Tamzor Duo

Each capsule contains: Dutasteride 500 mcg, Tamsulosin HCl 400 mcg (modified-release pellets).
Dutasteride and Tamsulosin hydrochloride capsules contain Dutasteride (a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5α-reductase, an intracellular enzyme that converts testosterone to DHT) and Tamsulosin (an antagonist of α1a-adrenoceptors in the prostate).
Dutasteride: Dutasteride, USP is a synthetic 4-azasteroid compound chemically designated as (5α, 17β)-N-(2,5 bis(trifluoromethyl)phenyl)-3-oxo-4-azaandrost-1-ene-17-carboxamide. The molecular formula of Dutasteride is C₂₇H₃₀F₆N₂O₂ representing a molecular weight of 528.5.
Dutasteride, USP is white to off-white colored powder. It is soluble in absolute ethanol and methanol and insoluble in water.
Tamsulosin hydrochloride: Tamsulosin hydrochloride, USP is a synthetic compound chemically designated as (-)-(R)-5-[2-[[2-(o-Ethoxyphenoxy)ethyl]amino]propyl]-2-methoxybenzenesulfonamide, monohydrochloride. The molecular formula of Tamsulosin hydrochloride is C₂₀H₂₈N₂O₅S·HCl. The molecular weight of Tamsulosin hydrochloride is 444.97.
Tamsulosin hydrochloride, USP is white crystalline powder, odorless or practically odorless. It is slightly soluble in water and anhydrous ethanol, sparingly soluble in methanol, freely soluble in dimethyl sulfoxide and formic acid, practically soluble in ether.
Each hard capsule contains Tamsulosin hydrochloride and Dutasteride.

Pharmacotherapeutic group: Urologicals, Alpha-adrenoreceptor antagonists. ATC Code: G04CA52.
Pharmacology: Dutasteride/Tamsulosin is a combination of two drugs: Dutasteride, a dual 5α-reductase inhibitor (5 ARI) and Tamsulosin hydrochloride, an antagonist of α1a and α1d adrenoreceptors. These drugs have complementary mechanisms of action that rapidly improve symptoms, urinary flow and reduce the risk of acute urinary retention (AUR) and the need for BPH related surgery.
Dutasteride: Dutasteride inhibits the conversion of testosterone to DHT. DHT is the androgen primarily responsible for the initial development and subsequent enlargement of the prostate gland. Testosterone is converted to DHT by the enzyme 5α-reductase, which exists as 2 isoforms, type 1 and type 2. The type 2 isoenzyme is primarily active in the reproductive tissues, while the type 1 isoenzyme is also responsible for testosterone conversion in the skin and liver. Dutasteride is a competitive and specific inhibitor of both type 1 and type 2 5-α-reductase isoenzymes, with which it forms a stable enzyme complex. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride does not bind to the human androgen receptor.
Tamsulosin: Smooth muscle tone is mediated by the sympathetic nervous stimulation of α1-adrenoceptors, which are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of BPH.
Tamsulosin, an α1-adrenoceptor blocking agent, exhibits selectivity for α1-receptors in the human prostate. At least 3 discrete α1-adrenoceptor subtypes have been identified: α1A, α1B, and α1D; their distribution differs between human organs and tissue. Approximately 70% of the α1-receptors in human prostate are of the α1a subtype. Tamsulosin is not intended for use as an antihypertensive.
Pharmacokinetics: The pharmacokinetics of Dutasteride and Tamsulosin from Dutasteride and Tamsulosin hydrochloride capsules are comparable to the pharmacokinetics of Dutasteride and Tamsulosin when administered separately.
Absorption: The pharmacokinetic parameters of Dutasteride and Tamsulosin observed after administration of Dutasteride and Tamsulosin hydrochloride capsules in a single-dose, randomized, 3-period, partial cross-over trial.
Dutasteride: Following administration of a single 0.5 mg dose of a soft gelatin capsule, time to peak absolute bioavailability in 5 healthy subjects is approximately 60% (range: 40% to 94%).
Tamsulosin: Absorption of Tamsulosin is essentially complete (>90%) following oral administration of 0.4 mg Tamsulosin hydrochloride capsules under fasting conditions. Tamsulosin exhibits linear kinetics following single and multiple dosing, with achievement of steady-state concentrations by the fifth day of once-daily dosing.
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 albumin (99%) and α-1-acid glycoprotein (AAG, 96.6%).
Tamsulosin: The mean steady-state apparent volume of distribution of Tamsulosin after intravenous administration to 10 healthy male adults was 16 L, which is suggestive of distribution into extracellular fluids in the body. Tamsulosin is extensively bound to human plasma proteins (94% to 99%), primarily AAG, with linear binding over a wide concentration range (20-600 ng/mL).
Metabolism: Dutasteride: Dutasteride is extensively metabolized in humans. In vitro, Dutasteride is metabolised by the cytochrome P450 3A4 and 3A5 to three monohydroxylated metabolites and one dihydroxylated metabolite. Following oral dosing of Dutasteride 0.5 mg/day to steady state, 1.0% to 15.4% (mean of 5.4%) of the administered dose is excreted as unchanged Dutasteride in the faeces. The remainder is excreted in the faeces 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 [R(-)isomer] to the S(+) isomer in humans. Tamsulosin 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 studies indicate that CYP3A4 and CYP2D6 are involved in metabolism of Tamsulosin as well as some minor participation of other CVP isoenzymes. Inhibition of hepatic drug-metabolizing enzymes may lead to increased exposure to Tamsulosin. The metabolites of Tamsulosin undergo extensive conjugation to glucuronide or sulfate prior to renal excretion.
Excretion: Dutasteride: The elimination of Dutasteride is dose dependent and the process appears to be described by two elimination pathways in parallel, one that is saturable at clinically relevant concentrations and one that is non saturable. At low serum concentration (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.
At therapeutic concentrations, following repeat dosing of 0.5 mg/day, 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 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 is 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 is one capsule (500 mcg/400 mcg daily). Where appropriate, Dutasteride/Tamsulosin 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 may be considered.
Renal impairment: The effect of renal impairment on Dutasteride/Tamsulosin 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 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 is contraindicated.
Paediatric population: Dutasteride/Tamsulosin is contraindicated in the paediatric 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 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. 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 0.5 mg. There is no specific antidote for Dutasteride, therefore, in suspected overdosage symptomatic and supportive treatment should be given as appropriate.
Tamsulosin: Acute overdose with 5 mg Tamsulosin hydrochloride has been reported. Acute hypotension (systolic blood pressure 70 mm Hg), vomiting and diarrhoea 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. Measures, such as emesis, can be taken to impede absorption. When large quantities are involved, gastric lavage can be applied and activated charcoal and an osmotic laxative, such as sodium sulphate, can be administered.

Dutasteride/Tamsulosin is contraindicated in: Women and children and adolescents.
Patients with hypersensitivity to the active substance, other 5-α-reductase inhibitors, soya, peanut or any of the other excipients.
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 tumours: The REDUCE study, a 4-year, multicentre, randomised, double-blind, placebo controlled study investigated the effect of Dutasteride 0.5 mg 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/Tamsulosin should be regularly evaluated for prostate cancer.
Prostrate specific antigen (PSA): Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Dutasteride/Tamsulosin causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment. Patients receiving Dutasteride/Tamsulosin should have a new PSA baseline established after 6 months of treatment with Dutasteride/Tamsulosin.
It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from the lowest PSA level while on Dutasteride/Tamsulosin may signal the presence of prostate cancer or noncompliance to therapy with Dutasteride/Tamsulosin and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5-α-reductase inhibitor.
In the interpretation of a PSA value for a patient taking Dutasteride, previous PSA values should be sought for comparison. Treatment with Dutasteride/Tamsulosin 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 ration of free to total PSA remains constant even under the influence of Dutasteride/Tamsulosin. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Dutasteride/Tamsulosin therapy, no adjustment to its value appears necessary. Digital rectal examination, as well as other evaluations for prostate cancer or other conditions which can cause the same symptoms as BPH, must be performed on patients prior to initiating therapy with Dutasteride/Tamsulosin and periodically thereafter.
Cardiovascular adverse events: In two 4-year clinical studies, the incidence of cardiac failure (a composite term of reported events, primarily cardiac failure and congestive cardiac failure) was marginally higher among subjects taking the combination of Dutasteride and an α1-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 α1-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 postmarketing period. However, epidemiological studies showed no increase in the risk of developing male breast cancer with the use of 5-α-reductase inhibitors. Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge.
Hypotension: Orthostatic: As with other α1-adrenoceptor 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 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 minimise the potential for developing postural hypotension the patient should be haemodynamically stable on an α1-adrenoceptor antagonist prior to initiating use of PDE5 inhibitors.
Symptomatic: Caution is advised when alpha adrenergic blocking agents including Tamsulosin are co-administered with PDE5 inhibitors (e.g. sildenafil, tadalafil, vardenafil). α1-adrenoceptor 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 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 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 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: 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, a strong or moderate CYP2D6 inhibitor, a combination of both CYP3A4 and CYP2D6 inhibitors, or in patients known to be poor metabolisers of CYP2D6.
Sodium: This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially "Sodium-free".
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.
Hepatic impairment: Dutasteride/Tamsulosin has not been studied in patients with liver disease. Caution should be used in the administration of Dutasteride/Tamsulosin to patients with mild to moderate hepatic impairment.
Effects on Ability to Drive and Use Machines: No studies on the effects of Dutasteride/Tamsulosin on the ability to drive and use machines have been performed. However, patients should be informed about the possible occurrence of symptoms related to orthostatic hypotension such as dizziness when taking Dutasteride/Tamsulosin.

Dutasteride/Tamsulosin is contraindicated for use by women. There have been no studies to investigate the effect of Dutasteride/Tamsulosin on pregnancy, lactation and fertility. The following statements reflect the information available from studies with the individual components.
Pregnancy: As with other 5-α-reductase inhibitors, Dutasteride inhibits the conversion of testosterone to dihydrotestosterone and may, if administered to a woman carrying a male foetus, inhibit the development of the external genitalia of the foetus. Small amounts of Dutasteride have been recovered from the semen in subjects receiving Dutasteride. It is not known whether a male foetus 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-α-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 foetal 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. The possibility of reduced male fertility cannot be excluded. Effects of Tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.

The frequencies of adverse events may increase when the combination therapy is used.
Common: ≥1/100 to <10/10, 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. (See table.)

Click on icon to see table/diagram/image

There have been no drug interaction studies for Dutasteride/Tamsulosin. 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 catalysed 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-α-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 pharmacokinetic of other drugs: In a small study (n=24) of two weeks duration in healthy men, Dutasteride (0.5 mg 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 which can reduce blood pressure, including anaesthetic agents. PDE5 inhibitors and other α1-arenoceptor antagonists could lead to enhanced hypotensive effects. Dutasteride/Tamsulosin should not be used in combination with other α1-adrenoceptor 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. A similar increase in exposure is expected in CYP2D6 poor metabolisers as compared to extensive metabolisers when co-administered with a strong CYP3A4 inhibitor. The effects of co-administration of both CYP3A4 and CYP2D6 inhibitors with Tamsulosin hydrochloride have not been evaluated clinically, however there is a potential for significant increase in Tamsulosin exposure. Concomitant administration of Tamsulosin hydrochloride (0.4 mg) 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. Caution should be exercised with concomitant administration of warfarin and Tamsulosin hydrochloride. No interactions have been seen when Tamsulosin hydrochloride was given concomitantly with either atenolol, enalapril, nifedipine or theophylline. Concomitant furosemide brings about a fall in plasma levels of Tamsulosin, but as levels remain within the normal range posology need to be adjusted. In vitro neither diazepam nor propranolol, trichlormethiazide, chlormadinone, amitriptyline, diclofenac, glibenclamide and simvastatin change the free fraction of Tamsulosin in human plasma. Neither does Tamsulosin change the free fractions of diazepam, propranolol, trichlormethiazide, and chlormadinone.

This medicine does not require any special storage condition.
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.

Rx