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VARDENAFIL CRESCENT 20MG FILM-COATED TABLETS

Active substance(s): VARDENAFIL HYDROCHLORIDE TRIHYDRATE / VARDENAFIL HYDROCHLORIDE TRIHYDRATE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Vardenafil Crescent 20mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 20mg of vardenafil (as hydrochloride trihydrate).
Excipients with known effect:

Each film-coated tablet contains 0.06 mg Tartrazine Aluminium Lake (E102)
and 0.03 mg Sunset Yellow FCF Aluminium Lake (E110).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Film-coated tablet.
Light orange to orange, film-coated round tablets debossed with “481” on side and
plain on the other side. Approximately 8.10 mm in diameter.

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 Crescent 20mg film-coated tablets to be effective,
sexual stimulation is required.

4.2

Posology and method of administration
Posology
Use in adult men
The recommended dose is 10mg taken as needed approximately 25 to 60
minutes before sexual activity. Based on efficacy and tolerability the dose may

be increased to 20mg or decreased to 5mg. The maximum recommended dose
is 20mg. The maximum recommended dosing frequency is once per day.
Vardenafil Tablets 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 20mg dose should be carefully considered depending on the
individual tolerability (see sections 4.4 and 4.8).
Hepatic impairment
A starting dose of 5mg 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
10mg (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 5mg should be considered. Based on tolerability and efficacy
the dose may be increased to 10mg and 20mg.
Paediatric population
Vardenafil Tablets are not indicated for individuals below 18 years of age.
There is no relevant indication for use of Vardenafil Tablets 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 5mg (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, 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 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 20mg 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 5mg film-coated tablets. Vardenafil may be
administered at any time with tamsulosin or with alfuzosin. With other alphablockers, 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 10mg and 80mg of vardenafil have been shown to prolong
the QTc interval by a mean of 8 msec and 10 msec, respectively. And single
doses of 10mg vardenafil co-administered concomitantly with 400mg
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 Tablets and
other PDE5 inhibitors. The patient should be advised that in the case of sudden
visual defect, he should stop taking Vardenafil Tablets 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.
Vardenafil Crescent film-coated tablets contains Tartrazine Aluminium Lake
(E102) and Sunset Yellow FCF Aluminium Lake (E110), which may cause
allergic reactions.

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 (800mg three times
a day), a potent CYP3A4 inhibitor, with vardenafil (10mg film-coated 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 (600mg 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 5mg. 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 (200mg), a potent CYP3A4 inhibitor, with
vardenafil (5mg) 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 (500mg three times a day), a CYP3A4
inhibitor, with vardenafil (5mg) 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 (400mg twice daily), a non-specific cytochrome P450
inhibitor, had no effect on vardenafil AUC and Cmax when co-administered
with vardenafil (20mg) 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 (20mg) was not affected by coadministration with the H2-antagonist ranitidine (150mg twice daily), digoxin,
warfarin, glibenclamide, alcohol (mean maximum blood alcohol level of
73mg/dl) or single doses of antiacid (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 (0.4mg) was observed when vardenafil (10mg) 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 20mg film-coated tablet potentiated
the blood pressure lowering effect of sublingual nitroglycerin (0.4mg) 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 20mg 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
20mg 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 5mg (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
5mg and terazosin administration was separated by 6 hours.



When vardenafil (film-coated tablets) was given at doses of 5 or 10mg
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 (25mg), which is
metabolised by CYP2C9, or digoxin (0.375mg) was co-administered with
vardenafil (20mg film-coated tablets). The relative bioavailability of
glibenclamide (3.5mg) was not affected when co-administered with vardenafil
(20mg). In a specific study, where vardenafil (20mg) was co-administered
with slow release nifedipine (30mg or 60mg) 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 (20mg film-coated tablets) and alcohol (mean maximum
blood alcohol level of 73mg/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 (10mg) did not potentiate the increase in bleeding time caused by
acetylsalicylic acid (2 x 81mg).
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 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:
System Organ Class

Infection and
infestations
Immune system
disorders
Psychiatric disorders
Nervous system
disorders

Very
Common
(≥1/10)

Common
(≥1/100 to
<1/ 10)

Uncommon
(≥1/1,000 to
<1/100)

Not Known
(cannot be
estimated
from the
available data)

Conjunctivitis

Headache

Dizziness

Eye disorders

Ear and labyrinth
disorders
Cardiac disorders

Allergic oedema
and angioedema
Sleep disorder
Somnolence
Paraesthesia and
dysaesthesia
Visual
disturbance
Ocular
hyperaemia
Visual colour
distortions
Eye pain and eye
discomfort
Photophobia
Tinnitus
Vertigo
Palpitation
Tachycardia

Vascular disorders

Flushing

Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Nasal
congestion

Dyspnoea
Sinus congestion

Dyspepsia

Gastrooesophageal
reflux disease
Gastritis
Gastrointestinal
and abdominal
pain
Diarrhoea
Vomiting
Nausea
Dry mouth
Increase in
transaminases

Hepatobiliary
disorders

Rare
(≥1/10,000 to
<1/1,000)

Allergic
reaction
Anxiety
Syncope
Seizure
Amnesia
Increase in
intraocular
pressure
Lacrimation
increased

Non-arteritic
anterior
ischemic optic
neuropathy
Visual defects

Sudden
deafness
Myocardial
infarction
Ventricular
tachyarrhythmias
Angina pectoris
Hypotension
Hypertension
Epistaxis

Increase in
gammaglutamyl

System Organ Class

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)

Not Known
(cannot be
estimated
from the
available data)

transferase
Skin and
subcutaneous tissue
disorders
Musculoskelet al and
connective tissue
disorders

Renal and urinary
disorders
Reproductive system
and breast disorders

General disorders
and administration
site conditions

Erythema
Rash

Photosensitivity
reaction

Back pain
Increase in
creatine
phosphokinase
Myalgia Increased
muscle tone and
cramping
Haematuria
Increase in
erection

Priapism

Feeling unwell

Chest pain

Penile
Haemorrhage
Haematosper
mia

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
Yellow
Card
Scheme
at:
www.mhra.gov.uk/yellowcard

4.9

Overdose
In single dose volunteer studies, doses up to and including 80mg 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 (40mg 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 20mg 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 20mg and 40mg
vardenafil were – 6.9 mmHg under 20mg and – 4.3 mmHg under 40mg 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 40mg 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 (10mg and 80mg),
sildenafil (50mg and 400mg) and placebo. Moxifloxacin (400mg) was
included as an active internal control. Effects on the QT interval were
measured one hour post-dose (average tmax 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 80mg 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 80mg 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 80mg doses compared to placebo, at one hour
post-dose. At tmax, only the mean change in QTcF for vardenafil 80mg 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
10mg vardenafil or 50mg sildenafil were co-administered concomitantly with
400mg 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 with vardenafil 10 mg orodispersible
tablets Efficacy and safety of vardenafil 10 mg orodispersible tablets were
separately demonstrated in a broad population in two studies including 701
randomized erectile dysfunction patients who were treated up to 12 weeks.
The distribution of patients in the predefined subgroups was covering elderly
patients (51%), patients with history of diabetes mellitus (29%), dyslipidemia
(39%) and hypertension (40%).

In pooled data from the two vardenafil 10 mg orodispersible tablets trials,
IIEF-EF domain scores were significantly higher with vardenafil 10 mg
orodispersible tablet versus placebo.
A percentage of 71% of all sexual attempts reported in the clinical trials had
successful penetration compared to 44% of all attempts in the placebo group.
These results were also reflected in subgroups, in elderly patients (65%), in
patients with history of diabetes mellitus (63%), patients with history of
dyslipidemia (66%) and hypertension (70%) of all sexual attempts reported
had successful penetration.
About 63% of all reported sexual attempts with vardenafil 10 mg
orodispersible tablets were successful in terms of erection maintenance
compared to about 26% of all placebo-controlled sexual attempts. In the
predefined subgroups 57% (elderly patients), 56% (patients with history of
diabetes mellitus), 59% (patients with history of dyslipidemia) and 60%
(patients with history of hypertension) of all reported attempts with vardenafil
10 mg orodispersible tablets were successful in terms of maintenance of
erection.

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 were treated with vardenafil for 6 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%),
hyperlipidaemia (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% (5mg), 76% (10mg) and 80% (20mg) 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% (5mg), 63% (10mg) and 65% (20mg)
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 (6983%), organic erectile dysfunction (64-75%), elderly (52-75%), ischaemic
heart disease (70-73%), hyperlipidaemia (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 10mg and 20mg. The response
rates for the ability to obtain and maintain an erection was 61% and 49% on
10mg and 64% and 54% on 20mg 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 10mg and 20mg. The response
rates for the ability to obtain and maintain an erection was 47% and 37% on
10mg and 48% and 34% on 20mg 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 Cmax increase almost dose
proportionally over the recommended dose range (5-20mg).
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 tmax
of 1 hour and a mean reduction in Cmax of 20%. Vardenafil AUC is not
affected. After a meal containing 30% fat, the rate and extent of absorption of
vardenafil (tmax, Cmax and AUC) are unchanged compared to administration
under fasting conditions.
Vardenafil is rapidly absorbed after administration of vardenafil 10 mg
orodispersible tablets without water. The median time to reach Cmax varied
between 45 to 90 minutes and was similar or slightly delayed (by 8 to 45 min)
compared to the film-coated tablets. Mean vardenafil AUC was increased by
21 to 29% (middle aged and elderly ED patients) or 44% (young healthy
subjects) with 10 mg orodispersible tablets compared to film-coated tablets as
a result of local oral absorption of a small amount of drug in the oral cavity.
There was no consistent difference in mean Cmax between orodispersible
tablets and film-coated tablets.
In subjects taking vardenafil 10 mg orodispersible tablets with a high fat meal
no effect on vardenafil AUC and tmax was observed, while vardenafil Cmax
was reduced by 35% in the fed condition. Based on these results vardenafil 10
mg orodispersible tablets can be taken with or without food.
If vardenafil 10 mg orodispersible tablets are taken with water, the AUC is
reduced by 29%, Cmax remains unchanged and median tmax is shortened by 60
minutes compared to intake without water. Vardenafil 10 mg orodispersible
tablets must be taken without liquid.
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).

The mean terminal half-life of vardenafil in patients receiving vardenafil 10
mg orodispersible tablets ranged between 4 – 6 hours. The elimination half-life
of the metabolite M1 is between 3 to 5 hours, similar to parent drug.
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
Cmax than younger males (see section 4.2).
Vardenafil AUC and Cmax in elderly patients (65 years or over) taking vardenafil
orodispersible tablets were increased by 31 to 39% and 16 to 21%, respectively, in
comparison to patients aged 45 years and below. Vardenafil was not found to
accumulate in the plasma in patients aged 45 years and below or 65 years or over
following once-daily dosing of vardenafil 10 mg orodispersible tablets over ten days.

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 Cmax
decreased by 23%, compared to volunteers with no renal impairment. No statistically
significant correlation was observed between creatinine clearance and vardenafil
exposure (AUC and Cmax) (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 Cmax increased by 17% and 22% respectively, compared to healthy control
subjects. In patients with moderate impairment (Child-Pugh B), the mean AUC and
Cmax 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
Hydroxypropylcellulose
Crospovidone Type B
Colloidal Silicon Dioxide
Magnesium Stearate

Film-coating
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)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
2 years.

6.4

Special precautions for storage
Do not store above 30ºC.

6.5

Nature and contents of container
Blister pack of Aluminium foil and Cold Form Blister foil of 4 or 8 tablets.
Blister pack of Aluminium foil and transparent PVC film of 4 or 8 tablets.
Blister pack of Aluminium foil and transparent PVC/PVdC film of 4 and 8
tablets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
Units 3 & 4, Quidhampton Business Units,
Polhampton Lane, Overton,
Hampshire RG25 3ED
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 20416/0534

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
25/08/2017

10

DATE OF REVISION OF THE TEXT
25/08/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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