This combination capsule is indicated in:

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

Tamsulosin & Dutasteride is a combination of two drugs with complementary mechanisms of action to improve symptoms in patients with Benign Prostatic Hyperplasia (BPH). Tamsulosin Hydrochloride is an antagonist of alpha-adrenoreceptors, and Dutasteride is a dual 5-alpha reductase inhibitor (5ARI). Treatment of BPH with alpha-adrenoreceptor blocking agents and 5ARIs results in an improvement in urine flow rate and a reduction in symptoms of BPH.

Tamsulosin: An alpha₁-adrenoreceptor blocking agent that affects the dynamic component of BPH by inhibiting alpha₁-adrenoreceptors in the stromal prostatic smooth muscle and bladder neck. Blockade of these adrenoreceptors can cause smooth muscles in the bladder neck and prostate to relax. Specifically, Tamsulosin exhibits selectivity for both alpha₁A and alpha₁D receptors over the alpha₁B-adrenoreceptor subtype. These three adrenoreceptor subtypes have a distinct distribution pattern in human tissue. Whereas approximately 70% of the alpha₁-receptors in the human prostate are of the alpha₁A subtype, the human bladder contains predominantly the alpha₁D subtype, while blood vessels express predominantly the alpha₁B subtype. It is further believed that blockade of the alpha₁D subtypes in the human obstructed bladder may be responsible for reducing detrusor overactivity and subsequent relief of storage symptoms.

Dutasteride: A synthetic 4-azasteroid compound is a competitive and specific inhibitor of both Type I and Type II 5-alpha-reductase isoenzymes that affects the static component of BPH by inhibiting the conversion of testosterone to dihydrotestosterone (DHT) by the enzyme 5-alpha-reductase. 5-alpha-reductase exists as 2 isoforms, Type I and Type II, both of which are present in the prostate. It has been observed that compared to normal tissue, the expression of both isoenzymes is increased in BPH tissue. Dissociation from this complex has been evaluated under in vitro and in vivo conditions and is extremely slow. Dutasteride lowers DHT levels and leads to a reduction in prostatic volume, thereby treating an underlying cause of BPH. Dutasteride does not bind to the human androgen receptor.

Adults (including elderly): The recommended dose is one capsule (Tamsulosin Hydrochloride 0.4 mg & Dutasteride 0.5 mg) taken orally approximately 30 minutes after the same meal each day. The capsules should be swallowed whole and not chewed or opened. Where appropriate, this capsule may be used to substitute concomitant Tamsulosin Hydrochloride and Dutasteride in existing dual therapy to simplify treatment. Where clinically appropriate, direct change from Tamsulosin Hydrochloride or Dutasteride monotherapy to this capsule may be considered.

Renal impairment: The effect of renal impairment on Tamsulosin-Dutasteride pharmacokinetics has not been studied. No adjustment in dosage is anticipated for patients with renal impairment.

Hepatic impairment: The effect of hepatic impairment on Tamsulosin-Dutasteride 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 this capsule is contra-indicated.

There have been no drug interaction studies for the Dutasteride-Tamsulosin combination.

Effects of other drugs on the pharmacokinetics of Dutasteride: Use together with CYP3A4 and/or P-glycoprotein inhibitors: 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 (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 anesthetic agents, PDE5 inhibitors, and other alpha-1 adrenergic blockers, could lead to enhanced hypotensive effects. Tamsulosin-Dutasteride should not be used in combination with other alpha-1 adrenergic blockers. 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 Tamsulosin-Dutasteride 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. 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 not 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. No interactions at the level of hepatic metabolism have been seen during in vitro studies with liver microsomal fractions, involving amitriptyline, salbutamol, and glibenclamide. Diclofenac, however, may increase the elimination rate of Tamsulosin.

Tamsulosin-Dutasteride combination is contraindicated in women and 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; patients with a history of orthostatic hypotension; and patients with severe hepatic impairment.

The most common adverse reactions reported in subjects receiving combination therapy were impotence, decreased libido, breast disorders (including breast enlargement and tenderness), ejaculation disorders, and dizziness. The percentages of subjects with ejaculation disorders, decreased libido, and impotence were higher in the combination therapy group compared with either monotherapy group.

Tamsulosin-Dutasteride combination is contraindicated for use by women. There have been no studies to investigate the effect of Tamsulosin-Dutasteride combination on pregnancy, lactation, and fertility. The following statements reflect the information available from studies with the individual components. 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.

Pregnancy: As with 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 in 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. 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.

Lactation: It is not known whether Tamsulosin or Dutasteride are excreted in human milk.

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.

Cardiac failure: In two 4-year clinical studies, the incidence of cardiac failure was higher among subjects taking the combination of Dutasteride and an alpha blocker, primarily Tamsulosin, than it was among subjects not taking the combination. In these two trials, the incidence of cardiac failure was low (1%) and variable between the studies.

Effects on prostate specific antigen (PSA) and prostate cancer detection: 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 Tamsulosin-Dutasteride combination and periodically thereafter. Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Tamsulosin-Dutasteride combination causes a decrease in mean serum PSA levels by approximately 50% after 6 months of treatment. Patients receiving Tamsulosin-Dutasteride combination should have a new PSA baseline established after 6 months of treatment. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from the lowest PSA level while on Tamsulosin-Dutasteride combination may signal the presence of prostate cancer or noncompliance to therapy with Tamsulosin-Dutasteride combination and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5-alpha reductase inhibitor. In the interpretation of a PSA value for a patient taking Tamsulosin-Dutasteride combination, previous PSA values while on Dutasteride treatment should be sought for comparison. Treatment with Tamsulosin-Dutasteride combination 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 Tamsulosin-Dutasteride combination. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Tamsulosin-Dutasteride combination therapy, no adjustment to its value appears necessary.

Prostate cancer and high grade tumours: Results of one clinical study in men at increased risk of prostate cancer revealed a higher incidence of Gleason 8-10 prostate cancers in Dutasteride-treated men compared to placebo. The relationship between Dutasteride and high-grade prostate cancer is not clear. Men taking Tamsulosin-Dutasteride combination should be regularly evaluated for prostate cancer risk, including PSA testing.

Renal impairment: The treatment of severely renally impaired patients (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 alpha-blockers, a reduction in blood pressure can occur during treatment with Tamsulosin, as a result of which, rarely, syncope can occur. Patients beginning treatment with Tamsulosin-Dutasteride combination 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 alpha-blocker therapy prior to initiating 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). 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) has been observed during cataract surgery in some patients on or previously treated with Tamsulosin. IFIS may lead to increased procedural complications during the operation. The initiation of therapy with Tamsulosin-Dutasteride combination in patients for whom cataract surgery is scheduled is therefore not recommended. 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: Tamsulosin-Dutasteride combination has not been studied in patients with liver disease. Caution should be used in the administration of Tamsulosin-Dutasteride combination to patients with mild to moderate hepatic impairment.

Breast neoplasia: Breast cancer has been reported in men taking Dutasteride in clinical trials and during the post-marketing period. Physicians should instruct their patients to promptly report any changes in their breast tissue such as lumps or nipple discharge. Currently, it is not clear if there is a causal relationship between the occurrence of male breast cancer and long-term use of Dutasteride.

No data are available with regard to overdosage of the Tamsulosin-Dutasteride combination. 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 diarrhea were observed, which were treated with fluid replacement, and the patient could be discharged the same day. In the 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 sulfate, can be administered.

BPH / Urinary retention / Urinary incontinence

Store in a cool and dry place, protected from light.