What are the recommended doses, contraindications, precautions, and common adverse effects of sildenafil for erectile dysfunction and pulmonary arterial hypertension in adult patients?

Sildenafil: Dosing, Contraindications, Precautions, and Adverse Effects

Recommended Dosing

For Pulmonary Arterial Hypertension (PAH)

The FDA-approved dose for PAH is 20 mg orally three times daily (TID), with dose titration up to 80 mg TID permitted for inadequate responders. 1, 2

• Start at 20 mg TID as the standard initial dose for adults with PAH 3, 1
• If clinical response is inadequate after proper trial, titrate in 20 mg increments up to a maximum of 80 mg TID 3
• The 2024 randomized multicenter trial demonstrated that 80 mg TID was noninferior to lower doses for mortality and superior for time to clinical worsening and 6-minute walk distance 2
• The FDA recently revoked approval of the 5 mg dose and reinforced 20 mg TID as the recommended starting dose, with titration to 80 mg TID now officially permitted 2
• When adding sildenafil to stable IV epoprostenol, start at 20 mg every 8 hours and titrate up to 80 mg every 8 hours over 8 weeks 3

For Erectile Dysfunction

• Start at 50 mg taken as needed approximately 1 hour before sexual activity, no more than once daily 4
• Maximum dose is 100 mg once daily 4
• Lower doses of 25 mg may be used in elderly patients, those with hepatic or renal impairment, or those receiving CYP3A4 inhibitors (ritonavir, saquinavir, ketoconazole, erythromycin, cimetidine) 4

Absolute Contraindications

Sildenafil is absolutely contraindicated with any nitrate medication due to synergistic vasodilation causing potentially life-threatening hypotension. 3, 5, 1

• Never combine sildenafil with organic nitrates including nitroglycerin (any form), isosorbide mononitrate/dinitrate, or amyl nitrate/nitrite ("poppers") 1
• Nitrates must not be taken within 24 hours after sildenafil use 5
• Sildenafil must not be taken within 24 hours after nitrate use 5
• The interaction amplifies cGMP accumulation and has been associated with profound hypotension, myocardial infarction, and death 5
• Do not administer with riociguat due to hypotension risk 3
• Contraindicated in patients with known hypersensitivity to sildenafil or any component 1

Precautions and Warnings

Cardiovascular Risks

• Use caution when combining with antihypertensive medications, as sildenafil causes additive blood pressure-lowering effects that may lead to symptomatic hypotension 5
• In PAH patients on chronic sildenafil 80 mg TID, systemic blood pressure fell by only approximately 2 mmHg, much less than the 8/5 mmHg reduction in healthy volunteers 5
• Postmarketing reports include myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, and hypertension in temporal association with sildenafil use, though causality is uncertain 1

Vision and Hearing Loss

• Advise patients to seek immediate medical attention for sudden vision loss in one or both eyes, as this may indicate non-arteritic anterior ischemic optic neuropathy (NAION) 1
• Very-low-quality evidence from 4 million veterans showed PDE-5 inhibitors were associated with increased risk for "possible NAION" 3
• Seek prompt medical attention for sudden hearing loss, which may be accompanied by tinnitus and dizziness 1

Hemorrhagic Events

• Retinal hemorrhage occurred in 1.4% of patients on 20 mg TID versus 0% on placebo 1
• Patients experiencing hemorrhagic reactions had risk factors including concurrent anticoagulant therapy 1

Other Serious Adverse Events

• Priapism (erections lasting >4 hours) requires immediate medical attention 3
• Risk of vaso-occlusive crisis in patients with sickle cell disease 1
• Seizure and seizure recurrence reported in postmarketing surveillance 1

Special Populations

• Sildenafil is not approved for use in children due to pediatric mortality concerns 1
• Pregnancy category: Unknown if sildenafil harms the unborn baby; discuss risks versus benefits 1

Common Adverse Effects

Headache is the most common adverse effect, occurring in 34-57% of patients, related to the drug's vasodilatory mechanism. 3, 5

Most Frequent Side Effects (All Vasodilation-Related)

• Headache: 34-57% of patients 5
• Flushing (facial redness/warmth) 3
• Dyspepsia (epigastric discomfort) 3
• Nasal congestion and epistaxis (nosebleeds) 3
• Rhinitis 3
• Abnormal vision (color-tinge, increased light sensitivity, blurred vision) - mild and transient 1, 4

Tolerability Profile

• Most adverse effects are transient, mild to moderate in severity 3
• Overall discontinuation rate due to adverse effects is approximately 3% in clinical trials 3, 1
• At doses higher than 20 mg TID, greater incidence of flushing, diarrhea, myalgia, and visual disturbances occurs 1
• When combined with IV epoprostenol, sildenafil causes more headaches and dyspepsia 3
• Adverse event-related drug discontinuations were numerically higher with 80 mg TID 2

Critical Clinical Pitfalls to Avoid

• Do not assume the FDA-approved 20 mg TID dose is optimal for all patients—titration up to 80 mg TID is now supported for inadequate responders 3, 2
• Do not use sildenafil tablets 20 mg (for PAH) concurrently with sildenafil citrate 25/50/100 mg (for erectile dysfunction) or other PDE-5 inhibitors 1
• Do not add tadalafil on background bosentan therapy, as data do not support additional benefit of this specific combination 3
• Do not add a second PAH-specific drug without first ensuring adequate trial of initial monotherapy at optimal doses 3
• Avoid taking sildenafil with large or high-fat meals, as this can reduce drug efficacy 6

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