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Pregnancy

8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies of sildenafil in pregnant women. No evidence of teratogenicity, embryotoxicity, or fetotoxicity was observed in pregnant rats or rabbits dosed with sildenafil 200 mg/kg/day during organogenesis, a level that is, on a mg/m 2 basis, 32- and 68-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. In a rat pre- and postnatal development study, the no-observed-adverse-effect dose was 30 mg/kg/day (equivalent to 5-times the RHD on a mg/m 2 basis).

Drug Interactions

7 DRUG INTERACTIONS Nitrates Concomitant use of sildenafil citrate with nitrates in any form is contraindicated [see Contraindications (4)] . Ritonavir and other Potent CYP3A Inhibitors Concomitant use of sildenafil citrate with ritonavir and other potent CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)] . Other drugs that reduce blood pressure Alpha blockers. 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. Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil citrate [see Warnings and Precautions (5.2)] . Concomitant alpha-blockers or amlodipine: Note additive blood pressure lowering effects. (7) Use with ritonavir and other potent CYP3A inhibitors: Not recommended. (7, 12.3) Concomitant PDE-5 inhibitors: Avoid use with Viagra or other PDE-5 inhibitors. (5.7)

Indications And Usage

1 INDICATIONS AND USAGE Sildenafil tablets are indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults to improve exercise ability and delay clinical worsening. The delay in clinical worsening was demonstrated when sildenafil tablets were added to background epoprostenol therapy [see Clinical Studies (14)]. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic etiology (71%) or associated with connective tissue disease (CTD) (25%). Limitation of Use Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity [see Clinical Studies (14)] . Sildenafil tablets are a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with NYHA Functional Class II-III symptoms. Etiologies were idiopathic (71%) or associated with connective tissue disease (25%). (1) Limitation of Use: Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity. ( 1, 14)

Clinical Studies

14 CLINICAL STUDIES Studies of Adults with Pulmonary Arterial Hypertension Study 1 (Sildenafil Citrate monotherapy (20 mg, 40 mg, and 80 mg three times a day)) A randomized, double-blind, placebo-controlled study of sildenafil citrate (Study 1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure of greater than or equal to 25 mmHg at rest with a pulmonary capillary wedge pressure less than 15 mmHg). Patients were predominantly World Health Organization (WHO) 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 less than 45% or left ventricular shortening fraction less than 0.2 also were not studied. Patients were randomized to receive placebo (n=70) or sildenafil citrate 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (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 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343). The primary efficacy endpoint was the change from baseline at week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45 to 50 meters were observed with all doses of sildenafil citrate. These increases were significantly different from placebo, but the sildenafil citrate dose groups were not different from each other (see Figure 9), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at week 8 and week 12. Figure 9. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in Study 1: Mean (95% Confidence Interval) Figure 10 displays subgroup efficacy analyses in Study 1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters. Figure 10. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by study subpopulation in Study 1: 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. 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 citrate. Without a control group, these data must be interpreted cautiously. Study 2 (Sildenafil Citrate co-administered with epoprostenol) A randomized, double-blind, placebo controlled study (Study 2) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil citrate (in a fixed titration starting from 20 mg, to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. At baseline patients had PPH (80%) or PAH secondary to CTD (20%);WHO functional class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil citrate group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil citrate group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009). Patients on sildenafil citrate 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 sildenafil citrate (95% CI: -5.7, -2.1) (p = 0.00003). 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). Table 4 displays the number of patients with clinical worsening events in Study 2. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil citrate-treated patients and that sildenafil citrate-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 11. Table 4. Clinical Worsening Events in Study 2 Placebo (N = 131) Sildenafil Citrate (N = 134) Number of subjects with clinical worsening first event 23 8 First Event All Events First Event All Events Death, n 3 4 0 0 Lung Transplantation, n 1 1 0 0 Hospitalization due to PAH, n 9 11 8 8 Clinical deterioration resulting in: Change of Epoprostenol Dose, n 9 16 0 2 Initiation of Bosentan, n 1 1 0 0 Proportion Worsened 95% Confidence Interval 0.187 (0.12 to 0.26) 0.062 (0.02 to 0.10) Figure 11. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in Study 2 Improvements in WHO functional class for PAH were also demonstrated in subjects on sildenafil citrate compared to placebo. More than twice as many sildenafil citrate-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study 3 (Sildenafil Citrate monotherapy (1 mg, 5 mg, and 20 mg three times a day) A randomized, double-blind, parallel dose study (Study 3) was planned in 219 patients with PAH. This study was prematurely terminated with 129 subjects enrolled. Patients were required to have a mPAP greater than or equal to 25 mmHg and a PCWP less than or equal to 15 mmHg at rest via right heart catheterization within 12 weeks before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 345 meters). Patients were randomized to 1 of 3 doses of sildenafil citrate: 1 mg, 5 mg, and 20 mg, three times a day. At baseline patients had PPH (74%) or secondary PAH (26%); WHO functional class II (57%), III (41%), or IV (2%); the mean age was 44 years; and 67% were female. The majority of subjects were Asian (67%), and 28% were Caucasian. The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Similar increases in walk distance (mean increase of 38 to 41 meters) were observed in the 5 and 20 mg dose groups. These increases were significantly better than those observed in the 1 mg dose group (Figure 12). Figure 12. Mean Change from Baseline in Six Minute Walk (meters) by Visit to Week 12 – ITT Population Sildenafil Protocol A1481244. Study 4 (Sildenafil Citrate added to bosentan therapy – lack of effect on exercise capacity) A randomized, double-blind, placebo controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of three months. The PAH patients included those with primary PAH, and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6MWD. The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone. f7c6df1a-figure-05 f7c6df1a-figure-06 f7c6df1a-figure-07 Figure 12

Warnings And Cautions

5 WARNINGS AND PRECAUTIONS Increased mortality with increasing doses in pediatric patients. Not recommended for use in pediatric patients. (5.1) Vasodilation effects may be more common in patients with hypotension or on antihypertensive therapy. (5.2) Use in pulmonary veno-occlusive disease may cause pulmonary edema and is not recommended. (5.3) Hearing or visual impairment: Seek medical attention if sudden decrease or loss of vision or hearing occurs. (5.5, 5.6) Pulmonary hypertension secondary to sickle cell disease: Sildenafil citrate may cause serious vaso-occlusive crises. (5.9) 5.1 Mortality with Pediatric Use In a long-term trial in pediatric patients with PAH, an increase in mortality with increasing sildenafil citrate dose was observed. Deaths were first observed after about 1 year and causes of death were typical of patients with PAH. Use of sildenafil citrate, particularly chronic use, is not recommended in children. [see Use in Specific Populations (8.4)] . 5.2 Hypotension Sildenafil citrate has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing sildenafil citrate, carefully consider whether patients with certain underlying conditions could be adversely affected by such vasodilatory effects (e.g., patients on antihypertensive therapy or with resting hypotension [BP less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co-administering blood pressure lowering drugs with sildenafil citrate. 5.3 Worsening Pulmonary Vascular Occlusive Disease 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 sildenafil citrate to patients with veno-occlusive disease, administration of sildenafil citrate to such patients is not recommended. Should signs of pulmonary edema occur when sildenafil citrate is administered, consider the possibility of associated PVOD. 5.4 Epistaxis The incidence of epistaxis was 13% in patients taking sildenafil citrate with PAH secondary to CTD. This effect was not seen in idiopathic PAH (sildenafil citrate 3%, placebo 2%) patients. The incidence of epistaxis was also higher in sildenafil citrate-treated patients with a concomitant oral vitamin K antagonist (9% versus 2% in those not treated with concomitant vitamin K antagonist). The safety of sildenafil citrate is unknown in patients with bleeding disorders or active peptic ulceration. 5.5 Visual Loss 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 (PDE-5) 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. Based on published literature, the annual incidence of NAION is 2.5 to 11.8 cases per 100,000 males aged ≥ 50 per year in the general population. An observational study evaluated whether recent, episodic use of PDE5 inhibitors (as a class), typical of erectile dysfunction treatment, was associated with acute onset of NAION. The results suggest an approximately 2-fold increase in the risk of NAION within 5 half-lives of PDE-5 inhibitor use. It is not possible to determine whether these events are related directly to the use of PDE-5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors. Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including sildenafil citrate. 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 PDE-5 inhibitors. There are no controlled clinical data on the safety or efficacy of sildenafil citrate in patients with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases. Prescribe sildenafil citrate with caution in these patients. 5.6 Hearing Loss Cases of sudden decrease or loss of hearing, which may be accompanied by tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors, including sildenafil citrate. In some of the cases, medical conditions and other factors were reported that may have played a role. 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 sildenafil citrate, to the patient’s underlying risk factors for hearing loss, a combination of these factors, or to other factors. Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking PDE-5 inhibitors, including sildenafil citrate. 5.7 Combination with other PDE-5 inhibitors Sildenafil is also marketed as VIAGRA ®. The safety and efficacy of combinations of sildenafil citrate with VIAGRA or other PDE-5 inhibitors have not been studied. Inform patients taking sildenafil citrate not to take VIAGRA or other PDE-5 inhibitors. 5.8 Priapism Use sildenafil citrate 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. 5.9 Vaso-occlusive Crisis in Patients with Pulmonary Hypertension Secondary to Sickle Cell Anemia In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vaso-occlusive crises requiring hospitalization were more commonly reported by patients who received sildenafil citrate than by those randomized to placebo. The effectiveness and safety of sildenafil citrate in the treatment of PAH secondary to sickle cell anemia has not been established.

Overdosage

10 OVERDOSAGE In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but 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.

Adverse Reactions

6 ADVERSE REACTIONS The following serious adverse events are discussed elsewhere in the labeling: Mortality with pediatric use [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)] Hypotension [see Warnings and Precautions (5.2)] Vision loss [see Warnings and Precautions (5.5)] Hearing loss [see Warnings and Precautions (5.6)] Priapism [see Warnings and Precautions (5.8)] Vaso-occlusive crisis [see Warnings and Precautions (5.9)] Most common adverse reactions greater than or equal to 3% and more frequent than placebo were epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea, and rhinitis. (6.1, 6.2) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 and www.amneal.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety data of sildenafil citrate in adults were obtained from the 12-week, placebo-controlled clinical study (Study 1) and an open-label extension study in 277 sildenafil citrate-treated patients with PAH, WHO Group I Diagnostic Classification [see Clinical Studies (14)] . The overall frequency of discontinuation in sildenafil citrate-treated patients 20 mg three times a day was 3% and was the same for the placebo group. In Study 1, the adverse reactions that were reported by at least 3% of sildenafil citrate-treated patients (20 mg three times a day) and were more frequent in sildenafil citrate-treated patients than in placebo-treated patients are shown in Table 1. Adverse reactions were generally transient and mild to moderate in nature. Table 1. Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in Sildenafil Citrate-Treated Patients than Placebo-Treated Patients and Incidence ≥3% in Sildenafil Citrate-Treated Patients) Placebo, % (n = 70) Sildenafil Citrate 20 mg three times a day, % (n = 69) Placebo- Subtracted, % Epistaxis 1 9 8 Headache 39 46 7 Dyspepsia 7 13 6 Flushing 4 10 6 Insomnia 1 7 6 Erythema 1 6 5 Dyspnea exacerbated 3 7 4 Rhinitis 0 4 4 Diarrhea 6 9 3 Myalgia 4 7 3 Pyrexia 3 6 3 Gastritis 0 3 3 Sinusitis 0 3 3 Paresthesia 0 3 3 At doses higher than the recommended 20 mg three times a day, there was a greater incidence of some adverse reactions including flushing, diarrhea, myalgia and visual disturbances. Visual disturbances were identified as mild and transient, and were predominately color-tinge to vision, but also increased sensitivity to light or blurred vision. The incidence of retinal hemorrhage with sildenafil citrate 20 mg three times a day was 1.4% versus 0% placebo and for all sildenafil citrate doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for sildenafil citrate versus 1.4% for placebo. The patients experiencing these reactions had risk factors for hemorrhage including concurrent anticoagulant therapy. In a placebo-controlled fixed dose titration study (Study 2) of sildenafil citrate (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the sildenafil citrate + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 [see Clinical Studies (14)] . Table 2. Adverse Reactions (%) in patients with PAH in Study 2 (incidence in Sildenafil citrate + Epoprostenol group at least 6% greater than Epoprostenol group) Sildenafil Citrate + Epoprostenol (n = 134) Epoprostenol (n = 131) (Sildenafil Citrate + Epoprostenol) minus Epoprostenol Headache 57 34 23 Edema includes peripheral edema 25 13 14 Dyspepsia 16 2 14 Pain in extremity 17 6 11 Diarrhea 25 18 7 Nausea 25 18 7 Nasal congestion 9 2 7 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of sildenafil (marketed for both PAH and erectile dysfunction). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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. Nervous system Seizure, seizure recurrence

Recent major changes

RECENT MAJOR CHANGES Indication and Use (1) 01/2014 Dosage and Administration ( 2.1) 01/2014 Warnings and Precautions, Visual Loss (5.5) 02/2014

Mechanism

12.1 Mechanism of Action Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with PAH, 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 PDE-5. Its effect is more potent on PDE-5 than on other known phosphodiesterases (10-fold for PDE6, greater than 80-fold for PDE1, greater than 700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE-5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE-5 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, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets. The inhibition of PDE-5 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.

Contraindications

4 CONTRAINDICATIONS Sildenafil tablets are contraindicated in patients with: Concomitant use of organic nitrates in any form, either regularly or intermittently, because of the greater risk of hypotension [see Warnings and Precautions (5.2)] . Known hypersensitivity to sildenafil or any component of the tablet. Hypersensitivity, including anaphylactic reaction, anaphylactic shock and anaphylactoid reaction, has been reported in association with the use of sildenafil. Use with organic nitrates (4) History of hypersensitivity reaction to sildenafil or any component of the tablet (4)