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