ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Levitra 5 mg film-coated tablets
2.
Each tablet contains 5 mg of vardenafil (as hydrochloride trihydrate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Orange round tablets marked with the BAYER-cross on one side and “5” on the other side.
4.
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 Levitra to be effective, sexual stimulation is required.
Levitra is not indicated for use by women.
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.
Levitra 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).
Use in elderly men
Dosage 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).
Use in children and adolescents
Levitra is not indicated for individuals below 18 years of age. There is no relevant indication for use of
Levitra in children.
Use in patients with 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).
1
Use in patients with renal impairment
No dosage 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.
Use in patients using other medicinal products
When used in combination with the CYP 3A4 inhibitors such as erythromycin or clarithromycin, the
dose of vardenafil should not exceed 5 mg (see section 4.5).
For oral use
Hypersensitivity to the active substance or to any of the excipients.
The coadministration of vardenafil with nitrates or nitric oxide donors (such as amyl nitrite) in any form
is contraindicated (see sections 4.5 and 5.1).
Levitra 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 PDE5 inhibitor exposure (see section 4.4).
Agents 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).
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.
Agents 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
2
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 with other treatments for erectile dysfunction
have not been studied. Therefore the use of such combinations is not recommended.
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.
Vardenafil may be administered at any time with tamsulosin. 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 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 sections 4.5 and 4.2).
Concomitant intake of grapefruit juice is expected to increase the plasma concentrations of vardenafil.
The combination should be avoided (see section 4.5).
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, a drug with comparable QT effect, showed an additive QTc
effect of 4 msec when compared to either drug 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).
Visual defects and cases of non-arteritic ischemic optic neuropathy (NAION) have been reported in
connection with the intake of Levitra and other PDE5 inhibitors. The patient should be advised that in
the case of sudden visual defect, he should stop taking Levitra and consult immediately a physician (see
section 4.3).
Tolerability of the maximum dose of 20 mg may be lower in elderly patients (≥ 65 years old) (see
sections 4.2 and 4.8).
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.
3
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) resulted in a 16-fold increase in vardenafil AUC and a 7-fold increase
in vardenafil C
max
. At 24 hours, the plasma levels of vardenafil had fallen to approximately 4% of the
maximum vardenafil plasma level (C
max
).
Co-administration of vardenafil with ritonavir (600 mg twice daily) resulted in a 13-fold increase in
vardenafil C
max
and a 49-fold increase in vardenafil AUC
0-24
when co-administered with vardenafil 5
mg. The interaction is a consequence of blocking hepatic metabolism of Levitra by ritonavir, a highly
potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life
of Levitra to 25.7 hours (see section 4.3).
Co-administration of ketoconazole (200 mg), a potent CYP3A4 inhibitor, with vardenafil (5 mg)
resulted in a 10-fold increase in vardenafil AUC and a 4-fold increase in vardenafil C
max
(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 CYP 3A4
inhibitors such as itraconazole and ketoconazole (oral use) should be avoided (see sections 4.3 and 4.4).
In men older than 75 years the concomitant use of vardenafil with itraconazole or ketoconazole is
contraindicated (see section 4.3).
Co-administration of erythromycin (500 mg three times a day), a CYP3A4 inhibitor, with vardenafil
(5 mg) resulted in a 4-fold increase in vardenafil AUC and a 3-fold increase in C
max
. Although a specific
interaction study has not been conducted, the co-administration of clarithromycin can be expected to
result in similar effects on vardenafil AUC and C
max
. When used in combination with a moderate CYP
3A4 inhibitor such as
erythromycin or clarithromycin, vardenafil dose adjustment might be necessary
(see sections 4.2 and 4.4). Cimetidine (400 mg twice daily), a non-specific cytochrome P450 inhibitor,
had no effect on vardenafil AUC and C
max
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 CYP 3A4
inhibitors, diuretics and medicinal products for the treatment of diabetes (sulfonylureas and metformin).
4
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 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 20 mg. 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 or terazosin 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.
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 5mg. Levitra may be administered at any time with tamsulosin.
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). 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) 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).
Levitra is not indicated for use by women. There are no studies of vardenafil in pregnant women.
5
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 Levitra, before driving or operating machinery.
Over 9,500 patients have received Levitra in clinical trials. The adverse reactions were generally
transient and mild to moderate in nature. The most commonly reported adverse drug reactions occurring
in 10% of patients are headache and flushing.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The following adverse reactions have been reported:
System Organ
Class
Very
Common
(
1/10)
Common
(
1/100 and
<1/10)
Uncommon
(
1/1,000 and
<1/100)*
Rare
(
1/10,000
and <1/1,000)*
Not Known
(can not be estimated
from the available
data)
Immune System
Disorders
Hypersensitivity
Psychiatric
Disorders
Anxiety
Nervous System
Disorders
Headache
Dizziness
Somnolence
Syncope
Seizure
Transient global
amnesia
Eye Disorders incl.
Related
Investigations
Lacrimation
increased
Visual
Disturbance
(incl. Visual
brightness)
Chromatopsia
Conjunctivitis
Blurred Vision
Intraocular
pressure
increased
Non-arteritic-anterior
ischemic optic
neuropathy
Visual defects
Ear and labyrinth
Disorders
Sudden deafness**
Cardiac Disorders
incl. related
Investigations
Tachycardia
Palpitations
Angina Pectoris
Myocardial
ischemia
Myocardial Infarction
Vascular Disorders
incl. related
Investigations
Flushing
Hypertension
Hypotension
Orthostatic
Hypotension
Respiratory,
Thoracic and
Mediastinal
Disorders
Nasal
Congestion
Dyspnoea
Epistaxis
Laryngeal
oedema
Gastrointestinal
Disorders incl.
related
Investigations
Dyspepsia
Nausea
Abnormal liver
function tests
GGTP
increased
Skin and
Subcutaneous
Tissue Disorders
Photosensitivity
reaction
Face oedema
Rash
6
System Organ
Class
Very
Common
(
1/10)
Common
(
1/100 and
<1/10)
Uncommon
(
1/1,000 and
<1/100)*
Rare
(
1/10,000
and <1/1,000)*
Not Known
(can not be estimated
from the available
data)
Musculoskeletal
and Connective
Tissue Disorders
incl. Related
Investigations
Blood creatine
phosphokinase
increased
Myalgia
Back Pain
Muscle Rigidity
Reproductive
System and Breast
Disorders
Priapism
Erections
increased
(prolonged or
painful
erections)
*For adverse reactions reported in <1% of patients, only those which warrant special attention, because
of their possible association with serious disease states or of otherwise clinical relevance are listed.
**Sudden deafness or loss of hearing has been reported in a small number of postmarketing and clinical
trial cases with the use of all PDE5 inhibitors, including vardenafil.
At the 20mg dose, 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).
Post marketing reports of another medicinal product of this class: Vascular Disorders: Serious
cardiovascular events, 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.
In single dose volunteer studies, doses up to and including 80 mg per day were tolerated without
exhibiting serious adverse reactions.
When vardenafil was administered in higher doses and more frequently than the recommended dosing
regimen (40 mg 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicinal product 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
7
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 postdose. 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 postmarketing 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 Fredericia QTc effect of 4 msec (vardenafil)
and 5 msec (sildenafil) when compared to either drug alone. The actual clinical impact of these QT
changes is unknown.
Further information on clinical trials
In clinical trials vardenafil was administered to over 3750 men with erectile dysfunction (ED) aged
18 - 89 years, many of whom had multiple co-morbid conditions. Over 1630 patients have been treated
with Levitra for six months or longer. Of these, over 730 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.
8
Across the pivotal trials, treatment with vardenafil 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 in a broad population of men with erectile dysfunction, 68% (5 mg), 76% (10 mg)
and 80% (20 mg) of patients experienced successful penetrations (SEP 2) compared to 49% on placebo
over a three month study period. The ability to maintain the erection (SEP 3) in this broad ED
population was given as 53% (5 mg), 63% (10 mg) and 65% (20 mg) compared to 29% on placebo.
In pooled data from the major efficacy trials, the proportion of patients experiencing successful
penetration on vardenafil were as follows: psychogenic erectile dysfunction (77-87%), mixed erectile
dysfunction (69-83%), organic erectile dysfunction (64-75%), elderly (52-75%), ischaemic heart
disease (70-73%), hyperlipidemia (62-73%), chronic pulmonary disease (74-78%), depression
(59-69%), and patients concomitantly treated with antihypertensives (62-73%).
In a clinical trial in patients with diabetes mellitus, vardenafil significantly improved the erectile
function domain score, the ability to obtain and maintain an erection long enough for successful
intercourse and penile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. The
response rates for the ability to obtain and maintain an erection was 61% and 49% on 10 mg and 64%
and 54% on 20 mg vardenafil compared to 36% and 23% on placebo for patients who completed three
months treatment.
In a clinical trial in post-prostatectomy patients, vardenafil significantly improved the erectile function
domain score, the ability to obtain and maintain an erection long enough for successful intercourse and
penile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. The response rates for the
ability to obtain and maintain an erection was 47% and 37% on 10 mg and 48% and 34% on 20 mg
vardenafil compared to 22% and 10% on placebo for patients who completed three months treatment.
In a flexible-dose clinical trial in patients with Spinal Cord Injury, vardenafil significantly improved the
erectile function domain score, the ability to obtain and maintain an erection long enough for successful
intercourse and penile rigidity compared to placebo. The number of patients who returned to a normal
IIEF domain score (
>
26) were 53% on vardenafil compared to 9% on placebo. The response rates for the
ability to obtain and maintain an erection were 76% and 59% on vardenafil compared to 41% and 22%
on placebo for patients who completed three months treatment which were clinically and statistically
significant (p<0.001).
The safety and efficacy of vardenafil was maintained in long term studies.
5.2 Pharmacokinetic properties
Absorption
Vardenafil is rapidly absorbed with maximum observed plasma concentrations reached in some men as
early as 15 minutes after oral administration. However, 90% of the time, maximum plasma
concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted
state. The mean absolute oral bioavailability is 15 %. After oral dosing of vardenafil AUC and C
max
increase almost dose proportionally over the recommended dose range (5 – 20 mg).
When vardenafil is taken with a high fat meal (containing 57% fat), the rate of absorption is reduced,
with an increase in the median t
max
of 1 hour and a mean reduction in C
max
of 20%. Vardenafil AUC is
not affected. After a meal containing 30% fat, the rate and extent of absorption of vardenafil (t
max
, C
max
and AUC) are unchanged compared to administration under fasting conditions.
9
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.
Metabolism
Vardenafil is metabolised predominantly by hepatic metabolism via cytochrome P450 (CYP) isoform
3A4 with some contribution from CYP3A5 and CYP2C isoforms.
In humans the one major circulating metabolite (M1) results from desethylation of vardenafil and is
subject to further metabolism with a plasma elimination half life of approximately 4 hours. Parts of M1
are in the form of the glucuronide in systemic circulation. Metabolite M1 shows a phosphodiesterase
selectivity profile similar to vardenafil and an
in vitro
potency for phosphodiesterase type 5 of
approximately 28% compared to vardenafil, resulting in an efficacy contribution of about 7%.
Elimination
The total body clearance of vardenafil is 56 l/h with a resultant terminal half life of approximately 4-5
hours. After oral administration, vardenafil is excreted as metabolites predominantly in the faeces
(approximately 91-95% of the administered dose) and to a lesser extent in the urine (approximately
2-6% of the administered dose).
Pharmacokinetics in special patient groups
Elderly
Hepatic clearance of vardenafil in healthy elderly volunteers (65 years and over) was reduced as
compared to healthy younger volunteers (18 - 45 years). On average elderly males had a 52% higher
AUC, and a 34% higher C
max
than younger males (see section 4.2).
Renal insufficiency
In volunteers with mild to moderate renal impairment (creatinine clearance 30 – 80 ml/min), the
pharmacokinetics of vardenafil were similar to that of a normal renal function control group. In
volunteers with severe renal impairment (creatinine clearance < 30 ml/min) the mean AUC was
increased by 21% and the mean C
max
decreased by 23%, compared to volunteers with no renal
impairment. No statistically significant correlation was observed between creatinine clearance and
vardenafil exposure (AUC and C
max
) (see section 4.2). Vardenafil pharmacokinetics has not been
studied in patients requiring dialysis (see section 4.3).
Hepatic insufficiency
In patients with mild to moderate hepatic impairment (Child-Pugh A and B), the clearance of vardenafil
was reduced in proportion to the degree of hepatic impairment. In patients with mild hepatic impairment
(Child-Pugh A), the mean AUC and C
max
increased 17% and 22% respectively, compared to healthy
control subjects. In patients with moderate impairment (Child-Pugh B), the mean AUC and C
max
increased 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.
10
6.
6.1 List of excipients
Tablet core:
crospovidone
magnesium stearate
microcrystalline cellulose
silica, colloidal anhydrous
Film coat:
macrogol 400
hypromellose
titanium dioxide (E171)
ferric oxide yellow (E172)
ferric oxide red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PP/Aluminium foil blisters in cartons of 2, 4, 8 and 12 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
8.
EU/1/03/248/001-004
9.
Date of first authorization: 6 March 2003
Date of last renewal: 6 March 2008
11
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu.
12
1.
Levitra 10 mg film-coated tablets
2.
Each tablet contains 10 mg of vardenafil (as hydrochloride trihydrate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Orange round tablets marked with the BAYER-cross on one side and “10” on the other side.
4.
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 Levitra to be effective, sexual stimulation is required.
Levitra is not indicated for use by women.
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.
Levitra 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).
Use in elderly men
Dosage 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).
Use in children and adolescents
Levitra is not indicated for individuals below 18 years of age. There is no relevant indication for use of
Levitra in children.
Use in patients with 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).
13
Use in patients with renal impairment
No dosage 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.
Use in patients using other medicinal products
When used in combination with the CYP 3A4 inhibitors such as erythromycin
or clarithromycin
, the
dose of vardenafil should not exceed 5 mg (see section 4.5).
For oral use.
Hypersensitivity to the active substance or to any of the excipients.
The coadministration of vardenafil with nitrates or nitric oxide donors (such as amyl nitrite) in any form
is contraindicated (see sections 4.5 and 5.1).
Levitra 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 PDE5 inhibitor exposure (see section 4.4).
Agents 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).
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.
Agents 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
14
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 with other treatments for erectile dysfunction
have not been studied. Therefore the use of such combinations is not recommended.
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.
Vardenafil may be administered at any time with tamsulosin. 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 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 sections 4.5 and 4.2).
Concomitant intake of grapefruit juice is expected to increase the plasma concentrations of vardenafil.
The combination should be avoided (see section 4.5).
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, a drug with comparable QT effect, showed an additive QTc
effect of 4 msec when compared to either drug 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).
Visual defects and cases of non-arteritic ischemic optic neuropathy (NAION) have been reported in
connection with the intake of Levitra and other PDE5 inhibitors. The patient should be advised that in
the case of sudden visual defect, he should stop taking Levitra and consult immediately a physician (see
section 4.3).
Tolerability of the maximum dose of 20 mg may be lower in elderly patients (≥ 65 years old) (see
sections 4.2 and 4.8).
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.
15
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) resulted in a 16-fold increase in vardenafil AUC and a 7-fold increase
in vardenafil C
max
. At 24 hours, the plasma levels of vardenafil had fallen to approximately 4% of the
maximum vardenafil plasma level (C
max
).
Co-administration of vardenafil with ritonavir (600 mg twice daily) resulted in a 13-fold increase in
vardenafil C
max
and a 49-fold increase in vardenafil AUC
0-24
when co-administered with vardenafil 5
mg. The interaction is a consequence of blocking hepatic metabolism of Levitra by ritonavir, a highly
potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life
of Levitra to 25.7 hours (see section 4.3).
Co-administration of ketoconazole (200 mg), a potent CYP3A4 inhibitor, with vardenafil (5 mg)
resulted in a 10-fold increase in vardenafil AUC and a 4-fold increase in vardenafil C
max
(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 CYP 3A4
inhibitors such as itraconazole and ketoconazole (oral use) should be avoided (see sections 4.3 and 4.4).
In men older than 75 years the concomitant use of vardenafil with itraconazole or ketoconazole is
contraindicated (see section 4.3).
Co-administration of erythromycin (500 mg three times a day), a CYP3A4 inhibitor, with vardenafil
(5 mg) resulted in a 4-fold increase in vardenafil AUC and a 3-fold increase in C
max
. Although a specific
interaction study has not been conducted, the co-administration of clarithromycin can be expected to
result in similar effects on vardenafil AUC and C
max
. When used in combination with a moderate CYP
3A4 inhibitor such as
erythromycin or clarithromycin, vardenafil dose adjustment might be necessary
(see sections 4.2 and 4.4). Cimetidine (400 mg twice daily), a non-specific cytochrome P450 inhibitor,
had no effect on vardenafil AUC and C
max
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 CYP 3A4
inhibitors, diuretics and medicinal products for the treatment of diabetes (sulfonylureas and metformin).
16
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 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 20 mg
.
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 or terazosin 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.
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 5mg. Levitra may be administered at any time with tamsulosin.
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). 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) 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).
Levitra is not indicated for use by women. There are no studies of vardenafil in pregnant women.
17
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 Levitra, before driving or operating machinery.
Over 9,500 patients have received Levitra in clinical trials. The adverse reactions were generally
transient and mild to moderate in nature. The most commonly reported adverse drug reactions occurring
in 10% of patients are headache and flushing.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The following adverse reactions have been reported:
System Organ
Class
Very
Common
(
1/10)
Common
(
1/100 and
<1/ 10)
Uncommon
(
1/1,000 and
<1/100)*
Rare
(
1/10,000 and
<1/1,000)*
Not Known
(can not be estimated
from available data)
Immune System
Disorders
Hypersensitivity
Psychiatric
Disorders
Anxiety
Nervous System
Disorders
Headache
Dizziness
Somnolence
Syncope
Seizure Transient
global amnesia
Eye Disorders
incl. Related
Investigations
Lacrimation
increased
Visual
Disturbance
(incl. Visual
brightness)
Chromatopsia
Conjunctivitis
Blurred vision
Intraocular
pressure
increased
Non-arteritic-anterior
ischemic optic
neuropathy
Visual defects
Ear and labyrinth
Disorders
Sudden deafness**
Cardiac Disorders
incl. related
Investigations
Tachycardia
Palpitations
Angina Pectoris
Myocardial
ischemia
Myocardial Infarction
Vascular
Disorders incl.
related
Investigations
Flushing
Hypertension
Hypotension
Orthostatic
Hypotension
Respiratory,
Thoracic and
Mediastinal
Disorders
Nasal
Congestion
Dyspnoea
Epistaxis
Laryngeal
oedema
Gastrointestinal
Disorders incl.
related
Investigations
Dyspepsia
Nausea
Abnormal liver
function tests
GGTP increased
Skin and
Subcutaneous
Tissue Disorders
Photosensitivity
reaction
Face oedema
Rash
18
System Organ
Class
Very
Common
(
1/10)
Common
(
1/100 and
<1/ 10)
Uncommon
(
1/1,000 and
<1/100)*
Rare
(
1/10,000 and
<1/1,000)*
Not Known
(can not be estimated
from available data)
Musculoskeletal
and Connective
Tissue Disorders
incl. Related
Investigations
Blood creatine
phosphokinase
increased
Myalgia
Back Pain
Muscle Rigidity
Reproductive
System and
Breast Disorders
Priapism
Erections
increased
(prolonged or
painful erections)
*For adverse reactions reported in <1% of patients, only those which warrant special attention, because
of their possible association with serious disease states or of otherwise clinical relevance are listed.
**Sudden deafness or loss of hearing has been reported in a small number of postmarketing and clinical
trial cases with the use of all PDE5 inhibitors, including vardenafil.
At the 20mg dose, 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).
Post marketing reports of another medicinal product of this class: Vascular Disorders: Serious
cardiovascular events, 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.
In single dose volunteer studies, doses up to and including 80 mg per day were tolerated without
exhibiting serious adverse reactions.
When vardenafil was administered in higher doses and more frequently than the recommended dosing
regimen (40 mg 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicinal product 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).
19
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
vardeanfil, 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 postdose. 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 postmarketing 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 Fredericia QTc effect of 4 msec (vardenafil)
and 5 msec (sildenafil) when compared to either drug alone. The actual clinical impact of these QT
changes is unknown.
Further information on clinical trials
In clinical trials vardenafil was administered to over 3750 men with erectile dysfunction (ED) aged
18 - 89 years, many of whom had multiple co-morbid conditions. Over 1630 patients have been treated
with Levitra for six months or longer. Of these, over 730 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 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
20
after dosing the success rate for penetration and maintenance of erection was consistently greater than
placebo.
In fixed dose studies in a broad population of men with erectile dysfunction, 68% (5 mg), 76% (10 mg)
and 80% (20 mg) of patients experienced successful penetrations (SEP 2) compared to 49% on placebo
over a three month study period. The ability to maintain the erection (SEP 3) in this broad ED
population was given as 53% (5 mg), 63% (10 mg) and 65% (20 mg) compared to 29% on placebo.
In pooled data from the major efficacy trials, the proportion of patients experiencing successful
penetration on vardenafil were as follows: psychogenic erectile dysfunction (77-87%), mixed erectile
dysfunction (69-83%), organic erectile dysfunction (64-75%), elderly (52-75%), ischaemic heart
disease (70-73%), hyperlipidemia (62-73%), chronic pulmonary disease (74-78%), depression
(59-69%), and patients concomitantly treated with antihypertensives (62-73%).
In a clinical trial in patients with diabetes mellitus, vardenafil significantly improved the erectile
function domain score, the ability to obtain and maintain an erection long enough for successful
intercourse and penile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. The
response rates for the ability to obtain and maintain an erection was 61% and 49% on 10 mg and 64%
and 54% on 20 mg vardenafil compared to 36% and 23% on placebo for patients who completed three
months treatment.
In a clinical trial in post-prostatectomy patients, vardenafil significantly improved the erectile function
domain score, the ability to obtain and maintain an erection long enough for successful intercourse and
penile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. The response rates for the
ability to obtain and maintain an erection was 47% and 37% on 10 mg and 48% and 34% on 20 mg
vardenafil compared to 22% and 10% on placebo for patients who completed three months treatment.
In a flexible-dose clinical trial in patients with Spinal Cord Injury, vardenafil significantly improved the
erectile function domain score, the ability to obtain and maintain an erection long enough for successful
intercourse and penile rigidity compared to placebo. The number of patients who returned to a normal
IIEF domain score (
>
26) were 53% on vardenafil compared to 9% on placebo. The response rates for the
ability to obtain and maintain an erection were 76% and 59% on vardenafil compared to 41% and 22%
on placebo for patients who completed three months treatment which were clinically and statistically
significant (p<0.001).
The safety and efficacy of vardenafil was maintained in long term studies.
5.2 Pharmacokinetic properties
Absorption
Vardenafil is rapidly absorbed with maximum observed plasma concentrations reached in some men as
early as 15 minutes after oral administration. However, 90% of the time, maximum plasma
concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted
state. The mean absolute oral bioavailability is 15 %. After oral dosing of vardenafil AUC and C
max
increase almost dose proportionally over the recommended dose range (5 – 20 mg).
When vardenafil is taken with a high fat meal (containing 57% fat), the rate of absorption is reduced,
with an increase in the median t
max
of 1 hour and a mean reduction in C
max
of 20%. Vardenafil AUC is
not affected. After a meal containing 30% fat, the rate and extent of absorption of vardenafil (t
max
, C
max
and AUC) are unchanged compared to administration under fasting conditions.
Distribution
The mean steady state volume of distribution for vardenafil is 208 l, indicating distribution into the
tissues. Vardenafil and its major circulating metabolite (M1) are highly bound to plasma proteins
(approximately 95% for vardenafil or M1). For vardenafil as well as M1, protein binding is independent
of total drug concentrations.
21
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.
Metabolism
Vardenafil is metabolised predominantly by hepatic metabolism via cytochrome P450 (CYP) isoform
3A4 with some contribution from CYP3A5 and CYP2C isoforms.
In humans the one major circulating metabolite (M1) results from desethylation of vardenafil and is
subject to further metabolism with a plasma elimination half life of approximately 4 hours. Parts of M1
are in the form of the glucuronide in systemic circulation. Metabolite M1 shows a phosphodiesterase
selectivity profile similar to vardenafil and an
in vitro
potency for phosphodiesterase type 5 of
approximately 28% compared to vardenafil, resulting in an efficacy contribution of about 7%.
Elimination
The total body clearance of vardenafil is 56 l/h with a resultant terminal half life of approximately 4-5
hours. After oral administration, vardenafil is excreted as metabolites predominantly in the faeces
(approximately 91-95% of the administered dose) and to a lesser extent in the urine (approximately
2-6% of the administered dose).
Pharmacokinetics in special patient groups
Elderly
Hepatic clearance of vardenafil in healthy elderly volunteers (65 years and over) was reduced as
compared to healthy younger volunteers (18 - 45 years). On average elderly males had a 52% higher
AUC, and a 34% higher C
max
than younger males (see section 4.2).
Renal insufficiency
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 C
max
) (see section 4.2). Vardenafil pharmacokinetics has not been
studied in patients requiring dialysis (see section 4.3).
Hepatic insufficiency
In patients with mild to moderate hepatic impairment (Child-Pugh A and B), the clearance of vardenafil
was reduced in proportion to the degree of hepatic impairment. In patients with mild hepatic impairment
(Child-Pugh A), the mean AUC and C
max
increased 17% and 22% respectively, compared to healthy
control subjects. In patients with moderate impairment (Child-Pugh B), the mean AUC and C
max
increased 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.
22
6.
6.1 List of excipients
Tablet core:
crospovidone
magnesium stearate
microcrystalline cellulose
silica, colloidal anhydrous
Film coat:
macrogol 400
hypromellose
titanium dioxide (E171)
ferric oxide yellow (E172)
ferric oxide red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PP/Aluminium foil blisters in cartons of 2, 4, 8 and 12 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
8.
EU/1/03/248/005-008
9.
Date of first authorization: 6 March 2003
Date of last renewal : 6 March 2008
23
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu.
24
1.
Levitra 20 mg film-coated tablets
2.
Each tablet contains 20 mg of vardenafil (as hydrochloride trihydrate).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Orange round tablets marked with the BAYER-cross on one side and “20” on the other side.
4.
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 Levitra to be effective, sexual stimulation is required.
Levitra is not indicated for use by women.
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.
Levitra 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).
Use in elderly men
Dosage 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).
Use in children and adolescents
Levitra is not indicated for individuals below 18 years of age. There is no relevant indication for use of
Levitra in children.
Use in patients with 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).
25
Use in patients with renal impairment
No dosage 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.
Use in patients using other medicinal products
When used in combination with the CYP 3A4 inhibitors such as erythromycin
or clarithromycin
, the
dose of vardenafil should not exceed 5 mg (see section 4.5).
For oral use
Hypersensitivity to the active substance or to any of the excipients.
The coadministration of vardenafil with nitrates or nitric oxide donors (such as amyl nitrite) in any form
is contraindicated (see sections 4.5 and 5.1).
Levitra 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 PDE5 inhibitor exposure (see section 4.4).
Agents 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).
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.
Agents 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
26
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 with other treatments for erectile dysfunction
have not been studied. Therefore the use of such combinations is not recommended.
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.
Vardenafil may be administered at any time with tamsulosin. 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 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 sections 4.5 and 4.2).
Concomitant intake of grapefruit juice is expected to increase the plasma concentrations of vardenafil.
The combination should be avoided (see section 4.5).
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, a drug with comparable QT effect, showed an additive QTc
effect of 4 msec when compared to either drug 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).
Visual defects and cases of non-arteritic ischemic optic neuropathy (NAION) have been reported in
connection with the intake of Levitra and other PDE5 inhibitors. The patient should be advised that in
the case of sudden visual defect, he should stop taking Levitra and consult immediately a physician (see
section 4.3).
Tolerability of the maximum dose of 20 mg may be lower in elderly patients (≥ 65 years old) (see
sections 4.2 and 4.8).
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.
27
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) resulted in a 16-fold increase in vardenafil AUC and a 7-fold increase
in vardenafil C
max
. At 24 hours, the plasma levels of vardenafil had fallen to approximately 4% of the
maximum vardenafil plasma level (C
max
).
Co-administration of vardenafil with ritonavir (600 mg twice daily) resulted in a 13-fold increase in
vardenafil C
max
and a 49-fold increase in vardenafil AUC
0-24
when co-administered with vardenafil 5
mg. The interaction is a consequence of blocking hepatic metabolism of Levitra by ritonavir, a highly
potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life
of Levitra to 25.7 hours (see section 4.3).
Co-administration of ketoconazole (200 mg), a potent CYP3A4 inhibitor, with vardenafil (5 mg)
resulted in a 10-fold increase in vardenafil AUC and a 4-fold increase in vardenafil C
max
(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 CYP 3A4
inhibitors such as itraconazole and ketoconazole (oral use) should be avoided (see sections 4.3 and 4.4).
In men older than 75 years the concomitant use of vardenafil with itraconazole or ketoconazole is
contraindicated (see section 4.3).
Co-administration of erythromycin (500 mg three times a day), a CYP3A4 inhibitor, with vardenafil
(5 mg) resulted in a 4-fold increase in vardenafil AUC and a 3-fold increase in C
max
. Although a specific
interaction study has not been conducted, the co-administration of clarithromycin can be expected to
result in similar effects on vardenafil AUC and C
max
. When used in combination with a moderate CYP
3A4 inhibitor such as
erythromycin or clarithromycin, vardenafil dose adjustment might be necessary
(see sections 4.2 and 4.4). Cimetidine (400 mg twice daily), a non-specific cytochrome P450 inhibitor,
had no effect on vardenafil AUC and C
max
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 CYP 3A4
inhibitors, diuretics and medicinal products for the treatment of diabetes (sulfonylureas and metformin).
28
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 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 20 mg. 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 or terazosin 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.
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 5mg. Levitra may be administered at any time with tamsulosin.
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). 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) 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).
Levitra is not indicated for use by women. There are no studies of vardenafil in pregnant women.
29
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 Levitra, before driving or operating machinery.
Over 9,500 patients have received Levitra in clinical trials. The adverse reactions were generally
transient and mild to moderate in nature. The most commonly reported adverse drug reactions occurring
in 10% of patients are headache and flushing.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
The following adverse reactions have been reported:
System Organ
Class
Very
Common
(
1/10)
Common
(
1/100 and
<1/ 10)
Uncommon
(
1/1,000 and
<1/100)*
Rare
(
1/10,000 and
<1/1,000)*
Not Known
(can not be estimated
from available data)
Immune System
Disorders
Hypersensitivity
Psychiatric
Disorders
Anxiety
Nervous System
Disorders
Headache Dizziness
Somnolence
Syncope
Seizure Transient
global amnesia
Eye Disorders
incl. Related
Investigations
Lacrimation
increased
Visual
Disturbance
(incl. Visual
brightness)
Chromatopsia
Conjunctivitis
Blurred vision
Intraocular
pressure
increased
Non-arteritic-anterior
ischemic optic
neuropathy
Visual defects
Ear and labyrinth
Disorders
Sudden deafness**
Cardiac Disorders
incl. related
Investigations
Tachycardia
Palpitations
Angina Pectoris
Myocardial
ischemia
Myocardial Infarction
Vascular
Disorders incl.
related
Investigations
Flushing
Hypertension
Hypotension
Orthostatic
Hypotension
Respiratory,
Thoracic and
Mediastinal
Disorders
Nasal
Congestion
Dyspnoea
Epistaxis
Laryngeal
oedema
Gastrointestinal
Disorders incl.
related
Investigations
Dyspepsia
Nausea
Abnormal liver
function tests
GGTP increased
Skin and
Subcutaneous
Tissue Disorders
Photosensitivity
reaction
Face oedema
Rash
30
System Organ
Class
Very
Common
(
1/10)
Common
(
1/100 and
<1/ 10)
Uncommon
(
1/1,000 and
<1/100)*
Rare
(
1/10,000 and
<1/1,000)*
Not Known
(can not be estimated
from available data)
Musculoskeletal
and Connective
Tissue Disorders
incl. Related
Investigations
Blood creatine
phosphokinase
increased
Myalgia
Back Pain
Muscle Rigidity
Reproductive
System and
Breast Disorders
Priapism
Erections
increased
(prolonged or
painful erections)
*For adverse reactions reported in <1% of patients, only those which warrant special attention, because
of their possible association with serious disease states or of otherwise clinical relevance are listed.
**Sudden deafness or loss of hearing has been reported in a small number of postmarketing and clinical
trial cases with the use of all PDE5 inhibitors, including vardenafil.
At the 20mg dose, 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).
Post marketing reports of another medicinal product of this class: Vascular Disorders: Serious
cardiovascular events, 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.
In single dose volunteer studies, doses up to and including 80 mg per day were tolerated without
exhibiting serious adverse reactions.
When vardenafil was administered in higher doses and more frequently than the recommended dosing
regimen (40 mg 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Medicinal product 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).
31
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
vardeanfil, 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 postdose. 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 postmarketing 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 Fredericia QTc effect of 4 msec (vardenafil)
and 5 msec (sildenafil) when compared to either drug alone. The actual clinical impact of these QT
changes is unknown.
Further information on clinical trials
In clinical trials vardenafil was administered to over 3750 men with erectile dysfunction (ED) aged
18 - 89 years, many of whom had multiple co-morbid conditions. Over 1630 patients have been treated
with Levitra for six months or longer. Of these, over 730 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 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
32
after dosing the success rate for penetration and maintenance of erection was consistently greater than
placebo.
In fixed dose studies in a broad population of men with erectile dysfunction, 68% (5 mg), 76% (10 mg)
and 80% (20 mg) of patients experienced successful penetrations (SEP 2) compared to 49% on placebo
over a three month study period. The ability to maintain the erection (SEP 3) in this broad ED
population was given as 53% (5 mg), 63% (10 mg) and 65% (20 mg) compared to 29% on placebo.
In pooled data from the major efficacy trials, the proportion of patients experiencing successful
penetration on vardenafil were as follows: psychogenic erectile dysfunction (77-87%), mixed erectile
dysfunction (69-83%), organic erectile dysfunction (64-75%), elderly (52-75%), ischaemic heart
disease (70-73%), hyperlipidemia (62-73%), chronic pulmonary disease (74-78%), depression
(59-69%), and patients concomitantly treated with antihypertensives (62-73%).
In a clinical trial in patients with diabetes mellitus, vardenafil significantly improved the erectile
function domain score, the ability to obtain and maintain an erection long enough for successful
intercourse and penile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. The
response rates for the ability to obtain and maintain an erection was 61% and 49% on 10 mg and 64%
and 54% on 20 mg vardenafil compared to 36% and 23% on placebo for patients who completed three
months treatment.
In a clinical trial in post-prostatectomy patients, vardenafil significantly improved the erectile function
domain score, the ability to obtain and maintain an erection long enough for successful intercourse and
penile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. The response rates for the
ability to obtain and maintain an erection was 47% and 37% on 10 mg and 48% and 34% on 20 mg
vardenafil compared to 22% and 10% on placebo for patients who completed three months treatment.
In a flexible-dose clinical trial in patients with Spinal Cord Injury, vardenafil significantly improved the
erectile function domain score, the ability to obtain and maintain an erection long enough for successful
intercourse and penile rigidity compared to placebo. The number of patients who returned to a normal
IIEF domain score (
>
26) were 53% on vardenafil compared to 9% on placebo. The response rates for the
ability to obtain and maintain an erection were 76% and 59% on vardenafil compared to 41% and 22%
on placebo for patients who completed three months treatment which were clinically and statistically
significant (p<0.001).
The safety and efficacy of vardenafil was maintained in long term studies.
5.2 Pharmacokinetic properties
Absorption
Vardenafil is rapidly absorbed with maximum observed plasma concentrations reached in some men as
early as 15 minutes after oral administration. However, 90% of the time, maximum plasma
concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted
state. The mean absolute oral bioavailability is 15 %. After oral dosing of vardenafil AUC and C
max
increase almost dose proportionally over the recommended dose range (5 – 20 mg).
When vardenafil is taken with a high fat meal (containing 57% fat), the rate of absorption is reduced,
with an increase in the median t
max
of 1 hour and a mean reduction in C
max
of 20%. Vardenafil AUC is
not affected. After a meal containing 30% fat, the rate and extent of absorption of vardenafil (t
max
, C
max
and AUC) are unchanged compared to administration under fasting conditions.
33
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.
Metabolism
Vardenafil is metabolised predominantly by hepatic metabolism via cytochrome P450 (CYP) isoform
3A4 with some contribution from CYP3A5 and CYP2C isoforms.
In humans the one major circulating metabolite (M1) results from desethylation of vardenafil and is
subject to further metabolism with a plasma elimination half life of approximately 4 hours. Parts of M1
are in the form of the glucuronide in systemic circulation. Metabolite M1 shows a phosphodiesterase
selectivity profile similar to vardenafil and an
in vitro
potency for phosphodiesterase type 5 of
approximately 28% compared to vardenafil, resulting in an efficacy contribution of about 7%.
Elimination
The total body clearance of vardenafil is 56 l/h with a resultant terminal half life of approximately 4-5
hours. After oral administration, vardenafil is excreted as metabolites predominantly in the faeces
(approximately 91-95% of the administered dose) and to a lesser extent in the urine (approximately
2-6% of the administered dose).
Pharmacokinetics in special patient groups
Elderly
Hepatic clearance of vardenafil in healthy elderly volunteers (65 years and over) was reduced as
compared to healthy younger volunteers (18 - 45 years). On average elderly males had a 52% higher
AUC, and a 34% higher C
max
than younger males (see section 4.2).
Renal insufficiency
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 C
max
) (see section 4.2). Vardenafil pharmacokinetics has not been
studied in patients requiring dialysis (see section 4.3).
Hepatic insufficiency
In patients with mild to moderate hepatic impairment (Child-Pugh A and B), the clearance of vardenafil
was reduced in proportion to the degree of hepatic impairment. In patients with mild hepatic impairment
(Child-Pugh A), the mean AUC and C
max
increased 17% and 22% respectively, compared to healthy
control subjects. In patients with moderate impairment (Child-Pugh B), the mean AUC and C
max
increased 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).
34
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.
6.1 List of excipients
Tablet core:
crospovidone
magnesium stearate
microcrystalline cellulose
silica, colloidal anhydrous
Film coat:
macrogol 400
hypromellose
titanium dioxide (E171)
ferric oxide yellow (E172)
ferric oxide red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PP/Aluminium foil blisters in cartons of 2, 4, 8 and 12 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Bayer Schering Pharma AG
13342 Berlin
Germany
35
8.
EU/1/03/248/009-012
9.
Date of first authorization: 6 March 2003
Date of last renewal : 6 March 2008
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.europa.eu.
36
1.
FURTHER INFORMATION
What Levitra orodispersible tablets contains
-
The active substance is vardenafil. Each orodispersible tablet contains 10 mg of vardenafil (as
hydrochloride).
89
-
The other ingredients of the tablets are:
Magnesium stearate, aspartame (E951), peppermint flavour, mannitol (E421) sorbitol (E420),
crospovidone and silica colloidal hydrated.
What Levitra 10 mg orodispersible tablets looks like and contents of the pack
Levitra 10 mg orodispersible tablets are round and white. They are provided in packs of 1, 2, 4 or
8
tablets (containing Alu/Alu blisters or Alu/Alu blisters in blister holders).
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Bayer Schering Pharma AG,
13342 Berlin,
Germany.
Manufacturer
Bayer Schering Pharma AG,
D-51368 Leverkusen,
Germany.
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
Luxembourg/Luxemburg
Bayer SA-NV
Tél/Tel: +32-(0)2-535 63 11
България
Байер България ЕООД
Tел.: +359-(0)2 81 401 01
Magyarország
Bayer Hungária Kft.
Tel.: +36-1-487-4100
Česká republika
Bayer s.r.o.
Tel: +420 271 730 661
Nederland
Bayer B.V., Bayer Schering Pharma
Tel: +31-(0)297-28 06 66
Deutschland
Bayer Vital GmbH
Tel: +49-(0)214-30 513 48
Norge
Bayer AS
Tlf:+47-24 11 18 00
Eesti
Bayer OÜ
Tel: +372 655 85 65
Österreich
Bayer Austria Ges. m. b. H.
Tel: +43-(0)1-711 460
Ελλάδα
Bayer Ελλάς ΑΒΕΕ
Τηλ: +30 210 618 75 00
Polska
Bayer Sp. z o.o.
Tel.: +48-22-572 35 00
España
Quimica Farmacéutica Bayer S.L.
Tel: +34-93-495 65 00
Portugal
Bayer Portugal S.A.
Tel: +351-21-416 42 00
France
Bayer Santé
Tél: +33-(0)3-28 16 34 00
România
SC Bayer SRL.
Tel: +40-21-528 59 00
Ireland
Bayer Limited
Tel: +353-1-299 93 13
Slovenija
Bayer d. o. o.
Tel: +386-1-58 14 400
90
Danmark
Bayer A/S
Tlf: +45-45-235 000
Malta
Alfred Gera and Sons Ltd.
Tel: +356-21 44 62 05
Ísland
Icepharma hf.
Sími: +354-540 8000
Slovenská republika
Bayer, spol. s r.o.
Tel: +421 2-59 21 31 11
Italia
Bayer S.p.A.
Tel: +39-02-397 81
Suomi/Finland
Bayer Oy, Bayer Schering Pharma
Puh/Tel: +358-20-785 21
Κύπρος
NOVAGEM Limited
Τηλ: +357-22-747 747
Sverige
Bayer AB
Tel: +46-(0)8-580 223 00
Latvija
SIA Bayer
Tel: +371 67 845 563
United Kingdom
Bayer plc
Tel: +44-(0)1635-56 30 00
Lietuva
UAB Bayer
Tel: +370 5 23 36 868
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
91
Source: European Medicines Agency
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