Vardenafil 20mg tablets

United Kingdom - English - eMC (Electronic Medicines Compendium)

Buy It Now

Active ingredient:
Vardenafil hydrochloride trihydrate
Available from:
Zentiva
ATC code:
G04BE09
INN (International Name):
Vardenafil hydrochloride trihydrate
Dosage:
20mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 07040500; GTIN: 8594739230958 8594739230965

Package Leaflet: Information for the user

Vardenafil 5 mg tablets

Vardenafil 10 mg tablets

Vardenafil 20 mg tablets

vardenafil

Read all of this leaflet carefully before you start using 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

1. What Vardenafil is and what it is used for

2. What you need to know before you take Vardenafil

3. How to take Vardenafil

4. Possible side effects

5. How to store Vardenafil

6. Contents of the pack and other information

1.

WHAT VARDENAFIL IS AND WHAT IT IS USED FOR

Vardenafil 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.

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

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

enough for you to satisfactorily complete sexual activity.

2.

WHAT YOU NEED TO KNOW BEFORE YOU TAKE VARDENAFIL

Do not take Vardenafil

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

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 Vardenafil 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

Vardenafil 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 Vardenafil.

Take special care with Vardenafil

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

If you suffer from irregular heart beat (cardiac arrhythmia) 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, including Vardenafil orodispersible

tablets (see section: Other medicines and Vardenafil).

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

immediately.

Children and adolescents

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

Other medicines and Vardenafil

Please tell your doctor or pharmacist if you are using, have recently used or might use any other

medicines, including medicines obtained without a prescription.

Some medicines may cause problems, especially these:

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

with Vardenafil could seriously affect your blood pressure. Talk to a doctor without taking Vardenafil.

Medicine for the treatment of arrhythmias, such as quinidine, procainamide, amiodarone or sotalol.

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

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 Vardenafil tablets combined with any other treatment for erectile dysfunction.

Vardenafil with food, drink and alcohol

You can take Vardenafil 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 Vardenafil. It can interfere with the usual effect of the

medicine.

Alcoholic drink can make erection difficulties worse.

Pregnancy and breast-feeding

Vardenafil is not for use by women.

Driving and using machines

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

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

Vardenafil contains aspartame (E951)

Vardenafil

contains

aspartame,

source

phenylalanine.

harmful

people

with

phenylketonuria. If you suffer from phenylketonuria (a rare, hereditary disorder of the metabolism)

talk to your doctor before you start to take this medicine.

3.

HOW TO TAKE VARDENAFIL

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

if you are not sure. The recommended dose is 10 mg.

Take a Vardenafil 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 Vardenafil.

Swallow one tablet with a glass of water.

Do not take Vardenafil

more than once a day.

Tell your doctor if you think Vardenafil is too strong or too weak. He or she may suggest a switch to

an alternative Vardenafil formulation with a different dose, depending on how well it works for you.

If you take more Vardenafil than you should

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

If you take more Vardenafil 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 Vardenafil 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 users):

Headache

Common

(may affect up to 1 in 10 users):

Dizziness

Flushing

Blocked or runny nose

Indigestion

Uncommon

(may affect up to 1 in 100 users):

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 users):

Inflammation of the eyes (conjunctivitis)

Allergic reaction

Anxiety

Fainting

Amnesia

Seizure

Increase pressure in the eye (glaucoma), lacrimation increased

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

Very rare or not known

(may affect less than 1 in 10,000 users or 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. This includes any possible side effects not listed in this leaflet.

You can also report side effects directly via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or

search for MHRA Yellow Card in the Google Play or Apple App Store.

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

5.

HOW TO STORE VARDENAFIL

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.

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 Vardenafil contains

The active substance is Vardenafil.

Vardenafil is available in three strengths, containing either 5 mg, 10 mg or 20 mg of Vardenafil.

The other ingredients of the tablets are:

Cellulose microcrystalline

Crospovidone

Silica colloidal anhydrous

Aspartame (E951)

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Magnesium Stearate

What Vardenafil looks like and contents of the pack

Vardenafil 5 mg is presented as 6 mm orange, round, biconvex tablets marked “5” on one side.

Vardenafil 10 mg is presented as 7 mm orange, round, biconvex tablets marked “10” on one side.

Vardenafil 20 mg is presented as 9 mm orange, round, biconvex tablets marked “20” on one side.

The tablets are provided in blister packs containing 2, 4, 8, 12 or 20 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Rivopharm UK Ltd.

Floor, 40 Bank Street, Canary Wharf

E14 5NR, London

United Kingdom

Manufacturer:

Rivopharm UK Ltd.

Floor, 40 Bank Street, Canary Wharf

E14 5NR, London

United Kingdom

Laboratories BTT

ZI de Krafft

67150 Erstein

France

This leaflet was last revised in {month YYYY}.

R/MA/0062-64/PIL/001

Package Leaflet: Information for the user

Vardenafil 5 mg tablets

Vardenafil 10 mg tablets

Vardenafil 20 mg tablets

vardenafil

Read all of this leaflet carefully before you start using 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

1. What Vardenafil is and what it is used for

2. What you need to know before you take Vardenafil

3. How to take Vardenafil

4. Possible side effects

5. How to store Vardenafil

6. Contents of the pack and other information

1.

WHAT VARDENAFIL IS AND WHAT IT IS USED FOR

Vardenafil 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.

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

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

enough for you to satisfactorily complete sexual activity.

2.

WHAT YOU NEED TO KNOW BEFORE YOU TAKE VARDENAFIL

Do not take Vardenafil

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

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 Vardenafil 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

Vardenafil 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 Vardenafil.

Take special care with Vardenafil

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

If you suffer from irregular heart beat (cardiac arrhythmia) 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, including Vardenafil orodispersible

tablets (see section: Other medicines and Vardenafil).

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

immediately.

Children and adolescents

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

Other medicines and Vardenafil

Please tell your doctor or pharmacist if you are using, have recently used or might use any other

medicines, including medicines obtained without a prescription.

Some medicines may cause problems, especially these:

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

with Vardenafil could seriously affect your blood pressure. Talk to a doctor without taking Vardenafil.

Medicine for the treatment of arrhythmias, such as quinidine, procainamide, amiodarone or sotalol.

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

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 Vardenafil tablets combined with any other treatment for erectile dysfunction.

Vardenafil with food, drink and alcohol

You can take Vardenafil 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 Vardenafil. It can interfere with the usual effect of the

medicine.

Alcoholic drink can make erection difficulties worse.

Pregnancy and breast-feeding

Vardenafil is not for use by women.

Driving and using machines

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

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

Vardenafil contains aspartame (E951)

Vardenafil

contains

aspartame,

source

phenylalanine.

harmful

people

with

phenylketonuria. If you suffer from phenylketonuria (a rare, hereditary disorder of the metabolism)

talk to your doctor before you start to take this medicine.

3.

HOW TO TAKE VARDENAFIL

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

if you are not sure. The recommended dose is 10 mg.

Take a Vardenafil 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 Vardenafil.

Swallow one tablet with a glass of water.

Do not take Vardenafil

more than once a day.

Tell your doctor if you think Vardenafil is too strong or too weak. He or she may suggest a switch to

an alternative Vardenafil formulation with a different dose, depending on how well it works for you.

If you take more Vardenafil than you should

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

If you take more Vardenafil 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 Vardenafil 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 users):

Headache

Common

(may affect up to 1 in 10 users):

Dizziness

Flushing

Blocked or runny nose

Indigestion

Uncommon

(may affect up to 1 in 100 users):

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 users):

Inflammation of the eyes (conjunctivitis)

Allergic reaction

Anxiety

Fainting

Amnesia

Seizure

Increase pressure in the eye (glaucoma), lacrimation increased

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

Very rare or not known

(may affect less than 1 in 10,000 users or 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. This includes any possible side effects not listed in this leaflet.

You can also report side effects directly via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or

search for MHRA Yellow Card in the Google Play or Apple App Store.

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

5.

HOW TO STORE VARDENAFIL

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.

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 Vardenafil contains

The active substance is Vardenafil.

Vardenafil is available in three strengths, containing either 5 mg, 10 mg or 20 mg of Vardenafil.

The other ingredients of the tablets are:

Cellulose microcrystalline

Crospovidone

Silica colloidal anhydrous

Aspartame (E951)

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Magnesium Stearate

What Vardenafil looks like and contents of the pack

Vardenafil 5 mg is presented as 6 mm orange, round, biconvex tablets marked “5” on one side.

Vardenafil 10 mg is presented as 7 mm orange, round, biconvex tablets marked “10” on one side.

Vardenafil 20 mg is presented as 9 mm orange, round, biconvex tablets marked “20” on one side.

The tablets are provided in blister packs containing 2, 4, 8, 12 or 20 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Rivopharm UK Ltd.

Floor, 40 Bank Street, Canary Wharf

E14 5NR, London

United Kingdom

Manufacturer:

Rivopharm UK Ltd.

Floor, 40 Bank Street, Canary Wharf

E14 5NR, London

United Kingdom

Laboratories BTT

ZI de Krafft

67150 Erstein

France

This leaflet was last revised in

11/2017

R/MA/0062-64/PIL/001

SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT

Vardenafil 20 mg tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 20 mg of vardenafil (as hydrochloride).

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Tablet.

Vardenafil 20 mg is presented as 9 mm orange, round, biconvex tablets

marked “20” on one side.

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 Vardenafil 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.

Vardenafil 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 mg.

Paediatric population

Vardenafil is not indicated for individuals below 18 years of age. There is no

relevant indication for use of Vardenafil 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).

Vardenafil 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,

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 Vardenafil 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

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

prolongation,

concomitant

administration

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. Analyses of

observational data suggest an increased risk of acute NAION in men with erectile dysfunction

following exposure to PDE5 inhibitors such as vardenafil, tadalafil and sildenafil (see section

4.8). As this may be relevant for all patients exposed to vardenafil the patient should be

advised that in

the case of sudden visual defect, he should stop taking Vardenafil and consult

immediately a physician (see

section 4.3).

Effect on bleeding

In vitro studies with human platelets indicate that vardenafil has no antiaggregatory effect on

own,

high

(super-therapeutic)

concentrations

vardenafil

potentiates

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 tablet) resulted in a

16-fold increase in vardenafil AUC and a 7-fold increase in vardenafil Cmax.

At 24 hours, the plasma levels of vardenafil had fallen to approximately 4% of

the maximum vardenafil plasma level (Cmax).

Co-administration of vardenafil with ritonavir (600 mg twice daily) resulted in

a 13-fold increase in vardenafil Cmax and a 49-fold increase in vardenafil

AUC0-24 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 Cmax (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 Cmax. 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 Cmax. 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 Cmax 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 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 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 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 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 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. Vardenafil 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 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 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

Vardenafil 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 Vardenafil , before

driving or operating machines.

4.8

Undesirable effects

The adverse reactions reported with Vardenafil 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 (cannot 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:

System

organ

class

Very

common

1/10)

Common

1/100

<1/10)

Uncommon

1/1,000

<1/100)

Rare

1/10,000 to

<1/1,000)

Not Known

(cannot be

estimated

from

available

data)

Infection

infestation

Conjunctivitis

System

organ

class

Very

common

1/10)

Common

1/100

<1/10)

Uncommon

1/1,000

<1/100)

Rare

1/10,000 to

<1/1,000)

Not Known

(cannot be

estimated

from

available

data)

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

disorders

Visual disturbance

Ocular hyperaemia

Visual

colour

distortions

pain

discomfort

Photophobia

Increas

intraoc

ular

pressur

Lacrimation

increased

Non-arteritic

anterior

ischemic

optic

neuropathy

Visual defects

labyrinth

disorders

Tinnitus

Vertigo

Sudden deafness

Cardiac

disorders

Palpitation

Tachycardia

Myocardial

infarction

Ventricular

tachy-

arrhythmias

Angina

Vascular

disorders

Flushing

Hypertension

Hypotension

Respiratory,

thoracic and

mediastinal

disorders

Nasal

congestion

Dyspnoea

Sinus congestion

Epistaxis

System

organ

class

Very

common

1/10)

Common

1/100

<1/10)

Uncommon

1/1,000

<1/100)

Rare

1/10,000 to

<1/1,000)

Not Known

(cannot be

estimated

from

available

data)

Gastroint

estinal

disorders

Dyspepsia

Gastro-oesopha

geal

reflux

disease

Gastritis

Gastrointestinal

abdominal

pain

Diarrhoea

Vomiting

Nausea

Dry mouth

Hepatobili

disorders

Increase

transaminases

Increase

gamma-

glutamyl

transferase

Skin

subc

utane

Erythema Rash

Photosensitivi

ty reaction

Musculosk

elet al and

connective

tissue

disorders

Back pain

Increase in creatine

phosphokinase

Myalgia

Increased

muscle

tone and cramping

Renal

urinary

disorders

Haematuria

Reproducti

system

breast

disorders

Increase in erection

Priapism

Penile

Haemorrhage

Haematospermi

General

disorders

administra

tion

site

conditions

Feeling unwell

Chest pain

Public Assessment Report

UKPAR

Vardenafil Crescent 5mg film-coated tablets

Vardenafil Crescent 10mg film-coated tablets

Vardenafil Crescent 20mg film-coated tablets

(vardenafil hydrochloride trihydrate)

UK licence Number:

PL 20416/0532-534

Crescent Pharma Limited

UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

PL 20416/0532-534

2

LAY SUMMARY

Vardenafil Crescent 5, 10 and 20mg film-coated tablets

(vardenafil hydrochloride trihydrate)

This is a summary of the Public Assessment Report (PAR) for Vardenafil Crescent 5,

10 and 20mg film-coated tablets (PL 20416/0532-534).

This summary explains how Vardenafil Crescent 5, 10 and 20mg film-coated tablets

were assessed and their authorisations recommended, as well as their conditions of

use. It is not intended to provide practical advice on how to use these products.

The products will be collectively referred to as Vardenafil Tablets throughout the

remainder of this lay summary.

For practical information about using Vardenafil Tablets , patients should read the

package leaflet available on the MHRA website

or contact their doctor or pharmacist.

What are Vardenafil Tablets and what are they used for?

Vardenafil Tablets are ‘generic medicines’. This means that Vardenafil Tablets are

similar to ‘reference medicines’ already authorised in the European Union (EU) called

Levitra 5, 10 and 20mg film coated tablets, which are currently granted Marketing

Authorisations to Bayer Pharma AG.

Vardenafil Tablets contain 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.

How do

Vardenafil Tablets work?

The active substance in this medicine is called Vardenafil. It reduces the action of the

natural chemical in your body which makes erections go away. Vardenafil Tablets

allows an erection to last long enough for you to satisfactorily complete sexual

activity. Vardenafil Tablets will only work when you are sexually stimulated.

How are Vardenafil Tablets used?

The pharmaceutical form of this medicine is a film-coated tablet and the route of

administration is oral.

This medicine should be taken exactly as advised by the patient’s doctor or

pharmacist. The patient should check with their doctor or pharmacist if they are not

sure.

The recommended dose is 10mg, the maximum dose is 20mg per day. The maximum

recommended of times to take a dose is once per day. Vardenafil Tablets should be

taken about 25 to 60 minutes before sexual activity. With sexual stimulation the

patient may achieve an erection anywhere from 25 minutes up to four to five hours

after taking Vardenafil Tablets.

UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

PL 20416/0532-534

3

One Vardenafil Tablet should be swallowed with a glass of water

Vardenafil Tablets must not be taken more than once a day.

The patient should tell their doctor if they think that Vardenafil Tablets, are too strong

or too weak. The doctor may suggest a switch to a different dose, depending on how

well it works for the patient.

Please read Section 3 of the package leaflet for detailed information on dosing

recommendations, the route of administration, and the duration of treatment.

The medicine can only be obtained with a prescription.

What benefits of Vardenafil Tablets have been shown in studies?

Because Vardenafil Tablets are generic medicines, studies in people have been limited

to tests to determine that the medicines are bioequivalent to the reference products

Levitra 5, 10 and 20mg film coated tablets (Bayer Pharma AG). Two medicines are

bioequivalent when they produce similar levels of active substance in the body.

What are the possible side effects of Vardenafil Tablets?

Because Vardenafil Tablets are generic medicines, their possible side effects are taken

as being the same as those of the reference products, Levitra 5, 10 and 20mg film

coated tablets (Bayer Pharma AG).

For the full list of all side effects reported with Vardenafil Tablets, see Section 4 of

the package leaflet available on the MHRA website.

For the full list of restrictions, see the package leaflet.

Why are Vardenafil Tablets approved?

It was concluded that, in accordance with EU requirements, Vardenafil Tablets have

been shown to have comparable quality and to be bioequivalent to Levitra 5, 10 and

20mg film coated tablets. Therefore, the MHRA considered that, as for the reference

medicines, Levitra 5, 10 and 20mg film coated tablets, the benefits are greater than the

risks and recommended that Vardenfil Tablets can be approved for use.

What measures are being taken to ensure the safe and effective use of Vardenafil

Tablets?

A Risk Management Plan (RMP) has been developed to ensure that Vardenafil

Tablets are used as safely as possible. Based on this plan, safety information has been

included in the Summaries of Product Characteristics and the package leaflet of

Vardenafil Tablets, including the appropriate precautions to be followed by patients.

Known side-effects are continuously monitored. Furthermore, new safety signals

reported by patients and healthcare professionals will be monitored and reviewed

continuously, as well.

Other information about Vardenafil Tablets

The UK granted Marketing Authorisations for Vardenafil Tablets on 25 August 2017.

The full PAR for Vardenafil Tablets follows this summary.

For more information about treatment with Vardenafil Tablets, read the package

UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

PL 20416/0532-534

4

leaflet or contact your doctor or pharmacist.

This summary was last updated in August 2017.

UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

PL 20416/0532-534

5

Vardenafil Crescent 5, 10 and 20mg film-coated tablets

TABLE OF CONTENTS

Introduction

Page 6

Quality aspects

Page 7

Non-clinical aspects

Page 9

User consultation

Page 13

Overall conclusion, benefit/risk assessment

and recommendation

Page 13

Table of content of the par update

Page 19

UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

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6

I

INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the MHRA considered

that the applications for Vardenafil Crescent 5, 10 and 20mg film-coated tablets (PL

20416/0532-534) could be approved. These products are ‘prescription only

medicines’ (legal status “POM”).

These applications were submitted according to Article 10(1) of Directive

2001/83/EC, as amended, claiming to be generic medicinal products of Levitra 5, 10

and 20mg film coated tablets (EU/1/03/248/001-023) which were granted a licence to

Bayer Pharma AG on 6 March 2003.

Vardenafil Crescent 5, 10 and 20mg film-coated tablets are used for the 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

Vardenafil Crescent 5mg film-coated tablets to be effective, sexual stimulation is

required.

Vardenafil is a potent and selective inhibitor of PDE5, an enzyme responsible for the

degradation of cGMP in the corpus cavernosum. When nitric oxide is released by

nerve endings or endothelium, as is the case with sexual stimulation, the cGMP

pathway is activated. PDE5 inactivates cGMP inside the cytoplasm. Inhibition of this

enzyme causes increased concentrations of cGMP, which in turn enhance smooth

muscle relaxation and hence the erectile response.

In support of these applications, two bioequivalence studies were performed:

An open-label, balanced, randomised, two-treatment, two-sequence, two

period, single-dose, crossover oral bioequivalence study comparing the

pharmacokinetics of the test product, Vardenafil Crescent 20mg Film-coated

Tablets, versus the reference product, Levitra 20 mg film-coated tablets (Bayer

Pharma AG), in healthy subjects under fasting conditions.

Open label, balanced, randomised, two-treatment, two-sequence, two period,

single-dose, crossover oral bioequivalence study comparing the

pharmacokinetics of the test product, Vardenafil Crescent 20mg Film-coated

Tablets, versus the reference product, Levitra 20mg Tablets (Bayer Pharma

AG), in healthy subjects under fed conditions.

With the exception of the bioequivalence studies above, no new clinical or non-

clinical studies were conducted which is acceptable given that the applications were

based on being generic medicinal products of reference products that have been

licensed for over 10 years.

The MHRA has been assured that acceptable standards of Good Manufacturing

Practice (GMP) are in place for these products at all sites responsible for the

manufacture and assembly of these products.

A satisfactory summary of the pharmacovigilance system and a detailed Risk

Management Plan (RMP) has been provided with these applications.

Marketing Authorisations were granted in the UK on 25 August 2017.

UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

PL 20416/0532-534

7

II

QUALITY ASPECTS

II.1

Introduction

Vardenafil 5mg Tablets are light orange to orange, film-coated round tablets debossed

with “L” on one side and “05” on the other side and are approximately 5.35 mm in

diameter. Each film-coated tablet contains 5mg vardenafil hydrochloride trihydrate.

Vardenafil 10mg Tablets are light orange to orange, film-coated round tablets

debossed with “480” on side and plain on the other side and are approximately 6.10

mm in diameter. Each film-coated tablet contains 10mg vardenafil hydrochloride

trihydrate.

Vardenafil 20mg Tablets are light orange to orange, film-coated round tablets

debossed with “481” on side and plain on the other side and are approximately 8.10

mm in diameter. Each film-coated tablet contains 20mg vardenafil hydrochloride

trihydrate.

Other ingredients consist of the following pharmaceutical excipients:

Tablet core: cellulose, microcrystalline hydroxypropylcellulose, crospovidone type b,

colloidal silicon dioxide, magnesium stearate

Film-coating: Opadry beige 03F570025 consisting of hypromellose (E464) Macrogol

(E1521) titanium dioxide (E171), iron oxide yellow (E172) iron oxide red (E172)

tartrazine aluminium lake (E102), sunset yellow FCF aluminium lake (E110).

The finished products are packaged into aluminium foil / cold form blister foil or

aluminium foil / transparent polyvinyl chloride (PVC) film or aluminium foil /

transparent PVC / polyvinylidene chloride (PVdC) film blisters which are packaged in

cardboard cartons containing 4 or 8 tablets.

Not all pack sizes may be marketed. However, the company have committed to

providing the licensing authority with the mock-ups for any pack size before

marketing.

Specifications and Certificates of Analysis for all packaging materials have been

provided. These are satisfactory. All primary product packaging complies with EU

legislation, Directive 2002/72/EC (as amended), and are suitable for contact with

foodstuffs.

II.2.

Drug Substance

INN:

vardenafil hydrochloride trihydrate

Chemical name:

2-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-5-methyl-

7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

monohydrochloride trihydrate

UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

PL 20416/0532-534

8

Structural formula:

Molecular formula:

S.3H

Relative molecular mass:

579.1

Appearance:

White or slightly brown or yellow powder.

Solubility:

Slightly soluble in water, freely soluble in anhydrous

ethanol. Practically insoluble in heptane.

All aspects of the manufacture and control of the active substance, vardenafil

hydrochloride trihydrate, are covered by European Directorate for the Quality of

Medicines and Healthcare (EDQM) Certificates of Suitability.

II.3.

Medicinal Product

Pharmaceutical Development

The objective of the development programme was to formulate safe, efficacious,

stable products that could be considered generic products of the reference products

Levitra 5, 10 and 20mg film coated tablets. A satisfactory account of the

pharmaceutical development has been provided.

Comparable

in vitro

dissolution profiles have been provided for the test and reference

products.

The tablet coating Opadry beige 03F570025, is controlled to a suitable in-house

specification; all constituents of the tablet coating comply with their respective

European Pharmacopoeia (Ph. Eur.) monographs, except for iron oxide yellow

(E172) and iron oxide red (E172) which are controlled in line with the Japanese

Pharmacopoeia, and tartrazine aluminium lake (E102) and sunset yellow FCF

aluminium lake (E110), which are controlled in line with Joint FAO/WHO Expert

Committee on Food Additives (JECFA) guidance. All colourants conform with the

requirements of Commission Regulation (EU) No 231/2012. All other excipients

comply with their respective Ph. Eur. monographs.

No materials of animal origin covered by the TSE guideline are used in the

manufacturing process of the medicinal product, or are contained in the finished

medicinal products.

No genetically modified organisms (GMO) have been used in the preparation of these

products.

UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

PL 20416/0532-534

9

Manufacture of the product

Satisfactory batch formulae have been provided for the manufacture of each product

strength, along with an appropriate account of the manufacturing process. The

manufacturing process has been validated at commercial scale for each strength and

has shown satisfactory results.

Finished Product Specifications

The finished product specifications proposed are acceptable. Test methods have been

described that have been adequately validated. Batch data have been provided that

comply with the release specifications. Certificates of Analysis have been provided

for all working standards used.

Stability of the Product

Finished product stability studies were performed in accordance with current

guidelines on batches of finished products in the packaging proposed for marketing.

The data from these studies support a shelf-life of 2 years. These medicinal products

do not require any special storage conditions.

Suitable post approval stability commitments to continue stability testing on batches

of the finished products have been provided.

II.4

Discussion on chemical, pharmaceutical and biological aspects

There are no objections to the approval of these products from a pharmaceutical

perspective.

III

NON-CLINICAL ASPECTS

III.1

Introduction

The pharmacodynamic, pharmacokinetic and toxicological properties of vardenafil

hydrochloride trihydrate are well-known. No new non-clinical data have been

submitted for these applications and none are required.

The applicant has provided an overview based on published literature. The

non-clinical overview has been written by an appropriately qualified person and is

satisfactory, providing an appropriate review of the products’ pharmacology and

toxicology.

III.2

Pharmacology

No new pharmacology data are required for these applications and none have been

submitted.

III.3

Pharmacokinetics

No new pharmacokinetic data are required for these applications and none have been

submitted.

III.4

Toxicology

No new toxicology data are required for these applications and none have been

submitted.

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III.5

Ecotoxicity/environmental risk assessment (ERA)

As these products are intended for generic substitution with other products already on

the market, no increase in environmental exposure is anticipated. An ERA is,

therefore, not deemed necessary.

III.6

Discussion on the non-clinical aspects

There are no objections to the approval of these products from a non-clinical

perspective.

IV

CLINICAL ASPECTS

IV.1

Introduction

The clinical pharmacology of vardenafil hydrochloride trihydrate is well-known. With

the exception of the bioequivalence study detailed below, no new clinical studies have

been performed and none are required for this type of application. The applicant’s

clinical overview has been written by an appropriately qualified person and is

considered acceptable.

IV.2

Pharmacokinetics

In support of these applications, the Marketing Authorisation Holder has submitted

results from two bioequivalence studies:

Study 1:

Open-label, balanced, randomised, two-treatment, two-sequence, two period, single-

dose, crossover oral bioequivalence study of the test product Vardenafil 20mg Film-

coated Tablets (Crescent Pharma Limited), and Levitra

20mg Tablets (Bayer Pharma

AG) in healthy, adult, human male subjects under fasting conditions.

After a fast of at least 10 hours, each subject received a single oral dose (1 x 20mg) of

the test formulation or a single oral dose (1 x 20mg) of the reference formulation

administered with 250 mL of water.

Blood samples were collected for plasma levels before dosing and up to and including

24 hours after each administration. The washout period between the treatment phases

was 7 days.

The following pharmacokinetic parameters were subjected to statistical analysis for

vardenafil:

Primary parameters: C

and AUC

Secondary parameters: AUC

0-∞

, % Residual area, t

and ƛ

Summary statistics for pharmacokinetic parameters for vardenafil for the test and

reference product are shown below:

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The 90% confidence intervals of the test/reference ratio for AUC and C

values for

vardenafil lie within the acceptable limits of 80.00% to 125.00%, in line with the

‘Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev

1/Corr**). Based on the data provided the applicant’s test product, Vardenafil 20mg

Film-coated Tablets can be considered bioequivalent to the reference product, Levitra

20mg Tablets (Bayer Pharma AG).

Study 2:

Open label, balanced, randomised, two-treatment, two-sequence, two period, single-

dose, crossover oral bioequivalence study of the test product Vardenafil

Hydrochloride 20mg Film-coated Tablets (Crescent Pharma Limited), and Levitra

20mg Tablets (Bayer Pharma AG) in healthy, adult, human male subjects under fed

conditions.

After a supervised overnight fast of at least 10 hours, each subject received a single

oral dose was (1 x 20mg) of the test formulation or a single oral dose (1 x 20mg) of

the reference formulation administered with 250 mL of water and a standardized high-

fat, high-calorie meal, 30 minutes before study drug administration in each study

period. Blood samples were collected prior to study drug administration and up to 24

hours after drug administration. The washout period between the treatment phases

was 7 days.

The following pharmacokinetic parameters were subjected to statistical analysis for

vardenafil:

Primary parameters: C

and AUC

Secondary parameters: AUC

0-∞

, %Residual area, t

and ƛ

Summary statistics for pharmacokinetic parameters for vardenafil for the test and

reference product are shown below:

UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

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The 90% confidence intervals of the test/reference ratio for AUC and C

values for

vardenafil lie within the acceptable limits of 80.00% to 125.00%, in line with the

‘Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev

1/Corr**). Based on the data provided the applicant’s test product, Vardenafil 20mg

Film-coated Tablets can be considered bioequivalent to the reference product, Levitra

20mg Tablets (Bayer Pharma AG).

As these products meet the bio-waiver criteria specified in the Guideline on the

Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1/Corr**), the

results and conclusions of the bioequivalence studies can be extrapolated to the 5 and

10mg strengths.

IV.3

Pharmacodynamics

No new pharmacodynamic data were submitted and none were required for this type of

application.

IV.4

Clinical efficacy

No new efficacy data were submitted and none were required for this type of

application.

IV.5

Clinical safety

With the exception of the safety data collected during the bioequivalence studies, no

new data on safety have been submitted and none are required for applications of this

type. No new or unexpected adverse events were observed during the bioequivalence

studies.

IV.6

Risk Management Plan (RMP)

The Marketing Authorisation Holder (MAH) has submitted a Risk Management Plan

(RMP), in accordance with the requirements of Directive 2001/83/EC, as amended,

describing the pharmacovigilance activities and interventions designed to identify,

characterise, prevent or minimise risks relating to these products.

A summary of safety concerns, as approved in the RMP is provided on the following

page:

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Routine pharmacovigilance and routine risk minimisation are proposed for all safety

concerns.

IV.7

Discussion on the clinical aspects

There are no objections to the approval of these products from a clinical perspective.

V

User consultation

The package leaflet has been evaluated via a user consultation study in accordance

with the requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The

language used for the purpose of user testing the PIL was English. The results show

that the package leaflet meets the criteria for readability as set out in the guideline on

the readability of the label and package leaflet of medicinal products for human use.

VI

Overall conclusion, benefit/risk assessment and recommendation

The quality of the products is acceptable, and no new non-clinical or clinical safety

concerns have been identified. Extensive clinical experience with vardenafil

hydrochloride trihydrate is considered to have demonstrated the therapeutic value of

the compound. The products are considered to be bioequivalent to the marketed

reference products and their benefits and risks are considered similar. The benefit/risk

balance is, therefore, considered to be positive.

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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL)

and Labels

In accordance with Directive 2010/84/EU the Summaries of Product Characteristics

(SmPCs) and Patient Information Leaflets (PIL) for products granted Marketing

Authorisations at a national level are available on the MHRA website.

The approved labelling for Vardenafil Crescent 5, 10 and 20mg film-coated tablets is

presented below:

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UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

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UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

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UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

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UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

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UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

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UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

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UKPAR Vardenafil Crescent 5, 10 and 20mg film-coated tablets

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Table of content of the PAR update

Steps taken after the initial procedure with an influence on the Public Assessment

Report (Type II variations, PSURs, commitments)

Scope

Procedure

number

Product

information

affected

Date of start of

the procedure

Date of end of

procedure

Approval/

non approval

Assessment

report

attached

Y/N (version)

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