Limitation of Use

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

2.1 Pulmonary Arterial Hypertension (PAH)

REVATIO Tablets

REVATIO tablets are supplied as white, film-coated, round tablets engraved with "RVT20" containing sildenafil citrate equivalent to 20 mg of sildenafil.

REVATIO Injection

REVATIO injection is supplied as a single use vial containing 10 mg (12.5 mL) of sildenafil.

4.1 Use with Organic Nitrates

Do not use REVATIO in patients taking organic nitrates in any form, either regularly or intermittently. 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 or injection.

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.

5.1 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.

5.2 Effects on Bleeding

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.

5.8 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 REVATIO than by those randomized to placebo. The effectiveness of REVATIO in PH secondary to sickle cell anemia has not been established.

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 were obtained from the 12 week, placebo-controlled clinical study and an open-label extension study in 277 treated patients with pulmonary arterial hypertension. Doses up to 80 mg TID were studied.

The overall frequency of discontinuation in REVATIO-treated patients at the recommended dose of 20 mg TID was 3% and was the same for the placebo group.

In the 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 TID) and were more frequent in REVATIO patients than placebo patients, are shown in Table 1. Adverse events were generally transient and mild to moderate in nature.

At doses higher than the recommended 20 mg TID, 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.

The incidence of retinal hemorrhage at the recommended sildenafil 20 mg TID 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.

In a placebo-controlled fixed dose titration study of REVATIO (starting with recommended dose of 20 mg TID and increased to 40 mg TID and then 80 mg TID) as an adjunct to intravenous epoprostenol in pulmonary arterial hypertension, the adverse events that were reported were more frequent than in the placebo arm (> 6% difference) are shown in Table 2.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval 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.

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.

8.1 Pregnancy

8.2 Labor and Delivery

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)].

12.1 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 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

12.3 Pharmacokinetics

13.1 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 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.

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 (mean 343).

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 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. 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 (mean 349). 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.

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

REVATIO Injection is supplied as a clear, colorless, sterile, ready to use solution containing 10 mg sildenafil (12.5mL) presented in a glass vial.