Mechanism of Action and Pharmacodynamics

An evaluation of visual function at doses up to 200 mg revealed no effects of sildenafil citrate on visual acuity, intraocular pressure, or pupillometry.

• Sildenafil citrate may cause a drop in blood pressure.
• Do not consume large quantities of grapefruit juice while on sildenafil.
• Pregnant or breastfeeding women should not use sildenafil without guidance.
• The drug does not improve libido, only facilitates blood flow.
• It is not intended for recreational use or enhancement.
• Psychological factors can also affect the efficacy of sildenafil.
• Regular medical check-ups are recommended for long-term users.

Sildenafil citrate is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (25% to 63%).

Effectiveness of Sildenafil

Data on other hemodynamic measures for the Sildenafil citrate 20 mg three times a day and placebo dosing regimens is displayed in Table 3. The relationship between these effects and improvements in 6minute walk distance is unknown. mPAP = mean pulmonary arterial pressure; PVR= pulmonary vascular resistance; SVR = systemic vascular resistance; RAP = right atrial pressure; CO = cardiac output; HR = heart rate *The number of patients per treatment group varied slightly for each parameter due to missing assessments. In another study evaluating lower doses of sildenafil 1 mg, 5 mg and 20 mg, there were no significant differences in the effects on hemodynamic variables between doses. 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 8/5 mmHg).

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The decrease in blood pressure was most notable approximately 1 to 2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates. Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg TID to patients with PAH, no clinically relevant effects on ECG were reported.

Postmarketing Experience

After chronic dosing of 80 mg TID sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9 mmHg and 8.4 mmHg, respectively. After chronic dosing of 80 mg TID sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively. After chronic dosing of 80 mg TID sildenafil to patients with PAH, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg). At single oral doses of 100 mg 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. 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%.

Detection in biological fluids

After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6: During the study, there were 42 reported deaths with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing sildenafil citrate doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH.

Interactions that increase your risk for side effects

Clinical studies of sildenafil citrate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. There is no FDA guidance on the use of Sildenafil with respect to specific gender populations. There is no FDA guidance on the use of Sildenafil with respect to specific racial populations.

Treatment & Diagnosis

No dose adjustment is required (including severe impairment CLcr < 30 mL/min). No dose adjustment for mild to moderate impairment is required. There is no FDA guidance on the use of Sildenafil in women of reproductive potentials and males. There is no FDA guidance one the use of Sildenafil in patients who are immunocompromised. FDA Package Insert for Sildenafil contains no information regarding drug monitoring. The mean steady-state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues.

• Sildenafil’s development marked a breakthrough in ED treatment.
• It has revolutionized sexual health for many men globally.
• The drug’s mechanism enhances nitric oxide effects.
• Many patients report improved confidence with sildenafil use.
• Research continues on new formulations and delivery methods.
• Public health campaigns promote safe and effective usage.
• Awareness of contraindications reduces health risks.

Bioequivalence was established between the 20 mg tablet and the 10 mg/mL oral suspension when administered as a 20 mg single oral dose of sildenafil (as citrate).

Ongoing Research and Future Applications

There is limited information about the IV Compatibility. In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities 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 sildenafil products over the counter is not eliminated in the urine. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation.

What are the serious side effects of sildenafil?

In patients with PAH, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation. Studies in vitro have shown that sildenafil is selective for PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina.

Brand Names

This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo. Sildenafil is also marketed as Sildenafil citrate® for erectile dysfunction. Sildenafil citrate, USP 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: Patients on all Sildenafil citrate doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo in a study with no background vasodilators [Study 1 in Clinical Studies (14)]. Sildenafil is cleared predominantly by the CYP3A (major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes.

The major circulating metabolite results from N-desmethylation of sildenafil, and is, itself, further metabolized.

Proper Use

There are no adequate and well-controlled studies of sildenafil in pregnant women. No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m2 basis, 32- and 68-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m2 basis). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sildenafil in women who are pregnant. The safety and efficacy of sildenafil citrate during labor and delivery has not been studied.

Common Side Effects

It is not known if sildenafil or its metabolites are excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when sildenafil citrate is administered to a nursing woman. In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of sildenafil citrate, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%).

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Sixty-two percent of patients were female. The primary objective of the study was to assess the effect of sildenafil citrate on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of sildenafil citrate did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to sildenafil citrate remained on his/her dose of sildenafil citrate or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose sildenafil citrate. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE-5 approximately 50% of the parent drug.

• Sildenafil binds to phosphodiesterase type 5 enzymes in tissues.
• It was initially developed by Pfizer.
• The drug’s patent expired in many countries, increasing generic availability.
• It can improve quality of life for men with ED and pulmonary hypertension.
• Discuss potential interactions and health conditions with your doctor.
• Usage guidelines differ for ED and pulmonary hypertension treatment.
• Follow the prescribed dose and avoid exceeding recommended limits.