Vardegin 5 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:
vardenafilhydrokloridtrihydrat
Tillgänglig från:
Krka d.d., Novo mesto
ATC-kod:
G04BE09
INN (International namn):
vardenafilhydrokloridtrihydrat
Dos:
5 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
vardenafilhydrokloridtrihydrat 5,93 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Bemyndigande status:
Avregistrerad
Godkännandenummer:
54690
Tillstånd datum:
2017-03-30

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

16-02-2017

Produktens egenskaper Produktens egenskaper - engelska

16-02-2017

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

30-03-2017

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Package leaflet: Information for the patient

Vardegin 5 mg film-coated tablets

Vardegin 10 mg film-coated tablets

Vardegin 20 mg film-coated tablets

Vardenafil

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 Vardegin is and what it is used for

What you need to know before you take Vardegin

How to take Vardegin

Possible side effects

How to store Vardegin

Contents of the pack and other information

1.

What Vardegin is and what it is used for

Vardegin contains vardenafil, a member of a class of medicines called phosphodiesterase type 5

inhibitors. They are used for the treatment of erectile dysfunction in adult men, a condition which

implies difficulties in getting or keeping an erection.

At least one in ten men has trouble getting or keeping an erection at some time. There may be physical

or psychological causes, or a mixture of both. Whatever the cause is, due to muscle and blood vessel

changes not enough blood stays in the penis to make it hard and keep it hard.

Vardegin will only work when you are sexually stimulated. It reduces the action of the natural

chemical in your body which makes erections go away. Vardegin allows an erection to last long

enough for you to satisfactorily complete sexual activity.

2.

What you need to know before you take Vardegin

Do not take Vardegin:

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

Signs of an allergic reaction include a rash, itching, swollen face or lips and shortness of

breath.

If you are taking medicines containing nitrates, such as glycerol trinitrate for angina, or nitric

oxide donors, such as amyl nitrite. Taking these medicines with Vardegin could seriously affect

your blood pressure.

If you are taking ritonavir or indinavir, medicines used to treat human immunodeficiency virus

(HIV) infections.

If you are over 75 years of age and are taking ketoconazole or itraconazole, anti-fungal

medicines.

If you have a severe heart or liver problem.

If you are having kidney dialysis.

If you have recently had a stroke or heart attack.

If you have or have had low blood pressure.

If your family has a history of degenerative eye diseases (such as retinitis pigmentosa).

If you have ever had a condition involving loss of vision due to damage to the optic nerve from

insufficient blood supply known as non-arteritic ischemic optic neuropathy (NAION).

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 Vardegin have

been shown to increase the hypotensive effects of this medicine. If you are taking riociguat or

are unsure tell your doctor.

Warnings and precautions

Talk to your doctor or pharmacist before taking Vardegin.

Take special care with Vardegin

If you have heart trouble. It may be risky for you to have sex.

If you suffer from irregular heart beat (cardiac arrythmia) or inherited heart diseases affecting

your electrocardiogram.

If you have a physical condition affecting the shape of the penis. This includes conditions called

angulation, Peyronie’s disease and cavernosal fibrosis.

If you have an illness that can cause erections which won’t go away (priapism). These include

sickle cell disease, multiple myeloma and leukaemia.

If you have stomach ulcers (also called gastric or peptic ulcers).

If you have a bleeding disorder (such as haemophilia).

If you are using any other treatments for erection difficulties (see section: Other medicines and

Vardegin).

If you experience sudden decrease or loss of vision, stop taking Vardegin and contact your

doctor immediately.

Children and adolescents

Vardegin is not intended for use by children or adolescents under 18.

Other medicines and Vardegin

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

medicines.

Some medicines may cause problems, especially these:

Nitrates, medicines for angina, or nitric oxide donors, such as amyl nitrite. Taking these

medicines with Vardegin could seriously affect your blood pressure. Talk to a doctor without

taking Vardegin.

Medicine for the treatment of arrythmias, such as quinidine, procainamide, amiodarone or

sotalol.

Ritonavir or indinavir, medicines for HIV. Talk to a doctor without taking Vardegin.

Ketoconazole or itraconazole, anti-fungal medicines.

Erythromycin, or clarithromycin, macrolide antibiotics.

Alpha-blockers, a type of medicine used to treat high blood pressure and enlargement of the

prostate (as benign prostatic hyperplasia).

Riociguat.

Do not use Vardegin film-coated tablets combined with any other treatment for erectile dysfunction.

Vardegin with food, drink and alcohol

You can take Vardegin with or without food – but preferably not after a heavy or high-fat meal

as this may delay the effect.

Don’t drink grapefruit juice when you use Vardegin. It can interfere with the usual effect of the

medicine.

Alcoholic drink can make erection difficulties worse.

Pregnancy and breast-feeding

Vardegin is not for use by women.

Driving and using machines

Vardegin might make some people feel dizzy or affect their vision. If you feel dizzy, or if your vision

is affected after taking Vardegin don’t drive or operate any tools or machines.

3.

How to take Vardegin

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 dose is 10 mg.

Take a Vardegin tablet about 25 to 60 minutes before sexual activity. With sexual stimulation you may

achieve an erection anywhere from 25 minutes up to four to five hours after taking Vardegin.

Swallow one tablet with a glass of water

Do not take Vardegin

more than once a day.

Tell your doctor if you think Vardegin is too strong or too weak.

If you take more Vardegin than you should

Men who take too much Vardegin may experience more side effects or may get severe back pain. If

you take more Vardegin than you should, tell your doctor.

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. Most of the

effects are mild or moderate.

Partial, sudden, temporary or permanent decrease or loss of vision in one or both eyes has been

experienced by patients. Stop taking Vardegin and contact your doctor immediately.

Sudden decrease or loss of hearing has been reported.

The chance of having a side effect is described by the following categories:

Very common

(may affect more than 1 in 10 people)

Headache

Common

(may affect up to 1 in 10 people)

Dizziness

Flushing

Blocked or runny nose

Indigestion

Uncommon

(may affect up to 1 in 100 people)

Swelling of skin and mucous tissue including swollen face, lips or throat

Sleep disorder

Numbness and impaired perception of touch

Sleepiness

Effects on vision; redness of the eye, effects on colour vision, eye pain and discomfort, light

sensitivity

Ringing in the ears; vertigo

Fast heart beat or pounding heart

Breathlessness

Stuffy nose

Acid reflux, gastritis, abdominal pain, diarrhoea, vomiting; feeling sick (

nausea

), dry mouth

Raised levels of liver enzymes in your blood

Rash, reddened skin

Back or muscle pain; increase in blood of a muscle enzyme (

creatine phosphokinase

), muscle

stiffness

Prolonged erections

Malaise

Rare

(may affect up to 1 in 1,000 people)

Inflammation of the eyes (

conjunctivitis

Allergic reaction

Anxiety

Fainting

Amnesia

Seizure

Increased pressure in the eye (

glaucoma

), increased tearing of the eyes

Effects on the heart (such as heart attack, altered heart beat or angina)

High or low blood pressure

Nose bleed

Effect on results of blood tests to check liver function

Sensitivity of the skin to sun light

Painful erections

Chest pain

Not known

(frequency cannot be estimated from the available data)

Blood in the urine

(Haematuria)

Penile bleeding

(Penile Haemorrhage)

Presence of blood in the semen

(Haematospermia)

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 Vardegin

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 packaging after EXP. The expiry

date refers to the last day of that month.

This medicinal product 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 protect the environment.

6.

Contents of the pack and other information

What Vardegin contains

The active substance is vardenafil.

Each film-coated tablet contains 5 mg, 10 mg or 20 mg vardenafil (as vardenafil hydrochloride

trihydrate).

The other ingredients (excipients) are microcrystalline cellulose, crospovidone (Type A),

colloidal anhydrous silica, magnesium stearate (E470b) in the tablet core and hypromellose,

macrogol 4000, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172) in the

film coating.

What Vardegin looks like and contents of the pack

5 mg film-coated tablets: Film-coated tablets (tablets) are orange-brown, round, slightly biconvex,

with bevelled edges, engraved with 5 on one side, 5.5 mm in diameter.

10 mg film-coated tablets: Film-coated tablets (tablets) are orange-brown, oval, slightly biconvex,

scored on one side and engraved with 10 on the other side, dimensions 10.5 mm x 5.5 mm. The tablet

can be divided into equal doses.

20 mg film-coated tablets: Film-coated tablets (tablets) are orange-brown, round, biconvex, with

bevelled edges, scored on one side and engraved with 20 on the other side, 10 mm in diameter. The

tablet can be divided into equal doses.

Vardegin

is available in boxes containing:

2, 4, 8, 12, 20, 24 and 48 film-coated tablets in blisters,

2 x 1, 4 x 1, 8 x 1, 12 x 1, 20 x 1, 24 x 1 and 48 x 1 film-coated tablet in unit-dose blisters.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

[To be completed nationally]

Manufacturers

[To be completed nationally]

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

names:

[To be completed nationally]

This leaflet was last revised in

2017-02-16

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1.

NAME OF THE MEDICINAL PRODUCT

Vardegin 5 mg film-coated tablets

Vardegin 10 mg film-coated tablets

Vardegin 20 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

5 mg film-coated tablets:

Each film-coated tablet contains 5 mg vardenafil (as vardenafil hydrochloride trihydrate).

10 mg film-coated tablets:

Each film-coated tablet contains 10 mg vardenafil (as vardenafil hydrochloride trihydrate).

20 mg film-coated tablets:

Each film-coated tablet contains 20 mg vardenafil (as vardenafil hydrochloride trihydrate).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet (tablet)

5 mg film-coated tablets:

Orange-brown, round, slightly biconvex, film-coated tablets with bevelled edges, engraved with 5 on

one side, 5.5 mm in diameter.

10 mg film-coated tablets:

Orange-brown, oval, slightly biconvex, film-coated tablets, scored on one side and engraved with 10

on the other side, dimensions 10.5 mm x 5.5 mm. The tablet can be divided into equal doses.

20 mg film-coated tablets:

Orange-brown, round, biconvex, film-coated tablets with bevelled edges, scored on one side and

engraved with 20 on the other side, 10 mm in diameter. The tablet can be divided into equal doses.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of erectile dysfunction in adult men. Erectile dysfunction is the inability to achieve or

maintain a penile erection sufficient for satisfactory sexual performance.

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

4.2

Posology and method of administration

Posology

Use in adult men

The recommended dose is 10 mg taken as needed approximately 25 to 60 minutes before sexual

activity. Based on efficacy and tolerability the dose may be increased to 20 mg or decreased to 5 mg.

The maximum recommended dose is 20 mg. The maximum recommended dosing frequency is once

per day. Vardegin can be taken with or without food. The onset of activity may be delayed if taken

with a high fat meal (see section 5.2).

Special populations

Elderly (≥65 years old)

Dose adjustments are not required in elderly patients. However, an increase to a maximum 20 mg dose

should be carefully considered depending on the individual tolerability (see sections 4.4 and 4.8).

Hepatic impairment

A starting dose of 5 mg should be considered in patients with mild and moderate hepatic impairment

(Child-Pugh A-B). Based on tolerability and efficacy, the dose may subsequently be increased. The

maximum dose recommended in patients with moderate hepatic impairment (Child-Pugh B) is 10 mg

(see sections 4.3 and 5.2).

Renal impairment

No dose adjustment is required in patients with mild to moderate renal impairment.

In patients with severe renal impairment (creatinine clearance < 30 ml/min), a starting dose of 5 mg

should be considered. Based on tolerability and efficacy the dose may be increased to 10 mg and 20

Paediatric population

Vardegin is not indicated for individuals below 18 years of age. There is no relevant indication for use

of Vardegin in children.

Use in patients using other medicinal products

Concomitant use of CYP3A4 inhibitors

When used in combination with the CYP3A4 inhibitors such as erythromycin or clarithromycin, the

dose of vardenafil should not exceed 5 mg (see section 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.

The co-administration of vardenafil with nitrates or nitric oxide donors (such as amyl nitrite) in any

form is contraindicated (see sections 4.5 and 5.1).

Vardegin 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 phosphodiesterase 5 (PDE5) inhibitor exposure (see section 4.4).

Medicinal products for the treatment of erectile dysfunction should generally 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 [New York Heart Association III or IV]).

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

therefore contraindicated until further information is available:

severe hepatic impairment (Child-Pugh C),

end stage renal disease requiring dialysis,

hypotension (blood pressure <90/50 mmHg),

recent history of stroke or myocardial infarction (within the last 6 months),

unstable angina and known hereditary retinal degenerative disorders such as retinitis

pigmentosa.

Concomitant use of vardenafil with the potent CYP3A4 inhibitors ketoconazole and itraconazole (oral

form) is contraindicated in men older than 75 years.

Concomitant use of vardenafil with HIV protease inhibitors such as ritonavir and indinavir is

contraindicated, as they are very potent inhibitors of CYP3A4 (see section 4.5).

The co-administration of PDE5 inhibitors, including vardenafil, with guanylate cyclase stimulators,

such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section

4.5).

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.

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 (see

section 4.3). Vardenafil has vasodilator properties, resulting in mild and transient decreases in blood

pressure (see section 5.1). Patients with left ventricular outflow obstruction, e.g., aortic stenosis and

idiopathic hypertrophic subaortic stenosis, can be sensitive to the action of vasodilators including Type

5 phosphodiesterase inhibitors.

Medicinal products for the treatment of erectile dysfunction 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).

The safety and efficacy of combinations of Vardegin film-coated tablets with other treatments for

erectile dysfunction have not been studied. Therefore, the use of such combinations is not

recommended.

Tolerability of the maximum dose of 20 mg may be lower in elderly patients (≥ 65 years old) (see

sections 4.2 and 4.8).

Concomitant use of alpha-blockers

The concomitant use of alpha-blockers and vardenafil may lead to symptomatic hypotension in some

patients because both are vasodilators. Concomitant treatment with vardenafil should only be initiated

if the patient has been stabilised on his alpha-blocker therapy. In those patients who are stable on

alpha-blocker therapy, vardenafil should be initiated at the lowest recommended starting dose of 5 mg

film-coated tablets. Vardenafil may be administered at any time with tamsulosin or with alfuzosin.

With other alpha-blockers, a time separation of dosing should be considered when vardenafil is

prescribed concomitantly (see section 4.5). In those patients already taking an optimized dose of

vardenafil, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-

blocker dose may be associated with further lowering of blood pressure in patients taking vardenafil.

Concomitant use of CYP3A4 inhibitors

Concomitant use of vardenafil with potent CYP3A4 inhibitors such as itraconazole and ketoconazole

(oral form) should be avoided as very high plasma concentrations of vardenafil are reached if the

medicinal products are combined (see sections 4.5 and 4.3).

Vardenafil dose adjustment might be necessary if moderate CYP3A4 inhibitors such as erythromycin

and clarithromycin, are given concomitantly (see sections 4.5 and 4.2).

Concomitant intake of grapefruit or grapefruit juice is expected to increase the plasma concentrations

of vardenafil. The combination should be avoided (see section 4.5).

Effect on QTc interval

Single oral doses of 10 mg and 80 mg of vardenafil have been shown to prolong the QTc interval by a

mean of 8 msec and 10 msec, respectively. And single doses of 10 mg vardenafil co-administered

concomitantly with 400 mg gatifloxacin, an active substance with comparable QT effect, showed an

additive QTc effect of 4 msec when compared to either active substance alone. The clinical impact of

these QT changes is unknown (see section 5.1).

The clinical relevance of this finding is unknown and cannot be generalised to all patients under all

circumstances, as it will depend on the individual risk factors and susceptibilities that may be present

at any time in any given patient. Medicinal products that may prolong QTc interval, including

vardenafil, are best avoided in patients with relevant risk factors, for example, hypokalaemia,

congenital QT prolongation, concomitant administration of antiarrhythmic medicinal products in Class

1A (e.g. quinidine, procainamide), or Class III (e.g. amiodarone, sotalol).

Effect on vision

Visual defects and cases of non-arteritic ischaemic optic neuropathy (NAION) have been reported in

connection with the intake of vardenafil and other PDE5 inhibitors. The patient should be advised that

in the case of sudden visual defect, he should stop taking Vardegin and consult a physician

immediately (see section 4.3).

Effect on bleeding

In vitro

studies with human platelets indicate that vardenafil has no antiaggregatory effect on its own,

but at high (super-therapeutic) concentrations vardenafil potentiates the antiaggregatory effect of the

nitric oxide donor sodium nitroprusside. In humans, vardenafil had no effect on bleeding time alone or

in combination with acetylsalicyclic acid (see section 4.5). There is no safety information available on

the administration of vardenafil to patients with bleeding disorders or active peptic ulceration.

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

assessment.

4.5

Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on vardenafil

In vitro

studies

Vardenafil is metabolised predominantly by hepatic enzymes via cytochrome P450 (CYP) isoform

3A4, with some contribution from CYP3A5 and CYP2C isoforms. Therefore, inhibitors of these

isoenzymes may reduce vardenafil clearance.

In vivo

studies

Co-administration of the HIV protease inhibitor indinavir (800 mg three times a day), a potent

CYP3A4 inhibitor, with vardenafil (10 mg film-coated tablet) resulted in a 16-fold increase in

vardenafil AUC and a 7-fold increase in vardenafil C

. At 24 hours, the plasma levels of vardenafil

had fallen to approximately 4% of the maximum vardenafil plasma level (C

Co-administration of vardenafil with ritonavir (600 mg twice daily) resulted in a 13-fold increase in

vardenafil C

and a 49-fold increase in vardenafil AUC

0-24

when co-administered with vardenafil 5

mg. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a

highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the

half-life of vardenafil to 25.7 hours (see section 4.3).

Co-administration of ketoconazole (200 mg), a potent CYP3A4 inhibitor, with vardenafil (5 mg)

resulted in a 10-fold increase in vardenafil AUC and a 4-fold increase in vardenafil C

(see section

4.4).

Although specific interaction studies have not been conducted, the concomitant use of other potent

CYP3A4 inhibitors (such as itraconazole) can be expected to produce vardenafil plasma levels

comparable to those produced by ketoconazole. Concomitant use of vardenafil with potent CYP3A4

inhibitors such as itraconazole and ketoconazole (oral use) should be avoided (see sections 4.3 and

4.4). In men older than 75 years the concomitant use of vardenafil with itraconazole or ketoconazole is

contraindicated (see section 4.3).

Co-administration of erythromycin (500 mg three times a day), a CYP3A4 inhibitor, with vardenafil (5

mg) resulted in a 4-fold increase in vardenafil AUC and a 3-fold increase in C

. Although a specific

interaction study has not been conducted, the co-administration of clarithromycin can be expected to

result in similar effects on vardenafil AUC and C

. When used in combination with a moderate

CYP3A4 inhibitor such as erythromycin or clarithromycin, vardenafil dose adjustment might be

necessary (see sections 4.2 and 4.4). Cimetidine (400 mg twice daily), a non-specific cytochrome P450

inhibitor, had no effect on vardenafil AUC and C

when co-administered with vardenafil (20 mg) to

healthy volunteers.

Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism, may give rise to modest

increases in plasma levels of vardenafil (see section 4.4).

The pharmacokinetics of vardenafil (20 mg) was not affected by co-administration with the H2-

antagonist ranitidine (150 mg twice daily), digoxin, warfarin, glibenclamide, alcohol (mean maximum

blood alcohol level of 73 mg/dl) or single doses of antacid (magnesium hydroxide/aluminium

hydroxide).

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

pharmacokinetic analysis showed no effect on vardenafil pharmacokinetics of the following

concomitant medicinal products: acetylsalicylic acid, ACE-inhibitors, beta-blockers, weak CYP3A4

inhibitors, diuretics and medicinal products for the treatment of diabetes (sulfonylureas and

metformin).

Effects of vardenafil on other medicinal products

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

as theophylline or dipyridamole.

In vivo

studies

No potentiation of the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) was

observed when vardenafil (10 mg) was given at varying time intervals (1 h to 24 h) prior to the dose of

nitroglycerin in a study in 18 healthy male subjects. Vardenafil 20 mg film-coated tablet potentiated

the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 1 and 4 hours after

vardenafil administration to healthy middle aged subjects. No effect on blood pressure was observed

when nitroglycerin was taken 24 hours after administration of a single dose of vardenafil 20 mg film-

coated tablet. However, there is no information on the possible potentiation of the hypotensive effects

of nitrates by vardenafil in patients, and concomitant use is therefore contraindicated (see section 4.3).

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

potential to have serious interaction with vardenafil.

Since alpha-blocker monotherapy can cause marked lowering of blood pressure, especially postural

hypotension and syncope, interaction studies were conducted with vardenafil. In two interaction

studies with healthy normotensive volunteers after forced titration of the alpha-blockers tamsulosin or

terazosin to high doses, hypotension (in some cases symptomatic) was reported in a significant

number of subjects after co-administration of vardenafil. Among subjects treated with terazosin,

hypotension was observed more frequently when vardenafil and terazosin were given simultaneously

than when the dosing was separated by a time interval of 6 hours.

Based on the results of interaction studies conducted with vardenafil in patients with benign prostatic

hyperplasia (BPH) on stable tamsulosin, terazosin or alfuzosin therapy:

When vardenafil (film-coated tablets) was given at doses of 5, 10 or 20 mg on a background of

stable therapy with tamsulosin, there was no symptomatic reduction in blood pressure, although

3/21 tamsulosin treated subjects exhibited transient standing systolic blood pressures of less

than 85 mmHg.

When vardenafil 5 mg (film-coated tablets) was given simultaneously with terazosin 5 or 10

mg, one of 21 patients experienced symptomatic postural hypotension. Hypotension was not

observed when vardenafil 5 mg and terazosin administration was separated by 6 hours.

When vardenafil (film-coated tablets) was given at doses of 5 or 10 mg on a background of

stable therapy with alfuzosin, compared to placebo, there was no symptomatic reduction in

blood pressure.

Therefore, concomitant treatment should be initiated only if the patient is stable on his alpha-blocker

therapy. In those patients who are stable on alpha-blocker therapy, vardenafil should be initiated at the

lowest recommended starting dose of 5 mg. Vardegin may be administered at any time with

tamsulosin or alfuzosin. With other alpha-blockers a time separation of dosing should be considered

when vardenafil is prescribed concomitantly (see section 4.4).

No significant interactions were shown when warfarin (25 mg), which is metabolised by CYP2C9, or

digoxin (0.375 mg) was co-administered with vardenafil (20 mg film-coated tablets). The relative

bioavailability of glibenclamide (3.5 mg) was not affected when co-administered with vardenafil (20

mg). In a specific study, where vardenafil (20 mg) was co-administered with slow release nifedipine

(30 mg or 60 mg) in hypertensive patients, there was an additional reduction on supine systolic blood

pressure of 6 mmHg and supine diastolic blood pressure of 5 mmHg accompanied with an increase in

heart rate of 4 bpm.

When vardenafil (20 mg film-coated tablets) and alcohol (mean maximum blood alcohol level of 73

mg/dl) were taken together, vardenafil did not potentiate the effects of alcohol on blood pressure and

heart rate and the pharmacokinetics of vardenafil were not altered.

Vardenafil (10 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid (2 x

81 mg).

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

vardenafil, is contraindicated (see section 4.3).

4.6

Fertility, pregnancy and lactation

Vardegin is not indicated for use by women. There are no studies of vardenafil in pregnant women.

There are no fertility data available.

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 abnormal vision have been reported in clinical trials with vardenafil, patients should

be aware of how they react to Vardegin, before driving or operating machines.

4.8

Undesirable effects

The adverse reactions reported with vardenafil film-coated tablets in clinical trials were generally

transient and mild to moderate in nature. The most commonly reported adverse drug reaction

occurring in ≥ 10% of patients is headache.

Adverse reactions are listed according to the MedDRA frequency convention: 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) and not

known (can not be estimated from available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

The following adverse reactions have been reported:

Very

common

Common

Uncommon

Rare

Not known

Infection and

infestations

Conjunctivitis

Immune system

disorders

Allergic

oedema and

angioedema

Allergic reaction

Psychiatric

disorders

Sleep disorder

Anxiety

Nervous system

disorders

Headache

Dizziness

Somnolence

Paraesthesia

dysaesthesia

Syncope

Seizure

Amnesia

Eye disorders

Visual

disturbance

Ocular

hyperaemia

Visual colour

distortions

Eye pain and

eye discomfort

Photophobia

Increase in

intraocular pressure

Lacrimation

increased

Non-arteritic

anterior ischaemic

optic neuropathy

Visual defects

Ear and

labyrinth

disorders

Tinnitus

Vertigo

Sudden deafness

Cardiac

disorders

Palpitation

Tachycardia

Myocardial

infarction

Ventricular tachy-

arrythmias

Angina pectoris

Vascular

disorders

Flushing

Hypertension

Hypotension

Respiratory,

thoracic and

mediastinal

disorders

Nasal

congestion

Dyspnoea

Sinus

congestion

Epistaxis

Gastrointestinal

disorders

Dyspepsia

Gastro-

oesophageal

reflux disease

Gastritis

Gastrointestinal

and abdominal

pain

Diarrhoea

Vomiting

Nausea

Dry mouth

Hepatobiliary

disorders

Increase in

transaminases

Increase in gamma-

glutamyl-

transferase

Skin and

subcutaneous

tissue disorders

Erythema

Rash

Photosensitivity

reaction

Musculoskeletal

and connective

tissue disorders

Back pain

Increase in

creatine

phosphokinase

Myalgia

Increased

muscle tone

and cramping

Renal and

urinary

disorders

Haematuria

Reproductive

system and

breast disorders

Increase in

erection

Priapism

Penile

Haemorrhage

Haematospermia

General

disorders and

administration

site conditions

Feeling unwell

Chest pain

Penile haemorrhage, haematospermia and haematuria have been reported in clinical trials and

spontaneous post-marketing data with the use of all PDE5 inhibitors, including vardenafil.

At the 20 mg dose vardenafil film-coated tablets, elderly (≥ 65 years old) patients had higher

frequencies of headaches (16.2% versus 11.8%) and dizziness (3.7% versus 0.7%) than younger

patients (< 65 years old). In general, the incidence of adverse reactions (especially “dizziness”) has

been shown to be slightly higher in patients with a history of hypertension.

Post-marketing reports of another medicinal product of this class

Vascular disorders

Serious cardiovascular reactions, including cerebrovascular haemorrhage, sudden cardiac death,

transient ischaemic attack, unstable angina and ventricular arrhythmia have been reported post-

marketing in temporal association with another medicinal product in this class.

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, doses up to and including 80 mg vardenafil (film-coated tablets) per

day were tolerated without exhibiting serious adverse reactions.

When vardenafil was administered in higher doses and more frequently than the recommended dose

regimen (40 mg film-coated tablets twice daily) cases of severe back pain have been reported. This

was not associated with any muscle or neurological toxicity.

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

not expected to accelerate clearance, as vardenafil is highly bound to plasma proteins and not

significantly eliminated in the urine.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: urologicals, drugs used in erectile dysfunction, ATC code: G04BE09.

Vardenafil is an oral therapy for the improvement of erectile function in men with erectile dysfunction.

In the natural setting, i.e., with sexual stimulation, it restores impaired erectile function by increasing

blood flow to the penis.

Penile erection is a haemodynamic process. During sexual stimulation, nitric oxide is released. It

activates the enzyme guanylate cyclase, resulting in an increased level of cyclic guanosine

monophosphate (cGMP) in the corpus cavernosum. This in turn results in smooth muscle relaxation,

allowing increased inflow of blood into the penis. The level of cGMP is regulated by the rate of

synthesis via guanylate cyclase and by the rate of degradation via cGMP hydrolysing

phosphodiesterases (PDEs).

Vardenafil is a potent and selective inhibitor of the cGMP specific phosphodiesterase type 5 (PDE5),

the most prominent PDE in the human corpus cavernosum. Vardenafil potently enhances the effect of

endogenous nitric oxide in the corpus cavernosum by inhibiting PDE5. When nitric oxide is released

in response to sexual stimulation, inhibition of PDE5 by vardenafil results in increased corpus

cavernosum levels of cGMP. Sexual stimulation is therefore required for vardenafil to produce its

beneficial therapeutic effects.

In vitro

studies have shown that vardenafil is more potent on PDE5 than on other known

phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to

PDE11, and >1000-fold relative to PDE2, PDE3, PDE4, PDE7, PDE8, PDE9 and PDE10).

In a penile plesthysmography (RigiScan) study, vardenafil 20 mg produced erections considered

sufficient for penetration (60% rigidity by RigiScan) in some men as early as 15 minutes after dosing.

The overall response of these subjects to vardenafil became statistically significant, compared to

placebo, 25 minutes after dosing.

Vardenafil causes mild and transient decreases in blood pressure which, in the majority of the cases,

do not translate into clinical effects. The mean maximum decreases in supine systolic blood pressure

following 20 mg and 40 mg vardenafil were – 6.9 mmHg under 20 mg and – 4.3 mmHg under 40 mg

of vardenafil, when compared to placebo. These effects are consistent with the vasodilatory effects of

PDE5-inhibitors and are probably due to increased cGMP levels in vascular smooth muscle cells.

Single and multiple oral doses of vardenafil up to 40 mg produced no clinically relevant changes in the

ECGs of normal male volunteers.

A single dose, double blind, crossover, randomised trial in 59 healthy males compared the effects on

the QT interval of vardenafil (10 mg and 80 mg), sildenafil (50 mg and 400 mg) and placebo.

Moxifloxacin (400 mg) was included as an active internal control. Effects on the QT interval were

measured one hour post-dose (average t

for vardenafil). The primary objective of this study was to

rule out a greater than 10 msec effect (i.e., to demonstrate lack of effect) of a single 80 mg oral dose of

vardenafil on QTc interval compared to placebo, as measured by the change in Fridericia's correction

formula (QTcF=QT/RR1/3) from baseline at the 1 hour post-dose time point. The vardenafil results

showed an increase in QTc (Fridericia) of 8 msec (90% CI: 6-9) and 10 msec (90% CI: 8-11) at 10 and

80 mg doses compared to placebo and an increase in QTci of 4 msec (90% CI: 3-6) and 6 msec (90%

CI: 4-7) at 10 and 80 mg doses compared to placebo, at one hour post-dose. At t

, only the mean

change in QTcF for vardenafil 80 mg was out of the study established limit (mean 10 msec, 90% CI:

8-11). When using the individual correction formulae, none of the values were out of the limit.

In a separate post-marketing study of 44 healthy volunteers, single doses of 10 mg vardenafil or 50 mg

sildenafil were co-administered concomitantly with 400 mg gatifloxacin, a drug with comparable QT

effect. Both vardenafil and sildenafil showed an increase of Fridericia QTc effect of 4 msec

(vardenafil) and 5 msec (sildenafil) when compared to either drug alone. The actual clinical impact of

these QT changes is unknown.

Further information on clinical trials

In clinical trials vardenafil was administered to over 17,000 men with erectile dysfunction (ED) aged

18 - 89 years, many of whom had multiple co-morbid conditions. Over 2,500 patients have been

treated with vardenafil for six months or longer. Of these, 900 patients have been treated for one year

or longer.

The following patient groups were represented: elderly (22%), patients with hypertension (35%),

diabetes mellitus (29%), ischaemic heart disease and other cardiovascular diseases (7%), chronic

pulmonary disease (5%), hyperlipidemia (22%), depression (5%), radical prostatectomy (9%). The

following groups were not well represented in clinical trials: elderly (>75 years, 2.4%), and patients

with certain cardiovascular conditions (see section 4.3). No clinical trials in CNS diseases (except

spinal cord injury), patients with severe renal or hepatic impairment, pelvic surgery (except nerve-

sparing prostatectomy) or trauma or radiotherapy and hypoactive sexual desire or penile anatomic

deformities have been performed.

Across the pivotal trials, treatment with vardenafil (film-coated tablets) resulted in an improvement of

erectile function compared to placebo. In the small number of patients who attempted intercourse up to

four to five hours after dosing the success rate for penetration and maintenance of erection was

consistently greater than placebo.

In fixed dose studies (film-coated tablets) in a broad population of men with erectile dysfunction, 68%

(5 mg), 76% (10 mg) and 80% (20 mg) of patients experienced successful penetrations (SEP 2)

compared to 49% on placebo over a three month study period. The ability to maintain the erection

(SEP 3) in this broad ED population was given as 53% (5 mg), 63% (10 mg) and 65% (20 mg)

compared to 29% on placebo.

In pooled data from the major efficacy trials, the proportion of patients experiencing successful

penetration on vardenafil were as follows: psychogenic erectile dysfunction (77-87%), mixed erectile

dysfunction (69-83%), organic erectile dysfunction (64-75%), elderly (52-75%), ischaemic heart

disease (70-73%), hyperlipidemia (62-73%), chronic pulmonary disease (74-78%), depression (59-

69%), and patients concomitantly treated with antihypertensives (62-73%).

In a clinical trial in patients with diabetes mellitus, vardenafil significantly improved the erectile

function domain score, the ability to obtain and maintain an erection long enough for successful

intercourse and penile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. The

response rates for the ability to obtain and maintain an erection was 61% and 49% on 10 mg and 64%

and 54% on 20 mg vardenafil compared to 36% and 23% on placebo for patients who completed three

months treatment.

In a clinical trial in post-prostatectomy patients, vardenafil significantly improved the erectile function

domain score, the ability to obtain and maintain an erection long enough for successful intercourse and

penile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. The response rates for the

ability to obtain and maintain an erection was 47% and 37% on 10 mg and 48% and 34% on 20 mg

vardenafil compared to 22% and 10% on placebo for patients who completed three months treatment.

In a flexible-dose clinical trial in patients with Spinal Cord Injury, vardenafil significantly improved

the erectile function domain score, the ability to obtain and maintain an erection long enough for

successful intercourse and penile rigidity compared to placebo. The number of patients who returned

to a normal IIEF domain score (≥26) were 53% on vardenafil compared to 9% on placebo. The

response rates for the ability to obtain and maintain an erection were 76% and 59% on vardenafil

compared to 41% and 22% on placebo for patients who completed three months treatment which were

clinically and statistically significant (p<0.001).

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

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies in all

subsets of the paediatric population in the treatment of the erectile dysfunction. See section 4.2 for

information on paediatric use.

5.2

Pharmacokinetic properties

Bioequivalence studies have shown that vardenafil 10 mg orodispersible tablet is not bioequivalent to

vardenafil 10 mg film-coated tablets; therefore, the orodispersible formulation should not be used as

an equivalent to vardenafil 10 mg film-coated tablets.

Absorption

In vardenafil film-coated tablets, vardenafil is rapidly absorbed with maximum observed plasma

concentrations reached in some men as early as 15 minutes after oral administration. However, 90% of

the time, maximum 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 15%. After oral dosing of

vardenafil AUC and C

increase almost dose proportionally over the recommended dose range (5 –

20 mg).

When vardenafil film-coated tablets are taken with a high fat meal (containing 57% fat), the rate of

absorption is reduced, with an increase in the median t

of 1 hour and a mean reduction in C

20%. Vardenafil AUC is not affected. After a meal containing 30% fat, the rate and extent of

absorption of vardenafil (t

and AUC) are unchanged compared to administration under fasting

conditions.

Distribution

The mean steady state volume of distribution for vardenafil is 208 l, indicating distribution into the

tissues.

Vardenafil and its major circulating metabolite (M1) are highly bound to plasma proteins

(approximately 95% for vardenafil or M1). For vardenafil as well as M1, protein binding is

independent of total drug concentrations.

Based on measurements of vardenafil in semen of healthy subjects 90 minutes after dosing, not more

than 0.00012% of the administered dose may appear in the semen of patients.

Biotransformation

Vardenafil in film-coated tablets is metabolised predominantly by hepatic metabolism via cytochrome

P450 (CYP) isoform 3A4 with some contribution from CYP3A5 and CYP2C isoforms.

In humans the one major circulating metabolite (M1) results from desethylation of vardenafil and is

subject to further metabolism with a plasma elimination half-life of approximately 4 hours. Parts of

M1 are in the form of the glucuronide in systemic circulation. Metabolite M1 shows a

phosphodiesterase selectivity profile similar to vardenafil and an

in vitro

potency for

phosphodiesterase type 5 of approximately 28% compared to vardenafil, resulting in an efficacy

contribution of about 7%.

Elimination

The total body clearance of vardenafil is 56 l/h with a resultant terminal half-life of approximately 4-5

hours. After oral administration, vardenafil is excreted as metabolites predominantly in the faeces

(approximately 91-95% of the administered dose) and to a lesser extent in the urine (approximately 2-

6% of the administered dose).

Pharmacokinetics in special patient groups

Elderly

Hepatic clearance of vardenafil in healthy elderly volunteers (65 years and over) was reduced as

compared to healthy younger volunteers (18 - 45 years). On average elderly males taking vardenafil

film-coated tablets had a 52% higher AUC, and a 34% higher C

than younger males (see section

4.2).

Renal impairment

In volunteers with mild to moderate renal impairment (creatinine clearance 30 – 80 ml/min), the

pharmacokinetics of vardenafil were similar to that of a normal renal function control group. In

volunteers with severe renal impairment (creatinine clearance < 30 ml/min) the mean AUC was

increased by 21% and the mean C

decreased by 23%, compared to volunteers with no renal

impairment. No statistically significant correlation was observed between creatinine clearance and

vardenafil exposure (AUC and C

) (see section 4.2). Vardenafil pharmacokinetics has not been

studied in patients requiring dialysis (see section 4.3).

Hepatic impairment

In patients with mild to moderate hepatic impairment (Child-Pugh A and B), the clearance of

vardenafil was reduced in proportion to the degree of hepatic impairment. In patients with mild hepatic

impairment (Child-Pugh A), the mean AUC and C

increased 17% and 22% respectively, compared

to healthy control subjects. In patients with moderate impairment (Child-Pugh B), the mean AUC and

increased by 160% and 133% respectively, compared to healthy control subjects (see section 4.2).

The pharmacokinetics of vardenafil in patients with severely impaired hepatic function (Child-Pugh C)

has not been studied (see section 4.3).

5.3

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core

Cellulose, microcrystalline

Crospovidone, Type A

Silica, colloidal anhydrous

Magnesium stearate (E470b)

Film coating

Hypromellose

Macrogol 4000

Titanium dioxide (E171)

Iron oxide, yellow (E172)

Iron oxide, red (E172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

Blister (PVC/PVDC//Alu foil): 2, 4, 8, 12, 20, 24 and 48 film-coated tablets, in a box.

Unit-dose blister (PVC/PVDC//Alu foil): 2 x 1, 4 x 1, 8 x 1, 12 x 1, 20 x 1, 24 x 1 and 48 x 1 film-

coated tablet, in a box.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements for disposal.

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

requirements.

7.

MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8.

MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

[To be completed nationally]

10.

DATE OF REVISION OF THE TEXT

2017-02-16

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