LEVITRA (Hydrochloride Trihydrate)

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

DETAILS

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:

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).

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.

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.

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.

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.

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. 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.

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.

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%. 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).

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.”