Composition

LEVITRA® 5 mg tablet: each tablet contains 5 mg of Vardenafil (5.926 mg of Vardenafil monohydrochloride trihydrate)

LEVITRA® 10 mg tablet: each tablet contains 10 mg of Vardenafil (11.852 mg of Vardenafil monohydrochloride trihydrate) LEVITRA® 20 mg tablet: each tablet contains 20 mg of Vardenafil (23.705 mg of Vardenafil monohydrochloride trihydrate)

Further constituents: 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)

Pharmacodynamic Properties

Penile erection is a hemodynamic process based on the relaxation of smooth muscle in the corpus cavemosum and its associated arterioles. During sexual stimulation, from nerve ends in the corpus cavernosum nitric oxide (NO) is released, which 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.

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.

LEVITRA® thus potentiates the natural response to sexual stimulation

Pharmacokinetic Properties

Absorption:

Vardenafil is rapidly absorbed after oral administration. C_max 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.

Due to a considerable first-pass effect, the mean absolute oral bioavailability is about 15%.

After oral dosing of Vardenafil AUC and C_max increase almost dose-proportionally over the recommended dose range (5-20 mg).

When Vardenafil is taken with a high fat meal (containing 57% fat), the rate of absorption is reduced with an increase in the median T_max of 60 minutes and a mean reduction in C_max of 20 % . Vardenafil AUC was not affected. After a normal meal (containing 30 % fat) Vardenafil pharmacokinetic parameter (C_max, T_max, and AUC) were not affected at all.

Based on these results Vardenafil can be taken with or without food.

Distribution:

The mean steady state volume of distribution (V_ss) for Vardenafil is 208 L, 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 0.00012% of the administered dose may appear in the semen of patients.

Metabolism:

Vardenafil is metabolized predominantly by hepatic enzymes via CYP3A4, with some contribution from CYP3A5 and CYP2C9 isoforms.

Mean elimination half life (t_½) 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 %.

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).

Pharmacokinetics in special populations:

Elderly:

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 C_max, decreased by 23%, compared to volunteers with no renal impairment. No statistically significant correlation between creatinine clearance and Vardenafil plasma exposure (AUC and C_max) was observed. The pharmacokinetics of vardenafil has not been studied in patients requiring dialysis.

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 C_max were increased 1.2-fold (AUC by 17%, and C_max by 22%), compared to healthy control subjects.

In patients with moderate hepatic impairment (Child-Pugh B), Vardenafil AUC was increased 2.6-fold (160%) and C_max 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-Pugh C).

Indications

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.

Posology and method of administration

Recommended usual dose:

The recommended starting dose is 10 mg taken as needed approximately 25-60 minutes before sexual activity. In clinical trials vardenafil 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. The onset of activity may be delayed if taken with a high fat meal. Sexual stimulation is required for a natural response to treatment (see "Interaction with other medicaments and other forms of interaction").

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. A maximum dose of 5 mg should not be exceeded when used in combination with the potent cytochrome P450 (GYP) 3A4 inhibitor erythromycin (increased AUC by 4 fold). Concomitant use with ketoconazole, itraconazole, indinavir or ritonavir, should be avoided as vardenafil AUC is increased by 10-16 fold if the drugs are combined (see "Special warnings and special precautions for use").

Method of administration:

For oral use

Elderly (above 65 years):

Hepatic clearance of healthy elderly volunteers was reduced. The AUC and C_max in the elderly are higher by 52% and 34% as compared to young male volunteers (18-45 years). Therefore, a starting dose of 5 mg is recommended. (see "Contraindications")

Children (from birth to 16 years):

LEVITRA® is not indicated for use in children.

Hepatic impairment:

No dose adjustment needed in patients with mild hepatic impairment (Child-Pugh A). Vardenafil clearance is reduced in patients with moderate hepatic impairment (ChildPugh B). Therefore a starting dose of 5 mg is recommended. (see "Contraindications") The pharmacokinetics has not been studied in patients with severe hepatic impairment (Child-Pugh C).

Renal impairment:

No dose adjustment is needed in patients with mild (CLcr > 50-80 ml/min) and moderate (CLcr > 30-50 ml/min) renal impairment. In patients with severe renal impairment (CLcr < 30 ml/min), a starting dose of 5 mg should be considered.

Use in Women

Levitra is not indicated for use in women.

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