Note: Contraindicated in patients taking nitrates (regularly or intermittently) due to potentially severe hypotension. If a patient taking sildenafil develops chest pain, delay therapy with a nitrate for 24 hours. For patients taking an alpha-blocking antihypertensive agent, use sildenafil with caution and consider a lower starting dose, as sildenafil can potentiate hypotensive effects (Khera 2020); some experts recommend against routinely using these drugs together, particularly in patients with cardiovascular disease (Sauer 2020).
Erectile dysfunction:
Oral: 50 mg once daily as needed 1 hour before sexual activity; may be taken up to 4 hours before sexual activity. Reduce to 25 mg once daily if side effects occur. May increase to a maximum dose of 100 mg once daily if there is incomplete response.
High-altitude pulmonary edema (adjunctive therapy) (alternative agent) (off-label use):
Prevention: Note: May use as an adjunct to gradual ascent in high-risk individuals (eg, history of high-altitude pulmonary edema) who cannot take nifedipine (WMS [Luks 2019]).
Oral: 50 mg every 8 hours starting the day of ascent; continue for 3 to 5 days after reaching maximal altitude (Gallagher 2022); can extend for up to 7 days in individuals who ascend faster than recommended (WMS [Luks 2019]).
Treatment: Note: Alternative agent when nifedipine is not available. Adjunctive to nonpharmacologic measures (eg, oxygen supplementation, portable hyperbaric chamber, gradual descent) or as monotherapy if nonpharmacologic measures are not possible (WMS [Luks 2019]).
Oral: 50 mg every 8 hours; continue until descent is complete, symptoms resolve, and oxygenation is normal for the altitude (Gallagher 2022; WMS [Luks 2019]).
Pulmonary arterial hypertension: Note: A clinician with expertise in pulmonary arterial hypertension should be consulted for all management decisions. Sildenafil is contraindicated in patients taking riociguat due to potentially severe hypotension (ACCP [Klinger 2019]).
Oral: 20 mg 3 times daily; some experts do not recommend titration to higher doses (ACCP [Klinger 2019]). However, in patients who fail to demonstrate or maintain an adequate clinical response, other experts consider slowly increasing the dose in 20 mg increments to a maximum dose of 80 mg 3 times daily (ACCP [Taichman 2014]; Galiè 2005; Rubin 2011).
IV: 10 mg 3 times daily.
Raynaud phenomenon (alternative agent) (off-label use):
Oral: Initial: 20 mg once or twice daily; based on response and tolerability, may increase to 20 mg 3 times daily as needed; if lower doses are ineffective, may increase further to 40 mg 3 times daily if tolerated (Wigley 2020); others have reported using 50 mg 2 to 3 times daily as tolerated (Andrigueti 2017; Fries 2005; Wigley 2020).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.
Note: Although only 13% of sildenafil is excreted in the urine, the AUC is approximately doubled in patients with CrCl <30 mL/minute, most likely due to a decrease in hepatic function associated with uremia (Muirhead 2002); use with caution when initiating therapy or with any increase in dose in these patients, including patients on renal replacement therapies. Additionally, although there are no specific dosage adjustments recommended for off-label indications (has not been studied), the same general dosing principles may apply for these indications in patients with altered kidney function or on renal replacement therapies (expert opinion).
Altered kidney function: Oral, IV:
CrCl ≥30 mL/minute: No dosage adjustment necessary.
CrCl <30 mL/minute:
Pulmonary arterial hypertension: No dosage adjustment necessary; use with caution (manufacturer's labeling; expert opinion).
Erectile dysfunction: Initial: 25 mg once daily as needed 1 hour before sexual activity; may be taken up to 4 hours before sexual activity (Muirhead 2002; manufacturer's labeling). May cautiously increase dose based on tolerability and response. Maximum dose: 100 mg once daily.
Hemodialysis, intermittent (thrice weekly): Oral, IV: Not dialyzable (Grossman 2004):
Pulmonary arterial hypertension: No dosage adjustment necessary; use with caution (manufacturer's labeling; expert opinion).
Erectile dysfunction: Initial: 25 mg once daily as needed 1 hour before sexual activity; may be taken up to 4 hours before sexual activity (Chen 2001; Rosas 2001; YenicerioGlu 2002; manufacturer's labeling). May cautiously increase dose based on tolerability and response. Maximum dose: 100 mg once daily (Ghafari 2010; Seibel 2002; Türk 2001).
Peritoneal dialysis: Oral, IV: Unlikely to be significantly dialyzable (highly protein bound) (expert opinion):
Pulmonary arterial hypertension: No dosage adjustment necessary; use with caution (manufacturer's labeling; expert opinion).
Erectile dysfunction: Initial: 25 mg once daily as needed 1 hour before sexual activity; may be taken up to 4 hours before sexual activity (Chen 2001; Juergense 2001; Rosas 2001; YenicerioGlu 2002; manufacturer's labeling). May cautiously increase dose based on tolerability and response. Maximum dose: 100 mg once daily (Mahon 2005; Türk 2001).
CRRT: Oral, IV:
Pulmonary arterial hypertension: There are no specific dosage adjustments recommended (has not been studied); however, dosage adjustment is likely unnecessary; use with caution (expert opinion).
PIRRT (eg, sustained, low-efficiency diafiltration): Oral, IV:
Pulmonary arterial hypertension: There are no specific dosage adjustments recommended (has not been studied); however, dosage adjustment is likely unnecessary; use with caution (expert opinion).
Mild to moderate impairment (Child-Pugh classes A and B):
Revatio: No dosage adjustment necessary.
Viagra: Starting dose of 25 mg should be considered.
Severe impairment (Child-Pugh class C):
Revatio: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).
Viagra: Starting dose of 25 mg should be considered.
(For additional information see "Sildenafil: Pediatric drug information")
Note: Use of Revatio, especially chronic use, is not recommended in pediatric patients due to a dose-dependent increased mortality risk observed in trials (Barst 2012b; Barst 2014; manufacturer's labeling). However, situations may exist in which the benefit-risk profile of Revatio make its use acceptable in individual pediatric patients with close monitoring. Oral suspensions may be available in multiple concentrations (commercially available: 10 mg/mL; extemporaneous preparation: 2.5 mg/mL); dosing should be presented in mg of sildenafil; use extra precaution when verifying product formulation and calculation of dose volumes. The 2 mL oral syringe included with the 10 mg/mL oral suspension only provides measurements for fixed doses of 5 mg and 20 mg; for patients not receiving either of these fixed doses, an appropriate-size calibrated oral syringe should be dispensed.
Pulmonary hypertension: Limited data available; dose and duration of therapy not established; interpatient variability has been reported; Oral:
Infants: Initial: 0.25 mg/kg/dose every 6 hours or 0.5 mg/kg/dose every 8 hours; titrate as needed; maximum reported dose range: 1 to 2 mg/kg/dose every 6 to 8 hours (Humpl, 2011; Mourani, 2009).
An open-label, prospective trial of 25 pediatric patients <5 years of age (median age: 6 months; age range: 10 days to 4.9 years) reported statistically significant improvement in echocardiography outcome measures; in 15 patients, sildenafil abolished rebound pulmonary hypertension following NO withdrawal; the initial dose of 0.25 mg/kg/dose four times daily was titrated as tolerated to a target of 1 mg/kg/dose four times daily; the reported median dose was 0.7 mg/kg/dose four times daily (range: 0.5 to 2.25 mg/kg/dose); reported duration of therapy was 9 days to 4.3 years (n=25); 11 patients were discontinued on sildenafil therapy due to clinical resolution; nine deaths were reported [severe lung hypoplasia (n=3); veno-occlusive disease post-chemotherapy (n=1); severe BPD (n=1); cause of death unrelated to pulmonary vascular disease (n=4)] (Humpl, 2011).
A retrospective trial of 25 pediatric patients <2 years of age (which included at least 16 infants) evaluated long-term safety and efficacy in patients with chronic lung disease (72% with BPD); at therapy initiation, the subject ages ranged from 14 days to 96 weeks (median: ~6 months); the initial dose of 0.5 mg/kg/dose every 8 hours was titrated as tolerated; the majority of patients were treated with 8 mg/kg/day (2 mg/kg/dose four times daily); echocardiogram showed clinical improvement in 88% of patients; reported duration of therapy was 28 to 950 days (median: 241 days); five deaths were reported during therapy (day 25 to 241 of therapy; median: 135 days); causes of death included sepsis, meningitis, and refractory respiratory disease (Mourani, 2009).
Children and Adolescents <18 years of age: Note: Dosage should not be increased; higher doses and long-term use are associated with an increased mortality risk (Barst, 2012a; Barst, 2012b).
8 to 20 kg: 10 mg three times daily.
>20 kg to 45 kg: 20 mg three times daily.
>45 kg: 40 mg three times daily.
Dosing based on the STARTS-1 and 2 trial, a randomized, double-blind, placebo-controlled study in 235 pediatric patients (1 to 17 years of age) which evaluated short-term and long-term safety and efficacy of 3 dose levels (low, medium, and high-dose); results suggested that the medium dose level (shown above) is efficacious at improving exercise capacity, functional class and hemodynamic status in the short-term (16 weeks duration); the low dosage level was not shown to be efficacious. The long-term safety and efficacy data showed a dose-dependent increased risk of mortality which was highest among the high-dose group. It was estimated that the dosing presented will produce serum concentration of 140 ng/mL and would be expected to inhibit 77% of phosphodiesterase type 5 activity in vitro (Barst, 2012a; Barst, 2012b).
Pulmonary hypertension, congenital heart surgery (postoperative): Limited data available; dosing regimens variable:
Oral (or nasogastric tube): Infants, Children, and Adolescents: Initial: 0.5 mg/kg/dose upon admission to ICU; increase in 0.5 mg/kg/dose increments every 4 to 6 hours up to a maximum dose of 2 mg/kg/dose as tolerated; upon discontinuation of mechanical ventilation, sildenafil therapy can be tapered over 5 to 7 days; dosing based on a retrospective report of 100 pediatric patients (including neonates through >10 years of age) which showed reduction in pulmonary arterial pressures and/or prevention of severe pulmonary hypertension (Nemoto, 2010). A lower dose of 0.35 mg/kg/dose every 4 hours for 1 week postoperatively was used in a retrospective, case-controlled trial of 38 pediatric patients (age range: 5 to 33 months) (Palma, 2011). In another retrospective report (n=45, median age: 32.6 months; range: 6 days to 17 years), a mean dose of 0.9 ± 0.3 mg/kg/dose four times daily was reported (Uhm, 2010). Note: Use of preoperative sildenafil therapy for the prevention of pulmonary hypertension following congenital heart surgery has produced variable efficacy results (Palma, 2011); a double-blind, placebo-controlled trial showed a negative impact on oxygenation and ventricular function (Vassalos, 2011).
IV: Infants >60 days and Children: Loading dose: Range: 0.04 to 0.35 mg/kg administered over 5 minutes, followed by a maintenance infusion: Reported range: 0.015 to 0.4 mg/kg/hour continued for 24 to 72 hours was used for pulmonary hypertension occurring within 48 hours of the end of cardiac surgery in a multicenter, randomized, double-blind, placebo-controlled dose-finding trial (n=17; median age: 5 months; age range: 3 months to 14 years; neonates and infants <60 days were excluded from the trial); dosages were either low, medium, or high dose (n=4 each treatment group; n=5 placebo) designed to attain serum concentrations of 40, 120, and 360 ng/mL, respectively; patients receiving sildenafil at all dosages were found to have lower pulmonary artery pressure and when compared to placebo, shorter duration of mechanical ventilation (median: 3 days vs 8 days), shorter ICU stay (median: 6 days vs 15 days), and shorter hospitalization (median: 12 days vs 21 days); study closed early due to slow patient accrual leading to underpowered results; no conclusions about dosage were able to be determined (Fraisse, 2011).
Pulmonary hypertension, facilitation of inhaled nitric oxide (iNO) wean (in patients who have not previously failed iNO wean): Limited data available: Infants and Children ≤15 months: Oral: Single dose: 0.4 mg/kg/dose (range: 0.3 to 0.5 mg/kg/dose) given once 60 minutes prior to iNO discontinuation; dosing based on a randomized, double-blind, placebo-controlled trial in 29 infants and young children (median age: 5.6 months; age range: 1 to 15 months; n=15 treatment arm) (Namachivayam, 2006).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no pediatric-specific dosage recommendations; based on experience in adult patients, no dosage adjustment necessary.
There are no pediatric-specific dosage recommendations; however, based on experience in adult patients, dosing adjustment suggested.
Elderly >65 years: Use with caution.
Erectile dysfunction (Viagra): Oral: Starting dose of 25 mg should be considered.
Pulmonary arterial hypertension (Revatio): Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Revatio: 10 mg/12.5 mL (12.5 mL)
Generic: 10 mg/12.5 mL (12.5 mL)
Suspension Reconstituted, Oral:
Revatio: 10 mg/mL (112 mL) [contains sodium benzoate; grape flavor]
Generic: 10 mg/mL (112 mL)
Tablet, Oral:
Revatio: 20 mg
Viagra: 25 mg, 50 mg, 100 mg [contains fd&c blue #2 (indigo carm) aluminum lake]
Generic: 20 mg, 25 mg, 50 mg, 100 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Revatio: 10 mg/12.5 mL (12.5 mL)
Tablet, Oral:
Revatio: 20 mg
Viagra: 25 mg, 50 mg, 100 mg [contains fd&c blue #2 (indigo carm) aluminum lake]
Generic: 20 mg, 25 mg, 50 mg, 100 mg
Oral:
Revatio: Administer doses at least 4 to 6 hours apart with or without food. Shake oral suspension well for ≥10 seconds before administering dose; do not mix with any other medication or additional flavoring agent.
Viagra: Administer with or without food 30 minutes to 4 hours before sexual activity
IV: Revatio: Administer as an IV bolus.
Oral: Revatio: Note: Oral suspensions may be available in multiple concentrations (commercially available: 10 mg/mL; extemporaneous preparation: 2.5 mg/mL); use extra precaution when verifying product formulation and calculation of dose volumes. The 2 mL oral syringe included with the 10 mg/mL oral suspension only provides measurements for fixed doses of 5 mg and 20 mg; for patients not receiving either of these fixed doses, an appropriate-size calibrated oral syringe should be dispensed.
Administer doses at least 4 to 6 hours apart; may be administered without regard to meals; shake oral suspension well prior to use.
IV: Revatio:
Neonates:
Continuous IV infusion:
Loading dose: Usually administered over 3 hours (Chetan 2022; Cochius-den Otter 2020; Steinhorn 2009).
Continuous IV infusion: Administer as a continuous IV infusion with the use of an infusion pump.
Intermittent IV infusions: Infusion time variable; infuse over 1 hour, longer infusion times are commonly used to minimize risk of hypotension; reported infusion times range: 15 minutes to 3 hours (Darland 2017; Fender 2016; Pierce 2021; PPHNet [Krishnan 2017]; Sharma 2021; Stultz 2013.
Infant, Children, and Adolescents: In clinical trials, loading dose was administered as a bolus over 5 minutes, followed by a continuous IV infusion (Fraisse 2011).
Erectile dysfunction: Viagra: Treatment of erectile dysfunction.
Pulmonary arterial hypertension: Revatio: Treatment of pulmonary arterial hypertension (WHO group I) in adults to improve exercise ability and delay clinical worsening; efficacy established predominately in patients with NYHA functional class II and III symptoms.
High-altitude pulmonary edema; Raynaud phenomenon
Revatio may be confused with ReVia, Revonto
Sildenafil may be confused with silodosin, tadalafil, vardenafil
Viagra may be confused with Allegra, Vaniqa
Sudden auditory impairment and hearing loss have occurred. Hearing changes are generally unilateral and may be accompanied by tinnitus and dizziness. A direct relationship between therapy and hearing loss has not been determined (Ref). The potential hearing loss affects high frequencies and is reversible (Ref).
Mechanism: Not clearly established; several proposed mechanisms. May be related to elevated middle inner ear pressure which results from congestion of nasal erectile tissue. Intensification of effects of nitric oxide and/or activation of intracellular cyclic guanosine monophosphate (cGMP) may also contribute (Ref).
Onset: Rapid; most cases occur within 12 to 24 hours (Ref).
Modest decreases in blood pressure (ie, reductions of 7 to 10 mmHg in systolic and 7 mm Hg in diastolic pressure) may occur (Ref). Blood pressure generally normalizes within 6 hours of administration (Ref). Concurrent organic nitrate or guanylate cyclase stimulator therapy may potentiate the vasodilatory effects of sildenafil and produce severe hypotension; use is contraindicated (Ref).
Mechanism: Related to the pharmacologic action; inhibition of phosphodiesterase-5 (PDE-5) activity in the vascular smooth muscle results in vasodilation, which can lead to hypotension (Ref).
Onset: Rapid; decreases in blood pressure generally occur within 1 to 2 hours after administration (Ref).
Risk factors:
• Concomitant medications that either potentiate the vasodilatory effects of sildenafil (eg, alpha-adrenergic antagonists) or increase sildenafil serum concentrations (eg, ritonavir) (Ref)
• Concurrent antihypertensives
• Left ventricular outflow obstruction (eg, aortic stenosis, idiopathic hypertrophic subaortic stenosis)
• Resting hypotension (BP <90/50 mm Hg)
• Fluid depletion
• Autonomic dysfunction
• Hemodynamic instability
Painful priapism lasting >4 hours in duration has been reported rarely (Ref).
Mechanism: Related to pharmacologic action; inhibition of phosphodiesterase-5 (PDE-5) activity, which leads to increased accumulation of cyclic guanosine monophosphate (cGMP) in response to release of nitric oxide (Ref).
Onset: Rapid; has occurred shortly after orgasm (Ref).
Risk factors:
• Sildenafil overdose (Ref)
• Concurrent medications that may cause priapism (eg, amitriptyline, nortriptyline, second-generation antipsychotics, trazodone) (Ref)
Visual disturbance (including reversible cyanopsia [blue-tinged vision], photophobia, and blurred vision may occur (Ref). Sudden vision loss in 1 or both eyes may occur and be a sign of nonarteritic anterior ischemic optic neuropathy (NAION); however, a direct relationship has not been determined (Ref). Most visual disturbances are transient (Ref). Cyanopsia, photophobia, and blurred vision typically resolve within 5 hours after discontinuation (Ref). NAION complete resolution may be delayed (weeks to a year) (Ref).
Mechanism:
• Cyanopsia, photophobia, blurred vision: Dose-related; related to the pharmacologic action. May be a result of minor inhibition of phosphodiesterase-6 (PDE-6) which is expressed in rod and cone photoreceptor cells in the retina (Ref).
• NAION: Not clearly established; may be due to hypoperfusion of ciliary arteries resulting from hypotension (Ref).
Onset: Cyanopsia, photophobia, blurred vision: Rapid; generally occur within 1 to 2 hours after ingestion (Ref). NAION: Varied; hours to months after ingestion (Ref).
Risk factors:
For NAION:
• Low cup-to-disc ratio ("crowded disc") (Ref)
• Older patients (>50 years of age) (Ref)
• Coronary heart disease (Ref)
• Diabetes (Ref)
• Hypertension (Ref)
• Hyperlipidemia (Ref)
• Smoking (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Flushing (10% to 19%; dose-related)
Gastrointestinal: Dyspepsia (3% to 17%; dose-related)
Nervous system: Headache (16% to 46%)
Ophthalmic: Visual disturbance (2% to 11%; including vision color changes, blurred vision, and photophobia; dose-related)
Respiratory: Epistaxis (9% to 13%)
1% to 10%:
Cardiovascular: Angina pectoris (<2%), atrioventricular block (<2%), cardiac failure (<2%), cardiomyopathy (<2%), cerebral thrombosis (<2%), chest pain (<2%), ECG abnormality (<2%), edema (<2%), facial edema (<2%), hypotension (<2%), ischemic heart disease (<2%), orthostatic hypotension (<2%), palpitations (<2%), peripheral edema (<2%), shock (<2%), syncope (<2%), tachycardia (<2%)
Dermatologic: Contact dermatitis (<2%), dermal ulcer (<2%), diaphoresis (<2%), erythema of skin (6%), exfoliative dermatitis (<2%), pruritus (<2%), skin photosensitivity (<2%), skin rash (2% to 3%), urticaria (<2%)
Endocrine & metabolic: Gout (<2%), hyperglycemia (<2%), hypernatremia (<2%), hyperuricemia (<2%), hypoglycemia (<2%), increased thirst (<2%), unstable diabetes (<2%)
Gastrointestinal: Abdominal pain (<2%), colitis (<2%), diarrhea (9%; dose-related), dysphagia (<2%), esophagitis (<2%), gastritis (3%), gastroenteritis (<2%), gingivitis (<2%), glossitis (<2%), nausea (2% to 3%), stomatitis (<2%), vomiting (<2%), xerostomia (<2%)
Genitourinary: Breast hypertrophy (<2%), cystitis (<2%), ejaculatory disorder (<2%), genital edema (<2%), nocturia (<2%), urinary frequency (<2%), urinary incontinence (<2%)
Hematologic & oncologic: Anemia (<2%), leukopenia (<2%), rectal hemorrhage (<2%)
Hepatic: Abnormal hepatic function tests (<2%)
Hypersensitivity: Hypersensitivity reaction (<2%)
Infection: Herpes simplex infection (<2%)
Nervous system: Abnormal dreams (<2%), absent reflexes (<2%), anorgasmia (<2%), ataxia (<2%), chills (<2%), depression (<2%), dizziness (2% to 4%) (table 1), drowsiness (<2%), falling (<2%), hypertonia (<2%), hypoesthesia (<2%), insomnia (7%), migraine (<2%), myasthenia (<2%), neuralgia (<2%), neuropathy (<2%), pain (<2%), paresthesia (3%), vertigo (<2%)
|
Drug (Sildenafil) |
Placebo |
Dose |
Dosage Form |
Indication |
Number of Patients (Sildenafil) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|---|
|
4% |
2% |
50 mg |
Tablets |
Erectile dysfunction |
511 |
607 |
|
3% |
2% |
100 mg |
Tablets |
Erectile dysfunction |
506 |
607 |
|
3% |
2% |
25 mg |
Tablets |
Erectile dysfunction |
312 |
607 |
|
2% |
1% |
N/A |
Tablets |
Erectile dysfunction |
734 |
725 |
Neuromuscular & skeletal: Arthritis (<2%), asthenia (<2%), back pain (3% to 4%), myalgia (2% to 7%; dose-related), ostealgia (<2%), osteoarthritis (<2%), rupture of tendon (<2%), synovitis (<2%), tenosynovitis (<2%), tremor (<2%)
Ophthalmic: Anterior chamber eye hemorrhage (<2%), cataract (<2%), conjunctivitis (<2%), dry eye syndrome (<2%), eye pain (<2%), mydriasis (<2%), retinal hemorrhage (1%)
Otic: Auditory impairment (<2%), hearing loss (<2%), otalgia (<2%), tinnitus (<2%)
Respiratory: Asthma (<2%), bronchitis (<2%), dyspnea (<2%), exacerbation of dyspnea (7%), increased bronchial secretions (<2%), increased cough (<2%), laryngitis (<2%), nasal congestion (4% to 9%), pharyngitis (<2%), rhinitis (4%), sinusitis (3%)
Miscellaneous: Accidental injury (<2%), fever (6%)
Postmarketing:
Cardiovascular: Acute myocardial infarction (Hayat 2007), hypertension, retinal vascular disease, subarachnoid hemorrhage (Adiya 2016), transient ischemic attacks (Morgan 2001), ventricular arrhythmia
Genitourinary: Hematuria, priapism (Rezaee 2020)
Hematologic & oncologic: Basal cell carcinoma of skin (Loeb 2015), hemorrhage, malignant melanoma (Li 2014; Loeb 2015), pulmonary hemorrhage, sickle cell crisis (vaso-occlusive crisis in patients with pulmonary hypertension associated with sickle cell disease) (Machado 2011)
Nervous system: Amnesia (transient global), anxiety, cerebral hemorrhage, cerebrovascular hemorrhage, seizure (including recurrent seizures)
Ophthalmic: Anterior ischemic optic neuropathy (nonarteritic; NAION) (Campbell 2015), burning sensation of eyes, diplopia, eye redness, increased intraocular pressure, retinal edema, swelling of eye, vision loss, vitreous detachment, vitreous traction
Hypersensitivity to sildenafil or any component of the formulation; concurrent use (regularly/intermittently) of organic nitrates in any form (eg, nitroglycerin, isosorbide dinitrate); concomitant use of riociguat (a guanylate cyclase stimulator).
According to the manufacturers of protease inhibitors (atazanavir, darunavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir): Concurrent use with a protease inhibitor regimen when sildenafil is used for pulmonary artery hypertension.
Canadian labeling: Additional contraindications (not in US labeling):
Viagra: Prior episode of non-arteritic anterior ischemic optic neuropathy (NAION).
Revatio: Prior episode of non-arteritic anterior ischemic optic neuropathy (NAION); concurrent use with potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir); pulmonary hypertension secondary to sickle cell anemia; severe hepatic impairment; recent history of stroke or MI, or life-threatening arrhythmia; coronary artery disease causing unstable angina; severe hypotension (<90/50 mm Hg) at initiation.
Concerns related to adverse effects:
• Color discrimination: May cause dose-related impairment of color discrimination. Use caution in patients with retinitis pigmentosa; a minority have genetic disorders of retinal phosphodiesterases (no safety information available).
• Hypotension: Caution patients that concurrent use of alcohol, particularly in larger quantities, may increase the risk for orthostatic hypotension, dizziness, tachycardia, and headache. Recommend limiting any alcohol use to smaller quantities and refraining from such combined use as possible.
Disease-related concerns:
• Anatomical penis deformation: Use with caution in patients with anatomical deformation of the penis (angulation, cavernosal fibrosis, or Peyronie disease).
• Bleeding disorders: Use with caution in patients with bleeding disorders; safety has not been established. In vitro studies have suggested a decreased effect on platelet aggregation.
• Cardiovascular disease: Use with caution in patients with hypotension (<90/50 mm Hg); uncontrolled hypertension (>170/110 mm Hg); life-threatening arrhythmias, stroke or MI within the last 6 months; cardiac failure or coronary artery disease causing unstable angina; safety and efficacy have not been studied in these patients. Use caution in patients with left ventricular outflow obstruction (eg, aortic stenosis). Patients should be hemodynamically stable prior to initiating therapy at the lowest possible dose. There is a degree of cardiac risk associated with sexual activity; therefore, health care providers should consider the cardiovascular status of their patients prior to initiating any treatment for erectile dysfunction.
• Conditions predisposing to priapism: Use with caution in patients who have conditions which may predispose them to priapism (sickle cell anemia, multiple myeloma, leukemia). All patients should be instructed to seek immediate medical attention if erection persists >4 hours.
• Hepatic impairment: Use with caution in patients with hepatic impairment; dose adjustment may be required.
• Peptic ulcer disease: Use with caution in patients with active peptic ulcer disease; safety has not been established.
• Pulmonary arterial hypertension: Sudden cessation of sildenafil monotherapy could result in an exacerbation of pulmonary arterial hypertension (PAH). Efficacy in adult patients determined through short-term (12 to 16 week) studies; safety of longer-term use is unclear. A long-term use trial in pediatric patients showed increased mortality in the higher dose groups (20 to 80 mg [depending upon weight] 3 times per day) after 2 years of use (Barst 2012a; Barst 2012b).
• Pulmonary veno-occlusive disease: Use in patients with pulmonary veno-occlusive disease (PVOD) is not recommended (has not been studied); if pulmonary edema occurs when treating PAH, consider the possibility of PVOD.
• Renal impairment: Use with caution in patients with renal impairment; dose adjustment may be needed.
• Sickle cell anemia: Treatment of pulmonary hypertension with sildenafil in this patient population may lead to more hospitalizations for management of vaso-occlusive crises. The effectiveness and safety of sildenafil have not been established in pulmonary hypertension secondary to sickle cell disease.
Concurrent drug therapy issues:
• Nitrates: Use of sildenafil is contraindicated in patients currently taking nitrate preparations. However, when nitrate administration becomes medically necessary, American College of Cardiology/American Heart Association guidelines support administration of nitrates only if 24 hours have elapsed after use of sildenafil (ACC/AHA [Amsterdam 2014]; ACCF/AHA [O'Gara 2013]); may need to wait longer than 24 hours in patients with renal or hepatic dysfunction.
Special populations:
• Pediatric: Use of Revatio, especially chronic use, is not recommended in children. After 2 years of treatment, increased mortality was seen in a long-term (median treatment exposure: 4.6 years) study at higher doses (20 to 80 mg [depending upon weight] 3 times/day) (Barst 2012a; Barst 2012b).
• Older adult: Use with caution; dose adjustment may be required.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
• Suspension: Oral suspensions may be available in multiple concentrations (commercially available: 10 mg/mL; extemporaneous preparation: 2.5 mg/mL); dosing should be presented in mg of sildenafil; use extra precaution when verifying product formulation and calculation of dose volumes.
Substrate of CYP1A2 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alcohol (Ethyl): May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk C: Monitor therapy
Alpha1-Blockers (Nonselective): Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Alpha1-Blockers (Nonselective). Management: Ensure patient is stable on one agent prior to initiating the other, and always initiate combination using the lowest possible dose of the drug being added. When tadalafil is used for treatment of BPH, concurrent alpha 1-blockers are not recommended. Risk D: Consider therapy modification
Alpha1-Blockers (Uroselective): May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk C: Monitor therapy
Alprostadil: Phosphodiesterase 5 Inhibitors may enhance the adverse/toxic effect of Alprostadil. Risk X: Avoid combination
Amyl Nitrite: Phosphodiesterase 5 Inhibitors may enhance the vasodilatory effect of Amyl Nitrite. Risk X: Avoid combination
Blood Pressure Lowering Agents: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bosentan: May decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Phosphodiesterase 5 Inhibitors may increase the serum concentration of Bosentan. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May increase the serum concentration of Sildenafil. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Cobicistat: May increase the serum concentration of Sildenafil. Management: Use of cobicistat and sildenafil for the treatment of PAH is contraindicated. If using sildenafil for the treatment of erectile dysfunction, limit the sildenafil dose to 25 mg and do not use more frequently than every 48 hours. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Sildenafil. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Sildenafil. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Sildenafil. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Sildenafil. Management: Use of sildenafil for pulmonary arterial hypertension (PAH) should be avoided with strong CYP3A4 inhibitors. When used for erectile dysfunction, consider using a lower starting dose of 25 mg and monitor patients for sildenafil toxicities. Risk D: Consider therapy modification
Dapoxetine: May enhance the orthostatic hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk X: Avoid combination
Erythromycin (Systemic): May increase the serum concentration of Sildenafil. Management: For pulmonary arterial hypertension, no dose adjustment required. For erectile dysfunction, consider using a lower starting dose of 25 mg in patients who are also taking erythromycin. Monitor patients for sildenafil toxicities when combined. Risk D: Consider therapy modification
Etravirine: May decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Grapefruit Juice: May increase the serum concentration of Sildenafil. Risk C: Monitor therapy
Lenacapavir: May increase the serum concentration of Sildenafil. Management: For pulmonary arterial hypertension, no dose adjustment required. For erectile dysfunction, use a lower starting dose of 25 mg in patients who are also taking lenacapavir. Monitor patients for sildenafil toxicities when combined. Risk D: Consider therapy modification
Lorcaserin (Withdrawn From US Market): May enhance the adverse/toxic effect of Phosphodiesterase 5 Inhibitors. Specifically, the risk of developing priapism may be increased. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk X: Avoid combination
Nitroprusside: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Nitroprusside. Risk X: Avoid combination
Phosphodiesterase 5 Inhibitors: May enhance the adverse/toxic effect of other Phosphodiesterase 5 Inhibitors. Risk X: Avoid combination
Protease Inhibitors: May increase the serum concentration of Sildenafil. Management: Use of protease inhibitors and sildenafil for the treatment of PAH is contraindicated. If using sildenafil for the treatment of erectile dysfunction, limit the sildenafil dose to 25 mg and do not use more frequently than every 48 hours. Risk D: Consider therapy modification
Riociguat: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Riociguat. Risk X: Avoid combination
Sapropterin: May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk C: Monitor therapy
Simeprevir: May increase the serum concentration of Phosphodiesterase 5 Inhibitors. Risk C: Monitor therapy
Vasodilators (Organic Nitrates): Phosphodiesterase 5 Inhibitors may enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Risk X: Avoid combination
Vericiguat: May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Risk X: Avoid combination
Grapefruit juice may increase serum levels/toxicity of orally administered sildenafil. Management: Monitor for increased effects/toxicity with concomitant oral use.
Sildenafil was shown to cross the placenta in an ex vivo placenta perfusion study (Russo 2018).
Because sildenafil causes vasodilation in the uterus, it is currently under study for various obstetric uses (Dunn 2016; Dunn 2017; Groom 2019; Maged 2018; Maher 2019; Pels 2017; Sharp 2018). However, due to adverse events in the newborn observed using preliminary data from a study evaluating sildenafil for fetal growth restriction, use of sildenafil in pregnant women outside of a controlled clinical study is not currently recommended (Groom 2018; Levin 2019).
Information related to the use of sildenafil for the treatment of pulmonary arterial hypertension (PAH) in pregnant women is limited (Cartago 2014; Hsu 2011; Lim 2019; Wollein 2016). Untreated PAH in pregnancy increases the risk for heart failure, stroke, preterm delivery, and maternal/fetal death. Women with PAH are encouraged to avoid pregnancy (McLaughlin 2009; Taichman 2014).
Sildenafil is present in breast milk.
The excretion of sildenafil and desmethylsildenafil in breast milk was described in a case report following maternal use for the treatment of PAH (Wollein 2016).
Monitor blood pressure and pulse when used concurrently with medications that lower blood pressure; monitor for pulmonary edema
Erectile dysfunction: Does not directly cause penile erections but affects the response to sexual stimulation. The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil enhances the effect of NO by inhibiting phosphodiesterase type 5 (PDE-5), which is responsible for degradation of cGMP in the corpus cavernosum; when sexual stimulation causes local release of NO, inhibition of PDE-5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum; at recommended doses, it has no effect in the absence of sexual stimulation.
Pulmonary arterial hypertension (PAH): Inhibits phosphodiesterase type 5 (PDE-5) in smooth muscle of pulmonary vasculature where PDE-5 is responsible for the degradation of cyclic guanosine monophosphate (cGMP). Increased cGMP concentration results in pulmonary vasculature relaxation; vasodilation in the pulmonary bed and the systemic circulation (to a lesser degree) may occur.
Onset of action: Erectile dysfunction: ~60 minutes.
Peak effect: Decrease blood pressure: Oral: 1 to 2 hours.
Duration: Erectile dysfunction: 2 to 4 hours; Decrease blood pressure: <8 hours.
Absorption: Rapid; slower with a high-fat meal; tablet and suspension are bioequivalent.
Distribution: Distributes into tissues.
Vd total:
Term neonates: 19.8 to 22.4 L (Mukherjee 2009; Rhee 2022).
Vdss: Adults: 105 L.
Protein binding, plasma:
Term neonates: Sildenafil: 93.9% ± 2.5%; N-desmethyl metabolite: 92% ± 3% (Mukherjee 2009).
Adults: Sildenafil and N-desmethyl metabolite: ~96%.
Metabolism: Hepatic via CYP3A4 (major) and CYP2C9 (minor route); major metabolite (UK-103320 or desmethylsildenafil) is formed via N-desmethylation pathway and has 50% of the activity as sildenafil.
Bioavailability: Oral: Mean: 41%; range: 25% to 63%; may be higher in patients with PAH compared to healthy volunteers; Note: A 10 mg dose of the injection is predicted to have an effect equal to a 20 mg oral dose taking into consideration the parent drug and active metabolite.
Half-life elimination:
Sildenafil: Terminal:
Term neonates (Mukherjee 2009):
PNA 1 day: 55.9 hours.
PNA 7 days: 47.7 hours.
Adults: 4 hours.
Active N-desmethyl metabolite: Terminal:
Neonates: 11.9 hours (Mukherjee 2009).
Adults: 4 hours.
Time to peak: Oral: Fasting: 30 to 120 minutes (median 60 minutes); delayed by 60 minutes with a high-fat meal.
Excretion: Feces (~80%, as metabolites); urine (~13%).
Clearance: Decreased in patients with hepatic cirrhosis or severe renal impairment; clearance may be lower in patients with PAH compared to normal volunteers. Sildenafil clearance in newborns is significantly decreased compared to adults, but approaches adult (allometrically scaled) values by the first week of life (Mukherjee 2009). Clearance of N-desmethyl active metabolite is decreased in patients with severe renal impairment.
Altered kidney function: Severe renal impairment is associated with increased plasma levels.
Hepatic function impairment: Hepatic impairment is associated with increased plasma levels.
Older adult: Age 65 years or older is associated with increased plasma levels.
Solution (Revatio Intravenous)
10 mg/12.5 mL (per mL): $23.20
Solution (Sildenafil Citrate Intravenous)
10 mg/12.5 mL (per mL): $17.60
Suspension (reconstituted) (Revatio Oral)
10 mg/mL (per mL): $101.87
Suspension (reconstituted) (Sildenafil Citrate Oral)
10 mg/mL (per mL): $79.42 - $87.94
Tablets (Revatio Oral)
20 mg (per each): $66.07
Tablets (Sildenafil Citrate Oral)
20 mg (per each): $19.00 - $22.05
25 mg (per each): $0.11 - $66.46
50 mg (per each): $0.11 - $66.46
100 mg (per each): $0.11 - $66.46
Tablets (Viagra Oral)
25 mg (per each): $93.38
50 mg (per each): $93.38
100 mg (per each): $93.38
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