Sildenafil Citrate

Class: Phosphodiesterase 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
Brands: Revatio, Viagra

Special Alerts:

[Posted 10/18/2007] FDA informed healthcare professionals of reports of sudden decreases or loss of hearing following the use of PDE5 inhibitors sildenafil (Viagra), tadalafil (Levitra), vardenafil (Cialis) for the treatment of erectile dysfunction, and sildenafil (Revatio) for the treatment of pulmonary arterial hypertension. In some cases, the sudden hearing loss was accompanied by tinnitus and dizziness. Medical follow-up on these reports was often limited which makes it difficult to determine if the loss of hearing was related to the use of one of the drugs, an underlying medical condition or other risk factors for hearing loss, a combination of these factors or other factors. The PRECAUTIONS and ADVERSE REACTIONS sections of the approved product labeling for sildenafil (Viagra), tadalafil, and vardenafil were revised. FDA is working with the manufacturer to revise the labeling for sildenafil (Revatio). For more information visit the FDA website at: , , , , , and .

Introduction

Vasodilating agent; a selective phosphodiesterase (PDE) type 5 inhibitor.^{1 2 4 5 7 8 10 24 27 33 41 56 57 67 91 131 184 203}

Uses for Sildenafil Citrate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Erectile Dysfunction

To facilitate attainment of a sexually functional erection in males with erectile dysfunction (ED, impotence).^{1 4 6 7 8 9 10 25 33 34 67 81 102 104 105 107 108 112 118 119 126 127 128 129 130 131 132 133 134 135 140 142 143 144 189}

Most experts currently recommend that selective PDE type 5 inhibitors be offered as first-line therapy for erectile dysfunction unless contraindicated.¹⁸⁹ Insufficient evidence to support the superiority of one selective PDE type 5 inhibitor over another.¹⁸⁹

Pulmonary Arterial Hypertension

Symptomatic treatment (e.g., to improve exercise capacity) of pulmonary arterial hypertension (PAH; WHO group I pulmonary hypertension).^{203 204 205 206 207 208 209 210 211 213}

Precise role (alone and combined with other therapies) remains to be fully elucidated.^{204 206 207 208 209 210 211 213} Whether long-term sildenafil therapy has a beneficial effect on mortality remains to be established;^{205 208 213} some preliminary data suggest a survival benefit.²⁰⁹

Sildenafil Citrate Dosage and Administration

General

Erectile Dysfunction

• 
  

  Carefully individualize dosage according to the patient’s tolerance and erectile response.^{1 33 67 77 81}

  
  


• 
  

  Sexual stimulation is required for response to therapy.¹

  
  

Administration

Oral Administration

Erectile Dysfunction

Administer orally ^{1 33 208} no more than once daily.^{1 67 81 93 94 102 107 114 130 131}

Administer about 1 hour (range: 4 hours to 30 minutes) before sexual activity.^{1 60 91 127 132}

Administration with a high-fat meal may delay the onset of action.^{1 114 115 117 131}

PAH

Administer orally 3 times daily (approximately 4–6 hours apart) without regard to meals.^{203 208}

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as sildenafil citrate; dosage expressed in terms of sildenafil.^{1 203}

Adults

Erectile Dysfunction

Oral

Initially, 50 mg.^{1 28 33 81 91 93 94 102 105 118 130 132 149 161} Depending on effectiveness and tolerance, increase dosage to a maximum of 100 mg or decrease to 25 mg.^{1 28 33 91 93 94 105 149 161}

PAH

Oral

20 mg 3 times daily.²⁰³ Efficacy of lower dosages not established.²⁰³

Prescribing Limits

Adults

Erectile Dysfunction

Oral

Maximum 100 mg daily.^{1 60 91 114 131}

PAH

Oral

Dosages up to 80 mg 3 times daily have been studied but have not been more effective than recommended dosage of 20 mg 3 times daily.^{203 207 208 209}

Special Populations

Hepatic Impairment

Erectile Dysfunction

Oral

Reduce initial dose to 25 mg.^{1 28 31 67}

PAH

Oral

No dosage adjustments necessary for mild to moderate hepatic impairment (Child-Pugh class A and B).²⁰³ Not studied in severe hepatic impairment (Child-Pugh class C).²⁰³

Renal Impairment

Erectile Dysfunction

Oral

If Cl_cr is <30 mL/minute, reduce initial dose to 25 mg.^{1 28 67 80 131}

PAH

Oral

No dosage adjustment needed, even in severe impairment (Cl_cr <30 mL/minute).²⁰³

Geriatric Patients

Erectile Dysfunction

Oral

Reduce initial dose to 25 mg in men ≥65 years of age.^{1 31 67}

PAH

Oral

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.²⁰³

Cautions for Sildenafil Citrate

Contraindications

• 
  

  Known hypersensitivity to sildenafil or any ingredient in the formulation.^{1 203}

  
  


• 
  

  Concomitant use of organic nitrates or nitrites.^{1 29 57 67 148 154 203} (See Specific Drugs under Interactions.)

  
  


• 
  

  Should not be used for treatment of erectile dysfunction in men for whom sexual activity is inadvisable because of their underlying cardiovascular status.^{1 67 154 189}

  
  

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Cardiovascular Effects

Serious, potentially fatal cardiovascular effects reported rarely.^{1 2 4 6 7 9 10 33 56 61 67 91 93 94 102 107 114 127 130 132 208}

Use with caution in the treatment of erectile dysfunction in patients with a recent (within 6 months) MI, stroke, or life-threatening arrhythmia;^{1 31 101 127 144 154 155 159} in patients with resting hypotension (BP <90/50 mm Hg) or hypertension (BP >170/110 mm Hg);^{1 31 101 127 144 154 155 159} or in patients with cardiac failure or CAD causing unstable angina.^{1 31 101 127 144 154 155 159} Assess cardiovascular and cerebrovascular status (including use of organic nitrates and nitrites) prior to initiating therapy.^{1 28 30 31 53 64 65 67 91 93 121 154 189}

Safety and efficacy for the treatment of PAH not established in patients with a recent (within 6 months) MI, stroke, or life-threatening arrhythmia; in patients with hypertension (BP >170/110 mm Hg) or with CAD causing unstable angina; or in those currently receiving bosentan (see Specific Drugs under Interactions).²⁰³ Caution advised.²⁰³

Possible symptomatic hypotension may occur in patients receiving concomitant^{1 31 67} α-adrenergic blocking agents; hypotension may be severe or fatal in patients receiving an organic nitrate or nitrite concomitantly.^{1 28 29 31 53 57 61 67 69 148} (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,²⁰³ especially in combination with sexual activity.^{1 67 154}

Use not recommended in patients with pulmonary veno-occlusive disease.²⁰³ Clinical data on use in this population are not available, and pulmonary vasodilators may worsen cardiovascular status of such patients.²⁰³ If pulmonary edema occurs during sildenafil therapy, consider the possibility of pulmonary veno-occlusive disease.²⁰³

Ocular Effects

Possible visual disturbances (e.g., blue/green vision, changes in light sensitivity), particularly at high doses.^{1 33 56 57 67 77 86 87 88 91 95 203 208} Possible persistent and/or serious retinal changes in older patients or with long-term use.^{32 87 88 95 106}

Nonarteritic anterior ischemic optic neuropathy (NAION) reported rarely in patients receiving PDE type 5 inhibitors for the treatment of erectile dysfunction.^{1 182 183 190 191 192 194 195 196 197 198 199 202 203} Potential increased risk of NAION in the second eye in patients who already have had NAION in one eye.^{1 182 183 196 202 203}

Use with caution in patients with retinitis pigmentosa.^{1 31 32 60 155 203} Periodically monitor retinal function in patients with ocular manifestations suggestive of retinal effects and in those at risk.^{88 115}

Priapism

Possible prolonged erections (>4 hours in duration) and priapism (painful erection >6 hours).^{1 31 139 146 147}

May result in penile tissue damage and permanent loss of potency if priapism is not treated immediately.^{1 31} Use with caution in patients with conditions predisposing to priapism (e.g., sickle cell anemia, multiple myeloma, leukemia).^{1 33 114 115 159 203}

Interactions with Potent CYP3A4 Inhibitors

Concomitant use with potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, ritonavir) substantially increases serum sildenafil concentrations.^{1 203} Depending on the particular use of sildenafil (e.g., erectile dysfunction, PAH) and the specific CYP3A4 inhibitor, concomitant use may not be recommended or precautions (e.g., dosage adjustments) may be required.^{1 203} (See Specific Drugs under Interactions.)

General Precautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Assessment of Patients with Erectile Dysfunction

Thorough medical history and physical examination recommended to diagnose erectile dysfunction, determine potential underlying causes, exclude potentially reversible or treatable causes, and identify appropriate treatment.^{1 12 28 30 31 36 57 58 65 66 70 78 82 83 94 114 115 119 144 145 160 161}

Review of patient’s current drug regimens recommended to detect possible drug-induced erectile dysfunction.^{12 28 70 81 118 119 144 152 161}

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.^{28 31 67} (See Specific Drugs under Interactions.) Monitor BP during initiation of therapy in these patients.^{28 67 159}

Bleeding Disorders

Use with caution in patients with bleeding disorders or active peptic ulcers.^{1 27 33 67 131}

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%).²⁰³

GU Precautions

Use with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie’s disease).^{1 33 114 115 159 203}

Concomitant Therapies for Erectile Dysfunction

Safety and efficacy not established for use in combination with other treatments for erectile dysfunction; combined therapy is not recommended.^{1 155}

Specific Populations

Pregnancy

Category B.^{1 203}

Lactation

Not known whether sildenafil is distributed into milk.²⁰³ Use with caution in nursing women.²⁰³

Pediatric Use

Safety and efficacy not established in patients <18 years of age;^{115 203} however, has been used effectively in a limited number of children† for symptomatic treatment of PAH.^{158 205 206}

Geriatric Use

Pooled clinical trial data indicate that efficacy in men ≥65 years of age with erectile dysfunction is similar to that in younger men.^{131 157} Decreased clearance and increased plasma concentrations may increase incidence of adverse effects in geriatric patients with erectile dysfunction.^{1 60 139} (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.²⁰³

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.²⁰³

Hepatic Impairment

Decreased clearance.^{1 31 60 67 69 203} (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Decreased clearance in patients with severe renal impairment.^{1 60 67 80 203} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Erectile dysfunction: Headache,^{1 4 6 7 9 10 31 33 56 91 93 104 105 107 130 132 208} flushing,^{1 4 7 9 33 56 67 93 105 107 130 132} dyspepsia/heartburn.^{1 7 10 31 33 67 91 93 102 107 132}

PAH: Headache,^{203 208 211} dyspepsia,^{203 208} flushing,^{203 208} epistaxis,²⁰³ insomnia,^{203 208} exacerbated dyspnea,²⁰³ diarrhea,^{203 208} myalgia,²⁰³ erythema,^{203 208} pyrexia.²⁰³

Interactions for Sildenafil Citrate

Metabolized principally by CYP3A4 and to some extent by CYP2C9; weakly inhibits CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 in vitro.^{1 26 59 67 91 203}

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4 and CYP2C9: Potential pharmacokinetic interaction (increased plasma sildenafil concentrations).^{1 26 59 67 91 203 212}

Inducers of CYP3A4: Potential pharmacokinetic interaction (decreased plasma sildenafil concentrations).^{1 26 59 67 91 203 212}

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4:^{1 26 67} Potential pharmacokinetic interaction (increased substrate concentrations).²⁰³

Specific Drugs

Drug	Interaction	Comments
α-Adrenergic blockers	Possible potentiation of systemic vasodilation189 203 and occurrence of symptomatic hypotension1 203	Do not administer doses >25 mg within 4 hours before or after α-adrenergic blocker1 Use with caution in PAH203
Alcohol	No additive hypotensive effects reported1 203	Consider possibility that heavy alcohol ingestion could add to stress of sexual activity and risk of cardiac ischemia during coitus67 115 and that alcohol consumption also may contribute to erectile dysfunction12 28 58 70 82 114 115 119
Amlodipine	Possible additive hypotensive effects1 29 114 154 203
Antacids	Oral bioavailability of sildenafil unaffected by single doses of aluminum and magnesium hydroxides-containing antacid1 114 203
Antidepressants (e.g., SSRIs, tricyclic antidepressants)	Pharmacokinetic interaction unlikely1
Antifungal agents (itraconazole, ketoconazole)	Possible increased AUC of sildenafil1 114 203	Consider lower initial sildenafil dose (25 mg) for treatment of erectile dysfunction1 67 Concomitant use not recommended in PAH203
Antihypertensive and hypotensive agents	Potential additive hypotensive effects1 29 67 203	Monitor during initial therapy, especially in patients receiving multiple agents and those with CHF28 67 159 or renal impairment28 67 80
Antiretroviral agents (HIV protease inhibitors)	Decreased clearance, increased plasma concentrations of sildenafil, and increased risk of sildenafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)26 59 67 84 114 136 137 139 166 167 168 169 170 171 172 173 174 175 200 201 203	Caution advised;84 166 167 168 169 170 171 172 173 174 175 closely monitor for adverse effects59 84 166 167 168 171 170 174 175 200 Amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir in fixed combination with ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir in combination with low-dose ritonavir: reduce initial sildenafil dose for treatment of erectile dysfunction to 25 mg and do not exceed a single 25-mg dose every 48 hours59 166 167 168 169 170 171 172 173 174 175 200 Concomitant ritonavir and sildenafil not recommended in PAH203 Concomitant saquinavir and sildenafil in PAH: No dosage adjustments necessary203
Antiretroviral agents (nonnucleoside reverse transcriptase inhibitors [NNRTIs])	Delavirdine: Possible increased sildenafil concentrations and risk of sildenafil-associated adverse effects (e.g., hypotension, visual changes, prolonged erection)29 169 Efavirenz, nevirapine: Possible decreased plasma sildenafil concentrations and/or altered plasma NNRTI concentrations203	Delavirdine: Reduce initial sildenafil dose for treatment of erectile dysfunction to 25 mg and do not exceed a single 25-mg dose every 48 hours; monitor for adverse effects29 169 Efavirenz, nevirapine: Possible dosage adjustments of either sildenafil or the NNRTI203
Antipsychotics	Pharmacokinetic interaction unlikely1 60 118
Aspirin	No increase in bleeding time reported1 60 65 67 114 203
Atorvastatin	Pharmacokinetic interaction unlikely203
Barbiturates	Possible decreased plasma sildenafil concentrations and/or altered plasma barbiturate concentrations203	Possible dosage adjustment of either sildenafil or the barbiturate203
Bosentan	Decreased plasma sildenafil concentrations203 212 Increased plasma bosentan concentrations203	Possible dosage adjustment of either agent203
Carbamazepine	Possible decreased plasma sildenafil concentrations and/or altered plasma carbamazepine concentrations 203	Possible dosage adjustment of either agent 203
Cimetidine	Increased plasma sildenafil concentrations1 67 203	Consider lower initial sildenafil dose (25 mg) for treatment of erectile dysfunction67
Contraceptives, oral	Pharmacokinetic interaction unlikely203
Erythromycin	Increased AUC of sildenafil1 69 114 203	Consider lower initial sildenafil dose (25 mg) for treatment of erectile dysfunction1 67 Dosage adjustment not necessary in PAH203
Heparin	Increased bleeding time reported in animals1 203	Current evidence does not preclude concomitant heparin67 114 115
Inhaled nitrites (e.g., amyl or butyl nitrite)	Possible sudden and marked BP reduction; potentially serious or even fatal26 67 92 Possible beneficial augmented cardiovascular effects in PAH204 210 211	Concomitant use contraindicated1 29 57 67 148 154 (see Cautions)
Nitrates and nitrites (e.g., nitroglycerin, isosorbide dinitrate)	Potentiation of vasodilatory effects (e.g., decrease in SBP of >25 mm Hg) of organic nitrates and nitrites; potentially life-threatening hypotension and/or hemodynamic compromise can result1 28 29 31 33 53 57 61 67 69 91 127 131 148	Concomitant use contraindicated1 29 57 67 148 154 203 (see Cautions) Some clinicians suggest that nitrates and nitrites may be given >24 hours after sildenafil, but the point at which these drugs can be given safely after sildenafil is unclear;1 29 31 67 154 avoid concomitant use unless benefits outweigh risks67 114
Phenytoin	Possible decreased plasma sildenafil concentrations and/or altered plasma phenytoin concentrations203	Possible dosage adjustment of either agent203
Phosphodiesterase (PDE) inhibitors (e.g., dipyridamole, theophylline)	Potential pharmacodynamic interaction (increased inotropic effects in cardiac muscle, vascular smooth muscle relaxation, and platelet-aggregation inhibition)67	Risk of cardiotoxic, hypotensive, or hemorrhagic event after concomitant use of specific or nonspecific PDE inhibitor (e.g., dipyridamole, theophylline) not known but appears unlikely67
Rifamycins (rifabutin, rifampin)	Possible decreased plasma sildenafil concentrations1 69 203 (theoretically less likely with rifabutin than rifampin103 ) and/or altered plasma rifabutin or rifampin concentrations203	Possible dosage adjustment of either sildenafil or the rifamycin203
Sodium nitroprusside	Potentiation of vasodilatory effects (e.g., decrease in SBP of >25 mm Hg) of organic nitrates and nitrites; potentially life-threatening hypotension and/or hemodynamic compromise can result1 28 29 31 33 53 57 61 67 69 91 127 131 148 Also may potentiate the inhibitory effect of nitric oxide and sodium nitroprusside (a nitric oxide donor) on platelet aggregation1 57 67 203	Concomitant use contraindicated1 29 57 67 148 154 (see Cautions) Some clinicians suggest that nitrates and nitrites may be given >24 hours after sildenafil, but the point at which these drugs can be given safely after sildenafil is unclear;1 29 31 67 154 avoid concomitant use unless benefits outweigh risks67 114
Tolbutamide	Pharmacokinetic interaction unlikely67 114 203
Warfarin	Pharmacokinetic interaction unlikely67 114 Increased bleeding (epistaxis) observed with concomitant use in patients with PAH203

Sildenafil Citrate Pharmacokinetics

Absorption

Bioavailability

Rapidly and almost completely absorbed following oral administration;^{1 4 56 67 91 116 117 203} however, only about 40% of a dose reaches systemic circulation unchanged.^{1 4 56 67 91 114 116 131 203}

Peak plasma concentration usually attained within 30–120 minutes.^{1 4 91 117 127 1}