Adverse Effects of Sildenafil
Sildenafil's adverse effects are predominantly mild to moderate and vasodilation-related, with the most common being headache, flushing, dyspepsia, nasal congestion, and epistaxis. 1, 2
Common Adverse Effects (Vasodilation-Related)
The most frequently reported adverse effects are directly related to the drug's vasodilatory mechanism and include:
- Headache - the most common adverse effect reported across all clinical trials 1, 3, 4
- Flushing (facial redness/warmth) 1, 3, 4
- Dyspepsia (upset stomach/epigastric discomfort) 1, 3, 4, 5
- Nasal congestion and epistaxis (nosebleeds) 1, 3, 4
- Rhinitis 1
These effects are typically transient and mild to moderate in severity, with only approximately 3-4% of patients discontinuing treatment due to adverse effects. 3, 4, 6
Visual Disturbances
Sildenafil can cause visual side effects, though these are generally mild and transient:
- Color-tinge to vision (most common visual effect) 3
- Increased sensitivity to light 3
- Blurred vision 3
- Abnormal vision 1, 4
At doses higher than the recommended 20 mg three times daily for pulmonary arterial hypertension, visual disturbances occur more frequently. 3 The incidence of retinal hemorrhage with sildenafil 20 mg three times daily was 1.4% versus 0% with placebo, though patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy. 3
Serious Adverse Effects
Vision Loss (NAION)
- Nonarteritic anterior ischemic optic neuropathy (NAION) - sudden decrease or loss of vision in one or both eyes has been reported in postmarketing surveillance 3
- Very-low-quality evidence from a study of 4 million veterans showed PDE-5 inhibitors were not associated with increased risk for NAION (relative risk 1.02), but were associated with increased risk for "possible NAION" (relative risk 1.34) 1
Hearing Loss
- Sudden sensorineural hearing loss has been reported in postmarketing surveillance 3
- Emerging evidence indicates PDE-5 inhibitors may be responsible for hearing changes and hearing loss 7
Cardiovascular Events
Serious cardiovascular events reported in postmarketing surveillance include:
- Myocardial infarction 3, 6
- Sudden cardiac death 3
- Ventricular arrhythmia 3
- Cerebrovascular hemorrhage 3
- Transient ischemic attack 3
- Stroke 3
- Hypertension 3
- Pulmonary hemorrhage 3
Most, but not all, of these patients had preexisting cardiovascular risk factors. 3, 6 Many events were reported to occur during or shortly after sexual activity, making it impossible to determine whether they are directly related to sildenafil, sexual activity, underlying cardiovascular disease, or a combination of factors. 3
Hypotension
- Sildenafil alone causes mean peak reductions in systolic/diastolic blood pressure of 10/7 mm Hg that are not dose-related 6
- Severe hypotension can occur when combined with nitrates - this combination is absolutely contraindicated 3, 6
- Incidence of hypotension, orthostatic hypotension, and syncope was <2% and similar to placebo 6
Priapism
- Erections lasting more than 4 hours require immediate medical attention 3
- Priapism was reported infrequently during postmarketing surveillance but was not reported in clinical trials 1, 6
Neurological Effects
- Seizure and seizure recurrence have been reported in postmarketing surveillance 3
Dose-Related Adverse Effects
At doses higher than the recommended 20 mg three times daily for pulmonary arterial hypertension, there is greater incidence of:
Pediatric Considerations
Increased mortality risk in pediatric patients - long-term use in pediatric patients with pulmonary arterial hypertension is associated with increased mortality, particularly at higher doses. 3
Additional Adverse Effects in Specific Populations
In children with pulmonary arterial hypertension, additional adverse effects include:
- Fever 3
- Erection increased 3
- Respiratory infection 3
- Nausea and vomiting 3
- Bronchitis 3
- Pharyngitis 3
- Runny nose 3
- Pneumonia 3
Critical Contraindications and Drug Interactions
- Absolute contraindication with nitrates (nitroglycerin, isosorbide dinitrate) due to synergistic potentiation of vasodilation and potentially life-threatening hypotension 1, 3, 6
- Contraindicated with riociguat due to risk of systemic hypotension 2, 8
- Dose adjustment required with CYP3A4 inhibitors (ritonavir, ketoconazole, erythromycin, cimetidine) due to increased systemic exposure 3, 4
Overall Safety Profile
The overall discontinuation rate due to adverse effects in clinical trials was approximately 3%, which was the same as the placebo group. 3 Most adverse effects are transient, mild to moderate in severity, and related to the drug's vasodilatory mechanism. 1, 4 Long-term studies (up to 1 year) demonstrated maintained tolerability. 4, 6