Sildenafil

Sildenafil citrate is an oral and intravenous phosphodiesterase type 5 (PDE5) inhibitor. FDA-approved products include Viagra (sildenafil citrate) tablets and Revatio (sildenafil) tablets, oral suspension and injection, with generic equivalents. Doses in FDA labeling are expressed as sildenafil base. Compounded forms include oral capsules, rapid dissolve tablets and topical creams; topical use has no FDA labeling.

• Viagra (oral): treatment of erectile dysfunction in men.
• Revatio (oral and intravenous): treatment of pulmonary arterial hypertension (WHO Group I) in adults, and in pediatric patients 1 to 17 years old.
• Prescribers also use compounded sildenafil preparations for erectile dysfunction when a commercial strength or dosage form does not fit, and topically in women, which is off-label; Viagra labeling states it is not indicated for use in women.

During sexual stimulation, nitric oxide released in the corpus cavernosum activates guanylate cyclase and raises cyclic guanosine monophosphate (cGMP), relaxing smooth muscle and increasing inflow of blood. Sildenafil inhibits PDE5, the enzyme that degrades cGMP, enhancing the effect of nitric oxide; it has no effect without sexual stimulation. PDE5 inhibition in the pulmonary vascular smooth muscle causes pulmonary vasodilation. Weaker inhibition of retinal PDE6 accounts for color-vision changes at higher exposures.

Oral sildenafil is rapidly absorbed (bioavailability about 41%), peaking at a median of 60 minutes fasting; a high-fat meal delays the peak by about 60 minutes and lowers it by about 29%. Protein binding is about 96%.

Sildenafil is cleared mainly by CYP3A4 (major) and CYP2C9 (minor); the N-desmethyl metabolite has about half the parent's PDE5 potency. Terminal half-life is about 4 hours, and metabolites are excreted mostly in feces. Exposure is higher in adults over 65 (free AUC about 40% higher), with hepatic cirrhosis (AUC about 84% higher) and with creatinine clearance below 30 mL/min (AUC about doubled).

• Concomitant use of organic nitrates or nitric oxide donors in any form, regularly or intermittently, including nitroglycerin, isosorbide mononitrate and dinitrate, and amyl or butyl nitrite; sildenafil potentiates their hypotensive effect.
• Concomitant use of guanylate cyclase stimulators such as riociguat, because of the risk of hypotension.
• Known hypersensitivity to sildenafil or any component of the product.

• Cardiovascular: evaluate cardiovascular status before treating erectile dysfunction, since sexual activity carries cardiac risk. Left ventricular outflow obstruction and severely impaired autonomic control of blood pressure increase sensitivity to vasodilators. Recent myocardial infarction, stroke or life-threatening arrhythmia, resting hypotension, uncontrolled hypertension and unstable angina were not studied. ACC/AHA guidance advises at least 24 hours after the last sildenafil dose before an emergency nitrate.
• Priapism: erections lasting more than 4 hours need emergency treatment. Use caution with penile anatomic deformity or conditions predisposing to priapism such as sickle cell anemia, multiple myeloma or leukemia.
• Vision and hearing: sudden vision loss from non-arteritic anterior ischemic optic neuropathy (NAION) and sudden hearing loss have been reported; stop the drug and evaluate promptly. Prior NAION raises recurrence risk. Retinitis pigmentosa has not been studied; use with caution.
• Hypotension with alpha-blockers and other antihypertensives (see Drug Interactions). Combination with other PDE5 inhibitors, including Viagra with Revatio, or with other erectile dysfunction treatments has not been studied and is not recommended.
• Safety in bleeding disorders or active peptic ulcer disease is not known. PAH (Revatio labeling): pulmonary edema may signal pulmonary veno-occlusive disease, where vasodilators are not recommended; vaso-occlusive crises were more frequent in pulmonary hypertension from sickle cell disease; in a long-term pediatric trial, mortality rose with increasing dose.

• Nitrates, nitric oxide donors and riociguat: contraindicated (see Contraindications).
• Alpha-blockers: symptomatic hypotension has occurred; patients should be stable on the alpha-blocker before sildenafil is started at the lowest dose. Other antihypertensives and heavy alcohol use add to blood-pressure lowering.
• CYP3A4 inhibitors: ritonavir raised sildenafil AUC about 11-fold; with ritonavir, Viagra labeling gives 25 mg before sexual activity and a maximum of 25 mg in 48 hours, and Revatio labeling does not recommend strong CYP3A inhibitors. Saquinavir and erythromycin raised AUC about 3-fold, and ketoconazole or itraconazole are expected to raise it more; a 25 mg starting dose is considered. Cimetidine raised concentrations about 56%.
• CYP3A4 inducers such as bosentan, rifampin, carbamazepine and phenytoin lower sildenafil concentrations.

• Erectile dysfunction trials (Viagra): headache and flushing were most common, followed by dyspepsia, abnormal vision (color tinge, light sensitivity, blurring), nasal congestion, back pain, myalgia, nausea, dizziness and rash.
• Pulmonary arterial hypertension trials (Revatio): epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea and rhinitis.
• Postmarketing: serious cardiovascular events (myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage), NAION, sudden hearing loss, priapism, seizure and transient global amnesia; many patients had pre-existing risk factors.

Viagra is not indicated for use in women. Revatio labeling notes that limited data in pregnancy have not shown a clear drug-associated risk of major birth defects or miscarriage, and that untreated pulmonary arterial hypertension in pregnancy carries serious maternal and fetal risk. Limited data show sildenafil and its active metabolite in breast milk at low levels.

Cardiovascular status before treatment; blood pressure and orthostatic symptoms, especially with alpha-blockers; visual or hearing changes; prolonged erection. Review medications for nitrates, riociguat, other PDE5 inhibitors and CYP3A4 inhibitors or inducers. Consider age and hepatic and renal function when selecting a dose.

• Viagra (sildenafil citrate) Tablets Prescribing Information, Viatris Specialty LLC.
• Revatio (sildenafil) Tablets, Oral Suspension and Injection Prescribing Information, Viatris Specialty LLC.
• Cheitlin MD, et al. ACC/AHA Expert Consensus Document: Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology and American Heart Association, 1999.