ADVERSE REACTIONS

Note: n = 52, 56, 55, 54, 56, and 56

• The future of sildenafil includes research into new therapeutic areas.
• Investigations are ongoing for its use in heart failure with preserved ejection fraction.
• Studies examine its potential benefits in Alzheimer's disease and vascular dementia.
• Its application in jet lag and sleep cycle disorders is being explored.
• Research continues for its use in various forms of female sexual dysfunction.
• Novel delivery systems, like microneedle patches, are in preclinical development.
• Combination therapies with other agents for enhanced effect are being tested.
• The search for more selective PDE5 inhibitors with fewer side effects continues.
• Genetic factors influencing drug response are an area of pharmacogenomic research.
• Sildenafil remains a valuable tool for basic research in vascular biology.
• Its story is a continuing one of scientific discovery and application.

placebo patients for PVRI, mPAP, CI, SVRI, RAP and HR, respectively.

Effects of Sildenafil Citrate on Blood Pressure Single

• Sildenafil may be less effective in men with certain health conditions like diabetes.
• Be aware of potential vision changes, such as blue-tinted vision.
• Discontinue use and consult a doctor if adverse reactions occur.
• Sildenafil can cause priapism, a painful prolonged erection needing urgent care.
• Safe sexual activity depends on your overall cardiovascular health.

oral doses of sildenafil 100 mg administered to healthy volunteers produced decreases in supine blood pressure (mean

5.3 Epistaxis

Most Common Adverse Reactions in Patients Treated with sildenafil tablets 20 mg, 40 mg, 80 mg and Placebo three times per day in SUPER-1 (More Frequent in sildenafil-Treated Patients than Placebo-Treated Patients) In a placebo-controlled fixed dose titration study (PACES-1) of sildenafil citrate (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, no new safety issues were identified except for edema, which occurred in 25% of subjects in the combined sildenafil citrate + epoprostenol group compared with 13% of subjects in the epoprostenol group [see Clinical Studies (14)]. In a study to assess the effects of multiple doses of sildenafil citrate on mortality in adults with PAH (StudyA1481324), the lower dose 5 mg TID group showed a higher observed number of deaths (all related to underlying disease/disease under study), serious adverse events, and severe adverse events than the 20 mg and 80 mg TID groups [see Clinical Studies (14)]. Overall, the safety data for sildenafil 80 mg TID dose in Study A1481324 was consistent with the established safety profile of sildenafil in previous adult PAH studies. Sildenafil citrate was studied in a total of 234 PAH pediatric patients 1 to 17 years of age in a 16-week, double-blind placebo-controlled study (STARTS-1); 220 patients continued in a longterm extension study (STARTS-2). Erection increased was observed in 9% of patients treated with sildenafil in STARTS-1.

Warnings for other groups

No other new adverse reactions were identified in pediatric patients [see Use in Specific Populations (8.4)]. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these or other factors. NAION [see Warnings and Precautions (5.4), Patient Counseling Information (17)]. Concomitant use of sildenafil citrate with nitrates in any form is contraindicated [see Contraindications (4)] . Strong CYP3A Inhibitors Concomitant use of sildenafil citrate with strong CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Moderate-to-Strong CYP3A Inducers Concomitant use of Sildenafil citrate with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of sildenafil citrate may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of sildenafil tablets to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. Risk Summary Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, chew sildenafil miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations). maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg).

The decrease in blood pressure was most notable approximately 1 to 2

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Sildenafil tablets, USP, phosphodiesterase-5 (PDE-5) inhibitor, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE-5). Sildenafil is also marketed as VIAGRA® for erectile dysfunction. Sildenafil citrate, USP is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1 H-pyrazolo [4,3- d] pyrimidin-5-yl)-4- ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate and has the following structural formula: Sildenafil citrate, USP 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. Sildenafil Tablets USP: Sildenafil sildenafil products over the counter citrate is formulated as white, film-coated round tablets for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, hypromellose, microcrystalline cellulose, sodium stearyl fumarate, titanium dioxide and triacetin.

Sildenafil side effects

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 PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-times as potent for PDE5 compared to PDE6, an enzyme found in the retina and involved in the phototransduction pathway of the retina. Effects of Sildenafil Citrate on Hemodynamic Measures 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 [see SUPER-1 in Clinical Studies (14)]. Data on other hemodynamic measures for the sildenafil tablets 20 mg three times a day and placebo dosing regimens is displayed in Table 2. hours after dosing and was not different from placebo at 8 hours.

• Myths and misconceptions about sildenafil are common and should be addressed.
• It is not a "party drug" or aphrodisiac; it requires sexual stimulation to work.
• It does not cause spontaneous erections without sexual arousal.
• More is not always better; higher doses increase side effect risk, not pleasure.
• It is not addictive, but psychological dependence on its use can develop.
• It does not permanently cure erectile dysfunction; effects are temporary.
• It is not safe to use just because it is widely available or discussed.
• Herbal "natural Viagra" products are not regulated and can be dangerous.
• It does not protect against sexually transmitted infections or prevent pregnancy.
• It is not approved or proven to enhance sexual performance in men without ED.
• Accurate information from a healthcare provider is essential.

Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses

• Sildenafil interacts with nitrate medications, causing dangerous drops in blood pressure.
• Store sildenafil in a cool, dry place away from children.
• 20mg is often recommended as a starting dose for ED treatment.
• Food, especially high-fat meals, can delay its onset of action.
• Regular use can improve erectile response over time if prescribed.

of sildenafil, therefore the effects are not related

Highlights of Prescribing Information

Changes from Baseline in Hemodynamic Parameters at Week 12 [mean (95% CI)] for the Sildenafil Tablets 20 mg Three Times a Day and Placebo Group 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. Patients on sildenafil tablets medium and high dose groups achieved a dose related improvements in pulmonary vascular resistance index (PVRI) and mean pulmonary arterial pressure (mPAP) compared to those on placebo [see STARTS-1 in Clinical Studies (14)]. Improvements were observed with cardiac index in all three sildenafil tablets dose groups over placebo. Data on other hemodynamic measures for the sildenafil tablets low, medium and high dose groups compared to placebo is displayed in Table 3. Placebo Corrected Changes in Hemodynamic Parameters by Dose Group Abbreviations: CI = cardiac index; HR = heart rate; mPAP = mean pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; RAP = right atrial pressure; SVRI = systemic vascular resistance index. to dose or plasma levels within this dosage range.

INFORMATION ABOUT SILDENAFIL

Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32-and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death. Data Animal Data 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 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day.

5.5 Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives

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). Risk Summary Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. Limited clinical data during lactation preclude a clear determination of the risk of sildenafil citrate to an infant during lactation. The safety and efficacy of Sildenafil citrate have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underly improvements in exercise Use of sildenafil citrate for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1), Clinical Studies (14)]. The safety and effectiveness of sildenafil citrate have not been established in pediatric patients younger than 1 year of age.

Less common

During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies(14)], an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324). Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients >45 kg up to a maximum of 40 mg three times a day. Clinical studies of sildenafil citrate did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.