Blugral 100 mg film-coated tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Buy It Now

Active ingredient:
Sildenafil citrate
Available from:
Niche Generics Limited
ATC code:
G04BE; G04BE03
INN (International Name):
Sildenafil citrate
Dosage:
100 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Drugs used in erectile dysfunction; sildenafil
Authorization status:
Not marketed
Authorization number:
PA1063/048/003
Authorization date:
2013-01-11

Package leaflet: Information for the user

Blugral 25 mg Film-Coated Tablets

Blugral 50 mg Film-Coated Tablets

Blugral 100 mg Film-Coated Tablets

Sildenafil

Read all of this leaflet carefully before you start taking this medicine because it

contains important information for you.

■ Keep this leaflet. You may need to read it again.

■ If you have any further questions, ask your doctor, pharmacist or nurse.

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

harm them, even if their signs of illness are the same as yours.

■ If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Blugral is and what it is used for

2. What you need to know before you take Blugral

3. How to take Blugral

4. Possible side effects

5. How to store Blugral

6. Contents of the pack and other information

1. What Blugral is and what it is used for

Blugral contains the active substance sildenafil which belongs to a group of medicines

called phosphodiesterase type 5 (PDE 5) inhibitors. It works by helping to relax the blood

vessels in your penis, allowing blood to flow into your penis when you get sexually

excited. Blugral will only help you to get an erection if you are sexually stimulated.

Blugral is a treatment for adult men with erectile dysfunction, sometimes known as

impotence. This is when a man cannot get, or keep a hard, erect penis suitable for sexual

activity.

2. What you need to know before you take Blugral

Do not take Blugral:

■ if you are allergic to sildenafil or any of the other ingredients of this medicine (listed in

section 6).

■ if you are taking medicines called nitrates, as the combination may lead to a dangerous

fall in your blood pressure. Tell your doctor if you are taking any of these medicines

which are often given for relief of angina pectoris (or “chest pain”). If you are not certain,

ask your doctor or pharmacist.

■ if you are using any of the medicines known as nitric oxide donors such as amyl nitrite

(“poppers”), as the combination may also lead to a dangerous fall in your blood pressure.

PA1063/048/001-003

- 1 -

March 2018

■ if you are taking riociguat. This drug is used to treat pulmonary arterial hypertension

(i.e., high blood pressure in the lungs) and chronic thromboembolic pulmonary

hypertension (i.e., high blood pressure in the lungs secondary to blood clots). PDE5

inhibitors, such as Blugral have been shown to increase the hypotensive effects of this

medicine. If you are taking riociguat or are unsure tell your doctor.

■ if you have a severe heart or liver problem.

■ if you have recently had a stroke or a heart attack, or if you have low blood pressure.

■ if you have certain rare inherited eye diseases (such as

retinitis pigmentosa

■ if you have ever had loss of vision because of non-arteritic anterior ischaemic optic

neuropathy (NAION).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Blugral

■ if you have sickle cell anaemia (an abnormality of red blood cells), leukaemia (cancer

of blood cells), multiple myeloma (cancer of bone marrow).

■ if you have a deformity of your penis or Peyronie’s Disease.

■ if you have problems with your heart. Your doctor should carefully check whether your

heart can take the additional strain of having sex.

■ if you currently have a stomach ulcer, or a bleeding problem (such as haemophilia).

■ if you experience sudden decrease or loss of vision, stop taking Blugral and contact

your doctor immediately.

You should not use Blugral with any other oral or local treatments for erectile

dysfunction.

You should not use Blugral with treatments for pulmonary arterial hypertension (PAH)

containing sildenafil or any other PDE5 inhibitors.

You should not take Blugral if you do not have erectile dysfunction.

You should not take Blugral if you are a woman.

Special considerations for patients with kidney or liver problems

You should tell your doctor if you have kidney or liver problems. Your doctor may

decide on a lower dose for you.

Children and adolescents

Blugral should not be given to individuals under the age of 18.

Other medicines and Blugral

Tell your doctor or pharmacist if you are taking, have recently taken or might take any

other medicines.

Blugral tablets may interfere with some medicines, especially those used to treat chest

pain. In the event of a medical emergency, you should tell your doctor, pharmacist or

nurse that you have taken Blugral and when you did. Do not take Blugral with other

medicines unless your doctor tells you that you can.

■ You should not take Blugral if you are taking medicines called

nitrates

as the

combination of these medicines may lead to a dangerous fall in your blood pressure.

PA1063/048/001-003

- 2 -

March 2018

Always tell your doctor, pharmacist or nurse if you are taking any of these medicines that

are often used for the relief of angina pectoris (or “chest pain”).

■ You should not take Blugral if you are using any of the medicines known as

nitric

oxide donors

such as amyl nitrite (“poppers”). The combination may also lead to a

dangerous fall in your blood pressure.

Tell your doctor or pharmacist if you are already taking riociguat.

■ If you are taking medicines known as protease inhibitors, such as for the treatment of

HIV, your doctor may start you on the lowest dose (25 mg) of Blugral.

■ Some patients who take alpha-blocker therapy for the treatment of high blood pressure

or prostate enlargement may experience dizziness or light-headedness, which may be

caused by low blood pressure upon sitting or standing up quickly. Certain patients have

experienced these symptoms when taking Blugral with alpha-blockers. This is most likely

to happen within 4 hours after taking Blugral. To reduce the chance that these symptoms

might happen, you should be on a regular daily dose of your alpha-blocker before you

start Blugral. Your doctor may start you on a lower dose (25 mg) of Blugral.

Blugral with food, drink and alcohol

Blugral can be taken with or without food. However, you may find that Blugral takes

longer to start working if you take it with a heavy meal.

Drinking alcohol can temporarily impair your ability to get an erection. To get the

maximum benefit from your medicine, you are advised not to drink excessive amounts of

alcohol before taking Blugral.

Pregnancy, breast-feeding and fertility

Blugral is not indicated for use by women.

Driving and using machines

Blugral can cause dizziness and can affect vision. You should be aware of how you react

to Blugral before you drive or use machinery.

Blugral contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, such as

lactose, contact your doctor before taking Blugral.

3. How to take Blugral

Always take this medicine exactly as your doctor or pharmacist has told you. Check with

your doctor or pharmacist if you are not sure.

The recommended starting dose is 50 mg.

You should not take Blugral more than once a day.

PA1063/048/001-003

- 3 -

March 2018

You should take Blugral about one hour before you plan to have sex. Swallow the tablet

whole with a glass of water.

If you feel that the effect of Blugral is too strong or too weak, talk to your doctor or

pharmacist.

Blugral will only help you to get an erection if you are sexually stimulated. The amount

of time Blugral takes to work varies from person to person, but it normally takes between

half an hour and one hour. You may find that Blugral takes longer to work if you take it

with a heavy meal.

If Blugral does not help you to get an erection, or if your erection does not last long

enough for you to complete sexual intercourse, you should tell your doctor.

If you take more Blugral than you should

You may experience an increase in side effects and their severity. Doses above 100 mg

do not increase the efficacy.

You should not take more tablets than your doctor tells you to.

Contact your doctor if

you take more tablets than you should.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist

or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets

them. The side effects reported in association with the use of Blugral are usually mild to

moderate and of a short duration.

If you experience any of the following serious side effects stop taking Blugral and

seek medical help immediately:

An allergic reaction - this occurs

uncommonly

(may affect up to 1 in 100 people)

Symptoms include sudden wheeziness, difficulty in breathing or dizziness,

swelling of the eyelids, face, lips or throat.

Chest pains - this occurs

uncommonly

If this occurs during or after intercourse:

- Get in a semi-sitting position and try to relax.

Do not use nitrates

to treat your chest pain.

Prolonged and sometimes painful erections - this occurs

rarely

(may affect up to

1 in 1,000 people)

If you have an erection which lasts for more than 4 hours, you should contact a

doctor immediately.

A sudden decrease or loss of vision - this occurs

rarely

Serious skin reactions - this occurs

rarely

Symptoms may include severe peeling and swelling of the skin, blistering of the

mouth, genitals and around the eyes, fever.

PA1063/048/001-003

- 4 -

March 2018

Seizures or fits - this occurs

rarely

Other Side effects

Very common

(may affect more than 1 in 10 people): headache.

Common

(may affect up to 1 in 10 people): nausea, facial flushing, hot flush (symptoms

include a sudden feeling of heat in your upper body), indigestion, colour tinge to vision,

blurred vision, visual disturbance, stuffy nose and dizziness.

Uncommon

(may affect up to 1in 100 people): vomiting, skin rash, eye irritation,

bloodshot eyes/red eyes, eye pain, seeing flashes of light, visual brightness, light

sensitivity, watery eyes, pounding heartbeat, rapid heartbeat, high blood pressure, low

blood pressure, muscle pain, feeling sleepy, reduced sense of touch, vertigo, ringing in

the ears, dry mouth, blocked or stuffy sinuses, inflammation of the lining of the nose

(symptoms include runny nose, sneezing and stuffy nose), upper abdominal pain, gastro-

oesophageal reflux disease (symptoms include heartburn), presence of blood in urine,

pain in the arms or legs, nosebleed, feeling hot and feeling tired.

Rare

(may affect up to 1 in 1,000 people): fainting, stroke, heart attack, irregular

heartbeat, temporary decreased blood flow to parts of the brain, feeling of tightening of

the throat, numb mouth, bleeding at the back of the eye, double vision, reduced sharpness

of vision, abnormal sensation in the eye, swelling of the eye or eyelid, small particles or

spots in your vision, seeing halos around lights, dilation of the pupil of the eye,

discolouration of the white of the eye, penile bleeding, presence of blood in semen, dry

nose, swelling of the inside of the nose, feeling irritable and sudden decrease or loss of

hearing.

From post-marketing experience cases of unstable angina (a heart condition) and sudden

death have been reported rarely. Of note, most, but not all, of the men who experienced

these side effects had heart problems before taking this medicine. It is not possible to

determine whether these events were directly related to Blugral.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any

possible side effects not listed in this leaflet.

You can also report side effects directly via HPRA Pharmacovigilance, Earlsfort Terrace,

IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie;

E-mail: medsafety@hpra.ie

By reporting side effects you can help provide more information on the safety of this

medicine.

5. How to store Blugral

Keep this medicine out of the sight and reach of children.

PA1063/048/001-003

- 5 -

March 2018

Do not use this medicine after the expiry date which is stated on the carton and blister

after EXP. The expiry date refers to the last day of that month.

Store below 30°C.

Store in the original package, in order to protect from moisture.

Do not throw away any medicines via wastewater or household waste. Ask your

pharmacist how to throw away medicines you no longer use. These measures will help

protect the environment.

6. Contents of the pack and other information

What Blugral contains

The active substance is sildenafil. Each tablet contains 25mg, 50 mg or 100mg of

sildenafil (as the citrate salt).

The other ingredients are:

Tablet core: Lactose monohydrate, Maize Starch, Sodium starch glycolate (Type A),

Povidone K29/32, colloidal anhydrous silica, Magnesium Stearate (E572).

Film-coating: hypromellose, Macrogol 400, Macrogol 6000, Titanium Dioxide (E171),

Indigo Carmine Aluminium Lake (E132), Sodium laurilsulfate

What Blugral looks like and contents of the pack

Blugral 25mg film-coated tablets are blue rounded diamond -shaped, biconvex, film-

coated tablets, marked “U” debossed on one side and “25” on the other.

Blugral 50mg film-coated tablets are blue rounded diamond-shaped, biconvex, film-

coated tablets, marked “U” debossed on one side and “50” on the other.

Blugral 100mg film-coated tablets are blue rounded diamond-shaped, biconvex, film-

coated tablets, marked “U” debossed on one side and “100” on the other.

The tablets are provided in blister packs containing 2, 4, 8 or 12 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Niche Generics Limited

1 The Cam Centre, Wilbury Way,

Hitchin, Hertfordshire SG4 0TW,

United Kingdom

Manufacturer

Niche Generics Limited, Unit 5, 151 Baldoyle Industrial Estate, Dublin 13, Ireland

This medicinal product is authorised in the Member States of the EEA under the

following names:

Ireland: Blugral 25mg, 50mg, 100mg Film-coated tablets

Italy: Blugral 25mg, 50mg, 100mg Compresse rivestite con film

Greece: Blugral 25mg, 50mg, 100mg Επικαλυμμένα δισκία

Cyprus: Blugral 25mg, 50mg, 100mg Επικαλυμμένα δισκία

PA1063/048/001-003

- 6 -

March 2018

This leaflet was last

revised in

March 2018

PA1063/048/001-003

- 7 -

March 2018

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Blugral 100 mg film coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 100mg tablet contains 100mg of sildenafil (as citrate)

Excipient with known effect: lactose monohydrate 268.92mg

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet.

Blue rounded diamond-shaped, biconvex, film-coated tablets, marked “U” debossed on one side and “100” on the

other.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Blugral is indicated in adult men with erectile dysfunction, which is the inability to achieve or maintain a penile

erection sufficient for satisfactory sexual performance.

In order for Blugral to be effective, sexual stimulation is required.

4.2 Posology and method of administration

Posology

Use in adults:

The recommended dose is 50 mg taken as needed approximately one hour before sexual activity. Based on efficacy and

tolerability, the dose may be increased to 100 mg or decreased to 25 mg.

The maximum recommended dose is 100 mg.

The maximum recommended dosing frequency is once per day. If Blugral is taken with food, the onset of activity may

be delayed compared to the fasted state (see section 5.2).

Special populations

Elderly:

Dosage adjustments are not required in elderly patients (

65 years old).

Renal impairment:

The dosing recommendations described in 'Use in adults'

apply to patients with mild to moderate renal impairment

(creatinine clearance = 30-80 mL/min).

Since sildenafil clearance is reduced in patients with severe renal impairment (creatinine clearance <30 mL/min) a 25

mg dose should be considered. Based on efficacy and tolerability, the dose may be increased step-wise to 50 mg up to

100 mg as necessary.

Hepatic impairment:

Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25 mg dose should be

considered. Based on efficacy and tolerability, the dose may be increased step-wise to 50 mg up to 100 mg as necessary

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

1

Paediatric population:

Blugral is not indicated for individuals below 18 years of age.

Use in patients taking other medicines:

With the exception of ritonavir for which co-administration with sildenafil is not advised (see section 4.4) a starting

dose of 25 mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors (see section

4.5).

In order to minimise the potential for developing postural hypotension in patients receiving alpha-blocker treatment,

patients should be stabilised on alpha-blocker therapy prior to initiating sildenafil treatment. In addition, initiation of

sildenafil at a dose of 25 mg should be considered (see sections 4.4 and 4.5).

Method of administration

For oral use.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway (see section

5.1), sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide

donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated.

The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, such as riociguat, is

contraindicated as it may potentially lead to symptomatic hypotension (see section 4.5).

Agents for the treatment of erectile dysfunction, including sildenafil, should not be used in men for whom sexual

activity is inadvisable (e.g. patients with severe cardiovascular disorders such as unstable angina or severe cardiac

failure).

Blugral is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic

optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor

exposure (see section 4.4).

The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore

contraindicated: severe hepatic impairment, hypotension (blood pressure <90/50 mmHg), recent history of stroke or

myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of

these patients have genetic disorders of retinal phosphodiesterases).

4.4 Special warnings and precautions for use

A medical history and physical examination should be undertaken to diagnose erectile dysfunction and determine

potential underlying causes, before pharmacological treatment is considered.

Cardiovascular risk factors

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascular status of their

patients, since there is a degree of cardiac risk associated with sexual activity.

Sildenafil has vasodilator properties,

resulting in mild and transient decreases in blood pressure (see section 5.1). Prior to prescribing sildenafil, physicians

should carefully consider whether their patients with certain underlying conditions could be adversely affected by such

vasodilatory effects, especially in combination with sexual activity. Patients with increased susceptibility to

vasodilators include those with left ventricular outflow obstruction (e.g., aortic stenosis, hypertrophic obstructive

cardiomyopathy), or those with the rare syndrome of multiple system atrophy manifesting as severely impaired

autonomic control of blood pressure.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

2

Sildenafil potentiates the hypotensive effect of nitrates (see section 4.3).

Serious cardiovascular events, including myocardial infarction, unstable angina, sudden cardiac death, ventricular

arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension have been reported

post-marketing in temporal association with the use of Sildenafil. Most, but not all, of these patients had pre-existing

cardiovascular risk factors. Many events were reported to occur during or shortly after sexual intercourse and a few

were reported to occur shortly after the use of Sildenafil without sexual activity. It is not possible to determine whether

these events are related directly to these factors or to other factors.

Priapism

Agents for the treatment of erectile dysfunction, including sildenafil, should be used with caution in patients with

anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or in patients who

have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple myeloma or leukaemia).

Prolonged erections and priapism have been reported with sildenafil in post-marketing experience. In the event of an

erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not

treated immediately, penile tissue damage and permanent loss of potency could result.

Concomitant use with other PDE5 inhibitors or other treatments for erectile dysfunction

The safety and efficacy of combinations of sildenafil with other PDE5 Inhibitors, or other pulmonary arterial

hypertension (PAH) treatments containing sildenafil, or other treatments for erectile dysfunction have not been studied.

Therefore the use of such combinations is not recommended.

Effects on vision

Cases of visual defects have been reported spontaneously in connection with the intake of sildenafil and other PDE5

inhibitors (see section 4.8).Cases of non-arteritic anterior ischaemic optic neuropathy, a rare condition, have been

reported spontaneously and in an observational study in connection with the intake of sildenafil and PDE5 inhibitors

(see section 4.8) Patients should be advised that in the event of any sudden visual defect, they should stop taking

Blugral and consult a physician immediately (see section 4.3).

Concomitant use with ritonavir

Co-administration of sildenafil with ritonavir is not advised (see section 4.5).

Concomitant use with alpha-blockers

Caution is advised when sildenafil is administered to patients taking an alpha-blocker, as the co-administration may

lead to symptomatic hypotension in a few susceptible individuals (see section 4.5). This is most likely to occur within 4

hours post sildenafil dosing. In order to minimise the potential for developing postural hypotension, patients should be

hemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Initiation of sildenafil at a

dose of 25 mg should be considered (see section 4.2). In addition, physicians should advise patients what to do in the

event of postural hypotensive symptoms.

Effect on bleeding

Studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside in

vitro. There is no safety information on the administration of sildenafil to patients with bleeding disorders or active

peptic ulceration.

Therefore sildenafil should be administered to these patients only after careful benefit-risk

assessment.

Lactose

Blugral film coated tablets contain lactose. Men with rare hereditary problems of galactose intolerance, Lapp lactase

deficiency or glucose-galactose malabsorption should not take this medicine.

Women

Blugral is not indicated for use by women.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on sildenafil

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

3

In vitro studies:

Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9

(minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance

and inducers of these isoenzymes

may increase sildenafil clearance

In vivo studies:

Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance when co-

administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, cimetidine).

Although no increased

incidence of adverse events was observed in these patients, when sildenafil is administered concomitantly with

CYP3A4 inhibitors, a starting dose of 25 mg should be considered.

Co-administration of the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500

mg twice daily) with sildenafil (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a

1,000% (11-fold) increase in sildenafil plasma AUC. At 24 hours, the plasma levels of sildenafil were still

approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was administered alone.

This is

consistent with ritonavir’s marked effects on a broad range of P450 substrates.

Sildenafil had no effect on ritonavir

pharmacokinetics. Based on these pharmacokinetic results co-administration of sildenafil with ritonavir is not advised

(see section 4.4) and in any event the maximum dose of sildenafil should under no circumstances exceed 25 mg within

48 hours.

Co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg three times a

day) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in

sildenafil AUC.

Sildenafil had no effect on saquinavir pharmacokinetics (see section 4.2).

Stronger CYP3A4

inhibitors such as ketoconazole and itraconazole would be expected to have greater effects.

When a single 100 mg dose of sildenafil was administered with erythromycin, a specific CYP3A4 inhibitor, at steady

state (500 mg twice daily for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC).

In normal

healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC,

Cmax, tmax, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating metabolite.

Cimetidine (800 mg), a cytochrome P450 inhibitor and non-specific CYP3A4 inhibitor, caused a 56% increase in

plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers.

Grapefruit juice is a weak inhibitor of CYP3A4 gut wall metabolism and may give rise to modest increases in plasma

levels of sildenafil.

Single doses of antacid (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability of sildenafil.

Although specific interaction studies were not conducted for all medicinal products, population pharmacokinetic

analysis showed no effect of concomitant medication on sildenafil pharmacokinetics when grouped as CYP2C9

inhibitors (such as tolbutamide, warfarin, phenytoin), CYP2D6 inhibitors (such as selective serotonin reuptake

inhibitors, tricyclic antidepressants), thiazide and related diuretics, loop and potassium sparing diuretics, angiotensin

converting enzyme inhibitors, calcium channel blockers, beta-adrenoreceptor antagonists or inducers of CYP450

metabolism (such as rifampicin, barbiturates). In a study of healthy male volunteers, co-administration of the

endothelin antagonist, bosentan, (an inducer of CYP3A4 [moderate], CYP2C9 and possibly of CYP2C19) at steady

state (125 mg twice a day) with sildenafil at steady state (80 mg three times a day) resulted in 62.6% and 55.4%

decrease in sildenafil AUC and Cmax, respectively. Therefore, concomitant administration of strong CYP3A4

inducers, such as rifampin, is expected to cause greater decreases in plasma concentrations of sildenafil.

Nicorandil is a hybrid of potassium channel activator and nitrate. Due to the nitrate component it has the potential to

result in a

serious interaction with sildenafil.

Effects of sildenafil on other medicinal products

In vitro studies:

Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC

> 150 µM).

Given sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that

sildenafil will alter the clearance of substrates of these isoenzymes.

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

4

There are no data on the interaction of sildenafil and non-specific phosphodiesterase inhibitors such as theophylline or

dipyridamole.

In vivo studies:

Consistent with its known effects on the nitric oxide/cGMP pathway (see section 5.1), sildenafil was shown to

potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors or nitrates in any form

is therefore contraindicated (see section 4.3).

Riociguat: Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors were

combined with riociguat.

In clinical studies, riociguat has been shown to augment the hypotensive effects of PDE5

inhibitors.

There was no evidence of favourable clinical effect of the combination in the population studied.

Concomitant use of riociguat with PDE5 inhibitors, including sildenafil, is contraindicated (see section 4.3).

Concomitant administration of sildenafil to patients taking alpha-blocker therapy may lead to symptomatic hypotension

in a few susceptible individuals. This is most likely to occur within 4 hours post sildenafil dosing (see sections 4.2 and

4.4). In three specific drug-drug interaction studies, the alpha-blocker doxazosin (4 mg and 8 mg) and sildenafil (25

mg, 50 mg, or 100 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH)

stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine blood pressure of 7/7

mmHg, 9/5 mmHg, and 8/4 mmHg, and mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4

mmHg, and 4/5 mmHg, respectively, were observed. When sildenafil and doxazosin were administered simultaneously

to patients stabilized on doxazosin therapy, there were infrequent reports of patients who experienced symptomatic

postural hypotension. These reports included dizziness and light-headedness, but not syncope.

No significant interactions were shown when sildenafil (50 mg) was co-administered with tolbutamide (250 mg) or

warfarin (40 mg), both of which are metabolised by CYP2C9.

Sildenafil (50 mg) did not potentiate the increase in bleeding time caused by acetyl salicylic acid (150 mg).

Sildenafil (50 mg) did not potentiate the hypotensive effects of alcohol in healthy volunteers with mean maximum

blood alcohol levels of 80 mg/dL.

Pooling of the following classes of antihypertensive medication: diuretics, beta-blockers, ACE inhibitors, angiotensin II

antagonists, antihypertensive medicinal products (vasodilator and centrally-acting), adrenergic neurone blockers,

calcium channel blockers and alpha-adrenoceptor blockers, showed no difference in the side effect profile in patients

taking sildenafil compared to placebo treatment.

In a specific interaction study, where sildenafil (100 mg) was co-

administered with amlodipine in hypertensive patients, there was an additional reduction on supine systolic blood

pressure of 8 mmHg. The corresponding additional reduction in supine diastolic blood pressure was 7 mmHg. These

additional blood pressure reductions were of a similar magnitude to those seen when sildenafil was administered alone

to healthy volunteers (see section 5.1).

Sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and

ritonavir, both of which are CYP3A4 substrates.

In healthy male volunteers, sildenafil at steady state (80 mg t.i.d.) resulted in a 49.8% increase in

bosentan AUC and a 42% increase in bosentan Cmax (125 mg b.i.d.).

4.6 Fertility, pregnancy and lactation

Blugral is not indicated for use by women.

There are no adequate and well controlled studies in pregnant or breast feeding women

No relevant adverse effects were found in reproduction studies in rats and rabbits following oral administration of

sildenafil.

There was no effects on sperm motility or morphology after single 100mg oral doses of sildenafil in healthy volunteers

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

5

(see section 5.1).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware of how they

react to Blugral, before driving or operating machinery.

4.8 Undesirable effects

Summary of the safety profile

The safety profile of sildenafil is based on 9570 patients in 74 placebo-controlled clinical studies. The most commonly

reported adverse reactions in clinical studies among sildenafil treated patients were headache, flushing, dyspepsia, nasal

congestion, dizziness, nausea, hot flush, visual disturbances, cyanopsia and vision blurred.

Adverse reactions from post-marketing surveillance has been gathered covering an estimated period >10 years.

Because not all adverse reactions are reported to the Marketing Authorisation Holder and included in the safety

database, the frequencies of these reactions cannot be reliably determined.

Tabulated list of adverse reactions

In the table below all medically important adverse reactions, which occurred in clinical trials at an incidence greater

than placebo are listed by system organ class and frequency (very common (

1/10), common (

1/100 to < 1/10),

uncommon (

1/1,000 to < 1/100), rare (

1/10,000 to < 1/1,000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Medically important adverse reactions reported at an incidence greater than placebo in controlled

clinical studies and medically important adverse reactions reported through post-marketing surveillance.

System Organ Class

Adverse Reactions

Infections and infestations

Uncommon

Rhinitis

Immune system disorders

Uncommon

Hypersensitivity

Nervous system disorders

Very common

Headache

Common

Dizziness

Uncommon

Somnolence, Hypoaesthesia

Rare

Cerebrovascular accident, Transient

ischaemic attack, Seizure

, Seizure

recurrence

, Syncope

Eye disorders

Common

Visual colour distortion

, Visual

disturbance, Vision blurred

Uncommon

Lacrimation disorders

Eye pain,

Photophobia, Photopsia, Ocular hyperaemia,

Visual brightness, Conjunctivitis

Rare

Non-arteritic anterior ischaemic optic

neuropathy (NAION)

, Retinal vascular

occlusion

, Retinal haemorrhage,

Arteriosclerotic retinopathy, Retinal

disorder, Glaucoma, Visual field defect,

Diplopia, Visual acuity reduced, Myopia,

Asthenopia, Vitreous floaters, Iris disorder,

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

6

*Reported during post-marketing surveillance only

**Visual colour distortions: Chloropsia, Chromatopsia, Cyanopsia, Erythropsia and Xanthopsia

***Lacrimation disorders: Dry eye, Lacrimal disorder and Lacrimation increased

Reporting of suspected adverse reactions

Mydriasis, Halo vision, Eye oedema, Eye

swelling, Eye disorder, Conjunctival

hyperaemia, Eye irritation, Abnormal

sensation in eye, Eyelid oedema, Scleral

discoloration

Ear and labyrinth disorders

Uncommon

Vertigo, Tinnitus

Rare

Deafness

Vascular disorders

Common

Flushing, Hot flush

Uncommon

Hypertension, Hypotension

Cardiac disorders

Uncommon

Palpitations, Tachycardia

Rare

Sudden cardiac death

, Myocardial

infarction, Ventricular arrhythmia

, Atrial

fibrillation, Unstable angina

Respiratory, thoracic and mediastinal

disorders

Common

Nasal congestion

Uncommon

Epistaxis, Sinus congestion

Rare

Throat tightness, Nasal oedema, Nasal

dryness

Gastrointestinal disorders

Common

Nausea, Dyspepsia

Uncommon

Gastro oesophagael reflux disease, Vomiting,

Abdominal pain upper, Dry mouth

Rare

Hypoaesthesia oral

Skin, subcutaneous and soft tissue

disorders

Uncommon

Rash

Rare

Steven Johnson Syndrome (SJS)

, Toxic

Epidermal Necrolysis (TEN)

Musculoskeletal and connective tissue

disorders

Uncommon

Myalgia, Pain in

extremity

Renal and Urinary disorders

Uncommon

Haematuria

Reproductive system and breast disorders

Rare

Haematospermia, Penile haemorrhage,

Priapism,

Erection increased

General disorders and administration site

conditions

Uncommon

Chest pain, Fatigue, Feeling hot

Rare

Irritability

Investigations

Uncommon

Heart rate increased

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

7

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued

monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any

suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

In single dose volunteer studies of doses up to 800mg, adverse reactions were similar to those seen at lower doses, but

the incidence rates and severities were increased.

Doses of 200mg did not result in increased efficacy but the incidence

of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, altered vision) was increased.

In cases of overdose, standard supportive measures should be adopted as required.

Renal dialysis is not expected to

accelerate clearance as sildenafil is highly bound to plasma proteins and not eliminated in the urine.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Urologicals; Drugs used in erectile dysfunction.

ATC Code: G04B E03

Mechanism of action

Sildenafil is an oral therapy for erectile dysfunction.

In the natural setting, i.e. with sexual stimulation, it restores

impaired erectile function by increasing blood flow to the penis.

The physiological mechanism responsible for erection of the penis involves the release of nitric oxide (NO) in the

corpus cavernosum during sexual stimulation.

Nitric oxide then activates the enzyme guanylate cyclase, which results

in increased levels of cyclic guanosine monphosphate (cGMP), producing smooth muscle relaxation in the corpus

cavernosum and allowing inflow of blood.

Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus

cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on

erections.

Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the

relaxant effect of NO on this tissue.

When the NO/cGMP pathway is activated, as occurs with sexual stimulation,

inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP.

Therefore sexual stimulation

is required in order for sildenafil to produce its intended beneficial pharmacological effects.

Pharmacodynamic effects

Studies in vitro have shown that sildenafil is selective for PDE5, which is involved in the erection process.

Its effect is

more potent on PDE5 than on other known phosphodiesterases.

There is a 10-fold selectivity over PDE6 which is

involved in the phototransduction pathway in the retina.

At maximum recommended doses, there is an 80-fold

selectivity over PDE1, and over 700-fold over PDE 2, 3, 4, 7, 8,9,10 and 11.

In particular, sildenafil has greater than

4,000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase isoform involved in the control of

cardiac contractility.

Clinical efficacy and safety

Two clinical studies were specifically designed to assess the time window after dosing during which sildenafil could

produce an erection in response to sexual stimulation.

In a penile plethysmography (RigiScan) study of fasted patients,

the median time to onset for those who obtained erections of 60% rigidity (sufficient for sexual intercourse) was 25

minutes (range 12-37 minutes) on sildenafil.

In a separate RigiScan study, sildenafil was still able to produce an

erection in response to sexual stimulation 4-5 hours post-dose.

Sildenafil causes mild and transient decreases in blood pressure which, in the majority of cases, do not translate into

clinical effects.

The mean maximum decreases in supine systolic blood pressure following 100mg oral dosing of

sildenafil was 8.4 mmHg.

The corresponding change in supine diastolic blood pressure was 5.5 mmHg.

These

decreases in blood pressure are consistent with the vasodilatory effects of sildenafil, probably due to increase cGMP

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

8

levels in vascular smooth muscle.

Single oral doses of sildenafil up to 100mg in healthy volunteers produced no

clinically relevant effects on ECG.

In a study of the hemodynamic effects of a single oral 100mg dose of sildenafil in 14 patients with severe coronary

artery disease (CAD) (>70% stenosis of at least one coronary artery), the mean resting systolic and diastolic blood

pressures decreased by 7% and 6% respectively compared to baseline.

Mean pulmonary systolic blood pressure

decreased by 9%.

Sildenafil showed no effect on cardiac output, and did not impair blood flow through the stenosed

coronary arteries.

A double-blind, placebo-controlled exercise stress trial evaluated 144 patients with erectile dysfunction and chronic

stable angina who regularly received anti-anginal medicinal products (except nitrates). The results demonstrated no

clinically relevant differences between sildenafil and placebo in time to limiting angina.

Mild and transient differences in colour discrimination (blue/green) were detected in some subjects using the

Farnsworth-Munsell 100 hue test at 1 hour following a 100mg dose, with no effects evident after 2 hours post-dose.

The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6, which is involved

in the phototransduction cascade of the retina.

Sildenafil has no effect on visual acuity or contrast sensitivity.

In a

small size placebo-controlled study of patients with documented early age-related macular degeneration (n=9),

sildenafil (single dose, 100mg) demonstrated no significant changes in visual tests conducted (visual acuity, Amsler

grid, colour discrimination simulated traffic light, Humphrey perimeter and photostress).

There was no effect on sperm motility or morphology after single 100mg oral doses of sildenafil in healthy volunteers

(see section 4.6).

Further information on clinical trials

In clinical trials sildenafil was administered to more than 8000 patients aged 19-87.

The following patient groups were

represented:

elderly (19.9%), patients with hypertension (30.9%), diabetes mellitus (20.3%), ischaemic heart disease

(5.8%), hyperlipidaemia (19.8%), spinal cord injury (0.6%), depression (5.2%), transurethral resection of the prostate

(3.7%), radical prostatectomy (3.3%).

The following groups were not well represented or excluded from clinical trials:

patients with pelvic surgery, patients post-radiotherapy, patients with severe renal or hepatic impairment and patients

with certain cardiovascular conditions (see Section 4.3).

In fixed dose studies, the proportions of patients reporting that treatment improved their erections were 62% (25mg),

74% (50mg) and 82% (100mg) compared to 25% on placebo.

In controlled clinical trials, the discontinuation rate due

to sildenafil was low and similar to placebo.

Across all trials, the proportion of patients reporting improvement on sildenafil were as follows: psychogenic erectile

dysfunction (84%), mixed erectile dysfunction (77%), organic erectile dysfunction (68%), elderly (67%), diabetes

mellitus (59%), ischaemic heart disease (69%), hypertension (68%), TURP (61%), radical prostatectomy (43%), spinal

cord injury (83%), depression (75%).

The safety and efficacy of sildenafil was maintained in long term studies.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with the reference

medicinal product containing sildenafil in all subsets of the paediatric population for the treatment of erectile

dysfunction. See 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Absorption

Sildenafil is rapidly absorbed.

Maximum observed plasma concentrations are reached within 30 to 120 minutes

(median 60 minutes) of oral dosing in the fasted state.

The mean absolute oral bioavailability is 41% (range 25-

63%). After oral dosing of sildenafil AUC and C

increase in proportion with dose over the recommended dose

range (25-100 mg).

When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in t

of 60 minutes and a

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

9

mean reduction in C

of 29%.

Distribution

The mean steady state volume of distribution (V

) for sildenafil is 105 L, indicating distribution into the tissues. After

a single oral dose of 100 mg, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/mL

(CV 40%). Since sildenafil (and its major circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this

results in the mean maximum free plasma concentration for sildenafil of 18 ng/mL (38 nM). Protein binding is

independent of total drug concentrations.

In healthy volunteers receiving sildenafil (100 mg single dose), less than 0.0002% (average 188 ng) of the administered

dose was present in ejaculate 90 minutes after dosing.

Biotransformation

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal

isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil.

This metabolite has a

phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% that of

the parent drug.

Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil.

The N-

desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 h.

Elimination

The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half-life of 3-5 h.

After either oral or

intravenous administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of

administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose).

Pharmacokinetics in special patient groups

Elderly:

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 90%

higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy

younger volunteers (18-45 years).

Due to age-differences in plasma protein binding, the corresponding increase in

free sildenafil plasma concentration was approximately 40%.

Renal insufficiency:

In volunteers with mild to moderate renal impairment (creatinine clearance = 30-80 mL/min), the pharmacokinetics

of sildenafil were not altered after receiving a 50 mg single oral dose.

The mean AUC and Cmax of the N-desmethyl

metabolite increased 126% and 73% respectively, compared to age-matched volunteers with no renal impairment.

However, due to high inter-subject variability, these differences were not statistically significant.

In volunteers with

severe renal impairment (creatinine clearance <30 mL/min), sildenafil clearance was reduced, resulting in mean

increases in AUC and Cmax of 100% and 88% respectively compared to age-matched volunteers with no renal

impairment.

In addition, N-desmethyl metabolite AUC and Cmax values were significantly increased by 200% and

79% respectively.

Hepatic insufficiency:

In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh A and B) sildenafil clearance was reduced,

resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic

impairment.

The pharmacokinetics of sildenafil in patients with severely impaired hepatic function have not been

studied.

5.3 Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology,

repeated dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

1

0

Tablet core:

Lactose monohydrate

Maize Starch

Sodium starch glycolate (Type A)

Povidone K-29/32

Colloidal anhydrous silica

Magnesium Stearate (E572)

Film coat:

Hypromellose

Macrogol 400

Macrogol 6000

Titanium Dioxide (E171)

Indigo Carmine Aluminium Lake (E132)

Sodium laurilsulfate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store below 30°C. Store in the original package, in order to protect from moisture.

6.5 Nature and contents of container

PVC/Aluminium foil blisters in cartons of 2, 4, 8 or 12 tablets.

Not all pack sizes

may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Niche Generics Limited

1, The Cam Centre

Wilbury Way

Hitchin

Hertfordshire SG4 0TW

United Kingdom

8 MARKETING AUTHORISATION NUMBER

PA1063/048/003

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

1

1

Date of first authorisation: 11

January 2013

Date of last renewal: 1

November 2017

10 DATE OF REVISION OF THE TEXT

May 2018

H

e

a

l

t

h

P

r

o

d

u

c

t

s

R

e

g

u

l

a

t

o

r

y

A

u

t

h

o

r

i

t

y

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

_

D

a

t

e

P

r

i

n

t

e

d

0

8

/

0

5

/

2

0

1

8

C

R

N

2

1

9

0

7

4

4

p

a

g

e

n

u

m

b

e

r

:

1

2

Similar products

Search alerts related to this product

View documents history

Share this information