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Sildenafil

Pronunciation

Pronunciation

(sil DEN a fil)

Index Terms

  • Sildenafil Citrate
  • UK92480

Dosage Forms

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]

Tablet, Oral:

Revatio: 20 mg

Viagra: 25 mg, 50 mg, 100 mg [contains fd&c blue #2 aluminum lake]

Generic: 20 mg

Brand Names: U.S.

  • Revatio
  • Viagra

Pharmacologic Category

  • Phosphodiesterase-5 Enzyme Inhibitor

Pharmacology

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.

Absorption

Rapid; slower with a high-fat meal; tablet and suspension are bioequivalent

Distribution

Vd total: Neonates: 22.4 L (or 456 L/70 kg) (Mukherjee 2009)

Vdss: Adults: 105 L

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

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.

Onset of Action

Onset: Erectile dysfunction: ~60 minutes; Peak effect: Decrease blood pressure: Oral: 1 to 2 hours

Time to Peak

Oral: Fasting: 30 to 120 minutes (median 60 minutes); delayed by 60 minutes with a high-fat meal

Duration of Action

Erectile dysfunction: 2 to 4 hours; Decrease blood pressure: <8 hours

Half-Life Elimination

Sildenafil: Terminal:

Neonates: PNA 1 day: 55.9 hours (Mukherjee 2009)

Neonates: PNA 7 days: 47.7 hours (Mukherjee 2009)

Adults: 4 hours

Active N-desmethyl metabolite: Terminal:

Neonates: 11.9 hours (Mukherjee 2009)

Adults: 4 hours

Protein Binding

Neonates: Sildenafil: 93.9% ± 2.5%; N-desmethyl metabolite: 92% ± 3% (Mukherjee 2009)

Adults: Sildenafil and N-desmethyl metabolite: ~96%

Special Populations: Renal Function Impairment

Severe renal impairment is associated with increased plasma levels.

Special Populations: Hepatic Function Impairment

Hepatic impairment is associated with increased plasma levels.

Special Populations: Elderly

Age 65 years or older is associated with increased plasma levels.

Use: Labeled Indications

Pulmonary arterial hypertension: Revatio: Treatment of pulmonary arterial hypertension (PAH) (WHO Group I; efficacy established predominately in patients with WHO/NYHA functional class II and III) in adults to improve exercise ability and delay clinical worsening.

Note: Based on the 2007 American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines on Medical Therapy for Pulmonary Hypertension, in patients with pulmonary arterial hypertension (NYHA functional class II and III) who are not candidates for, or who have failed, calcium channel blocker therapy, sildenafil is an effective and recommended treatment option in the management of this condition. The level of evidence for NYHA functional class IV is low and therefore cannot be recommended for routine use in this population. The 2009 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Expert Consensus Document on Pulmonary Hypertension and the 5th World Symposium on Pulmonary Hypertension (WSPH) suggests the use of oral phosphodiesterase type 5 inhibitors (when appropriate) in patients with WHO Group I pulmonary arterial hypertension (ie, idiopathic PAH and PAH related to connective tissue disease or anorexigens) as an alternative to an endothelin receptor antagonist in lower risk (WHO functional class II and III) patients who did not have a positive acute vasodilator testing. First-line therapy in patients with higher risk (WHO functional class IV) continues to be intravenous prostacyclin therapy; however, if the patient is not a candidate for intravenous prostacyclin therapy, the use of other therapies including phosphodiesterase-5 inhibitors should be considered (ACCF/AHA [McLaughlin 2009]; ACCP [Badesch 2007]; WSPH [Gaile 2013]).

Erectile dysfunction: Viagra: Treatment of erectile dysfunction (ED)

Use: Unlabeled

Pulmonary hypertension (WHO Group II, III, and IV); persistent pulmonary hypertension after recent left ventricular assist device placement

Contraindications

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 (eg, Revatio).

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.

Dosing: Adult

Erectile dysfunction (Viagra): Oral: Usual dose: 50 mg once daily 1 hour (range: 30 minutes to 4 hours) before sexual activity as needed; dosing range: 25 to 100 mg once daily; maximum dose: 100 mg once daily.

Pulmonary arterial hypertension (PAH) (Revatio):

IV:

US labeling: 2.5 mg or 10 mg 3 times daily

Canadian labeling: 10 mg 3 times daily

Oral:

US labeling: 5 mg or 20 mg 3 times daily, administered 4 to 6 hours apart; maximum dose: 20 mg 3 times daily

Canadian labeling: 20 mg 3 times daily, administered 6 to 8 hours apart

Raynaud phenomenon (off-label use): Oral: 50 mg twice daily. Clinical trials were up to 4 weeks. (Fries 2005; Roustit 2013)

Dosage considerations for patients stable on alpha-blockers: Viagra: Initial: 25 mg

Dosage adjustment for concomitant use of potent CYP34A inhibitors: Viagra:

Strong CYP3A inhibitors (eg, itraconazole, ketoconazole, saquinavir) or erythromycin: Starting dose of 25 mg should be considered

Protease inhibitors: Maximum sildenafil dose: 25 mg every 48 hours

Dosing: Geriatric

Elderly >65 years: Use with caution.

Erectile dysfunction (Viagra): Oral: Starting dose of 25 mg should be considered.

PAH (Revatio): Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute:

Revatio: No dosage adjustment necessary.

Viagra: Starting dose of 25 mg should be considered.

Dosing: Hepatic Impairment

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:

US labeling: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Canadian labeling: Use is contraindicated.

Viagra: Starting dose of 25 mg should be considered.

Extemporaneously Prepared

Note: Commercial oral suspension is available (10 mg/mL)

A 2.5 mg/mL sildenafil citrate oral suspension may be made with tablets and either a 1:1 mixture of methylcellulose 1% and simple syrup NF or a 1:1 mixture of Ora-Sweet and Ora-Plus. Crush thirty sildenafil 25 mg tablets (Viagra) in a mortar and reduce to a fine powder. Add small portions of chosen vehicle and mix to a uniform paste; mix while adding vehicle in incremental proportions to almost 300 mL; transfer to a graduated cylinder, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 300 mL. Store in amber plastic bottles and label "shake well". Stable for 90 days at room temperature or refrigerated.

Nahata MC, Morosco RS, and Brady MT, “Extemporaneous Sildenafil Citrate Oral Suspensions for the Treatment of Pulmonary Hypertension in Children,” Am J Health-Syst Pharm, 2006, 63(3):254-7.16434784

Administration

Oral:

Revatio: Administer doses at least 4 to 6 hours apart (US labeling) or 6 to 8 hours apart (Canadian labeling) 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.

Dietary Considerations

Avoid grapefruit juice.

Storage

Tablets/injection: Store at 20°C to 25°C (68°F to 77°F); excursions are permitted to 15°C to 30°C (59°F to 86°F).

Oral suspension: Store unreconstituted powder below 30°C (86°F); protect from moisture. Store reconstituted oral suspension below 30°C (86°F) or at 2°C to 8°C (36°F to 46°F). Do not freeze. Discard unused Revatio oral suspension after 60 days.

Drug Interactions

Alcohol (Ethyl): May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Monitor therapy

Alpha1-Blockers: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Alpha1-Blockers. 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. Consider therapy modification

Alprostadil: Phosphodiesterase 5 Inhibitors may enhance the adverse/toxic effect of Alprostadil. Avoid combination

Amyl Nitrite: Phosphodiesterase 5 Inhibitors may enhance the vasodilatory effect of Amyl Nitrite. Avoid combination

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Blood Pressure Lowering Agents: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Boceprevir: May increase the serum concentration of Sildenafil. Management: Avoid sildenafil when used for treatment of pulmonary arterial hypertension in patients receiving boceprevir. Sildenafil for erectile dysfunction should be limited to 25 mg every other day with close monitoring for sildenafil toxicity. Avoid combination

Bosentan: May decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Phosphodiesterase 5 Inhibitors may increase the serum concentration of Bosentan. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Clarithromycin: May increase the serum concentration of Sildenafil. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Sildenafil. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Sildenafil. Management: Use of sildenafil for pulmonary hypertension should be avoided with strong CYP3A4 inhibitors. When used for erectile dysfunction, starting adult dose should be reduced to 25 mg. Maximum adult dose with ritonavir or cobicistat is 25 mg per 48 hours. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dapoxetine: May enhance the orthostatic hypotensive effect of Phosphodiesterase 5 Inhibitors. Avoid combination

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erythromycin (Systemic): May increase the serum concentration of Sildenafil. Management: For pulmonary arterial hypertension, US label recommends no dose adjustment and Canadian label recommends reducing to 20mg twice/day. For erectile dysfunction, consider using a lower starting dose of 25mg in patients who are also taking erythromycin. Consider therapy modification

Etravirine: May decrease the serum concentration of Phosphodiesterase 5 Inhibitors. Management: No empiric dosage adjustments are recommended with concomitant therapy; however, dose of the phosphodiesterase inhibitor may need to be altered based on clinical response. Monitor therapy

Fluconazole: May increase the serum concentration of Sildenafil. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Itraconazole: May increase the serum concentration of Sildenafil. Management: Concurrent itraconazole is not recommended when sildenafil is used for treatment of pulmonary arterial hypertension. If sildenafil is used to treat erectile dysfunction, an initial dose of 25 mg is recommended with concurrent itraconazole. Consider therapy modification

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Sildenafil. Management: Concurrent ketoconazole is not recommended when sildenafil is used for treatment of pulmonary arterial hypertension. If sildenafil is used to treat erectile dysfunction, an initial dose of 25 mg is recommended with concurrent ketoconazole. Consider therapy modification

Lorcaserin: May enhance the adverse/toxic effect of Phosphodiesterase 5 Inhibitors. Specifically, the risk of developing priapism may be increased. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Avoid combination

Nefazodone: May increase the serum concentration of Sildenafil. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the adverse/toxic effect of other Phosphodiesterase 5 Inhibitors. Avoid combination

Posaconazole: May increase the serum concentration of Sildenafil. Management: Concurrent posaconazole is not recommended when sildenafil is used for treatment of pulmonary arterial hypertension. If sildenafil is used to treat erectile dysfunction, an initial dose of 25 mg is recommended with concurrent posaconazole. Consider therapy modification

Protease Inhibitors: May increase the serum concentration of Sildenafil. Management: Erectile dysfunction: sildenafil max = 25 mg/48 hrs with ritonavir, atazanavir, or darunavir; starting dose = 25 mg with other protease inhibitors (adult doses). Contraindicated if sildenafil being used for pulmonary arterial hypertension. Consider therapy modification

Riociguat: Phosphodiesterase 5 Inhibitors may enhance the hypotensive effect of Riociguat. Avoid combination

Sapropterin: May enhance the hypotensive effect of Phosphodiesterase 5 Inhibitors. Monitor therapy

Saquinavir: May increase the serum concentration of Sildenafil. Management: Used for PAH: no dose adjustment recommended per US label, Canadian label recommends decrease to 20 mg twice/day. Used for ED: consider a lower starting dose of 25 mg with concurrent saquinavir. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of Phosphodiesterase 5 Inhibitors. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Telaprevir: May increase the serum concentration of Sildenafil. Management: Concurrent use of sildenafil for treatment of pulmonary arterial hypertension is contraindicated with telaprevir. Sildenafil for erectile dysfunction should be limited to 25 mg per 48 hours, with close monitoring for sildenafil toxicity. Avoid combination

Telithromycin: May increase the serum concentration of Sildenafil. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Vasodilators (Organic Nitrates): Phosphodiesterase 5 Inhibitors may enhance the vasodilatory effect of Vasodilators (Organic Nitrates). Avoid combination

Voriconazole: May increase the serum concentration of Sildenafil. Management: Concurrent voriconazole is not recommended when sildenafil is used for treatment of pulmonary arterial hypertension. If sildenafil is used to treat erectile dysfunction, an initial dose of 25 mg is recommended with concurrent voriconazole. Consider therapy modification

Adverse Reactions

Based upon normal doses for either indication or route. (Adverse effects such as flushing, diarrhea, myalgia, and visual disturbances may be increased with adult doses >100 mg/24 hours.)

>10%:

Cardiovascular: Flushing (10% to 19%)

Central nervous system: Headache (16% to 46%)

Gastrointestinal: Dyspepsia (3% to 17%; dose related)

Ophthalmic: Visual disturbance (2% to 11%; including vision color changes, blurred vision, and photophobia; dose related)

Respiratory: Epistaxis (9% to 13%)

2% to 10%:

Central nervous system: Insomnia (≤7%), dizziness (2% to 4%), paresthesia (≤3%)

Dermatologic: Erythema (6%), skin rash (1% to 3%)

Gastrointestinal: Diarrhea (3% to 9%), gastritis (≤3%), nausea (2% to 3%)

Genitourinary: Urinary tract infection (3%)

Hepatic: Increased liver enzymes (2% to 10%)

Neuromuscular & skeletal: Myalgia (2% to 7%), back pain (3% to 4%)

Respiratory: Nasal congestion (4% to 9%), exacerbation of dyspnea (≤7%), nasal congestion (4%), rhinitis (4%), sinusitis (3%)

Miscellaneous: Fever (6%)

<2% (Limited to important or life-threatening): Abnormal hepatic function tests, absent reflexes, amnesia (transient global), anemia, anorgasmia, anterior chamber eye hemorrhage, anterior ischemic optic neuropathy, arthritis, auditory impairment, basal cell carcinoma (Loeb 2015), breast hypertrophy, burning sensation of eyes, cardiac failure, cataract, cerebrovascular hemorrhage, colitis, cystitis, depression, diaphoresis, diplopia, dry eye syndrome, dysphagia, ECG abnormality, ejaculatory disorder, exfoliative dermatitis, falling, gastroenteritis, genital edema, gingivitis, glossitis, gout, herpes simplex infection, hyperglycemia, hypernatremia, hypersensitivity reaction, hypertension, hypertonia, hypoglycemia, increased bronchial secretions, increased intraocular pressure, ischemic heart disease, laryngitis, leukopenia, malignant melanoma (Li 2014; Loeb 2015), migraine, myasthenia, mydriasis, myocardial infarction, neuralgia, neuropathy, orthostatic hypotension, otalgia, peripheral edema, pharyngitis, photophobia, priapism, prolonged erection, pulmonary hemorrhage, rectal hemorrhage, retinal edema, retinal hemorrhage, retinal vascular disease, rupture of tendon, seizure, severe sickle cell crisis (vaso-occlusive crisis in patients with pulmonary hypertension associated with sickle cell disease), skin photosensitivity, stomatitis, syncope, synovitis, tachycardia, transient ischemic attacks, unstable diabetes, urinary incontinence, ventricular arrhythmia, vitreous detachment, vitreous traction

Warnings/Precautions

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).

• Hearing loss: Sudden decrease or loss of hearing has been reported; hearing changes may be accompanied by tinnitus and dizziness. A direct relationship between therapy and hearing loss has not been determined.

• Hypersensitivity: Hypersensitivity reactions, including anaphylactic reaction and anaphylactic shock, have been reported.

• Hypotension: Decreases in blood pressure may occur due to vasodilator effects; use with caution in patients with left ventricular outflow obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), those on antihypertensive therapy, with resting hypotension (BP <90/50 mm Hg), fluid depletion, or autonomic dysfunction; may be more sensitive to hypotensive actions. Patients should be hemodynamically stable prior to initiating therapy at the lowest possible dose. Monitor blood pressure when combining with medications that lower blood pressure. Substantial consumption of ethanol may increase the risk of hypotension and orthostasis. Lower ethanol consumption has not been associated with significant changes in blood pressure or increase in orthostatic symptoms. Have patients avoid or limit ethanol consumption.

• Priapism: Painful erection >6 hours in duration has been reported rarely. Educate patient to seek medical assistance for erection lasting >4 hours.

• Vision loss: Vision loss, including permanent loss of vision, may occur and be a sign of nonarteritic anterior ischemic optic neuropathy (NAION). Risk may be increased with history of vision loss. Other risk factors for NAION include low cup-to-disc ratio (“crowded disc”), coronary artery disease, diabetes, hypertension, hyperlipidemia, smoking, and >50 years of age. Patients suffering sudden vision loss should discontinue therapy and consult health care provider immediately. The Canadian labeling contraindicates use in patients with a prior episode of NAION. A direct relationship between therapy and vision loss has not been determined.

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. Revatio Canadian labeling contraindicates use in patients with recent history of MI, stroke, or life-threatening arrhythmia, coronary artery disease causing unstable angina, or severe hypotension (<90/50 mm Hg) at initiation of therapy. Use caution in patients with left ventricular outflow obstruction (eg, aortic stenosis). 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 Viagra with caution in patients with hepatic impairment; use lowest starting dose (25 mg). Revatio Canadian labeling contraindicates use in severe hepatic impairment.

• Peptic ulcer disease: Use with caution in patients with active peptic ulcer disease; safety has not been established.

• PAH: Sudden cessation of sildenafil monotherapy could result in an exacerbation of PAH. Efficacy in adult patients determined through short-term (12-16 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 (20-80 mg [depending upon weight] 3 times/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 pulmonary arterial hypertension (PAH), consider the possibility of PVOD.

• Renal impairment: Use Viagra with caution in patients with renal impairment; dose adjustment may be needed; use lowest starting dose (25 mg) in severe dysfunction (CrCl <30 mL/minute).

• 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 (Revatio Canadian labeling contraindicates use in patients with pulmonary hypertension secondary to sickle cell anemia).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Nitrates: Use of sildenafil is contraindicated in patients currently taking nitrate preparations. However, when nitrate administration becomes medically necessary, the ACCF/AHA 2013 guidelines on treatment of ST-segment elevation MI and the ACCF/AHA 2012 guidelines on treatment of unstable angina/non ST-segment elevation MI support administration of nitrates only if 24 hours have elapsed after use of sildenafil (ACCF/AHA [Anderson 2013]; ACCF/AHA [O'Gara 2013]).

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).

• Elderly: 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. The 2 mL oral syringe provided by the manufacturer 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 will need to be dispensed.

Other warnings/precautions:

• Appropriate use: In the treatment of erectile dysfunction potential underlying causes of erectile dysfunction should be evaluated prior to initiating sildenafil treatment.

• Limitations of use: In the treatment of pulmonary arterial hypertension the addition of sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity.

Monitoring Parameters

PAH: Monitor blood pressure and pulse when used concurrently with medications that lower blood pressure; monitor for pulmonary edema

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Information related to the use of sildenafil for the treatment of pulmonary arterial hypertension (PAH) in pregnant women is limited (Hsu 2011). Current guidelines recommend that women with PAH use effective contraception and avoid pregnancy (Badesch 2007; McLaughlin 2009). Less than 0.001% appears in the semen.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience diarrhea, flushing, abdominal pain, heartburn, nausea, muscle pain, nosebleed, rhinitis, rhinorrhea, back pain, insomnia, or injection site pain, edema, or irritation. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), angina, tachycardia, arrhythmia, severe dizziness, passing out, severe headache, coughing up blood, severe nausea, severe vomiting, vision changes, blindness, hearing impairment, tinnitus, memory impairment, seizures, shortness of breath, swelling of hands and feet, or priapism (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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