Levitra (Vardenafil HCl)

LEVITRA® Tablets

(Vardenafil, BAYER)

Name of the Drug
Vardenafil (CAS number: 224785-90-4), as vardenafil hydrochloride trihydrate. The empirical formula of vardenafil hydrochloride trihydrate is C23H32N6O4S.HCl.3H2O and its molecular weight is 579.1 g/mol.

Description
Vardenafil hydrochloride trihydrate is 2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one hydrochloride trihydrate. It is a nearly colourless solid. Vardenafil hydrochloride trihydrate is soluble in 0.1M HCl, very slightly soluble in water, freely soluble in methanol, soluble in ethanol and slightly soluble in acetone.

LEVITRA tablets are available in strengths of:

• 5 mg of vardenafil (5.926 mg of vardenafil hydrochloride trihydrate)
• 10 mg of vardenafil (11.852 mg of vardenafil hydrochloride trihydrate)
• 20 mg of vardenafil (23.705 mg of vardenafil hydrochloride trihydrate).

Besides the active ingredient, LEVITRA tablets also contain the following excipients: crospovidone, magnesium stearate, microcrystalline cellulose, colloidal anhydrous silica, macrogol 400, hypromellose, titanium dioxide (CI77891), iron oxide yellow (CI77492), iron oxide red (CI77491).

Pharmacology
Penile erection is a haemodynamic process based on the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles. During sexual stimulation, from nerve ends in the corpus cavernosum nitric oxide (NO) is released, which activates the enzyme guanylate cyclase 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 resulting in erection. The actual cGMP level is regulated by the rate of synthesis via the guanylate cyclase 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 (PDE5).

By inhibiting PDE5, the enzyme responsible for cGMP degradation in the corpus cavernosum, vardenafil potently enhances the effect of endogenous NO, locally 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. Vardenafil thus potentiates the natural response to sexual stimulation.

In vitro assays have shown that vardenafil is a selective inhibitor of PDE5, with an IC50 of 0.7 nM for human platelet PDE5.

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 Visual Perception
In a specific clinical trial, evaluation of visual function at a vardenafil dose of 40 mg (twice the maximum recommended daily dose) revealed no effects of vardenafil 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 other trials, daily use of vardenafil 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
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 with 20 mg and – 4.3 mmHg with 40 mg of vardenafil, when compared to placebo.

Effects on Cardiac Parameters
Single oral doses of vardenafil up to 80 mg (four times the maximum recommended daily dose) did not produce clinically relevant effects on the ECGs of healthy volunteers.

Effects on Exercise Performance in Patients with Coronary Artery Disease
In a two-period, placebo-controlled, cross-over trial, 10 mg vardenafil did not alter the total treadmill exercise time compared to placebo in 39 male patients aged 48-77 years with coronary artery disease and exercise induced ischaemia. The total time to angina was not altered compared to placebo; however, the total time to 1 mm or greater ST-segment depression was prolonged 15% in the vardenafil group compared to the placebo group (p<0.001). All patients who entered the trial completed the exercise treadmill tests without significant drug-related side effects.

Pharmacokinetics
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 fasted state.

Absorption

There is extensive first-pass metabolism of vardenafil, resulting in considerable inter-subject and intra-subject variability in the observed pharmacokinetic parameters. The mean absolute bioavailability is approximately 15% after a 10 mg dose. After oral dosing of vardenafil, AUC and Cmax increase almost dose proportionally over the recommended dose range (5 mg – 20 mg).

When vardenafil was taken with a high fat meal (~57% fat), the rate of absorption (mean Cmax) was reduced by approximately 20%, median tmax was delayed by approximately 1 hour, and mean AUC was not affected. After a ‘normal meal’ (~30% fat) pharmacokinetic parameters were not significantly affected. Based on these results vardenafil can be taken with or without food.

Distribution
The mean steady state volume of distribution (Vss) for vardenafil is about 2.5 L/kg, indicating distribution into the tissues.

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 0.0002% of the administered dose may appear in the semen of patients.

Metabolism
Vardenafil is metabolised predominantly by hepatic enzymes via CYP3A4, with some contribution from CYP3A5 and CYP2C9 isoforms. Mean terminal elimination half-life from plasma is approximately 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 terminal plasma elimination half-life of the metabolite M1 is approximately 4 hours, comparable to the parent drug. M1 is also present in its glucuronide-conjugated (glucuronic acid) form 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%.

Excretion
The total body clearance of vardenafil is 56 L/hour 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).

Pharmacokinetics in special populations

Elderly
Vardenafil half life in healthy elderly volunteers (65 years or over) was not significantly 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. Therefore no dose adjustment is required in elderly patients.

Renal insufficiency
In patients with mild (CLcr 50 – 80 mL/min), moderate (CLcr 30 – 50 mL/min), or severe (CLcr < 30 mL/min) renal impairment, vardenafil pharmacokinetics were similar to that of a normal renal function control group. No statistically significant correlation between creatinine clearance and vardenafil plasma exposure (AUC and Cmax) was observed. Based on these data, no dose adjustment is needed in patients with impaired renal function.

The pharmacokinetics of vardenafil have not been studied in patients requiring dialysis and vardenafil should not be used in this situation.

Hepatic insufficiency
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%) following a 10 mg vardenafil dose, compared to healthy control subjects. No dose adjustment is required in patients with mild hepatic impairment.

In patients with moderate hepatic impairment (Child-Pugh B), vardenafil AUC was increased 2.6-fold (an increase of 160%) and Cmax was increased 2.3-fold (an increase of 130%), compared to healthy control subjects. Therefore, in patients with moderate hepatic impairment, a 5 mg starting dose should be used, which may subsequently be increased to 10 mg and then 20 mg based on tolerability and efficacy.

The pharmacokinetics of vardenafil have not been studied in patients with severe hepatic impairment (Child-Pugh C) and vardenafil should not be used in this situation.

Clinical Studies
In a placebo controlled Rigiscan study, LEVITRA (vardenafil) 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 vardenafil became statistically significant compared to placebo at 25 minutes post dosing.

Vardenafil demonstrated clinically meaningful and statistically significant improvement of erectile function compared to placebo in all major efficacy trials including special populations.

Across all trials, vardenafil was administered to over 3750 men with erectile dysfunction (ED) aged 18 to 89 years, many of whom had multiple other medical conditions. Over 1630 patients were treated with vardenafil for 6 months or longer.

In all major efficacy trials, including studies in post-prostatectomy patients and patients with diabetes, vardenafil 10 mg and 20 mg produced statistically significant and clinically meaningful improvements, compared to placebo, in the International Index of Erectile Function (IIEF) erectile function domain score, the percentage of patients achieving successful penetration and maintenance of erections, and the percentage of patients who rated their erections as improved (Tables 1 and 2).

Table 1. IIEF erectile function domain score and global assessment at Week 12 (Intention-to-treat population).*

 

Study Population	IIEF erectile function domain score			Percentage of patients rating erections as improved
	Placebo	Vardenafil 10 mg	Vardenafil 20 mg	Placebo	Vardenafil 10 mg	Vardenafil 20 mg
General	15.0	20.6	21.4	30%	72%	78%
General	13.2	20.9	21.5	19%	73%	73%
Diabetic	12.6	17.1	19.0	13%	54%	70%
Prostatectomy	9.2	15.3	15.3	9%	58%	60%

* Last available observation used in patients with no data at Week 12.

Table 2. Percentage of patients achieving successful penetration and maintenance of erection at Week 12 (Intention-to-treat population). *

Study Population	Penetration			Maintenance of erection
	Placebo	Vardenafil 10 mg	Vardenafil 20 mg	Placebo	Vardenafil 10 mg	Vardenafil 20 mg
General	52%	76%	81%	32%	65%	65%
General	45%	76%	80%	25%	62%	64%
Diabetic	36%	61%	64%	23%	49%	54%
Prostatectomy	22%	47%	48%	10%	37%	34%

* Last available observation used in patients with no data at Week 12.

In a randomised, double blind, placebo controlled, fixed dose trial in 749 patients, based on a global assessment question (GAQ), vardenafil improved erections in 56%, 77%, and 81% of the patients on 5 mg, 10 mg, and 20 mg, respectively, at 6 months compared to 23% on placebo.

In pooled data from the major efficacy trials, including special population studies, those patients who had successful penetration on first dose of treatment were 37% on placebo, 68% for 10 mg, and 70% for 20 mg. For those patients who had successful penetration on first dose, on average, patients on vardenafil 10 mg and 20 mg responded successfully in 86% and 90% of all subsequent attempts, respectively, over a 3 month study period. Vardenafil was efficacious in patients regardless of baseline severity, aetiology (organic, psychogenic and mixed), duration of ED, ethnicity and age as determined in subgroup analyses.

In post-prostatectomy patients, vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a 3 month 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 57% on 10 mg, and 60% on 20 mg compared to 9% 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 at 3 months were 61% for 10 mg, and 66% for 20 mg, compared to 8% for placebo.

In patients with diabetes mellitus, vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a 3 month 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, when 10 mg and 20 mg vardenafil doses were compared to placebo. These improvements were seen 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 54% on 10 mg, and 70% on 20 mg vardenafil 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 vardenafil for a total of 6 months. These patients demonstrated response rates of 66% and 74% for 10 mg and 20 mg, respectively.

Indications
LEVITRA is indicated for the treatment of erectile dysfunction in adult males (inability to achieve or maintain penile erection sufficient for satisfactory sexual performance).

LEVITRA is not indicated for use by women.

Contraindications
Vardenafil is contraindicated in patients with known hypersensitivity to any of the drug’s components (active or inactive ingredients).

Nitrates and vardenafil must not be used concomitantly. Co-administration of vardenafil with nitric oxide donors, organic nitrates, or organic nitrites in any form either regularly or intermittently is contraindicated. Drugs which must not be used concomitantly include, but are not limited to, glyceryl trinitrate (injection, tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite, nicorandil or organic nitrates in any form. Consistent with the effects of PDE inhibition on the nitric oxide / cGMP – pathway, PDE5 inhibitors may potentiate the hypotensive effects of nitrates.

Vardenafil is contraindicated in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors (see PRECAUTIONS). The possibility of undiagnosed cardiovascular disorders in men with erectile dysfunction should be considered before prescribing vardenafil.

The safety of vardenafil has not been studied in patients with the following conditions and its use in such patients is therefore contraindicated until further information is available: unstable angina; resting or orthostatic hypotension (systolic blood pressure <90 mmHg); uncontrolled hypertension; myocardial infarction, stroke, cardiac ischaemia (except stable angina), or life-threatening arrhythmia within the previous 6 months; uncontrolled arrhythmia; severe hepatic impairment; end-stage renal disease requiring dialysis; known hereditary degenerative retinal disorders such as retinitis pigmentosa.

Precautions

Cardiovascular Disease
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.

Other Pre-existing Medical Conditions
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 myeloma or leukaemia).

The safety and efficacy of combinations of vardenafil with other treatments for erectile dysfunction (including other PDE5 inhibitors) have not been studied. Therefore the use of such combinations is not recommended.

Vardenafil has not been administered to patients with bleeding disorders or significant active peptic ulceration. Therefore vardenafil should be given to these patients only after careful benefit-risk assessment. In humans, vardenafil has no effect on bleeding time alone or with aspirin. 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.

Use with alpha-Blockers
The concomitant use of vardenafil with alpha-blockers may lead to symptomatic hypotension in some patients. Until further information is available, the concomitant use of vardenafil and alpha-blockers is not recommended.

Use with Potent CYP 3A4 Inhibitors
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. Higher plasma levels may increase both the efficacy and incidence of adverse events. A maximum vardenafil dose of 5 mg should not be exceeded if used in combination with ketoconazole, itraconazole and erythromycin. Concomitant use with the HIV protease inhibitors indinavir or ritonavir should be avoided. (see INTERACTIONS WITH OTHER DRUGS).

Ability to Drive and Use Machines
Patients should be aware of how they react to vardenafil before driving or operating machinery.

Carcinogenesis, Mutagenesis
Vardenafil showed no carcinogenic activity when administered orally to rats at doses up to 75 (males) or 25 (females) mg/kg/day or via the drinking water to mice at doses up to 150 (males) or 193 (females) mg/kg/day. The highest doses in these studies were associated with systemic exposure (AUC) to vardenafil >300 (rats) or about 25 (mice) times that expected in men taking 20 mg/day vardenafil.

Vardenafil was not genotoxic in assays for gene mutation (reverse mutations in bacterial cells and forward mutations in Chinese hamster V79 cells in vitro) or chromosomal damage (Chinese hamster V79 cells in vitro and mouse micronucleus assay in vivo).

Impairment of Fertility
In a specific clinical trial, single oral doses of 20 mg of vardenafil did not produce any effects on sperm motility or morphology or a variety of parameters indicative for male reproductive function. Based upon measurements of vardenafil in semen of healthy subjects 90 minutes after dosing, not more than 0.0002% of the administered dose appeared in the semen of patients.

Studies in rats showed no effects on fertility, reproductive performance or reproductive organ morphology in males or females given oral doses of vardenafil up to 100 mg/kg/day (systemic exposure >200 times that expected at the maximum recommended dose of 20 mg, based on AUC).

Use in Pregnancy (Category B3)

Vardenafil is not indicated for use by women.

Studies in rats have shown that vardenafil and/or its metabolites cross the placenta and distribute to the fetus. No evidence of embryofetal toxicity or teratogenicity was observed in pregnant rats or rabbits given oral doses of vardenafil up to 18 mg/kg/day. These doses were associated with systemic exposure to vardenafil 125- (rat) or 7- (rabbit) fold greater than that expected at the maximum recommended dose of 20 mg, based on AUC. Higher doses were associated with maternal toxicity, increased embryonic resorptions and delayed fetal development in both species.

Administration of vardenafil 60 mg/kg/day to pregnant rats during late gestation and throughout lactation resulted in increased postnatal pup mortality and delayed physical development. The no-effect-dose of 8 mg/kg/day was associated with systemic exposure approximately 28-fold that expected in humans at the maximum recommended dose of 20 mg vardenafil.

There are no studies of vardenafil in pregnant women.

Use in Lactation

Vardenafil is not indicated for use by women.

Vardenafil and/or its metabolites are excreted in the milk of lactating rats at concentrations up to 19-fold higher that the corresponding maternal plasma concentrations. Increased pre- and post-natal mortality and delayed physical development was observed in offspring from rats treated with oral vardenafil at 60 mg/kg/day during gestation and lactation.

There are no human data on the excretion of vardenafil into breast milk or on the safety of vardenafil exposure in infants.

Interactions with other Drugs

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.

Demonstrated Interactions
Erythromycin (500 mg t.i.d.), a CYP3A4 inhibitor, caused a 4-fold increase in vardenafil AUC and a 3-fold increase in Cmax when co-administered with vardenafil (5 mg) to healthy volunteers. When used in combination with erythromycin, a maximum vardenafil dose of 5 mg should not be exceeded.

Erythromycin

Ketoconazole
Ketoconazole (200 mg), which is a potent CYP3A4 inhibitor, caused a 10-fold increase in vardenafil AUC and a 4-fold increase in Cmax when co-administered with Vardenafil (5 mg) to healthy volunteers. When used in combination with ketoconazole, a maximum vardenafil dose of 5 mg should not be exceeded.

Indinavir
Co-administration of vardenafil (10 mg) with the HIV protease inhibitor indinavir (800 mg t.i.d.) resulted in a 16-fold increase in vardenafil AUC and a 7-fold 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). Combination use of indinavir and vardenafil is best avoided. If vardenafil is used in combination with indinavir, a maximum vardenafil dose of 5 mg should not be exceeded.

Potential Interactions
Concomitant use of other potent CYP 3A4 inhibitors (such as itraconazole, or ritonavir) can be expected to produce vardenafil plasma levels comparable to those produced by ketoconazole and indinavir (See Demonstrated Interactions). Higher plasma levels may increase both the efficacy and incidence of adverse events. A maximum vardenafil dose of 5 mg should not be exceeded if used in combination with ketoconazole, itraconazole and erythromycin. Concomitant use with the HIV protease inhibitors indinavir or ritonavir should be avoided.

CYP 3A4 Inhibitors

Nitrates, Nitric Oxide Donors
There is limited information on the potential hypotensive effects of vardenafil when given in combination with nitrates. Based on experience with other PDE5 inhibitors, some patients may experience clinically significant hypotension if vardenafil and nitrates are coadministered and concomitant use is therefore contraindicated (see CONTRAINDICATIONS).

Nitrates should not be administered for at least 24 hours (approximately 5 half-lives) after the last dose of vardenafil. A longer washout period should observed if the patient has been taking concomitant drugs, such as CYP3A4 inhibitors, which impair vardenafil metabolism.

Antihypertensive agents
Limited information is available on concomitant use of vardenafil and antihypertensive agents. Population pharmacokinetic investigations of phase III data revealed no significant effect of ACE-inhibitors, beta-blockers or diuretics on the pharmacokinetics of vardenafil. However, a potential for additive hypotensive effect exists, and until further information is available, caution should be exercised when prescribing vardenafil in combination with antihypertensive agents.

Interactions shown not to exist
Vardenafil (20 mg), when co-administered with glibenclamide (3.5 mg), did not affect the relative bioavailability of glibenclamide (no effect on AUC and Cmax of glibenclamide).

Glibenclamide

Warfarin
No pharmacokinetic or pharmacodynamic (prothrombin time and clotting factor II, VII and X) interactions were shown when warfarin (25 mg) was co-administered with vardenafil (20 mg). Vardenafil pharmacokinetics were not affected by co-administration of warfarin.

Nifedipine
Coadministration of vardenafil (20 mg) did not alter the bioavailability (AUC and Cmax) of nifedipine (30 mg 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).

Digoxin
Lack of pharmacokinetic interaction was shown when digoxin (0.375 mg daily) in steady state was co-administered with vardenafil (20 mg) over 14 days every other day.

Antacids
Single doses of Mylanta (magnesium hydroxide/aluminium hydroxide) did not affect the bioavailability (AUC) or the maximum concentration (Cmax) of vardenafil.

Ranitidine, Cimetidine
Bioavailability of vardenafil (20 mg) was not affected by co-administration of the H2-antagonists ranitidine (150 mg b.i.d.) and cimetidine, a non-specific cytochrome P450 inhibitor (400 mg b.i.d.).

Aspirin
Vardenafil (10 mg) did not influence bleeding time when taken alone or in combination with low dose aspirin (2 x 81 mg tablets).

Ethanol
Vardenafil (20 mg) did not potentiate the hypotensive effects of ethanol (0.5 g/kg bodyweight). The pharmacokinetics of ethanol and vardenafil were not significantly altered by coadministration.

Other Drugs
Population pharmacokinetic investigations of phase III data revealed no significant effect of aspirin, weak CYP 3A4-inhibitors, and medications for the treatment of diabetes (sulfonylureas and metformin) on the pharmacokinetics of vardenafil.

Adverse Reactions
Vardenafil was administered to over 3750 patients during clinical trials worldwide. Of these, over 730 have been treated for one year or longer. Vardenafil was generally very well tolerated. Adverse events were generally transient and mild to moderate in nature.

Placebo controlled clinical trials (adverse events)
When vardenafil was taken as recommended, the following adverse events were reported more commonly with vardenafil than placebo in placebo controlled clinical trials (as of 29 November 2001) (Table 3):

Table 3: Adverse events reported by = 2% of patients treated with vardenafil and more frequent on drug than placebo in fixed dose phase III trials of 5 mg, 10 mg, and 20 mg vardenafil.

 

Adverse event	Vardenafil	Placebo
any event	57.6%	39.7%
headache	15.6%	5.5%
flushing	11.7%	0.6%
rhinitis	10.3%	3.8%
dyspepsia	3.9%	0.8%
accidental injury	3.2%	2.4%
sinusitis	3.1%	0.8%
flu syndrome	2.7%	2.3%
nausea	2.3%	0.8%
dizziness	2.4%	0.9%
increased creatine kinase	2.0%	1.1%
arthralgia	2.0%	1.0%

The rate of these adverse drug reactions was dose dependent.

All clinical trials (Adverse Drug Reactions)
The following adverse drug reactions (treatment-related adverse events) were reported in patients given vardenafil and occurred in > 2 cases in all clinical trials (as of 29 November 2001) (Table 4):

Table 4: Adverse Drug Reactions reported in patients in all clinical phase III trials worldwide.

 

Category of frequency ? 10% (very common):
Body system:	Adverse drug reactions:
Body as a whole:	headache
Cardiovascular:	flushing
Category of frequency ? 1% – < 10% (common):
Body system:	Adverse drug reactions:
Digestive:	dyspepsia, nausea
Nervous System:	dizziness
Respiratory:	rhinitis
Category of frequency ? 0.1% – < 1% (uncommon):
Body system:	Adverse drug reactions:
Body as a whole:	abdominal pain, asthenia, back pain, chest pain, face oedema, pain, photosensitivity reaction
Cardiovascular:	hypertension, palpitation, tachycardia
Digestive:	abnormal liver function tests, diarrhoea, dry mouth, oesophagitis, flatulence, gastritis, GGT increased, vomiting
Metabolic and Nutritional:	increased creatine kinase
Musculoskeletal:	arthralgia, myalgia
Nervous System:	hypaesthesia, insomnia, nervousness, paraesthesia, somnolence, vertigo
Respiratory:	dyspnea, epistaxis, sinusitis
Skin and Appendages:	pruritus, rash, skin discoloration, sweating
Special Senses:	abnormal vision, amblyopia, chromatopsia, conjunctivitis, eye disorder, eye pain, lacrimation disorder, photophobia, tinnitus
Urogenital:	abnormal ejaculation
Category of frequency ? 0.01% – < 0.1% (rare):
Body system:	Adverse drug reactions (n > 2 cases):
Body as a whole:	flu syndrome, leg pain
Cardiovascular:	atrial fibrillation, hypotension, peripheral oedema, syncope
Digestive:	eructation, gastrointestinal disorder
Musculoskeletal:	leg cramps
Nervous System:	anxiety, hypertonia
Special senses:	ear pain
Urogenital:	erectile disturbance

In a phase I study with 40 mg vardenafil, twice the maximum recommended dose, priapism was observed in 2 cases as an adverse drug reaction.

Post-Marketing Experience
The following serious adverse events have been reported in temporal association with the use of another drug of this class during post-marketing experience (n > 2 cases):

Body system: Adverse Events:
Cardiovascular: cerebrovascular haemorrhage, myocardial infarction, sudden cardiac death, transient ischaemic attack, ventricular arrhythmia

Dosage and Administration
The recommended starting dose of LEVITRA is 10 mg, taken orally 25 to 60 minutes before sexual activity. Sexual activity can be initiated as soon as 15 minutes and as long as 4-5 hours after taking LEVITRA.

The maximum recommended dose frequency is once per day.

LEVITRA can be taken with or without food.

Sexual stimulation is required for a natural response to treatment.

Dose Range
Based on efficacy and tolerability, the LEVITRA dose may be increased to 20 mg or decreased to 5 mg. The maximum recommended dose is 20 mg once daily.

Concomitant use of the potent cytochrome P450 (CYP) 3A4 inhibitors ketoconazole, itraconazole, indinavir and ritonavir can be expected to produce markedly increased plasma levels of vardenafil. Since higher plasma levels may increase both the efficacy and incidence of adverse events, a maximum dose of 5 mg should not be exceeded when LEVITRA is used in combination with ketoconazole, itraconazole and erythromycin. Concomitant use with the HIV protease inhibitors indinavir or ritonavir should be avoided.

Elderly (above 65 years)
No dose adjustment is required in elderly patients.

Children (from birth to 16 years)
Vardenafil is not indicated for use in children.

Hepatic impairment
No dose adjustment is needed in patients with mild hepatic impairment (Child-Pugh A).

Vardenafil clearance is reduced in patients with moderate hepatic impairment (Child-Pugh B), supporting a starting dose of 5 mg, which may subsequently be increased to 10 mg and then 20 mg, based on tolerability and efficacy.

The pharmacokinetics of vardenafil have not been studied in patients with severe hepatic impairment (Child-Pugh C), therefore vardenafil should not be used in these patients.

Renal impairment
No dose adjustment is needed in patients with mild (CLcr > 50-80 ml/min), moderate (CLcr > 30-50 ml/min), or severe (CLcr < 30 ml/min) renal impairment.

The pharmacokinetics of vardenafil have not been studied in patients requiring dialysis, therefore vardenafil should not be used in these patients.

Overdosage
In single dose volunteer studies, vardenafil was tested in doses up to and including 80 mg per day. Even the highest dosage tested (80 mg per day) was generally 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.

Presentation
LEVITRA is sold in blister packs of 2 and 4 tablets.

LEVITRA 5 mg, LEVITRA 10 mg and LEVITRA 20 mg tablets contain vardenafil hydrochloride trihydrate equivalent to 5 mg, 10 mg and 20 mg of vardenafil, respectively. All LEVITRA tablets are orange film-coated round tablets with an embossed BAYER cross on one side and the dose strength (“5″, “10″, or “20″) on the other side.

Shelf life: 30 months, Store below 30 °C.