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製造会社の製品説明(英語原文)
Sildenafil Citrate
Sildenafil Citrate Tablets
Composition
Sildenafil Citrate 100 Tablet
Each film-coated tablet contains
Sildenafil citrate equivalent to
Sildenafil ...................... 100 mg
Sildenafil citrate, an oral therapy for erectile dysfunction, is a selective inhibitor of cyclic guanosine monophosphate (cGMP) - specific phosphodiesterase type 5 (PDE5).
Dosage Form
Sildenafil Citrate is available as and 100mg film-coated tablets.
Pharmacology
Pharmacodynamics
Mechanism of Action
The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation.
In vitro studies have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6, > 80 -fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PE9, PDE10 and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility . Sildenafil is only about 10-fold potent for PDE5 compared to PDE6, an enzyme found in the retina; this lower selectivity is thought to be the basis for abnormalities related to colour vision observed with higher doses or plasma levels.
Effects of sidenafil on Erectile Response :
In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScanR), after sidenafil administration compared with placebo.
Effects of sidenafil on Blood Pressure :
Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.4/5.5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different than placebo at 8 hours. Larger effects were recorded among patients receiving concomitant nitrates .
Effects of sidenafil on Cardiac Parameters :
Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers.
Effects of sidenafil on Vision:
At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels .
Pharmacokinetics
Absorption and Distribution: Sidenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When sidenafil is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in T max of 60 minutes and a mean reduction in C max of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.
Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.
Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects.
After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach
Indications
Sildenafil Citrate is indicated for the treatment of erectile dysfunction in men.
Dosage And Method of Administration
For most patients, the recommended dose is 50 mg taken, as needed approximately 1 hour before sexual activity. However, Sildenafil Citrate may be taken anywhere from 4 hours to 0.5 hour before sexual activity. Based on effectiveness and toleration, the dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. The maximum recommended dosing frequency is once per day.
The following factors are associated with increased plasma levels of sildenafil : age > 65 (40% increase in AUC), hepatic impairment (e.g., cirrhosis, 80%), severe renal impairment (creatinine clearance < 30 mL/min, 100%), and concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin, ketoconazole, itraconazole, ritonavir, saquinavir > 200%). Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered in these patients. Doses of or 100mg Sildenafil Citrate should not be taken within 4 hours of alpha-blocker administration.
Contraindications
Use of Sildenafil Citrate is contraindicated in patients with a known hypersensitivity to any component of the tablet. Consistent with its known effects on the nitric oxide/cGMP pathway , sildenafil was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are concurrently using organic nitrates in any form is therefore contraindicated. Sildenafil is not indicated for use in women and individuals below 18 years of age.
