REVATIO®, an oral therapy for pulmonary arterial hypertension, is the citrate salt of sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type-5 (PDE5). Sildenafil is also marketed as VIAGRA® for male erectile dysfunction.

Sildenafil citrate is designated chemically as 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 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. REVATIO (sildenafil citrate) is formulated as white, film-coated round tablets equivalent to 20 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 monohydrate, and triacetin.

REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) to improve exercise ability.

The efficacy of REVATIO has not been evaluated in patients currently on bosentan therapy.

The recommended dose of REVATIO is 20 mg three times a day (t.i.d.). 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 t.i.d. is not recommended. Dosages lower than 20 mg t.i.d. were not tested. Whether dosages lower than 20 mg t.i.d. are effective is not known.

In general, dose selection for elderly patients 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)

No dose adjustments are required for renal impaired patients (including severe renal impairment, creatinine clearance <30 mL/min), or for hepatic impaired patients (Child Pugh class A and B).

No dose adjustments are required for the co-administration of REVATIO with erythromycin or saquinavir.

Co-administration of REVATIO with CYP3A4 inducers (including bosentan; and more potent inducers such as barbiturates, carbamazepine, phenytoin, efavirenz, nevirapine, rifampin, rifabutin) may alter plasma levels of either or both medications. Dosage adjustments may be necessary (see PRECAUTIONS: DRUG INTERACTIONS).

Co-administration of potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) with REVATIO substantially increases serum concentrations of sildenafil and is therefore not recommended (see WARNINGS and PRECAUTIONS: DRUG INTERACTIONS).

Sildenafil was shown to potentiate the hypotensive effects of nitrates and its administration in patients who use nitric oxide donors, or nitrates in any form, is therefore contraindicated.

REVATIO (sildenafil citrate) is supplied as white, film-coated, round tablets containing sildenafil citrate equivalent to the nominally indicated amount of sildenafil as follows:

REVATIO Tablets

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 October 2007. FDA rev date: 12/18/2007

Clinical Trials

Safety data were obtained from the pivotal study and an open-label extension study in 277 treated patients with pulmonary arterial hypertension. Doses up to 80 mg t.i.d. were studied.

The overall frequency of discontinuation in REVATIO-treated patients at the recommended dose of 20 mg t.i.d. was low (3%) and the same as placebo (3%).

In the pivotal placebo-controlled trial in pulmonary arterial hypertension, the adverse drug reactions that were reported by at least 3% of REVATIO patients treated at the recommended dosage (20 mg t.i.d.) and were more frequent in REVATIO patients than placebo patients, are shown in Table 2. Adverse events were generally transient and mild to moderate in nature.

Table 2. Sildenafil Adverse Events in ≥ 3% of Patients and More Frequent than Placebo

At doses higher than the recommended 20 mg t.i.d. there was a greater incidence of some adverse events 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.

In the pivotal study, the incidence of retinal hemorrhage at the recommended sildenafil 20 mg t.i.d. dose was 1.4% versus 0% placebo and for all sildenafil doses studied was 1.9% versus 0% placebo. The incidence of eye hemorrhage at both the recommended dose and at all doses studied was 1.4% for sildenafil versus 1.4% for placebo. The patients experiencing these events had risk factors for hemorrhage including concurrent anticoagulant therapy.

Post-Marketing Experience

In post-marketing experience with sildenafil citrate at doses indicated for male 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 citrate, to sexual activity, to the patient's underlying cardiovascular disease, or to a combination of these or other factors.

When used to treat male-erectile dysfunction, 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 sildenafil citrate. 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 PRECAUTIONS/Information for Patients).

Cases of sudden decrease or loss of hearing have been reported post-marketing 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 PRECAUTIONS, Information for Patients).

Other events:

The following list includes other adverse events that have been identified during post-marketing 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: seizure, seizure recurrence

In PAH patients, the concomitant use of vitamin K antagonists and sildenafil resulted in a greater incidence of reports of bleeding (primarily epistaxis) versus placebo.

Effects of Other Drugs on REVATIO

In vitro studies: Sildenafil metabolism is principally mediated by the CYP3A4 (major route) and CYP2C9 (minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil clearance.

In vivo studies: Population pharmacokinetic analysis of clinical trial data indicated a reduction in sildenafil clearance and/or an increase of oral bioavailability when co-administered with CYP3A4 substrates and the combination of CYP3A4 substrates and beta-blockers. These were the only factors with a statistically significant impact on sildenafil pharmacokinetics.

Population data from patients in clinical trials indicated a reduction in sildenafil clearance when it was co-administered with CYP3A4 inhibitors. Sildenafil exposure without concomitant medication is shown to be 5-fold higher at a dose of 80 mg t.i.d. compared to its exposure at a dose of 20 mg t.i.d. This concentration range covers the same increased sildenafil exposure observed in specifically-designed drug interaction studies with CYP3A4 inhibitors (except for potent inhibitors such as ketoconazole, itraconazole, and ritonavir). Cimetidine (800 mg), a nonspecific CYP inhibitor, caused a 56% increase in plasma sildenafil concentrations when co-administered with sildenafil (50 mg) to healthy volunteers. When a single 100 mg dose of sildenafil was co-administered with erythromycin, a CYP3A4 inhibitor, at steady state (500 mg twice daily [b.i.d.] for 5 days), there was a 182% increase in sildenafil systemic exposure (AUC). In a study performed in healthy volunteers, co-administration of the HIV protease inhibitor saquinavir, a CYP3A4 inhibitor, at steady state (1200 mg t.i.d.) with sildenafil (100 mg single dose) resulted in a 140% increase in sildenafil Cmax and a 210% increase in sildenafil AUC. Stronger CYP3A4 inhibitors will have still greater effects on plasma levels of sildenafil (see DOSAGE AND ADMINISTRATION).

In another study in healthy volunteers, co-administration with the HIV protease inhibitor ritonavir, a potent CYP3A4 inhibitor, at steady state (500 mg b.i.d.) with sildenafil (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 (see WARNINGS and DOSAGE AND ADMINISTRATION). Although the interaction between other protease inhibitors and REVATIO 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 the endothelin receptor antagonist bosentan (a moderate inducer of CYP3A4, CYP2C9 and possibly of cytochrome P450 2C19) at steady state (125 mg b.i.d.) resulted in a 63% decrease of sildenafil AUC and a 55% decrease in sildenafil Cmax. The combination of both drugs did not lead to clinically significant changes in blood pressure (supine or standing). Concomitant administration of potent CYP3A4 inducers is expected to cause greater decreases in plasma levels of sildenafil.

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 (see PRECAUTIONS: General).

Concomitant administration of oral contraceptives (ethinyl estradiol 30 µg and levonorgestrel 150 µg) did not affect the pharmacokinetics of sildenafil.

Concomitant administration of a single 100 mg dose of sildenafil with 10 mg of atorvastatin did not alter the pharmacokinetics of either sildenafil or atorvastatin.

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

Effects of REVATIO on Other Drugs

In vitro studies: Sildenafil is a weak inhibitor of the cytochrome P450 isoforms 1A2, 2C9, 2C19, 2D6, 2E1 and 3A4 (IC₅₀ >150 µM).

In vivo studies: 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.

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

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

Sildenafil (50 mg) did not potentiate the hypotensive effect of alcohol in healthy volunteers with mean maximum blood alcohol levels of 0.08%.

In healthy subjects, co-administration of 125 mg b.i.d. bosentan and 80 mg t.i.d. sildenafil resulted in a 63% decrease in AUC of sildenafil and a 50% increase in AUC of bosentan.

In a study of healthy 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.

Sildenafil had no impact on the plasma levels of oral contraceptives (ethinyl estradiol 30 µg and levonorgestrel 150 µg).

The concomitant administration of the protease inhibitor ritonavir (a highly potent CYP3A4 inhibitor) substantially increases serum concentrations of sildenafil, therefore co-administration with REVATIO is not recommended (see DRUG INTERACTIONS and DOSAGE AND ADMINISTRATION).

REVATIO has vasodilator properties, resulting in mild and transient decreases in blood pressure (see PRECAUTIONS). Prior to prescribing REVATIO, physicians should carefully consider whether their patients with certain underlying conditions could be adversely affected by such vasodilatory effects, for example patients with resting hypotension (BP <90/50), or with 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 sildenafil is administered, the possibility of associated PVOD should be considered.

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

• 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 with retinitis pigmentosa (a minority of these patients have genetic disorders of retinal phosphodiesterases).
• Patients currently on bosentan therapy.

General

Before prescribing REVATIO, it is important to note the following:

• Caution is advised when phosphodiesterase type 5 (PDE5) inhibitors are co-administered with alpha-blockers. PDE5 inhibitors, including sildenafil, 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 be anticipated. In some patients, concomitant use of these two drug classes can lower blood pressure significantly, leading to symptomatic hypotension. In the sildenafil interaction studies with alpha-blockers (see DRUG INTERACTIONS), cases of symptomatic hypotension consisting of dizziness and lightheadedness were reported. No cases of syncope or fainting were reported during these interaction studies. Consideration should be given to the fact that safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and concomitant use of anti-hypertensive drugs.
• REVATIO 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). In the event of an erection that persists longer than 4 hours, the patient should seek immediate medical assistance. If priapism (painful erections greater than 6 hours in duration) is not treated immediately, penile tissue damage and permanent loss of potency could result.
• 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 higher in patients with PAH secondary to CTD (sildenafil 13%, placebo 0%) than in PPH patients (sildenafil 3%, placebo 2%). The incidence of epistaxis was also higher in sildenafil-treated patients with 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 and patients with active peptic ulceration.

Information for Patients

Physicians should discuss with patients the contraindication of REVATIO with regular and/or intermittent use of organic nitrates.

Sildenafil is also marketed as VIAGRA® for male erectile dysfunction.

Physicians should advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking all 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 rarely post-marketing in temporal association with the use of all PDE5 inhibitors when used in the treatment of male- 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 with patients the increased risk of NAION in individuals 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).

Physicians should advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking all 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, Clinical Trials and Post-Marketing Experience)

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 Recommended Human Dose (RHD) of 20 mg t.i.d. 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 t.i.d.

Pregnancy

Pregnancy Category B. No evidence of teratogenicity, embryotoxicity or fetotoxicity was observed in pregnant rats or rabbits, dosed with 200 mg sildenafil/kg/day during organogenesis, a level that is, on a mg/m² basis, 32- and 68-times, respectively, the RHD of 20 mg t.i.d. 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/m² basis). There are no adequate and well-controlled studies of sildenafil in pregnant women.

Nursing Mothers

It is not known if sildenafil citrate and/or metabolites are excreted in human breast milk. Since many drugs are excreted in human milk, caution should be used when REVATIO is administered to nursing women.

Pediatric Use

Safety and Effectiveness of sildenafil in pediatric pulmonary hypertension patients has not been established.

Geriatric Use

Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, but studies did not include sufficient numbers of subjects to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger pulmonary arterial hypertension 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.

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

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

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

Mechanism of Action

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 Pharmacodynamics).

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.

Pharmacokinetics and Metabolism

Absorption and Distribution: REVATIO is rapidly absorbed after oral administration, with absolute bioavailability of about 40%. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When REVATIO 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.

Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4 (major route) and cytochrome P450 2C9 (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 phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. In healthy volunteers, 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. In patients with pulmonary arterial hypertension, however, the ratio of the metabolite to sildenafil is higher. Both sildenafil and the active metabolite have terminal half-lives of about 4 hours. The concomitant use of potent cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil (See DOSAGE AND ADMINISTRATION and PRECAUTIONS: DRUG INTERACTIONS).

After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of the administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose).

Pharmacokinetics in Special Populations

Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, with free plasma concentrations approximately 40% greater than those seen in healthy younger volunteers (18-45 years).

Renal Insufficiency: 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 sildenafil (50 mg) was 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.

Hepatic Insufficiency: In volunteers with hepatic cirrhosis (Child-Pugh class A and B), sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.

Population pharmacokinetics

Age, gender, race, and renal and hepatic function were included as factors assessed in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in pulmonary arterial hypertension patients. The data set available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated with hepatic and renal function. None of these factors had a statistically significant impact on sildenafil pharmacokinetics in patients with pulmonary hypertension.

In patients with pulmonary hypertension, the average steady-state concentrations were 20-50% higher when compared to those of healthy volunteers. There was also a doubling of Cmin levels compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of sildenafil in patients with pulmonary hypertension compared to healthy volunteers.

Pharmacodynamics

Effects of REVATIO on Blood Pressure: Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in supine blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.4/5.5 mmHg). The decrease in blood pressure was most notable approximately 1-2 hours after dosing, and was not different from placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, 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).

Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg t.i.d. to patients with pulmonary arterial hypertension, no clinically relevant effects on ECG were reported.

After chronic dosing of 80 mg t.i.d. sildenafil to healthy volunteers, the largest mean change from baseline in supine systolic and supine diastolic blood pressures was a decrease of 9.0 mmHg and 8.4 mmHg, respectively.

After chronic dosing of 80 mg t.i.d. sildenafil to patients with systemic hypertension, the mean change from baseline in systolic and diastolic blood pressures was a decrease of 9.4 mmHg and 9.1 mmHg, respectively.

After chronic dosing of 80 mg t.i.d. sildenafil to patients with pulmonary arterial hypertension, lesser reductions than above in systolic and diastolic blood pressures were observed (a decrease in both of 2 mmHg).

Effects of REVATIO on Vision: At single oral doses of 100 mg and 200 mg, transient dose- related impairment of color discrimination (blue/green) 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. An evaluation of visual function at doses up to 200 mg revealed no effects of REVATIO on visual acuity, intraocular pressure, or pupillometry.

Clinical Studies

A randomized, double-blind, placebo-controlled study was conducted in 277 patients with pulmonary arterial hypertension (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 anticoagulation, digoxin, calcium channel blockers, diuretics or 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) t.i.d. for a period of 12 weeks. They had either primary pulmonary hypertension (63%), PAH associated with connective tissue disease (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 test 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 sildenafil. These increases were highly significantly different from placebo, but the dose groups were not different from each other (Figure 1). 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 pivotal study were also evaluated 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. Doses of 20 mg, 40 mg, and 80 mg t.i.d. produced a placebo-corrected decrease in mPAP of -2.7 mmHg, -3.0 mmHg, and -5.1 mmHg, respectively. There was no evidence of a difference in effect between sildenafil 20 mg t.i.d. and the higher doses tested. Data from other hemodynamic parameters can be found in Table 1. The relationship between these effects and improvements in 6-minute walk distance is unknown.

Table 1. Changes from Baseline to Week 12 in Hemodynamic Parameters at Sildenafil 20 mg t.i.d. Dose

259 of the 277 treated patients 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.

REVATIO®
(re-VAH-tee-oh)
(sildenafil citrate) tablets

Read the Patient Information that comes with REVATIO before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment. If you have any questions about REVATIO, ask your doctor or pharmacist.

What is the most important information I should know about REVATIO (sildenafil citrate)?

• Never take REVATIO with any nitrate medicines. Your blood pressure could drop quickly. It could fall to an unsafe level. Nitrate medicines include:
• Medicines that treat chest pain (angina)
• Nitroglycerin in any form
• Isosorbide mononitrate or dinitrate
• Street drugs called "poppers" (amyl nitrate or nitrite)

Ask your doctor or pharmacist if you are not sure if you are taking a nitrate medicine.

What is REVATIO (sildenafil citrate)?

REVATIO is a prescription medicine used to treat pulmonary arterial hypertension (PAH). REVATIO improves the ability to exercise. With PAH, the blood pressure in your lungs is too high. Your heart has to work hard to pump blood into your lungs.

REVATIO has not been studied

•  in children under 18 years old
•  in patients who are also taking a medicine called bosentan (Tracleer®)

REVATIO contains the same medicine as VIAGRA® (sildenafil citrate), which is used to treat erectile dysfunction (impotence).

Who should not take REVATIO (sildenafil citrate)?

Do not take REVATIO if you

• take nitrate medicines. See "What is the most important information I should know about REVATIO?"
• are allergic to sildenafil citrate or any other ingredient in REVATIO. See "What are the ingredients in REVATIO?" at the end of this leaflet.

What should I tell my doctor before taking REVATIO (sildenafil citrate)?

Tell your doctor about all of your medical conditions, including if you

• have had a heart attack, stroke, or irregular heartbeats in the last 6 months
• have chest pain (angina)
• have a disease called pulmonary veno-occlusive disease (PVOD)
• have high or low blood pressure or blood circulation problems
• have an eye problem called retinitis pigmentosa
• have or had loss of sight in one or both eyes
• have liver or kidney problems
• have any problem with the shape of your penis
• lose a large amount of body fluids (dehydration). This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot or don't drink enough liquids.
• have any blood cell problems such as cancer of blood cells or bone marrow or sickle cell anemia
• have a stomach ulcer or any bleeding problems
• are pregnant or planning to become pregnant. It is not known if REVATIO could harm your unborn baby.
• are breastfeeding. It is not known if REVATIO passes into your breast milk or if it could harm your baby.

Tell your doctor about all of the medicines you take, including prescription and non- prescription medicines, vitamins, and herbal products. REVATIO and certain other medicines can cause side effects if you take them together. The doses of some of your medicines may need to be adjusted while you take REVATIO. Especially tell your doctor if you

• Take nitrate medicines. See "What is the most important information I should know about REVATIO?"
• Take ritonavir (Norvir®) or other medicines used to treat HIV infection
• Use ketoconazole (Nizoral®)

Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine.

How should I take REVATIO (sildenafil citrate)?

• Take REVATIO exactly as your doctor tells you.
• REVATIO is a tablet you take by mouth. Take a REVATIO tablet 3 times a day about 4 to 6 hours apart.
• Take REVATIO at the same times every day, with or without food.
• If you miss a dose, take it as soon as you remember. If it is close to your next dose, skip the missed dose, and take your next dose at the regular time.
• Do not take more than one dose of REVATIO at a time.
• Do not change your dose or stop taking REVATIO on your own. Talk to your doctor first.
• If you take too much REVATIO, call your doctor or poison control center, or go to an emergency room.

What are the possible side effects of REVATIO (sildenafil citrate)?

The following side effects were reported in patients taking REVATIO. Some of these were serious.

• low blood pressure. Low blood pressure may cause you to feel faint or dizzy. Lie down if you feel faint or dizzy.
• more shortness of breath than usual. Tell your doctor if you get more short of breath after you start REVATIO. More shortness of breath than usual may be due to your underlying medical condition.

The following side effects were reported rarely in patients taking sildenafil:

• decreased eyesight or loss of sight in one or both eyes (NAION). If you notice a sudden decrease or loss of eyesight, talk to your doctor right away. It is not possible to determine if these events are related to oral medicines for the treatment of erectile dysfunction, including sildenafil, or to other medical problems, or combination of these factors.
• sudden decrease or loss of hearing. If you notice a sudden decrease or loss of hearing, talk to your doctor right away. It is not possible to determine whether these events are related directly to this class of oral medicines, including sildenafil, or to other diseases or medications, to other factors, or to a combination of factors.
• heart attack, stroke, irregular heartbeats, and death. Most of these happened in men who already had heart problems.
• erections that last several hours. Tell your doctor right away if you have an erection that lasts more than 4 hours.

The most common side effects are nosebleed, headache, upset stomach, getting red or hot in the face (flushing), and trouble sleeping.

Tell your doctor if you have any side effect that bothers you or doesn't go away.

These are not all the possible side effects of REVATIO. For more information, ask your doctor or pharmacist.

How should I store REVATIO (sildenafil citrate)?

• Store REVATIO at room temperature, 59-86°F (15-30°C).
• Keep REVATIO and all medicines away from children.

General information about REVATIO (sildenafil citrate)

Medicines are sometimes prescribed for conditions that are not in the patient leaflet. Do not use REVATIO for a condition for which it was not prescribed. Do not give REVATIO to other people, even if they have the same symptoms you have. It could harm them.

This patient leaflet summarizes the most important information about REVATIO. If you would like more information about REVATIO:

• Ask your doctor or pharmacist for information about REVATIO that is written for health professionals.
• Go to www.REVATIO.com or call 1-800-879-3477.

What are the ingredients in REVATIO (sildenafil citrate)?

Active ingredients: sildenafil citrate

Inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hypromellose, titanium dioxide, lactose monohydrate, and triacetin

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

SILDENAFIL - ORAL

(sill-DEN-uh-fil)

COMMON BRAND NAME(S): Viagra

USES: Sildenafil is used to treat male sexual function problems (impotence or erectile dysfunction) by blocking a certain enzyme (phosphodiesterase-PDE5) in the body. In combination with sexual stimulation, sildenafil works by helping the blood flow into the penis to achieve and maintain an erection.

This drug is not indicated for use in women.

Use of this drug does not protect against sexually transmitted diseases (e.g., HIV, hepatitis B, gonorrhea, syphilis). Practice "safe sex" such as using latex condoms. Consult your doctor or pharmacist for more details.

HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start taking sildenafil and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

This drug is taken by mouth as needed, at least 30 minutes, but no more than 4 hours, before sexual activity (1 hour before is the most effective). Do not take more often than once daily, and take as directed.

A high fat meal may delay the time of onset of this drug.

Avoid eating grapefruit or drinking grapefruit juice while you are being treated with this medication unless your doctor instructs you otherwise.

The dosage is based on your medical condition, response to therapy, and other medications you may be taking (see also Drug Interactions section). Consult your doctor or pharmacist for more details.

SIDE EFFECTS: Headache, flushing, stomach upset, heartburn, nasal stuffiness, diarrhea, dizziness, or lightheadedness may occur. Vision changes such as increased sensitivity to light, blurred vision, or impaired blue/green color discrimination may also occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Rarely, a sudden loss of eyesight in one or both eyes (NAION) may occur. This may or may not be due to sildenafil. If this serious problem occurs, seek immediate medical attention. You have a slightly greater chance of developing this serious eye problem if you have heart disease, diabetes, high cholesterol, certain eye problems ("crowded disk"), high blood pressure, are over 50 years of age, or if you smoke.

Sexual activity may put extra strain on your heart, especially if you have heart problems. If you have heart problems and experience any of these serious side effects while having sex, stop and seek immediate medical attention: severe dizziness, fainting, chest pain, nausea.

For males, in the very unlikely event you have a painful or prolonged erection lasting 4 or more hours, stop using this drug and seek immediate medical attention, or permanent problems could occur.

Rarely, sildenafil may cause sudden hearing problems, or ringing in the ears. Seek immediate medical attention if these effects occur.

A serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction include: rash, itching, unusual swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking sildenafil, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: penis conditions (e.g., angulation, fibrosis/scarring, Peyronie's disease), history of painful/prolonged erection (priapism), sickle cell anemia, blood system cancers (e.g., leukemia or myeloma), eye problems (e.g., retina diseases like retinitis pigmentosa), kidney disease, liver disease, bleeding disorders, active stomach ulcers, heart problems (e.g., recent heart attack or serious arrhythmia within past 6 months, heart failure, coronary artery disease with unstable angina, aortic stenosis, idiopathic hypertrophic subaortic stenosis), recent stroke within past 6 months, very high or low blood pressure.

This drug may make you dizzy or cause vision changes; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

To minimize dizziness and lightheadedness, get up slowly when rising from a seated or lying position.

Do not take this medication with any other product that contains sildenafil or other similar medications for erection problems (e.g., tadalafil, vardenafil).

Caution is advised when using this drug in the elderly because they may be more sensitive to the side effects of the drug.

This drug is not indicated for use in women or children.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.

See also How To Use section for drug-food interactions.

This drug should not be used with the following medications because very serious (possibly fatal) interactions may occur: nitrates (e.g., nitroglycerin, isosorbide), nitroprusside (or any "nitric oxide donor" drugs), recreational drugs called "poppers" containing amyl or butyl nitrite.

If you are currently using any of these medications, tell your doctor or pharmacist before starting sildenafil.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: alpha-blocker medication (e.g., doxazosin, prazosin, terazosin), other medications for impotence, bosentan, high blood pressure medicines, drugs affecting liver enzymes that remove sildenafil from your body (such as azole antifungals including ketoconazole/itraconazole, macrolide antibiotics including erythromycin, cimetidine, delavirdine, rifamycins including rifabutin/rifampin, St. John's wort, certain anti-seizure medicines including carbamazepine).

If you are taking an HIV protease inhibitor (e.g., ritonavir, saquinavir), do not take more than a 25 milligrams dose of sildenafil in a 48 hour period.

If you are taking more than a 25 milligrams dose of sildenafil and are also taking an alpha-blocker medication (e.g., doxazosin, prazosin, terazosin) for various conditions (e.g., enlarged prostate), separate the time between taking these medications by more than 4 hours.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include severe dizziness, fainting, or prolonged erection.

NOTES: Do not share this medication with others, since they may have a problem that is not effectively treated by this drug, or they may have a condition that is complicated by this drug.

MISSED DOSE: Not applicable.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59 and 86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.