Sildenafil Citrate

The following serious adverse events are discussed elsewhere in the labeling:

• Mortality with pediatric use [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]
• Hypotension [see WARNINGS AND PRECAUTIONS]
• Vision loss [see WARNINGS AND PRECAUTIONS]
• Hearing loss [see WARNINGS AND PRECAUTIONS]
• Priapism [see WARNINGS AND PRECAUTIONS]
• Vaso-occlusive crisis [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety data of REVATIO in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 REVATIO-treated patients with PAH, WHO Group I [see Clinical Studies].

The overall frequency of discontinuation in REVATIO-treated patients on 20 mg three times a day was 3% and was the same for the placebo group.

In Study 1, the adverse reactions that were reported by at least 3% of REVATIO-treated patients (20 mg three times a day) and were more frequent in REVATIO-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature.

Table 1: Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in REVATIO-Treated Patients than Placebo-Treated Patients and Incidence ≥ 3% in REVATIO-Treated Patients)

At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision.

The incidence of retinal hemorrhage with REVATIO 20 mg three times a day was 1.4% versus 0% placebo and for all REVATIO doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for REVATIO versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy.

In a placebo-controlled fixed dose titration study (Study 2) of REVATIO (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the REVATIO + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 [see Clinical Studies].

Table 2: Adverse Reactions (%) in patients with PAH in Study 2 (incidence in REVATIO + Epoprostenol group at least 6% greater than Epoprostenol group)

REVATIO injection was studied in a 66-patient, placebo-controlled study in patients with PAH at doses targeting plasma concentrations between 10 and 500 ng/mL (up to 8 times the exposure of the recommended dose). Adverse events with REVATIO injection were similar to those seen with oral tablets.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In postmarketing experience with sildenafil at doses indicated for erectile dysfunction, serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, pulmonary hemorrhage, and subarachnoid and intracerebral hemorrhages have been reported in temporal association with the use of the drug. Most, but not all, of these patients had preexisting cardiovascular risk factors. Many of these events were reported to occur during or shortly after sexual activity, and a few were reported to occur shortly after the use of sildenafil without sexual activity. Others were reported to have occurred hours to days after use concurrent with sexual activity. It is not possible to determine whether these events are related directly to sildenafil, to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these or other factors.

Seizure, seizure recurrence

Your pharmacist can provide more information about sildenafil.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 10.03. Revision date: 9/17/2012.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

Do not take sildenafil if you are also using a nitrate drug for chest pain or heart problems. This includes nitroglycerin (Nitrostat, Nitrolingual, Nitro-Dur, Nitro-Bid, and others), isosorbide dinitrate (Dilatrate-SR, Isordil, Sorbitrate), and isosorbide mononitrate (Imdur, ISMO, Monoket). Nitrates are also found in some recreational drugs such as amyl nitrate or nitrite ("poppers"). Taking sildenafil with a nitrate medicine can cause a sudden and serious decrease in blood pressure.

During sexual activity, if you become dizzy or nauseated, or have pain, numbness, or tingling in your chest, arms, neck, or jaw, stop and call your doctor right away. You could be having a serious side effect of sildenafil.

Do not take sildenafil more than once a day. Allow 24 hours to pass between doses. Do not take Viagra while also taking Revatio, unless your doctor tells you to.

Contact your doctor or seek emergency medical attention if your erection is painful or lasts longer than 4 hours. A prolonged erection (priapism) can damage the penis.

Sildenafil can decrease blood flow to the optic nerve of the eye, causing sudden vision loss. This has occurred in a small number of people taking sildenafil, most of whom also had heart disease, diabetes, high blood pressure, high cholesterol, or certain pre-existing eye problems, and in those who smoke or are over 50 years old. It is not clear whether sildenafil is the actual cause of vision loss.

Stop using sildenafil and get emergency medical help if you have sudden vision loss.

Do not take sildenafil if you are also using a nitrate drug for chest pain or heart problems. This includes nitroglycerin (Nitrostat, Nitrolingual, Nitro-Dur, Nitro-Bid, and others), isosorbide dinitrate (Dilatrate-SR, Isordil, Sorbitrate), and isosorbide mononitrate (Imdur, ISMO, Monoket). Nitrates are also found in some recreational drugs such as amyl nitrate or nitrite ("poppers"). Taking sildenafil with a nitrate medicine can cause a sudden and serious decrease in blood pressure.

To make sure sildenafil is safe for you, tell your doctor about your other medical conditions, especially:

• heart disease or heart rhythm problems, coronary artery disease;
• a recent history (in the past 6 months) of a heart attack, stroke, or congestive heart failure;
• high or low blood pressure;
• liver or kidney disease;
• a blood cell disorder such as sickle cell anemia, multiple myeloma, or leukemia;
• a bleeding disorder such as hemophilia;
• a stomach ulcer;
• retinitis pigmentosa (an inherited condition of the eye);
• a physical deformity of the penis (such as Peyronie's disease); or
• if you have been told you should not have sexual intercourse for health reasons.

Sildenafil can decrease blood flow to the optic nerve of the eye, causing sudden vision loss. This has occurred in a small number of people taking sildenafil, most of whom also had heart disease, diabetes, high blood pressure, high cholesterol, or certain pre-existing eye problems, and in those who smoke or are over 50 years old. It is not clear whether sildenafil is the actual cause of vision loss. Stop using sildenafil and get emergency medical help if you have sudden vision loss.

FDA pregnancy category B: This medication is not expected to be harmful to an unborn baby. Do not use sildenafil without telling your doctor if you are pregnant or plan to become pregnant during treatment.

It is not known if sildenafil passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Do not give this medication to anyone under 18 years old without medical advice.

Since Viagra is used as needed, you are not likely to miss a dose.

If you miss a dose of Revatio, take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

• Sexual Problems in Men

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

Erectile Dysfunction (ED)

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 ED 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 management of PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity and delay clinical worsening.203 204 205 206 207 208 209 210 211 213 235

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

Efficacy established principally in patients with NYHA/WHO functional class II–III PAH (idiopathic or associated with connective tissue diseases).203 208 235

Recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy has failed.242 Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.242 245

In patients with inadequate response to initial monotherapy, may consider combination therapy with a prostanoid or endothelin-receptor antagonist (added sequentially).242 By targeting different pathophysiologic pathways of the disease, such combination therapy may provide additive and/or synergistic benefits.243 244 246

Because increased mortality has been observed in children receiving higher (more effective) dosages of sildenafil, FDA currently does not recommend use of the drug in patients <18 years of age.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

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 Concomitant use of riociguat.247 (See Specific Drugs under Interactions.)

• Do not use for treatment of ED in men for whom sexual activity is inadvisable because of underlying cardiovascular status.1 67 154 189

Warnings/Precautions

Warnings

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 ED 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

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

Nonarteritic anterior ischemic optic neuropathy (NAION) reported rarely in patients receiving PDE type 5 inhibitors for the treatment of ED.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

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

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

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

Possible prolonged (>4 hours) erections 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

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., ED, 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

Thorough medical history and physical examination recommended to diagnose ED, 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 ED.12 28 70 81 118 119 144 152 161

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

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

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

Safety and efficacy not established for use in combination with other treatments for ED; combined therapy is not recommended.1 155

Specific Populations

Category B.1 203

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

Manufacturer states that safety and efficacy not established in children.1 203 229 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 patients <18 years of age.233 248 However, FDA states that there may be situations in which the risk-benefit profile may be acceptable in individual children (e.g., when other treatment options are limited and sildenafil can be used with close monitoring).248

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

Pooled clinical trial data indicate that efficacy in men ≥65 years of age with ED 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 ED.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

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

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

Common Adverse Effects

ED: 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

• Selective inhibitor of 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