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MW=666.7 C22H30N6O4S,C6H8O7
Mechanism of action:
Sildenafil 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.
Pharmacokinetics:
Sildenafil citrate is rapidly absorbed after oral administration, with absolute bioavailability of about 40%. Its pharmacokinetics are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism and is converted to an active metabolite with properties similar to the parent, sildenafil. Both sildenafil and the metabolite have terminal half lives of about 4 hours.
Sildenafil citrate is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. Protein binding is 96% and it is independent of total drug concentrations.
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 administered oral dose).
Pharmacokinetics in Special Population:
Age 65 years or over, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. A starting oral dose of 25 mg should be considered in those patients.
Indications:
Sildenafil Citrate is indicated for the treatment of erectile dysfunction.
Erectile dysfunction that is medication-induced or caused by endocrine problems, should be evaluated and appropriately treated before sildenafil treatment is considered.
Contraindications:
Sildenafil citrate was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using organic nitrates, either regularly and/or intermittently, in any form is therefore contraindicated.
After patients have taken sildenafil citrate, it is unknown when nitrates, if necessary, can be safely administered. Sildenafil citrate is contraindicated in patients with a known hypersensitivity to any component of the tablet.
Warnings:
Treatment for erectile dysfunction, including sildenafil citrate should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status. Prior to prescribing sildenafil citrate physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by vasodilatory effects, especially in combinations with sexual activity.
There is no controlled clinical data on the safety or efficacy of sildenafil citrate in the following groups: if prescribed, this should be done with caution.
∑ Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months;
∑ Patients with resting hypotension (BP<90/50) or hypertension (BP>170/110);
∑ Patients with cardiac failure or coronary artery disease causing unstable angina;
∑ Patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal
phosphodiesterasesÆ®
In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.
Pregnancy, Nursing Mothers and Pediatric Use: Sildenafil citrate is not indicated for use in newborns, children, or women.
Precautions:
Before prescribing sildenafil, it is important to note the following:
∑ Patients on multiple antihypertensive medicationsÆ
∑ Patients with bleeding disorders and patients with active peptic ulcerationÆ
∑ Patients with anatomical deformation of penisÆ
∑ Patients who have conditions which may predispose them to priapismÆ
Information for patients:
Physicians should discuss with patients the contraindication of sildenafil citrate with regular and/or intermittent use of organic nitrates.
Physicians should discuss with patients the potential cardiac risk of sexual activity in patients with preexisting cardiovascular risk factors.
Physicians should warn patients that prolonged erections greater than 4 hours and priapism have been reported infrequently.
The use of sildenafil citrate offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered.
Concurrent use of other impotence therapy agents is not presently recommended.
Drug Interactions:
Nonspecific CYP inhibitors (such as cimetidine), specific CYP3A4 inhibitors (such as ketoconazole, erythromycine, and itraconazole) and protease inhibitors (such as saquinavir and ritonavir) caused an increase in plasma sildenafil concentrations when coadministered with sildenafil citrate.
It can be expected that concomitant administration of CYP3A4 inducers, such as rifampin, will decrease plasma levels of sildenafil.
Sildenafil citrate (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Sildenafil citrate (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.
Adverse Reactions:
In flexible-dose studies, the following adverse events were reported:
Headache, flushing, dyspepsia, nasal congestion, urinary tract infection, abnormal vision, diarrhea, dizziness,rash.
In fixed-dose studies, dyspepsia and abnormal vision were more common at 100 mg than at lower doses.
In post-marketing experiences, myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack and hypotension, seizure and anxiety, prolonged erection, priapism and hematuria, diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure, increased intraocular pressure, retinal vascular disease or bleeding, vitreous detachment/traction and paramacular edema.
Dosage and Administration:
Usual adult dose: 50 mg (base) one hour (range, one half to four hours) before sexual intercourse once a day if needed. As tolerated, subsequent doses may be increased to 100 mg or decreased to 25 mg once a day.
Usual adult prescribing limits: 100 mg once a day.
Usual geriatric dose: Oral, 25 mg (base) one hour (range, one half to four hours) before sexual intercourse once a day if needed, as tolerated, subsequent doses may be increased.
Storage:
Store at controlled room temperature, 15 to 30°C.
How supplied:
Sildenafil citrate 50 mg is available as blue, scored, barrel-shaped, film coated tablets in boxes of 5.
References:
1- USP DI 1999
2- PDR 2000
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