Viagra (Sildenafil Citrate): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Description for Viagra

VIAGRA (sildenafil citrate), an oral therapy for erectile dysfunction, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5).

Sildenafil citrate is designated chemically as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate and has the following structural formula:

Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7.

VIAGRA is formulated as blue, film-coated rounded-diamond-shaped tablets equivalent to 25 mg, 50 mg, and 100 mg of sildenafil for oral administration. In addition to the active ingredient, sildenafil citrate, each tablet contains the following inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD & C Blue #2 aluminum lake.

Uses for Viagra

VIAGRA is indicated for thetreatment of erectile dysfunction.

Dosage for Viagra

Dosage Information

For most patients, the recommended dose is 50 mg taken,as needed, approximately 1 hour before sexual activity. However, VIAGRA may betaken anywhere from 30 minutes to 4 hours before sexual activity. The maximumrecommended dosing frequency is once per day.

Based on effectiveness and toleration, the dose may beincreased to a maximum recommended dose of 100 mg or decreased to 25 mg.

Use With Food

VIAGRA may be taken with or without food.

Dosage Adjustments In Specific Situations

VIAGRA was shown to potentiate the hypotensive effects ofnitrates and its administration in patients who use nitric oxide donors such asorganic nitrates or organic nitrites in any form is therefore contraindicated [seeCONTRAINDICATIONS, DRUG INTERACTIONS, and CLINICALPHARMACOLOGY].

When VIAGRA is co-administered with an alpha-blocker,patients should be stable on alpha-blocker therapy prior to initiating VIAGRAtreatment and VIAGRA should be initiated at 25 mg [see WARNINGS ANDPRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

Dosage Adjustments Due To Drug Interactions

Ritonavir

The recommended dose for ritonavir-treated patients is 25mg prior to sexual activity and the recommended maximum dose is 25 mg within a48 hour period because concomitant administration increased the blood levels ofsildenafil by 11-fold [see WARNINGS AND PRECAUTIONS, DRUGINTERACTIONS, and CLINICAL PHARMACOLOGY].

CYP3A4 Inhibitors

Consider a starting dose of 25 mg in patients treatedwith strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, or saquinavir)or erythromycin. Clinical data have shown that co-administration withsaquinavir or erythromycin increased plasma levels of sildenafil by about 3fold [see DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Dosage Adjustments In Special Populations

Consider a starting dose of 25 mg in patients > 65years, patients with hepatic impairment (e.g., cirrhosis), and patients withsevere renal impairment (creatinine clearance < 30 mL/minute) becauseadministration of VIAGRA in these patients resulted in higher plasma levels ofsildenafil [see Use in Specific Populations and CLINICAL PHARMACOLOGY].

HOW SUPPLIED

Dosage Forms And Strengths

VIAGRA is supplied as blue, film-coated,rounded-diamond-shaped tablets containing sildenafil citrate equivalent to 25mg, 50 mg, or 100 mg of sildenafil. Tablets are debossed with PFIZER on oneside and VGR25, VGR50 or VGR100 on the other to indicate the dosage strengths.

Storage And Handling

VIAGRA (sildenafil citrate) issupplied as blue, film-coated, rounded-diamond-shaped tablets containingsildenafil citrate equivalent to the nominally indicated amount of sildenafiland debossed on the obverse and reverse sides as follows:

Recommended Storage

Store at 25°C (77°F); excursions permitted to 15-30°C(59-86°F) [see USP Controlled Room Temperature].

Distributed by: Pfizer Labs, Division of Pfizer Inc., NY,NY 10017. Revised: Sep 2015

Side Effects for Viagra

The following are discussed in more detail in othersections of the labeling:

• Cardiovascular [see WARNINGS AND PRECAUTIONS]
• Prolonged Erection and Priapism [see WARNINGS AND PRECAUTIONS]
• Effects on the Eye [see WARNINGS AND PRECAUTIONS]
• Hearing Loss [see WARNINGS AND PRECAUTIONS]
• Hypotension when Co-administered with Alpha-blockers or Anti-hypertensives [see WARNINGS AND PRECAUTIONS]
• Adverse Reactions with the Concomitant Use of Ritonavir [see WARNINGS AND PRECAUTIONS]
• Combination with other PDE5 Inhibitors or Other Erectile Dysfunction Therapies [see WARNINGS AND PRECAUTIONS]
• Effects on Bleeding [see WARNINGS AND PRECAUTIONS]
• Counseling Patients About Sexually Transmitted Diseases [see WARNINGS AND PRECAUTIONS]

The most common adverse reactions reported in clinicaltrials ( > 2%) are headache, flushing, dyspepsia, abnormal vision, nasal congestion, back pain, myalgia, nausea, dizziness, and rash.

Clinical Trials Experience

Because clinical trials are conducted under widelyvarying conditions, adverse reaction rates observed in the clinical trials of adrug cannot be directly compared to rates in the clinical trials of anotherdrug and may not reflect the rates observed in clinical practice.

VIAGRA was administered to over 3700 patients (aged 19-87years) during pre-marketing clinical trials worldwide. Over 550 patients weretreated for longer than one year.

In placebo-controlled clinical studies, thediscontinuation rate due to adverse reactions for VIAGRA (2.5%) was notsignificantly different from placebo (2.3%).

In fixed-dose studies, the incidence of some adversereactions increased with dose. The type of adverse reactions in flexible-dosestudies, which reflect the recommended dosage regimen, was similar to that forfixed-dose studies. At doses above the recommended dose range, adversereactions were similar to those detailed in Table 1 below but generally werereported more frequently.

Table 1: Adverse Reactions Reported by ≥ 2% ofPatients Treated with VIAGRA and More Frequent than Placebo in Fixed-Dose PhaseII/III Studies

When VIAGRA was taken asrecommended (on an as-needed basis) in flexible-dose, placebo-controlledclinical trials of two to twenty-six weeks duration, patients took VIAGRA atleast once weekly, and the following adverse reactions were reported:

Table 2: Adverse ReactionsReported by ≥ 2% of Patients Treated with VIAGRA and More Frequent thanPlacebo in Flexible-Dose Phase II/III Studies

The following events occurredin < 2% of patients in controlled clinical trials; a causal relationship toVIAGRA is uncertain. Reported events include those with a plausible relation todrug use; omitted are minor events and reports too imprecise to be meaningful:

Body as a Whole: face edema,photosensitivity reaction, shock, asthenia, pain, chills, accidental fall,abdominal pain, allergic reaction, chest pain, accidental injury.

Cardiovascular: angina pectoris, AVblock, migraine, syncope, tachycardia, palpitation, hypotension, posturalhypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heartfailure, abnormal electrocardiogram, cardiomyopathy.

Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, drymouth, liver function tests abnormal, rectal hemorrhage, gingivitis.

Hemic and Lymphatic: anemia and leukopenia.

Metabolic and Nutritional: thirst, edema, gout, unstable diabetes, hyperglycemia, peripheral edema, hyperuricemia, hypoglycemic reaction, hypernatremia.

Musculoskeletal: arthritis, arthrosis, myalgia, tendon rupture, tenosynovitis, bone pain, myasthenia, synovitis.

Nervous: ataxia, hypertonia, neuralgia, neuropathy, paresthesia, tremor, vertigo, depression, insomnia, somnolence, abnormal dreams, reflexes decreased, hypesthesia.

Respiratory: asthma, dyspnea, laryngitis, pharyngitis, sinusitis, bronchitis, sputum increased, coughincreased.

Skin and Appendages: urticaria, herpes simplex, pruritus, sweating, skin ulcer, contact dermatitis, exfoliativedermatitis.

Special Senses: sudden decrease or lossof hearing, mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, earpain, eye hemorrhage, cataract, dry eyes.

Urogenital: cystitis, nocturia,urinary frequency, breast enlargement, urinary incontinence, abnormalejacul*tion, genital edema and anorg*smia.

Analysis of the safety databasefrom controlled clinical trials showed no apparent difference in adversereactions in patients taking VIAGRA with and without anti-hypertensive medication.This analysis was performed retrospectively, and was not powered to detect anypre-specified difference in adverse reactions.

Postmarketing Experience

The following adverse reactionshave been identified during post approval use of VIAGRA. Because thesereactions are reported voluntarily from a population of uncertain size, it isnot always possible to reliably estimate their frequency or establish a causalrelationship to drug exposure. These events have been chosen for inclusioneither due to their seriousness, reporting frequency, lack of clear alternativecausation, or a combination of these factors.

Cardiovascular and Cerebrovascular

Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, suddencardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transientischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, andpulmonary hemorrhage have been reported post-marketing in temporal associationwith the use of VIAGRA. Most, but not all, of these patients had preexistingcardiovascular risk factors. Many of these events were reported to occur duringor shortly after sexual activity, and a few were reported to occur shortlyafter the use of VIAGRA without sexual activity. Others were reported to haveoccurred hours to days after the use of VIAGRA and sexual activity. It is notpossible to determine whether these events are related directly to VIAGRA, tosexual activity, to the patient's underlying cardiovascular disease, to acombination of these factors, or to other factors [see WARNINGS ANDPRECAUTIONS and PATIENT INFORMATION].

Hemic and Lymphatic: vaso-occlusive crisis: In a small, prematurely terminatedstudy of REVATIO (sildenafil) in patients with pulmonary arterial hypertension (PAH) secondary to sickle cell disease, vaso-occlusive crises requiringhospitalization were more commonly reported in patients who received sildenafilthan in those randomized to placebo. The clinical relevance of this finding tomen treated with VIAGRA for ED is not known.

Nervous: seizure, seizurerecurrence, anxiety, and transient global amnesia.

Respiratory: epistaxis

Special senses

Hearing: Cases of sudden decreaseor loss of hearing have been reported postmarketing in temporal associationwith the use of PDE5 inhibitors, including VIAGRA. In some of the cases,medical conditions and other factors were reported that may have also played arole in the otologic adverse events. In many cases, medical follow-upinformation was limited. It is not possible to determine whether these reportedevents are related directly to the use of VIAGRA, to the patient's underlyingrisk factors for hearing loss, a combination of these factors, or to otherfactors [see WARNINGS AND PRECAUTIONSand PATIENT INFORMATION].

Ocular: diplopia, temporary vision loss/decreased vision, ocular redness or bloodshot appearance, ocular burning, ocular swelling/pressure,increased intraocular pressure, retinal edema, retinal vascular disease orbleeding, and vitreous traction/detachment.

Non-arteritic anterior ischemicoptic neuropathy (NAION), a cause of decreased vision including permanent lossof vision, has been reported rarely post-marketing in temporal association withthe use of phosphodiesterase type 5 (PDE5) inhibitors, including VIAGRA. Most,but not all, of these patients had underlying anatomic or vascular risk factorsfor developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary arterydisease, hyperlipidemia and smoking. It is not possible to determine whetherthese events are related directly to the use of PDE5 inhibitors, to thepatient's underlying vascular risk factors or anatomical defects, to acombination of these factors, or to other factors [see WARNINGS ANDPRECAUTIONS and PATIENT INFORMATION].

Urogenital: prolonged erection, priapism [see WARNINGSAND PRECAUTIONS and PATIENT INFORMATION], and hematuria.

Drug Interactions for Viagra

Nitrates

Administration of VIAGRA with nitric oxide donors such asorganic nitrates or organic nitrites in any form is contraindicated. Consistentwith its known effects on the nitric oxide/cGMP pathway, VIAGRA was shown topotentiate the hypotensive effects of nitrates [see DOSAGE ANDADMINISTRATION, CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].

Alpha-blockers

Use caution when co-administering alpha-blockers withVIAGRA because of potential additive blood pressure-lowering effects. WhenVIAGRA is co-administered with an alpha-blocker, patients should be stable onalpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should beinitiated at the lowest dose [see DOSAGE AND ADMINISTRATION, WARNINGSAND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Amlodipine

When VIAGRA 100 mg was co-administered with amlodipine (5mg or 10 mg) to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic [see WARNINGS ANDPRECAUTIONS, CLINICAL PHARMACOLOGY].

Ritonavir And Other CYP3A4 Inhibitors

Co-administration of ritonavir, a strong CYP3A4inhibitor, greatly increased the systemic exposure of sildenafil (11-foldincrease in AUC). It is therefore recommended not to exceed a maximum singledose of 25 mg of VIAGRA in a 48 hour period [see DOSAGE AND ADMINISTRATION,WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

Co-administration of erythromycin, a moderate CYP3A4 inhibitor,resulted in a 160% and 182% increases in sildenafil Cmax and AUC, respectively.Co-administration of saquinavir, a strong CYP3A4 inhibitor, resulted in 140%and 210% increases in sildenafil Cmax and AUC, respectively. Stronger CYP3A4inhibitors such as ketoconazole or itraconazole could be expected to havegreater effects than seen with saquinavir. A starting dose of 25 mg of VIAGRAshould be considered in patients taking erythromycin or strong CYP3A4inhibitors (such as saquinavir, ketoconazole, itraconazole) [see DOSAGE ANDADMINISTRATION, CLINICAL PHARMACOLOGY].

Alcohol

In a drug-drug interaction study sildenafil 50 mg givenwith alcohol 0.5 g/kg in which mean maximum blood alcohol levels of 0.08% wasachieved, sildenafil did not potentiate the hypotensive effect of alcohol inhealthy volunteers [see CLINICAL PHARMACOLOGY].

Warnings for Viagra

Included as part of the PRECAUTIONS section.

Precautions for Viagra

Cardiovascular

There is a potential for cardiac risk of sexual activity inpatients with preexisting cardiovascular disease. Therefore, treatments for erectile dysfunction, including VIAGRA, should not be generally used in men forwhom sexual activity is inadvisable because of their underlying cardiovascular status. The evaluation of erectile dysfunction should include a determinationof potential underlying causes and the identification of appropriate treatmentfollowing a complete medical assessment.

VIAGRA has systemic vasodilatory properties that resultedin transient decreases in supine blood pressure in healthy volunteers (meanmaximum decrease of 8.4/5.5 mmHg), [see CLINICAL PHARMACOLOGY]. Whilethis normally would be expected to be of little consequence in most patients,prior to prescribing VIAGRA, physicians should carefully consider whether theirpatients with underlying cardiovascular disease could be affected adversely bysuch vasodilatory effects, especially in combination with sexual activity.

Use with caution in patients with the followingunderlying conditions which can be particularly sensitive to the actions of vasodilators including VIAGRA – those with left ventricular outflow obstruction(e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and thosewith severely impaired autonomic control of blood pressure.

There are no controlled clinical data on the safety orefficacy of VIAGRA in the following groups; if prescribed, this should be donewith caution.

• Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months;
• Patients with resting hypotension (BP < 90/50 mmHg) or hypertension (BP > 170/110 mmHg);
• Patients with cardiac failure or coronary artery disease causing unstable angina.

Prolonged Erection And Priapism

Prolonged erection greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reportedinfrequently since market approval of VIAGRA. In the event of an erection thatpersists longer than 4 hours, the patient should seek immediate medicalassistance. If priapism is not treated immediately, penile tissue damage andpermanent loss of potency could result.

VIAGRA should be used with caution in patients withanatomical deformation of the penis (such as angulation, cavernosal fibrosis orPeyronie's disease), or in patients who have conditions which may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).However, there are no controlled clinical data on the safety or efficacy ofVIAGRA in patients with sickle cell or related anemias.

Effects On The Eye

Physicians should advise patients to stop use of allphosphodiesterase type 5 (PDE5) inhibitors, including VIAGRA, and seek medicalattention in the event of a sudden loss of vision in one or both eyes. Such anevent may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanentloss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. Based on published literature,the annual incidence of NAION is 2.5-11.8 cases per 100,000 in males aged ≥ 50. An observational study evaluated whether recent use of PDE5inhibitors, as a class, was associated with acute onset of NAION. The resultssuggest an approximate 2 fold increase in the risk of NAION within 5 half-livesof PDE5 inhibitor use. From this information, it is not possible to determinewhether these events are related directly to the use of PDE5 inhibitors or toother factors [see ADVERSE REACTIONS].

Physicians should consider whether their patients withunderlying NAION risk factors could be adversely affected by use of PDE5inhibitors. Individuals who have already experienced NAION are at increasedrisk of NAION recurrence. Therefore, PDE5 inhibitors, including VIAGRA, shouldbe used with caution in these patients and only when the anticipated benefitsoutweigh the risks. Individuals with “crowded” optic disc are also consideredat greater risk for NAION compared to the general population, however, evidenceis insufficient to support screening of prospective users of PDE5 inhibitors,including VIAGRA, for this uncommon condition.

There are no controlled clinical data on the safety orefficacy of VIAGRA in patients with retinitis pigmentosa (a minority of thesepatients have genetic disorders of retinal phosphodiesterases); if prescribed,this should be done with caution.

Hearing Loss

Physicians should advise patients to stop taking PDE5inhibitors, including VIAGRA, and seek prompt medical attention in the event ofsudden decrease or loss of hearing. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to theintake of PDE5 inhibitors, including VIAGRA. It is not possible to determinewhether these events are related directly to the use of PDE5 inhibitors or toother factors [see ADVERSE REACTIONS].

Hypotension When Co-administered With Alpha-blockers Or Anti-hypertensives

Alpha-blockers

Caution is advised when PDE5 inhibitors areco-administered with alpha-blockers. PDE5 inhibitors, including VIAGRA, andalpha-adrenergic blocking agents are both vasodilators with blood pressurelowering effects. When vasodilators are used in combination, an additive effecton blood pressure may occur. In some patients, concomitant use of these twodrug classes can lower blood pressure significantly [see DRUG INTERACTIONSand CLINICAL PHARMACOLOGY] leading to symptomatic hypotension (e.g.,dizziness, lightheadedness, fainting).

Consideration should be given to the following:

• Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors. Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor.
• In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest dose [see DOSAGE AND ADMINISTRATION].
• In those patients already taking an optimized dose of a PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose. Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure when taking a PDE5 inhibitor.
• Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

Anti-hypertensives

VIAGRA has systemic vasodilatory properties and mayfurther lower blood pressure in patients taking antihypertensive medications.

In a separate drug interaction study, when amlodipine, 5mg or 10 mg, and VIAGRA, 100 mg were orally administered concomitantly tohypertensive patients mean additional blood pressure reduction of 8 mmHg systolic and 7 mmHg diastolic were noted [see DRUG INTERACTIONS and CLINICALPHARMACOLOGY].

Adverse Reactions With The Concomitant Use Of Ritonavir

The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-foldincrease in AUC). If VIAGRA is prescribed to patients taking ritonavir, cautionshould be used. Data from subjects exposed to high systemic levels ofsildenafil are limited. Decreased blood pressure, syncope, and prolongederection were reported in some healthy volunteers exposed to high doses ofsildenafil (200-800 mg). To decrease the chance of adverse reactions inpatients taking ritonavir, a decrease in sildenafil dosage is recommended [seeDOSAGE AND ADMINISTRATION, DRUG INTERACTIONS, and CLINICALPHARMACOLOGY].

Combination With Other PDE5 Inhibitors Or Other Erectile Dysfunction Therapies

The safety and efficacy of combinations of VIAGRA withother PDE5 Inhibitors, including REVATIO or other pulmonary arterialhypertension (PAH) treatments containing sildenafil, or other treatments forerectile dysfunction have not been studied. Such combinations may further lowerblood pressure. Therefore, the use of such combinations is not recommended.

Effects On Bleeding

There have been postmarketing reports of bleeding eventsin patients who have taken VIAGRA. A causal relationship between VIAGRA andthese events has not been established. In humans, VIAGRA has no effect onbleeding time when taken alone or with aspirin. However, in vitro studies withhuman platelets indicate that sildenafil potentiates the antiaggregatory effectof sodium nitroprusside (a nitric oxide donor). In addition, the combination of heparin and VIAGRA had an additive effect on bleeding time in the anesthetizedrabbit, but this interaction has not been studied in humans.

The safety of VIAGRA is unknown in patients with bleedingdisorders and patients with active peptic ulceration.

Counseling Patients About Sexually Transmitted Diseases

The use of VIAGRA offers no protection against sexuallytransmitted diseases. Counseling of patients about the protective measuresnecessary to guard against sexually transmitted diseases, including the HumanImmunodeficiency Virus (HIV), may be considered.

Patient Counseling Information

See FDA-approved patientlabeling (PATIENT INFORMATION)

Nitrates

Physicians should discuss withpatients the contraindication of VIAGRA with regular and/or intermittent use ofnitric oxide donors, such as organic nitrates or organic nitrites in any form [seeCONTRAINDICATIONS].

Guanylate Cyclase (GC) Stimulators

Physicians should discuss withpatients the contraindication of VIAGRA with use of guanylate cyclasestimulators such as riociguat [see CONTRAINDICATIONS].

Concomitant Use with Drugs Which Lower Blood Pressure

Physicians should advisepatients of the potential for VIAGRA to augment the blood pressure loweringeffect of alpha-blockers and anti-hypertensive medications. Concomitantadministration of VIAGRA and an alpha-blocker may lead to symptomatichypotension in some patients. Therefore, when VIAGRA is co-administered withalpha-blockers, patients should be stable on alpha-blocker therapy prior toinitiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose [seeWARNINGS AND PRECAUTIONS].

Cardiovascular Considerations

Physicians should discuss withpatients the potential cardiac risk of sexual activity in patients withpreexisting cardiovascular risk factors. Patients who experience symptoms(e.g., angina pectoris, dizziness, nausea) upon initiation of sexual activityshould be advised to refrain from further activity and should discuss theepisode with their physician [see WARNINGS AND PRECAUTIONS].

Sudden Loss of Vision

Physicians should advisepatients to stop use of all PDE5 inhibitors, including VIAGRA, and seek medicalattention in the event of a sudden loss of vision in one or both eyes. Such anevent may be a sign of non-arteritic anterior ischemic optic neuropathy(NAION), a cause of decreased vision including possible permanent loss ofvision, that has been reported rarely post-marketing in temporal associationwith the use of all PDE5 inhibitors. It is not possible to determine whetherthese events are related directly to the use of PDE5 inhibitors or to otherfactors. Physicians should discuss with patients the increased risk of NAION inindividuals who have already experienced NAION in one eye. Physicians shouldalso discuss with patients the increased risk of NAION among the generalpopulation in patients with a “crowded” optic disc, although evidence isinsufficient to support screening of prospective users of PDE5 inhibitor,including VIAGRA, for this uncommon condition [see WARNINGS ANDPRECAUTIONS and ADVERSE REACTIONS].

Sudden Hearing Loss

Physicians should advisepatients to stop taking PDE5 inhibitors, including VIAGRA, and seek promptmedical attention in the event of sudden decrease or loss of hearing. Theseevents, which may be accompanied by tinnitus and dizziness, have been reportedin temporal association to the intake of PDE5 inhibitors, including VIAGRA. Itis not possible to determine whether these events are related directly to theuse of PDE5 inhibitors or to other factors [see WARNINGS ANDPRECAUTIONS and ADVERSE REACTIONS].

Priapism

Physicians should warn patientsthat prolonged erections greater than 4 hours and priapism (painful erectionsgreater than 6 hours in duration) have been reported infrequently since marketapproval of VIAGRA. In the event of an erection that persists longer than 4hours, the patient should seek immediate medical assistance. If priapism is nottreated immediately, penile tissue damage and permanent loss of potency mayresult [see WARNINGS AND PRECAUTIONS].

Avoid Use with other PDE5 Inhibitors

Physicians should informpatients not to take VIAGRA with other PDE5 inhibitors including REVATIO orother pulmonary arterial hypertension (PAH) treatments containing sildenafil.Sildenafil is also marketed as REVATIO for the treatment of PAH. The safety andefficacy of VIAGRA with other PDE5 inhibitors, including REVATIO, have not beenstudied [see WARNINGS AND PRECAUTIONS].

Sexually Transmitted Disease

The use of VIAGRA offers noprotection against sexually transmitted diseases. Counseling of patients aboutthe protective measures necessary to guard against sexually transmitteddiseases, including the Human Immunodeficiency Virus (HIV), may be considered [seeWARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Sildenafil was not carcinogenic when administered to rats for 24 months at a dose resulting in total systemicdrug exposure (AUCs) for unbound sildenafil and its major metabolite of 29-and42-times, for male and female rats, respectively, the exposures observed inhuman males given the Maximum Recommended Human Dose (MRHD) of 100 mg.Sildenafil was not carcinogenic when administered to mice for 18-21 months atdosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately0.6 times the MRHD on a mg/m² basis.

Mutagenesis

Sildenafil was negative in invitro bacterial and Chinese hamster ovary cell assays to detect mutagenicity,and in vitro human lymphocytes and in vivo mouse micronucleus assays to detectclastogenicity.

Impairment of Fertility

There was no impairment offertility in rats given sildenafil up to 60 mg/kg/day for 36 days to femalesand 102 days to males, a dose producing an AUC value of more than 25 times thehuman male AUC.

Use In Specific Populations

Pregnancy

Pregnancy Category B.

VIAGRA is not indicated for use in women. There are noadequate and well-controlled studies of sildenafil in pregnant women.

Risk Summary

Based on animal data, VIAGRA is not predicted to increasethe risk of adverse developmental outcomes in humans.

Animal Data

No evidence of teratogenicity, embryotoxicity or fetotoxicitywas observed in rats and rabbits which received up to 200 mg/kg/day duringorganogenesis. These doses represent, respectively, about 20 and 40 times theMaximum Recommended Human Dose (MRHD) on a mg/m² basis in a 50 kgsubject. In the rat pre-and postnatal development study, the no observed adverse effect dose was 30 mg/kg/day given for 36 days. In the nonpregnant ratthe AUC at this dose was about 20 times human AUC.

Pediatric Use

VIAGRA is not indicated for use in pediatric patients.Safety and effectiveness have not been established in pediatric patients.

Geriatric Use

Healthy elderly volunteers (65 years or over) had areduced clearance of sildenafil resulting in approximately 84% and 107% higherplasma AUC values of sildenafil and its active N-desmethyl metabolite,respectively, compared to those seen in healthy young volunteers (18-45 years)[see CLINICAL PHARMACOLOGY]. Due to age-differences in plasma proteinbinding, the corresponding increase in the AUC of free (unbound) sildenafil andits active N-desmethyl metabolite were 45% and 57%, respectively [seeCLINICAL PHARMACOLOGY].

Of the total number of subjects in clinical studies ofViagra, 18% were 65 years and older, while 2% were 75 years and older. Nooverall differences in safety or efficacy were observed between older ( > 65years of age) and younger ( < 65 years of age) subjects.

However, since higher plasma levels may increase theincidence of adverse reactions, a starting dose of 25 mg should be consideredin older subjects due to the higher systemic exposure [see DOSAGE ANDADMINISTRATION].

Renal Impairment

No dose adjustment is required for mild (CLcr=50-80mL/min) and moderate (CLcr=30-49 mL/min) renal impairment. In volunteers withsevere renal impairment (Clcr < 30 mL/min), sildenafil clearance was reduced,resulting in higher plasma exposure of sildenafil (~2 fold), approximatelydoubling of Cmax and AUC. A starting dose of 25 mg should be considered inpatients with severe renal impairment [see DOSAGE AND ADMINISTRATION andCLINICAL PHARMACOLOGY].

Hepatic Impairment

In volunteers with hepatic impairment (Child-Pugh Class Aand B), sildenafil clearance was reduced, resulting in higher plasma exposureof sildenafil (47% for C max and 85% for AUC). The pharmaco*kinetics ofsildenafil in patients with severely impaired hepatic function (Child-PughClass C) have not been studied. A starting dose of 25 mg should be consideredin patients with any degree of hepatic impairment [see DOSAGE ANDADMINISTRATION and CLINICAL PHARMACOLOGY].

Overdose Information for Viagra

In studies with healthy volunteers of single doses up to 800mg, adverse reactions were similar to those seen at lower doses but incidencerates and severities were increased.

In cases of overdose, standard supportive measures shouldbe adopted as required. Renal dialysis is not expected to accelerate clearanceas sildenafil is highly bound to plasma proteins and it is not eliminated inthe urine.

Contraindications for Viagra

Nitrates

Consistent with its known effects on the nitricoxide/cGMP pathway [see CLINICAL PHARMACOLOGY], VIAGRA was shown topotentiate the hypotensive effects of nitrates, and its administration topatients who are using nitric oxide donors such as organic nitrates or organicnitrites in any form either regularly and/or intermittently is thereforecontraindicated.

After patients have taken VIAGRA, it is unknown whennitrates, if necessary, can be safely administered. Although plasma levels ofsildenafil at 24 hours post dose are much lower than at peak concentration, itis unknown whether nitrates can be safely co-administered at this time point [seeDOSAGE AND ADMINISTRATION, DRUG INTERACTIONS, and CLINICALPHARMACOLOGY].

Hypersensitivity Reactions

VIAGRA is contraindicated in patients with a knownhypersensitivity to sildenafil, as contained in VIAGRA and REVATIO, or anycomponent of the tablet. Hypersensitivity reactions have been reported,including rash and urticaria [see ADVERSE REACTIONS].

Concomitant Guanylate Cyclase (GC) Stimulators

Do not use VIAGRA in patients who are using a GCstimulator, such as riociguat. PDE5 inhibitors, including VIAGRA, maypotentiate the hypotensive effects of GC stimulators.

Clinical Pharmacology for Viagra

Mechanism Of Action

The physiologic mechanism oferection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylatecyclase, which results in increased levels of cyclic guanosine monophosphate(cGMP), producing smooth muscle relaxation in the corpus cavernosum andallowing inflow of blood.

Sildenafil enhances the effectof NO by inhibiting phosphodiesterase type 5 (PDE5), which is responsible fordegradation of cGMP in the corpus cavernosum. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum. When sexual stimulation causeslocal release of NO, inhibition of PDE5 by sildenafil causes increased levelsof cGMP in the corpus cavernosum, resulting in smooth muscle relaxation andinflow of blood to the corpus cavernosum. Sildenafil at recommended doses hasno effect in the absence of sexual stimulation.

Binding Characteristics

Studies in vitro have shownthat sildenafil is selective for PDE5. Its effect is more potent on PDE5 thanon other known phosphodiesterases (10-fold for PDE6, > 80-fold for PDE1, > 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11).Sildenafil is approximately 4,000-fold more selective for PDE5 compared toPDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is onlyabout 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. Thislower selectivity is thought to be the basis for abnormalities related to colorvision [see Pharmacodynamics].

In addition to human corpuscavernosum smooth muscle, PDE5 is also found in other tissues includingplatelets, vascular and visceral smooth muscle, and skeletal muscle, brain,heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminalvesicle. The inhibition of PDE5 in some of these tissues by sildenafil may bethe basis for the enhanced platelet antiaggregatory activity of NO observed invitro, an inhibition of platelet thrombus formation in vivo and peripheralarterial-venous dilatation in vivo.

Pharmacodynamics

Effects of VIAGRA on Erectile Response

In eight double-blind,placebo-controlled crossover studies of patients with either organic orpsychogenic erectile dysfunction, sexual stimulation resulted in improvederections, as assessed by an objective measurement of hardness and duration oferections (RigiScan®), after VIAGRA administration compared withplacebo. Most studies assessed the efficacy of VIAGRA approximately 60 minutespost dose. The erectile response, as assessed by RigiScan®,generally increased with increasing sildenafil dose and plasma concentration.The time course of effect was examined in one study, showing an effect for upto 4 hours but the response was diminished compared to 2 hours.

Effects of VIAGRA on Blood Pressure

Single oral doses of sildenafil(100 mg) administered to healthy volunteers produced decreases in sitting bloodpressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3mmHg). The decrease in sitting blood pressure was most notable approximately1-2 hours after dosing, and was not different than placebo at 8 hours. Similareffects on blood pressure were noted with 25 mg, 50 mg and 100 mg of VIAGRA,therefore the effects are not related to dose or plasma levels within thisdosage range. Larger effects were recorded among patients receiving concomitantnitrates [see CONTRAINDICATIONS].

Figure 1: Mean Change fromBaseline in Sitting Systolic Blood Pressure, Healthy Volunteers

Effects of VIAGRA on Blood Pressure When Nitroglycerin is Subsequently Administered

Based on the pharmaco*kineticprofile of a single 100 mg oral dose given to healthy normal volunteers, theplasma levels of sildenafil at 24 hours post dose are approximately 2 ng/mL(compared to peak plasma levels of approximately 440 ng/mL). In the followingpatients: age > 65 years, hepatic impairment (e.g., cirrhosis), severe renalimpairment (e.g., creatinine clearance < 30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24hours post dose have been found to be 3 to 8 times higher than those seen inhealthy volunteers. Although plasma levels of sildenafil at 24 hours post doseare much lower than at peak concentration, it is unknown whether nitrates canbe safely co-administered at this time point [see CONTRAINDICATIONS].

Effects of VIAGRA on Blood Pressure When Co-administered with Alpha-Blockers

Three double-blind,placebo-controlled, randomized, two-way crossover studies were conducted toassess the interaction of VIAGRA with doxazosin, an alpha-adrenergic blockingagent.

Study 1: VIAGRA with Doxazosin

In the first study, a singleoral dose of VIAGRA 100 mg or matching placebo was administered in a 2-periodcrossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, VIAGRA 100mg or matching placebo was administered simultaneously with doxazosin.Following a review of the data from these first 4 subjects (details providedbelow), the VIAGRA dose was reduced to 25 mg. Thereafter, 17 subjects weretreated with VIAGRA 25 mg or matching placebo in combination with doxazosin 4 mg(15 subjects) or doxazosin 8 mg (2 subjects). The mean subject age was 66.5years.

For the 17 subjects whor*ceived VIAGRA 25 mg and matching placebo, the placebo-subtracted mean maximumdecreases from baseline (95% CI) in systolic blood pressure were as follows:

The mean profiles of the changefrom baseline in standing systolic blood pressure in subjects treated withdoxazosin in combination with 25 mg VIAGRA or matching placebo are shown inFigure 2.

Figure 2: Mean StandingSystolic Blood Pressure Change from Baseline

Blood pressure was measuredimmediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and8 hours after VIAGRA or matching placebo. Outliers were defined as subjectswith a standing systolic blood pressure of < 85 mmHg or a decrease frombaseline in standing systolic blood pressure of > 30 mmHg at one or moretimepoints. There were no subjects treated with VIAGRA 25 mg who had a standingSBP < 85mmHg. There were three subjects with a decrease from baseline instanding systolic BP > 30mmHg following VIAGRA 25 mg, one subject with adecrease from baseline in standing systolic BP > 30 mmHg following placeboand two subjects with a decrease from baseline in standing systolic BP > 30mmHg following both VIAGRA and placebo. No severe adverse events potentiallyrelated to blood pressure effects were reported in this group.

Of the four subjects whor*ceived VIAGRA 100 mg in the first part of this study, a severe adverse eventrelated to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with VIAGRA with symptomslasting for 8 hours), and mild adverse events potentially related to bloodpressure effects were reported in two others (dizziness, headache and fatigueat 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hoursafter dosing). There were no reports of syncope among these patients. For thesefour subjects, the placebo-subtracted mean maximum decreases from baseline in supine and standing systolic blood pressures were 14.8 mmHg and 21.5 mmHg,respectively. Two of these subjects had a standing SBP < 85mmHg. Both ofthese subjects were protocol violators, one due to a low baseline standing SBP,and the other due to baseline orthostatic hypotension.

Study 2: VIAGRA with Doxazosin

In the second study, a singleoral dose of VIAGRA 50 mg or matching placebo was administered in a 2-periodcrossover design to 20 generally healthy males with BPH. Following at least 14consecutive days of doxazosin, VIAGRA 50 mg or matching placebo wasadministered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin8 mg (3 subjects). The mean subject age in this study was 63.9 years.

Twenty subjects received VIAGRA50 mg, but only 19 subjects received matching placebo. One patient discontinuedthe study prematurely due to an adverse event of hypotension following dosingwith VIAGRA 50 mg. This patient had been taking minoxidil, a potentvasodilator, during the study.

For the 19 subjects whor*ceived both VIAGRA and matching placebo, the placebo-subtracted mean maximumdecreases from baseline (95% CI) in systolic blood pressure were as follows:

The mean profiles of the changefrom baseline in standing systolic blood pressure in subjects treated withdoxazosin in combination with 50 mg VIAGRA or matching placebo are shown inFigure 3.

Figure 3: Mean StandingSystolic Blood Pressure Change from Baseline

Blood pressure was measuredafter administration of VIAGRA at the same times as those specified for thefirst doxazosin study. There were two subjects who had a standing SBP of <85 mmHg. In these two subjects, hypotension was reported as a moderately severeadverse event, beginning at approximately 1 hour after administration of VIAGRA50 mg and resolving after approximately 7.5 hours. There was one subject with adecrease from baseline in standing systolic BP > 30mmHg following VIAGRA 50mg and one subject with a decrease from baseline in standing systolic BP >30 mmHg following both VIAGRA 50 mg and placebo. There were no severe adverseevents potentially related to blood pressure and no episodes of syncopereported in this study.

Study 3: VIAGRA with Doxazosin

In the third study, a singleoral dose of VIAGRA 100 mg or matching placebo was administered in a 3-periodcrossover design to 20 generally healthy males with BPH. In dose period 1,subjects were administered open-label doxazosin and a single dose of VIAGRA 50mg simultaneously, after at least 14 consecutive days of doxazosin. If asubject did not successfully complete this first dosing period, he wasdiscontinued from the study. Subjects who had successfully completed theprevious doxazosin interaction study (using VIAGRA 50 mg), including nosignificant hemodynamic adverse events, were allowed to skip dose period 1.Treatment with doxazosin continued for at least 7 days after dose period 1.Thereafter, VIAGRA 100 mg or matching placebo was administered simultaneouslywith doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standardcrossover fashion. The mean subject age in this study was 66.4 years.

Twenty-five subjects werescreened. Two were discontinued after study period 1: one failed to meetpre-dose screening qualifications and the other experienced symptomatichypotension as a moderately severe adverse event 30 minutes after dosing withopen-label VIAGRA 50 mg. Of the twenty subjects who were ultimately assigned totreatment, a total of 13 subjects successfully completed dose period 1, andseven had successfully completed the previous doxazosin study (using VIAGRA 50mg).

For the 20 subjects whor*ceived VIAGRA 100 mg and matching placebo, the placebo-subtracted meanmaximum decreases from baseline (95% CI) in systolic blood pressure were asfollows:

The mean profiles of the changefrom baseline in standing systolic blood pressure in subjects treated withdoxazosin in combination with 100 mg VIAGRA or matching placebo are shown inFigure 4.

Figure 4: Mean StandingSystolic Blood Pressure Change from Baseline

Blood pressure was measuredafter administration of VIAGRA at the same times as those specified for theprevious doxazosin studies. There were three subjects who had a standing SBP of < 85 mmHg. All three were taking VIAGRA 100 mg, and all three reported mildadverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease frombaseline in standing systolic BP > 30 mmHg following VIAGRA 100 mg, onesubject with a decrease from baseline in standing systolic BP > 30 mmHgfollowing placebo and one subject with a decrease from baseline in standingsystolic BP > 30 mmHg following both VIAGRA and placebo. While there were nosevere adverse events potentially related to blood pressure reported in thisstudy, one subject reported moderate vasodilatation after both VIAGRA 50 mg and100 mg. There were no episodes of syncope reported in this study.

Effect of VIAGRA on Blood Pressure When Co-administered with Anti-hypertensives

When VIAGRA 100 mg oral wasco-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients,the mean additional reduction on supine blood pressure was 8 mmHg systolic and7 mmHg diastolic.

Effect of VIAGRA on Blood Pressure When Co-administered with Alcohol

VIAGRA (50 mg) did notpotentiate the hypotensive effect of alcohol (0.5 g/kg) in healthy volunteerswith mean maximum blood alcohol levels of 0.08%. The maximum observed decreasein systolic blood pressure was -18.5 mmHg when sildenafil was co-administeredwith alcohol versus -17.4 mmHg when alcohol was administered alone. The maximumobserved decrease in diastolic blood pressure was -17.2 mmHg when sildenafil wasco-administered with alcohol versus -11.1 mmHg when alcohol was administeredalone. There were no reports of postural dizziness or orthostatic hypotension.The maximum recommended dose of 100 mg sildenafil was not evaluated in thisstudy [see DRUG INTERACTIONS].

Effects of VIAGRA on Cardiac Parameters

Single oral doses of sildenafilup to 100 mg produced no clinically relevant changes in the ECGs of normal malevolunteers.

Studies have produced relevantdata on the effects of VIAGRA on cardiac output. In one small, open-label,uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization. A total dose of 40 mg sildenafil wasadministered by four intravenous infusions.

The results from this pilot studyare shown in Table 3; the mean resting systolic and diastolic blood pressuresdecreased by 7% and 10% compared to baseline in these patients. Mean restingvalues for right atrial pressure, pulmonary artery pressure, pulmonary arteryoccluded pressure and cardiac output decreased by 28%, 28%, 20% and 7%respectively. Even though this total dosage produced plasma sildenafilconcentrations which were approximately 2 to 5 times higher than the meanmaximum plasma concentrations following a single oral dose of 100 mg in healthymale volunteers, the hemodynamic response to exercise was preserved in thesepatients.

Table 3: Hemodynamic Data inPatients with Stable Ischemic Heart Disease after Intravenous Administration of40 mg of Sildenafil

In a double-blind study, 144patients with erectile dysfunction and chronic stable angina limited byexercise, not receiving chronic oral nitrates, were randomized to a single doseof placebo or VIAGRA 100 mg 1 hour prior to exercise testing. The primaryendpoint was time to limiting angina in the evaluable cohort. The mean times(adjusted for baseline) to onset of limiting angina were 423.6 and 403.7seconds for sildenafil (N=70) and placebo, respectively. These resultsdemonstrated that the effect of VIAGRA on the primary endpoint wasstatistically non-inferior to placebo.

Effects of VIAGRA on Vision

At single oral doses of 100 mgand 200 mg, transient dose-related impairment of color discrimination wasdetected using the Farnsworth-Munsell 100-hue test, with peak effects near thetime of peak plasma levels. This finding is consistent with the inhibition ofPDE6, which is involved in phototransduction in the retina. Subjects in thestudy reported this finding as difficulties in discriminating blue/green. Anevaluation of visual function at doses up to twice the maximum recommended doserevealed no effects of VIAGRA on visual acuity, intraocular pressure, orpupillometry.

Effects of VIAGRA on Sperm

There was no effect on sperm motility or morphology after single 100 mg oral doses of VIAGRA in healthyvolunteers.

Pharmaco*kinetics

VIAGRA is rapidly absorbedafter oral administration, with a mean absolute bioavailability of 41% (range2563%). The pharmaco*kinetics of sildenafil are dose-proportional over therecommended dose range. It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with propertiessimilar to the parent, sildenafil. Both sildenafil and the metabolite haveterminal half lives of about 4 hours.

Mean sildenafil plasmaconcentrations measured after the administration of a single oral dose of 100mg to healthy male volunteers is depicted below:

Figure 5: Mean SildenafilPlasma Concentrations in Healthy Male Volunteers

Absorption and Distribution

VIAGRA is rapidly absorbed.Maximum observed plasma concentrations are reached within 30 to 120 minutes(median 60 minutes) of oral dosing in the fasted state. When VIAGRA is takenwith a high fat meal, the rate of absorption is reduced, with a mean delay in Tmaxof 60 minutes and a mean reduction in Cmax of 29%. The mean steady state volumeof distribution (Vss) for sildenafil is 105 L, indicating distribution into thetissues. Sildenafil and its major circulating N-desmethyl metabolite are bothapproximately 96% bound to plasma proteins. Protein binding is independent oftotal drug concentrations.

Based upon measurements ofsildenafil in sem*n of healthy volunteers 90 minutes after dosing, less than0.001% of the administered dose may appear in the sem*n of patients.

Metabolism and Excretion

Sildenafil is clearedpredominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepaticmicrosomal isoenzymes. The major circulating metabolite results fromN-desmethylation of sildenafil, and is itself further metabolized. Thismetabolite has a PDE selectivity profile similar to sildenafil and an in vitro potencyfor PDE5 approximately 50% of the parent drug. Plasma concentrations of thismetabolite are approximately 40% of those seen for sildenafil, so that themetabolite accounts for about 20% of sildenafil's pharmacologic effects.

After either oral orintravenous administration, sildenafil is excreted as metabolites predominantlyin the feces (approximately 80% of administered oral dose) and to a lesserextent in the urine (approximately 13% of the administered oral dose). Similarvalues for pharmaco*kinetic parameters were seen in normal volunteers and in thepatient population, using a population pharmaco*kinetic approach.

Pharmaco*kinetics in Special Populations

Geriatrics: Healthy elderlyvolunteers (65 years or over) had a reduced clearance of sildenafil, resultingin approximately 84% and 107% higher plasma AUC values of sildenafil and itsactive N-desmethyl metabolite, respectively, compared to those seen in healthyyounger volunteers (18-45 years). Due to age-differences in plasma proteinbinding, the corresponding increase in the AUC of free (unbound) sildenafil andits active N-desmethyl metabolite were 45% and 57%, respectively [see DOSAGEAND ADMINISTRATION, and Use In Specific Populations]

Renal Impairment: In volunteers with mild(CLcr=50-80 mL/min) and moderate (CLcr=30-49 mL/min) renal impairment, thepharmaco*kinetics of a single oral dose of VIAGRA (50 mg) were not altered. Involunteers with severe (CLcr < 30 mL/min) renal impairment, sildenafilclearance was reduced, resulting in approximately doubling of AUC and Cmax comparedto age-matched volunteers with no renal impairment [see DOSAGE ANDADMINISTRATION, and Use In Specific Populations].

In addition, N-desmethylmetabolite AUC and Cmax values significantly increased by 200% and 79%,respectively in subjects with severe renal impairment compared to subjects withnormal renal function.

Hepatic Impairment: In volunteers withhepatic impairment (Child-Pugh Class A and B), sildenafil clearance wasreduced, resulting in increases in AUC (85%) and Cmax (47%) compared toage-matched volunteers with no hepatic impairment. The pharmaco*kinetics ofsildenafil in patients with severely impaired hepatic function (Child-PughClass C) have not been studied [see DOSAGE AND ADMINISTRATION, and Usein Specific Populations].

Therefore, age > 65, hepaticimpairment and severe renal impairment are associated with increased plasmalevels of sildenafil. A starting oral dose of 25 mg should be considered inthose patients [see DOSAGE AND ADMINISTRATION].

Drug Interaction Studies

Effects of Other Drugs on VIAGRA

Sildenafil metabolism isprincipally mediated by CYP3A4 (major route) and CYP2C9 (minor route).Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance andinducers of these isoenzymes may increase sildenafil clearance. The concomitantuse of erythromycin or strong CYP3A4 inhibitors (e.g., saquinavir,ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor,cimetidine, is associated with increased plasma levels of sildenafil [see DOSAGEAND ADMINISTRATION].

In vivo Studies

Cimetidine (800 mg), anonspecific CYP inhibitor, caused a 56% increase in plasma sildenafilconcentrations when co-administered with VIAGRA (50 mg) to healthy volunteers.

When a single 100 mg dose ofVIAGRA was administered with erythromycin, a moderate CYP3A4 inhibitor, atsteady state (500 mg bid for 5 days), there was a 160% increase in sildenafil Cmaxand a 182% increase in sildenafil AUC. In addition, in a study performed inhealthy male volunteers, co-administration of the HIV protease inhibitor saquinavir, also a CYP3A4 inhibitor, at steady state (1200 mg tid) with Viagra(100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210%increase in sildenafil AUC. Viagra had no effect on saquinavirpharmaco*kinetics. A stronger CYP3A4 inhibitor such as ketoconazole oritraconazole could be expected to have greater effect than that seen withsaquinavir. Population pharmaco*kinetic data from patients in clinical trialsalso indicated a reduction in sildenafil clearance when it was co-administeredwith CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [seeDOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

In another study in healthymale volunteers, co-administration with the HIV protease inhibitor ritonavir,which is a highly potent P450 inhibitor, at steady state (500 mg bid) withVIAGRA (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafilCmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours theplasma levels of sildenafil were still approximately 200 ng/mL, compared toapproximately 5 ng/mL when sildenafil was dosed alone. This is consistent withritonavir's marked effects on a broad range of P450 substrates. VIAGRA had noeffect on ritonavir pharmaco*kinetics [see DOSAGE AND ADMINISTRATION and DRUGINTERACTIONS].

Although the interactionbetween other protease inhibitors and sildenafil has not been studied, theirconcomitant use is expected to increase sildenafil levels.

In a study of healthy malevolunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) withendothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9and possibly of CYP2C19) at steady state (125 mg b.i.d.) resulted in a 63%decrease of sildenafil AUC and a 55% decrease in sildenafil Cmax . Concomitantadministration of strong CYP3A4 inducers, such as rifampin, is expected tocause greater decreases in plasma levels of sildenafil.

Single doses of antacid(magnesium hydroxide/aluminum hydroxide) did not affect the bioavailability ofVIAGRA.

In healthy male volunteers,there was no evidence of a clinically significant effect of azithromycin (500mg daily for 3 days) on the systemic exposure of sildenafil or its majorcirculating metabolite.

Pharmaco*kinetic data frompatients in clinical trials showed no effect on sildenafil pharmaco*kinetics ofCYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such asselective serotonin reuptake inhibitors, tricyclic antidepressants), thiazideand related diuretics, ACE inhibitors, and calcium channel blockers. The AUC ofthe active metabolite, N-desmethyl sildenafil, was increased 62% by loop andpotassium-sparing diuretics and 102% by nonspecific beta-blockers. Theseeffects on the metabolite are not expected to be of clinical consequence.

Effects of VIAGRA on Other Drugs

In Vitro Studies

Sildenafil is a weak inhibitorof the CYP isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC50 > 150 μM).Given sildenafil peak plasma concentrations of approximately 1 μM afterrecommended doses, it is unlikely that VIAGRA will alter the clearance ofsubstrates of these isoenzymes.

In Vivo Studies

No significant interactionswere shown with tolbutamide (250 mg) or warfarin (40 mg), both of which aremetabolized by CYP2C9.

In a study of healthy malevolunteers, sildenafil (100 mg) did not affect the steady statepharmaco*kinetics of the HIV protease inhibitors, saquinavir and ritonavir, bothof which are CYP3A4 substrates.

VIAGRA (50 mg) did notpotentiate the increase in bleeding time caused by aspirin (150 mg).

Sildenafil at steady state, ata dose not approved for the treatment of erectile dysfunction (80 mg t.i.d.)resulted in a 50% increase in AUC and a 42% increase in C max of bosentan (125mg b.i.d.).

Clinical Studies

In clinical studies, VIAGRA wasassessed for its effect on the ability of men with erectile dysfunction (ED) toengage in sexual activity and in many cases specifically on the ability toachieve and maintain an erection sufficient for satisfactory sexual activity. VIAGRAwas evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized,double-blind, placebo-controlled trials of up to 6 months in duration, using avariety of study designs (fixed dose, titration, parallel, crossover). VIAGRAwas administered to more than 3,000 patients aged 19 to 87 years, with ED ofvarious etiologies (organic, psychogenic, mixed) with a mean duration of 5years. VIAGRA demonstrated statistically significant improvement compared toplacebo in all 21 studies. The studies that established benefit demonstratedimprovements in success rates for sexual intercourse compared with placebo.

Efficacy Endpoints in Controlled Clinical Studies

The effectiveness of VIAGRA wasevaluated in most studies using several assessment instruments. The primarymeasure in the principal studies was a sexual function questionnaire (theInternational Index of Erectile Function -IIEF) administered during a 4-weektreatment-free run-in period, at baseline, at follow-up visits, and at the endof double-blind, placebo-controlled, at-home treatment. Two of the questionsfrom the IIEF served as primary study endpoints; categorical responses wereelicited to questions about (1) the ability to achieve erections sufficient forsexual intercourse and (2) the maintenance of erections after penetration. Thepatient addressed both questions at the final visit for the last 4 weeks of thestudy. The possible categorical responses to these questions were (0) noattempted intercourse, (1) never or almost never, (2) a few times, (3)sometimes, (4) most times, and (5) almost always or always. Also collected aspart of the IIEF was information about other aspects of sexual function,including information on erectile function, org*sm, desire, satisfaction withintercourse, and overall sexual satisfaction. Sexual function data were alsorecorded by patients in a daily diary. In addition, patients were asked aglobal efficacy question and an optional partner questionnaire wasadministered.

Efficacy Results from Controlled Clinical Studies

The effect on one of the majorend points, maintenance of erections after penetration, is shown in Figure 6,for the pooled results of 5 fixed-dose, dose-response studies of greater thanone month duration, showing response according to baseline function. Resultswith all doses have been pooled, but scores showed greater improvement at the50 and 100 mg doses than at 25 mg. The pattern of responses was similar for theother principal question, the ability to achieve an erection sufficient forintercourse. The titration studies, in which most patients received 100 mg,showed similar results. Figure 6 shows that regardless of the baseline levelsof function, subsequent function in patients treated with VIAGRA was better thanthat seen in patients treated with placebo. At the same time, on-treatmentfunction was better in treated patients who were less impaired at baseline.

Figure 6: Effect of VIAGRAand Placebo on Maintenance of Erection by Baseline Score

The frequency of patientsreporting improvement of erections in response to a global question in four ofthe randomized, double-blind, parallel, placebo-controlled fixed dose studies(1797 patients) of 12 to 24 weeks duration is shown in Figure 7. These patientshad erectile dysfunction at baseline that was characterized by median categoricalscores of 2 (a few times) on principal IIEF questions. Erectile dysfunction wasattributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%)etiologies. Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mgand 100 mg of VIAGRA, respectively, reported an improvement in their erections,compared to 24% on placebo. In the titration studies (n=644) (with mostpatients eventually receiving 100 mg), results were similar.

Figure 7: Percentage ofPatients Reporting an Improvement in Erections

The patients in studies hadvarying degrees of ED. One-third to one-half of the subjects in these studiesreported successful intercourse at least once during a 4-week, treatment-freerun-in period.

In many of the studies, of bothfixed dose and titration designs, daily diaries were kept by patients. In thesestudies, involving about 1600 patients, analyses of patient diaries showed noeffect of VIAGRA on rates of attempted intercourse (about 2 per week), butthere was clear treatment-related improvement in sexual function: per patientweekly success rates averaged 1.3 on 50-100 mg of VIAGRA vs 0.4 on placebo;similarly, group mean success rates (total successes divided by total attempts)were about 66% on VIAGRA vs about 20% on placebo.

During 3 to 6 months ofdouble-blind treatment or longer-term (1 year), open-label studies, fewpatients withdrew from active treatment for any reason, including lack ofeffectiveness. At the end of the long-term study, 88% of patients reported thatVIAGRA improved their erections.

Men with untreated ED hadrelatively low baseline scores for all aspects of sexual function measured(again using a 5-point scale) in the IIEF. VIAGRA improved these aspects ofsexual function: frequency, firmness and maintenance of erections; frequency oforg*sm; frequency and level of desire; frequency, satisfaction and enjoyment ofintercourse; and overall relationship satisfaction.

One randomized, double-blind,flexible-dose, placebo-controlled study included only patients with erectiledysfunction attributed to complications of diabetes mellitus (n=268). As in theother titration studies, patients were started on 50 mg and allowed to adjustthe dose up to 100 mg or down to 25 mg of VIAGRA; all patients, however, werereceiving 50 mg or 100 mg at the end of the study. There were highlystatistically significant improvements on the two principal IIEF questions(frequency of successful penetration during sexual activity and maintenance oferections after penetration) on VIAGRA compared to placebo. On a globalimprovement question, 57% of VIAGRA patients reported improved erections versus10% on placebo. Diary data indicated that on VIAGRA, 48% of intercourseattempts were successful versus 12% on placebo.

One randomized, double-blind,placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patientswith erectile dysfunction resulting from spinal cord injury (n=178) wasconducted. The changes from baseline in scoring on the two end point questions(frequency of successful penetration during sexual activity and maintenance oferections after penetration) were highly statistically significantly in favorof VIAGRA. On a global improvement question, 83% of patients reported improvederections on VIAGRA versus 12% on placebo. Diary data indicated that on VIAGRA,59% of attempts at sexual intercourse were successful compared to 13% onplacebo.

Across all trials, VIAGRAimproved the erections of 43% of radical prostatectomy patients compared to 15%on placebo.

Subgroup analyses of responsesto a global improvement question in patients with psychogenic etiology in twofixed-dose studies (total n=179) and two titration studies (total n=149) showed84% of VIAGRA patients reported improvement in erections compared with 26% ofplacebo. The changes from baseline in scoring on the two end point questions(frequency of successful penetration during sexual activity and maintenance oferections after penetration) were highly statistically significantly in favorof VIAGRA. Diary data in two of the studies (n=178) showed rates of successfulintercourse per attempt of 70% for VIAGRA and 29% for placebo.

Efficacy Results in Subpopulations in Controlled Clinical Studies

A review of populationsubgroups demonstrated efficacy regardless of baseline severity, etiology, raceand age. VIAGRA was effective in a broad range of ED patients, including thosewith a history of coronary artery disease, hypertension, other cardiac disease, peripheral vascular disease, diabetes mellitus, depression, coronary arterybypass graft (CABG), radical prostatectomy, transurethral resection of theprostate (TURP) and spinal cord injury, and in patients taking antidepressants/antipsychotics and anti-hypertensives/diuretics.

Patient Information for Viagra

VIAGRA®
(vi-AG-rah)
(sildenafil citrate) Tablets

What is the most importantinformation I should know about VIAGRA?

VIAGRA can cause your bloodpressure to drop suddenly to an unsafe level if it is taken with certain othermedicines. Donot take VIAGRA if you take any other medicines called “nitrates.” Nitrates areused to treat chest pain (angina). A sudden drop in blood pressure can causeyou to feel dizzy, faint, or have a heart attack or stroke.

Do not take VIAGRA if you takemedicines called guanylate cyclase stimulators which include:

• Riociguat (Adempas®) a medicine that treats pulmonary arterial hypertension and chronicthromboembolic pulmonary hypertension.

Tell all your healthcareproviders that you take VIAGRA. If you need emergency medical care for a heart problem, itwill be important for your healthcare provider to know when you last tookVIAGRA.

Stop sexual activity and getmedical help right away if you get symptoms such as chest pain, dizziness, ornausea during sex.

Sexual activity can put anextra strain on your heart, especially if your heart is already weak from aheart attack or heart disease. Ask your doctor if your heart is healthy enoughto handle the extra strain of having sex.

VIAGRA does not protect you oryour partner from getting sexually transmitted diseases, including HIV—thevirus that causes AIDS.

What is VIAGRA?

VIAGRA is a prescriptionmedicine used to treat erectile dysfunction (ED). You will not get an erectionjust by taking this medicine. VIAGRA helps a man with erectile dysfunction getand keep an erection only when he is sexually excited (stimulated).

VIAGRA is not for use in womenor children.

It is not known if VIAGRA issafe and effective in women or children under 18 years of age.

Who should not take VIAGRA?

Do not take VIAGRA if you:

• take medicines called nitrates (such as nitroglycerin)
• use street drugs called “poppers” such as amyl nitrate or amyl nitrite, and butyl nitrate
• take any medicines called guanylate cyclase stimulators such as riociguat (Adempas)
• are allergic to sildenafil, as contained in VIAGRA and REVATIO, or any of the ingredients in VIAGRA. See the end of this leaflet for a complete list of ingredients in VIAGRA.

What should I tell myhealthcare provider before taking VIAGRA?

Before you take VIAGRA, tellyour healthcare provider if you:

• have or have had heart problems such as a heart attack, irregular heartbeat, angina, chest pain, narrowing of the aortic valve or heart failure
• have had heart surgery within the last 6 months
• have pulmonary hypertension
• have had a stroke
• have low blood pressure, or high blood pressure that is not controlled
• have a deformed penis shape
• have had an erection that lasted for more than 4 hours
• have problems with your blood cells such as sickle cell anemia, multiple myeloma, or leukemia
• have retinitis pigmentosa, a rare genetic (runs in families) eye disease
• have ever had severe vision loss, including an eye problem called non-arteritic anterior ischemic optic neuropathy (NAION)
• have bleeding problems
• have or have had stomach ulcers
• have liver problems
• have kidney problems or are having kidney dialysis
• have any other medical conditions

Tell your healthcareprovider about all the medicines you take*,including prescription and over-the-countermedicines, vitamins, and herbal supplements.

VIAGRA may affect the way othermedicines work, and other medicines may affect the way VIAGRA works causingside effects. Especially tell your healthcare provider if you take any of thefollowing:

• medicines called nitrates (see “What is the most important information I should know about VIAGRA?”)
• medicines called guanylate cyclase stimulators, such as riociguat (Adempas)
• medicines called alpha blockers such as Hytrin (terazosin HCl), Flomax (tamsulosin HCl), Cardura (doxazosin mesylate), Minipress (prazosin HCl), Uroxatral (alfuzosin HCl), Jalyn (dutasteride and tamsulosin HCl), or Rapaflo (silodosin). Alpha-blockers are sometimes prescribed for prostate problems or high blood pressure. In some patients, the use of VIAGRA with alpha-blockers can lead to a drop in blood pressure or to fainting.
• medicines called HIV protease inhibitors, such as ritonavir (Norvir), indinavir sulfate (Crixivan), saquinavir (Fortovase or Invirase) or atazanavir sulfate (Reyataz)
• some types of oral antifungal medicines, such as ketoconazole (Nizoral), and itraconazole (Sporanox)
• some types of antibiotics, such as clarithromycin (Biaxin), telithromycin (Ketek), or erythromycin
• other medicines that treat high blood pressure
• other medicines or treatments for ED
• VIAGRA contains sildenafil, which is the same medicine found in another drug called REVATIO. REVATIO is used to treat a rare disease called pulmonary arterial hypertension (PAH). VIAGRA should not be used with REVATIO or with other PAH treatments containing sildenafil or any other PDE5 inhibitors (such as Adcirca [tadalafil]).

Ask your healthcare provider orpharmacist for a list of these medicines, if you are not sure.

Know the medicines you take.Keep a list of them to show to your healthcare provider and pharmacist when youget a new medicine.

How should I take VIAGRA?

• Take VIAGRA exactly as your healthcare provider tells you to take it.
• Your healthcare provider will tell you how much VIAGRA to take and when to take it.
• Your healthcare provider may change your dose if needed.
• Take VIAGRA about 1 hour before sexual activity. You may take VIAGRA between 30 minutes to 4 hours before sexual activity if needed.
• VIAGRA can be taken with or without food. If you take VIAGRA after a high fat meal (such as a cheeseburger and french fries), VIAGRA may take a little longer to start working
• Do not take VIAGRA more than 1 time a day.
• If you accidentally take too much VIAGRA, call your doctor or go to the nearest hospital emergency room right away.

What are the possible sideeffects of VIAGRA?

VIAGRA can cause seriousside effects. Rarely reported side effects include:

• an erection that will not go away (priapism). If you have an erection that lasts more than 4 hours, get medical help right away. If it is not treated right away, priapism can permanently damage your penis.
• sudden vision loss in one or both eyes. Sudden vision loss in one or both eyes can be a sign of a serious eye problem called non-arteritic anterior ischemic optic neuropathy (NAION). Stop taking VIAGRA and call your healthcare provider right away if you have sudden vision loss in one or both eyes.
• sudden hearing decrease or hearing loss. Some people may also have ringing in their ears (tinnitus) or dizziness. If you have these symptoms, stop taking VIAGRA and contact a doctor right away.

The most common side effectsof VIAGRA are:

• headache
• flushing
• upset stomach
• abnormal vision, such as changes in color vision (such as having a blue color tinge) and blurred vision
• stuffy or runny nose
• back pain
• muscle pain
• nausea
• dizziness
• rash

In addition, heart attack,stroke, irregular heartbeats and death have happened rarely in men takingVIAGRA. Most, but not all, of these men had heart problems before takingVIAGRA. It is not known if VIAGRA caused these problems.

Tell your healthcare providerif you have any side effect that bothers you or does not go away.

These are not all the possibleside effects of VIAGRA. For more information, ask your healthcare provider orpharmacist.

Call your doctor for medicaladvice about side effects. You may report side effects to FDA at 1800-FDA-1088.

How should I store VIAGRA?

• Store VIAGRA at room temperature between 68°F to 77°F (20°C to 25°C).

Keep VIAGRA and allmedicines out of the reach of children.

General information aboutthe safe and effective use of VIAGRA.

Medicines are sometimesprescribed for purposes other than those listed in a Patient Informationleaflet. Do not use VIAGRA for a condition for which it was not prescribed. Donot give VIAGRA to other people, even if they have the same symptoms that youhave. It may harm them.

This Patient Informationleaflet summarizes the most important information about VIAGRA. If you wouldlike more information, talk with your healthcare provider. You can ask yourhealthcare provider or pharmacist for information about VIAGRA that is writtenfor health professionals.

For more information, go towww.viagra.com, or call 1-888-4VIAGRA

What are the ingredients inVIAGRA?

Active ingredient: sildenafil citrate

Inactive ingredients: microcrystallinecellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium,magnesium stearate, hypromellose, titanium dioxide, lactose, triacetin, and FD& C Blue #2 aluminum lake

This Patient Information hasbeen approved by the U.S. Food and Drug Administration.