warnings and cautions
5 WARNINGS AND PRECAUTIONS • Cardiovascular effects: Carefully consider whether patients with certain underlying conditions (e.g., resting hypotension, fluid depletion) could be adversely affected by vasodilatory effects of REVATIO. Not recommended in patients with pulmonary veno-occlusive disease. ( 5.1 ) • Use with alpha-blockers: Note additive blood pressure-lowering effects. ( 5.1 ) • Bleeding: In patients with PAH secondary to CTD, higher rates of epistaxis with REVATIO than placebo, including with concomitant oral vitamin K antagonists. ( 5.2 ) • Use with ritonavir and other potent CYP3A inhibitors: Coadministration not recommended. ( 5.3 ) • Effects on the eye: Consider discontinuing REVATIO if sudden loss of vision occurs, which could be non-arteritic ischemic optic neuropathy (NAION). ( 5.4 ) • Hearing impairment: Discontinue REVATIO if sudden decrease or loss of hearing occurs. ( 5.5 ) • Use with PDE5 inhibitors: Avoid use with VIAGRA or other PDE5 inhibitors. ( 5.6 ) • Prolonged erection: Advise patients to seek emergency treatment if an erection lasts > 4 hours. Use REVATIO with caution in patients predisposed to priapism. ( 5.7 ) • Pulmonary hypertension secondary to sickle cell disease: REVATIO may cause serious vaso-occlusive crises. ( 5.8 ) 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. Use 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, cases of symptomatic hypotension consisting of dizziness and lightheadedness were reported [see Drug Interactions (7) ] . No cases of syncope or fainting were reported during these interaction studies. The 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. 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.