Microsoft word - levitra - pi clean.doc
The format of this leaflet was determined by the Ministry of Health and its content was checked and
approved by it in July 2010.
NAME OF THE MEDICINAL PRODUCT
QUANTITATIVE COMPOSITION IN TERMS OF THE ACTIVE INGREDIENT(S) PER DOSAGE
5 mg tablet: each tablet contains 5 mg of vardenafil (5.926 mg of vardenafil monohydrochloride trihydrate) 10 mg tablet: each tablet contains 10 mg of vardenafil (11.852 mg of vardenafil monohydrochloride trihydrate) 20 mg tablet: each tablet contains 20 mg of vardenafil (23.705 mg of vardenafil monohydrochloride trihydrate)
LEVITRA: orange film-coated round tablets with embossed BAYER-cross on one side and „5“, „10“, or „20“ on the other side)
Treatment of erectile dysfunction
(inability to achieve or maintain 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. 4.2
DOSAGE AND METHOD OF ADMINISTRATION
4.2.1 Recommended usual dose:
The recommended starting dose is 10 mg taken as needed approximately 25-60 minutes before sexual
In clinical trials Levitra was shown to be efficacious when taken up to 4-5 hours before sexual activity.
The maximum recommended dose frequency is once per day.
Levitra can be taken with or without food (see Pharmacokinetic Properties).
Sexual stimulation is required for a natural response to treatment (see Pharmacodynamic Properties).
Range of dose:
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 once daily. 4.2.2 Method of administration:
For oral use 4.2.3 Dose
special monitoring advice:
4.2.4 Elderly (above 65 years):
Dosage adjustments are not required in elderly patients
4.2.5 Children (from birth to 16 years):
Levitra is not indicated for use in children. 4.2.6 Hepatic impairment (see Pharmacokinetic Properties):
No dose adjustment needed in patients with mild hepatic impairement (Child-Pugh A).
As vardenafil clearance is reduced in patients with moderate hepatic impairment (Child-Pugh B), a starting dose of 5 mg is recommended, which may subsequently be increased to a maximum dose of 10 mg, based on tolerability and efficacy.
The pharmacokinetics of vardenafil has not been studied in patients with severe hepatic impairment (Child-
Pugh C). 4.2.7 Renal impairment (see Pharmacokinetic Properties):
No dose adjustment is needed in patients with mild (CLcr > 50-80 ml/min) or moderate (CLcr > 30-50
ml/min) or severe (CLcr < 30 ml/ min) renal impairment.
The pharmacokinetics of vardenafil has not been studies in patients requiring dialysis.
Consistent with vasodilatory effects of alpha-blockers and vardenafil, the concomitant use of Vardenafil with alpha-blockers may lead to symptomatic hypotension in some patients. Concomitant treatment should only be initiated if the patient is stable on his alpha blocker therapy (see Interaction with Other Medicinal Products and Other Forms of Interaction). In those patients who are stable on alpha-blocker therapy, vardenafil should be initiated at the lowest recommended starting dose of 5mg 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 Interaction with Other Medicinal products and Other Forms of Interaction). 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 a PDE5 inhibitor including vardenafil.
The dosage of LEVITRA may require adjustment in patients receiving certain CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir, indinavir erythromycin, and clarithromycin).
A maximum dose of 5 mg should not be exceeded when used in combination with the Cytochrome P450 (CYP) 3A4 inhibitors erythromycin or clarithromycin.
A maximum dose of 5 mg should not be exceeded when used in combination with the potent Cytochrome P450 (CYP) 3A4 inhibitors ketoconazole and itraconazole. Vardenafil must not be taken with dosages of ketoconazole and itraconazole higher than 200 mg. Concomitant use with HIV protease inhibitors such as indinavir and ritonavir, which are very potent inhibitors of CYP3A4, is contraindicated (see Contraindications, Special Warnings and Precautions for Use, Interactions with Other Medicinal Products and Other Forms of Interactions).
Contraindicated in patients with hypersensitivity to any of the drug's components (active or inactive
Consistent with the effects of PDE inhibition on the nitric oxide / cGMP – pathway, PDE5 inhibitors may
potentiate the hypotensive effects of nitrates. Levitra is thus contraindicated in patients who are
concomitantly treated with nitrates or nitric oxide donors. (see Interactions with Medicinal Products and
Other Forms of Interaction).
Concomitant use of Vardenafil with HIV Protease inhibitors such as indinavir or ritonavir is contraindicated,
as they are potent inhibitors of CYP3A4 . 4.4
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
A medical history and physical examination should be undertaken to diagnose erectile dysfunction and
determine potential underlying causes, before pharmacological treatment is considred.
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. Levitra has vasodilator properties which may result in mild and transient decreases in blood pressure. 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. In men for whom sexual activity is not recommendable because of their underlying cardiovascular status, agents for the treatment of erectile dysfunction should generally not be used. In a study of the effect of LEVITRA on QT interval in 59 healthy males, therapeutic (10 mg) and supratherapeutic (80 mg) doses of LEVITRA produced increases in QTc interval (see Pharmacodynamic properties, Effects on blood pressure and cardiac parameters). A postmarketing study evaluating the effect of combining vardenafil with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone (see Pharmacodynamic Properties). These observations should be considered in clinical decisions when prescribing vardenafil to patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval. Patients taking Class IA (e.g. quinidine, procainamide) or Class III (e.g. amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation, should avoid using vardenafil. Agents for the treatment of erectile dysfunction should generally be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie’s disease) or in patients who have conditions which may predispose them to priapism (such as sickle cell anaemia, multiple
The safety and efficacy of combinations of Levitra with other treatments for erectile dysfunction have not been studied. Therefore the use of such combinations is not recommended. The safety of Levitra has not been studied in the following sub- groups of patients and its use is therefore not recommended until further information is available: severe hepatic impairment, endstage renal disease requiring dialysis, hypotension (resting systolic blood pressure of <90 mmHg), recent history of stroke or myocardial infarction (within last 6 months), unstable angina, and known hereditary degenerative retinal disorders such as retinitis pigmentosa.
Transient vision loss and cases of non-arteritic ischemic optic neuropathy 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 vision loss, he should stop taking LEVITRA and consult immediately a physician (see section Undesirable Effects)
Consistent with vasodilatory effects of alpha-blockers and vardenafil, the concomitant use of Vardenafil with alpha-blockers may lead to symptomatic hypotension in some patients. Concomitant treatment should only be initiated if the patient is stable on his alpha blocker therapy (see Interaction with Other Medicinal Products and Other Forms of Interaction). In those patients who are stable on alpha-blocker therapy, vardenafil should be initiated at the lowest recommended starting dose of 5mg 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 Interaction with Other Medicinal Products and Other Forms of Interaction). 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 a PDE5 inhibitor including vardenafil.
Physicians should advise patients to stop taking LEVITRA, and seek prompt medical attention in the event of sudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including LEVITRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors (see ADVERSE REACTIONS).
Concomitant use of the potent cytochrome P450 3A4 (CYP 3A4) inhibitors ketoconazole, itraconazole, indinavir, or ritonavir can be expected to produce markedly increased Vardenafil plasma levels. A maximum dose of 5 mg should not be exceeded if used in combination with erythromycin or clarithromycin. A maximum dose of 5 mg should not be exceeded if used in combination with ketoconazole, and itraconazole . Vardenafil must not be taken with dosages of ketoconazole and itraconazole higher than 200 mg (see Posology and Method of Administrationand Oneraction with Other Medicinal Products). Concomitant use with indinavir or ritonavir, which are highly potent inhibitors of CYP3A4, is contraindicated. (see Posology and Method of Administration, Contraindications, Interactions with Medicinal Products and Other Forms of Interaction).
Vardenafil has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore Levitra should be given to these patients only after careful benefit-risk assessment.
In humans, vardenafil has no effect on bleeding time alone or with acetylsalicyclic acid.
In vitro studies with human platelets indicate that vardenafil alone did not inhibit platelet aggregation
induced by a variety of platelet agonists. With supertherapeutic concentrations of vardenafil a small
concentration dependent enhancement of the antiaggregatory effect of sodium nitroprusside, a nitric oxide
donor, was observed.
The combination of heparin and vardenafil had no effect on bleeding time in rats, but this interaction has not
been studied in humans.
Concomitant intake of grapefruit juice is expected to increase the plasma
concentration of vardenafil. The combination should be avoided.
INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF
Vardenafil is metabolized predominantly by hepatic enzymes via cytochrome P450 (CYP) isoform 3A4, with some contribution from CYP3A5 and CYP2C isoforms. Therefore, inhibitors of these enzymes may reduce vardenafil clearance. Cimetidine (400 mg b.i.d.), a non-specific cytochrome P450 inhibitor, had no effect on vardenafil AUC and Cmax when co-administered with Levitra (20 mg) to healthy volunteers.
Erythromycin (500 mg t.i.d.), a CYP3A4 inhibitor, caused a 4-fold (300%) increase in vardenafil AUC and a 3-fold (200%) increase in Cmax when co-administered with Levitra (5 mg) to healthy volunteers.
Ketoconazole (200 mg), which is a potent CYP3A4 inhibitor, caused a 10-fold (900%) increase in vardenafil AUC and a 4-fold (300%) increase in Cmax when co-administered with Levitra (5 mg) to healthy volunteers.
Co-administration of Levitra (10 mg) with the HIV protease inhibitor Indinavir (800 mg t.i.d.) resulted in a 16-fold (1500%) increase in vardenafil AUC and a 7-fold (600%) increase in vardenafil Cmax. At 24 hours after
co-administration, the plasma levels of vardenafil were approximately 4% of the maximum vardenafil plasma level (Cmax).
Ritonavir (600 mg b.i.d.) resulted in a 13-fold increase in vardenafil Cmax and a 49-fold increase in vardenafil
AUC0-24 when co-administered with Levitra 5 mg. The interaction is a consequence of blocking hepatic
metabolism of vardenafil by ritonavir, a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9. Ritonavir significantly prolonged the half-life of vardenafil to 25.7 hours.
Concomitant use of potent CYP 3A4 inhibitors such as Ketoconazole, Itraconazole, Indinavir or Ritonavir
can be expected to produce markedly increased Vardenafil plasma levels.
A maximum dose of 5 mg should not be exceeded if used in combination with erythromycin or
clarithromycin (see Special Warnings and Precautions for Use).
A maximum dose of 5 mg should not be exceeded if used in combination with ketoconazole and, itraconazole, and erythromycin. Vardenafil must not be taken with dosages of ketoconazole and
itraconazole higher than 200 mg (see Posology and Method of Administration).
Concomitant use with indinavir or ritonavir, which are highly potent inhibitors of CYP3A4, is contraindicated (see Posology and Method of Administration, Special Warnings and Precautions for Use,
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. 4.5.2 Nitrates, Nitric Oxide Donors
No potentiation of the blood pressure lowering effect of sublingual Nitroglycerin (0.4 mg) was observed
when Levitra 10 mg was given at varying time intervals (24 h to down to 1 h) prior to the Nitroglycerin dose
in a study in 18 healthy male subjects.
The blood pressure lowering effect of sublingual nitrates (0.4 mg) taken 1 and 4 hours after Levitra
administration was potentiated by a 20 mg dose of Levitra in healthy middle aged subjects. These effects
were not observed when Levitra 20 mg was taken 24 hours before the Nitroglycerin.
However, there is no information on the potential hypotensive effects of Levitra when given in combination
with Nitrates in patients, and concomitant use is therefore contraindicated (see Contraindications).
Levitra 20 mg, when co-administered with Glibenclamide (Glyburide, 3.5 mg), did not affect the relative
bioavailability of Glibenclamide (no effect on AUC and Cmax of Glibenclamide). There was no evidence that
vardenafil pharmacokinetics were altered by co-administration of Glibenclamide.
No pharmacokinetic and pharmacodynamic (prothrombin time and clotting factor II, VII and X) interaction
was shown when Warfarin (25 mg) was co-administered with Levitra 20 mg. Vardenafil pharmacokinetics
was not affected by co-administration of Warfarin.
No relevant pharmacokinetic interaction was shown when Levitra 20 mg, was co-administered with
Nifedipine (30 or 60 mg). The combined treatment of vardenafil and nifedipine did not lead to
pharmacodynamic interaction (as compared to placebo, vardenafil produced mean additional blood
pressure reductions of 5.9 mmHg and 5.2 mmHg for supine systolic and diastolic blood pressure,
respectively). 4.5.4 Alpha-blockers
Since alpha blocker monotherapy can cause marked lowering of blood pressure, especially postural hypotension and syncope, interaction studies were conducted with vardenafil.
In patients with benign prostatic hyperplasia (BPH) on stable tamsulosin or terazosin therapy, as well as in normotensive volunteers after short-term alpha blockade.-
In two interaction studies with healthy normotensive volunteers after forced titration of the alpha-blockers tamsulosin or terazosin to high doses over 14 days or fewer, hypotension (in some cases symptomatic) was reported in a significant number of subjects after co-administration of LEVITRA. Among subjects treated with terazosin, hypotension (standing systolic blood pressure below 85 mm Hg) was observed more frequently when LEVITRA and terazosin were given to achieve simultaneous Cmax than when the dosing was administered to separate Cmax by 6 hours. Because these studies were conducted using healthy volunteers after forced titration of the alpha blocker to high doses (subjects were not stable on alpha-blocker therapy), these studies may have limited clinical relevance.
Interaction studies were conducted with LEVITRA in patients with benign prostatic hyperplasia (BPH) on stable tamsulosin or terazosin therapy. When LEVITRA was given at doses of 5, 10 or 20 mg on a background of stable therapy with tamsulosin, there was no clinically relevant mean maximal additional reduction in blood pressure. When LEVITRA 5 mg was dosed simultaneously with tamsulosin 0.4 mg, 2 of 21 patients experienced a standing systolic blood pressure below 85 mm Hg. When LEVITRA 5 mg was given with a six hour dose separation from tamsulosin, 2 of 21 patients experienced a standing systolic blood pressure below 85 mm Hg. In a subsequent study in patients with BPH, when LEVITRA 10 mg and 20 mg was dosed simultaneously with tamsulosin 0.4 or 0.8 mg there were no cases of standing systolic blood pressure below 85 mm Hg.When LEVITRA 5 mg was given simultaneously with terazosin 5 or 10 mg, one of 21 patients experienced symptomatic postural hypotension. Hypotension was not observed when LEVITRA 5 mg and terazosin administration was separated by 6 hours. This should be considered when deciding about a time separation of dosing.
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, LEVITRA 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 LEVITRA is prescribed concomitantly (see Special Warnings and Precautions for Use).
Lack of pharmacokinetic interaction was shown when Digoxin (0.375 mg) in steady-state was co-administered with Levitra 20 mg over 14 days every other day. There was no evidence that vardenafil pharmacokinetics were altered by co-administration of Digoxin. Single doses of Maalox (antacid; magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability (AUC) or the maximum concentration (Cmax) of vardenafil.
Bioavailability of Levitra 20 mg was not affected by co-administration of the H2-antagonists Ranitidine (150
mg b.i.d.) and Cimetidine (400 mg b.i.d.). Levitra 10 mg and 20 mg did not influence the bleeding time when taken alone or in combination with low dose Acetylsalicylic Acid (2x81 mg tablets). Levitra 20 mg did not potentiate the hypotensive effects of Alcohol (0.5 g/kg bw). The pharmacokinetics of vardenafil were not altered.
Population pharmacokinetic investigations of phase III data revealed no significant effect of Acetysalicylic
Acid, ACE-inhibitors, beta-blockers, weak CYP 3A4-inhibitors, diuretics and medications for the treatment of
diabetes (sulfonylureas and metformin) on the pharmacokinetics of vardenafil.
Grapefruit juice being a weak inhibitor of CYP3A4 gut wall metabolism, may give
rise to modest increases in plasma levels of vardenafil.
There are no data on the interaction of vardenafil and non- specific phosphodiesterase
inhibitors such as theophylline or dipyridamole
PREGNANCY AND LACTATION
LEVITRA is not indicated for use by women. 4.7 EFFECTS
ON ABILITY TO DRIVE AND USE MACHINES:
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
Levitra was administered to over 9500 patients during clinical trials worldwide (Status March 2004). Levitra
was generally very well tolerated. Adverse events were generally transient and mild to moderate in nature.
Placebo controlled clinical trials (ADRs):
When Levitra was taken as recommended, the following adverse drug reactions were reported in placebo
controlled clinical trials (Status: March 2004):
Table: Adverse Drug Reactions reported by ≥ 1% of patients treated with
Levitra and more frequent on drug than placebo in all placebo
controlled trials of 5 mg, 10 mg, and 20 mg Levitra
(n = 3293)
(n = 1861)
The following adverse drug reactions were reported in patients given Levitra in all clinical trials (Status:
March 2004): System Organ
≥1% to <10%
≥0.1% to <1%
≥0.01% to <0.1%
Disorders Eye Disorders
≥1% to <10%
≥0.1% to <1%
≥0.01% to <0.1%
increased ] GGTP increased
CHEST PAIN [incl. Chest Discomfort] FEELING ABNORMAL
AUDITORY: sudden decrease or loss of hearing, tinnitus
Myocardial infarction (MI) has been reported in temporal association with the use of Vardenafil and sexual activity, but it is not possible to determine whether MI is related directly to Vardenafil, or to sexual activity, to
the patient´s underlying cardiovascular disease, or to a combination of these factors.
Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 inhibitors, including LEVITRA. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION, including: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.
Visual disturbances including vision loss (temporary or permanent) have been reported rarely post-marketing in temporal association with the use of phosphodiesterase type 5 inhibitors, including LEVITRA. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or to other factors. 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 LEVITRA. It is not possible to determine whether these reported events are related directly to the use of LEVITRA, to the underlying risk factors for hearing loss, a combination of these factors, or to other factors
From post-marketing experience with another drug of this class the following serious
adverse events have been reported in temporal association with the use of this other
PULMONARY HEMORRHAGE SUBARACHNOID AND INTRACEREBRAL HEMORRHAGES SUDDEN CARDIAC DEATH TRANSIENT ISCHEMIC ATTACK VENTRICULAR ARRHYTHMIA
DECREASED VISION / TEMPORARY VISION LOSS
In single dose volunteer studies, Levitra was tested in doses up to and including
80 mg per day. Even the highest dosage tested (80 mg per day) was tolerated without producing serious
adverse side effects. This was confirmed in a study with 40 mg once daily doses over 4 weeks.
When 40 mg was administered twice daily, cases of severe back pain were observed . No muscle or
neurological toxicity was identified, however.
In cases of overdose, standard supportive measures should be taken 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.
Penile erection is a hemodynamic process based on the relaxation of smooth muscle in the corpus
cavernosum and its associated arterioles. During sexual stimulation, nitric oxide (NO) released from nerve
ends in the corpus cavernosum activates the enzyme guanylate cylase resulting in an increased level of
cyclic guanosine monophosphate (cGMP) in the corpus cavernosum. This in turn triggers smooth muscle
relaxation, allowing increased inflow of blood into the penis. The actual cGMP level is regulated by the rate
of synthesis via the guanylate cylase on the one hand, and by the rate of degradation via cGMP hydrolyzing
phosphodiesterases (PDEs) on the other hand.
The most prominent PDE in the human corpus cavernosum is the cGMP specific phosphodiesterase type 5
By inhibiting PDE5, the enzyme responsible for cGMP degradation in the corpus cavernosum, vardenafil
potently enhances the effect of endogenous NO, local y released in corpus cavernosum upon sexual
stimulation. The inhibition of PDE5 by vardenafil leads to increased cGMP levels in the corpus cavernosum,
resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum.
Levitra thus potentiates the natural response to sexual stimulation.
Trials on purified enzyme preparations have shown that vardenafil is a very potent and highly selective
inhibitor of PDE5, with an IC50 for human PDE5 of 0.7 nM.
The inhibitory effect of 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 >1,000-fold relative to
PDE2, 3, 4, 7, 8, 9, and 10). In vitro
, vardenafil causes an elevation of cGMP in the isolated human corpus
cavernosum resulting in muscle relaxation.
In the conscious rabbit, vardenafil causes a penile erection which is dependent upon endogenous nitric
oxide synthesis and is potentiated by nitric oxide donors.
Effects on erectile response:
In a placebo controlled Rigiscan study, Levitra 20 mg produced erections sufficient for penetration (≥ 60%
rigidity by Rigiscan) in some men as early as 15 minutes. The overall response of these subjects to Levitra
became statistically significant compared to placebo at 25 minutes post dosing. Clinical studies:
Levitra demonstrated clinically meaningful and statistically significant improvement of erectile function
compared to placebo in all major efficacy trials including special populations.
Across clinical trials worldwide, Levitra was administered to over 7800 men with erectile dysfunction (ED),
many of whom had multiple other medical conditions. Over 2500 patients were treated with Levitra for 6
months or longer. Of these, 900 patients have been treated for one year or longer.
In a randomized, double blind, placebo controlled, fixed dose trial, based on a global assessment question
(GAQ), Levitra improved erections in 65%, 80%, and 85% of the patients on 5 mg, 10 mg, and 20 mg,
respectively, at 6 months compared to 28% on placebo.
In pooled data from the major efficacy trials, including special population studies, of those patients who had
successful penetration on first dose of treatment 37% were on placebo, 68% on 10 mg, and 70% on 20 mg
Levitra. For those patients who had successful penetration on first dose, on average, patients on Levitra 10
mg and 20 mg responded successfully in 86% and 90% of all subsequent attempts, respectively, over a 3
month study period. Levitra was efficacious in patients regardless of baseline severity, etiology (organic,
psychogenic, and mixed), duration of ED, ethnicity and age as determined in subgroup analyses. Patients with ED after Radical Prostatectomy:
In post-prostatectomy patients, Levitra demonstrated clinically meaningful and statistically significant
improvement in erectile function in a prospective, fixed dose, placebo controlled, double blind trial. Erectile
function domain score, the rate of obtaining an erection sufficient for penetration, the rate of maintaining an
erection sufficient for successful intercourse, and hardness were significantly improved compared to
placebo for the tested doses of 10 mg and 20 mg at all time points. Improved erectile function response
rates as based on GAQ were 59% on 10 mg, and 65% on 20 mg compared to 13% on placebo at 3 months.
In the subgroup of patients with bilateral nerve-sparing prostatectomy the response rates as based on GAQ
in patients who completed 3 months were 60% for 10 mg, and 71% for 20 mg, compared to 12% for
placebo. Patients with ED and Diabetes Mellitus:
In patients with diabetes mellitus, Levitra demonstrated clinically meaningful and statistically significant
improvement in erectile function in a prospective, fixed dose, placebo controlled, double blind trial.
Significant improvements were shown in the erectile function domain score, the rate of obtaining an erection
sufficient for penetration, the rate of maintaining an erection sufficient for successful intercourse, and
hardness compared to placebo for the tested doses of 10 mg and 20 mg at all time points during three
months of treatment. In this population, which is typically more resistant to therapy, response rates for
improvement of erection as based on GAQ were 57% on 10 mg, and 72% on 20 mg Levitra compared to
13% on placebo for patients who completed three months of the trial.
Patients in the active treatment group were continued on blinded active therapy of Levitra for a total of 6
months. These patients demonstrated response rates of 66% and 74% for 10 mg and 20 mg, respectively. Patients with Spinal Cord Injury
In patients with ED secondary to traumatic spinal cord injury, vardenafil demostrated clinically meaningful
and statistically significant improvement in erectile function in a placebo controlled, double blind, flexible-
dose clinical trial. Significant improvements were shown in 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
3 months treatment which were clinically and statistically significant (p<0.001). In this population, which is
typically more resistant to therapy, response rates for improvement of erection as based on GAQ were 83%
on vardenafil compared to 26% on placebo for patients who completed 3 months of the trial
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 additive Fridericia QTc effect (vardenafil: 4 msec, sildenafil: 5
msec) when compared to either drug alone. The clinical impact of these QT changes is unknown (see
Special Warnings and Precautions for use).
Effects on vision:
In a specific clinical trial, evaluation of visual function at a Levitra dose of 40 mg (twice the maximum
recommended daily dose) revealed no effects of Levitra on visual acuity, visual fields, intraocular pressure,
ERG latency, fundoscopic and slit lamp findings. A subset of patients was found to have mild and transient
impairment of colour discrimination in the blue/green range and in the purple range 1 hour after dosing.
These changes had improved by 6 hours and no changes were present at 24 hours. The majority of these
patients had no subjective visual symptoms.
In another double blind placebo controlled clinical trial, at least 15 doses of 20mg vardenafil were
administered over 8 weeks versus placebo. Retinal function was measured by ERG and FM-100 test 2, 6
and 24 hours after dosing. Vardenafil did not produce clinically significant retinal effects in healthy men
compared to placebo.
In other trials, daily use of Levitra at doses of 10 mg to 40 mg for 31 days was not associated with changes in visual acuity, intraocular pressure, or findings on fundoscopic or slit lamp examination.
Effects on blood pressure and cardiac parameters:
In placebo-controlled clinical pharmacology studies with Levitra 10 mg and 20 mg, the mean maximum
decreases in supine systolic and diastolic blood pressure were negligible in comparison to placebo. There
was only a small compensatory increase in heart beat per minute.
Single oral doses of Levitra of up to 80 mg (four times the maximum recommended daily dose) did not
produce clinically relevant effects on the ECGs of healthy volunteers.
The effect of 10 mg and 80 mg vardenafil on QT interval was evaluated in a single-dose, double-blind,
randomized, placebo- and active-controlled (moxifloxacin 400 mg) crossover study in 59 healthy males
aged 45-60 years. This study also included another drug in the same class in approximately equipotent
therapeutic doses (sildenafil 50mg and 400mg). The QT interval was measured at one hour post dose
because this time point approximates the average time of peak vardenafil concentration. The 80 mg dose of
LEVITRA (four times the highest recommended dose) was chosen because this dose yields plasma
concentrations covering those observed upon co-administration of a low-dose of LEVITRA (5 mg) and 600
mg BID of ritonavir. Of the CYP3A4 inhibitors that have been studied, ritonavir causes the most significant
drug-drug interaction with vardenafil. Table 1 summarizes the effect on mean uncorrected QT and mean
corrected QT interval (QTc) with different methods of correction (Fridericia and a linear individual correction
method) at one hour post-dose. No single correction method is known to be more valid than the other. Mean QT and QTc changes in msec (90% CI) from baseline relative to placebo at 1 hour post-dose with
different methodologies to correct for the effect of heart rate.
Moxifloxacin produced the expected 5-10msec prolongation, indicating that the study had the required
sensitivity. Therapeutic and supratherapeutic doses of vardenafil and sildenafil produced similar decreases
in uncorrected QT but increases in QTc interval. This study, however, was not designed to make direct
statistical comparisons between the drugs or the dose levels. The actual clinical impact of these changes is
Effects on sperm motility or morphology:
In a specific clinical trial, single oral doses of 20 mg of Levitra did not produce any effects on sperm motility
or morphology or a variety of parameters indicative for male reproductive function. Based upon
measurements of Levitra in semen of healthy subjects 90 minutes after dosing, not more than 0.00012% of
the administered dose appeared in the semen of patients.
There were no clinically relevant effects on sperm concentration, count, motility or morphology in humans in
a placebo-controlled study of daily dosing of vardenafil 20 mg for 6 months. In addition, vardenafil had no
effect on serum levels of testosterone, luteinizing hormone, or follicle stimulating hormone. 5.2 PHARMACOKINETIC
Vardenafil is rapidly absorbed after oral administration. Cmax is reached as early as 15 minutes, in 90% of
the time Cmax is reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasting state.
Due to a considerable first-pass effect, the mean absolute oral bioavailability is about 15%. After oral dosing of vardenafil AUC and Cmax increase almost dose-proportionally over the recommended
When vardenafil is taken with a high fat meal (containing 57% fat), the rate of absorption is reduced with an increase in the median Tmax of 60 minutes and a mean reduction in Cmax of 20%. Vardenafil AUC was not
affected. After a normal meal (containing 30% fat) vardenafil pharmacokinetic parameter (Cmax, Tmax, and
AUC) were not affected at all.
Based on these results Levitra can be taken with or without food. 5.2.2 Distribution:
The mean steady state volume of distribution (Vss) for vardenafil is 208 L, indicating distribution into the
Vardenafil and its major circulating metabolite (M1) are highly bound to plasma proteins (about 95% for
parent drug or M1). This protein binding is reversible and independent of total drug concentrations.
Based upon 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. 5.2.3 Metabolism:
Vardenafil is metabolized predominantly by hepatic enzymes via CYP3A4, with some contribution from
CYP3A5 and CYP2C9 isoforms.
Mean elimination half life (t½) is about 4-5 hours. In humans, the major circulating metabolite (M1) results from desethylation at the piperazine moiety of vardenafil, and is subject to further metabolism. The plasma elimination half life of the metabolite M1 is approximately 4 h, comparable to the parent drug. Parts of M1 are in form of its glucuronide-conjugate (glucuronic acid) in systemic circulation.
The plasma concentration of non-glucuronidated M1 is about 26% that of the parent compound. The
metabolite M1 shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro
inhibitory potency for PDE5 of approximately 28% compared to vardenafil, resulting in an efficacy
contribution of about 7%. 5.2.4 Excretion:
The total body clearance of vardenafil is 56 l/h with a resultant terminal half life of about 4 – 5 hours.
After oral administration, vardenafil is excreted as metabolites predominantly in the faeces (approximately
91 – 95% of administered oral dose) and to a lesser extent in the urine (approximately 2 – 6% of
administered oral dose).
5.2.5 Pharmacokinetics in special populations:
Elderly (above 65 years):
Vardenafil hepatic clearance in healthy elderly volunteers (65 years or over) was reduced as compared to
volunteers of younger age (45 years and below). On average, elderly males had a 52% higher AUC than
younger males which is within the variability observed in clinical trials. No overall differences in safety or
effectiveness were observed between elderly and younger subjects in placebo controlled clinical trials. Renal insufficiency:
In patients with mild (CLcr > 50 – 80 ml/min) to moderate (CLcr > 30 – 50 ml/min) renal impairment,
vardenafil pharmacokinetics were similar to that of a normal renal function control group. In volunteers with
severe renal impairment (CLcr < 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
between creatinine clearance and vardenafil plasma exposure (AUC and Cmax) was observed.
The pharmacokinetics of vardenafil has not been studied in patients requiring dialysis.
In patients with mild to moderate hepatic impairment (Child-Pugh A and B), vardenafil clearance was
reduced in proportion to the degree of hepatic impairment.
In patients with mild hepatic impairment (Child-Pugh A), vardenafil AUC and Cmax were increased 1.2-fold
(AUC by 17%, and Cmax by 22%), compared to healthy control sunjects. In patients with moderate hepatic impairment (Child-Pugh B), vardenafil AUC was increased 2.6-fold (160%) and Cmax was increased 2.3-fold (130%), compared to healthy control subjects.
The pharmacokinetics of vardenafil has not been studied in patients with severe hepatic impairment (Child-
PRECLINICAL SAFETY DATA
Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, and toxicity to reproduction. In acute toxicity studies the LD50 was 190 mg/kg in the rat. Light microscopic, electron-microscopic, and
ophthalmologic investigations revealed no oculotoxic effects. In chronic toxicity studies NOEL is 3 mg/kg bw day in male rats and NOEL is 3 mg/kg bw day in the dog. The toxicities observed in experimental animals revealed cardiovascular effects to be the prominent toxicological findings as known for PDE5 inhibitors. Other toxicological findings on the pancreas, exocrine glands and the thyroid in rats could be expected by the pharmacologic properties of a phosphodiesterase inhibitor, and were not observed in mice or dogs.
Vardenafil is not carcinogenic in rats and mice when administered daily for 24 months at 225 (rats) and 450
(mice) times the maximum recommended human dose of 20 mg, respectively (calculation based on 60 kg
body weight in men). The exposure in terms of AUC achieved in rats and mice was more than 360 (male
rats) and more than 25 (male mice) times the exposure in men given the maximum recommended human
dose of 20 mg.
No relevant adverse effects with regard to fertility and embryonic development were found in reproduction
studies in rats and rabbits following oral administration of vardenafil.
No indication for genotoxic/mutagenic activity of vardenafil could be found in vitro (Ames, HPRT, Cyt. in
vitro) and in vivo (MNT).
List of excipients:
crospovidone, magnesium stearate, microcrystalline cellulose, colloidal silicon dioxide (silica colloidal anhydrous)
polyethylene glycol (macrogol 400), hypromellose (hydroxy-propyl-methylcellulose), titanium dioxide (E171), ferric oxide yellow (E172), ferric oxide red (E172)
Not applicable 6.3 Shelf life:
Storage: store at a cool, dry place 6.4 Special precautions for use:
Not applicable 6.5 Instructions for use/handling:
Bayer Schering Pharma AG, Leverkusen, Germany REGISTRATION HOLDER
Bayer Israel Ltd. 36 Hacharash St., Hod Hasharon 45240
Pillen & proefpersonen u i t I n d i a Wie denkt dat medicijnontwikkeling typisch is voorbehouden aan westerse landen,heeft het mis. En ook de veronderstelling dat India vooral goed is in IT-dienstverle-ning, is een misvatting. Farmaceutische R&D behoort tot de meest kostbare proces-sen en leent zich daarmee uitstekend voor verplaatsing naar lagelonenlanden. DeIndiase farma-ind
A BAUMANNII ciprofloxacin, ofloxacin, levofloxacin Multidrug resistance defined as being resistant to one or more drug in at least three of the following classes: antipseudomonal penicillins, third generation cephalosporins with antipseudmonal aciton (ceftazidime), carbapenems, fluoroquinolones, aminoglycosides, sulbactams E COLI ciprofloxacin, ofloxacin, levofloxacin fotaxime,