DUODART

Patient leaflet in accordance with

the Pharmacists' Regulations (Preparations) – 1986

The medicine is dispensed according to a physician's prescription only

Duodart

capsules

Each capsule contains 0.5 mg dutasteride and 0.4 mg tamsulosin hydrochloride.

For a list of the inactive and allergenic ingredients, see section 2 “Important information about

some ingredients of the medicine” and section 6 “Additional information”.

Read the entire leaflet carefully before using the medicine. This leaflet contains concise

information about the medicine. If you have any other questions, refer to the physician or

the pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them

even if it seems to you that their medical condition is similar.

This medicine is intended for men only.

1. What is the medicine intended for?

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.

Duodart is used to treat men with an enlarged prostate (benign prostatic hyperplasia) - a

non-cancerous growth of the prostate gland, caused by producing too much of a hormone

called dihydrotestosterone.

Growth of the prostate can lead to urinary problems, such as difficulty in passing urine and

a need to go to the toilet frequently. It can also cause the flow of the urine to be slower and

less forceful. If left untreated, there is a risk that your urine flow will be completely blocked

(acute urinary retention). This requires immediate medical treatment. Sometimes surgery is

necessary to remove or reduce the size of the prostate gland.

Dutasteride lowers the production of a hormone called dihydrotestosterone, which helps

to shrink the prostate and relieve the symptoms. This will reduce the risk of acute urinary

retention and the need for surgery. Tamsulosin acts by relaxing the muscles in the prostate

gland, making it easier to pass urine and rapidly improving your symptoms.

Therapeutic group: Duodart is a combination of two different medicines called dutasteride

and tamsulosin. Dutasteride belongs to a group of medicines called 5-alpha reductase

inhibitors and tamsulosin belongs to a group of medicines called alpha-blockers.

2. Before using the medicine

Do not use Duodart:

if you are sensitive (allergic) to the active ingredients dutasteride and tamsulosin

hydrochloride, to other 5-alpha reductase inhibitors, soya, peanuts or to any of

the additional ingredients contained in the medicine as listed in section 6.

in women (as the medicine is intended for men only).

in children or adolescents under the age of 18.

if you have low blood pressure which makes you feel dizzy, lightheaded or faint

(orthostatic hypotension).

if you have a severe liver disease.

→

If you think any of these apply to you do not take the medicine and tell your

physician.

Special warnings regarding the use of the medicine

Talk to your physician before you take Duodart.

In some clinical studies, more patients taking dutasteride and another medicine called

an alpha-blocker, like tamsulosin, experienced heart failure than patients taking only

dutasteride or only an alpha-blocker. Heart failure means your heart does not pump

blood as well as it should.

Make sure your physician knows if you have liver problems. If you have had any

illness that affected your liver, you may need some additional check-ups while you are

taking Duodart.

Make sure your physician knows if you have severe problems with your kidney.

Cataract (opacity of the lens of the eye) surgery. If you are going to have surgery to

remove a cataract, your physician may ask you to stop taking Duodart for a while before

your operation. Tell your ophthalmologist before your operation that you are taking Duodart

or tamsulosin (or have previously taken these medicines). Your ophthalmologist will need

to take appropriate precautions to help prevent complications during your operation.

Women, children and adolescents must avoid contact with leaking Duodart capsules,

because the active ingredient can be absorbed through the skin. Wash the affected

area immediately with soap and water if there is any contact with the skin.

Use a condom during sexual intercourse. Dutasteride has been found in the semen

of men taking Duodart. If your partner is or may be pregnant, you must avoid exposing

her to your semen as dutasteride may affect the normal development of a male fetus.

Dutasteride has been shown to decrease sperm count, semen volume and sperm motility.

This could reduce your fertility.

Duodart affects a blood test for PSA (prostate-specific antigen), which is sometimes

used to detect prostate cancer. Your physician should be aware of this effect and can

still use the test to detect prostate cancer. If you are having a blood test for PSA, tell

your physician that you are taking Duodart. Men taking Duodart should have their PSA

tested regularly.

In a clinical study of men at increased risk of prostate cancer, men who took dutasteride

developed a severe form of prostate cancer more often than men who did not take

dutasteride. The effect of dutasteride on this serious form of prostate cancer is not

clear.

Duodart may cause breast enlargement and tenderness. If this becomes troublesome,

or if you notice breast lumps or nipple discharge you should talk to your physician about

these changes as these may be signs of a serious condition, such as breast cancer.

→

Contact your physician or pharmacist if you have any questions about taking

Duodart.

Children and adolescents

Do not use Duodart in children and adolescents under the age of 18.

Drug interactions:

If you are taking, or have recently taken, other medicines including non-prescription

medicines and nutritional supplements, tell the physician or the pharmacist.

Don’t take Duodart with these medicines:

other alpha-blockers (for enlarged prostate or high blood pressure)

Duodart is not recommended with these medicines:

ketoconazole (used to treat fungal infections)

Some medicines can react with Duodart and may make it more likely that you’ll have side

effects. These medicines include:

PDE5 inhibitors (used to help achieve or maintain an erection) such as: vardenafil,

sildenafil citrate and tadalafil

verapamil or diltiazem (for high blood pressure)

ritonavir or indinavir (for HIV - human immunodeficiency virus)

itraconazole (for fungal infections)

nefazodone (an antidepressant)

cimetidine (for stomach ulcers)

warfarin (for blood clotting)

erythromycin (an antibiotic used to treat infections)

paroxetine (an antidepressant)

terbinafine (used to treat fungal infections)

diclofenac (used to treat pain and inflammation).

→

Tell your physician if you are taking any of these medicines.

Using the medicine and food

Take Duodart 30 minutes after the same meal each day.

Pregnancy, breast-feeding and fertility

Duodart is prohibited for use in women.

Pregnancy

Women who are pregnant (or may be pregnant) must avoid contact with leaking

capsules. Dutasteride is absorbed through the skin and can affect the normal development

of a male fetus. This risk is increased during the first 16 weeks of pregnancy.

Use a condom during sexual intercourse. Dutasteride has been found in the semen of

men taking Duodart. If your partner is or may be pregnant, you must avoid exposing her

to your semen.

→

Tell your physician if a pregnant woman has come into contact with Duodart.

Fertility

Duodart has been shown to reduce sperm count, semen volume and sperm movement.

Therefore male fertility may be reduced.

Driving and using machines

Duodart may cause dizziness in some people, so it may affect your ability to drive or operate

machinery safely.

→

Don’t drive or operate machinery if you are affected in this way.

Important information about some ingredients of the medicine

Duodart contains the colouring agent Sunset yellow (E110), which is also called FD&C yellow 6,

which may cause an allergic reaction.

Duodart contains lecithin from soya, which may contain soya oil. If you are allergic to peanuts

or soya, do not use this medicinal product.

3. How should you use the medicine?

Always use this preparation according to the physician’s instructions. Check with the

physician or the pharmacist if you are uncertain about the dosage and treatment regimen

of the preparation.

The dosage and treatment regimen will be determined only by the physician.

The usual dosage is generally one capsule taken once a day, 30 minutes after the

same meal each day.

Do not exceed the recommended dose

Swallow the capsule whole with water. Do not chew and do not open and disperse the

contents of the capsule since contact with the contents of the capsule may make your

mouth or throat sore.

Instructions for opening the bottle package - to remove the cap, press down, while

simultaneously twisting to the left (turning counterclockwise).

Instructions for closing the bottle package - place cap on top of open end and twist to

the right (turning clockwise) until it locks.

If you have taken an overdose you should consult your physician or pharmacist.

If you took an overdose, or if a child has accidentally swallowed the medicine, refer immediately

to a physician or to a hospital emergency room and bring the package of the medicine

with you.

If you forgot to take this medicine at the scheduled time, do not take a double dose. Take

the next dose at the usual time and consult the physician.

Persist with the treatment as recommended by the physician. Even if there is an improvement in

your health, do not stop the treatment with the medicine without consulting the physician.

If you do not take the medicine regularly, the monitoring of your PSA levels may be

affected.

Do not take medicines in the dark! Check the label and the dose each time you take

a medicine. Wear glasses if you need them.

If you have any other questions regarding the use of the medicine, consult the physician

or the pharmacist.

4. Side effects

As with any medicine, use of Duodart may cause side effects in some of the users. Do not

be alarmed by reading the list of side effects. You may not experience any of them.

Allergic reaction

The signs of an allergic reaction can include:

skin rash (which can be itchy)

hives (like a nettle rash)

swelling of the eyelids, face, lips, arms or legs.

→

Tell your physician immediately if you get any of these symptoms, and stop using

Duodart.

Dizziness, lightheadedness and fainting

Duodart can cause dizziness, lightheadedness and on rare occasions fainting. Take care when

moving from a lying down or sitting position to a sitting or standing position, particularly if

you wake up in the night, until you know how this medicine affects you. If you feel dizzy or

lightheaded at any time during treatment, sit or lie down until the symptoms pass.

Serious skin reactions

The signs of serious skin reactions can include:

a widespread rash with blisters and peeling skin, particularly around the mouth,

nose, eyes and genitals (Stevens-Johnson syndrome).

→

Contact your physician immediately if you notice any of these symptoms and stop

using Duodart.

Additional side effects

Common side effects

effects that occur in up to 1 user in ten men taking Duodart:

impotence (not able to achieve or maintain an erection)*

decreased sex drive (libido)*

difficulty with ejaculation, such as a decrease in the amount of semen released during

sex*

tenderness or enlargement of the breast (gynecomastia)

dizziness.

* In a small number of people some of these events may continue after discontinuation of

Duodart.

Uncommon side effects

effects that occur in up to 1 user in 100 men:

heart failure (heart becomes less efficient at pumping blood around the body. You may

have symptoms such as shortness of breath, extreme tiredness and swelling in your

ankles and legs)

low blood pressure on standing

fast heartbeat (palpitations)

constipation, diarrhoea, vomiting, nausea

weakness or loss of strength

headache

itchy, blocked or runny nose (rhinitis)

skin rash, hives, itching

hair loss (usually from the body) or hair growth.

Rare side effects

effects that occur in up to 1 user in 1,000 men:

swelling of the eyelids, face, lips, arms or legs (angioedema)

fainting.

Very rare side effects

effects that occur in up to 1 user in 10,000 men:

persistent painful erection

serious skin reactions (Stevens-Johnson syndrome).

Side effects of unknown frequency

Other side effects have occurred in a small number of men, but their frequency is not known

(The frequency cannot be estimated from available data):

abnormal or fast heartbeat (arrhythmia or tachycardia or atrial fibrillation)

shortness of breath

depression

pain and swelling in your testicles

nosebleed

severe skin rash

vision changes (blurred vision or impaired vision)

dry mouth.

→

If a side effect occurs, if any of the side effects get worse or when you suffer from

a side effect that has not been mentioned in the leaflet, you should consult the

physician.

Side effects can be reported to the Ministry of Health by clicking on the link

“Report Side Effects of Drug Treatment” found on the Ministry of Health homepage

(www.health.gov.il) that directs you to the online form for reporting side effects, or by entering

the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMe

dic@moh.gov.il

5. How to store the medicine?

Avoid poisoning! This medicine and any other medicine should be kept in a closed place

out of the reach and sight of children and/or infants in order to avoid poisoning. Do not

induce vomiting without an explicit instruction from the physician.

Do not use the medicine after the expiry date (exp. date) appearing on the package. The

expiry date refers to the last day of that month.

Do not store above 30°C. Use within 3 months from first opening and no later than the

expiry date of the product.

6. Additional information

In addition to the active ingredients the medicine also contains:

hard capsule shell: hypromellose, carrageenan (E407), potassium chloride, titanium

dioxide (E171), iron oxide red (E172), FD&C yellow 6 [Sunset yellow (E110)], carnauba

wax, maize starch.

inside the hard capsule: mono-di-glycerides of caprylic/capric acid and butylhydroxytoluene,

gelatin, glycerol, titanium dioxide (E171), iron oxide yellow (E172), triglycerides (medium

chain), lecithin (may contain soya oil), cellulose microcrystalline, methacrylic acid - ethyl

acrylate copolymer (containing polysorbate 80 and sodium laurilsulfate), talc, triethyl

citrate.

black print ink (SW-9010 or SW-9008): shellac, propylene glycol, iron oxide black (E172),

potassium hydroxide (in Black Ink SW-9008 only).

What does the medicine look like and what is the content of the package:

This medicine is an oblong, hard, brown and orange capsule on which GS 7CZ is printed

in black ink. The capsules are available in packs of 7, 30 and 90 capsules.

Not all pack sizes may be marketed.

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

Manufacturer: Catalent Germany Schorndorf GmbH, Schorndorf, Germany.

The format of this leaflet was determined by the Ministry of Health and its content was

checked and approved by the Ministry of Health in April 2017 and was updated in

accordance with Ministry of Health guidelines in March 2018.

Registration number of the medicine in the National Drug Registry of the Ministry of

Health: 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 PT v5.1C

Duo PT v5.1C

Page 1 of 19

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

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.

Page 2 of 19

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 3 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 alpha

- 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 alpha

-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.

Page 4 of 19

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). Alpha

- 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

Page 5 of 19

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 alpha

- adrenoceptor antagonists could lead to

enhanced hypotensive effects. Dutasteride-tamsulosin should not be used in combination with other alpha

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.

Page 6 of 19

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

Page 7 of 19

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.

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+

tasmulosin

a

Dutasteride

Tamsulosin

c

Nervous system

disorders

Syncope

Rare

Dizziness

Common

Common

Headache

Uncommon

Cardiac disorders

Cardiac failure (Composite

term

Uncommon

Uncommon

Palpitations

Uncommon

Vascular disorders

Orthostatic hypotension

Uncommon

Respiratory, thoracic

and mediastinal

disorders

Rhinitis

Uncommon

Gastrointestinal

disorders

Constipation

Uncommon

Diarrhoea

Uncommon

Nausea

Uncommon

Vomitting

Uncommon

Skin and

subcutaneous

disorders

Angioedema

Rare

Stevens-Johnson syndrome

Very Rare

Urticaria

Uncommon

Page 8 of 19

Rash

Uncommon

Pruritis

Uncommon

Reproductive system

and breast disorders

Priapism

Very rare

Impotence

Common

Common

Altered (decreased) libido

Common

Common

Ejaculation disorders

Common

Common

Common

Breast disorders

Common

Common

General disorders

and administration

site disorders

Asthenia

Uncommon

Dutasteride + tamsulosin: from CombAT study - the frequencies of these adverse events decrease over time

of treatment, from year 1 to year 4.

Dutasteride: from BPH monotherapy clinical studies.

Tamsulosin: from EU Core Safety Profile for tamsulosin.

REDUCE study (see section 5.1).

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.

Includes breast tenderness and breast enlargement.

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.

Page 9 of 19

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 alpha

- 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/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

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

Page 10 of 19

Dutasteride-tamsulosin is a combination of two drugs: dutasteride, a dual 5 α-reductase inhibitor (5 ARI) and

tamsulosin hydrochloride, an antagonist of α

and α

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 α

and α

adrenergic receptors in the stromal

prostatic smooth muscle and bladder neck. Approximately 75% of the α

-receptors in the prostate are of the

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:

Page 11 of 19

Parameter

Time-point

Combination

Dutasteride

Tamsulosin

AUR or BPH related

surgery (%)

Incidence at Month 48

11.9a

Clinical progression*

Month 48

12.6

17.8b

21.5a

IPSS (units)

[Baseline]

Month 48 (Change from Baseline)

[16.6]

-6.3

[16.4]

-5.3b

[16.4]

-3.8a

Qmax (mL/sec)

[Baseline]

Month 48 (Change from Baseline)

[10.9]

[10.6]

[10.7]

0.7a

Prostate Volume (ml)

[Baseline]

Month 48 (% Change from Baseline)

[54.7]

-27.3

[54.6]

-28.0

[55.8]

+4.6a

Prostate Transition

Zone Volume (ml)#

[Baseline]

Month 48 (% Change from Baseline)

[27.7]

-17.9

[30.3]

-26.5

[30.5]

18.2a

BPH Impact Index

(BII) (units)

[Baseline]

Month 48 (Change from Baseline)

[5.3]

-2.2

[5.3]

-1.8b

[5.3]

-1.2a

IPSS Question 8

(BPH-related Health

Status) (units)

[Baseline]

Month 48 (Change from Baseline)

[3.6]

-1.5

[3.6]

-1.3b

[3.6]

-1.1a

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.

Page 12 of 19

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

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

Page 13 of 19

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.

Page 14 of 19

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.

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

Page 15 of 19

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 (C

) 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.

Page 16 of 19

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 ≤ CL

< 70 mL/min/1.73m

) or moderate-severe (10 ≤ CL

< 30 mL/min/1.73m

) renal impairment and

6 normal subjects (CL

> 90 mL/min/1.73m

). 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 (CL

< 10 mL/min/1.73m

) 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 17 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 alpha

- 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)

Page 18 of 19

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

Page 19 of 19

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