Buy Levitra online
Vardenafil against impotence and erectile dysfunction
The potency medication Levitra, developed by Bayer, is highly effective against impotence (erectile dysfuntion). Levitra increases the potency and sexual performance in men.
Vardenafil (Levitra®), like Sildanafil (Viagra®) and Tadalafil (Cialis®), belongs to the substance group of selective phosphodiesterase inhibitors.
Prescribing Information Levitra
Description
LEVITRA is an oral therapy for the treatment of erectile dysfunction. This monohydrochloride salt of vardenafil is a selective®inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Vardenafil HCl is designated chemically as piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-, monohydrochloride and has the following structural formula:
Vardenafil HCl is a nearly colorless, solid substance with a molecular weight of 579.1 g/mol and a solubility of 0.11 mg/mL inwater. LEVITRA is formulated as orange, round, film-coated tablets with NBAYER” cross debossed on one side and "2.5", "5","10", and "20" on the other side corresponding to 2.5 mg, 5 mg, 10 mg, and 20 mg of vardenafil, respectively. In addition to theactive ingredient, vardenafil HCl, each tablet contains microcrystalline cellulose, crospovidone, colloidal silicon dioxide, magne-sium stearate, hypromellose, polyethylene glycol, titanium dioxide, yellow ferric oxide, and red ferric oxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and itsassociated arterioles. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpuscavernosum. Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosinemonophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum. The cGMP in turn triggers smooth musclerelaxation, allowing increased blood flow into the penis, resulting in erection. The tissue concentration of cGMP is regulated byboth the rates of synthesis and degradation via phosphodiesterases (PDEs). The most abundant PDE in the human corpuscavernosum is the cGMP-specific phosphodiesterase type 5 (PDE5); therefore, the inhibition of PDE5 enhances erectile functionby increasing the amount of cGMP. Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibitionof PDE5 has no effect in the absence of sexual stimulation.
In vitro studies have shown that vardenafil is a selective inhibitor of PDE5. The inhibitory effect of vardenafil is more selective onPDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative toPDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10).
Pharmacokinetics
The pharmacokinetics of vardenafil are approximately dose proportional over the recommended dose range. Vardenafil iseliminated predominantly by hepatic metabolism, mainly by CYP3A4 and to a minor extent, CYP2C isoforms. Concomitant usewith strong CYP3A4 inhibitors such as ritonavir, indinavir, ketoconazole, itraconazole as well as moderate CYP3A inhibitorssuch as erythromycin results in significant increases of plasma levels of vardenafil (see PRECAUTIONS, WARNINGS and DOSAGE AND ADMINISTRATION). Mean vardenafil plasma concentrations measured after the administration of a single oraldose of 20 mg to healthy male volunteers are depicted in Figure 1
Figure 1: Plasma Vardenafil Concentration (Mean ±SD) Curve for a
Single 20 mg LEVITRA Dose
Absorption: Vardenafil is rapidly absorbed with absolute bioavailability of approximately 15%. Maximum observed plasmaconcentrations after a single 20 mg dose in healthy volunteers are usually reached between 30 minutes and 2 hours (median 60minutes) after oral dosing in the fasted state. Two food-effect studies were conducted which showed that high-fat meals caused a reduction in Cmax by 18%-50%.
Distribution: The mean steady-state volume of distribution (Vss) for vardenafil is 208 L, indicating extensive tissue distribution. Vardenafil and its major circulating metabolite, M1, are highly bound to plasma proteins (about 95% for parent drug and M1). This protein binding is reversible and independent of total drug concentrations.
Following a single oral dose of 20 mg vardenafil in healthy volunteers, a mean of 0.00018% of the administered dose wasobtained in semen 1.5 hours after dosing.
Metabolism: Vardenafil is metabolized predominantly by the hepatic enzyme CYP3A4, with contribution from the CYP3A5 andCYP2C isoforms. The major circulating metabolite, M1, results from desethylation at the piperazine moiety of vardenafil. M1 issubject to further metabolism. The plasma concentration of M1 is approximately 26% that of the parent compound. Thismetabolite shows a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE528% of that of vardenafil. Therefore, M1 accounts for approximately 7% of total pharmacologic activity.
Excretion: The total body clearance of vardenafil is 56 L/h, and the terminal half-life of vardenafil and its primary metabolite(M1) is approximately 4-5 hours. After oral administration, vardenafil is excreted as metabolites predominantly in the feces(approximately 91-95% of administered oral dose) and to a lesser extent in the urine (approximately 2-6% of administeredoral dose). Pharmacokinetics in Special Populations
Pediatrics: Vardenafil trials were not conducted in the pediatric population.
Geriatrics: In a healthy volunteer study of elderly males (> 65 years) and younger males (18–45 years), mean Cmax and AUC were 34% and 52% higher, respectively, in the elderly males (see PRECAUTIONS, Geriatric Use and DOSAGE AND ADMINISTRATION). Consequently, a lower starting dose of LEVITRA (5 mg) in patients =65 years of age should be considered.
Renal Insufficiency: In volunteers with mild renal impairment (CLcr = 50-80 ml/min), the pharmacokinetics of vardenafil werecrsimilar to those observed in a control group with normal renal function. In the moderate (CLcr = 30-50 ml/min) or severecr(CLcr <30 ml/min) renal impairment groups, the AUC of vardenafil was 20–30% higher compared to that observed in acrcontrol group with normal renal function (CLcr >80 ml/min). Vardenafil pharmacokinetics have not been evaluated in patientscrrequiring renal dialysis (see PRECAUTIONS, Renal Insufficiency, and DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency: In volunteers with mild hepatic impairment (Child-Pugh A), the Cmax and AUC following a 10 mg vardenafil dose were increased by 22% and 17%, respectively, compared to healthy control subjects. In volunteers with moderate hepaticimpairment (Child-Pugh B), the Cmax and AUC following a 10 mg vardenafil dose were increased by 130% and 160%, respectively,compared to healthy control subjects. Consequently, a starting dose of 5 mg is recommended for patients with moderate hepaticimpairment, and the maximum dose should not exceed 10 mg (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).Vardenafil has not been evaluated in patients with severe (Child-Pugh C) hepatic impairment.
