Sildenafil is indicated in adult men with erectile dysfunction, which is the inabilitty to achieve or maintain a penile erection sufficient for satisfactory sexual performance. In oreder for Sildenafil to be effective, sexual stimulation is required.
Hypersensitivity to the active subastance or to any of the excepients.
Consistent with its known effects on the nitric oxide/cyclic guanosine monophosphate (cGMP) pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated.
The co-administration of PDE5 inhibitors, including sildenafil, with guanylate cyclase stimulators, such as riociguat, is contraindicated as it may potentially lead to symptomatic hypotension
Agents for the treatment of erectile dysfuction, including sildenafil, should not be used in men for whom sexual activity is inadvisable (e.g patients with severe cardiovascular disorders such as unstable angina or severe cardiac failure)
Sildenafil is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure
The safety of sildenafil has not been studied in the following sub-groups of patients and its use is therefore contraindicated: Severe hepatic impairment, hypotension (blood pressure below 90/50mmHg), recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases)
Psology and method of administration
Use in adults
The recommended dose is 50mg taken as needed approximately one hour before sexual activity. Based on efficacy and tolerability, the dose may be increased to 100mg or decreased to 25mg. The maximum recommended dose is 100mg. The maximum recommended dosing frequency is once per day. If sildenafil is taken with food, the onset of activity may be delayed compared to the fasted state
Elderly: Dosage adjustments are not required in elderly patients below 65 years of age
Renal impairement: The dosing recommendations described in “use in adults” apply to patients with mild to moderate renal impairment (creatinine clearance = 30-80 mL/min). Since sildenafil clearance is reduced in patients with severe renal impairment a 25mg dose should be considered. Based on efficacy and tolerability, the dose may be increased step-wise to 50mg up to 100mg as necessary.
Hepatic impairment: Since sildenafil clearance is reduced in patients with hepatic impairment (e.g. cirrhosis) a 25mg dose should be considered. Based on efficacy and tolerability, the dose may be increased step-wise to 50mg up to 100mg as necessary.
Paediatric population: Sildenafil is not indicated for individuals below 18 years of age.
Use in patients taking other medicinal products: With the exception of ritonavir for which co-administration with sildenafil is not advised, a starting dose of 25mg should be considered in patients receiving concomitant treatment with CYP3A4 inhibitors
In order to minimise the potential of developing postural hypotension in patients receiving alpha-blocker treatment patients should be established on alpha-blocker therapy prior to initiating sildenafil treatment. In addition, initiation of sildenafil at a dose of 25mg should be considered.
Mechanism of action
Sildenafil is an oral therapy for erectile dysfuction. In the natural setting, i.e. with sexual stimulation, it restores impaired erectile function by increasing blood flow to the penis. The physiological mechanism responsible for erection of the penis involves the relase of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. Nitric oxide 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 is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum, where PDE5 is responsible for degradation of cGMP. Sildenafil has a peripheral site of action on erections. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum but potently enhances the relaxant effect of NO on the tissue. When the NO/cGMP pathway is activated, as occurs with sexual stimulation, inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore sexual stimulation is required in order for sildenafil to produce its intended beneficial pharmacological effects
Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in fasted state. The mean absolute oral bioavailability is 41% (range 25-63%). After oral dosing of sildenafil AUC and Cmax increase in proportion with dose over the recommended dose range (25-100mg). when Sildenafil is taken with food, the rate of absorption is reduced with a mean delay in tmax of 60 minutes and a mean reduction in Cmax of 29%
The mean steady state volume of distribution (Vd) for sildenafilis 105 I, indicating distribution into the tissues. After a single oral dose of 100mg, the mean maximum total plasma concentration of sildenafil is approximately 440ng/mL (CV 40%). Since sildenafil ( and its major circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this results in the mean maximum free plasma concentration for sildenafil of 18ng/mL (38nM). Protein binding is independent of total drug concentrations. In healthy volunteers receiving sildenafil (100mg single dose), less than 0.0002% (average 188ng) of the administered dose was present in ejaculate 90 minutes after dosing.
Sildenafil is cleared predominantly by the CYP2A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approxiamtely 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolised, with a terminal half life of approximately 4h
The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half life of 3-5 h. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose)
Fertility,pregnancy and lactation
Sildenafil is not indicated for use by women. There are no adequate and well-controlled studies in pregnant or breast-feeding women. No relevant adverse effects were found in reproduction studies in rats and rabbits following oral administration of sildenafil. There was no effect on sperm motility or morphology after a single 100mg oral doses of sildenafil in healthy volunteers.
Effects on ability to drive and use machine
No studies on the effects on the ability to drive and use machines have been performed. As dizziness and altered vision were reported in clinical trials with sildenafil, patients should be aware of how they react to sildenafil before driving or operating machinery.
The safety profile of sildenafil is based on 9570 patients in 74 double blind placebo-controlled clinical studies. The most commonly reported adverse reactions in clinical studies among sildenafil treated patients were headache, flushing, dyspepsia, nasal congestion, dizzness, nausea, hot flush, visual disturbance, cyanopsia and blurred vision.