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Included as part of the PRECAUTIONS section.

Cardiovascular Effects

REVATIO (sildenafil citrate) has vasodilatory properties, resulting in mild and transient decreases in blood pressure. Before prescribing REVATIO (sildenafil citrate) , 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 (sildenafil citrate) to patients with veno-occlusive disease, administration of REVATIO (sildenafil citrate) to such patients is not recommended. Should signs of pulmonary edema occur when REVATIO (sildenafil citrate) is administered, consider the possibility of associated PVOD.

As there are no controlled clinical data on the safety or efficacy of REVATIO (sildenafil citrate) 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]. 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.

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 (sildenafil citrate) is unknown in patients with bleeding disorders or active peptic ulceration.

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 and CLINICAL PHARMACOLOGY].

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 (sildenafil citrate) . 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].

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

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 (sildenafil citrate) . These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including REVATIO (sildenafil citrate) . 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].

Combination with other PDE5 inhibitors

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

Prolonged Erection

Use REVATIO (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.

Pulmonary Hypertension Secondary to Sickle Cell Anemia

In a small, prematurely terminated study of patients with pulmonary hypertension (PH) secondary to sickle cell disease, vasoocclusive crises requiring hospitalization were more commonly reported by patients who received REVATIO (sildenafil citrate) than by those randomized to placebo. The effectiveness of REVATIO (sildenafil citrate) in PH secondary to sickle cell anemia has not been established.

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

Pregnancy Category B

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/m² basis, 32- and 68-times, respectively, the recommended human dose (RHD) of 20 mg TID. 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, however, no adequate and well-controlled studies of sildenafil in pregnant women. Because animal reproduction studies are not always predictive of human response, REVATIO (sildenafil citrate) should be used during pregnancy only if clearly needed.

Labor and Delivery

The safety and efficacy of Revatio (sildenafil citrate) during labor and delivery has not been studied.

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 (sildenafil citrate) is administered to a nursing woman.

Pediatric Use

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

Geriatric Use

Clinical studies of REVATIO (sildenafil citrate) 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].

Hepatic Impairment

No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see CLINICAL PHARMACOLOGY].

Renal Impairment

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

Last reviewed on RxList: 12/29/2010
This monograph has been modified to include the generic and brand name in many instances.