Sildenafil Citrate

Pronunciation

Class: Phosphodiesterase Type 5 Inhibitors
VA Class: GU900
Chemical Name: 2 - Hydroxy - 1,2,3 - propanetricarboxylate - 1 - [[3 - (6,7 - dihydro - 1 - methyl - 7 - oxo - 3 - propyl - 1H - pyrazolo[4,3 - d - pyrimidin - 5 - yl) - 4 - ethoxyphenyl]sulfonyl] - 4 - methyl - piperazine
Molecular Formula: C22H30N6O4S•C6H8O7
CAS Number: 171599-83-0
Brands: Revatio, Viagra

Warning(s)

Special Alerts:

[Posted 03/31/2014] ISSUE: FDA is clarifying its previous recommendation related to prescribing Revatio (sildenafil) for children with pulmonary arterial hypertension (PAH). Revatio is FDA-approved only to treat PAH in adults, not in children; however, health care professionals must consider whether the benefits of treatment with the drug are likely to outweigh its potential risks for each patient.

FDA revised the Revatio drug label in August 2012, adding a warning stating that “use of Revatio, particularly chronic use, is not recommended in children.” This recommendation was based on an observation of increasing mortality with increasing Revatio doses in a long-term clinical trial in pediatric patients with PAH. FDA issued a Drug Safety Communication at that time. There may be situations in which the benefit-risk profile of Revatio may be acceptable in individual children, for example, when other treatment options are limited and Revatio can be used with close monitoring.

BACKGROUND: The purpose of the August 2012 recommendation was to raise awareness of clinical trial results showing a higher risk of mortality in pediatric patients taking a high dose of Revatio when compared to pediatric patients taking a low dose. This recommendation was not intended to suggest that Revatio should never be used in children; however, some health care professionals have interpreted this information as a contraindication, and have refused to prescribe or administer the drug.

RECOMMENDATION: The evidence behind FDAs initial recommendation has not changed; this communication is clarifying the strength of the warning communicated in the Revatio drug label..

Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program.

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

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

Slideshow: 18 Herbal Supplements with Risky Drug Interactions

Herbal and Dietary Supplements Deserve Your Attention

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

Sexual Dysfunction in Women

Has been used for the management of sexual dysfunction in women; however, additional study needed to establish role, if any, of such therapy.28 67 79 97 150

Although sildenafil may improve physiologic response (e.g., increased blood flow to sexual organs),224 such changes have not been associated with overall improvement in sexual dysfunction in women.79 219 222 224

Also has been used in women with sexual dysfunction induced by SSRI antidepressants97 108 118 150 152 226 and in women with neurogenic sexual dysfunction (e.g., due to spinal cord injury or multiple sclerosis); however, data limited.227 228

Pulmonary Arterial Hypertension (PAH)

Symptomatic treatment (e.g., to improve exercise capacity) of PAH (WHO group I pulmonary hypertension).203 204 205 206 207 208 209 210 211 213 Also shown to delay clinical worsening when used as an adjunct to IV epoprostenol.235

Parenteral preparation is used for continued treatment in patients with PAH who are temporarily unable to take oral medication.203

Efficacy established principally in patients with NYHA functional class II–III primary (idiopathic) pulmonary hypertension or PAH associated with connective tissue disease.203 208 235

Recommended by the American College of Chest Physicians (ACCP) and other experts as one of several treatment options for management of PAH in patients with NYHA functional class II or early class III symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.236 237 238 However, precise role (alone or combined with other therapies) remains to be fully elucidated.204 206 207 208 209 210 211 213

Because increased mortality has been observed in children receiving higher (more effective) dosages of sildenafil, FDA currently does not recommend use of the drug in pediatric patients <18 years of age.203 233 (See Pediatric Use under Cautions.) Whether long-term sildenafil therapy has a beneficial effect on mortality in adults remains to be established.205 208 213 233

When selecting an appropriate choice of PAH therapy, consider factors such as disease severity, route of administration, potential adverse effects of treatment, and patient preference.236 237

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

Administer orally or IV.203

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 (as tablets or oral suspension) 3 times daily (approximately 4–6 hours apart) without regard to meals.203 208

If a dose is missed, take missed dose as soon as it is remembered, then resume regular dosing schedule; do not double dose to replace missed dose.229

Reconstitution of Oral Suspension

To reconstitute powder for oral suspension, tap bottle to release the powder.203 Add 60 mL of water to the bottle; recap and shake vigorously for at least 30 seconds.203 Add another 30 mL to bottle, recap and shake for at least 30 seconds; add a total of 90 mL of water to the bottle regardless of dose.203 The reconstituted suspension contains sildenafil 10mg/mL.203

Use provided bottle adapter to fill 2-mL oral syringe with the reconstituted suspension.203

IV Administration

PAH

May administer by direct IV injection in patients who temporarily cannot take oral medication.203

Dosage

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 No benefit with higher dosages.203 Efficacy of lower dosages not established.203

IV

10 mg 3 times daily by direct IV injection.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 or B).203 Not studied in severe hepatic impairment (Child-Pugh class C).203

Renal Impairment

Erectile Dysfunction
Oral

If Clcr <30 mL/minute, reduce initial dose to 25 mg.1 28 67 80 131

PAH
Oral

No dosage adjustment needed, even with severe impairment (Clcr <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

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

Possible symptomatic hypotension may occur in patients receiving concomitant1 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

Vaso-occlusive crisis requiring hospitalization reported in patients with pulmonary hypertension secondary to sickle cell disease who received sildenafil.1 203 Efficacy and safety of sildenafil in patients with sickle cell anemia not established.1 203

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

Otic Effects

Sudden decrease or loss of hearing reported with all PDE type 5 inhibitors, including sildenafil.1 203 214 216 217 218 Adverse otic effects (e.g., deafness, otic pain, tinnitus) observed in a few patients in controlled clinical trials.1 217 In at least 1 case, permanent, bilateral sensorineural deafness occurred.217 218

Although not clear whether such effects are directly related to PDE type 5 inhibitors or to other factors (e.g., patient’s underlying medical condition, concomitant use of other ototoxic drugs), a strong temporal relationship has been observed.1 203 214 216 217

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

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

Manufacturer states that safety and efficacy not established in patients <18 years of age.115 203 Although sildenafil has been used effectively in a limited number of children for symptomatic treatment of PAH,158 205 206 FDA currently recommends that the drug not be used for treatment of PAH in pediatric patients <18 years of age.233 Increased risk of mortality observed in children receiving high dosages of sildenafil that also are the most effective dosages in this population.203 233 234 Deaths were related to disease progression in most cases.203 233 At this time, FDA does not believe that this safety concern applies to use of sildenafil (Viagra) for treatment of erectile dysfunction.233

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 symptomatic hypotension1 203

Doxazosin: No change or slight increase in plasma doxazosin concentrations depending on sildenafil dose203

In patients stable on an α-adrenergic blocker, initiate sildenafil at lowest recommended dosage for treatment of ED; in those currently receiving sildenafil, initiate α-adrenergic blocker at the lowest dosage 1

Use concomitantly with caution and monitor BP1 203

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

Antacids

Oral bioavailability of sildenafil unaffected by single doses of aluminum and magnesium hydroxide-containing antacid1 114 203

Dosage adjustments not necessary203

Antidepressants (e.g., SSRIs, tricyclic antidepressants)

No effect on sildenafil pharmacokinetics1

No change in efficacy of sildenafil for treatment of erectile dysfunction1

Antifungals, azole (itraconazole, ketoconazole)

Possible increased systemic exposure of sildenafil1 114 203

Consider lower initial sildenafil dose (25 mg) for treatment of erectile dysfunction1 67

Concomitant use not recommended in patients receiving sildenafil for PAH203

Antihypertensive and hypotensive agents

Potential additive hypotensive effects1 29 67 203

Amlodipine: Additional reductions in supine BP observed1 29 114 154 203

Thiazides and related diuretics, ACE inhibitors, calcium channel-blocking agents: No effect on sildenafil pharmacokinetics1

Loop and potassium-sparing diuretics, nonspecific β-adrenergic blocking agents: Increased AUC of active sildenafil metabolite (N-desmethyl sildenafil),1 but effect not expected to be clinically important1

Monitor BP203

Antipsychotics

Efficacy of sildenafil for treatment of erectile dysfunction not affected by concomitant use1 60 118

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)1 26 59 67 84 114 136 137 139 166 167 168 169 170 171 172 173 174 175 200 201 203 230 240

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, darunavir, fosamprenavir, indinavir, lopinavir/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 166 167 168 169 170 171 172 173 174 175 200 230 231 240

Ritonavir-boosted tipranavir in patients receiving sildenafil for PAH: Concomitant use contraindicated230

Ritonavir in patients receiving sildenafil for PAH: Concomitant use not recommended203

Saquinavir in patients receiving sildenafil for 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

Etravirine: Decreased plasma sildenafil concentrations232

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

Etravirine: May administer concomitantly without dosage adjustment, but increase in sildenafil dosage may be needed based on clinical effect175 232

Aspirin

No increase in bleeding time reported1 60 65 67 114 203

No dosage adjustments necessary203

Atorvastatin

AUC and peak plasma concentrations of either drug not substantially altered203

No dosage adjustments necessary203

Bosentan

Decreased plasma sildenafil concentrations; increased plasma bosentan concentrations203 212

Clinical importance of pharmacokinetic interaction unclear241

No dosage adjustments required203

Cimetidine

Increased plasma sildenafil concentrations1 67 203

Consider lower initial sildenafil dose (25 mg) for treatment of erectile dysfunction67

No dosage adjustment necessary when used concomitantly with sildenafil for PAH203

Contraceptives, oral (ethinyl estradiol/levonorgestrel)

AUC and peak plasma concentrations of sildenafil not substantially altered203

Pharmacokinetics of ethinyl estradiol and levonorgestrel not substantially altered203

No dosage adjustments necessary203

Epoprostenol

Slight decrease in sildenafil exposure; not considered clinically important203

Effect on epoprostenol pharmacokinetics not known203

Heparin

Increased bleeding time reported in animals1

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)

Macrolides (azithromycin, erythromycin)

Azithromycin: No pharmacokinetic interaction observed to date114 138 203 239

Erythromycin: Increased AUC of sildenafil1 69 114 203 239

Azithromycin: No dosage adjustments necessary203 239

Erythromycin: Consider lower initial sildenafil dose (25 mg) for treatment of erectile dysfunction;1 239 no dosage adjustment necessary when used concomitantly with sildenafil for PAH203

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

PDE inhibitors

Nonspecific PDE inhibitors (e.g., dipyridamole, theophylline): Possible increased inotropic effects in cardiac muscle, vascular smooth muscle relaxation, and platelet-aggregation inhibition; risk of cardiotoxicity, hypotensive, or hemorrhagic event after concomitant use not known, but appears unlikely67

PDE type 5 inhibitors: Safety and efficacy of concomitant use not evaluated1 203

PDE type 5 inhibitors: Do not use concomitantly with other PDE type 5 inhibitors1 203

PDE type 5 inhibitors: Do not use concomitantly with other PDE type 5 inhibitors

Rifamycins (rifabutin, rifampin)

Possible decreased plasma sildenafil concentrations1 69 (theoretically less likely with rifabutin than rifampin103 )

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

No effect on sildenafil pharmacokinetics1 67 114 203

No dosage adjustments necessary203

Vitamin K antagonists (e.g., acenocoumarol, phenprocoumon, warfarin)

No substantial effect on INR;1 67 114 203 however, increased bleeding (epistaxis) observed with concomitant use in patients with PAH203

Warfarin: No pharmacokinetic interaction observed1 67 114 173

No dosage adjustments necessary203

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 91 117 127 130 203

Duration

Erectile responsiveness: Approximately 2 hours.1 60 114

Onset

Erectile responsiveness: 14–20 minutes, self-recorded in the home setting.178

Food

Administration with a high-fat meal delays GI absorption;1 114 117 131 peak plasma concentrations reduced by about 30% and time to peak plasma concentration delayed by about 60 minutes.1 114 117 131

Distribution

Extent

Appears to be widely distributed in the body.1 4 67 116 131 203

Distributed to a limited extent in semen,1 67 but such concentrations are unlikely to cause any effects in sexual partners.67

Plasma Protein Binding

Approximately 96%.1 67 91 114 116 131 203

Elimination

Metabolism

Undergoes extensive metabolism in GI mucosa during absorption and on first pass through liver.91 114 116

Metabolized in the liver 116 117 131 principally by CYP3A4 and to a lesser extent by CYP2C9.1 91 131 203

Elimination Route

Excreted as metabolites in the feces (approximately 80%) and urine (approximately 13%).1 67 116 131 203

Half-life

Biphasic; terminal elimination half-life about 4 hours.1 4 67 91 116 117 127 130 131 203

Special Populations

Clearance in patients ≥65 years of age is reduced compared with that in younger adults.1 31 60 67 91 114 131 139 203

In patients with severe renal impairment (Clcr <30 mL/minute), clearance was reduced resulting in a two-fold increase in AUC and peak plasma concentrations compared with values in healthy adults.1 31 60 67 91 114 131 139 203 Pharmacokinetics not altered in mild to moderate renal impairment.1 31 131 203

Reduced clearance in patients with hepatic cirrhosis (Child-Pugh class A or B).1 31 60 114 131 203 Not studied in severe hepatic impairment (Child-Pugh class C).203

Stability

Storage

Oral

For Suspension

<30°C in original package to protect from moisture.203 After reconstitution, store at <30°C or in refrigerator (2–8°C); do not freeze.203 Discard any remaining oral suspension 30 days after reconstitution.203

Tablets

25°C (may be exposed to 15–30°C).1 203

Parenteral

Injection

25°C (may be exposed to 15–30°C).203

Actions

  • Selective inhibitor of phosphodiesterases (PDEs), with a great selectivity for PDE type 5,1 2 4 5 7 8 10 24 27 33 41 56 57 67 87 88 91 131 the principal isoenzyme involved in the metabolism of cGMP to GMP in the corpora cavernosa of the penis and clitoris.1 2 4 5 33 41 42 54 57 67 91 98 131

  • No direct relaxant effect on isolated human corpora cavernosa of the penis, but enhances the effect of nitric oxide by inhibiting PDE type 5-mediated hydrolysis of cGMP.1 2 4 5 7 8 10 33 41 42 98 127 131

  • Potentiates accumulation of cGMP only when cGMP production in the penis is increased by sexual arousal.34 91 131 No effect on erectile function in the absence of sexual stimulation.1 4 33 34 91 127 130 131 132

  • Modest peripheral vasodilation at usual dosages.1 29 31 33 53 56 67 91 203 In patients with pulmonary hypertension, induces vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilation in the systemic circulation.203 In such patients, pulmonary and systemic vascular resistance and resting arterial pressure are decreased, allowing an increase in cardiac output.203 Vasodilation and decreases in BP probably result from inhibition of PDE type 5 present in vascular smooth muscle.1 27 31 53

  • Because sildenafil can increase ocular cGMP concentrations via inhibition of PDE type 6,1 33 57 67 77 86 87 88 91 95 106 can produce transient visual abnormalities (mainly color-tinged vision, increased light perception, and blurred vision), particularly at doses >100 mg.1 33 57 67 77 86 87 88 91 95 106 107 131

Advice to Patients

  • Importance of informing clinicians if risk factors for cardiovascular disease are present prior to initiating any treatment for erectile dysfunction.1 28 30 31 53 64 65 67 91 93 121 154

  • Importance of informing clinician of any history of stroke, presence of low or high BP, blood diseases (e.g., sickle cell anemia, leukemia),195 or presence of retinitis pigmentosa or history of severe vision loss.1 193 195 196 198 199 203

  • Possibility of 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 and of possible impairment of ability to perform tasks such as piloting a plane or operating a motor vehicle.77 115 156

  • Potential for sudden vision loss or decreased vision (i.e., nonarteritic ischemic optic neuropathy [NAION]).1 182 183 189 196 203 If NAION already has occurred in one eye, risk of NAION developing in the second eye may be increased.1 182 183 196 202 203

  • Importance of informing patients to refrain from further activity and contact their clinician if symptoms (e.g., angina pectoris, dizziness, nausea) occur upon initiation of sexual activity.1 67

  • Importance of informing patients of the potential for life-threatening hypotension and/or hemodynamic compromise with concurrent use of organic nitrates and nitrites in any form,1 28 29 31 33 53 57 61 67 69 91 127 131 148 including the recreational use of inhaled nitrites (“poppers”).26 67

  • Importance of informing patients that doses of sildenafil >25 mg should not be taken within 4 hours of administration of an α-adrenergic blocking agent.1

  • Importance of taking the drug exactly as prescribed and not exceeding recommended doses or frequency of use.106

  • Importance of seeking immediate medical attention if an erection persists longer than 4 hours or is extremely painful.1 31

  • Importance of immediately contacting a clinician if sudden loss of vision or decreased vision occurs in one or both eyes.1 182 183 193 194 195 198 199 202 203

  • Potential for transmission of sexually transmitted diseases and the possible need to use protective measures to guard against such transmission.1 26 68

  • Importance of contacting a clinician for assessment of therapeutic benefit, the need for possible dosage adjustment, and potential adverse effects.81 114 115

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1 203

  • Importance of informing patients of other important precautionary information.1 203 (See Cautions.)

Preparations

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

Sildenafil Citrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

For suspension

10 mg (of sildenafil) per mL

Revatio

Pfizer

Tablets, film-coated

20 mg (of sildenafil)

Revatio

Pfizer

25 mg (of sildenafil)

Viagra

Pfizer

50 mg (of sildenafil)

Viagra

Pfizer

100 mg (of sildenafil)

Viagra

Pfizer

Parenteral

Injection

0.8 mg per mL (of sildenafil)

Revatio

Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Revatio 20MG Tablets (PFIZER U.S.): 30/$555.98 or 90/$1,528.00

Viagra 100MG Tablets (PFIZER U.S.): 10/$223.99 or 30/$671.97

Viagra 25MG Tablets (PFIZER U.S.): 10/$219.99 or 30/$659.97

Viagra 50MG Tablets (PFIZER U.S.): 10/$223.99 or 30/$671.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 5, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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