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 Devarin ODT to be effective, sexual stimulation is required.

Posology
Devarin ODT 10 mg orodispersible tablets are not bioequivalent to Devarin 10 mg film-coated
tablets (see section 5.1). The maximum dose for Devarin ODT is 10 mg/day.
Use in adult men
Devarin ODT 10 mg orodispersible tablets are taken as needed approximately 25 to 60
minutes before sexual activity.
Special populations
Elderly (≥65 years old)
Dose adjustments are not required in elderly patients. However, an increase to a maximum
dose of vardenafil 20 mg film- coated tablets should be carefully considered depending on the
individual tolerability (see sections 4.4 and 4.8).
Hepatic impairment
Vardenafil orodispersible tablets are not indicated as a starting dose in patients with mild
hepatic impairment (Child- Pugh A).
Patients with mild hepatic impairment should start treatment with vardenafil 5 mg film-coated
tablets. Based on tolerability and efficacy, the dose may be increased to vardenafil 10
mg and 20 mg film-coated tablets, or vardenafil orodispersible tablets.
The maximum dose recommended in patients with moderate hepatic impairment (Child-Pugh
B) is vardenafil orodispersible 10 mg as film- coated tablets (see section 5.2).
Vardenafil orodispersible tablets are not for use in patients with moderate (Child-Pugh B) and
severe hepatic impairment (Child-Pugh C; see section 4.3).
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
vardenafil 5 mg film-coated tablets should be considered. Based on tolerability and efficacy,
the dose may be increased to vardenafil 10 mg and 20 mg film-coated tablets, or vardenafil
10 mg orodispersible tablets.
Vardenafil orodispersible is not for use in patients with end-stage renal failure (see section
4.3).
Paediatric population
Vardenafil orodispersible tablets are not indicated for individuals below 18 years of age. There
is no relevant indication for use of vardenafil orodispersible tablets in children and
adolescents.
Use in patients using other medicinal products Concomitant use of moderate or potent CYP
3A4 inhibitors
Vardenafil dose adjustment is necessary if moderate or potent CYP 3A4 inhibitors are given
concomitantly (see section 4.5).
Method of administration For oral use.
The orodispersible tablet should be placed in the mouth on the tongue, where it will rapidly
disintegrate, and then swallowed. Devarin ODT must be taken without liquid and immediately
upon release from the blister.
Devarin ODT can be taken with or without food.

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 orodispersible is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischemic 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).

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 orodispersible tablets with vardenafil
film-coated tablets or other treatments for erectile dysfunction have not been studied.
Therefore the use of such combinations is not recommended.
Tolerability of the maximum dose of vardenafil 20 mg film-coated tablets may be lower in
elderly patients (≥ 65 years old) (see sections 4.2 and 4.8).
Concomitant use of alpha-blockers
The concomitant use of alpha-blockers and vardenafil may lead to symptomatic hypotension
in some patients because both are vasodilators. Concomitant treatment with vardenafil should
only be initiated if the patient has been stabilised on his alpha-blocker therapy. In those
patients who are stable on alpha-blocker therapy, vardenafil should be initiated at the lowest
recommended starting dose of 5 mg film-coated tablets. Patients treated with alpha-blockers
should not use vardenafil 10 mg orodispersible tablets as a starting dose. Vardenafil may be
administered at any time with tamsulosin or with alfuzosin. With other alpha-blockers a time
separation of dose should be considered when vardenafil is prescribed concomitantly (see
section 4.5). In those patients already taking an optimised 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 CYP 3A4 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 CYP 3A4 inhibitors such as
erythromycin and clarithromycin, are given concomitantly (see section 4.2 and 4.5).
Concomitant intake of grapefruit or grapefruit juice is expected to increase the plasma
concentrations of vardenafil. The combination should be avoided (see section 4.5).
Effect on QTc interval
Single oral doses of 10 mg and 80 mg of vardenafil have been shown to prolong the QTc
interval by a mean of 8 msec and 10 msec, respectively. And single doses of 10 mg vardenafil
co-administered concomitantly with 400 mg gatifloxacin, an active substance with comparable
QT effect, showed an additive QTc effect of 4 msec when compared to either active substance
alone. The clinical impact of these QT changes is unknown (see section 5.1).
The clinical relevance of this finding is unknown and cannot be generalised to all patients
under all circumstances, as it will depend on the individual risk factors and susceptibilities that
may be present at any time in any given patient.
Medicinal products that may prolong QTc interval, including vardenafil, are best avoided in
patients with relevant risk factors, for example, hypokalaemia, congenital QT prolongation,
concomitant administration of antiarrhythmic medicinal products in Class IA (e.g. quinidine,
procainamide), or Class III (e.g. amiodarone, sotalol).
Effect on vision
Visual defects and cases of non-arteritic ischemic 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
orodispersible tablets 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
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 acetylsalicylic 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.
Aspartame
Devarin ODT contains aspartame, a source of phenylalanine which may be harmful for people
with phenylketonuria.
Lactose monohydrate
Devarin ODT contains lactose monohydrate. Patients with rare hereditary problems of galactose
intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

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 reduce vardenafil clearance.
In vivo studies
Co-administration of the HIV protease inhibitor indinavir (800 mg three times a day), a potent
CYP3A4 inhibitor, with vardenafil (10 mg film-coated tablets) 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 coadministered
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 film-coated
tablets potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg)
taken 1 and 4 hours after vardenafil administration to healthy middle aged subjects. No effect
on blood pressure was observed when nitroglycerin was taken 24 hours after administration of
a single dose of vardenafil 20 mg film- coated tablets. However, there is no information on the
possible potentiation of the hypotensive effects of nitrates by vardenafil in patients, and
concomitant use of vardenafil orodispersible tablets and nitrates 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 alphablockers
tamsulosin or terazosin to high doses, hypotension (in some cases symptomatic) was
reported in a significant number of subjects after co-administration of vardenafil. Among
subjects treated with terazosin, hypotension was observed more frequently when vardenafil
and terazosin were given simultaneously than when the dosing was separated by a time
interval of 6 hours.
Based on the results of interaction studies conducted with vardenafil in patients with benign
prostatic hyperplasia (BPH) on stable tamsulosin, terazosin or alfuzosin therapy:
• When vardenafil (film-coated tablets) was given at doses of 5, 10 or 20 mg on a
background of stable therapy with tamsulosin, there was no symptomatic reduction in blood
pressure, although 3/21 tamsulosin treated subjects exhibited transient standing systolic blood
pressures of less than 85 mmHg.
• When vardenafil 5 mg (film-coated tablets) was given simultaneously with terazosin 5
or 10 mg, one of 21 patients experienced symptomatic postural hypotension. Hypotension was
not observed when vardenafil 5 mg and terazosin administration was separated by 6 hours.
• When vardenafil (film-coated tablets) was given at doses of 5 or 10 mg on a
background of stable therapy with alfuzosin, compared to placebo, there was no symptomatic
reduction in blood pressure.
Therefore, concomitant treatment should be initiated only if the patient is stable on his alphablocker
therapy. In those patients who are stable on alpha-blocker therapy, vardenafil should
be initiated at the lowest recommended starting dose of 5mg. Vardenafil orodispersible tablets
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).
Vardenafil 10 mg orodispersible tablets should not be taken as starting dose in patients treated
with alpha- blockers (see section 4.4).
No significant interactions were shown when warfarin (25 mg), which is metabolised by
CYP2C9, or digoxin (0.375 mg) was co-administered with vardenafil (20 mg film-coated
tablets). The relative bioavailability of glibenclamide (3.5 mg) was not affected when coadministered
with vardenafil (20 mg). In a specific study, where vardenafil (20 mg) was coadministered
with slow release nifedipine (30 mg or 60 mg) in hypertensive patients, there
was an additional reduction on supine systolic blood pressure of 6 mmHg and supine diastolic
blood pressure of 5 mmHg accompanied with an increase in heart rate of 4 bpm.
When vardenafil (20 mg film-coated tablets) and alcohol (mean maximum blood alcohol level
of 73 mg/dl) were taken together, vardenafil did not potentiate the effects of alcohol on blood
pressure and heart rate and the pharmacokinetics of vardenafil were not altered.
Vardenafil (10 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic
acid (2 x 81 mg). Riociguat
Preclinical studies showed additive systemic blood pressure lowering effect when PDE5
inhibitors were combined with riociguat. In clinical studies, riociguat has been shown to
augment the hypotensive effects of PDE5 inhibitors. There was no evidence of favourable
clinical effect of the combination in the population studied. Concomitant use of riociguat with
PDE5 inhibitors, including vardenafil, is contraindicated (see section 4.3).

Vardenafil orodispersible tablets are not indicated for use by women. There are no studies of
vardenafil in pregnant women. There are no fertility data available.

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 orodispersible tablets, before driving or
operating machines.

Summary of the safety profile
The adverse reactions reported with vardenafil film-coated tablets or vardenafil 10 mg
orodispersible 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.
Tabulated list of adverse reactions
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 Very common Common Uncommon Rare Not known
Class (≥1/10) (≥1/100 to (≥1/1,000 to (≥1/10,000 to (can not be
<1/10) <1/100) <1/1,000) estimated from the
available data)
Infection and
infestations
Conjunctivitis
Immune system
disorders
Allergic oedema
and angioedema
Allergic reaction
Psychiatric
disorders
Sleep disorder Anxiety
Nervous system
disorders
Headache Dizziness Somnolence
Paraesthesia and
dysaesthesia
Syncope
Seizure
Amnesia
Eye disorders Visual disturbance
Ocular hyperaemia
Increase in
intraocular pressure
Lacrimation
increased
Non-arteritic
anterior ischemic
optic neuropathy
Visual defects
Visual colour
distortions
Eye pain and eye
discomfort
Photophobia
Ear and
labyrinth
disorders
Tinnitus Vertigo Sudden deafn
Cardiac
disorders
Palpitation
Tachycardia
Myocardial
infarction
Ventricular tachyarrhythmias
Angina pectoris
Vascular
disorders
Flushing Hypotension
Hypertension
Respiratory,
thoracic and
mediastinal
disorders
Nasal
congestion
Dyspnoea
Sinus congestion
Epistaxis
Gastrointestinal
disorders
Dyspepsia Gastrooesophageal
reflux
disease
Gastritis
Gastrointestinal
and abdominal
pain
Diarrhoea
Vomiting Nausea
Dry mouth
Hepatobiliary
disorders
Increase in
transaminases
Increase in gammaglutamyl
Skin and
subcutaneous
tissue disorders
Erythema Rash Photosensitivity
reaction
Musculoskeletal
and connective
tissue disorders
Back pain
Increase in
creatine
phosphokinase
Myalgia Increased
muscle
tone and cramping
Renal and
urinary
disorders
Haematuria
Reproductive
system and
breast disorders
Increase in
erection
Priapism Penile Haemo
Haematosperm
General
disorders and
Feeling unwell Chest pain
Description of selected adverse reactions
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 a dose of 20 mg 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 observations
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:
To report any side effect(s):
− The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

In single dose volunteer studies, doses up to and including 80 mg vardenafil (film-coated
tablets) per day were tolerated without exhibiting serious adverse reactions.
When vardenafil was administered in higher doses and more frequently than the recommended
dose regimen (40 mg film-coated tablets twice daily) cases of severe back pain have been
administration
site conditions
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.

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC code:
G04BE09.
Vardenafil is an oral therapy for the improvement of erectile function in men with erectile
dysfunction. In the natural setting, i.e. with sexual stimulation it restores impaired erectile
function by increasing blood flow to the penis.
Penile erection is a haemodynamic process. During sexual stimulation, nitric oxide is released.
It activates the enzyme guanylate cyclase, resulting in an increased level of cyclic guanosine
monophosphate (cGMP) in the corpus cavernosum. This in turn results in smooth muscle
relaxation, allowing increased inflow of blood into the penis. The level of cGMP is regulated
by the rate of synthesis via guanylate cyclase and by the rate of degradation via cGMP
hydrolysing phosphodiesterases (PDEs).
Vardenafil is a potent and selective inhibitor of the cGMP specific phosphodiesterase type 5
(PDE5), the most prominent PDE in the human corpus cavernosum. Vardenafil potently
enhances the effect of endogenous nitric oxide in the corpus cavernosum by inhibiting PDE5.
When nitric oxide is released in response to sexual stimulation, inhibition of PDE5 by
vardenafil results in increased corpus cavernosum levels of cGMP. Sexual stimulation is
therefore required for vardenafil to produce its beneficial therapeutic effects.
In vitro studies have shown that vardenafil is more potent on PDE5 than on other known
phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative
to PDE11, and >1000-fold relative to PDE2, PDE3, PDE4, PDE7, PDE8, PDE9 and PDE10).
In a penile plesthysmography (RigiScan) study, vardenafil 20 mg produced erections
considered sufficient for penetration (60% rigidity by RigiScan) in some men as early as 15
minutes after dosing. The overall response of these subjects to vardenafil became statistically
significant, compared to placebo, 25 minutes after dosing.
Vardenafil causes mild and transient decreases in blood pressure which, in the majority of the
cases, do not translate into clinical effects. The mean maximum decreases in supine systolic
blood pressure following 20 mg and 40 mg vardenafil were – 6.9 mmHg under 20 mg and –
4.3 mmHg under 40 mg of vardenafil, when compared to placebo.
These effects are consistent with the vasodilatory effects of PDE5-inhibitors and are probably
due to increased cGMP levels in vascular smooth muscle cells. Single and multiple oral doses
of vardenafil up to 40 mg produced no clinically relevant changes in the ECGs of normal male
volunteers.
A single dose, double blind, crossover, randomised trial in 59 healthy males compared the
effects on the QT interval of vardenafil (10 mg and 80 mg), sildenafil (50 mg and 400 mg)
and placebo. Moxifloxacin (400 mg) was included as an active internal control. Effects on the
QT interval were measured one hour post-dose (average 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 80 mg oral dose of vardenafil on QTc interval compared to placebo, as
measured by the change in Fridericia's correction formula (QTcF=QT/RR1/3) from baseline at
the 1 hour post-dose time point. The vardenafil results showed an increase in QTc (Fridericia)
of 8 msec (90% CI: 6-9) and 10 msec (90% CI: 8-11) at 10 and 80 mg doses compared to
placebo and
an increase in QTci of 4 msec (90% CI: 3-6) and 6 msec (90% CI: 4-7) at 10 and 80 mg doses
compared to placebo, at one hour post-dose. At tmax, only the mean change in QTcF for
vardenafil 80 mg was out of the study established limit (mean 10 msec, 90% CI 8-11). When
using the individual correction formulae, none of the values were out of the limit.
In a separate post-marketing study of 44 healthy volunteers, single doses of 10 mg vardenafil
or 50 mg sildenafil were co-administered concomitantly with 400 mg gatifloxacin, a drug with
comparable QT effect. Both vardenafil and sildenafil showed an increase of Fridericia QTc
effect of 4 msec (vardenafil) and 5 msec (sildenafil) when compared to either drug alone. The
actual clinical impact of these QT changes is unknown.
Further information on clinical trials 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% (5 mg), 76% (10 mg) and 80% (20 mg) of patients experienced successful
penetrations (SEP 2) compared to 49% on placebo over a three month study period. The
ability to maintain the erection (SEP 3) in this broad ED population was given as 53% (5 mg),
63% (10 mg) and 65% (20 mg) compared to 29% on placebo.
In pooled data from the major efficacy trials, the proportion of patients experiencing
successful penetration on vardenafil were as follows: psychogenic erectile dysfunction (77-
87%), mixed erectile dysfunction (69-83%), organic erectile dysfunction (64-75%), elderly
(52-75%), ischaemic heart disease (70-73%), 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 10 mg
and 20 mg. The response rates for the ability to obtain and maintain an erection was 61% and
49% on 10 mg and 64% and 54% on 20 mg vardenafil compared to 36% and 23% on placebo
for patients who completed three months treatment.
In a clinical trial in post-prostatectomy patients, vardenafil significantly improved the erectile
function domain score, the ability to obtain and maintain an erection long enough for
successful intercourse and penile rigidity compared to placebo at vardenafil doses of 10 mg
and 20 mg. The response rates for the ability to obtain and maintain an erection was 47% and
37% on 10 mg and 48% and 34% on 20 mg vardenafil compared to 22% and 10% on placebo
for patients who completed three months treatment.
In a flexible-dose clinical trial in patients with Spinal Cord Injury, vardenafil significantly
improved the erectile function domain score, the ability to obtain and maintain an erection
long enough for successful intercourse and penile rigidity compared to placebo. The number
of patients who returned to a normal IIEF domain score (>26) were 53% on vardenafil
compared to 9% on placebo. The response rates for the ability to obtain and maintain an
erection were 76% and 59% on vardenafil compared to 41% and 22% on placebo for patients
who completed three months treatment which were clinically and statistically significant
(p<0.001).
The safety and efficacy of vardenafil was maintained in long-term studies. Paediatric
population
The European Medicines Agency has waived the obligation to submit the results of studies in
all subsets of the paediatric population in the treatment of the erectile dysfunction. See section
4.2 for information on paediatric use

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 (5-20 mg).
When vardenafil film-coated tablets are taken with a high fat meal (containing 57% fat), the
rate of absorption is reduced, with an increase in the median 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%.
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.
Elimination
The total body clearance of vardenafil is 56 l/h with a resultant terminal half-life of
approximately 4-5 hours. After oral administration, vardenafil is excreted as metabolites
predominantly in the faeces (approximately 91-95% of the administered dose) and to a lesser
extent in the urine (approximately 2-6% of the administered dose).
Pharmacokinetics in special patient groups
Elderly
Hepatic clearance of vardenafil in healthy elderly volunteers (65 years and over) was reduced
as compared to healthy younger volunteers (18-45 years). On average elderly males taking
vardenafil film-coated tablets had a 52% higher AUC, and a 34% higher 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).

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.

Lactose monohydrate
Calcium silicate
Hydroxypropyl cellulose
Crospovidone
Aspartame
Mint flavor
Aniseed flavor
Colloidal silicon dioxide
Magnesium stearate

Not applicable.

30 months

Do not store above 30°C

Devarin ODT: PP/Aluminium foil blisters in cartons of 4 tablets.

No special requirements for disposal.