Limitation of Use

The efficacy of REVATIO has not been adequately eva luated in patients taking bosentan concurrently.

2 DOSAGE AND ADMINISTRATION

2.1 Pulmonary Arterial Hypertension (PAH)

The recommended dose of REVATIO is 20 mg three times a day (TID). REVATIO tablets should be taken approximately 4–6 hours apart, with or without food.

In the clinical trial no greater efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg TID is not recommended. Dosages lower than 20 mg TID were not tested. Whether dosages lower than 20 mg TID are effective is not known.

3 DOSAGE FORMS AND STRENGTHS

Do not use REVATIO in patients taking organic nitrates in any form. Consistent with its known effects on the nitric oxide/cGMP pathway, sildenafil was shown to potentiate the hypotensive effects of nitrates.

4.2 Hypersensitivity Reactions

REVATIO is contraindicated in patients with a known hypersensitivity to sildenafil or any component of the tablet.

Rare cases of hypersensitivity have been reported in association with the use of sildenafil including anaphylactic reaction/shock events and anaphylactoid reaction. The majority of reported events were non-serious hypersensitivity reactions.

5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular Effects

REVATIO has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing REVATIO, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients with resting hypotension [BP < 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction).

Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Since there are no clinical data on administration of REVATIO to patients with veno-occlusive disease, administration of REVATIO to such patients is not recommended. Should signs of pulmonary edema occur when REVATIO is administered, consider the possibility of associated PVOD.

As there are no controlled clinical data on the safety or efficacy of REVATIO in the following groups, prescribe with caution for:

• Patients who have suffered a myocardial infarction, stroke, or life-threatening arrhythmia within the last 6 months;
• Patients with coronary artery disease causing unstable angina;
• Patients with hypertension (BP > 170/110);
• Patients currently on bosentan therapy.

In humans, sildenafil has no effect on bleeding time when taken alone or with aspirin. In vitro studies with human platelets indicate that sildenafil potentiates the anti-aggregatory effect of sodium nitroprusside (a nitric oxide donor). The combination of heparin and sildenafil had an additive effect on bleeding time in the anesthetized rabbit, but this interaction has not been studied in humans.

The incidence of epistaxis was 13% in patients taking sildenafil with PAH secondary to connective tissue disease (CTD). This effect was not seen in primary pulmonary hypertension (PPH) (sildenafil 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist).

The safety of REVATIO is unknown in patients with bleeding disorders or active peptic ulceration.

5.3 Use with Ritonavir and Other Potent CYP3A Inhibitors

The concomitant administration of the protease inhibitor ritonavir (a highly potent CYP3A inhibitor) substantially increases serum concentrations of sildenafil; therefore, co-administration of ritonavir or other potent CYP3A inhibitors with REVATIO is not recommended [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

5.4 Effects on the Eye

Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE5 inhibitors, including REVATIO. Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, that has been reported postmarketing in temporal association with the use of all PDE5 inhibitors, including sildenafil, when used in the treatment of erectile dysfunction. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors. Physicians should also discuss the increased risk of NAION with patients who have already experienced NAION in one eye, including whether such individuals could be adversely affected by use of vasodilators, such as PDE5 inhibitors [see Adverse Reactions (6.2)].

There are no controlled clinical data on the safety or efficacy of REVATIO in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe REVATIO with caution in these patients.

5.5 Hearing Impairment

Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE5 inhibitors, including REVATIO. These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including REVATIO. 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 (6.2)].

5.6 Combination with other PDE5 inhibitors

Sildenafil is also marketed as VIAGRA®. The safety and efficacy of combinations of REVATIO with VIAGRA or other PDE5 inhibitors have not been studied. Inform patients taking REVATIO not to take VIAGRA or other PDE5 inhibitors.

5.7 Prolonged Erection

Use REVATIO with caution in patients with anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, or Peyronie's disease) or in patients who have conditions, which may predispose them to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erection greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result.

6 ADVERSE REACTIONS

Cardiovascular Events

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

Decreases in and Loss of Vision

When used to treat erectile dysfunction, non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors, including sildenafil. 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 (5.4)].

Loss of Hearing

Cases of sudden decrease or loss of hearing have been reported postmarketing in temporal association with the use of PDE5 inhibitors, including REVATIO. 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 REVATIO, to the patient's underlying risk factors for hearing loss, a combination of these factors, or to other factors [see Warnings and Precautions (5.5)].

Other Events

The following list includes other adverse events that have been identified during postmarketing use of REVATIO. The list does not include adverse events that are reported from clinical trials and that are listed elsewhere in this section. 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. Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Nervous system: Seizure, seizure recurrence

7 DRUG INTERACTIONS

Nitrates

Concomitant use of REVATIO with nitrates in any form is contraindicated [see Contraindications (4)].

Ritonavir and other Potent CYP3A Inhibitors

Concomitant use of REVATIO with ritonavir and other potent CYP3A inhibitors is not recommended [see Warnings and Precautions (5.3)].

Alpha-blockers

Use caution when co-administering alpha-blockers with REVATIO because of additive blood pressure-lowering effects [see Warnings and Precautions (5.1)].

In drug-drug interaction studies, sildenafil (25 mg, 50 mg, or 100 mg) and the alpha-blocker doxazosin (4 mg or 8 mg) were administered simultaneously to patients with benign prostatic hyperplasia (BPH) stabilized on doxazosin therapy. In these study populations, mean additional reductions of supine systolic and diastolic blood pressure of 7/7 mmHg, 9/5 mmHg, and 8/4 mmHg, respectively, were observed. Mean additional reductions of standing blood pressure of 6/6 mmHg, 11/4 mmHg, and 4/5 mmHg, respectively, were also observed. There were infrequent reports of patients who experienced symptomatic postural hypotension. These reports included dizziness and light-headedness, but not syncope.

Amlodipine

When sildenafil 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

The safety and efficacy of Revatio during labor and delivery has not been studied.

8.3 Nursing Mothers

It is not known if sildenafil or its metabolites are excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when REVATIO is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of sildenafil in pediatric pulmonary hypertension patients have not been established.

8.5 Geriatric Use

Clinical studies of REVATIO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE5) in the smooth muscle of the pulmonary vasculature, where PDE5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary hypertension, this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.

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). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because 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 and involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels [see Clinical Pharmacology (12.2)].

In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro, and the mild peripheral arterial-venous dilatation in vivo.

12.2 Pharmacodynamics

Sildenafil was not carcinogenic when administered to rats for up to 24 months at 60 mg/kg/day, a dose resulting in total systemic exposure (AUC) to unbound sildenafil and its major metabolite 33 and 37 times, for male and female rats respectively, the human exposure at the RHD of 20 mg TID. Sildenafil was not carcinogenic when administered to male and female mice for up to 21 and 18 months, respectively, at doses up to a maximally tolerated level of 10 mg/kg/day, a dose equivalent to the RHD on a mg/m2 basis.

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.

There was no impairment of fertility in male or female rats given up to 60 mg sildenafil/kg/day, a dose producing a total systemic exposure (AUC) to unbound sildenafil and its major metabolite of 19 and 38 times for males and females, respectively, the human exposure at the RHD of 20 mg TID.

14 CLINICAL STUDIES

Study 1

A randomized, double-blind, placebo-controlled study was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of ≥ 25 mmHg at rest with a pulmonary capillary wedge pressure < 15 mmHg). Patients were predominantly functional classes II–III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Subjects who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction < 45% or left ventricular shortening fraction < 0.2 also were not studied.

Patients were randomized to receive placebo (n=70) or REVATIO 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) TID for a period of 12 weeks. They had either PPH (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18–81 years) and baseline 6-minute walk distance between 100 and 450 meters.

The primary efficacy endpoint was the change from baseline at week 12 in 6-minute walk distance at least 4 hours after the last dose. Placebo-corrected mean increases in walk distance of 45–50 meters were observed with all doses of REVATIO. These increases were significantly different from placebo, but the dose groups were not different from each other (Figure 1), indicating no additional clinical benefit from doses higher than 20 mg TID. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12.

Figure 1. Change from Baseline in 6-Minute Walk Distance (meters): Mean (95% Confidence Interval)

Pre-defined subpopulations in the study were also eva luated for efficacy, including patient differences in baseline walk distance, disease etiology, functional class, gender, age, and secondary hemodynamic parameters (Figure 2).

Figure 2. Placebo Corrected Change From Baseline in 6-Minute Walk Distance (meters) by study subpopulation: Mean (95% Confidence Interval)

Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.

Patients on all REVATIO doses achieved a statistically significant reduction in mean pulmonary arterial pressure (mPAP) compared to those on placebo. Data from other hemodynamic parameters can be found in Table 3. The relationship between these effects and improvements in 6-minute walk distance is unknown.

Of the 277 treated patients, 259 entered a long-term, uncontrolled extension study. At the end of 1 year, 94% of these patients were still alive. Additionally, walk distance and functional class status appeared to be stable in patients taking sildenafil. Without a control group, these data must be interpreted cautiously.

Study 2

A randomized, double-blind, placebo controlled study was conducted in 267 patients with PAH who were stabilized on intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg and a pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance ≥ 100 m and ≤ 450 m. Patients were randomized to placebo or REVATIO (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) when used in combination with intravenous epoprostenol

Patients had primary pulmonary hypertension (80%) or PAH secondary to CTD (20%). Patients had WHO functional class I (1%), II (26%), III (67%), or IV (6%) at baseline. The mean age was 48 years, 80% were female, and 79% were Caucasian.

Analysis of the primary endpoint showed that there was a statistically significant greater increase in 6-minute walk distance for the REVATIO group compared with the placebo group at Week 16. The mean change from baseline at Week 16 (last observation carried forward) was 30 m for the sildenafil group compared with 4.m for the placebo group giving an adjusted treatment difference of 26 m (95% CI: 10.8, 41.2) (p = 0.0009).

Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of REVATIO (95% CI: -5.7, -2.1) (p = 0.00003).

Clinical Worsening

Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Patients with clinical worsening events are summarized in Table 4. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo patients were 3 times more likely to experience an event and that patients receiving REVATIO experienced a significant delay in time to clinical worsening versus placebo (p = 0.0074).

Figure 3. Kaplan-Meier Plot of Time to Clinical Worsening (Days), ITT Population

Improvements in functional class were also demonstrated in subjects on sildenafil compared to placebo. More than twice as many sildenafil treated patients (36%) as the placebo group (14%) showed an improvement of at least one functional class.

16 HOW SUPPLIED/STORAGE AND HANDLING

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

部分中文瑞肺得处方信息（仅供参考）
药物成分：西地那非   
药理作用：
西地那非是一种环状单磷酸鸟苷(cGMP)特异性第五型磷酸二酯酶(phospho-diesterase type 5, PDE5)的选择性抑制剂。PDE5负责分解细胞内的cGMP。西地那非可抑制PDE5，增加肺血管平滑肌细胞内的cGMP，促使血管扩张。  
药物动力学：
口服吸收迅速，但经胃肠黏膜与肝脏代谢，绝对生体可用率约40％。在空腹状态下服药，可于30至120分钟(中位数60分钟)内到达最大血中浓度。当与高脂饮食并服，吸收速率减慢，但吸收总量不变。体内分布很广，稳定状态之分布体积为105公升。血浆蛋白结合率约96％。主要经由肝脏酵素CYP3A4和CYP2C9代谢；其主要代谢物对磷酸二酯酶的选择性与西地那非类似，约20％的药理作用来自于此代谢物。主要以代谢物形式经粪便排除(约为口服剂量的80％)，少部份由尿液排除(约为口服剂量的13％)。排除半衰期约4小时。
适应症：
治疗肺动脉高血压，改善运动能力。   
不良反应：
常见的不良反应包括头痛、潮红、鼻塞、失眠、晕眩、眼睛周围疼痛、消化不良、腹泻、皮疹、肌肉疼痛、视觉异常。视觉异常一般是视觉发生轻微而短暂的变色，对光敏感度增加或视力模糊。
注意事项
1.　Sildenafil用于有下列患者应特别谨慎：
(1) 最近6个月内发生心肌梗塞、中风或危及生命心律不整的患者。
(2)　发生不稳定型心绞痛之冠状动脉疾病患者。
(3)　严重高血压 (BP>170/110mmHg)或低血压(BP<90/50mmHg) 患者。
(4)　肺静脉阻塞性疾病(PVOD)患者。
(5)　阴茎构造畸形(如阴茎弯曲、海绵体纤维变性或Peyronie氏病)或容易引起阴茎异发性骨髓瘤或白血病)患者。若发现阴茎持续勃起超过4小时，需立即寻求医疗协助，以免造成组织伤害，丧失勃起能力。
(6)　色素性视网膜炎患者。
(7)　出血性疾病或活动性消化性溃疡患者。
2.　Sildenafil与α阻断剂并用时须小心，可能会对血压下降产生加成效应。3.　在结缔组织继发的肺动脉高血压患者中，使用sildenafil发生鼻出血机率高于原发性肺动脉高血压患者。
4.　合并使用口服维生素K拮抗剂的患者，发生鼻出血的机率较高。
5. 服药期间若出现单眼或双眼视力减退，应立即就医。
禁忌
1.　正在使用任何剂型的有机硝酸盐患者(无论常规或间歇性服用)。
2.　对药品成份过敏者。
3.　同时服用蛋白酶抑制剂ritonavir(强效之CYP-3A4 抑制剂)，会使sildenafil血清浓度大幅升高，故不建议并用。 
交互作用
西地那非主要由肝脏酵素CYP3A4和CYP2C9代谢，因此，这类酵素抑制剂(如：itraconazole、ketoconazole、cimetidine、saquinavir、ritonavir…)会减少sildenafil的清除，而酵素诱导剂(如：rifampin、carbamazepine、phenytoin、bosentan…)则会增加sildenafil的清除。
剂量及用法
1.若有特殊情况的病人（如肝肾功能不全、老年人等）需详细说明，密切监测药物的副作用和毒性。注射剂需详细说明给药方法及输注时间。
2.建议剂量：每日三次，每次服用20毫克。每次给药需间隔4到6小时，随餐或空腹服用皆可。肝、肾脏功能不全患者不需调整剂量。
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FDA警告：西地那非禁用于肺动脉高压儿童
8月30日，美国食品与药物管理局（FDA）发布安全信息称，不推荐Revatio（有效成分：西地那非) 用于年龄在1~17岁的患肺动脉高压（PAH）儿童。
该推荐是基于一项儿科长期临床试验得出的，该试验结果显示，
1、服用大剂量Revatio的儿童比服用小剂量该药的儿童死亡危险高；
2、小剂量Revatio并不改善患者运动功能。Revatio的药物标签也将增加上述相关信息。
FDA表示，Revatio从未获准用于治疗PAH儿童，FDA的警告是针对该药的标签外使用。Revatio是获准用于改善成人运动功能和延缓其PAH临床恶化的药物。目前Revatio药物标签推荐的成人药物剂量为20 mg，每日服用3次。成人长期应用该药对死亡危险关系尚未知。FDA也正要求该药生产厂家（辉瑞制药公司）评估这一效应。
FDA还建议患者在未咨询医务人员情况下勿自行改变服用剂量或停止治疗。
Revatio是通过扩张肺部血管降低血压的用于治疗PAH的磷酸二酯酶—5抑制剂。Revatio具有与治疗男性勃起功能障碍药物万艾可（Viagra）相同的有效成分。同时，FDA不赞成这一安全信息适用于万艾可（Viagra），因为两药的适用人群和推荐剂量均不同。
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产地国家: 美国
原产地英文商品名:
REVATIO 20 MG TABLET MINIMUMS APPLY
原产地英文药品名:
SILDENAFIL CITRATE
原产地英文化合物名称:
1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine citrate
中文参考商品译名:
瑞肺得20毫克/片 最低适用
中文参考药品译名:
枸橼酸西地那非
生产厂家中文参考译名:
辉瑞
生产厂家英文名:
PFIZER