DUTASTERIDE/TAMSULOSIN HYDROCHLORIDE GLENMARK 0.5 MG / 0.4 MG HARD CAPSULES - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Dutasteride/Tam­sulosin hydrochloride Glenmark 0.5 mg/0.4 mg hard capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride (equivalent to 0.367 mg tamsulosin).

Excipient(s) with known effect

Each capsule contains soya lecithin and propylene glycol.

This medicine contains 299.46 mg propylene glycol in each hard capsule which is equivalent to 4.27 mg/kg.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Hard capsule

Dutasteride/Tam­sulosin hydrochloride Glenmark are oblong, hard gelatin capsules, of 24.2 mm x 7.7 mm approx., with brown body and beige cap printed with C001 in black ink.

Each hard capsule contains tamsulosin hydrochloride modified release pellets and one dutasteride soft gelatin capsule.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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.

For information on effects of treatment and patient populations studied in clinical trials please see section 5.1.

4.2 Posology and method of administration

Posology

Adults (including elderly)

The recommended dose of Dutasteride/Tam­sulosin hydrochloride Glenmark is one capsule (0.5 mg/ 0.4 mg) daily.

Where appropriate, Dutasteride/Tam­sulosin hydrochloride Glenmark 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 hydrochloride Glenmark 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 (see section 4.4 and 5.2).

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 (see section 4.4 and section 5.2). In patients with severe hepatic impairment, the use of Dutasteride/Tam­sulosin hydrochloride Glenmark is contraindicated (see section 4.3).

Paediatric population

Dutasteride/tam­sulosin is contraindicated in the paediatric population (under 18 years of age) (see section 4.3).

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.

4.3 Contraindications

Dutasteride/Tam­sulosin hydrochloride Glenmark is contraindicated in:

– women and children and adolescents (see section 4.6).

– patients with hypersensitivity to the active substances, other 5-alpha reductase inhibitors, soya, peanut or any of the other excipients listed in section 6.1.

– patients with a history of orthostatic hypotension.

– patients with severe hepatic impairment.

4.4 Special warnings and precautions for use

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 hydrochloride Glenmark should be regularly evaluated for prostate cancer (see section 5.1).

Prostate specific antigen (PSA)

Serum prostate-specific antigen (PSA) concentration is an important component in the detection of prostate cancer. Dutasteride/Tam­sulosin hydrochloride Glenmark causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of treatment.

Patients receiving Dutasteride/Tam­sulosin hydrochloride Glenmark should have a new PSA baseline established after 6 months of treatment with Dutasteride/Tam­sulosin hydrochloride Glenmark. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from lowest PSA level while on Dutasteride/Tam­sulosin hydrochloride Glenmark may signal the presence of prostate cancer or noncompliance to therapy with Dutasteride/Tam­sulosin hydrochloride Glenmark and should be carefully evaluated, even if those values are still within the normal range for men not taking a 5-alpha reductase inhibitor (see section 5.1). In the interpretation of a PSA value for a patient taking dutasteride, previous PSA values should be sought for comparison.

Treatment with Dutasteride/Tam­sulosin hydrochloride Glenmark 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 hydrochloride Glenmark. If clinicians elect to use percent free PSA as an aid in the detection of prostate cancer in men undergoing Dutasteride/Tam­sulosin hydrochloride Glenmark 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 hydrochloride Glenmark 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 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 (see section 5.1).

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 (see section 5.1). 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– 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 hydrochloride Glenmark 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 alpha1– 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). Alpha1– 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 (see section 4.5).

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 hydrochloride Glenmark 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 hydrochloride Glenmark 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 (see section 4.6). 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 (see section 4.5). 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.

Hepatic impairment

Dutasteride/tam­sulosin has not been studied in patients with liver disease. Caution should be used in the administration of Dutasteride/Tam­sulosin hydrochloride Glenmark to patients with mild to moderate hepatic impairment (see section 4.2, section 4.3 and section 5.2).

Sodium

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction 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, please see section 4.4.

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-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 anaesthetic agents, PDE5 inhibitors and other alpha1– adrenoceptor antagonists could lead to enhanced hypotensive effects. Dutasteride/tam­sulosin should not be used in combination with other alpha1-adrenoceptor antagonists.

Concomitant administration of tamsulosin hydrochloride and ketoconazole (a strong CYP3A4 inhibitor) resulted in an increase of the Cmax 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 Cmax 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 (see section 4.4).

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 not be adjusted.

In vitro neither diazepam nor propranolol, trichlormethiazide, chlormadinon, amitryptyline, 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 chlormadinon.

4.6 Fertility, pregnancy and lactation

Dutasteride/Tam­sulosin hydrochloride Glenmark 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 (see section 5.3).

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 foetus, inhibit the development of the external genitalia of the foetus (see section 4.4). 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 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 foetal harm.

For information on preclinical data, see section 5.3.

Breast-feeding

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 (see section 5.1). The possibility of reduced male fertility cannot be excluded.

Effects of tamsulosin hydrochloride on sperm counts or sperm function have not been evaluated.

4.7 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 hydrochloride Glenmark.

4.8 Undesirable effects

The data presented here relate to the co-administration of dutasteride and tamsulosin from the 4 year analysis of the CombAT (Combination of Avodart and Tamsulosin) study, a comparison of dutasteride 0.5 mg and tamsulosin 0.4 mg once daily for four years as co-administration or as monotherapy. Bioequivalence of dutasteride/tam­sulosin with coadministered dutasteride and tamsulosin has been demonstrated (see section 5.2). Information on the adverse event profiles of the individual components (dutasteride and tamsulosin) is also provided. Note that not all the adverse events reported with the individual components have been reported with dutasteride/tam­sulosin and these are included for information for the prescriber.

Data from the 4 year CombAT study have shown that the incidence of any investigator-judged drug-related adverse event during the first, second, third and fourth years of treatment respectively was 22%, 6%, 4% and 2% for dutasteride + tamsulosin co-administration therapy, 15%, 6%, 3% and 2% for dutasteride monotherapy and 13%, 5%, 2% and 2% for tamsulosin monotherapy. The higher incidence of adverse events in the coadministration therapy group in the first year of treatment was due to a higher incidence of reproductive disorders, specifically ejaculation disorders, observed in this group.

The investigator-judged drug-related adverse events have been reported with an incidence of greater than or equal to 1% during the first year of treatment in the CombAT Study, BPH monotherapy clinical studies and REDUCE study are shown in the table below.

In addition the undesirable effects for tamsulosin below are based on information available in the public domain. The frequencies of adverse events may increase when the combination therapy is used.

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.

d

a. Dutasteride + tamsulosin: from CombAT study – the frequencies of these adverse events decrease over time of treatment, from year 1 to year 4.

b.

Dutasteride: from BPH monotherapy clinical studies.

c.

Tamsulosin: from EU Core Safety Profile for tamsulosin.

REDUCE study (see section 5.1).

1. Cardiac failure composite term comprised of cardiac failure congestive, cardiac failure, left ventricular failure, cardiac failure acute, cardiogenic shock, left ventricular failure acute, right ventricular failure, right ventricular failure acute, ventricular failure, cardiopulmonary failure, congestive cardiomyopathy.

2

2. Includes breast tenderness and breast enlargement.

3

3. These sexual adverse events are associated with dutasteride treatment (including monotherapy and combination with tamsulosin). These adverse events may persist after treatment discontinuation. The role of dutasteride in this persistence is not known.

. Includes semen volume decreased.

OTHER DATA

The REDUCE study revealed a higher incidence of Gleason 8–10 prostate cancers in dutasteride treated men compared to placebo (see sections 4.4 and 5.1). Whether the effect of dutasteride to reduce prostate volume, or study related factors, impacted the results of this study has not been established.

The following has been reported in clinical trials and post-marketing use: male breast cancer (see section 4.4).

Post marketing Data

Adverse events from world-wide post-marketing experience are identified from spontaneous post-marketing reports; therefore the true incidence is not known.

Dutasteride

Immune system disorders

Not known: Allergic reactions, including rash, pruritus, urticaria, localised oedema, and angioedema.

Psychiatric disorders

Not known: Depression

Skin and subcutaneous tissue disorders

Uncommon: Alopecia (primarily body hair loss), hypertrichosis.

Reproductive system and breast disorders

Not known: Testicular pain and testicular swelling

Tamsulosin

During postmarketing surveillance, reports of Intraoperative Floppy Iris Syndrome (IFIS), a variant of small pupil syndrome, during cataract surgery have been associated with alpha1– adrenoceptor antagonists, including tamsulosin (see section 4.4).

In addition atrial fibrillation, arrhythmia, tachycardia, dyspnoea, epistaxis, vision blurred, visual impairment, erythema multiforme, dermatitis exfoliative, ejaculation disorder, retrograde ejaculation, ejaculation failure and dry mouth have been reported in association with tamsulosin use. The frequency of events and the role of tamsulosin in their causation cannot be reliably determined.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1   Pharmacodynamic properties

5.2 Pharmacokinetic properties

Bioequivalence was demonstrated between dutasteride/tam­sulosin and concomitant dosing with separate dutasteride and tamsulosin capsules.

The single dose bioequivalence study 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

Following oral administration of a single 0.5 mg 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 hydrochloride Glenmark 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 Cmax 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 (Css) 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 0.2l/kg).

Biotransformation

Dutasteride

Dutasteride is extensively metabolised in vivo. 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 hydrochloride [R(-) isomer] to the S(+) isomer in humans. Tamsulosin hydrochloride 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 that CYP3A4 and CYP2D6 are involved in metabolism of tamsulosin as well as some minor participation of other CYP isoenzymes. Inhibition of hepatic drug metabolising enzymes may lead to increased exposure to tamsulosin (see section 4.4 and 4.5). 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 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 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.

At therapeutic concentrations, following repeat dosing of 0.5 mg/day, the slower, linear elimination pathway is dominating and the half-life is approx. 35 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.

Elderly

Dutasteride

Dutasteride pharmacokinetics 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. No significant influence of age was seen on the exposure of dutasteride but the half-life was shorter in men under 50 years of age. Halflife was not statistically different when comparing the 50–69 year old group to the greater than 70 years old.

Tamsulosin

Cross-study comparison of tamsulosin hydrochloride overall exposure (AUC) and half-life indicate that the pharmacokinetic disposition of tamsulosin hydrochloride may be slightly prolonged in elderly males compared to young, healthy male volunteers. Intrinsic clearance is independent of tamsulosin hydrochloride binding to AAG, but diminishes with age, resulting in a 40% overall higher exposure (AUC) in subjects of age 55 to 75 years compared to subjects of age 20 to 32 years.

Renal impairment

Dutasteride

The effect of renal impairment on dutasteride pharmacokinetics has not been studied. However, less than 0.1% of a steady-state 0.5 mg dose of dutasteride is recovered in human urine, so no clinically significant increase of the dutasteride plasma concentrations is anticipated for patients with renal impairment (see section 4.2).

Tamsulosin

The pharmacokinetics of tamsulosin hydrochloride have been compared in 6 subjects with mild-moderate (30 < CLcr < 70 ml/min/1.73m2) or moderate-severe (10 < CLcr < 30 ml/min/1.73m2) renal impairment and 6 normal subjects (CLcr > 90 ml/min/1.73m2). While a change in the overall plasma concentration of tamsulosin hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride, as well as the intrinsic clearance, remained relatively constant. Therefore, patients with renal impairment do not require an adjustment in tamsulosin hydrochloride capsules dosing. However, patients with endstage renal disease (CLcr < 10 ml/min/1.73m2) have not been studied.

Hepatic impairment

Dutasteride

The effect on the pharmacokinetics of dutasteride in hepatic impairment has not been studied (see section 4.3). Because dutasteride is eliminated mainly through metabolism the plasma levels of dutasteride are expected to be elevated in these patients and the half-life of dutasteride be prolonged (see section 4.2 and section 4.4).

Tamsulosin

The pharmacokinetics of tamsulosin hydrochloride 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 hydrochloride was observed as the result of altered binding to AAG, the unbound (active) concentration of tamsulosin hydrochloride does not change significantly with only a modest (32%) change in intrinsic clearance of unbound tamsulosin hydrochloride. Therefore, patients with moderate hepatic dysfunction do not require an adjustment in tamsulosin hydrochloride dosage. Tamsulosin hydrochloride has not been studied in patients with severe hepatic dysfunction.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hard capsule shell:

Black iron oxide (E172)

Red iron oxide (E172)

Titanium dioxide (E171)

Yellow iron oxide (E172)

Gelatin

Contents in dutasteride soft capsule:

Propylene glycol monocaprylate, type II

Butylhydroxytoluene (E321)

Soft capsule shell:

Gelatin

Glycerol

Titanium dioxide (E171)

Triglycerides (medium chain)

Lecithin (may contain soya oil).

Tamsulosin pellets:

Methacrylic acid – ethyl acrylate copolymer (1:1) dispersion 30 per cent (contains sodium laurilsulfate, polysorbate 80)

Microcrystalline cellulose

Dibutyl sebacate

Polysorbate 80

Colloidal hydrated silica

Calcium stearate

Black ink:

Shellac (E904)

Black iron oxide (E172)

Propylene glycol (E1520)

Concentrated ammonia solution, (E527)

Potassium hydroxide (E525)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

This medicine does not require any special storage condition.

6.5 Nature and contents of container

HDPE bottle with silica gel desiccant contained in the polypropylene cap.

7 hard capsules in 35 ml bottle

30 hard capsules in 100 ml bottle

90 hard capsules in 250 ml bottle Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Dutasteride is absorbed through the skin, therefore contact with leaking capsules must be avoided. If contact is made with leaking capsules, the contact area should be washed immediately with soap and water (see section 4.4).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Glenmark Pharmaceuticals Europe Limited

Laxmi House, 2B Draycott Avenue, Kenton, Middlesex, HA3 0BU

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 25258/0301

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/09/2019