Brand names: Revatio, Viagra
Drug class: Phosphodiesterase Type 5 Inhibitors
VA class: GU900
Chemical name: 2-Hydroxy-1,2,3-propanetricarboxylate-1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d-pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methyl-piperazine
Molecular formula: C₂₂H₃₀N₆O₄S•C₆H₈O₇
CAS number: 171599-83-0

Medically reviewed by Drugs.com on Mar 29, 2023. Written by ASHP.

Introduction

Vasodilating agent; a selective phosphodiesterase (PDE) type 5 inhibitor.

Uses for Sildenafil

Erectile Dysfunction (ED)

To facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence).

Most experts currently recommend that selective PDE type 5 inhibitors be offered as first-line therapy for ED unless contraindicated. Insufficient evidence to support the superiority of one selective PDE type 5 inhibitor over another.

Sexual Dysfunction in Women

Has been used for the management of sexual dysfunction in women^{† [off-label]}; however, additional study needed to establish role, if any, of such therapy.

Although sildenafil may improve physiologic response (e.g., increased blood flow to sexual organs), such changes have not been associated with overall improvement in sexual dysfunction in women.

Also has been used in women with sexual dysfunction induced by SSRI antidepressants and in women with neurogenic sexual dysfunction (e.g., due to spinal cord injury or multiple sclerosis); however, data limited.

Pulmonary Arterial Hypertension (PAH)

Symptomatic management of PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity and delay clinical worsening.

Parenteral preparation used for continued treatment in patients with PAH who are temporarily unable to take oral medication.

Efficacy established principally in patients with NYHA/WHO functional class II–III PAH (idiopathic or associated with connective tissue diseases).

Recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy has failed. Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.

In patients with inadequate response to initial monotherapy, may consider combination therapy with a prostanoid or endothelin-receptor antagonist (added sequentially). By targeting different pathophysiologic pathways of the disease, such combination therapy may provide additive and/or synergistic benefits.

Because increased mortality has been observed in children receiving higher (more effective) dosages of sildenafil, FDA currently does not recommend use of the drug in patients <18 years of age. (See Pediatric Use under Cautions.) Whether long-term sildenafil therapy has a beneficial effect on mortality in adults remains to be established.

Sildenafil Dosage and Administration

General

ED

• Carefully individualize dosage according to the patient’s tolerance and erectile response.

• Sexual stimulation is required for response to therapy.

Administration

Administer orally or IV.

Oral Administration

ED

Administer orally about 1 hour (range: 4 hours to 30 minutes) before sexual activity.

Administration with a high-fat meal may delay the onset of action.

PAH

Administer orally (as tablets or oral suspension) without regard to meals.

If a dose is missed, take missed dose as soon as it is remembered, then resume regular dosing schedule; do not double dose to replace missed dose.

Reconstitution of Oral Suspension

To reconstitute powder for oral suspension, tap bottle to release the powder. Add 60 mL of water to the bottle; recap and shake vigorously for at least 30 seconds. Add another 30 mL to bottle, recap and shake for at least 30 seconds; add a total of 90 mL of water to the bottle regardless of dose. The reconstituted suspension (112 mL) contains sildenafil 10 mg/mL.

Use provided bottle adapter to fill 2-mL oral syringe (with 0.5- and 2-mL dose markings) with the reconstituted suspension.

IV Administration

PAH

May administer by direct IV injection in patients who temporarily cannot take oral medication.

Dosage

Available as sildenafil citrate; dosage expressed in terms of sildenafil.

Adults

ED

Oral

Initially, 50 mg as a single dose no more than once daily. Depending on effectiveness and tolerance, increase dosage to a maximum of 100 mg once daily or decrease to 25 mg once daily.

PAH

Oral

5 or 20 mg 3 times daily. No additional benefit with higher dosages.

IV

2.5 or 10 mg 3 times daily by direct IV injection.

Prescribing Limits

Adults

ED

Oral

Maximum 100 mg daily.

PAH

Oral

Dosages up to 80 mg 3 times daily not more effective than recommended dosage of 20 mg 3 times daily.

Special Populations

Hepatic Impairment

ED

Oral

Reduce initial dose to 25 mg.

PAH

Oral

Mild to moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustments necessary.

Severe hepatic impairment (Child-Pugh class C): Not studied.

Renal Impairment

ED

Oral

Cl_cr <30 mL/minute: reduce initial dose to 25 mg.

PAH

Oral

No dosage adjustment needed, even with severe impairment (Cl_cr <30 mL/minute).

Geriatric Patients

ED

Reduce initial dose to 25 mg in men ≥65 years of age.

PAH

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions for Sildenafil

Contraindications

• Known hypersensitivity to sildenafil or any ingredient in the formulation.

• Concomitant use of organic nitrates or nitrites. Concomitant use of riociguat. (See Specific Drugs under Interactions.)

• Do not use for treatment of ED in men for whom sexual activity is inadvisable because of underlying cardiovascular status.

Warnings/Precautions

Warnings

Cardiovascular Effects

Serious, potentially fatal cardiovascular effects reported rarely.

Use with caution in the treatment of ED in patients with a recent (within 6 months) MI, stroke, or life-threatening arrhythmia; in patients with resting hypotension (BP <90/50 mm Hg) or hypertension (BP >170/110 mm Hg); or in patients with cardiac failure or CAD causing unstable angina. Assess cardiovascular and cerebrovascular status (including use of organic nitrates and nitrites) prior to initiating therapy.

Symptomatic hypotension may occur in patients receiving concomitant α-adrenergic blocking agents; hypotension may be severe or fatal in patients receiving an organic nitrate or nitrite concomitantly. (See Specific Drugs under Interactions.)

Consider whether patients with underlying cardiovascular disease (e.g., severe left ventricular outflow obstruction, autonomic dysfunction, resting hypotension [BP <90/50 mm Hg], fluid depletion) could be adversely affected by sildenafil’s vasodilatory activity, especially in combination with sexual activity.

Use not recommended in patients with pulmonary veno-occlusive disease. Clinical data on use in this population are not available, and pulmonary vasodilators may worsen cardiovascular status of such patients. If pulmonary edema occurs during sildenafil therapy, consider the possibility of pulmonary veno-occlusive disease.

Vaso-occlusive crisis requiring hospitalization reported in patients with pulmonary hypertension secondary to sickle cell disease who received sildenafil. Efficacy and safety of sildenafil in patients with sickle cell anemia not established.

Ocular Effects

Nonarteritic anterior ischemic optic neuropathy (NAION) reported rarely in patients receiving PDE type 5 inhibitors for the treatment of ED. Potential increased risk of NAION in the second eye in patients who already have had NAION in one eye.

Possible visual disturbances (e.g., blue/green vision, changes in light sensitivity), particularly at high doses. Possible persistent and/or serious retinal changes in older patients or with long-term use.

Use with caution in patients with retinitis pigmentosa. Periodically monitor retinal function in patients with ocular manifestations suggestive of retinal effects and in those at risk.

Otic Effects

Sudden decrease or loss of hearing reported with all PDE type 5 inhibitors, including sildenafil. Adverse otic effects (e.g., deafness, otic pain, tinnitus) observed in a few patients in controlled clinical trials. In at least 1 case, permanent, bilateral sensorineural deafness occurred.

Although not clear whether such effects are directly related to PDE type 5 inhibitors or to other factors (e.g., patient’s underlying medical condition, concomitant use of other ototoxic drugs), a strong temporal relationship has been observed.

Priapism

Possible prolonged (>4 hours) erections and priapism (painful erection >6 hours).

May result in penile tissue damage and permanent loss of potency if priapism is not treated immediately. Use with caution in patients with conditions predisposing to priapism (e.g., sickle cell anemia, multiple myeloma, leukemia).

Interactions with Potent CYP3A4 Inhibitors

Concomitant use with potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, ritonavir) substantially increases serum sildenafil concentrations. Depending on the particular use of sildenafil (e.g., ED, PAH) and the specific CYP3A4 inhibitor, concomitant use may not be recommended or precautions (e.g., dosage adjustments) may be required. (See Specific Drugs under Interactions.)

General Precautions

Assessment of Patients with ED

Thorough medical history and physical examination recommended to diagnose ED, determine potential underlying causes, exclude potentially reversible or treatable causes, and identify appropriate treatment.

Review of patient’s current drug regimens recommended to detect possible drug-induced ED.

Hypotensive Effects

Possible hypotensive reaction in patients receiving concomitant antihypertensive therapy, in patients with CHF and a borderline low blood volume and low BP status, and in patients with left-ventricular outflow obstruction. (See Specific Drugs under Interactions.) Monitor BP during initiation of therapy in these patients.

Bleeding Disorders

Use with caution in patients with bleeding disorders or active peptic ulcers.

Incidence of epistaxis in sildenafil-treated patients is higher in those with PAH secondary to connective tissue disease (13%) than in those with primary pulmonary hypertension (3%).

GU Precautions

Use with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie’s disease).

Concomitant Therapies for ED

Safety and efficacy not established for use in combination with other treatments for ED; combined therapy is not recommended.

Specific Populations

Pregnancy

Category B.

Lactation

Not known whether sildenafil is distributed into milk. Use with caution in nursing women.

Pediatric Use

Manufacturer states that safety and efficacy not established in children. Although sildenafil has been used effectively in a limited number of children^{† [off-label]} for symptomatic treatment of PAH, FDA currently recommends that the drug not be used for treatment of PAH in patients <18 years of age. However, FDA states that there may be situations in which the risk-benefit profile may be acceptable in individual children (e.g., when other treatment options are limited and sildenafil can be used with close monitoring).

Increased risk of mortality observed in children receiving high dosages of sildenafil that also are the most effective dosages in this population. Deaths were related to disease progression in most cases.

Geriatric Use

Pooled clinical trial data indicate that efficacy in men ≥65 years of age with ED is similar to that in younger men. Decreased clearance and increased plasma concentrations may increase incidence of adverse effects in geriatric patients with ED. (See Geriatric Patients under Dosage and Administration.)

Insufficient data from clinical trials to determine whether geriatric patients with PAH respond differently than younger adults, but other clinical experience has not identified overall differences in response relative to younger patients.

Select dosage carefully due to greater frequency of decreased renal, hepatic, and/or cardiac function and of concomitant disease or drug therapy observed in geriatric patients.

Hepatic Impairment

Decreased clearance. (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Decreased clearance in patients with severe renal impairment. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

ED: Headache, flushing, dyspepsia/heartburn.

PAH: Headache, dyspepsia, flushing, epistaxis, insomnia, exacerbated dyspnea, diarrhea, myalgia, erythema, pyrexia.

Interactions for Sildenafil

Metabolized principally by CYP3A4 and to some extent by CYP2C9; weakly inhibits CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4 and CYP2C9: Potential pharmacokinetic interaction (increased plasma sildenafil concentrations).

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma sildenafil concentrations).

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4: Potential pharmacokinetic interaction (increased substrate concentrations).

Specific Drugs

Sildenafil Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed following oral administration; however, only about 40% of a dose reaches systemic circulation unchanged.

Peak plasma concentration usually attained within 30–120 minutes.

Duration

Erectile responsiveness: Approximately 2 hours.

Onset

Erectile responsiveness: 14–20 minutes, self-recorded in the home setting.

Food

Administration with a high-fat meal delays GI absorption; peak plasma concentrations reduced by about 30% and time to peak plasma concentration delayed by about 60 minutes.

Distribution

Extent

Appears to be widely distributed in the body.

Distributed to a limited extent in semen, but such concentrations are unlikely to cause any effects in sexual partners.

Plasma Protein Binding

Approximately 96%.

Elimination

Metabolism

Undergoes extensive metabolism in GI mucosa during absorption and on first pass through liver.

Metabolized in the liver principally by CYP3A4 and to a lesser extent by CYP2C9.

Elimination Route

Excreted as metabolites in the feces (approximately 80%) and urine (approximately 13%).

Half-life

Biphasic; terminal elimination half-life about 4 hours.

Special Populations

Clearance in patients ≥65 years of age is reduced compared with that in younger adults.

In patients with severe renal impairment (Cl_cr <30 mL/minute), clearance was reduced resulting in a two-fold increase in AUC and peak plasma concentrations compared with values in healthy adults. Pharmacokinetics not altered in mild to moderate renal impairment.

Reduced clearance in patients with hepatic cirrhosis (Child-Pugh class A or B). Not studied in severe hepatic impairment (Child-Pugh class C).

Stability

Storage

Oral

For Suspension

<30°C in original package to protect from moisture. After reconstitution, store at <30°C or in refrigerator (2–8°C); do not freeze. Discard any remaining oral suspension 60 days after reconstitution.

Tablets

25°C (may be exposed to 15–30°C).

Parenteral

Injection

25°C (may be exposed to 15–30°C).

Actions

• Selective inhibitor of PDEs, with a great selectivity for PDE type 5, the principal isoenzyme involved in the metabolism of cGMP to GMP in the corpora cavernosa of the penis and clitoris.

• No direct relaxant effect on isolated human corpora cavernosa of the penis, but enhances the effect of nitric oxide by inhibiting PDE type 5-mediated hydrolysis of cGMP.

• Potentiates accumulation of cGMP only when cGMP production in the penis is increased by sexual arousal. No effect on erectile function in the absence of sexual stimulation.

• Modest peripheral vasodilation at usual dosages. In patients with pulmonary hypertension, induces vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilation in the systemic circulation. In such patients, pulmonary and systemic vascular resistance and resting arterial pressure are decreased, allowing an increase in cardiac output. Vasodilation and decreases in BP probably result from inhibition of PDE type 5 present in vascular smooth muscle.

• Because sildenafil can increase ocular cGMP concentrations via inhibition of PDE type 6, can produce transient visual abnormalities (mainly color-tinged vision, increased light perception, and blurred vision), particularly at doses >100 mg.

Advice to Patients

• Importance of informing clinicians if risk factors for cardiovascular disease are present prior to initiating any treatment for ED.

• Importance of informing clinician of any history of stroke, presence of low or high BP, blood diseases (e.g., sickle cell anemia, leukemia), or presence of retinitis pigmentosa or history of severe vision loss.

• Possibility of visual disturbances (e.g., blue/green vision, changes in light sensitivity), particularly at high doses, and of possible impairment of ability to perform tasks such as piloting a plane or operating a motor vehicle.

• Potential for sudden vision loss or decreased vision (i.e., nonarteritic ischemic optic neuropathy [NAION]). If NAION already has occurred in one eye, risk of NAION developing in the second eye may be increased.

• Importance of informing patients to refrain from further activity and contact their clinician if symptoms (e.g., angina pectoris, dizziness, nausea) occur upon initiation of sexual activity.

• Importance of informing patients of the potential for life-threatening hypotension and/or hemodynamic compromise with concurrent use of organic nitrates and nitrites in any form, including the recreational use of inhaled nitrites (“poppers”).

• Importance of informing patients that doses of sildenafil >25 mg should not be taken within 4 hours of administration of an α-adrenergic blocking agent.

• Importance of taking the drug exactly as prescribed and not exceeding recommended doses or frequency of use.

• Importance of seeking immediate medical attention if an erection persists longer than 4 hours or is extremely painful.

• Importance of immediately contacting a clinician if sudden loss of vision or decreased vision occurs in one or both eyes.

• Potential for transmission of sexually transmitted diseases and the possible need to use protective measures to guard against such transmission.

• Importance of contacting a clinician for assessment of therapeutic benefit, the need for possible dosage adjustment, and potential adverse effects.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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