Viagara Information

Viagara » Technical Information

Basic Information

Viagara
Brand Name:	Viagara
Active Ingredient:	sildenafil citrate
Strength(s):	25mg, 50mg & 100mg
Dosage Form(s):	Oral tablet
Company Name:	Pfizer Inc.
Availability:	Prescription only
Date Approved by FDA:	March 27, 1998

Viagara Molecule

© 1998 PFIZER INC

Description
Viagara™, 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 and has the following structural formula:

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. Viagara (sildenafil citrate) is formulated as blue, film-coated rounded-diamond-shaped tablets equivalent to 25 mg, 50 mg 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 #2 aluminum lake.

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.

Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (>80-fold for PDE1, >1,000- fold for PDE2, PDE3, and PDE4). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because that PDE is involved in control of cardiac contractility. Sildenafil is only about 10-fold as 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 color vision observed with higher doses or plasma levels (see Pharmacodynamics).

Pharmacokinetics and Metabolism
Viagara 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. Both sildenafil and the metabolite have terminal half lives of about 4 hours.

Absorption and Distribution:
Viagara 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 Viagara 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 Viagara (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.

Pharmacodynamics
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 penile plethysmography, after Viagara administration compared with placebo. Most studies assessed the efficacy of Viagara approximately 60 minutes post dose. The erectile response, as assessed by penile plethysmography, 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.

Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Single oral doses of sildenafil (100 mg) produced an average decrease of about 10 mmHg in normals, similar to the effect in patients with ischemic heart disease given 40 mg of sildenafil I.V. Larger but similarly transient effects on blood pressure were recorded among patients receiving concomitant nitrates (see CONTRAINDICATIONS). These effects are possibly related to PDE5 in vascular smooth muscle.

A comprehensive battery of visual function tests was conducted at doses up to twice the maximum recommended dose. Mild, 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. In flexible titration studies of 4 to 26 weeks, 3% of patients on sildenafil reported visual disturbances, described as color tinge or light sensitivity, compared to no such findings in placebo-treated patients.

Clinical Studies
In clinical studies, Viagara 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. Viagara was evaluated primarily at doses of 25 mg, 50 mg 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). Viagara was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. Viagara demonstrated statistically significant improvement compared to placebo in all 21 studies.

The effectiveness of Viagara 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, at 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 endpoints; 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. Both questions were addressed by the patient 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, includeing 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 endpoints, maintenance of erections after penetration, is shown in Figure 1, for the pooled results of 5 fixed dose, dose-response studies of greater than one 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. Figure 1 shows that regardless of the baseline levels of function, subsequent function in patients treated with Viagara 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.

Figure 1.
Effect of Viagara and placebo on maintenance of erection by baseline score.

The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 2. 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, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of Viagara, 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.

Figure 2.
Percentage of Patients Reporting an Improvement in Erections.

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 Viagara 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 Viagara vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on Viagara vs about 20% 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 Viagara 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. Viagara 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 Viagara; all patients, however, were receiving 50 mg or 100 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on Viagara compared to placebo. On a global improvement question, 57% of Viagara patients reported improved erections versus 10% on placebo. Diary data indicated that on Viagara, 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 two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of Viagara. On a global improvement question, 83% of patients reported improved erections on Viagara versus 12% on placebo. Diary data indicated that on Viagara, 59% of attempts at sexual intercourse were successful compared to 13% on placebo.

Across all trials, Viagara 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 Viagara patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of Viagara. Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for Viagara and 29% for placebo.

A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. Viagara 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, trans-urethral resection of the prostate (TURP) and spinal cord injury, and in patients taking anti-depressants/anti-psychotics and anti-hypertensives/diuretics.

Indication and Usage
Viagara is indicated for the treatment of erectile dysfunction. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo.

Contraindications
Use of Viagara 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, Viagara 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.

Precautions
General
A thorough medical history and physical examination should be undertaken to diagnose erectile dysfunction, determine potential underlying causes, and identify appropriate treatment.

There is a degree of cardiac risk associated with sexual activity; therefore, physicians may wish to consider the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction.

Agents for the treatment of erectile dysfunction should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

The safety and efficacy of combinations of Viagara with other treatments for erectile dysfunction have not been studied. Therefore, the use of such combinations is not recommended.

Viagara has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the antiaggregatory effect of sodium nitroprusside (a nitric oxide donor). There is no safety information on the administration of Viagara to patients with bleeding disorders or active peptic ulceration. Therefore, Viagara should be administered with caution to these patients. A minority of patients with the inherited condition retinitis pigmentosa have genetic disorders of retinal phosphodiesterases. There is no safety information on the administration of Viagara to patients with retinitis pigmentosa. Therefore, Viagara should be administered with caution to these patients.

Information for Patients
Physicians should discuss with patients the contraindication of Viagara with concurrent organic nitrates.

The use of Viagara 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.

Drug Interactions
Effects of Other Drugs on Viagara

In vitro studies:
Sildenafil metabolism is principally mediated by the cytochrome P450 (CYP) isoforms 3A4 (major route) and 2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance.

In vivo studies:
Cimetidine (800 mg), a non-specific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with Viagara (50 mg) to healthy volunteers.

When a single 100 mg dose of Viagara 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). Stronger CYP3A4 inhibitors such as ketoconazole, itraconazole or mibefradil 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 co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine). 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 Viagara.

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 non-specific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.

Effects of Viagara on Other Drugs
In vitro studies:
Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 >150 µ M). Given sildenafil peak plasma concentrations of approximately 1 µ M after recommended doses, it is unlikely that Viagara will alter the clearance of substrates of these isoenzymes.

In vivo studies:
No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.
Viagara (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).
Viagara (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.

No interaction was seen when Viagara (100 mg) was co-administered with amlodipine in hypertensive patients. The mean additional reduction on supine blood pressure (systolic, 8 mmHg; diastolic, 7 mmHg) was of a similar magnitude to that seen when Viagara was administered alone to healthy volunteers (see CLINICAL PHARMACOLOGY).

Analysis of the safety database showed no difference in the side effect profile in patients taking Viagara with and without anti-hypertensive medication.

Carcinogenesis, Mutagenesis, 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 Viagara in healthy volunteers.

Pregnancy, Nursing Mothers and Pediatric Use
Viagara 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 non-pregnant 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.

Adverse Reactions
Viagara was administered to over 3700 patients (aged 19-87 years) during clinical trials worldwide. Over 550 patients were treated for longer than one year.

In placebo-controlled clinical studies, the discontinuation rate due to adverse events for Viagara (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 Viagara 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 reflect the recommended dosage regimen, was similar to that for fixed-dose studies.
When Viagara was taken as recommended (on an as-needed basis) in flexible-dose, placebo-controlled clinical trials the following adverse events were reported:

Table 1. Adverse Events Reported by > 2% of patients treated with Viagara and more frequent on drug than placebo in PRN flexible - dose phase II / III studies

Adverse Event	Percentage of Patients Reporting Event
	Viagara N=734	Placebo N=725
Headache	16%	4%
Flushing	10%	1%
Dyspepsia	7%	2%
Nasal Congestion	4%	2%
Urinary Tract Infection	3%	2%
Abnormal Vision†	3%	0%
Diarrhea	3%	1%
Dizziness	2%	1%
Rash	2%	1%

†Abnormal Vision: Mild and transient, predominantly color tinge to vision, but also increased sensitivity to light or blurred vision. In these studies, only one patient discontinued due to abnormal vision.

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.

No cases of priapism were reported.

The following events occurred in <2% of patients in controlled clinical trials; a causal relationship to Viagara is uncertain. Reported events include those with a plausible relation to drug use; omitted are minor events and reports too imprecise to be meaningful:

Body as a whole: face edema, photosensitivity reaction, shock, asthenia, pain, chills, accidental fall, abdominal pain, allergic reaction, chest pain, accidental injury.
Cardiovascular: angina pectoris, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy.

Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, liver function tests abnormal, rectal hemorrhage, gingivitis.

Hemic and Lymphatic: anemia and leukopenia.

Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia.

Musculoskeletal: arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Nervous: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia.

Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, cough increased.

Skin and appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliative dermatitis.

Special senses: mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, deafness, ear pain, eye hemorrhage, cataract, dry eyes.

Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormal ejaculation, genital edema and anorgasmia.

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, Viagara 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, 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.

Viagara 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.

How supplied
Viagara™ (sildenafil citrate) 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 controlled room temperature, 15° to 30°C (59° to 86°F).

CAUTION: Federal law prohibits dispensing without prescription.