Sildenafil - Drug Monograph

Introduction

Sildenafil citrate is a phosphodiesterase type 5 (PDE5) inhibitor first approved by the FDA in 1998 for the treatment of erectile dysfunction. It was later approved for pulmonary arterial hypertension (PAH) under the brand name Revatio. Sildenafil revolutionized the treatment of erectile dysfunction and remains one of the most prescribed medications in its class.

Mechanism of Action

Sildenafil selectively inhibits phosphodiesterase type 5 (PDE5), an enzyme that degrades cyclic guanosine monophosphate (cGMP). In erectile tissue, sexual stimulation causes release of nitric oxide (NO), which activates guanylate cyclase to produce cGMP. Increased cGMP levels lead to smooth muscle relaxation in the corpus cavernosum, allowing increased blood flow and erection. By inhibiting PDE5, sildenafil enhances the effects of cGMP, facilitating erection. In pulmonary hypertension, sildenafil promotes pulmonary vasodilation by the same mechanism.

Indications

• Erectile dysfunction (ED)
• Pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability

Dosage and Administration

• Initial dose: 50 mg taken approximately 1 hour before sexual activity
• Dose range: 25-100 mg based on efficacy and tolerability
• Maximum dosing frequency: Once daily

• Revatio: 20 mg three times daily, 4-6 hours apart
• Tablets should not be split

• Renal impairment: Consider starting dose of 25 mg for ED
• Hepatic impairment: Consider starting dose of 25 mg for ED
• Elderly: Consider starting dose of 25 mg for ED
• Avoid use in patients taking potent CYP3A4 inhibitors

Pharmacokinetics

• Absorption: Rapidly absorbed; time to peak plasma concentration: 30-120 minutes
• Distribution: Volume of distribution: 105 L; protein binding: 96%
• Metabolism: Primarily hepatic via CYP3A4 (major) and CYP2C9 (minor)
• Elimination: Half-life: 4 hours; primarily fecal excretion (80%) with minor renal excretion (13%)
• Food effects: High-fat meal delays Tmax and reduces Cmax by 29%

Contraindications

• Concomitant use of organic nitrates or nitric oxide donors
• History of serious hypersensitivity reaction to sildenafil
• Concomitant use with riociguat
• Severe hepatic impairment
• Hypotension (SBP <90 mmHg)
• Recent history of stroke or myocardial infarction
• Hereditary degenerative retinal disorders

Warnings and Precautions

• Cardiovascular effects: Use with caution in patients with cardiovascular disease. Sexual activity may increase cardiac risk
• Priapism: Prolonged erection (>4 hours) requires immediate medical attention
• Sudden hearing loss: Reports of sudden decrease or loss of hearing
• Vision changes: Non-arteritic anterior ischemic optic neuropathy (NAION) reported
• Pulmonary hypertension: Should not be used in patients with pulmonary veno-occlusive disease
• Hepatic impairment: Use with caution in moderate hepatic impairment
• Renal impairment: Use with caution in severe renal impairment
• Bleeding disorders: Use with caution in patients with bleeding disorders or active peptic ulceration

Drug Interactions

• Nitrates: Contraindicated - profound hypotension
• Alpha-blockers: Additive hypotension; separate dosing by 4 hours
• CYP3A4 inhibitors: Increased sildenafil exposure (ketoconazole, ritonavir, erythromycin)
• CYP3A4 inducers: Decreased sildenafil efficacy (rifampin, carbamazepine)
• Antihypertensives: Additive hypotensive effects
• Riociguat: Contraindicated due to risk of hypotension

Adverse Effects

• Headache (16%)
• Flushing (10%)
• Dyspepsia (7%)
• Nasal congestion (4%)
• Back pain (3%)
• Myalgia (3%)
• Visual disturbances (3%)

• Myocardial infarction
• Sudden hearing loss
• Vision loss (NAION)
• Priapism
• Severe hypotension
• Seizures

Monitoring Parameters

• Blood pressure and heart rate (especially with concomitant antihypertensives)
• Visual changes
• Hearing changes
• Cardiovascular status in at-risk patients
• Efficacy assessment for intended indication
• Adverse effect profile

Patient Education

• Take approximately 1 hour before sexual activity (for ED indication)
• Sexual stimulation is required for medication to work
• Do not take more than once daily
• Avoid high-fat meals before taking medication
• Seek immediate medical attention for erection lasting >4 hours
• Report any visual or hearing changes promptly
• Do not take with nitrates under any circumstances
• Inform all healthcare providers about sildenafil use
• Store at room temperature away from moisture

References

1. Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med. 1998;338(20):1397-1404. 2. FDA Prescribing Information: Viagra (sildenafil citrate) tablets. Revised 2014. 3. Galiè N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353(20):2148-2157. 4. Jackson G, Montorsi P, Cheitlin MD. Cardiovascular safety of sildenafil citrate (Viagra): an updated perspective. Urology. 2006;68(3 Suppl):47-60. 5. Muirhead GJ, Rance DJ, Walker DK. The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil. Br J Clin Pharmacol. 2002;53 Suppl 1:21S-30S. 6. Pfizer Laboratories. Revatio (sildenafil) prescribing information. Revised 2021.