13 NONCLINICAL TOXICOLOGY

VIAGRA was administered to more than 3,000 patients aged 19 to 87 years, with

Sildenafil (Viagra®) 100 mg Price Example

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. Given sildenafil peak plasma concentrations of approximately 1 µM after recommended doses, it is unlikely that VIAGRA will alter the clearance of substrates of these isoenzymes. 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. VIAGRA (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg). ED of various etiologies (organic, psychogenic, mixed)

• Men on sildenafil should avoid grapefruit or grapefruit juice.
• Sildenafil 10mg is less likely to cause side effects compared to higher doses.
• Regular exercise and healthy lifestyle can improve erectile function.
• Sildenafil has been in use for over two decades with proven safety.
• Patients should consult a healthcare provider if unsure about dosage.

with a mean duration of 5 years.

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VIAGRA demonstrated statistically significant improvement compared to placebo in all 21 studies.

Condition	Risk Factors	Recommendations
Use with nitrates	Severe hypotension, risk of significant blood pressure drop	Avoid combining, consult healthcare provider
Severe cardiovascular disease	Risk of adverse cardiovascular events	Use only under medical supervision
Liver impairment	Altered metabolism, increased side effects	Dose adjustment or avoid use
Retinitis pigmentosa	Potential for increased visual side effects	Use with caution, consult ophthalmologist

The studies that established benefit demonstrated improvements in

Frequently asked questions

An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of VIAGRA on visual acuity, intraocular pressure, or pupillometry. VIAGRA is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25–63%). The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) 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.

Professional resources

Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below: Figure 5: Mean Sildenafil Plasma Concentrations in Healthy Male Volunteers. Absorption and Distribution: VIAGRA is rapidly absorbed. When VIAGRA 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%. 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. success rates for sexual intercourse compared with placebo.

8.6 Patients with Hepatic Impairment

The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [see Dosage and Administration (2.5), and Use in Specific Populations (8.7)]. 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 (2.5)]. Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with VIAGRA (50 mg) to healthy volunteers.

The Bottom Line

When a single 100 mg dose of VIAGRA was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil Cmax and a 182% increase in sildenafil AUC. In addition, in a study performed in healthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Viagra (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Viagra had no effect on saquinavir pharmacokinetics. A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole could be expected to have greater effect than that seen with saquinavir. Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [see Dosage and Administration (2.4) and Drug Interactions (7.4)]. The effectiveness of VIAGRA was evaluated

Warnings & Precautions

In another study in healthy male volunteers, co-administration with sildenafil 100mg blue pill the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with VIAGRA (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. VIAGRA had no effect on ritonavir pharmacokinetics [see Dosage and Administration (2.4) and Drug Interactions (7.4)]. Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels.

Can vardenafil and sildenafil be taken together?

In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of CYP2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil Cmax. Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil. Single doses of antacid (magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability of VIAGRA. In healthy male volunteers, there was no evidence of a clinically significant effect of azithromycin (500 mg daily for 3 days) on the systemic exposure of sildenafil or its major circulating metabolite. 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. in most studies using several assessment instruments.

Dosage	Recommended Use	Onset of Action	Duration of Effect	Typical Frequency
10 mg	Mild to moderate ED cases	30-60 minutes	Up to 4-6 hours	Once per day, as needed
20 mg	Moderate to severe ED	30-60 minutes	Up to 4-6 hours	Once per day, as needed
5 mg	For elderly or sensitive users	30-60 minutes	Up to 4 hours	Once per day, as needed

The primary measure in the principal studies was a sexual

• The pill should be swallowed whole with water.
• Use caution if you have liver or kidney disease.
• Synergistic effects can occur with other blood pressure medications.
• Sildenafil is not a sexual stimulant; stimulation is required.
• Always read the patient information leaflet thoroughly before use.

function questionnaire (the International Index of Erectile Function - IIEF)

Proper Use

Sildenafil at steady state, at a dose not approved for the treatment of erectile dysfunction (80 mg t.i.d.) resulted in a 50% increase in AUC and a 42% increase in Cmax of bosentan (125 mg b.i.d.). 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 20- and 38- 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 0.4 times the MRHD on a mg/m2 basis in a 50 kg subject. In clinical studies, VIAGRA 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. VIAGRA 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). administered during a 4-week treatment-free run-in period, at baseline, at

Side Effect	Severity	Likelihood	Management Tips
Headache	Mild to moderate	Common	Mild analgesics, hydration
Flushing	Mild	Common	Cool environment, stay hydrated
Nasal congestion	Mild	Moderately common	Decongestants if necessary
Dizziness	Mild	Possible	Avoid sudden movements
Visual disturbances	Mild	Rare	Rest and monitor if occurs

follow-up visits, and at the

• The medication can be part of a treatment plan for ED.
• Do not share sildenafil with others, even if they have similar symptoms.
• Taking sildenafil on an empty stomach may increase effectiveness.
• Be aware of possible allergic reactions, such as rash.
• Follow-up with your healthcare provider regularly when using sildenafil.

end of double-blind, placebo-controlled, at-home treatment.

2.1 Recommended Dosage in Adults

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.

Sildenafil Tablets or Oral Suspension for PAH

Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18–45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [see Dosage and Administration (2.5), and Use in Specific Populations (8.5)] Renal Impairment: 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 VIAGRA (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 [see Dosage and Administration (2.5), and Use in Specific Populations (8.6)]. In addition, N-desmethyl metabolite AUC and Cmax values significantly increased by 200% and 79%, respectively in subjects with severe renal impairment compared to subjects with normal renal function. Hepatic Impairment: In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment.