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]. 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 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.
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 in patients
with retinitis pigmentosa, a minority whom have genetic disorders of retinal phosphodiesterases.
Prescribe REVATIO with caution in these patients.
Hearing Impairment
Adivise 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].
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.
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.
DRUG INTERACTIONS
Nitrates
Concomitant use of REVATIO with nitrates in any form is contraindicated
[see Contraindications].
Ritonavir and other Potent CYP3A Inhibitors
Concomitant use of REVATIO with ritonavir and other potent CYP3A inhibitors is not
recommended [see Warnings and Precautions].
Alpha-blockers
Use caution when co-administering alpha-blockers with REVATIO because of additive blood
pressure-lowering effects [see Warnings and Precautions].
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.
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, this drug should be used during pregnancy only if clearly needed.
Labor and Delivery
The safety and efficacy of Revatio 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 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 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].
PATIENT COUNSELING INFORMATION
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Inform patients of contraindication of REVATIO with regular and/or intermittent use of organic nitrates.
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Inform patients that sildenafil is also marketed as VIAGRA for erectile dysfunction. Advise patients taking REVATIO not to take VIAGRA or other PDE5 inhibitors.
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Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking REVATIO. Such an event may be a sign of NAION.
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Advise patients to seek prompt medical attention in the event of sudden decrease or loss of hearing while taking REVATIO. These events may be accompanied by tinnitus and dizziness.