Pulmopresil 20 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

22-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

22-04-2018

Aktiva substanser:
sildenafilcitrat
Tillgänglig från:
Actavis Group PTC ehf.
ATC-kod:
G04BE03
INN (International namn):
sildenafil citrate
Dos:
20 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
laktosmonohydrat Hjälpämne; sildenafilcitrat 28,1 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 30 tabletter; Blister, 90 tabletter; Blister, 100 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
53707
Tillstånd datum:
2016-12-16

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

15-10-2020

Produktens egenskaper Produktens egenskaper - engelska

01-12-2016

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

09-02-2017

Läs hela dokumentet

Package leaflet: Information for the patient

Pulmopresil 20 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 or pharmacist.

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 or pharmacist. This includes any possible side effects

not listed in this leaflet. See section 4.

What is in this leaflet

What Pulmopresil is and what it is used for

What you need to know before you take Pulmopresil

How to take Pulmopresil

Possible side effects

How to store Pulmopresil

Contents of the pack and other information

1.

What Pulmopresil is and what it is used for

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

phosphodiesterase type 5 (PDE5) inhibitors.

Pulmopresil brings down blood pressure in the lungs by widening the blood vessels in the lungs. Pulmopresil

is used to treat adults and children and adolescents from 1 to 17 years old, with high blood pressure in the

blood vessels in the lungs (pulmonary arterial hypertension).

2.

What you need to know before you take Pulmopresil

Do not take Pulmopresil

if you are allergic to sildenafil or any of the other ingredients of this medicine (listed in section 6).

if you are taking medicines containing nitrates (such as nicorandil), or nitric oxide donors such as

amyl nitrite (“poppers”). These medicines are often given for relief of chest pain (or “angina

pectoris”). Pulmopresil can cause a serious increase in the effects of these medicines. Tell your doctor

if you are taking any of these medicines. If you are not certain, ask your doctor or pharmacist.

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 sildenafil 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 recently had a stroke, a heart attack or if you have severe liver disease or very low blood

pressure (< 90/50 mmHg).

if you are taking a medicine to treat fungal infections such as ketoconazole or itraconazole or

medicines containing ritonavir (for HIV).

if you have ever had loss of vision because of a problem with blood flow to the nerve in the eye called

non-arteritic anterior ischaemic optic neuropathy (NAION).

Warnings and precautions

Talk to your doctor before taking Pulmopresil if you

have a disease due to a blocked or narrow vein in the lungs rather than a blocked or narrow artery.

Sildenafil, SE/H/1586/001, 03.06.20

have a severe heart problem.

have a problem with the pumping chambers of your heart

have high blood pressure in the blood vessels in the lungs.

have low blood pressure at rest.

lose a large amount of body fluids (dehydration) which can occur when you sweat a lot or do not drink

enough liquids. This can happen if you are sick with a fever, vomiting, or diarrhoea.

have a rare inherited eye disease (

retinitis pigmentosa

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

of bone marrow (multiple myeloma), or any disease or deformity of the penis.

currently have a stomach ulcer, a bleeding disorder (such as haemophilia) or problems with nose

bleeds.

take medicines for erectile dysfunction.

When used to treat male erectile dysfunction (ED), the following visual side effects have been reported with

PDE5 inhibitors, including sildenafil at an unknown frequency; partial, sudden, temporary, or permanent

decrease or loss of vision in one or both eyes.

If you experience sudden decrease or loss of vision,

stop taking Pulmopresil and contact your doctor

immediately

(see also section 4).

Prolonged and sometimes painful erections have been reported in men after taking sildenafil. If you have an

erection, which lasts continuously for more than 4 hours,

stop taking Pulmopresil and contact your doctor

immediately

(see also section 4).

Special considerations for patients with kidney or liver problems

You should tell your doctor if you have kidney or liver problems, as your dose may need to be adjusted.

Children

Pulmopresil should not be given to children below 1 year of age

Other medicines and Pulmopresil

Do not take Pulmopresil with

(see also “Do not take Pulmopresil” in this section)

Medicines containing nitrates (such as nicorandil), or nitric oxide donors such as amyl nitrite

(“poppers”).

Medicines containing riociguat.

Medicines containing ketoconazole, itraconazole or ritonavir.

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

Medicines containing, such as bosentan, ambrisentan, iloprost (for pulmonary hypertension).

Medicines belonging to the same group as Pulmopresil (PDE5 inhibitors).

Medicines containing St. John’s Wort (herbal medicine), rifampicin (used to treat bacterial infections),

carbamazepine, phenytoin and phenobarbital (used, among others, to treat epilepsy).

Medicines containing erythromycin, clarithromycin, telithromycin (these are antibiotics used to treat

certain bacterial infections), saquinavir (for HIV) or nefazodone (for mental depression), as your dose

may need to be adjusted.

Medicines containing beta-blockers (a group of medicines used, among others, to treat high blood

pressure, heart failure, irregular heart rhythm, migraine).

Blood thinning medicines (such as warfarin) although these did not result in any side effect.

Medicines containing alpha-blockers (such as doxazosin) for the treatment of high blood pressure or

prostate problems, as the combination of the two medicines may cause symptoms resulting in the

lowering of your blood pressure (such as dizziness, light-headedness).

Pulmopresil with food and drink

You should not drink grapefruit juice while you are being treated with Pulmopresil.

Sildenafil, SE/H/1586/001, 03.06.20

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before taking this medicine. Pulmopresil should not be used during

pregnancy unless strictly necessary.

Pulmopresil should not be given to women of child bearing potential unless using appropriate contraceptive

methods.

Sildenafil passes into your breast milk at very low levels and would not be expected to harm your baby.

Driving and using machines

Pulmopresil can cause dizziness and can affect vision. You should be aware of how you react to the medicine

before you drive or use machines.

Pulmopresil contains lactose and sodium

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before

taking this medicinal product.

This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially

‘sodium-free’.

3.

How to take Pulmopresil

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

are not sure.

For adults, the recommended dose is 20 mg three times a day (taken 6 to 8 hours apart) taken with or without

food.

Use in children and adolescents

For children and adolescents aged 1 year to 17 years old, the recommended dose is either 10 mg three times a

day for children and adolescents ≤ 20 kg or 20 mg three times a day for children and adolescents > 20 kg,

taken with or without food. Higher doses should not be used in children. This medicine should be used only

in case of administration of 20 mg three times a day. Other pharmaceutical forms may be more appropriate

for administration to patients ≤ 20 kg and other younger patients who are not able to swallow tablets.

If you take more Pulmopresil than you should

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

If you take more medicine than you have been told to take contact your doctor immediately. Taking more

Pulmopresil than you should may increase the risk of known side effects.

If you forget to take Pulmopresil

If you forget to take Pulmopresil, take a dose as soon as you remember, then continue to take your medicine

at the usual times. Do not take a double dose to make up for a forgotten dose.

If you stop taking Pulmopresil

Suddenly stopping your treatment with Pulmopresil may lead to your symptoms getting worse. Do not stop

taking Pulmopresil unless your doctor tells you to. Your doctor may tell you to reduce the dose over a few

days before stopping completely.

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

4.

Possible side effects

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

Sildenafil, SE/H/1586/001, 03.06.20

If you experience any of the following side effects you should stop taking Pulmopresil and contact a doctor

immediately (see also section 2):

if you experience sudden decrease or loss of vision (frequency not known)

if you have an erection, which lasts continuously for more than 4 hours. Prolonged and sometimes

painful erections have been reported in men after taking sildenafil (frequency not known).

Adults

Side effects reported very commonly (may affect more than 1 in 10 people) were headache, facial flushing,

indigestion, diarrhoea and pain in the arms or legs.

Side effects reported commonly (may affect up to 1 in 10 people) included: infection under the skin, flu-like

symptoms, inflammation of the sinuses, reduced number of red blood cells (anaemia), fluid retention,

difficulty sleeping, anxiety, migraine, shaking, “pins and needles”-like sensation, burning sensation, reduced

sense of touch, bleeding at the back of the eye, effects on vision, blurred vision and light sensitivity, effects

on colour vision, eye irritation, bloodshot eyes /red eyes, vertigo, bronchitis, nosebleed, runny nose, cough,

stuffy nose, stomach inflammation, gastroenteritis, heartburn, piles, abdominal distension, dry mouth, hair

loss, redness of the skin, night sweats, muscle aches, back pain and increased body temperature.

Side effects reported uncommonly (may affect 1 in 100 people) included: reduced sharpness of vision,

double vision, abnormal sensation in the eye, penile bleeding, presence of blood in semen and/or urine, and

breast enlargement in men.

Skin rash and sudden decrease or loss of hearing and decreased blood pressure have also been reported at an

unknown frequency (frequency cannot be estimated from the available data).

Children and adolescents

The following serious adverse events have been reported commonly (may affect up to 1 in 10 people);

pneumonia, heart failure, right heart failure, heart related shock, high blood pressure in the lungs, chest pain,

fainting, respiratory infection, bronchitis, viral infection in the stomach and intestines, urinary tract infections

and tooth cavities.

The following serious adverse events were considered to be treatment related and were reported

uncommonly (may affect up to 1 in 100 people), allergic reaction (such as skin rash, swelling of the face, lips

and tongue, wheezing, difficulty breathing or swallowing), convulsion, irregular heart-beat, hearing

impairment, shortness of breath, inflammation of the digestive tract, wheezing due to disrupted airflow.

Side effects reported very commonly (may affect more than 1 in 10 people) were headache, vomiting,

infection of the throat, fever, diarrhoea, flu and nosebleed.

Side effects reported commonly (may affect up to 1 in 10 people) were nausea, increased erections,

pneumonia and runny nose.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed

in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix

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

5.

How to store Pulmopresil

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

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers

to the last day of that month.

Sildenafil, SE/H/1586/001, 03.06.20

This medicine does not require any special storage conditions.

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 to protect the environment.

6.

Contents of the pack and other information

What Pulmopresil contains

The active substance is sildenafil.

Each tablet contains 20 mg of sildenafil (as citrate).

The other ingredients are:

Tablet core

: lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium,

magnesium stearate.

Film-coating:

hypromellose, titanium dioxide (E171), macrogol.

What Pulmopresil looks like and contents of the pack

Pulmopresil film-coated tablets are 6.5 mm, white, round and biconvex in shape. The tablets are marked with

“SL20” on one side.

The tablets are provided in blister packs containing 30, 90 and 100 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

[To be completed nationally]

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

<{Name of the Member State}> <{Name of the medicinal product}>

<{Name of the Member State}> <{Name of the medicinal product}>

This leaflet was last revised 2020-10-01

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NAME OF THE MEDICINAL PRODUCT

Pulmopresil 20 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 20 mg of sildenafil (as citrate).

Excipient with known effect:

Each tablet contains 49.9 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet.

White, round, biconvex film-coated tablets of 6.5 mm, marked “SL20” on one side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Adults

Treatment of adult patients with pulmonary arterial hypertension classified as WHO functional class

II and III, to improve exercise capacity. Efficacy has been shown in primary pulmonary hypertension

and pulmonary hypertension associated with connective tissue disease.

Paediatric population

Treatment of paediatric patients aged 1 year to 17 years old with pulmonary arterial hypertension.

Efficacy in terms of improvement of exercise capacity or pulmonary haemodynamics has been shown

in primary pulmonary hypertension and pulmonary hypertension associated with congenital heart

disease (see section 5.1).

4.2

Posology and method of administration

Treatment should only be initiated and monitored by a physician experienced in the treatment of

pulmonary arterial hypertension. In case of clinical deterioration in spite of Pulmopresil treatment,

alternative therapies should be considered.

Posology

Adults

The recommended dose is 20 mg three times a day. Physicians should advise patients who forget to

take Pulmopresil to take a dose as soon as possible and then continue with the normal dose. Patients

should not take a double dose to compensate for the missed dose.

Paediatric population

(1 year to 17 years)

For paediatric patients aged 1 year to 17 years old, the recommended dose in patients ≤ 20 kg is

10 mg three times a day and for patients > 20 kg is 20 mg three times a day. Higher than

recommended doses should not be used in paediatric patients with PAH (see also sections 4.4 and

5.1). The 20 mg tablet should not be used in cases where 10 mg three times a day should be

administered in younger patients. Other pharmaceutical forms are recommended for administration to

patients ≤ 20 kg and other younger patients who are not able to swallow tablets.

Patients using other medicinal products

In general, any dose adjustment should be administered only after a careful benefit-risk assessment. A

downward dose adjustment to 20 mg twice daily should be considered when sildenafil is

co-administered to patients already receiving CYP3A4 inhibitors like erythromycin or saquinavir. A

downward dose adjustment to 20 mg once daily is recommended in case of co-administration with

more potent CYP3A4 inhibitors clarithromycin, telithromycin and nefazodone. For the use of

sildenafil with the most potent CYP3A4 inhibitors, see section 4.3. Dose adjustments for sildenafil

may be required when co-administered with CYP3A4 inducers (see section 4.5).

Special populations

Elderly (≥ 65 years)

Dose adjustments are not required in elderly patients. Clinical efficacy as measured by 6-minute walk

distance could be less in elderly patients.

Renal impairment

Initial dose adjustments are not required in patients with renal impairment, including severe renal

impairment (creatinine clearance < 30 ml/min). A downward dose adjustment to 20 mg twice daily

should be considered after a careful benefit-risk assessment only if therapy is not well-tolerated.

Hepatic impairment

Initial dose adjustments are not required in patients with hepatic impairment (Child-Pugh class A and

B). A downward dose adjustment to 20 mg twice daily should be considered after a careful

benefit-risk assessment only if therapy is not well-tolerated.

Pulmopresil is contraindicated in patients with severe hepatic impairment (Child-Pugh class C) (see

section 4.3).

Paediatric population

The safety and efficacy of Pulmopresil in children below 1 year of age has not been established. No

data are available.

Discontinuation of treatment

Limited data suggests that the abrupt discontinuation of Pulmopresil is not associated with rebound

worsening of pulmonary arterial hypertension. However to avoid the possible occurrence of sudden

clinical deterioration during withdrawal, a gradual dose reduction should be considered. Intensified

monitoring is recommended during the discontinuation period.

Method of administration

Pulmopresil is for oral use only. Tablets should be taken approximately 6 to 8 hours apart with or

without food.

4.3

Contraindications

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

Co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form due to the

hypotensive effects of nitrates (see section 5.1).

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).

Combination with the most potent of the CYP3A4 inhibitors (e.g., ketoconazole, itraconazole,

ritonavir) (see section 4.5).

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,

Recent history of stroke or myocardial infarction,

Severe hypotension (blood pressure < 90/50 mmHg) at initiation.

4.4

Special warnings and precautions for use

The efficacy of Pulmopresil has not been established in patients with severe pulmonary arterial

hypertension (functional class IV). If the clinical situation deteriorates, therapies that are

recommended at the severe stage of the disease (e.g. epoprostenol) should be considered (see section

4.2). The benefit-risk balance of sildenafil has not been established in patients assessed to be at WHO

functional class I pulmonary arterial hypertension.

Studies with sildenafil have been performed in forms of pulmonary arterial hypertension related to

primary (idiopathic), connective tissue disease associated or congenital heart disease associated forms

of PAH (see section 5.1). The use of sildenafil in other forms of PAH is not recommended.

Paediatric population

In the long term paediatric extension study, an increase in deaths was observed in patients

administered doses higher than the recommended dose. Therefore, doses higher than the

recommended doses should not be used in paediatric patients with PAH (see also sections 4.2 and

5.1).

Retinitis pigmentosa

The safety of sildenafil has not been studied in patients with known hereditary degenerative retinal

disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal

phosphodiesterases) and therefore its use is not recommended.

Vasodilatory action

When prescribing sildenafil, physicians should carefully consider whether patients with certain

underlying conditions could be adversely affected by sildenafil’s mild to moderate vasodilatory

effects, for example patients with hypotension, patients with fluid depletion, severe left ventricular

outflow obstruction or autonomic dysfunction (see section 4.4).

Cardiovascular risk factors

In post-marketing experience with sildenafil for male erectile dysfunction, serious cardiovascular

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

arrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, hypertension and hypotension

have been reported 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

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 (see section 4.8).

Vaso-occlusive crises in patients with sickle cell anaemia

Sildenafil should not be used in patients with pulmonary hypertension secondary to sickle cell

anaemia. In a clinical study events of vaso-occlusive crises requiring hospitalisation were reported

more commonly by patients receiving Pulmopresil than those receiving placebo leading to the

premature termination of this study.

Visual events

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

and other PDE5 inhibitors. 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 other PDE5 inhibitors (see section 4.8). In the event of any sudden visual

defect, the treatment should be stopped immediately and alternative treatment should be considered

(see section 4.3).

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 susceptible individuals (see section 4.5). In

order to minimise the potential for developing postural hypotension, patients should be

haemodynamically stable on alpha-blocker therapy prior to initiating sildenafil treatment. Physicians

should advise patients what to do in the event of postural hypotensive symptoms.

Bleeding disorders

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.

Vitamin K antagonists

In pulmonary arterial hypertension patients, there may be a potential for increased risk of bleeding

when sildenafil is initiated in patients already using a Vitamin K antagonist, particularly in patients

with pulmonary arterial hypertension secondary to connective tissue disease.

Veno-occlusive disease

No data are available with sildenafil in patients with pulmonary hypertension associated with

pulmonary veno-occlusive disease. However, cases of life threatening pulmonary oedema have been

reported with vasodilators (mainly prostacyclin) when used in those patients. Consequently, should

signs of pulmonary oedema occur when sildenafil is administered in patients with pulmonary

hypertension, the possibility of associated veno-occlusive disease should be considered.

Use of sildenafil with bosentan

The efficacy of sildenafil in patients already on bosentan therapy has not been conclusively

demonstrated (see sections 4.5 and 5.1).

Concomitant use with other PDE5 inhibitors

The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitor products,

including Viagra, has not been studied in PAH patients and such concomitant use is not recommended

(see section 4.5).

Galactose intolerance

Pulmopresil contains lactose monohydrate. Patients with rare hereditary problems of galactose

intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this

medicine.

4.5

Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on sildenafil

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. For dose

recommendations, see sections 4.2 and 4.3.

In vivo studies

Co-administration of oral sildenafil and intravenous epoprostenol has been evaluated (see sections

4.8 and 5.1).

The efficacy and safety of sildenafil co-administered with other treatments for pulmonary arterial

hypertension (e.g., ambrisentan, iloprost) has not been studied in controlled clinical trials. Therefore,

caution is recommended in case of co-administration.

The safety and efficacy of sildenafil when co-administered with other PDE5 inhibitors has not been

studied in pulmonary arterial hypertension patients (see section 4.4).

Population pharmacokinetic analysis of pulmonary arterial hypertension clinical trial data indicated a

reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with

CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the

only factors with a statistically significant impact on sildenafil pharmacokinetics in patients with

pulmonary arterial hypertension. The exposure to sildenafil in patients on CYP3A4 substrates and

CYP3A4 substrates plus beta-blockers was 43 % and 66 % higher, respectively, compared to patients

not receiving these classes of medicines. Sildenafil exposure was 5-fold higher at a dose of 80 mg

three times a day compared to the exposure at a dose of 20 mg three times a day. This concentration

range covers the increase in sildenafil exposure observed in specifically designed drug interaction

studies with CYP3A4 inhibitors (except with the most potent of the CYP3A4 inhibitors e.g.,

ketoconazole, itraconazole, ritonavir).

CYP3A4 inducers seemed to have a substantial impact on the pharmacokinetics of sildenafil in

pulmonary arterial hypertension patients, which was confirmed in the in-vivo interaction study with

CYP3A4 inducer bosentan.

Co-administration of bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19)

125 mg twice daily with sildenafil 80 mg three times a day (at steady state) concomitantly

administered during 6 days in healthy volunteers resulted in a 63 % decrease of sildenafil AUC. A

population pharmacokinetic analysis of sildenafil data from adult PAH patients in clinical trials

including a 12 week study to assess the efficacy and safety of oral sildenafil 20 mg three times a day

when added to a stable dose of bosentan (62.5 mg-125 mg twice a day) indicated a decrease in

sildenafil exposure with bosentan co-administration, similar to that observed in healthy volunteers

(see sections 4.4 and 5.1).

Efficacy of sildenafil should be closely monitored in patients using concomitant potent

CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, St John’s wort and rifampicine.

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 C

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. Based on these pharmacokinetic results co-administration of

sildenafil with ritonavir is contraindicated in pulmonary arterial hypertension patients (see section

4.3). 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 C

and a 210 % increase in sildenafil AUC. Sildenafil had no effect on saquinavir

pharmacokinetics. For dose recommendations, see section 4.2.

When a single 100 mg dose of sildenafil was administered with erythromycin, a moderate

CYP3A4 inhibitor, at steady state (500 mg twice daily for 5 days), there was a 182 % increase in

sildenafil systemic exposure (AUC). For dose recommendations, see section 4.2. In healthy male

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

max,

, elimination rate constant, or subsequent half-life of sildenafil or its principal circulating

metabolite. No dose adjustment is required. Cimetidine (800 mg), a cytochrome P450 inhibitor and a

non-specific CYP3A4 inhibitor, caused a 56 % increase in plasma sildenafil concentrations when co-

administered with sildenafil (50 mg) to healthy volunteers. No dose adjustment is required.

The most potent of the CYP3A4 inhibitors such as ketoconazole and itraconazole would be expected

to have effects similar to ritonavir (see section 4.3). CYP3A4 inhibitors like clarithromycin,

telithromycin and nefazodone are expected to have an effect in between that of ritonavir and

CYP3A4 inhibitors like saquinavir or erythromycin, a seven-fold increase in exposure is assumed.

Therefore dose adjustments are recommended when using CYP3A4 inhibitors (see section 4.2).

The population pharmacokinetic analysis in pulmonary arterial hypertension patients suggested that

co-administration of beta-blockers in combination with CYP3A4 substrates might result in an

additional increase in sildenafil exposure compared with administration of CYP3A4 substrates alone.

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

increases in plasma levels of sildenafil. No dose adjustment is required but the concomitant use of

sildenafil and grapefruit juice is not recommended.

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

bioavailability of sildenafil.

Co-administration of oral contraceptives (ethinyloestradiol 30 µg and levonorgestrel 150 µg) did not

affect the pharmacokinetics of sildenafil.

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

the potential to have serious interaction with sildenafil (see section 4.3).

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).

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

as theophylline or dipyridamole.

In vivo studies

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 had no significant effect on atorvastatin exposure (AUC increased 11 %), suggesting that

sildenafil does not have a clinically relevant effect on CYP3A4.

No interactions were observed between sildenafil (100 mg single dose) and acenocoumarol.

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.

In a study of healthy volunteers sildenafil at steady state (80 mg three times a day) resulted in a 50 %

increase in bosentan AUC (125 mg twice daily). A population pharmacokinetic analysis of data from

a study of adult PAH patients on background bosentan therapy (62.5 mg-125 mg twice a day)

indicated an increase (20 % (95 % CI: 9.8-30.8)) of bosentan AUC with co-administration of

steady-state sildenafil (20 mg three times a day) of a smaller magnitude than seen in healthy

volunteers when co-administered with 80 mg sildenafil three times a day (see sections 4.4 and 5.1).

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.

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 systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and

8/4 mmHg, respectively, 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. Concomitant administration of sildenafil to patients taking

alpha-blocker therapy may lead to symptomatic hypotension in susceptible individuals (see section

4.4).

Sildenafil (100 mg single dose) did not affect the steady state pharmacokinetics of the HIV protease

inhibitor saquinavir, which is a CYP3A4 substrate/inhibitor.

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 favorable clinical effect of the

combination in the population studied. Concomitant use of riociguat with PDE5 inhibitors, including

sildenafil, is contraindicated (see section 4.3).

Sildenafil had no clinically significant impact on the plasma levels of oral contraceptives

(ethinyloestradiol 30 µg and levonorgestrel 150 µg).

Paediatric population

Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation

Women of childbearing potential and contraception in males and females

Due to lack of data on effects of Pulmopresil in pregnant women, Pulmopresil is not recommended for

women of childbearing potential unless also using appropriate contraceptive measures.

Pregnancy

There are no data from the use of sildenafil in pregnant women. Animal studies do not indicate direct

or indirect harmful effects with respect to pregnancy and embryonal/foetal development. Studies in

animals have shown toxicity with respect to postnatal development (see section 5.3).

Due to lack of data, Pulmopresil should not be used in pregnant women unless strictly necessary.

Breastfeeding

It is not known whether sildenafil enters the breast milk. Pulmopresil should not be administered to

breast-feeding mothers.

Fertility

Non-clinical data revealed no special hazard for humans based on conventional studies of fertility (see

section 5.3).

4.7

Effects on ability to drive and use machines

Pulmopresil has moderate influence on the ability to drive and use machines.

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

aware of how they might be affected by Pulmopresil, before driving or using machines.

4.8

Undesirable effects

Summary of the safety profile

In the pivotal placebo-controlled study of sildenafil in pulmonary arterial hypertension, a total of

207 patients were randomized to and treated with 20 mg, 40 mg, or 80 mg three times a day doses of

sildenafil and 70 patients were randomized to placebo. The duration of treatment was 12 weeks. The

overall frequency of discontinuation in sildenafil treated patients at doses of 20 mg, 40 mg and 80 mg

three times a day was 2.9 %, 3.0 % and 8.5 % respectively, compared to 2.9 % with placebo. Of the

277 subjects treated in the pivotal study, 259 entered a long-term extension study. Doses up to 80 mg

three times a day (4 times the recommended dose of 20 mg three times a day) were administered and

after 3 years 87 % of 183 patients on study treatment were receiving sildenafil 80 mg three times a

day.

In a placebo-controlled study of sildenafil as an adjunct to intravenous epoprostenol in pulmonary

arterial hypertension, a total of 134 patients were treated with sildenafil (in a fixed titration starting

from 20 mg, to 40 mg and then 80 mg, three times a day, as tolerated) and epoprostenol, and

131 patients were treated with placebo and epoprostenol. The duration of treatment was 16 weeks.

The overall frequency of discontinuations in sildenafil/epoprostenol treated patients due to adverse

events was 5.2 % compared to 10.7 % in the placebo/epoprostenol treated patients. Newly reported

adverse reactions, which occurred more frequently in the sildenafil/ epoprostenol group, were ocular

hyperaemia, vision blurred, nasal congestion, night sweats, back pain and dry mouth. The known

adverse reactions headache, flushing, pain in extremity and oedema were noted in a higher frequency

in sildenafil/epoprostenol treated patients compared to placebo/epoprostenol treated patients. Of the

subjects who completed the initial study, 242 entered a long-term extension study. Doses up to 80 mg

three times a day were administered and after 3 years 68 % of 133 patients on study treatment were

receiving sildenafil 80 mg three times a day.

In the two placebo-controlled studies adverse events were generally mild to moderate in severity. The

most commonly reported adverse reactions that occurred (greater or equal to 10 %) on sildenafil

compared to placebo were headache, flushing, dyspepsia, diarrhoea and pain in extremity.

Tabulated list of adverse reactions

Adverse reactions which occurred in > 1 % of sildenafil-treated patients and were more frequent

(> 1 % difference) on sildenafil in the pivotal study or in the sildenafil combined data set of both the

placebo-controlled studies in pulmonary arterial hypertension, at doses of 20, 40 or 80 mg three times

a day are listed in the table below by class (MedDRA system organ class) and frequency grouping

(very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) and not

known (cannot be estimated from the available data). Within each frequency grouping, adverse

reactions are presented in order of decreasing seriousness.

Reports from post-marketing experience are included in italics.

Very common

Common

Uncommon

Not known

Infections and infestations

cellulitis, influenza,

bronchitis, sinusitis,

rhinitis, gastroenteritis

Blood and lymphatic system disorders

anaemia

Metabolism and nutrition disorders

fluid retention

Psychiatric disorders

insomnia, anxiety

Nervous system disorders

headache

migraine, tremor,

paraesthesia, burning

sensation,

hypoaesthesia

Eye disorders

retinal haemorrhage,

visual impairment,

vision blurred,

photophobia,

chromatopsia,

cyanopsia, eye

irritation, ocular

hyperaemia

visual acuity reduced,

diplopia, abnormal

sensation in eye

Non-arteritic anterior

ischaemic optic

neuropathy (NAION)*,

Retinal vascular

occlusion*, Visual field

defect*

Ear and labyrinth disorders

vertigo

sudden hearing loss

Vascular disorders

flushing

hypotension

Respiratory, thoracic and mediastinal disorders

epistaxis, cough, nasal

congestion

Gastrointestinal disorders

diarrhoea, dyspepsia

gastritis,

gastro-oesophageal

Very common

Common

Uncommon

Not known

reflux disease,

haemorrhoids,

abdominal distension,

dry mouth

Skin and subcutaneous tissue disorders

alopecia, erythema,

night sweats

rash

Musculoskeletal and connective tissue disorders

pain in extremity

myalgia, back pain

Renal and urinary disorders

haematuria

Reproductive system and breast disorders

penile haemorrhage,

haematospermia,

gynaecomastia

priapism, erection

increased

General disorders and administration site conditions

pyrexia

*These adverse events/reactions have been reported in patients taking sildenafil for the treatment of male erectile

dysfunction (MED).

Paediatric population

In the placebo-controlled study of sildenafil in patients 1 to 17 years of age with pulmonary arterial

hypertension, a total of 174 patients were treated three times a day with either low (10 mg in patients

> 20 kg; no patients ≤ 20 kg received the low dose), medium (10 mg in patients ≥ 8-20 kg; 20 mg in

patients ≥ 20-45 kg; 40 mg in patients > 45 kg) or high dose (20 mg in patients ≥ 8-20 kg; 40 mg in

patients ≥ 20-45 kg; 80 mg in patients > 45 kg) regimens of sildenafil and 60 were treated with

placebo.

The adverse reactions profile seen in this paediatric study was generally consistent with that in adults

(see table above). The most common adverse reactions that occurred (with a frequency ≥ 1 %) in

sildenafil patients (combined doses) and with a frequency > 1 % over placebo patients were pyrexia,

upper respiratory tract infection (each 11.5 %), vomiting (10.9 %), erection increased (including

spontaneous penile erections in male subjects) (9.0 %), nausea, bronchitis (each 4.6 %), pharyngitis

(4.0 %), rhinorrhoea (3.4 %), and pneumonia, rhinitis (each 2.9 %).

Of the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered

the long-term extension study. Subjects on active sildenafil therapy continued on the same treatment

regimen, while those in the placebo group in the short-term study were randomly reassigned to

sildenafil treatment.

The most common adverse reactions reported across the duration of the short-term and long-term

studies were generally similar to those observed in the short-term study. Adverse reactions reported in

> 10 % of 229 subjects treated with sildenafil (combined dose group, including 9 patients that did not

continue into the long-term study) were upper respiratory infection (31 %), headache (26 %),

vomiting (22 %), bronchitis (20 %), pharyngitis (18 %), pyrexia (17 %), diarrhoea (15 %), and

influenza, epistaxis (12 % each). Most of these adverse reactions were considered mild to moderate in

severity.

Serious adverse events were reported in 94 (41 %) of the 229 subjects receiving sildenafil. Of the

94 subjects reporting a serious adverse event, 14/55 (25.5 %) subjects were in the low dose group,

35/74 (47.3 %) in the medium dose group, and 45/100 (45 %) in the high dose group. The most

common serious adverse events that occurred with a frequency ≥ 1 % in sildenafil patients (combined

doses) were pneumonia (7.4 %), cardiac failure, pulmonary hypertension (each 5.2 %), upper

respiratory tract infection (3.1 %), right ventricular failure, gastroenteritis (each 2.6 %), syncope,

bronchitis, bronchopneumonia, pulmonary arterial hypertension (each 2.2 %), chest pain, dental caries

(each 1.7 %), and cardiogenic shock, gastroenteritis viral, urinary tract infection (each 1.3 %).

The following serious adverse events were considered to be treatment related; enterocolitis,

convulsion, hypersensitivity, stridor, hypoxia, neurosensory deafness and ventricular arrhythmia.

Reporting of suspected adverse reactions

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

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

4.9

Overdose

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

lower doses, but the incidence rates and severities were increased. At single doses of 200 mg the

incidence of adverse reactions (headache, flushing, dizziness, dyspepsia, nasal congestion, and 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: G04BE03

Mechanism of action

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP) specific

phosphodiesterase type 5 (PDE5), the enzyme that is responsible for degradation of cGMP. Apart

from the presence of this enzyme in the corpus cavernosum of the penis, PDE5 is also present in the

pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth

muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension this can lead to

vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic

circulation.

Pharmacodynamic effects

Studies

in vitro

have shown that sildenafil is selective for PDE5. 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. 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.

Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of

cases, do not translate into clinical effects. After chronic dosing of 80 mg three times a day to patients

with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure

was a decrease of 9.4 mmHg and 9.1 mmHg respectively. After chronic dosing of 80 mg three times a

day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were

observed (a reduction in both systolic and diastolic pressure of 2 mmHg). At the recommended dose

of 20 mg three times a day no reductions in systolic or diastolic pressure were seen. Single oral doses

of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After

chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no

clinically relevant effects on the ECG were reported.

In a study of the hemodynamic effects of a single oral 100 mg 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.

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 100 mg 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, 100 mg)

demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, colour

discrimination simulated traffic light, Humphrey perimeter and photostress).

Clinical efficacy and safety

Efficacy in adult patients with pulmonary arterial hypertension (PAH)

A randomised, double-blind, placebo-controlled study was conducted in 278 patients with primary

pulmonary hypertension, PAH associated with connective tissue disease, and PAH following surgical

repair of congenital heart lesions. Patients were randomised to one of four treatment groups: placebo,

sildenafil 20 mg, sildenafil 40 mg or sildenafil 80 mg, three times a day. Of the 278 patients

randomised, 277 patients received at least 1 dose of study drug. The study population consisted of

68 (25 %) men and 209 (75 %) women with a mean age of 49 years (range: 18-81 years) and baseline

6-minute walk test distance between 100 and 450 metres inclusive (mean: 344 metres). 175 patients

(63 %) included were diagnosed with primary pulmonary hypertension, 84 (30 %) were diagnosed

with PAH associated with connective tissue disease and 18 (7 %) of the patients were diagnosed with

PAH following surgical repair of congenital heart lesions. Most patients were WHO Functional Class

II (107/277, 39 %) or III (160/277, 58 %) with a mean baseline 6 minute walking distance of

378 meters and 326 meters respectively; fewer patients were Class I (1/277, 0.4 %) or IV (9/277, 3 %)

at baseline. Patients with left ventricular ejection fraction < 45 % or left ventricular shortening

fraction < 0.2 were not studied.

Sildenafil (or placebo) was added to patients’ background therapy which could have included a

combination of anticoagulation, digoxin, calcium channel blockers, diuretics or oxygen. The use of

prostacyclin, prostacyclin analogues and endothelin receptor antagonists was not permitted as add-on

therapy, and neither was arginine supplementation. Patients who previously failed bosentan therapy

were excluded from the study.

The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance

(6MWD). A statistically significant increase in 6MWD was observed in all 3 sildenafil dose groups

compared to those on placebo. Placebo corrected increases in 6MWD were 45 metres (p < 0.0001),

46 metres (p < 0.0001) and 50 metres (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg three times

a day respectively. There was no significant difference in effect between sildenafil doses. For patients

with a baseline 6MWD < 325 m improved efficacy was observed with higher doses (placebo-

corrected improvements of 58 metres, 65 metres and 87 metres for 20 mg, 40 mg and 80 mg doses

three times a day, respectively).

When analysed by WHO functional class, a statistically significant increase in 6MWD was observed

in the 20 mg dose group. For class II and class III, placebo corrected increases of 49 metres

(p = 0.0007) and 45 metres (p = 0.0031) were observed respectively.

The improvement in 6MWD was apparent after 4 weeks of treatment and this effect was maintained

at weeks 8 and 12. Results were generally consistent in subgroups according to aetiology (primary and

connective tissue disease-associated PAH), WHO functional class, gender, race, location, mean PAP

and PVRI.

Patients on all sildenafil doses achieved a statistically significant reduction in mean pulmonary

arterial pressure (mPAP) and pulmonary vascular resistance (PVR) compared to those on placebo.

Placebo-corrected treatment effects with mPAP were –2.7 mmHg (p = 0.04), -3.0 mm Hg (p = 0.01)

and -5.1 mm Hg (p < 0.0001) for sildenafil 20 mg, 40 mg and 80 mg three times a day respectively.

Placebo-corrected treatment effects with PVR were -178 dyne.sec/cm

(p = 0.0051), -

195 dyne.sec/cm

(p = 0.0017) and -320 dyne.sec/cm

(p< 0.0001) for sildenafil 20 mg, 40 mg and

80 mg three times a day, respectively. The percent reduction at 12 weeks for sildenafil 20 mg, 40 mg

and 80 mg three times a day in PVR (11.2 %, 12.9 %, 23.3 %) was proportionally greater than the

reduction in systemic vascular resistance (SVR) (7.2 %, 5.9 %, 14.4 %). The effect of sildenafil on

mortality is unknown.

A greater percentage of patients on each of the sildenafil doses (i.e. 28 %, 36 % and 42 % of subjects

who received sildenafil 20 mg, 40 mg and 80 mg three times a day doses, respectively) showed an

improvement by at least one WHO functional class at week 12 compared to placebo (7 %). The

respective odds ratios were 2.92 (p = 0.0087), 4.32 (p = 0.0004) and 5.75 (p< 0.0001).

Long-term survival data in naive population

Patients enrolled into the pivotal study were eligible to enter a long term open label extension study.

At 3 years 87 % of the patients were receiving a dose of 80 mg three times a day. A total of

207 patients were treated with sildenafil in the pivotal study, and their long term survival status was

assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of 1, 2 and 3 year

survival were 96 %, 91 % and 82 %, respectively. Survival in patients of WHO functional class II at

baseline at 1, 2 and 3 years was 99 %, 91 %, and 84 % respectively, and for patients of WHO

functional class III at baseline was 94 %, 90 %, and 81 %, respectively.

Efficacy in adult patients with PAH (when used in combination with epoprostenol)

A randomised, double-blind, placebo controlled study was conducted in 267 patients with PAH who

were stabilised on intravenous epoprostenol. The PAH patients included those with Primary

Pulmonary Arterial Hypertension (212/267, 79 %) and PAH associated with connective tissue disease

(55/267, 21 %). Most patients were WHO Functional Class II (68/267, 26 %) or III (175/267, 66 %);

fewer patients were Class I (3/267, 1 %) or IV (16/267, 6 %) at baseline; for a few patients (5/267,

2 %), the WHO Functional Class was unknown. Patients were randomised to placebo or sildenafil (in

a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day as tolerated) when

used in combination with intravenous epoprostenol.

The primary efficacy endpoint was the change from baseline at week 16 in 6-minute walk distance.

There was a statistically significant benefit of sildenafil compared to placebo in 6-minute walk

distance. A mean placebo corrected increase in walk distance of 26 metres was observed in favour of

sildenafil (95 % CI: 10.8, 41.2) (p = 0.0009). For patients with a baseline walking distance ≥

325 metres, the treatment effect was 38.4 metres in favour of sildenafil; for patients with a baseline

walking distance < 325 metres, the treatment effect was 2.3 metres in favour of placebo. For patients

with primary PAH, the treatment effect was 31.1 metres compared to 7.7 metres for patients with

PAH associated with connective tissue disease. The difference in results between these randomisation

subgroups may have arisen by chance in view of their limited sample size.

Patients on sildenafil achieved a statistically significant reduction in mean Pulmonary Arterial

Pressure (mPAP) compared to those on placebo. A mean placebo-corrected treatment effect of -

3.9 mmHg was observed in favour of sildenafil (95 % CI: -5.7, -2.1) (p = 0.00003). Time to clinical

worsening was a secondary endpoint as defined as the time from randomisation to the first occurrence

of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical

deterioration requiring a change in epoprostenol therapy). Treatment with sildenafil significantly

delayed the time to clinical worsening of PAH compared to placebo (p = 0.0074). 23 subjects

experienced clinical worsening events in the placebo group (17.6 %) compared with 8 subjects in the

sildenafil group (6.0 %).

Long-term Survival data in the background epoprostenol study

Patients enrolled into the epoprostenol add-on therapy study were eligible to enter a long term open

label extension study. At 3 years 68 % of the patients were receiving a dose of 80 mg three times a

day. A total of 134 patients were treated with sildenafil in the initial study, and their long term

survival status was assessed for a minimum of 3 years. In this population, Kaplan-Meier estimates of

1, 2 and 3 year survival were 92 %, 81 % and 74 %, respectively.

Efficacy and safety in adult patients with PAH (when used in combination with bosentan)

A randomized, double-blind, placebo controlled study was conducted in 103 clinically stable subjects

with PAH (WHO FC II and III) who were on bosentan therapy for a minimum of three months. The

PAH patients included those with primary PAH, and PAH associated with connective tissue disease.

Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with

bosentan (62.5-125 mg twice a day). The primary efficacy endpoint was the change from baseline at

Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from

baseline on 6MWD observed between sildenafil (20 mg three times a day) and placebo (13.62 m

(95 %CI: -3.89 to 31.12) and 14.08 m (95 %CI: -1.78 to 29.95), respectively).

Differences in 6MWD were observed between patients with primary PAH and PAH associated with

connective tissue disease. For subjects with primary PAH (67 subjects), mean changes from baseline

were 26.39 m (95 %CI: 10.70 to 42.08) and 11.84 m (95 %CI: -8.83 to 32.52) for the sildenafil and

placebo groups, respectively. However, for subjects with PAH associated with connective tissue

disease (36 subjects) mean changes from baseline were -18.32 m (95 %CI: -65.66 to 29.02) and

17.50 m (95 %CI: -9.41 to 44.41) for the sildenafil and placebo groups, respectively.

Overall, the adverse events were generally similar between the two treatment groups (sildenafil plus

bosentan vs. bosentan alone), and consistent with the known safety profile of sildenafil when used as

monotherapy (see sections 4.4 and 4.5).

Paediatric population

A total of 234 subjects aged 1 to 17 years were treated in a randomized, double-blind, multi-centre,

placebo controlled parallel group, dose ranging study. Subjects (38 % male and 62 % female) had a

body weight ≥ 8 kg, and had primary pulmonary hypertension (PPH) [33 %], or PAH secondary to

congenital heart disease [systemic-to-pulmonary shunt 37 %, surgical repair 30 %]. In this trial, 63 of

234 (27 %) patients were < 7 years old (sildenafil low dose = 2; medium dose = 17; high dose = 28;

placebo = 16) and 171 of 234 (73 %) patients were 7 years or older (sildenafil low dose = 40; medium

dose = 38; and high dose = 49; placebo = 44). Most subjects were WHO Functional Class I (75/234,

32 %) or II (120/234, 51 %) at baseline; fewer patients were Class III (35/234, 15 %) or IV (1/234,

0.4 %); for a few patients (3/234, 1.3 %), the WHO Functional Class was unknown.

Patients were naïve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues and

endothelin receptor antagonists was not permitted in the study, and neither was arginine

supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors.

The primary objective of the study was to assess the efficacy of 16 weeks of chronic treatment with

oral sildenafil in paediatric subjects to improve exercise capacity as measured by the

Cardiopulmonary Exercise Test (CPET) in subjects who were developmentally able to perform the

test, n = 115). Secondary endpoints included haemodynamic monitoring, symptom assessment, WHO

functional class, change in background treatment, and quality of life measurements.

Subjects were allocated to one of three sildenafil treatment groups, low (10 mg), medium (10-40 mg)

or high dose (20-80 mg) regimens of sildenafil given three times a day, or placebo. Actual doses

administered within a group were dependent on body weight (see Section 4.8). The proportion of

subjects receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium

channel blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group

(47.7 %) and the placebo treatment group (41.7 %).

The primary endpoint was the placebo-corrected percentage change in peak VO2 from baseline to

week 16 assessed by CPET testing in the combined dose groups (Table 2). A total of 106 out of

234 (45 %) subjects were evaluable for CPET, which comprised those children ≥ 7 years old and

developmentally able to perform the test. Children < 7 years (sildenafil combined dose = 47;

placebo = 16) were evaluable only for the secondary endpoints. Mean baseline peak volume of

oxygen consumed (VO2) values were comparable across the sildenafil treatment groups (17.37 to

18.03 ml/kg/min), and slightly higher for the placebo treatment group (20.02 ml/kg/min). The results

of the main analysis (combined dose groups versus placebo) were not statistically significant

(p = 0.056) (see Table 2). The estimated difference between the medium sildenafil dose and placebo

was 11.33 % (95 % CI: 1.72 to 20.94) (see Table 2).

Table 2: Placebo Corrected % Change from Baseline in Peak VO

2

by Active Treatment Group

Treatment group

Estimated difference

95 %confidence interval

Low dose

(n=24)

3.81

-6.11, 13.73

Medium dose

(n=26)

11.33

1.72, 20.94

High dose

(n=27)

7.98

-1.64, 17.60

Combined dose groups

(n=77)

7.71

(p = 0.056)

-0.19, 15.60

n=29 for placebo group

Estimates based on ANCOVA with adjustments for the covariates baseline peak VO

2

, etiology and

weight group

Dose related improvements were observed with pulmonary vascular resistance index (PVRI) and

mean pulmonary arterial pressure (mPAP). The sildenafil medium and high dose groups both showed

PVRI reductions compared to placebo, of 18 % (95 % CI: 2 % to 32 %) and 27 % (95 % CI: 14 % to

39 %), respectively; whilst the low dose group showed no significant difference from placebo

(difference of 2 %). The sildenafil medium and high dose groups displayed mPAP changes from

baseline compared to placebo, of -3.5 mmHg (95 % CI: -8.9, 1.9) and -7.3 mmHg (95 % CI: -12.4, -

2.1), respectively; whilst the low dose group showed little difference from placebo (difference of

1.6 mmHg). Improvements were observed with cardiac index with all three sildenafil groups over

placebo, 10 %, 4 % and 15 % for the low, medium and high dose groups respectively.

Significant improvements in functional class were demonstrated only in subjects on sildenafil high

dose compared to placebo. Odds ratios for the sildenafil low, medium and high dose groups compared

to placebo were 0.6 (95 % CI: 0.18, 2.01), 2.25 (95 % CI: 0.75, 6.69) and 4.52 (95 % CI: 1.56, 13.10),

respectively.

Long term extension data

Of the 234 paediatric subjects treated in the short-term, placebo-controlled study, 220 subjects entered

the long-term extension study. Subjects who had been in the placebo group in the short-term study

were randomly reassigned to sildenafil treatment; subjects weighing ≤ 20 kg entered the medium or

high dose groups (1:1), while subjects weighing > 20 kg entered the low, medium or high dose groups

(1:1:1). Of the total 229 subjects who received sildenafil, there were 55, 74, and 100 subjects in the

low, medium and high dose groups, respectively. Across the short-term and long-term studies, the

overall duration of treatment from start of double-blind for individual subjects ranged from 3 to

3129 days. By sildenafil treatment group, median duration of sildenafil treatment was 1696 days

(excluding the 5 subjects who received placebo in double-blind and were not treated in the long-term

extension study).

Kaplan-Meier estimates of survival at 3 years in patients > 20 kg in weight at baseline were 94 %,

93 % and 85 % in the low, medium and high dose groups, respectively; for patients ≤ 20 kg in weight

at baseline, the survival estimates were 94 % and 93 % for subjects in the medium and high dose

groups respectively (see sections 4.4 and 4.8).

During the conduct of the study, there were a total of 42 deaths reported, whether on treatment or

reported as part of the survival follow-up. 37 deaths occurred prior to a decision taken by the Data

Monitoring Committee to down titrate subjects to a lower dosage, based on an observed mortality

imbalance with increasing sildenafil doses. Among these 37 deaths, the number (%) of deaths was

5/55 (9.1 %), 10/74 (13.5 %), and 22/100 (22 %) in the sildenafil low, medium, and high dose groups,

respectively. An additional 5 deaths were reported subsequently. The causes of deaths were related to

PAH. Higher than recommended doses should not be used in paediatric patients with PAH (see

sections 4.2 and 4.4).

Peak VO

was assessed 1 year after the start of the placebo-controlled study. Of those sildenafil

treated subjects developmentally able to perform the CPET 59/114 subjects (52 %) had not shown any

deterioration in Peak VO

from start of sildenafil. Similarly 191 of 229 subjects (83 %) who had

received sildenafil had either maintained or improved their WHO Functional Class at 1 year

assessment.

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

sildenafil in newborns with pulmonary arterial hypertension (see section 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 three times a day dosing of sildenafil, AUC and

increase in proportion with dose over the dose range of 20-40 mg. After oral doses of 80 mg

three times a day a more than dose proportional increase in sildenafil plasma levels has been

observed. In pulmonary arterial hypertension patients, the oral bioavailability of sildenafil after 80 mg

three times a day was on average 43 % (90 % CI: 27 %-60 %) higher compared to the lower doses.

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

60 minutes and a mean reduction in C

of 29 % however, the extent of absorption was not

significantly affected (AUC decreased by 11 %).

Distribution

The mean steady state volume of distribution (Vss) for sildenafil is 105 l, indicating distribution into

the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma

concentration of sildenafil at steady state is approximately 113 ng/ml. Sildenafil and its major

circulating N-desmethyl metabolite are approximately 96 % bound to plasma proteins. Protein binding

is independent of total drug concentrations.

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. The N-desmethyl metabolite is further

metabolised, with a terminal half-life of approximately 4 h. In patients with pulmonary arterial

hypertension, plasma concentrations of N-desmethyl metabolite are approximately 72 % those of

sildenafil after 20 mg three times a day dosing (translating into a 36 % contribution to sildenafil’s

pharmacological effects). The subsequent effect on efficacy is unknown.

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. In volunteers

with severe renal impairment (creatinine clearance < 30 ml/min), sildenafil clearance was reduced,

resulting in mean increases in AUC and C

of 100 % and 88 % respectively compared to age-

matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C

values were significantly increased by 200 % and 79 % respectively in subjects with severe renal

impairment compared to subjects with normal renal function.

Hepatic insufficiency

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

was reduced, resulting in increases in AUC (85 %) and C

(47 %) compared to age-matched

volunteers with no hepatic impairment. In addition, N-desmethyl metabolite AUC and C

values

were significantly increased by 154 % and 87 %, respectively in cirrhotic subjects compared to

subjects with normal hepatic function. The pharmacokinetics of sildenafil in patients with severely

impaired hepatic function have not been studied.

Population pharmacokinetics

In patients with pulmonary arterial hypertension, the average steady state concentrations were

20-50 % higher over the investigated dose range of 20–80 mg three times a day compared to healthy

volunteers. There was a doubling of the C

compared to healthy volunteers. Both findings suggest a

lower clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary arterial

hypertension compared to healthy volunteers.

Paediatric population

From the analysis of the pharmacokinetic profile of sildenafil in patients involved in the paediatric

clinical trials, body weight was shown to be a good predictor of drug exposure in children. Sildenafil

plasma concentration half-life values were estimated to range from 4.2 to 4.4 hours for a range of

10 to 70 kg of body weight and did not show any differences that would appear as clinically relevant.

after a single 20 mg sildenafil dose administered PO was estimated at 49, 104 and 165 ng/ml for

70, 20 and 10 kg patients, respectively. C

after a single 10 mg sildenafil dose administered PO was

estimated at 24, 53 and 85 ng/ml for 70, 20 and 10 kg patients, respectively. T

was estimated at

approximately 1 hour and was almost independent from body weight.

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 and carcinogenic potential, toxicity to

reproduction and development.

In pups of rats which were pre- and postnatally treated with 60 mg/kg sildenafil, a decreased litter

size, a lower pup weight on day 1 and a decreased 4-day survival were seen at exposures which were

approximately fifty times the expected human exposure at 20 mg three times a day. Effects in non-

clinical studies were observed at exposures considered sufficiently in excess of the maximum human

exposure indicating little relevance to clinical use.

There were no adverse reactions, with possible relevance to clinical use, seen in animals at clinically

relevant exposure levels which were not also observed in clinical studies.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

Lactose monohydrate

Microcrystalline cellulose

Povidone

Croscarmellose sodium

Magnesium stearate

Film coat:

Hypromellose

Titanium dioxide (E171)

Macrogol

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years.

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions

6.5

Nature and contents of container

Aluminium/PVC/PVDC blisters of 30, 90 or 100 tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

No special requirements for disposal.

7.

MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

{Name and address}

<{tel}>

<{fax}>

<{e-mail}>

8.

MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<Date of first authorisation: {DD month YYYY}>

<Date of latest renewal: {DD month YYYY}>

<[To be completed nationally]>

10.

DATE OF REVISION OF THE TEXT

2016-12-01

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