In the following patients: age >65, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance <30 mL/min), and concomitant use of potent cytochrome P450 3A4 inhibitors (erythromycin), plasma levels of Sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. Although plasma levels of Sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be safely coadministered at this time point.

Sildenafil is contraindicated in patients with a known hypersensitivity to any component of the tablet.

DESCRIPTION: Sildenafil is the citrate salt of Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

CLINICAL PHARMACOLOGY:

 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.

Pharmacokinetics and Metabolism

Sildenafil 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 (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, Sildenafil. The concomitant use of potent cytochrome P450 3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of Sildenafil. Both Sildenafil and the metabolite have terminal half lives of about 4 hours.

Absorption and Distribution:    Sildenafil 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 Sildenafil is taken with a high fat meal, the rate of absorption is reduced. 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.

Metabolism and Excretion:    Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes.

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).

Pharmacokinetics in Special Populations

Geriatrics (65 years or over) had a reduced clearance of Sildenafil, with free plasma concentrations approximately 40% greater than those seen in healthy younger volunteers (18-45 years).

Renal Insufficiency: In severe (CLcr=<30 mL/min) renal impairment, Sildenafil clearance was reduced, resulting in approximately doubling of AUC and C max compared to age-matched volunteers with no renal impairment.

Hepatic Insufficiency:    In hepatic cirrhosis, Sildenafil clearance was reduced, resulting in increases in AUC (84%) and C max (47%) compared to age-matched volunteers with no hepatic impairment.

Therefore, age >65, 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.

Clinical Studies

Sildenafil demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo.

Sixty-three percent, 74%, and 82% of the patients (1797 patients) on 25 mg, 50 mg and 100 mg of Sildenafil, respectively, reported an improvement in their erections, compared to 24% on placebo. During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that Sildenafil improved their erections.

Sildenafil was effective in those with a history of coronary artery disease, hypertension, other cardiac disease, peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft (CABG), radical prostatectomy, transurethral resection of the prostate (TURP) and spinal cord injury, and in patients taking antidepressants/antipsychotics and antihypertensives/diuretics.

WARNINGS:

There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including Sildenafil, should not be generally used in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.

Sildenafil has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mmHg). While this normally would be expected to be of little consequence in most patients, prior to prescribing Sildenafil, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects, especially in combination with sexual activity.

Patients with the following underlying conditions can be particularly sensitive to the actions of vasodilators including Sildenafil - those with left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure.

There is no controlled clinical data on the safety or efficacy of Sildenafil 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 phosphodiesterases).

Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of Sildenafil.

The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of Sildenafil (11-fold increase in AUC ). If Sildenafil is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of Sildenafil are limited. Visual disturbances occurred more commonly at higher levels of Sildenafil exposure. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of Sildenafil (200-800 mg). To decrease the chance of adverse events in patients taking ritonavir, a decrease in Sildenafil dosage is recommended.

PRECAUTIONS:

General

Before prescribing Sildenafil, it is important to note the following:

Patients on multiple antihypertensive medications were included in the pivotal clinical trials for Sildenafil. In a separate drug interaction study, when amlodipine, 5 mg or 10 mg, and Sildenafil, 100 mg were orally administered concomitantly to hypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Sildenafil was not carcinogenic, mutagenicity, no effect on sperm motility or morphology and no impairment of fertility.

Pregnancy, Nursing Mothers and Pediatric Use

Sildenafil is not indicated for use in newborns, children, or women.

Pregnancy Category B.   

Drug Interactions:

Effects of Other Drugs on Sildenafil

In vivo studies: Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma Sildenafil concentrations when coadministered with Sildenafil (50 mg) to healthy volunteers.

When a single 100 mg dose of Sildenafil was administered with erythromycin, a specific CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 182% increase in Sildenafil systemic exposure (AUC). In addition, in a study performed in healthy male volunteers, coadministration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Sildenafil (100 mg single dose) resulted in a 140% increase in Sildenafil C max and a 210% increase in Sildenafil AUC. Sildenafil had no effect on saquinavir pharmacokinetics. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole would be expected to have still greater effects, and population data from patients in clinical trials did indicate a reduction in Sildenafil clearance when it was coadministered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine).

Although the interaction between other protease inhibitors and Sildenafil has not been studied, their concomitant use is expected to increase Sildenafil levels.

It can be expected that concomitant administration of CYP3A4 inducers, such as rifampin, will decrease plasma levels of Sildenafil.

Pharmacokinetic data from patients in clinical trials showed no effect on Sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl Sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.

Effects of Sildenafil on Other Drugs

In vivo studies: When Sildenafil 100 mg oral was coadministered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.

No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.

SIDE EFFECTS:

POST-MARKETING EXPERIENCE:

Cardiovascular and cerebrovascular

Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of Sildenafil. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of Sildenafil without sexual activity. Others were reported to have occurred hours to days after the use of Sildenafil and sexual activity. It is not possible to determine whether these events are related directly to Sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors.

Other events

Other events reported post-marketing to have been observed in temporal association with Sildenafil and not listed in the pre-marketing adverse reactions section above include:

Nervous: seizure and anxiety.

Urogenital: prolonged erection, priapism and hematuria.

Special Senses: 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, paramacular edema and epistaxis.

OVERDOSAGE:

In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but incidence rates were increased.

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as Sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.  

DOSAGE AND ADMINISTRATION:

 For most patients, the recommended dose is 50 mg taken, as needed, approximately 1 hour before sexual activity. However, Sildenafil 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,  hepatic impairment, severe renal impairment, and concomitant use of potent cytochrome P450 3A4 inhibitors [ketoconazole, itraconazole, erythromycin (182%), saquinavir (210%)]. 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.

Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 25 mg of Sildenafil in a 48 hour period.

Sildenafil was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors or nitrates in any form is therefore contraindicated.

Simultaneous administration of Sildenafil doses above 25 mg and an alpha-blocker may lead to symptomatic hypotension in some patients. Doses of 50 mg or 100 mg of Sildenafil should not be taken within 4 hours of alpha-blocker administration. A 25 mg dose of Sildenafil may be taken at any time.

How Supplied: Pack of 4 tablets in 1 blister.

Storage: Store at 25°C; excursions permitted to 15-30°C.

Reference: USPDI for Professional Health Care, 2004, Page 2539-42

                  Martindale 2005, Page 1744-5

                  PDR 2000, page 2381-4