The content of this leaflet was approved by the Ministry of Health in April 2017 and updated

according to the guidelines of the Ministry of Health in March 2018

Duodart

1. NAME OF THE MEDICINAL PRODUCT

Duodart

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 with known effect:

Each capsule contains lecithin (which may contain soya oil) and Sunset Yellow (E 110). Each capsule
contains ≤ 0.1 mg sunset yellow.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Capsule, hard

Oblong, hard capsules with a brown body and an orange cap imprinted with GS 7CZ 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 Duodart is one capsule (0.5 mg/ 0.4 mg) once daily.

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Where appropriate, Duodart 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
Duodart 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 Duodart 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

Duodart is contraindicated in:

- women and children and adolescents (see section 4.6 ).
- patients with hypersensitivity to dutasteride, other 5-alpha reductase inhibitors, tamsulosin (including
tamsulosin-induced angio-edema), 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
Page 2 of 19
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 Duodart 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. Duodart causes a decrease in mean serum PSA levels by approximately 50%, after 6 months of
treatment.

Patients receiving Duodart should have a new PSA baseline established after 6 months of treatment with
Duodart. It is recommended to monitor PSA values regularly thereafter. Any confirmed increase from
lowest PSA level while on Duodart may signal the presence of prostate cancer or noncompliance to therapy
with Duodart 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 Duodart 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 Duodart. If clinicians elect to use percent free PSA
as an aid in the detection of prostate cancer in men undergoing Duodart 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 Duodart
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
Duodart should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness,
weakness) until the symptoms have resolved.
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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 Duodart 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 Duodart 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 Capsule
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
Duodart has not been studied in patients with liver disease. Caution should be used in the administration of
Duodart to patients with mild to moderate hepatic impairment (see section 4.2, section 4.3 and section 5.2).

Excipients
This medicinal product contains the colouring agent Sunset Yellow (E110), which may cause allergic
reactions.

4.5 Interaction with other medicinal products and other forms of interaction

There have been no drug interaction studies for Duodart. 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

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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.

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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

Duodart is contraindicated for use by women. There have been no studies to investigate the effect of Duodart
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 Duodart 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 Duodart.

4.8 Undesirable effects

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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 0.5mg and
tamsulosin 0.4mg once daily for four years as co-administration or as monotherapy. Bioequivalence of
Duodart with co-administered 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 Duodart 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 co-administration 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.
System organ class Adverse reactions Dutasteride+ Dutasteride Tamsulosinc
a
tasmulosin
Nervous system Syncope
disorders - - Rare
Dizziness Common - Common
Headache - - Uncommon
Cardiac disorders Cardiac failure (Composite Uncommon Uncommond -
term1)

Palpitations - - Uncommon

Vascular disorders Orthostatic hypotension - - Uncommon

Respiratory, thoracic Rhinitis - - Uncommon

and mediastinal
disorders
Gastrointestinal Constipation - - Uncommon
disorders
Diarrhoea - - Uncommon

Nausea - - Uncommon
Vomitting - - Uncommon
Skin and Angioedema - - Rare
subcutaneous
disorders Stevens-Johnson syndrome - - Very Rare

Urticaria - - Uncommon
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 Rash - - Uncommon
Pruritis - - Uncommon
Reproductive system Priapism - - Very rare
and breast disorders
Impotence3 Common Commonb -
Altered (decreased) libido3 Common Commonb -

Ejaculation disorders3^ Common Commonb Common

Breast disorders2 Common Commonb -

General disorders Asthenia - - Uncommon

and administration
site disorders
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.
d
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
Includes breast tenderness and breast enlargement.
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.

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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 any suspected adverse reactions
should be reported to the Ministry of Health according to the National Regulation by using an online form
http://forms.gov.il/globaldata/getsequence/[email protected]

4.9 Overdose

No data are available with regard to overdosage of Duodart. 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Alpha-adrenoreceptor antagonists, ATC code: G04CA52

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Dutasteride-tamsulosin is a combination of two drugs: dutasteride, a dual 5 α-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 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 α1a and α1d adrenergic receptors in the stromal
prostatic smooth muscle and bladder neck. Approximately 75% of the α1-receptors in the prostate are of the
α1a subtype.

Dutasteride co-administration with tamsulosin

The following statements reflect the information available on dutasteride and tamsulosin co-administration
therapy.

Dutasteride 0.5 mg/day (n = 1,623), tamsulosin 0.4 mg/day (n = 1,611) or the co-administration of
Dutasteride 0.5 mg plus tamsulosin 0.4 mg (n = 1,610) were evaluated in male subjects with moderate to
severe symptoms of BPH who had prostates 30ml and a PSA value within the range 1.5 - 10 ng/mL in a 4
year multicentre, multinational, randomized double-blind, parallel group study. Approximately 53% of
subjects had previous exposure to 5-alpha reductase inhibitor or alpha1- adrenoceptor antagonist.. The
primary efficacy endpoints during the first 2 years of treatment was change in International Prostate
Symptom Score (IPSS), an 8-item instrument based on AUA-SI with an additional question on quality of
life. Secondary efficacy endpoints at 2 years included maximum urine flow rate (Qmax) and prostate
volume. The combination achieved significance for IPSS from Month 3 compared to dutasteride and from
Month 9 compared to tamsulosin. For Qmax combination achieved significance from Month 6 compared to
both dutasteride and tamsulosin.

The combination of dutasteride and tamsulosin provides superior improvement in symptoms 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.

The adjusted mean improvement in flow rate from baseline was 2.4 ml/sec for co-administration therapy, 1.9
ml/sec for dutasteride and 0.9 ml/sec for tamsulosin. The adjusted mean improvement in BPH Impact Index
(BII) from baseline was -2.1 units for co-administration therapy, -1.7 for dutasteride and -1.5 for tamsulosin.
These improvements in flow rate and BII were statistically significant for co-administration therapy
compared to both monotherapies.

The reduction in total prostate volume and transition zone volume after 2 years of treatment was statistically
significant for co-administration therapy compared to tamsulosin monotherapy alone.

The primary efficacy endpoint at 4 years of treatment was time to first event of AUR or BPH-related surgery.
After 4 years of treatment, combination therapy statistically significantly reduced the risk of AUR or BPH-
related surgery (65.8% reduction in risk p<0.001 [95% CI 54.7% to 74.1%]) compared to tamsulosin
monotherapy. The incidence of AUR or BPH-related surgery by Year 4 was 4.2% for combination therapy
and 11.9% for tamsulosin (p<0.001). Compared to dutasteride monotherapy, combination therapy reduced
the risk of AUR or BPH-related surgery by 19.6% (p=0.18 [95% CI -10.9% to 41.7%]). The incidence of
AUR or BPH-related surgery by Year 4 was 5.2% for dutasteride.

Secondary efficacy endpoints after 4 years of treatment included time to clinical progression (defined as a
composite of: IPSS deterioration by 4 points, BPH-related events of AUR, incontinence, urinary tract
infection (UTI), and renal insufficiency) change in International Prostate Symptom Score (IPSS), maximum
urine flow rate (Qmax) and prostate volume. IPSS is an 8-item instrument based on the AUA-SI with an
additional question on quality of life. Results following 4 years of treatment are presented below:

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Parameter Time-point Combination Dutasteride Tamsulosin

AUR or BPH related Incidence at Month 48 4.2 5.2 11.9a

surgery (%)
Clinical progression* Month 48 12.6 17.8b 21.5a
(%)
IPSS (units) [Baseline] [16.6] [16.4] [16.4]
Month 48 (Change from Baseline) -6.3 -5.3b -3.8a
Qmax (mL/sec) [Baseline] [10.9] [10.6] [10.7]
Month 48 (Change from Baseline) 2.4 2.0 0.7a
Prostate Volume (ml) [Baseline] [54.7] [54.6] [55.8]
Month 48 (% Change from Baseline) -27.3 -28.0 +4.6a
Prostate Transition [Baseline] [27.7] [30.3] [30.5]
Zone Volume (ml)# Month 48 (% Change from Baseline) -17.9 -26.5 18.2a
BPH Impact Index [Baseline] [5.3] [5.3] [5.3]
(BII) (units) Month 48 (Change from Baseline) -2.2 -1.8b -1.2a
IPSS Question 8 [Baseline] [3.6] [3.6] [3.6]
(BPH-related Health Month 48 (Change from Baseline) -1.5 -1.3b -1.1a
Status) (units)

Baseline values are mean values and changes from baseline are adjusted mean changes.
* Clinical progression was defined as a composite of: IPSS deterioration by 4 points, BPH-related events of
AUR, incontinence, UTI, and renal insufficiency.
# Measured at selected sites (13% of randomized patients)
a. Combination achieved significance (p<0.001) vs. tamsulosin at Month 48
b. Combination achieved significance (p<0.001) vs. dutasteride at Month 48

Dutasteride

Dutasteride 0.5 mg/day or placebo was evaluated in 4325 male subjects with moderate to severe symptoms
of BPH who had prostates ≥30ml and a PSA value within the range 1.5 - 10 ng/mL in three primary efficacy
2-year multicenter, multinational, placebo controlled, double-blind studies. The studies then continued with
an open-label extension to 4 years with all patients remaining in the study receiving dutasteride at the same
0.5 mg dose. 37% of initially placebo-randomized patients and 40% of dutasteride-randomized patients
remained in the study at 4 years. The majority (71%) of the 2,340 subjects in the open-label extensions
completed the 2 additional years of open-label treatment.

The most important clinical efficacy parameters were American Urological Association Symptom Index
(AUA-SI), maximum urinary flow (Qmax) and the incidence of acute urinary retention and BPH-related
surgery.

AUA-SI is a seven-item questionnaire about BPH-related symptoms with a maximum score of 35. At
baseline the average score was approx. 17. After six months, one and two years treatment the placebo group
had an average improvement of 2.5, 2.5 and 2.3 points respectively while the Avodart group improved 3.2,
3.8 and 4.5 points respectively. The differences between the groups were statistically significant. The
improvement in AUA-SI seen during the first 2 years of double-blind treatment was maintained during an
additional 2 years of open-label extension studies.

Qmax (maximum urine flow):

Mean baseline Qmax for the studies was approx 10 ml/sec (normal Qmax  15 ml/sec). After one and two
years treatment the flow in the placebo group had improved by 0.8 and 0.9 ml/sec respectively and 1.7 and
2.0 ml/sec respectively in the Avodart group. The difference between the groups was statistically significant
from Month 1 to Month 24. The increase in maximum urine flow rate seen during the first 2 years of double-
blind treatment was maintained during an additional 2 years of open-label extension studies.
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Acute Urinary Retention and Surgical Intervention

After two years of treatment, the incidence of AUR was 4.2% in the placebo group against 1.8% in the
Avodart group (57% risk reduction). This difference is statistically significant and means that 42 patients
(95% CI 30-73) need to be treated for two years to avoid one case of AUR.

The incidence of BPH-related surgery after two years was 4.1% in the placebo group and 2.2% in the
Avodart group (48% risk reduction). This difference is statistically significant and means that 51 patients
(95% CI 33-109) need to be treated for two years to avoid one surgical intervention.

Hair distribution

The effect of dutasteride on hair distribution was not formally studied during the phase III programme,
however, 5 alpha-reductase inhibitors could reduce hair loss and may induce hair growth in subjects with
male pattern hair loss (male androgenetic alopecia).

Thyroid function:

Thyroid function was evaluated in a one year study in healthy men. Free thyroxine levels were stable on
dutasteride treatment but TSH levels were mildly increased (by 0.4 MCIU/mL) compared to placebo at the
end of one year's treatment. However, as TSH levels were variable, median TSH ranges (1.4 - 1.9
MCIU/mL) remained within normal limits (0.5 - 5/6 MCIU/mL), free thyroxine levels were stable within the
normal range and similar for both placebo and dutasteride treatment, the changes in TSH were not
considered clinically significant. In all the clinical studies, there has been no evidence that dutasteride
adversely affects thyroid function.

Breast neoplasia:

In the 2 year clinical trials, providing 3374 patient years of exposure to dutasteride, and at the time of
registration in the 2 year open label extension, there were 2 cases of male breast cancer reported in
dutasteride-treated patients and 1 case in a patient who received placebo. In the 4 year CombAT and
REDUCE clinical trials providing 17489 patient years exposure to dutasteride and 5027 patient years
exposure to dutasteride and tamsulosin combination there were no cases of breast cancer reported in any
treatment groups.

Two case control, epidemiological studies, one conducted in a US (n=339 breast cancer cases and n=6,780
controls) and the other in a UK (n=398 breast cancer cases and n=3,930 controls) healthcare database,
showed no increase in the risk of developing male breast cancer with the use of 5 ARIs (see section 4.4).
Results from the first study did not identify a positive association for male breast cancer (relative risk for  1
year of use before breast cancer diagnosis compared with < 1 year of use: 0.70: 95% CI 0.34, 1.45). In the
second study, the estimated odds ratio for breast cancer associated with the use of 5-ARIs compared with
non-use was 1.08: 95% CI 0.62, 1.87).
A causal relationship between the occurrence of male breast cancer and long term use of dutasteride has not
been established.

Effects on male fertility

The effects of dutasteride 0.5 mg/day on semen characteristics were evaluated in healthy volunteers aged 18
to 52 (n=27 dutasteride, n=23 placebo) throughout 52 weeks of treatment and 24 weeks of post-treatment
follow-up. At 52 weeks, the mean percent reduction from baseline in total sperm count, semen volume and
sperm motility were 23%, 26% and 18%, respectively, in the dutasteride group when adjusted for changes
from baseline in the placebo group. Sperm concentration and sperm morphology were unaffected. After 24
weeks of follow-up, the mean percent change in total sperm count in the dutasteride group remained 23%
lower than baseline. While mean values for all parameters at all time points remained within the normal
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ranges and did not meet the predefined criteria for a clinically significant change (30%), two subjects in the
dutasteride group had decreases in sperm count of greater than 90% from baseline at 52 weeks, with partial
recovery at the 24 week follow-up. The possibility of reduced male fertility cannot be excluded.

Cardiovascular adverse events

In a 4 year BPH study of dutasteride in combination with tamsulosin in 4844 men (the CombAT study) the
incidence of the composite term cardiac failure in the combination group (14/1610, 0.9%) was higher than in
either monotherapy group: dutasteride, (4/1623, 0.2%) and tamsulosin, (10/1611, 0.6%).

In a separate 4-year study in 8231 men aged 50 to 75, with a prior negative biopsy for prostate cancer and
baseline PSA between 2.5 ng/mL and 10.0 ng/mL in the case of men 50 to 60 years of age, or 3 ng/mL and
10.0 ng/mL in the case of men older than 60 years of age) (the REDUCE study), there was a higher
incidence of the composite term cardiac failure in subjects taking dutasteride 0.5 mg once daily (30/4105,
0.7%) compared to subjects taking placebo (16/4126, 0.4%). A post-hoc analysis of this study showed a
higher incidence of the composite term cardiac failure in subjects taking dutasteride and an alpha1-
adrenoceptor antagonist concomitantly (12/1152, 1.0%), compared to subjects taking dutasteride and no
alpha1- adrenoceptor antagonist (18/2953, 0.6%), placebo and an alpha1- adrenoceptor antagonist (1/1399,
<0.1%), or placebo and no alpha1- adrenoceptor antagonist (15/2727, 0.6%).

In a meta-analysis of 12-randomised, placebo- or comparator-controlled clinical studies (n=18,802) that

evaluated the risks of developing cardiovascular adverse events from the use of dutasteride (by comparison
with controls), no consistent statistically significant increase in the risk of heart failure (RR 1.05; 95% CI
0.71, 1.57), acute myocardial infarction (RR 1.00; 95% CI 0.77, 1.30) or stroke (RR 1.20; 95% CI 0.88,
1.64) were found.

Prostate cancer and high grade tumours

In a 4-year comparison of placebo and dutasteride in 8231 men aged 50 to 75, with a prior negative biopsy
for prostate cancer and baseline PSA between 2.5 ng/mL and 10.0 ng/mL in the case of men 50 to 60 years
of age, or 3 ng/mL and 10.0 ng/mL in the case of men older than 60 years of age) (the REDUCE study),
6,706 subjects had prostate needle biopsy (primarily protocol mandated) data available for analysis to
determine Gleason Scores. There were 1517 subjects diagnosed with prostate cancer in the study. The
majority of biopsy-detectable prostate cancers in both treatment groups were diagnosed as low grade
(Gleason 5-6, 70%).

There was a higher incidence of Gleason 8-10 prostate cancers in the dutasteride group (n=29, 0.9%)
compared to the placebo group (n=19, 0.6%) (p=0.15). In Years 1-2, the number of subjects with Gleason 8-
10 cancers was similar in the dutasteride group (n=17, 0.5%) and the placebo group (n=18, 0.5%). In Years
3-4, more Gleason 8-10 cancers were diagnosed in the dutasteride group (n=12, 0.5%) compared with the
placebo group (n=1, <0.1%) (p=0.0035). There are no data available on the effect of dutasteride beyond 4
years in men at risk of prostate cancer. The percentage of subjects diagnosed with Gleason 8-10 cancers was
consistent across study time periods (Years 1-2 and Years 3-4) in the dutasteride group (0.5% in each time
period), while in the placebo group, the percentage of subjects diagnosed with Gleason 8-10 cancers was
lower during Years 3-4 than in Years 1-2 (<0.1% versus 0.5%, respectively) (see section 4.4). There was no
difference in the incidence of Gleason 7-10 cancers (p=0.81).

The additional 2-year follow-up study of the REDUCE trial did not identify any new cases of Gleason 8–10
prostate cancers.

In a 4 year BPH study (CombAT) where there were no protocol-mandated biopsies and all diagnoses of
prostate cancer were based on for-cause biopsies, the rates of Gleason 8-10 cancer were (n=8, 0.5%) for
dutasteride, (n=11, 0.7%) for tamsulosin and (n=5, 0.3%) for combination therapy.

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Four different epidemiological, population-based studies (two of which were based on a total population of
174,895, one on a population of 13,892, and one on a population of 38,058) showed that the use of 5-alpha
reductase inhibitors is not associated with the occurrence of high grade prostate cancer, nor with prostate
cancer, or overall mortality.

The relationship between dutasteride and high grade prostate cancer is not clear.

Effects on sexual function:

The effects of Duodart on sexual function were assessed in a double-blind, placebo-controlled study in
sexually active men with BPH (n=243Duodart , n=246 placebo). A statistically significant (p<0.001) greater
reduction (worsening) in the Men’s Sexual Health Questionnaire (MSHQ) score was observed at 12 months
in the combination group. The reduction was mainly related to a worsening of the ejaculation and overall
satisfaction domains rather than the erection domains. These effects did not affect study participants’
perception of Duodart , which was rated with a statistically significant greater satisfaction throughout
12 months compared with placebo (p<0.05). In this study the sexual adverse events occurred during the
12 months of treatment and approximately half of these resolved within 6 months post-treatment.

Dutasteride-tamsulosin combination and dutasteride monotherapy are known to cause sexual function
adverse effects (see section 4.8).

As observed in other clinical studies, including CombAT and REDUCE, the incidence of adverse events
related to sexual function decreases over time with continued therapy.

Tamsulosin

Tamsulosin increases maximum urinary flow rate. It relieves obstruction by relaxing smooth muscle in the
prostate and urethra, thereby improving voiding symptoms. It also improves the storage symptoms in which
bladder instability plays an important role. These effects on storage and voiding symptoms are maintained
during long-term therapy. The need for surgery or catheterization is significantly delayed.

Α1-adrenoreceptor antagonists can reduce blood pressure by lowering peripheral resistance. No reduction in
blood pressure of any clinical significance was observed during studies with tamsulosin.

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

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be promoted by the patient always taking Duodart 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. 3-5 weeks.

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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 range 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.

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. Half-life 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
Page 16 of 19
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

Non-clinical studies have not been conducted with Duodart. Dutasteride and tamsulosin hydrochloride
individually have been extensively evaluated in animal toxicity tests and findings were consistent with the
known pharmacological actions of 5 alpha-reductase inhibitors and alpha1- adrenoceptor antagonists. The
following statements reflect the information available on the individual components.

Dutasteride

Current studies of general toxicity, genotoxicity and carcinogenicity did not show any particular risk to
humans.

Reproduction toxicity studies in male rats have shown a decreased weight of the prostate and seminal
vesicles, decreased secretion from accessory genital glands and a reduction in fertility indices (caused by the
pharmacological effect of dutasteride). The clinical relevance of these findings is unknown.

As with other 5 alpha reductase inhibitors, feminisation of male foetuses in rats and rabbits has been noted
when dutasteride was administered during gestation. Dutasteride has been found in blood from female rats
after mating with dutasteride treated males. When dutasteride was administered during gestation to primates,
no feminisation of male foetuses was seen at blood exposures sufficiently in excess of those likely to occur
via human semen. It is unlikely that a male foetus will be adversely affected following seminal transfer of
dutasteride.

Tamsulosin

Studies of general toxicity and genotoxicity did not show any particular risk to humans other than those
related to the pharmacological properties of tamsulosin.

In carcinogenicity studies in rats and mice, tamsulosin hydrochloride produced an increased incidence of
proliferative changes of the mammary glands in females. These findings, which are probably mediated by
hyperprolactinaemia and only occurred at high dose levels, are regarded as not clinically relevant

High doses of tamsulosin hydrochloride resulted in a reversible reduction in fertility in male rats considered
possibly due to changes of semen content or impairment of ejaculation. Effects of tamsulosin on sperm
counts or sperm function have not been evaluated.

Administration of tamsulosin hydrochloride to pregnant female rats and rabbits at higher than the therapeutic
dose showed no evidence of foetal harm.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hard Capsule Shell:

Hypromellose
Carrageenan (E407)
Potassium Chloride
Titanium Dioxide (E171)
Iron Oxide Red (E172)
FD&C Yellow (E110)
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 Carnauba Wax
Maize Starch

Contents in Dutasteride Soft Capsule:

Mono-di-glycerides of caprylic/capric acid
Butylhydroxytoluene

Soft Capsule Shell:

Gelatin
Glycerol
Titanium dioxide (E171)
ferric oxide (E172)
Triglycerides, medium chain
Lecithin (may contain soya oil)

Tamsulosin Pellets:
Cellulose, Microcrystalline
Methacrylic acid - ethyl acrylate copolymer 1:1 dispersion 30 per cent (also contains polysorbate 80 and
sodium laurilsulfate)
Talc
Triethyl citrate

Black Inks (SW-9010 or SW-9008):

Shellac
Propylene Glycol
Iron Oxide Black (E172)
Potassium Hydroxide (in Black Ink SW-9008 only)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

The expiry date of the product is indicated on the label and packaging.
Do not use the product after three months from opening.

6.4 Special precautions for storage

Do not store above 30°C.

6.5 Nature and contents of container

Opaque, white high density polyethylene (HDPE) bottles with polypropylene child-resistant closures with
polyethylene-faced, foil induction heat-seal liners. The bottles contain either 7, 30,90 capsules.

6.6 Special precautions for disposal and other handling

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).

7. MANUFACTURER
Catalent Germany Schorndorf GmbH, Schorndorf, Germany

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8. LICENSE HOLDER AND IMPORTER

GlaxoSmithKline (Israel) Ltd., 25 Basel St., Petach Tikva

9. LICENSE NUMBER

146-34-33278

Trade marks are owned by or licensed to the GSK group of companies.

©2018 GSK group of companies or its licensor.

Duo DR v5.1A

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