately 10 hours and in the steady state in patients approximately 13 hours.

Treatment of moderate to severe symptoms of benign prostatic hyperplasia (BPH).
Reduction in the risk of acute urinary retention (AUR) and surgery in patients with moderate to severe symptoms of BPH.

Adults (including Elderly): The recommended dose of Dutasteride + Tamsulosin HCl is one capsule (500 mcg/400 mcg) once daily.
Where appropriate, Dutasteride + Tamsulosin HCl may be used to substitute concomitant Dutasteride and Tamsulosin hydrochloride in existing dual therapy to simplify treatment.
Where clinically appropriate, direct change from Dutasteride or Tamsulosin hydrochloride monotherapy to Dutasteride + Tamsulosin HCl may be considered.
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. In patients with severe hepatic impairment, the use of Dutasteride + Tamsulosin HCl is contraindicated.
Pediatric Population: Dutasteride + Tamsulosin HCl is contraindicated in the pediatric population (under 18 years of age).
Method of Administration: For oral use.
Patients should be instructed to swallow the capsules whole, approximately 30 minutes after the same time of meal each day. The capsules should not be chewed or opened. Contact with the contents of the Dutasteride capsule contained within the hard-shell capsule may result in irritation of the oropharyngeal mucosa.

No data are available with regard to overdosage of Dutasteride + Tamsulosin HCl. The following statements reflect the information available on the individual components.
Dutasteride: In volunteer studies, single daily doses of Dutasteride up to 40 mg/day (80 times the therapeutic dose) have been administered for 7 days without significant safety concerns. In clinical studies, doses of 5 mg daily have been administered to subjects for 6 months with no additional adverse effects to those seen at therapeutic doses of 500 mcg. There is no specific antidote for Dutasteride, therefore, in suspected overdosage symptomatic and supportive treatment should be given as appropriate.
Tamsulosin: Acute overdose of 5 mg Tamsulosin hydrochloride has been reported. Acute hypotension (systolic blood pressure 70 mm Hg), vomiting, and diarrhea were observed which were treated with fluid replacement and the patient could be discharged the same day. In case of acute hypotension occurring after overdosage cardiovascular support should be given. Blood pressure can be restored and heart rate brought back to normal by lying the patient down. If this does not help then volume expanders, and when necessary, vasopressors could be employed. Renal function should be monitored and general supportive measures applied. Dialysis is unlikely to be of help as Tamsulosin is very highly bound to plasma proteins.

Dutasteride + Tamsulosin HCl is contraindicated in: Women, children, and adolescents; Patients with hypersensitivity to Dutasteride, other 5-alpha reductase inhibitors, Tamsulosin (including Tamsulosin-induced angioedema), soya, peanut, or any of the other excipients used in the formulation; Patients with a history of orthostatic hypotension; Patients with severe hepatic impairment.

Combination therapy should be prescribed after careful benefit-risk assessment due to the potential increased risk of adverse events (including cardiac failure) and after consideration of alternative treatment options including monotherapies.
Prostate Cancer and High-Grade Tumors: The REDUCE study, a 4-year, multicentre, randomized, double-blind, placebo-controlled study investigated the effect of Dutasteride 500 mcg daily on patients with a high risk for prostate cancer (including men 50 to 75 years of age with PSA levels of 2.5 to 10 ng/mL and a negative prostate biopsy 6 months before study enrolment) compared to placebo. Results of this study revealed a higher incidence of Gleason 8-10 prostate cancers in Dutasteride-treated men (n=29, 0.9%) compared to placebo (n=19, 0.6%). The relationship between Dutasteride and Gleason 8-10 prostate cancers is not clear. Thus, men taking Dutasteride should be regularly evaluated for prostate cancer.
Cardiovascular Adverse Events: In two 4-year clinical studies, the incidence of cardiac failure was marginally higher among subjects taking the combination of Dutasteride and an alpha1-adrenoceptor antagonist, primarily Tamsulosin, than it was among subjects not taking the combination. However, the incidence of cardiac failure in these trials was lower in all actively treated groups compared to the placebo group, and other data available for Dutasteride or alpha1-adrenoceptor antagonists do not support a conclusion on increased cardiovascular risks.
Breast Neoplasia: There have been rare reports of male breast cancer reported in men taking Dutasteride in clinical trials and during the post-marketing period. However, epidemiological studies showed no increase in the risk of developing male breast cancer with the use of 5-alpha reductase inhibitors. Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge.
Renal Impairment: The treatment of patients with severe renal impairment (creatinine clearance of less than 10 mL/min) should be approached with caution as these patients have not been studied.
Hypotension: Orthostatic: As with other alpha₁-adrenoreceptor antagonists, a reduction in blood pressure can occur during treatment with Tamsulosin, as a result of which, rarely, syncope can occur. Patients beginning treatment with Dutasteride + Tamsulosin HCl should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until the symptoms have resolved.
In order to minimize the potential for developing postural hypotension the patient should be hemodynamically stable on an alpha₁-adrenoreceptor antagonist prior to initiating the use of PDE5 inhibitors.
Symptomatic: Caution is advised when alpha adrenergic blocking agents including tamsulosin are coadministered with PDE5 inhibitors (e.g., sildenafil, tadalafil, vardenafil). Alpha₁-adrenoreceptor antagonists 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 on or previously treated with Tamsulosin. IFIS may increase the risk of eye complications during and after the operation. The initiation of therapy with Dutasteride + Tamsulosin HCl in patients for whom cataract surgery is scheduled is therefore not recommended.
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 1-2 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 Capsule: 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.
Hepatic Impairment: Dutasteride + Tamsulosin HCl has not been studied in patients with liver disease. Caution should be used in the administration of Dutasteride + Tamsulosin HCl to patients with mild to moderate hepatic impairment.

Dutasteride + Tamsulosin HCl is contraindicated for use by women. There have been no studies to investigate the effect of Dutasteride + Tamsulosin HCl on pregnancy, lactation, and fertility.
Pregnancy: As with the other 5 alpha-reductase inhibitors, Dutasteride inhibits the conversion of testosterone to dihydrotestosterone and may, if administered to a woman carrying a male fetus, inhibit the development of the external genitalia of the fetus. Small amounts of Dutasteride have been recovered from the semen of subjects receiving Dutasteride. It is not known whether a male fetus will be adversely affected if his mother is exposed to the semen of a patient being treated with Dutasteride (the risk of which is greatest during the first 16 weeks of pregnancy).
As with all 5 alpha reductase inhibitors, when the patient's partner is or may potentially be pregnant it is recommended that the patient avoids exposure of his partner to semen by use of a condom.
Administration of Tamsulosin hydrochloride to pregnant female rats and rabbits showed no evidence of fetal harm.
Breastfeeding: It is not known whether Dutasteride or Tamsulosin are excreted in human milk.
Fertility: Dutasteride has been reported to affect semen characteristics (reduction in sperm count, semen volume, and sperm motility) in healthy men.
Effects of Tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.

The frequency of adverse reactions identified from clinical trials: Common ≥1/100 to <1/10; Uncommon ≥1/1000 to <1/100; Rare ≥1/10,000 to <1/1000; Very rare <1/10,000. Within each SOC grouping, undesirable effects are presented in order of decreasing seriousness.
Nervous System Disorders: Common: Dizziness.
Cardiac Disorders: Uncommon: Cardiac failure.
Reproductive System and Breast Disorders: Common: Impotence, Altered (decreased) libido, Ejaculation disorders, Breast disorders.

There have been no drug interaction studies for Dutasteride + Tamsulosin HCl. The following statements reflect the information available on the individual components.
Dutasteride: For information on the decrease of serum PSA levels during treatment with Dutasteride and guidance concerning prostate cancer detection.
Effects of Other Drugs on the Pharmacokinetics of Dutasteride: Dutasteride is mainly eliminated via metabolism. In vitro studies indicate that this metabolism is catalyzed by CYP3A4 and CYP3A5. No formal interaction studies have been performed with potent CYP3A4 inhibitors. However, in a population pharmacokinetic study, Dutasteride serum concentrations were on average 1.6 to 1.8 times greater, respectively, in a small number of patients treated concurrently with verapamil or diltiazem (moderate inhibitors of CYP3A4 and inhibitors of P-glycoprotein) than in other patients.
Long-term combination of Dutasteride with drugs that are potent inhibitors of the enzyme CYP3A4 (e.g., ritonavir, indinavir, nefazodone, itraconazole, ketoconazole administered orally) may increase serum concentrations of Dutasteride. Further inhibition of 5-alpha reductase at increased Dutasteride exposure, is not likely. However, a reduction of the Dutasteride dosing frequency can be considered if side effects are noted. It should be noted that in the case of enzyme inhibition, the long half-life may be further prolonged and it can take more than 6 months of concurrent therapy before a new steady state is reached.
Administration of 12 g cholestyramine one hour after a 5 mg single dose of Dutasteride did not affect the pharmacokinetics of Dutasteride.
Effects of Dutasteride on the Pharmacokinetics of Other Drugs: In a small study (n=24) of two weeks duration in healthy men, Dutasteride (500 mcg daily) had no effect on the pharmacokinetics of Tamsulosin or terazosin. There was also no indication of a pharmacodynamic interaction in this study. Dutasteride has no effect on the pharmacokinetics of warfarin or digoxin. This indicates that Dutasteride does not inhibit/induce CYP2C9 or the transporter P-glycoprotein. In vitro interaction studies indicate that Dutasteride does not inhibit the enzymes CYP1A2, CYP2D6, CYP2C9, CYP2C19, or CYP3A4.
Tamsulosin: Concomitant administration of Tamsulosin hydrochloride with drugs that can reduce blood pressure, including anesthetic agents, PDE5 inhibitors, and other alpha₁-adrenoreceptor antagonists could lead to enhanced hypotensive effects. Dutasteride-Tamsulosin should not be used in combination with other alpha₁-adrenoreceptor antagonists.
Concomitant administration of Tamsulosin hydrochloride and ketoconazole (a strong CYP3A4 inhibitor) resulted in an increase of the C_max and AUC of Tamsulosin hydrochloride by a factor of 2.2 and 2.8 respectively.
Concomitant administration of Tamsulosin hydrochloride and paroxetine (a strong CYP2D6 inhibitor) resulted in an increase of the C_max and AUC of Tamsulosin hydrochloride by a factor of 1.3 and 1.6 respectively.
Concomitant administration of Tamsulosin hydrochloride (400 mcg) and cimetidine (400 mg every six hours for six days) resulted in a decrease in the clearance (26%) and an increase in the AUC (44%) of Tamsulosin hydrochloride. Caution should be used when Dutasteride-Tamsulosin is used in combination with cimetidine.
A definitive drug-drug interaction study between Tamsulosin hydrochloride and warfarin has not been conducted. Results from limited in vitro and in vivo studies are inconclusive. Diclofenac and warfarin, however, may increase the elimination rate of Tamsulosin.

Store at temperatures not exceeding 30°C.

Drugs for Bladder & Prostate Disorders

G04CA52 - tamsulosin and dutasteride ; Belongs to the class of alpha-adrenoreceptor antagonists. Used in the treatment of benign prostatic hypertrophy.

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