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【功效】
    治疗男性阴茎勃起功能障碍。viagra以现代高科技制药方法，浓缩精制而成的壮阳之极品，对于阳痿、早泄、勃起能力、勃起坚度，持久能力效果显著。

【规格】50mg

【成分】枸橼酸西地那非（sildenafil citrate）

【生产厂商】美国辉瑞制药厂

    辉瑞公司日前宣布，“伟哥”(viagra)使用说明书的修改已得到美国食品及药物管理局（fda）的批准，修改后的使用说明书提供了最新的医疗消息，可以帮助医生更好地诊断和治疗男性勃起功能障碍。

【药品名称】 枸橼酸西地那非片 
【英文名称】 sildenafil citrate tablets 
【药品别名】 伟哥(万艾可，viagra)
本品主要成分及化学名称：1-[4-乙氧基-3-[5-（6，7-二氢-1-甲基-7-氧代-3-丙基-1h-吡唑并[4，3d]嘧啶）]苯磺酰]-4-甲基哌嗪枸橼酸盐 
【性状】 本品为浅蓝色菱形薄膜衣,除去薄膜衣后为白色结晶粉末。
【药理作用】 
    本品是治疗阴茎勃起功能障碍（ed）的口服药。它是西地那非枸橼酸盐，一种对环磷酸鸟苷（cgmp）特异的5型磷酸二酯酶（pde5）选择性抑制剂。作用机制：阴茎勃起的生理机制涉及性刺激过程中阴茎海绵体内一氧化氮（no） 的释放。no激活鸟苷酸环化酶导致环磷酸鸟苷（cgmp）水平增高，使海绵体内平滑肌松弛，血液充盈。

    药效学 西地那非对阴茎勃起反应的作用：西地那非（sildenafil，viagra,万艾可）是高度选择性磷酸二酯酶5(pde5)抑制剂，pde5在阴茎海绵体中高度表达，而在其它组织中（包括血小板、血管和内脏平滑肌、骨骼肌），表达低下。西地那非通过选择性抑制pde5，增强一氧化氮(no)－cgmp途径，升高cgmp水平而导致阴茎海绵体平滑肌松弛，使勃起功能障碍患者对性刺激产生自然的勃起反应。勃起反应一般随西地那非 剂量和血浆浓度的增加而增强。实验显示，药效可持续至4小时，但反应较2小时时弱。 西地那非对心肌的反应：不论正常或病变的心脏传导组织、心肌细胞、内皮细胞、淋巴组织中均不存在pde5,因而西地那非（pde5抑制剂）无正性肌力作用，不能直接 影响心肌收缩功能。

    西地那非对心脏参数的影响：正常男性志愿者单剂口服西地那非100mg，未发生有临床意义的心电图改变。8位稳定性缺血性心脏病患者在swan－ganz导管监测下， 分4次静脉注射了总量为40mg的西地那非，结果：静息状态下，患者的收缩和舒张压 较基线时分别下降了7%和10%。静息右心房、肺动脉压、肺动脉楔压和心排出量分别 平均下降28%、28%、20%和7%。尽管此静脉注射剂量较健康男性志愿者单剂口服西地那非100mg的平均峰值血药浓度高2～5倍，但患者运动时上述的血流动力学应答仍存在。

    西地那非对血压的反应：健康男性患者单剂口服西地那非100mg，导致卧位血压下降（平均最大幅度8.4/5.5mmhg）服药后1-2小时血压下降最明显，服药后8小时与 安慰剂组无差别。25mg、50mg、100mg西地那非对血压的影响相似，似与药物剂量和 血药浓度无关。同时服用硝酸酯类药物的患者降压作用更大。低血压（90/50mmhg）和硝酸酯类或提供硝酸根的药物是应用西地那非的严格禁忌证。西地那非对血压的最大作用发生在约服药后1小时，即与药物血浆峰值一致。因此，在西地那非的血浆药物峰值 浓度时，性活动可能诱发心脏事件。虽然西地那非引起的低血压反应轻而短暂（一般4小时内血压回到基线），但西地那非和硝酸酯类间的相互作用可产生明显的和更长时间 的血压降低。西地那非半衰期短，24小时内（约6个半衰期）可洗脱药物。美国心脏学院和美国心脏学会已明确指出24小时内使用过硝酸酯类药物者禁用西地那非。

    西地那非对视觉的影响：研究表明，服用2倍于最大推荐剂量的药物时，本品对视力、视网膜电流图、眼压和视乳头大小无影响。可能偶尔存在蓝/绿颜色辨别异常。无论单独使用或与阿司匹林合用，本品对人出血时间没有影响。体外实验中，本 品增强硝普钠（no供体）的抗人类血小板凝聚作用。在麻醉下的家兔，肝素与西地那 非合用对出血时间的延长有叠加作用，但未进行过类似的人体研究。 健康志愿者单剂口服西地那非100mg后，精子的活动力和形态未受影响。

【药代动力学】 
    西地那非口服后吸收迅速，绝对生物利用度约40%。其药代动力学参数在推荐剂 量范围内与剂量成比例。消除以肝脏代谢为主（细胞色素p450同功酶3a4途径），生 成一有活性的代谢产物，其性质与西地那非近似，细胞色素p450同功酶3a4（cyp450 3a4）的强效抑制剂（如红霉素、酮康唑、伊曲康唑）以及细胞色素p450（cyp450） 的非特异性抑制物如西咪替丁与西地那非合用时，可能会导致西地那非血浆水平升高。 西地那非及其代谢产物的消除半衰期约4小时。空腹状态给予25～100mg时，约1小 时内达最大血浆浓度（cmax）127～560ng/ml。西地那非或它的主要代谢产物n-去甲基 代谢产物（n-desmethyl）对pde5选择性强度约为50%，蛋白结合率为96%。在总西地那非最大血浆浓度时，游离西地那非cmax是22ng/ml。口服或静脉给药后，西地那 非主要以代谢产物的形式从粪便中排泄（约为口服剂量的80%），一小部分从尿中排泄 （约为口服剂量的13%）。 
    特殊人群的药代动力学：老年人：健康老年志愿者（≥65岁）的西地那非清除率 降低，游离血药浓度比年青健康志愿者（18－45岁）约高40%。 
    肾功能不全：有轻度（肌酐清除率等于50-80ml/分）和中度（肌酐清除率等于 30-49ml/分）肾损害的志愿受试者单剂口服西地那非50mg的药代动力学没有改变。重 度肾损害（肌酐清除率等于≤30ml/分）的志愿受试者，西地那非的清除率降低，与无 肾脏受损的同年龄组志愿者相比，药时曲线下面积（auc）和cmax几乎加倍。 
肝功能不全：肝硬变（child-pugh 分级a级和b级）志愿受试者的西地那非清除 率降低，与同年龄组无肝损害的志愿者相比，auc和cmax分别增高84%和47%。 因此，年龄65岁以上、肝功能损害、重度肾功能损害会导致血浆西地那非水平升 高。这类患者的起始剂量以25mg为宜。

【适应症】 适用于治疗阴茎勃起功能障碍（ed）

【用法用量】 
    对大多数患者，推荐初始剂量为50mg，在性活动前约1小时服用；但在性活动前0.5～ 4小时内的任何时候服用均可。基于药效和耐受性，剂量可增加至100毫克（最大推荐 剂量）或降低至25毫克。每日最多服用1次。 
    下列因素与血浆西地那非水平（auc）增加有关：年龄65岁以上（增加40%）、 肝脏受损（如肝硬化，增加80%）、重度肾损害（肌酐清除率﹤30ml/分，增加100%）、 同时服用强效细胞色素p450 3a4抑制剂（酮康唑、伊曲康唑增加200%）、红霉素增加 182%、saquinavir增加210%。由于血浆水平较高可能同时增加药效和不良事件发生率， 故这些患者的起始剂量以25mg为宜。研究表明，hiv蛋白酶抑制剂ritonavir可使西地那非血药水平显著增高（auc增 加了11倍）。有鉴于此，建议服用ritonavir的患者，每48小时内用药剂量最多不超过 25mg。

【不良反应】 
    头痛、潮红、消化不良、鼻塞及视觉异常等。视觉异常为轻度和一过性的，主要表现为视物色淡、光感增强或视物模糊。

【禁忌症】 
    服用任何剂型硝酸酯类药物的患者，无论是规律或间断服用，均为禁忌症。对西地那非（万艾可）中任何成分过敏的患者禁用。

【注意事项】 
    西地那非-硝酸酯类影响血压的相互作用，可从给药开始持续到整个6小时的观察期内。所以，在任何情况下，联合给予西地那非和有机硝酸酯类或提供no类药物（如硝 普钠）均属禁忌。 
    以下患者慎用西地那非：阴茎解剖畸形（如阴茎偏曲、海绵体纤维化、peyronie氏病）， 易引起阴茎异常勃起的疾病（如镰状细胞性贫血、多发性骨髓瘤、白血病）。其他治疗 勃起功能障碍的方法与本品合用的安全性和有效性尚未研究，不推荐联合使用。 在已有心血管危险因素存在时，用药后性活动有发生非致命性/致命性心脏事件的 危险。在性活动开始时如出现心绞痛、头晕、恶心等症状，须终止性活动。国外批准本 品上市后，有少量勃起时间延长（超过４小时）和异常勃起（痛性勃起超过６小时）的 报告。如持续勃起超过４小时，患者应立即就诊。如异常勃起未得到即刻处理，阴茎组织将可能受到损害并可能导致永久性勃起功能丧失。 西地那非对性传播疾病无保护作用。

【老年患者用药】 
    健康老年志愿者（≧65岁）的西地那非清除率降低。血药浓度较高，可能同时增加不良事件的发生，故起始剂量以25mg为宜。

【药物相互作用】 
    其他药物对西地那非的作用： 
    体外实验：本品代谢主要通过细胞色素p450 3a4（主要途径）和2c9（次要途径）, 故这些同功酶的抑制剂会降低西地那非的清除。 
    体内实验：健康志愿者同时服用本品50mg和西咪替丁（一种非特异性细胞色素 p450抑制剂）800mg，导致血浆内西地那非浓度增高56%。 
    单剂西地那非100mg与细胞色素p450 3a4的特异性抑制剂红霉素（500mg，一日 两次，共5天达到稳态）合用时，西地那非的药时曲线下面积（auc）升高182%； 单剂西地那非100mg与另一种cyp450 3a4抑制剂hiv蛋白酶抑制剂saquinavir合用， 达到稳态时（1200mg，一日三次），则后者的cmax提高140%，auc增加210%，西地那非不影响后者的药代动力学；酮康唑、伊曲康唑等更强效的cyp450 3a4抑制剂， 上述作用可能更大；当与cyp450 3a4抑制剂 （如酮康唑、红霉素、西咪替丁）合用时，西地那非的清除率降低。可预测同时服用cyp450 3a4的诱导剂（如利福平）将 降低血浆西地那非水平。 
    单剂抗酸药（氢氧化铝/氢氧化镁）对本品生物利用度没有影响；cyp450 2c9抑制 剂（如甲苯磺丁脲、华法令）、cyp450 2d6抑制剂（如选择性5－羟色胺再摄取抑制剂、> 三环抗抑郁药）、噻嗪类药物及噻嗪类利尿剂、血管紧张素转换酶抑制剂、钙通道阻滞 剂等，对西地那非的药代动力学没有影响。 
    襻利尿剂和保钾利尿剂可使西地那非活性代谢产物（n－去甲基西地那非）的auc 增加62%，而非选择性 受体阻滞剂使其增加102%。这些对西地那非代谢产物的影响不会引起临床变化。

西地那非对其他药物的作用： 
    体外实验：本品是一种细胞色素p450 1a2、2c9 、2c19、2d6 、2e1和3a4（ic50 ＞150μm）的弱抑制剂。由于服用推荐剂量西地那非后其血浆峰浓度约为1μm，故西地那非不会改变这些同功酶作用底物的清除。 
    体内试验：高血压患者同时服用西地那非（100mg）和氨氯地平5mg或10mg，仰 卧位收缩压平均进一步降低8mmhg，舒张压平均进一步降低7mmhg。未发现经cyp450 2c9代谢的甲苯磺丁脲（250mg）和华法令（40mg）与西地那非有明显的相互作用。西地那非（50mg）不增加阿司匹林（150mg）所致的出血时间延长。健康志愿者平均最大血 浆酒精浓度为0.08%时，西地那非（50mg）不增强酒精的降压作用。西地那非（100mg）不影 响hiv蛋白酶抑制剂saquinavir、 ritonavir稳态时的药代动力学，后二者都是cyp450 3a4的底物。

【药物过量】 
    当发生药物过量时，应根据需要采取常规支持疗法。因西地那非与血浆蛋白结合率高，故肾脏透析不会增加清除率 

VIAGRA® 
(sildenafil citrate) Tablets

DESCRIPTION

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.

Indications & Dosage

INDICATIONS

VIAGRA is indicated for the treatment of erectile dysfunction.

DOSAGE AND ADMINISTRATION

Dosage Information

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

Based on effectiveness and toleration, the dose may be increased 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 of nitrates and its administration in patients who use nitric oxide donors such as organic nitrates or organic nitrites in any form is therefore contraindicated [see CONTRAINDICATIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

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

Dosage Adjustments Due To Drug Interactions

Ritonavir

The recommended dose for ritonavir-treated patients is 25 mg prior to sexual activity and the recommended maximum dose is 25 mg within a 48 hour period because concomitant administration increased the blood levels of sildenafil by 11-fold [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

CYP3A4 Inhibitors

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

Dosage Adjustments In Special Populations

Consider a starting dose of 25 mg in patients > 65 years, patients with hepatic impairment (e.g., cirrhosis), and patients with severe renal impairment (creatinine clearance < 30 mL/minute) because administration of VIAGRA in these patients resulted in higher plasma levels of sildenafil [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 25 mg, 50 mg, or 100 mg of sildenafil. Tablets are debossed with PFIZER on one side and VGR25, VGR50 or VGR100 on the other to indicate the dosage strengths.

Storage And Handling

VIAGRA (sildenafil citrate) is supplied as blue, film-coated, rounded-diamond-shaped tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil and 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

SIDE EFFECTS

The following are discussed in more detail in other sections 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 clinical trials ( > 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 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 clinical practice.

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

In placebo-controlled clinical studies, the discontinuation rate due to adverse reactions for VIAGRA (2.5%) was not significantly different from placebo (2.3%).

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

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

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

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

The following events occurred in < 2% of patients in controlled clinical trials; a causal relationship to VIAGRA is uncertain. Reported events include those with a plausible relation to drug 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, AV block, migraine, syncope, tachycardia, palpitation, hypotension, postural hypotension, myocardial ischemia, cerebral thrombosis, cardiac arrest, heart failure, abnormal electrocardiogram, cardiomyopathy.

Digestive: vomiting, glossitis, colitis, dysphagia, gastritis, gastroenteritis, esophagitis, stomatitis, dry mouth, 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, cough increased.

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

Special Senses: sudden decrease or loss of hearing, mydriasis, conjunctivitis, photophobia, tinnitus, eye pain, ear pain, eye hemorrhage, cataract, dry eyes.

Urogenital: cystitis, nocturia, urinary frequency, breast enlargement, urinary incontinence, abnormalejaculation, genital edema and anorgasmia.

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

Postmarketing Experience

The following adverse reactions have been identified during post approval use of VIAGRA. 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. These events have been chosen for inclusion either due to their seriousness, reporting frequency, lack of clear alternative causation, or a combination of these factors.

Cardiovascular and Cerebrovascular

Serious cardiovascular, cerebrovascular, and vascular events, including myocardial infarction, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage, transient ischemic attack, hypertension, subarachnoid and intracerebral hemorrhages, and pulmonary hemorrhage have been reported post-marketing in temporal association with the use of VIAGRA. 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 VIAGRA without sexual activity. Others were reported to have occurred hours to days after the use of VIAGRA and sexual activity. It is not possible to determine whether these events are related directly to VIAGRA, to sexual activity, to the patient's underlying cardiovascular disease, to a combination of these factors, or to other factors [see WARNINGS AND PRECAUTIONS and PATIENT INFORMATION].

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

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

Respiratory: epistaxis

Special senses

Hearing: Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including VIAGRA. In some of the cases, medical conditions and other factors were reported that may have also played a role in the otologic adverse events. In many cases, medical follow-up information was limited. It is not possible to determine whether these reported events are related directly to the use of VIAGRA, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors [see WARNINGS AND PRECAUTIONS and 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 or bleeding, and vitreous traction/detachment.

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

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

Drug Interactions

DRUG INTERACTIONS

Nitrates

Administration of VIAGRA with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Consistent with its known effects on the nitric oxide/cGMP pathway, VIAGRA was shown to potentiate the hypotensive effects of nitrates [see DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].

Alpha-blockers

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

Amlodipine

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

Ritonavir And Other CYP3A4 Inhibitors

Co-administration of ritonavir, a strong CYP3A4 inhibitor, greatly increased the systemic exposure of sildenafil (11-fold increase in AUC). It is therefore recommended not to exceed a maximum single dose 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 CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. A starting dose of 25 mg of VIAGRA should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole) [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Alcohol

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

Warnings & Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Cardiovascular

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

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

Use with caution in patients with the following underlying 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 those with severely impaired autonomic control of blood pressure.

There are no controlled clinical data on the safety or efficacy of VIAGRA in the following groups; if prescribed, this should be done with caution.

· Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmiawithin 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 reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency could result.

VIAGRA should be used with caution in patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis or Peyronie'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 of VIAGRA in patients with sickle cell or related anemias.

Effects On The Eye

Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including VIAGRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision including permanent loss 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 PDE5 inhibitors, as a class, was associated with acute onset of NAION. The results suggest an approximate 2 fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see ADVERSE REACTIONS].

Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors. Individuals who have already experienced NAION are at increased risk of NAION recurrence. Therefore, PDE5 inhibitors, including VIAGRA, should be used with caution in these patients and only when the anticipated benefits outweigh the risks. Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is 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 or efficacy of VIAGRA in patients with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases); if prescribed, this should be done with caution.

Hearing Loss

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

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

Alpha-blockers

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including VIAGRA, and alpha-adrenergic blocking agents are both vasodilators with blood pressure lowering effects. When vasodilators are used in combination, an additive effect on blood pressure may occur. In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see DRUG INTERACTIONS and 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 may further lower blood pressure in patients taking antihypertensive medications.

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

Adverse Reactions With The Concomitant Use Of Ritonavir

The concomitant administration of the protease inhibitor ritonavir substantially increases serum concentrations of sildenafil (11-fold increase in AUC). If VIAGRA is prescribed to patients taking ritonavir, caution should be used. Data from subjects exposed to high systemic levels of sildenafil are limited. Decreased blood pressure, syncope, and prolonged erection were reported in some healthy volunteers exposed to high doses of sildenafil (200-800 mg). To decrease the chance of adverse reactions in patients taking ritonavir, a decrease in sildenafil dosage is recommended [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

Combination With Other PDE5 Inhibitors Or Other Erectile Dysfunction Therapies

The safety and efficacy of combinations of VIAGRA with other PDE5 Inhibitors, including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil, or other treatments for erectile dysfunction have not been studied. Such combinations may further lower blood pressure. Therefore, the use of such combinations is not recommended.

Effects On Bleeding

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

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

Counseling Patients About Sexually Transmitted Diseases

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

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION)

Nitrates

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

Guanylate Cyclase (GC) Stimulators

Physicians should discuss with patients the contraindication of VIAGRA with use of guanylate cyclase stimulators such as riociguat [see CONTRAINDICATIONS].

Concomitant Use with Drugs Which Lower Blood Pressure

Physicians should advise patients of the potential for VIAGRA to augment the blood pressure lowering effect of alpha-blockers and anti-hypertensive medications. Concomitant administration of VIAGRA and an alpha-blocker may lead to symptomatic hypotension in some patients. Therefore, when VIAGRA is co-administered with alpha-blockers, patients should be stable on alpha-blocker therapy prior to initiating VIAGRA treatment and VIAGRA should be initiated at the lowest dose [seeWARNINGS AND PRECAUTIONS].

Cardiovascular Considerations

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

Sudden Loss of Vision

Physicians should advise patients to stop use of all PDE5 inhibitors, including VIAGRA, and seek medical attention in the event of a sudden loss of vision in one or both eyes. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including possible permanent loss of vision, that has been reported rarely post-marketing in temporal association with the use of all PDE5 inhibitors. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye. Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a “crowded” optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including VIAGRA, for this uncommon condition [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Sudden Hearing Loss

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

Priapism

Physicians should warn patients that prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) have been reported infrequently since market approval of VIAGRA. In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result [see WARNINGS AND PRECAUTIONS].

Avoid Use with other PDE5 Inhibitors

Physicians should inform patients not to take VIAGRA with other PDE5 inhibitors including REVATIO or other pulmonary arterial hypertension (PAH) treatments containing sildenafil. Sildenafil is also marketed as REVATIO for the treatment of PAH. The safety and efficacy of VIAGRA with other PDE5 inhibitors, including REVATIO, have not been studied [see WARNINGS AND PRECAUTIONS].

Sexually Transmitted Disease

The use of VIAGRA offers no protection against sexually transmitted diseases. Counseling of patients about the protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), may be considered [see WARNINGS 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 systemic drug exposure (AUCs) for unbound sildenafil and its major metabolite of 29-and 42-times, for male and female rats, respectively, the exposures observed in human males given the Maximum Recommended Human Dose (MRHD) of 100 mg. Sildenafil was not carcinogenic when administered to mice for 18-21 months at dosages up to the Maximum Tolerated Dose (MTD) of 10 mg/kg/day, approximately 0.6 times the MRHD on a mg/m² basis.

Mutagenesis

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

Impairment of Fertility

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

Use In Specific Populations

Pregnancy

Pregnancy Category B.

VIAGRA is not indicated for use in women. There are no adequate and well-controlled studies of sildenafil in pregnant women.

Risk Summary

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

Animal Data

No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits which received up to 200 mg/kg/day during organogenesis. These doses represent, respectively, about 20 and 40 times the Maximum Recommended Human Dose (MRHD) on a mg/m² basis in a 50 kg subject. 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 rat the 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 a reduced clearance of sildenafil resulting in approximately 84% and 107% higher plasma 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 protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [see CLINICAL PHARMACOLOGY].

Of the total number of subjects in clinical studies of Viagra, 18% were 65 years and older, while 2% were 75 years and older. No overall differences in safety or efficacy were observed between older ( > 65 years of age) and younger ( < 65 years of age) subjects.

However, since higher plasma levels may increase the incidence of adverse reactions, a starting dose of 25 mg should be considered in older subjects due to the higher systemic exposure [seeDOSAGE AND ADMINISTRATION].

Renal Impairment

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

Hepatic Impairment

In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in higher plasma exposure of sildenafil (47% for C max and 85% for AUC). The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied. A starting dose of 25 mg should be considered in patients with any degree of hepatic impairment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Overdosage & Contraindications

OVERDOSE

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

In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.

CONTRAINDICATIONS

Nitrates

Consistent with its known effects on the nitric oxide/cGMP pathway [see CLINICAL PHARMACOLOGY], VIAGRA was shown to potentiate the hypotensive effects of nitrates, and its administration to patients who are using nitric oxide donors such as organic nitrates or organic nitrites in any form either regularly and/or intermittently is therefore contraindicated.

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

Hypersensitivity Reactions

VIAGRA is contraindicated in patients with a known hypersensitivity to sildenafil, as contained in VIAGRA and REVATIO, or any component 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 GC stimulator, such as riociguat. PDE5 inhibitors, including VIAGRA, may potentiate the hypotensive effects of GC stimulators.

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

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

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

Binding Characteristics

Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on 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 to PDE3. PDE3 is involved in control of cardiac contractility. Sildenafil is only about 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. This lower selectivity is thought to be the basis for abnormalities related to color vision [see Pharmacodynamics].

In addition to human corpus cavernosum smooth muscle, PDE5 is also found in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle, brain, heart, liver, kidney, lung, pancreas, prostate, bladder, testis, and seminal vesicle. The inhibition of PDE5 in some of these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of NO observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-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 improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan®), after VIAGRA administration compared with placebo. Most studies assessed the efficacy of VIAGRA approximately 60 minutes post 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 up to 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 blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1-2 hours after dosing, and was not different than placebo at 8 hours. Similar effects 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 this dosage range. Larger effects were recorded among patients receiving concomitant nitrates [see CONTRAINDICATIONS].

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

Effects of VIAGRA on Blood Pressure When Nitroglycerin is Subsequently Administered

Based on the pharmacokinetic profile of a single 100 mg oral dose given to healthy normal volunteers, the plasma 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 following patients: age > 65 years, hepatic impairment (e.g., cirrhosis), severe renal impairment (e.g., creatinine clearance < 30 mL/min), and concomitant use of erythromycin or strong CYP3A4 inhibitors, plasma levels of sildenafil at 24 hours post dose have been found to be 3 to 8 times higher than those seen in healthy volunteers. Although plasma levels of sildenafil at 24 hours post dose are much lower than at peak concentration, it is unknown whether nitrates can be 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 to assess the interaction of VIAGRA with doxazosin, an alpha-adrenergic blocking agent.

Study 1: VIAGRA with Doxazosin

In the first study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 2-period crossover design to 4 generally healthy males with benign prostatic hyperplasia (BPH). Following at least 14 consecutive daily doses of doxazosin, VIAGRA 100 mg or matching placebo was administered simultaneously with doxazosin. Following a review of the data from these first 4 subjects (details provided below), the VIAGRA dose was reduced to 25 mg. Thereafter, 17 subjects were treated 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 66.5 years.

For the 17 subjects who received VIAGRA 25 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 25 mg VIAGRA or matching placebo are shown in Figure 2.

Figure 2: Mean Standing Systolic Blood Pressure Change from Baseline

Blood pressure was measured immediately pre-dose and at 15, 30, 45 minutes, and 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours after VIAGRA or matching placebo. Outliers were defined as subjects with a standing systolic blood pressure of < 85 mmHg or a decrease from baseline in standing systolic blood pressure of > 30 mmHg at one or more timepoints. There were no subjects treated with VIAGRA 25 mg who had a standing SBP < 85mmHg. There were three subjects with a decrease from baseline in standing systolic BP > 30mmHg following VIAGRA 25 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and two subjects with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. No severe adverse events potentially related to blood pressure effects were reported in this group.

Of the four subjects who received VIAGRA 100 mg in the first part of this study, a severe adverse event related to blood pressure effect was reported in one patient (postural hypotension that began 35 minutes after dosing with VIAGRA with symptoms lasting for 8 hours), and mild adverse events potentially related to blood pressure effects were reported in two others (dizziness, headache and fatigue at 1 hour after dosing; and dizziness, lightheadedness and nausea at 4 hours after dosing). There were no reports of syncope among these patients. For these four 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 of these 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 single oral dose of VIAGRA 50 mg or matching placebo was administered in a 2-period crossover design to 20 generally healthy males with BPH. Following at least 14 consecutive days of doxazosin, VIAGRA 50 mg or matching placebo was administered simultaneously with doxazosin 4 mg (17 subjects) or with doxazosin 8 mg (3 subjects). The mean subject age in this study was 63.9 years.

Twenty subjects received VIAGRA 50 mg, but only 19 subjects received matching placebo. One patient discontinued the study prematurely due to an adverse event of hypotension following dosing with VIAGRA 50 mg. This patient had been taking minoxidil, a potent vasodilator, during the study.

For the 19 subjects who received both VIAGRA and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 50 mg VIAGRA or matching placebo are shown in Figure 3.

Figure 3: Mean Standing Systolic Blood Pressure Change from Baseline

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

Study 3: VIAGRA with Doxazosin

In the third study, a single oral dose of VIAGRA 100 mg or matching placebo was administered in a 3-period crossover design to 20 generally healthy males with BPH. In dose period 1, subjects were administered open-label doxazosin and a single dose of VIAGRA 50 mg simultaneously, after at least 14 consecutive days of doxazosin. If a subject did not successfully complete this first dosing period, he was discontinued from the study. Subjects who had successfully completed the previous doxazosin interaction study (using VIAGRA 50 mg), including no significant 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 simultaneously with doxazosin 4 mg (14 subjects) or doxazosin 8 mg (6 subjects) in standard crossover fashion. The mean subject age in this study was 66.4 years.

Twenty-five subjects were screened. Two were discontinued after study period 1: one failed to meet pre-dose screening qualifications and the other experienced symptomatic hypotension as a moderately severe adverse event 30 minutes after dosing with open-label VIAGRA 50 mg. Of the twenty subjects who were ultimately assigned to treatment, a total of 13 subjects successfully completed dose period 1, and seven had successfully completed the previous doxazosin study (using VIAGRA 50 mg).

For the 20 subjects who received VIAGRA 100 mg and matching placebo, the placebo-subtracted mean maximum decreases from baseline (95% CI) in systolic blood pressure were as follows:

The mean profiles of the change from baseline in standing systolic blood pressure in subjects treated with doxazosin in combination with 100 mg VIAGRA or matching placebo are shown in Figure 4.

Figure 4: Mean Standing Systolic Blood Pressure Change from Baseline

Blood pressure was measured after administration of VIAGRA at the same times as those specified for the previous 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 mild adverse events at the time of reductions in standing SBP, including vasodilation and lightheadedness. There were four subjects with a decrease from baseline in standing systolic BP > 30 mmHg following VIAGRA 100 mg, one subject with a decrease from baseline in standing systolic BP > 30 mmHg following placebo and one subject with a decrease from baseline in standing systolic BP > 30 mmHg following both VIAGRA and placebo. While there were no severe adverse events potentially related to blood pressure reported in this study, one subject reported moderate vasodilatation after both VIAGRA 50 mg and 100 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 was co-administered with amlodipine, 5 mg or 10 mg oral, to hypertensive patients, the mean additional reduction on supine blood pressure was 8 mmHg systolic and 7 mmHg diastolic.

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

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

Effects of VIAGRA on Cardiac Parameters

Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers.

Studies have produced relevant data 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 was administered by four intravenous infusions.

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

Table 3: Hemodynamic Data in Patients with Stable Ischemic Heart Disease after Intravenous Administration of 40 mg of Sildenafil

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

Effects of VIAGRA on Vision

At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. Subjects in the study reported this finding as difficulties in discriminating blue/green. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of VIAGRA on visual acuity, intraocular pressure, or pupillometry.

Effects of VIAGRA on Sperm

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

Pharmacokinetics

VIAGRA is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 2563%). The pharmacokinetics of sildenafil are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly CYP3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. Both sildenafil and the metabolite have terminal half lives of about 4 hours.

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

Figure 5: Mean Sildenafil Plasma 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 taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.

Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.

Metabolism and Excretion

Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects.

After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach.

Pharmacokinetics in Special Populations

Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively [see DOSAGE AND 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, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered. In volunteers with severe (CLcr < 30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Cmax compared to age-matched volunteers with no renal impairment [see DOSAGE AND ADMINISTRATION, and Use In Specific Populations].

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

Hepatic Impairment: In volunteers with hepatic impairment (Child-Pugh Class A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child-Pugh Class C) have not been studied [see DOSAGE AND ADMINISTRATION, and Use in Specific Populations].

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

Drug Interaction Studies

Effects of Other Drugs on VIAGRA

Sildenafil metabolism is principally mediated by CYP3A4 (major route) and CYP2C9 (minor route). Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance. The concomitant use 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 DOSAGE AND ADMINISTRATION].

In vivo Studies

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

When a single 100 mg dose of VIAGRA was administered with erythromycin, a moderate CYP3A4 inhibitor, at steady state (500 mg bid for 5 days), there was a 160% increase in sildenafil Cmax and a 182% increase in sildenafil AUC. In addition, in a study performed in healthy 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 saquinavir pharmacokinetics. A stronger CYP3A4 inhibitor such as ketoconazole or itraconazole could be expected to have greater effect than that seen with saquinavir. Population pharmacokinetic data from patients in clinical trials also indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors (such as ketoconazole, erythromycin, or cimetidine) [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

In another study in healthy male volunteers, co-administration with the HIV protease inhibitor ritonavir, which is a highly potent P450 inhibitor, at steady state (500 mg bid) with VIAGRA (100 mg single dose) resulted in a 300% (4-fold) increase in sildenafil Cmax and a 1000% (11-fold) increase in sildenafil plasma AUC. At 24 hours the plasma levels of sildenafil were still approximately 200 ng/mL, compared to approximately 5 ng/mL when sildenafil was dosed alone. This is consistent with ritonavir's marked effects on a broad range of P450 substrates. VIAGRA had no effect on ritonavir pharmacokinetics [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Although the interaction between other protease inhibitors and sildenafil has not been studied, their concomitant use is expected to increase sildenafil levels.

In a study of healthy male volunteers, co-administration of sildenafil at steady state (80 mg t.i.d.) with endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and 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 . Concomitant administration of strong CYP3A4 inducers, such as rifampin, is expected to cause greater decreases in plasma levels of sildenafil.

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

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

Pharmacokinetic data from patients in clinical trials showed no effect on sildenafil pharmacokinetics of CYP2C9 inhibitors (such as tolbutamide, warfarin), CYP2D6 inhibitors (such as selective serotonin reuptake inhibitors, tricyclic antidepressants), thiazide and related diuretics, ACE inhibitors, and calcium channel blockers. The AUC of the active metabolite, N-desmethyl sildenafil, was increased 62% by loop and potassium-sparing diuretics and 102% by nonspecific beta-blockers. These effects on the metabolite are not expected to be of clinical consequence.

Effects of VIAGRA on Other Drugs

In Vitro Studies

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

In Vivo Studies

No significant interactions were shown with tolbutamide (250 mg) or warfarin (40 mg), both of which are metabolized by CYP2C9.

In a study of healthy male volunteers, sildenafil (100 mg) did not affect the steady state pharmacokinetics of the HIV protease inhibitors, saquinavir and ritonavir, both of which are CYP3A4 substrates.

VIAGRA (50 mg) did not potentiate the increase in bleeding time caused by aspirin (150 mg).

Sildenafil at steady state, at a 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 (125 mg b.i.d.).

Clinical Studies

In clinical studies, VIAGRA was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. VIAGRA was 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 a variety of study designs (fixed dose, titration, parallel, crossover). VIAGRA was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. VIAGRA demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo.

Efficacy Endpoints in Controlled Clinical Studies

The effectiveness of VIAGRA was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function -IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes,  (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered.

Efficacy Results from Controlled Clinical Studies

The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 6, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results. Figure 6 shows that regardless of the baseline levels of function, subsequent function in patients treated with VIAGRA was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline.

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

The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 7. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions. Erectile dysfunction was attributed 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 mg and 100 mg of VIAGRA, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar.

Figure 7: Percentage of Patients Reporting an Improvement in Erections

The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period.

In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of VIAGRA on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly 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 of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that VIAGRA improved their erections.

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

One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n=268). As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of VIAGRA; all patients, however, were receiving 50 mg or 100 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on VIAGRA compared to placebo. On a global improvement question, 57% of VIAGRA patients reported improved erections versus 10% on placebo. Diary data indicated that on VIAGRA, 48% of intercourse attempts were successful versus 12% on placebo.

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

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

Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of VIAGRA patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA. Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for VIAGRA and 29% for placebo.

Efficacy Results in Subpopulations in Controlled Clinical Studies

A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. VIAGRA was effective in a broad range of ED patients, including those with a history of coronary artery disease, hypertension, other cardiac disease, peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft (CABG), radical prostatectomy, transurethral resection of the prostate (TURP) and spinal cord injury, and in patients takingantidepressants/antipsychotics and anti-hypertensives/diuretics.

Medication Guide

PATIENT INFORMATION

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

What is the most important information I should know about VIAGRA?

VIAGRA can cause your blood pressure to drop suddenly to an unsafe level if it is taken with certain other medicines. Do not take VIAGRA if you take any other medicines called “nitrates.” Nitrates are used to treat chest pain (angina). A sudden drop in blood pressure can cause you to feel dizzy, faint, or have a heart attack or stroke.

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

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

Tell all your healthcare providers that you take VIAGRA. If you need emergency medical care for a heart problem, it will be important for your healthcare provider to know when you last took VIAGRA.

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

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

VIAGRA does not protect you or your partner from getting sexually transmitted diseases, including HIV—the virus that causes AIDS.

What is VIAGRA?

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

VIAGRA is not for use in women or children.

It is not known if VIAGRA is safe 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 my healthcare provider before taking VIAGRA?

Before you take VIAGRA, tell your 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 healthcare provider about all the medicines you take*, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

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

· 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 or pharmacist 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 you get 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 side effects of VIAGRA?

VIAGRA can cause serious side 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 effects of 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 taking VIAGRA. Most, but not all, of these men had heart problems before taking VIAGRA. It is not known if VIAGRA caused these problems.

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

These are not all the possible side effects of VIAGRA. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice 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 all medicines out of the reach of children.

General information about the safe and effective use of VIAGRA.

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

This Patient Information leaflet summarizes the most important information about VIAGRA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about VIAGRA that is written for health professionals.

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

What are the ingredients in VIAGRA?

Active ingredient: sildenafil citrate

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