CATEGORIES: Erectile dysfunction; Pregnancy Category B; FDA Approved March 1998
Drug Classes: Impotence agents; Phosphodiesterase inhibitors
BRAND NAMES: Viagra
FOREIGN BRAND AVAILABILITY:
Aphrodil (Israel);
Edegra (India);
Ejertol (Colombia);
Erilin (Colombia);
Eroxim (Colombia);
Penegra (South Africa, India);
Viagra (Canada, Colombia, Hong Kong, Indonesia, Japan, Korea, Mexico, Peru, Philippines, Singapore, Taiwan, Thailand);
Vigain (Israel);
Zwagra (Israel)
COST OF THERAPY:
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Viagra, an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).
Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate.
Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/ml in water and a molecular weight of 666.7. Viagra is formulated as blue, film-coated, rounded-diamond-shaped tablets equivalent to 25, 50, and 100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, lactose, triacetin, and FD&C blue no. 2 aluminum lake.
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 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 NO by inhibiting 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.
Studies in vitro 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, PDE9, PDE10, and PDE11). The approximately 4000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in the control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels (see Pharmacodynamics).
In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.
Pharmacokinetics and Metabolism
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 (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 (see DOSAGE AND ADMINISTRATION). Both sildenafil and the metabolite have terminal half lives of about 4 hours.
Absorption and Distribution
Sildenafil citrate is rapidly absorbed. Maximum observed plasma concentrations are reached within 30-120 minutes (median 60 minutes) of oral dosing in the fasted state. When sildenafil citrate is taken with a high fat meal, 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 (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.
Pharmacokinetics in Special Populations
Geriatrics
Healthy elderly volunteers (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 volunteers with mild (CLCR = 50-80 ml/min) and moderate (CLCR = 30-49 ml/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil citrate (50 mg) were not altered. In volunteers with severe (CLCR = <30 ml/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment.
Hepatic Insufficiency
In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (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 (see DOSAGE AND ADMINISTRATION).
Pharmacodynamics
Effects of Sildenafil Citrate 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 (RigiScan), after sildenafil citrate administration compared with placebo. Most studies assessed the efficacy of sildenafil citrate approximately 60 minutes post dose. The erectile response, as assessed by RigiScan, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.
Effects of Sildenafil Citrate 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 mm Hg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25, 50, and 100 mg of sildenafil citrate, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates (see CONTRAINDICATIONS).
Effects of Sildenafil Citrate on Cardiac Parameters
Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers.
Studies have produced relevant data on the effects of sildenafil citrate on cardiac output. In one small, open-label, uncontrolled pilot study, 8 patients with stable ischemic heart disease underwent Swan-Ganz catheterization. A total dose of 40 mg sildenafil was administered by 4 intravenous infusions.
The results from this pilot study are shown in TABLE 1A and TABLE 1B; the mean resting systolic and diastolic blood pressures decreased by 7 and 10% compared to baseline in these patients. Mean resting values for right atrial pressure, pulmonary artery pressure, pulmonary artery occluded pressure, and cardiac output decreased by 28%, 28%, 20%, and 7% respectively. Even though this total dosage produced plasma sildenafil concentrations which were approximately 2-5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients.
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In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or sildenafil citrate 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort. The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for sildenafil (n=70) and placebo, respectively. These results demonstrated that the effect of sildenafil citrate on the primary endpoint was statistically non-inferior to placebo.
Effects of Sildenafil Citrate on Vision
At single oral doses of 100 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. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of sildenafil citrate on visual acuity, intraocular pressure, or pupillometry.
In clinical studies, sildenafil citrate was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. Sildenafil citrate was evaluated primarily at doses of 25, 50, and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). Sildenafil citrate was administered to more than 3000 patients aged 19-87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. Sildenafil citrate 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.
The effectiveness of sildenafil citrate was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire [the International Index of Erectile Function (IIEF)] administered during a 4 week treatment-free run-in period, at baseline, follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study end points; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered.
The effect on one of the major end points, maintenance of erections after penetration was pooled as results of 5 fixed-dose, dose-response studies of greater than 1 month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results. Regardless of the baseline levels of function, subsequent function in patients treated with sildenafil citrate was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline.
The frequency of patients reporting improvement of erections in response to a global question were pooled in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12-24 weeks duration. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions. Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies. Sixty-three percent (63%), 74%, and 82% of the patients on 25 mg, 50 mg, and 100 mg of sildenafil citrate, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n=644, with most patients eventually receiving 100 mg), results were similar.
The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4 week, treatment-free run-in period.
In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of sildenafil citrate on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50-100 mg of sildenafil citrate versus 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on sildenafil citrate versus about 20% on placebo.
During 3-6 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 citrate improved their erections.
Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. Sildenafil citrate improved these aspects of sexual function: frequency, firmness, and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction, and enjoyment of intercourse; and overall relationship satisfaction.
One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n=268). As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of sildenafil citrate; all patients, however, were receiving 50 or 100 mg at the end of the study. There were highly statistically significant improvements on the 2 principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on sildenafil citrate compared to placebo. On a global improvement question, 57% of sildenafil citrate patients reported improved erections versus 10% on placebo. Diary data indicated that on sildenafil citrate, 48% of intercourse attempts were successful versus 12% on placebo.
One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted. The changes from baseline in scoring on the 2 end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of sildenafil citrate. On a global improvement question, 83% of patients reported improved erections on sildenafil citrate versus 12% on placebo. Diary data indicated that on sildenafil citrate, 59% of attempts at sexual intercourse were successful compared to 13% on placebo.
Across all trials, sildenafil citrate improved the erections of 43% of radical prostatectomy patients compared to 15% on placebo.
Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of sildenafil citrate patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the 2 end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of sildenafil citrate. Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for sildenafil citrate and 29% for placebo.
A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. Sildenafil citrate was effective in a broad range of ED patients, including 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.
Analysis of the safety database showed no apparent difference in the side effect profile in patients taking sildenafil citrate with and without antihypertensive medication. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions.
Sildenafil citrate is indicated for the treatment of erectile dysfunction.
Non-FDA Approved Indications
Although not uses approved by the FDA, sildenafil has been studied for use as a diagnostic aid in evaluating erectile dysfunction arising from vascular insufficiency, as well as treatment for sexual arousal disorder in premenopausal women.
Consistent with its known effects on the nitric oxide/cGMP pathway (see CLINICAL PHARMACOLOGY), 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. Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma levels of sildenafil at 24 hours post dose are approximately 2 ng/ml (compared to peak plasma levels of approximately 440 ng/ml) (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism). 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 3-8 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 citrate is contraindicated in patients with a known hypersensitivity to any component of the tablet.
There is a potential for cardiac risk of sexual activity in patients with preexisting cardiovascular disease. Therefore, treatments 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.
Sildenafil citrate has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 8.4/5.5 mm Hg), (see CLINICAL PHARMACOLOGY, Pharmacodynamics). While this normally would be expected to be of little consequence in most patients, prior to prescribing sildenafil citrate, 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 citrate — 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 citrate in the following groups; if prescribed, this should be done with caution:
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 citrate. 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.
The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC). If sildenafil citrate 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 (see DRUG INTERACTIONS,ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION).
General
The evaluation of erectile dysfunction should include a determination of potential underlying causes and the identification of appropriate treatment following a complete medical assessment.
Before prescribing sildenafil citrate, it is important to note the following:
Information for the Patient
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. Patients who experience symptoms (e.g., angina pectoris, dizziness, nausea) upon initiation of sexual activity should be advised to refrain from further activity and should discuss the episode with their physician.
Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of sildenafil citrate. 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 may result.
Physicians should advise patients that simultaneous administration of sildenafil citrate doses above 25 mg and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, sildenafil citrate doses above 25 mg should not be taken within 4 hours of taking an alpha-blocker.
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.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29 and 42 times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m2 basis.
Sildenafil was negative in in vitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity, and in vitro human lymphocytes and in vivo mouse micronucleus assays to detect clastogenicity.
There was no impairment of fertility in rats given sildenafil up to 60 mg/kg/day for 36 days to females and 102 days to males, a dose producing an AUC value of more than 25 times the human male AUC.
There was no effect on sperm motility or morphology after single 100 mg oral doses of sildenafil citrate in healthy volunteers.
Pregnancy, Nursing Mothers, and Pediatric Use
Sildenafil citrate is not indicated for use in newborns, children, or women.
Pregnancy Category B
No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 20 and 40 times the MRHD on a mg/m2 basis in a 50 kg subject. In the rat pre- and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days. In the nonpregnant rat the AUC at this dose was about 20 times human AUC. There are no adequate and well-controlled studies of sildenafil in pregnant women.
Geriatric Use
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations). Since higher plasma levels may increase both the efficacy and incidence of adverse events, a starting dose of 25 mg should be considered (see DOSAGE AND ADMINISTRATION).
Effects of Other Drugs on Sildenafil Citrate
When a single 100 mg dose of sildenafil citrate 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 citrate (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Sildenafil citrate 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) (see DOSAGE AND ADMINISTRATION).
In another study of healthy male volunteers, coadministration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with sildenafil citrate (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/ml, compared to approximately 5 ng/ml when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. Sildenafil citrate had no effect on ritonavir pharmacokinetics (see DOSAGE AND ADMINISTRATION).
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.
Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of sildenafil citrate.
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 Citrate on Other Drugs
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
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%.
In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.
Pre-Marketing Experience
Sildenafil citrate was administered to over 3700 patients (aged 19-87 years) during clinical trials worldwide. Over 550 patients were treated for longer than 1 year.
In placebo-controlled clinical studies, the discontinuation rate due to adverse events for sildenafil citrate (2.5%) was not significantly different from placebo (2.3%). The adverse events were generally transient and mild to moderate in nature.
In trials of all designs, adverse events reported by patients receiving sildenafil citrate were generally similar. In fixed-dose studies the incidence of some adverse events increased with dose. The nature of the adverse events in flexible-dose studies, which more closely reflects the recommended dosage regimen, was similar to that for fixed-dose studies.
When sildenafil citrate was taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials, the adverse events in TABLE 2 were reported.
Other adverse reactions occurred at a rate of >2%, but equally common on placebo: Respiratory tract infection, back pain, flu syndrome, and arthralgia.
In fixed-dose studies, dyspepsia (17%) and abnormal vision (11%) were more common at 100 mg than at lower doses. At doses above the recommended dose range, adverse events were similar to those detailed above but generally were reported more frequently.
The following events occurred in <2% of patients in controlled clinical trials; a causal relationship to sildenafil citrate is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful:
Post-Marketing Experience
Cardiovascular and Cerebrovascular
Serious cardiovascular, crerebrovascular, 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 citrate. 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 citrate without sexual activity. Others were reported to have occurred hours to days after the use of sildenafil citrate and sexual activity. It is not possible to determine whether these events are related directly to sildenafil citrate, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors (see WARNINGS for further important cardiovascular information).
Other Events
Other events reported post-marketing to have been observed in temporal association with sildenafil citrate and not listed in Pre-Marketing Experience include:
In studies with healthy volunteers of single doses of 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.
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 [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.
Ritonavir greatly increased the systemic level of sildenafil in a study of healthy non-HIV infected volunteers (11-fold increase in AUC, see DRUG INTERACTIONS). Based on these pharmacokinetic data, it is recommended not to exceed a maximum single dose of 25 mg of sildenafil citrate in a 48 hour period.
Sildenafil citrate 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 therfore contraindicated.
Simultaneous administration of sildenafil citrate 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 citrate should not be taken within 4 hours of alpha-blocker administration. A 25 mg dose of sildenafil citrate may be taken at any time.
Viagra is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows:
Recommended Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).
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