LEVITRA 20mg tablets medication leaflet

Levitra 10 mg orodispersible tablets

Each orodispersible tablet contains 10 mg of vardenafil (as hydrochloride).

7.96 mg sorbitol (E420), and 1.80 mg aspartame (E951) per orodispersible tablet.

For the full list of excipients, see section 6.1.

Orodispersible tablet.

White round tablets.

Treatment of erectile dysfunction in adult men. Erectile dysfunction is the inability to achieve ormaintain a penile erection sufficient for satisfactory sexual performance.

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

Levitra 10 mg orodispersible tablets are not bioequivalent to Levitra 10 mg film-coated tablets (seesection 5.1). The maximum dose for Levitra orodispersible tablet is 10 mg/day.

Use in adult men

Levitra 10 mg orodispersible tablets are taken as needed approximately 25 to 60 minutes before sexualactivity.

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

Levitra 20 mg film-coated tablets should be carefully considered depending on the individualtolerability (see sections 4.4 and 4.8).

Levitra 10 mg orodispersible tablets are not indicated as a starting dose in patients with mild hepaticimpairment (Child-Pugh A).

Patients with mild hepatic impairment should start treatment with Levitra 5 mg film-coated tablets.

Based on tolerability and efficacy, the dose may be increased to Levitra 10 mg and 20 mg film-coatedtablets, or Levitra 10 mg orodispersible tablets.

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

Levitra 10 mg as film-coated tablets (see section 5.2).

Levitra 10 mg orodispersible tablets are not for use in patients with moderate (Child-Pugh B) and severehepatic impairment (Child-Pugh C; see section 4.3).

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

In patients with severe renal impairment (creatinine clearance <30 ml/min) a starting dose of Levitra5 mg film-coated tablets should be considered. Based on tolerability and efficacy, the dose may beincreased to Levitra 10 mg and 20 mg film-coated tablets, or Levitra 10 mg orodispersible tablets.

Levitra orodispersible tablet is not for use in patients with end-stage renal failure (see section 4.3).

Levitra orodispersible tablets are not indicated for individuals below 18 years of age. There is norelevant indication for use of Levitra orodispersible tablets in children and adolescents.

Use in patients using other medicinal products

Concomitant use of moderate or potent CYP3A4 inhibitors

Vardenafil dose adjustment is necessary if moderate or potent CYP3A4 inhibitors are givenconcomitantly (see section 4.5).

For oral use.

The orodispersible tablet should be placed in the mouth on the tongue, where it will rapidly disintegrate,and then swallowed. Levitra orodispersible tablets must be taken without liquid and immediately uponrelease from the blister.

Levitra orodispersible tablets can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

The co-administration of vardenafil with nitrates or nitric oxide donors (such as amyl nitrite) in any formis 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 anteriorischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not withprevious phosphodiesterase 5 (PDE5) inhibitor exposure (see section 4.4).

Medicinal products for the treatment of erectile dysfunction should generally not be used in men forwhom sexual activity is inadvisable (e.g. patients with severe cardiovascular disorders such as unstableangina 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 istherefore 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 (oralform) is contraindicated in men older than 75 years.

Concomitant use of vardenafil with HIV protease inhibitors such as ritonavir and indinavir iscontraindicated, as they are very potent inhibitors of CYP3A4 (see section 4.5).

The co-administration of PDE5 inhibitors, including vardenafil, with guanylate cyclase stimulators,such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension (see section4.5).

A medical history and physical examination should be undertaken to diagnose erectile dysfunction anddetermine potential underlying causes, before pharmacological treatment is considered.

Prior to initiating any treatment for erectile dysfunction, physicians should consider the cardiovascularstatus of their patients, since there is a degree of cardiac risk associated with sexual activity (see section4.3). 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 idiopathichypertrophic subaortic stenosis, can be sensitive to the action of vasodilators including Type 5phosphodiesterase inhibitors.

Serious cardiovascular events including sudden death, tachycardia, myocardial infarction, ventriculartachy-arrythmia, angina pectoris, and cerebrovascular disorders (including transient ischaemic attackand cerebral haemorrhage), have been reported in temporal association with vardenafil. Most of thepatients in whom these events have been reported had pre-existing cardiovascular risk factors. However,it is not possible to definitively determine whether these events are related directly to these risk factors,to vardenafil, to sexual activity, or to a combination of these or other factors.

Medicinal products for the treatment of erectile dysfunction should be used with caution in patients withanatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease), or inpatients 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 Levitra orodispersible tablets with Levitra film-coatedtablets or other treatments for erectile dysfunction have not been studied. Therefore the use of suchcombinations is not recommended.

Tolerability of the maximum dose of Levitra 20 mg film-coated tablets may be lower in elderly patients(≥65 years old) (see sections 4.2 and 4.8).

Concomitant use of alpha-blockers

The concomitant use of alpha-blockers and vardenafil may lead to symptomatic hypotension in somepatients because both are vasodilators. Concomitant treatment with vardenafil should only be initiated ifthe patient has been stabilised on his alpha-blocker therapy. In those patients who are stable onalpha-blocker therapy, vardenafil should be initiated at the lowest recommended starting dose of 5 mgfilm-coated tablets. Patients treated with alpha-blockers should not use Levitra 10 mg orodispersibletablets as a starting dose. Vardenafil may be administered at any time with tamsulosin or with alfuzosin.

With other alpha-blockers a time separation of dosing should be considered when vardenafil isprescribed concomitantly (see section 4.5). In those patients already taking an optimised dose ofvardenafil, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase inalpha-blocker dose may be associated with further lowering of blood pressure in patients takingvardenafil.

Concomitant use of CYP3A4 inhibitors

Concomitant use of vardenafil with potent CYP3A4 inhibitors such as itraconazole and ketoconazole(oral form) should be avoided as very high plasma concentrations of vardenafil are reached if themedicinal products are combined (see sections 4.5 and 4.3).

Vardenafil dose adjustment might be necessary if moderate CYP3A4 inhibitors such as erythromycinand clarithromycin, are given concomitantly (see section 4.2 and 4.5).

Concomitant intake of grapefruit or grapefruit juice is expected to increase the plasma concentrations ofvardenafil. The combination should be avoided (see section 4.5).

Effect on QTc interval

Single oral doses of 10 mg and 80 mg of vardenafil have been shown to prolong the QTc interval by amean of 8 msec and 10 msec, respectively. And single doses of 10 mg vardenafil co-administeredconcomitantly with 400 mg gatifloxacin, an active substance with comparable QT effect, showed anadditive QTc effect of 4 msec when compared to either active substance alone. The clinical impact ofthese QT changes is unknown (see section 5.1).

The clinical relevance of this finding is unknown and cannot be generalised to all patients under allcircumstances, as it will depend on the individual risk factors and susceptibilities that may be present atany 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 QTprolongation, concomitant administration of antiarrhythmic medicinal products in Class IA (e.g.

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

Effect on vision

Visual defects and cases of non-arteritic ischemic optic neuropathy (NAION) have been reported inconnection with the intake of Levitra and other PDE5 inhibitors. Analyses of observational data suggestan increased risk of acute NAION in men with erectile dysfunction following exposure to PDE5inhibitors such as vardenafil, tadalafil and sildenafil (see section 4.8). As this may be relevant for allpatients exposed to vardenafil the patient should be advised that in the case of sudden visual defect, heshould stop taking Levitra orodispersible tablets and consult immediately a physician (see section 4.3).

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 thenitric oxide donor sodium nitroprusside. In humans vardenafil had no effect on bleeding time alone or incombination with acetylsalicylic acid (see section 4.5). There is no safety information available on theadministration of vardenafil to patients with bleeding disorders or active peptic ulceration. Thereforevardenafil should be administered to these patients only after careful benefit-risk assessment.

Aspartame

This medicine contains 1.80 mg aspartame in each 10 mg orodispersible tablet. Aspartame is a source ofphenylalanine. It may be harmful for people with phenylketonuria (PKU), a rare genetic disorder inwhich phenylalanine builds up because the body cannot remove it properly.

Sorbitol

This medicine contains 7.96 mg sorbitol in each 10 mg orodispersible tablet.

Effects of other medicinal products on vardenafil

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 isoenzymesreduce vardenafil clearance.

Co-administration of the HIV protease inhibitor indinavir (800 mg three times a day), a potent CYP3A4inhibitor, with vardenafil (10 mg film-coated tablets) resulted in a 16-fold increase in vardenafil AUCand a 7-fold increase in vardenafil Cmax. At 24 hours, the plasma levels of vardenafil had fallen toapproximately 4% of the maximum vardenafil plasma level (Cmax).

Co-administration of vardenafil with ritonavir (600 mg twice daily) resulted in a 13-fold increase invardenafil Cmax and a 49-fold increase in vardenafil AUC0-24 when co-administered with vardenafil5 mg. The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, ahighly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged thehalf-life of vardenafil to 25.7 hours (see section 4.3).

Co-administration of ketoconazole (200 mg), a potent CYP3A4 inhibitor, with vardenafil (5 mg)resulted in a 10-fold increase in vardenafil AUC and a 4-fold increase in vardenafil Cmax (see section4.4).

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 levelscomparable to those produced by ketoconazole. Concomitant use of vardenafil with potent CYP3A4inhibitors 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 iscontraindicated (see section 4.3).

Co-administration of erythromycin (500 mg three times a day), a CYP3A4 inhibitor, with vardenafil(5 mg) resulted in a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax. Although a specificinteraction study has not been conducted, the co-administration of clarithromycin can be expected toresult in similar effects on vardenafil AUC and Cmax. When used in combination with a moderate

CYP3A4 inhibitor such as erythromycin or clarithromycin, vardenafil dose adjustment might benecessary (see sections 4.2 and 4.4).

Cimetidine (400 mg twice daily), a non-specific cytochrome P450 inhibitor, had no effect on vardenafil

AUC and Cmax when co-administered with vardenafil (20 mg) to healthy volunteers.

Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism, may give rise to modestincreases 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 (meanmaximum blood alcohol level of 73 mg/dl) or single doses of antacid (magnesium hydroxide/aluminiumhydroxide).

Although specific interaction studies were not conducted for all medicinal products, populationpharmacokinetic analysis showed no effect on vardenafil pharmacokinetics of the followingconcomitant medicinal products: acetylsalicylic acid, ACE-inhibitors, beta-blockers, weak CYP3A4inhibitors, diuretics and medicinal products for the treatment of diabetes (sulfonylureas and metformin).

Effects of vardenafil on other medicinal products

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

No potentiation of the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) was observedwhen vardenafil (10 mg) was given at varying time intervals (1 h to 24 h) prior to the dose ofnitroglycerin in a study in 18 healthy male subjects. Vardenafil 20 mg film-coated tablets potentiated theblood pressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 1 and 4 hours after vardenafiladministration to healthy middle aged subjects. No effect on blood pressure was observed whennitroglycerin was taken 24 hours after administration of a single dose of vardenafil 20 mg film-coatedtablets. However, there is no information on the possible potentiation of the hypotensive effects ofnitrates by vardenafil in patients, and concomitant use of Levitra orodispersible tablets and nitrates istherefore contraindicated (see section 4.3).

Nicorandil is a hybrid of potassium channel opener and nitrate. Due to the nitrate component it has thepotential to have serious interaction with vardenafil.

Since alpha-blocker monotherapy can cause marked lowering of blood pressure, especially posturalhypotension and syncope, interaction studies were conducted with vardenafil. In two interaction studieswith healthy normotensive volunteers after forced titration of the alpha-blockers tamsulosin or terazosinto high doses, hypotension (in some cases symptomatic) was reported in a significant number of subjectsafter co-administration of vardenafil. Among subjects treated with terazosin, hypotension was observedmore frequently when vardenafil and terazosin were given simultaneously than when the dosing wasseparated by a time interval of 6 hours.

Based on the results of interaction studies conducted with vardenafil in patients with benign prostatichyperplasia (BPH) on stable tamsulosin, terazosin or alfuzosin therapy:

* When vardenafil (film-coated tablets) was given at doses of 5, 10 or 20 mg on a background ofstable therapy with tamsulosin, there was no symptomatic reduction in blood pressure, although3/21 tamsulosin treated subjects exhibited transient standing systolic blood pressures of less than85 mmHg.

* When vardenafil 5 mg (film-coated tablets) was given simultaneously with terazosin 5 or 10 mg,one of 21 patients experienced symptomatic postural hypotension. Hypotension was not observedwhen vardenafil 5 mg and terazosin administration was separated by 6 hours.

* When vardenafil (film-coated tablets) was given at doses of 5 or 10 mg on a background of stabletherapy with alfuzosin, compared to placebo, there was no symptomatic reduction in bloodpressure.

Therefore, concomitant treatment should be initiated only if the patient is stable on his alpha-blockertherapy. In those patients who are stable on alpha-blocker therapy, vardenafil should be initiated at thelowest recommended starting dose of 5mg. Levitra may be administered at any time with tamsulosin oralfuzosin. With other alpha-blockers a time separation of dosing should be considered when vardenafilis prescribed concomitantly (see section 4.4).

Levitra 10 mg orodispersible tablets should not be taken as starting dose in patients treated withalpha-blockers (see section 4.4).

No significant interactions were shown when warfarin (25 mg), which is metabolised by CYP2C9, ordigoxin (0.375 mg) was co-administered with vardenafil (20 mg film-coated tablets). The relativebioavailability 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 bloodpressure of 6 mmHg and supine diastolic blood pressure of 5 mmHg accompanied with an increase inheart rate of 4 bpm.

When vardenafil (20 mg film-coated tablets) and alcohol (mean maximum blood alcohol level of73 mg/dl) were taken together, vardenafil did not potentiate the effects of alcohol on blood pressure andheart rate and the pharmacokinetics of vardenafil were not altered.

Vardenafil (10 mg) did not potentiate the increase in bleeding time caused by acetylsalicylic acid(2 x 81 mg).

Riociguat

Preclinical studies showed additive systemic blood pressure lowering effect when PDE5 inhibitors werecombined with riociguat. In clinical studies, riociguat has been shown to augment the hypotensiveeffects of PDE5 inhibitors. There was no evidence of favourable clinical effect of the combination in thepopulation studied. Concomitant use of riociguat with PDE5 inhibitors, including vardenafil, iscontraindicated (see section 4.3).

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

There are no fertility data available.

No studies on the effects on the ability to drive and use machines have been performed.

As dizziness and abnormal vision have been reported in clinical trials with vardenafil, patients should beaware of how they react to Levitra orodispersible tablets, before driving or operating machines.

The adverse reactions reported with Levitra film-coated tablets or 10 mg orodispersible tablets inclinical trials were generally transient and mild to moderate in nature. The most commonly reportedadverse drug reaction occurring in  10% of patients is headache.

Adverse reactions are listed according to the MedDRA frequency convention: very common (≥1/10),common (≥1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000) and notknown (can not be estimated from available data).

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

The following adverse reactions have been reported:

System Organ Very common Common Uncommon Rare Not known

Class(1/10) (1/100 to (1/1,000 to (1/10,000 to (cannot be<1/10) <1/100) <1/1,000) estimated fromthe availabledata)

Infection and Conjunctivitisinfestations

Immune Allergic Allergic reactionsystem oedema anddisorders angioedema

Psychiatric Sleep disorder Anxietydisorders

Nervous Headache Dizziness Somnolence Syncope Cerebralsystem Paraesthesia Seizure haemorrhagedisorders and Amnesiadysaesthesia

Transientischaemic attack

Eye disorders Visual Increase in Non-arteriticdisturbance intraocular anterior ischemic

Ocular pressure optic neuropathyhyperaemia Lacrimation Visual defects

Visual colour increaseddistortions

Eye pain andeye discomfort

Photophobia

Ear and Tinnitus Sudden deafness

System Organ Very common Common Uncommon Rare Not known

Class(1/10) (1/100 to (1/1,000 to (1/10,000 to (cannot be<1/10) <1/100) <1/1,000) estimated fromthe availabledata)labyrinth Vertigodisorders

Cardiac Palpitation Myocardial Sudden deathdisorders Tachycardia infarction

Ventriculartachy-arrhythmias

Angina pectoris

Vascular Flushing Hypotensiondisorders Hypertension

Respiratory, Nasal Dyspnoea Epistaxisthoracic and congestion Sinusmediastinal congestiondisorders

Gastrointesti- Dyspepsia Gastro-oesophanal disorders geal refluxdisease

Gastritis

Gastrointestinaland abdominalpain

Nausea

Dry mouth

Hepatobiliary Increase in Increase indisorders transaminases gamma-glutamyltransferase

Skin and Erythema Photosensitivitysubcutaneous Rash reactiontissuedisorders

Musculoskele- Back paintal and Increase inconnective creatinetissue phosphokinasedisorders

Myalgia

Increasedmuscle tone andcramping

Renal and Haematuriaurinarydisorders

System Organ Very common Common Uncommon Rare Not known

Class(1/10) (1/100 to (1/1,000 to (1/10,000 to (cannot be<1/10) <1/100) <1/1,000) estimated fromthe availabledata)

Reproductive Increase in Priapism Penilesystem and erection Haemorrhagebreast Haematospermiadisorders

General Feeling unwell Chest paindisorders andadministra-tion siteconditions

Penile haemorrhage, haematospermia and haematuria have been reported in clinical trials andspontaneous post-marketing data with the use of all PDE5 inhibitors, including vardenafil.

At a dose of 20 mg Levitra film-coated tablets, elderly ( 65 years old) patients had higher frequenciesof headaches (16.2% versus 11.8%) and dizziness (3.7% versus 0.7%) than younger patients (<65 yearsold). In general, the incidence of adverse reactions (especially “dizziness”) has been shown to be slightlyhigher in patients with a history of hypertension.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting system listedin Appendix V.

In single dose volunteer studies, doses up to and including 80 mg vardenafil (film-coated tablets) perday were tolerated without exhibiting serious adverse reactions.

When vardenafil was administered in higher doses and more frequently than the recommended doseregimen (40 mg film-coated tablets twice daily) cases of severe back pain have been reported. This wasnot associated with any muscle or neurological toxicity.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is notexpected to accelerate clearance, as vardenafil is highly bound to plasma proteins and not significantlyeliminated in the urine.

Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction, ATC code: G04BE09.

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

In the natural setting, i.e. with sexual stimulation it restores impaired erectile function by increasingblood flow to the penis.

Penile erection is a haemodynamic process. During sexual stimulation, nitric oxide is released. Itactivates the enzyme guanylate cyclase, resulting in an increased level of cyclic guanosinemonophosphate (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 ofsynthesis via guanylate cyclase and by the rate of degradation via cGMP hydrolysingphosphodiesterases (PDEs).

Vardenafil is a potent and selective inhibitor of the cGMP specific phosphodiesterase type 5 (PDE5), themost prominent PDE in the human corpus cavernosum. Vardenafil potently enhances the effect ofendogenous nitric oxide in the corpus cavernosum by inhibiting PDE5. When nitric oxide is released inresponse to sexual stimulation, inhibition of PDE5 by vardenafil results in increased corpus cavernosumlevels of cGMP. Sexual stimulation is therefore required for vardenafil to produce its beneficialtherapeutic effects.

In vitro studies have shown that vardenafil is more potent on PDE5 than on other knownphosphodiesterases (>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 consideredsufficient 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 toplacebo, 25 minutes after dosing.

Vardenafil causes mild and transient decreases in blood pressure which, in the majority of the cases, donot translate into clinical effects. The mean maximum decreases in supine systolic blood pressurefollowing 20 mg and 40 mg vardenafil were - 6.9 mmHg under 20 mg and - 4.3 mmHg under 40 mg ofvardenafil, 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. Singleand multiple oral doses of vardenafil up to 40 mg produced no clinically relevant changes in the ECGsof 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 hourpost-dose (average tmax for vardenafil). The primary objective of this study was to rule out a greater than10 msec effect (i.e. to demonstrate lack of effect) of a single 80 mg oral dose of vardenafil on QTcinterval 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 anincrease in QTc (Fridericia) of 8 msec (90% CI: 6-9) and 10 msec (90% CI: 8-11) at 10 and 80 mg dosescompared to placebo and an increase in QTci of 4 msec (90% CI: 3-6) and 6 msec (90% CI: 4-7) at 10and 80 mg doses compared to placebo, at one hour post-dose. At tmax, only the mean change in QTcF forvardenafil 80 mg was out of the study established limit (mean 10 msec, 90% CI 8-11). When using theindividual correction formulae, none of the values were out of the limit.

In a separate post-marketing study of 44 healthy volunteers, single doses of 10 mg vardenafil or 50 mgsildenafil were co-administered concomitantly with 400 mg gatifloxacin, a drug with comparable QTeffect. Both vardenafil and sildenafil showed an increase of Fridericia QTc effect of 4 msec (vardenafil)and 5 msec (sildenafil) when compared to either drug alone. The actual clinical impact of these QTchanges is unknown.

Further information on clinical trials with vardenafil 10 mg orodispersible tablets

Efficacy and safety of vardenafil 10 mg orodispersible tablets were separately demonstrated in a broadpopulation in two studies including 701 randomized erectile dysfunction patients who were treated up to12 weeks. The distribution of patients in the predefined subgroups was covering elderly patients (51%),patients with history of diabetes mellitus (29%), dyslipidemia (39%) and hypertension (40%).

In pooled data from the two vardenafil 10 mg orodispersible tablets trials, IIEF-EF domain scores weresignificantly higher with vardenafil 10 mg orodispersible tablet versus placebo.

A percentage of 71% of all sexual attempts reported in the clinical trials had successful penetrationcompared to 44% of all attempts in the placebo group. These results were also reflected in subgroups, inelderly patients (65%), in patients with history of diabetes mellitus (63%), patients with history ofdyslipidemia (66%) and hypertension (70%) of all sexual attempts reported had successful penetration.

About 63% of all reported sexual attempts with vardenafil 10 mg orodispersible tablets were successfulin terms of erection maintenance compared to about 26% of all placebo-controlled sexual attempts. Inthe predefined subgroups 57% (elderly patients), 56% (patients with history of diabetes mellitus), 59%(patients with history of dyslipidemia) and 60% (patients with history of hypertension) of all reportedattempts with vardenafil 10 mg orodispersible tablets were successful in terms of maintenance oferection.

In clinical trials vardenafil was administered to over 17,000 men with erectile dysfunction (ED) aged18 - 89 years, many of whom had multiple co-morbid conditions. Over 2,500 patients have been treatedwith vardenafil for 6 months or longer. Of these, 900 patients have been treated for one year or longer.

The following patient groups were represented: elderly (22%), patients with hypertension (35%),diabetes mellitus (29%), ischaemic heart disease and other cardiovascular diseases (7%), chronicpulmonary disease (5%), hyperlipidaemia (22%), depression (5%), radical prostatectomy (9%). Thefollowing groups were not well represented in clinical trials: elderly (>75 years, 2.4%), and patients withcertain cardiovascular conditions (see section 4.3). No clinical trials in CNS diseases (except spinal cordinjury), patients with severe renal or hepatic impairment, pelvic surgery (except nerve-sparingprostatectomy) or trauma or radiotherapy and hypoactive sexual desire or penile anatomic deformitieshave been performed.

Across the pivotal trials, treatment with vardenafil (film-coated tablets) resulted in an improvement oferectile function compared to placebo. In the small number of patients who attempted intercourse up tofour to five hours after dosing the success rate for penetration and maintenance of erection wasconsistently greater than placebo.

In fixed dose studies (film-coated tablets) in a broad population of men with erectile dysfunction, 68%(5 mg), 76% (10 mg) and 80% (20 mg) of patients experienced successful penetrations (SEP 2)compared to 49% on placebo over a three month study period. The ability to maintain the erection(SEP 3) in this broad ED population was given as 53% (5 mg), 63% (10 mg) and 65% (20 mg)compared to 29% on placebo.

In pooled data from the major efficacy trials, the proportion of patients experiencing successfulpenetration on vardenafil were as follows: psychogenic erectile dysfunction (77-87%), mixed erectiledysfunction (69-83%), organic erectile dysfunction (64-75%), elderly (52-75%), ischaemic heartdisease (70-73%), hyperlipidaemia (62-73%), chronic pulmonary disease (74-78%), depression(59-69%), and patients concomitantly treated with antihypertensives (62-73%).

In a clinical trial in patients with diabetes mellitus, vardenafil significantly improved the erectilefunction domain score, the ability to obtain and maintain an erection long enough for successfulintercourse and penile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. Theresponse 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 threemonths treatment.

In a clinical trial in post-prostatectomy patients, vardenafil significantly improved the erectile functiondomain score, the ability to obtain and maintain an erection long enough for successful intercourse andpenile rigidity compared to placebo at vardenafil doses of 10 mg and 20 mg. The response rates for theability to obtain and maintain an erection was 47% and 37% on 10 mg and 48% and 34% on 20 mgvardenafil 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 theerectile function domain score, the ability to obtain and maintain an erection long enough for successfulintercourse 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 theability 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 statisticallysignificant (p<0.001).

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

The European Medicines Agency has waived the obligation to submit the results of studies in all subsetsof the paediatric population in the treatment of the erectile dysfunction. See section 4.2 for informationon paediatric use.

Bioequivalence studies have shown that vardenafil 10 mg orodispersible tablet is not bioequivalent tovardenafil 10 mg film-coated tablets. Therefore the orodispersible formulation should not be used as anequivalent to vardenafil 10 mg film-coated tablets.

In vardenafil film-coated tablets, vardenafil is rapidly absorbed with maximum observed plasmaconcentrations reached in some men as early as 15 minutes after oral administration. However, 90% ofthe time, maximum plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) oforal dosing in the fasted state. The mean absolute oral bioavailability is 15%. After oral dosing ofvardenafil AUC and Cmax increase almost dose proportionally over the recommended dose range(5 - 20 mg).

When vardenafil film-coated tablets are taken with a high fat meal (containing 57% fat), the rate ofabsorption is reduced, with an increase in the median tmax of 1 hour and a mean reduction in Cmax of 20%.

Vardenafil AUC is not affected. After a meal containing 30% fat, the rate and extent of absorption ofvardenafil (tmax, Cmax and AUC) are unchanged compared to administration under fasting conditions.

Vardenafil is rapidly absorbed after administration of Levitra 10 mg orodispersible tablets withoutwater. The median time to reach Cmax varied between 45 to 90 minutes and was similar or slightlydelayed (by 8 to 45 min) compared to the film-coated tablets. Mean vardenafil AUC was increased by21 to 29% (middle aged and elderly ED patients) or 44% (young healthy subjects) with 10 mgorodispersible tablets compared to film-coated tablets as a result of local oral absorption of a smallamount of drug in the oral cavity. There was no consistent difference in mean Cmax betweenorodispersible tablets and film-coated tablets.

In subjects taking vardenafil 10 mg orodispersible tablets with a high fat meal no effect on vardenafil

AUC and tmax was observed, while vardenafil Cmax was reduced by 35% in the fed condition. Based onthese results vardenafil 10 mg orodispersible tablets can be taken with or without food.

If vardenafil 10 mg orodispersible tablets are taken with water, the AUC is reduced by 29%, Cmaxremains unchanged and median tmax is shortened by 60 minutes compared to intake without water.

Vardenafil 10 mg orodispersible tablets must be taken without liquid.

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

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 independentof total drug concentrations.

Based on measurements of vardenafil in semen of healthy subjects 90 minutes after dosing, not morethan 0.00012% of the administered dose may appear in the semen of patients.

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

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

In humans the one major circulating metabolite (M1) results from desethylation of vardenafil and issubject to further metabolism with a plasma elimination half-life of approximately 4 hours. Parts of M1are in the form of the glucuronide in systemic circulation. Metabolite M1 shows a phosphodiesteraseselectivity profile similar to vardenafil and an in vitro potency for phosphodiesterase type 5 ofapproximately 28% compared to vardenafil, resulting in an efficacy contribution of about 7%.

The mean terminal half-life of vardenafil in patients receiving Levitra 10 mg orodispersible tabletsranged between 4 - 6 hours. The elimination half-life of the metabolite M1 is between 3 to 5 hours,similar to parent drug.

The total body clearance of vardenafil is 56 l/h with a resultant terminal half-life of approximately4-5 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 (approximately2-6% of the administered dose).

Hepatic clearance of vardenafil in healthy elderly volunteers (65 years and over) was reduced ascompared to healthy younger volunteers (18 - 45 years). On average elderly males taking vardenafilfilm-coated tablets had a 52% higher AUC, and a 34% higher Cmax than younger males (see section 4.2).

Vardenafil AUC and Cmax in elderly patients (65 years or over) taking vardenafil orodispersible tabletswere increased by 31 to 39% and 16 to 21%, respectively, in comparison to patients aged 45 years andbelow. Vardenafil was not found to accumulate in the plasma in patients aged 45 years and below or 65years or over following once-daily dosing of vardenafil 10 mg orodispersible tablets over ten days.

In volunteers with mild to moderate renal impairment (creatinine clearance 30 - 80 ml/min), thepharmacokinetics of vardenafil were similar to that of a normal renal function control group. Involunteers with severe renal impairment (creatinine clearance <30 ml/min) the mean AUC wasincreased by 21% and the mean Cmax decreased by 23%, compared to volunteers with no renalimpairment. No statistically significant correlation was observed between creatinine clearance andvardenafil exposure (AUC and Cmax) (see section 4.2). Vardenafil pharmacokinetics has not beenstudied in patients requiring dialysis (see section 4.3).

In patients with mild to moderate hepatic impairment (Child-Pugh A and B), the clearance of vardenafilwas reduced in proportion to the degree of hepatic impairment. In patients with mild hepatic impairment(Child-Pugh A), the mean AUC and Cmax increased by 17% and 22% respectively, compared to healthycontrol subjects. In patients with moderate impairment (Child-Pugh B), the mean AUC and Cmaxincreased by 160% and 133% respectively, compared to healthy control subjects (see section 4.2). Thepharmacokinetics of vardenafil in patients with severely impaired hepatic function (Child-Pugh C) hasnot been studied (see section 4.3).

In vitro data suggest that effects of vardenafil on P-glycoprotein substrates more sensitive than digoxincannot be excluded. Dabigatran etexilate is an example for highly sensitive intestinal P-glycoproteinsubstrates.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Aspartame (E951)

Peppermint flavour.

Magnesium stearate.

Crospovidone.

Mannitol (E421)

Silica colloidal hydrated.

Sorbitol (E420)

Not applicable.

3 years

Store in the original package in order to protect from humidity and light.

1 x 1 orodispersible tablet in alu/alu perforated unit dose blister,2 x 1 orodispersible tablets in alu/alu perforated unit dose blisters,4 x 1 orodispersible tablets in alu/alu perforated unit dose blisters,8 x 1 orodispersible tablets in alu/alu perforated unit dose blisters.

Not all pack sizes may be marketed.

No special requirements for disposal.

Bayer AG51368 Leverkusen

Germany

EU/1/03/248/013-016

Date of first authorisation: 6 March 2003

Date of latest renewal: 6 March 2008

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu