Brief Summary of Prescribing Information.
Consult Full Prescribing Information at REVATIOHCP.com
INDICATION AND USAGE
REVATIO is indicated for the treatment of pulmonary arterial hypertension (WHO Group I) in adults
to improve exercise ability and delay clinical worsening. The delay in clinical worsening was
demonstrated when REVATIO was added to background epoprostenol therapy.
Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately
patients with New York Heart Association (NYHA) Functional Class II-III symptoms and idiopathic
etiology (71%) or associated with connective tissue disease (CTD) (25%).
Limitation of Use: Adding sildenafil to bosentan therapy does not result in any beneficial effect
on exercise capacity.
DOSAGE AND ADMINISTRATION
REVATIO Tablets and Oral Suspension The recommended dose of REVATIO is 5 mg or 20 mg
three times a day. Administer REVATIO doses 4–6 hours apart. In the clinical trial no greater
efficacy was achieved with the use of higher doses. Treatment with doses higher than 20 mg three
times a day is not recommended.
Reconstitution of the Powder for Oral Suspension 1. Tap the bottle to release the powder.
2. Remove the cap. 3. Accurately measure out 60 mL of water and pour the water into the bottle.
4. Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. 5. Remove the
cap. 6. Accurately measure out another 30 mL of water and add this to the bottle. You should always
add a total of 90 mL of water irrespective of the dose prescribed. 7. Replace the cap and shake the
bottle vigorously for a minimum of 30 seconds. 8. Remove the cap. 9. Press the bottle adaptor into
the neck of the bottle. The adaptor is provided so that you can fill the oral syringe with medicine
from the bottle. Replace the cap on the bottle. 10. Write the expiration date of the constituted oral
suspension on the bottle label (the expiration date of the constituted oral suspension is 60 days
from the date of constitution).
Incompatibilities Do not mix with any other medication or additional flavoring agent.
CONTRAINDICATIONS
REVATIO is contraindicated in patients with concomitant use of organic nitrates in any form,
either regularly or intermittently, because of the greater risk of hypotension [see Warnings and
Precautions], Concomitant use of riociguat, a guanylate cyclase stimulator. PDE5 inhibitors,
including sildenafil, may potentiate the hypotensive effects of riociguat. REVATIO is also
contraindicated in patients with known hypersensitivity to sildenafil or any component of the tablet,
injection, or oral suspension. Hypersensitivity, including anaphylactic reaction, anaphylactic shock
and anaphylactoid reaction, has been reported in association with the use of sildenafil.
WARNINGS AND PRECAUTIONS
Mortality with Pediatric Use In a long-term trial in pediatric patients with PAH, an increase in
mortality with increasing REVATIO dose was observed. Deaths were first observed after about
1 year and causes of death were typical of patients with PAH. Use of REVATIO, particularly chronic
use, is not recommended in children [see Use in Specific Populations].
Hypotension 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 on
antihypertensive therapy or with resting hypotension [BP less than 90/50], fluid depletion, severe
left ventricular outflow obstruction, or automatic dysfunction). Monitor blood pressure when coadministering blood pressure lowering drugs with REVATIO.
Worsening Pulmonary Vascular Occlusive Disease 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.
Epistaxis The incidence of epistaxis was 13% in patients taking REVATIO with PAH secondary
to CTD. This effect was not seen in idiopathic PAH (REVATIO 3%, placebo 2%) patient s. The
incidence of epistaxis was also higher in REVATIO-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.
Visual Loss When used to treat erectile dysfunction, non-arteritic anterior ischemic optic
neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been
reported postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE-5)
inhibitors, including sildenafil. 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. Based on published literature, the annual incidence of NAION is
2.5–11.8 cases per 100,000 males aged ≥ 50 per year in the general population. An observational
study evaluated whether recent, episodic use of PDE5 inhibitors (as a class), typical of erectile
dysfunction treatment, was associated with acute onset of NAION. The results suggest an
approximately 2-fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use. It is
not possible to determine whether these events are related directly to the use of PDE-5 inhibitors,
to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these
factors, or to other factors. Advise patients to seek immediate medical attention in the event of
a sudden loss of vision in one or both eyes while taking PDE-5 inhibitors, including REVATIO.
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 PDE-5 inhibitors.
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 Loss Cases of sudden decrease or loss of hearing, which may be accompanied by
tinnitus and dizziness, have been reported in temporal association with the use of PDE-5 inhibitors,
including REVATIO. In some of the cases, medical conditions and other factors were reported
that may have played a role. 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. Advise patients to seek prompt medical attention in the event of sudden decrease or loss
of hearing while taking PDE-5 inhibitors, including REVATIO.
Combination with Other PDE-5 Inhibitors Sildenafil is also marketed as VIAGRA®. The safety
and efficacy of combinations of REVATIO with VIAGRA or other PDE-5 inhibitors have not been
studied. Inform patients taking REVATIO not to take VIAGRA or other PDE-5 inhibitors.
Priapism 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.
Vaso-occlusive Crisis in Patients with 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 and safety of REVATIO in the treatment of PAH secondary to sickle cell anemia
has not been established.
ADVERSE REACTIONS
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 of REVATIO in adults were obtained from the 12-week, placebo-controlled clinical
study (Study 1) and an open-label extension study in 277 REVATIO-treated patients with PAH,
WHO Group I.
The overall frequency of discontinuation in REVATIO-treated patients on 20 mg three times a
day was 3% and was the same for the placebo group. In Study 1, the adverse reactions that
were reported by at least 3% of REVATIO-treated patients (20 mg three times a day) and were
more frequent in REVATIO-treated patients than in placebo-treated patients are shown in Table 1.
Adverse reactions were generally transient and mild to moderate in nature.
Table 1: Most Common Adverse Reactions in Patients with PAH in Study 1 (More Frequent in
REVATIO-Treated Patients than Placebo-Treated Patients and Incidence ≥3% in REVATIOTreated Patients)
Placebo,
% (n=70)
REVATIO 20 mg three
times a day, % (n=69)
Placebo-Subtracted,
%
Epistaxis
1
9
8
Headache
39
46
7
Dyspepsia
7
13
6
Flushing
4
10
6
6
Insomnia
1
7
Erythema
1
6
5
Dyspnea exacerbated
3
7
4
Rhinitis
0
4
4
Diarrhea
6
9
3
Myalgia
4
7
3
Pyrexia
3
6
3
Gastritis
0
3
3
Sinusitis
0
3
3
Paresthesia
0
3
3
At doses higher than the recommended 20 mg three times a day, there was a greater incidence
of some adverse reactions 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 hemo rrhage with REVATIO 20 mg three times a day was 1.4% versus
0% placebo and for all REVATIO doses studied was 1.9% versus 0% placebo. The incidence
of eye hemorrhage at both 20 mg three times a day and at all doses studied was 1.4% for
REVATIO versus 1.4% for placebo. The patients experiencing these reactions had risk factors for
hemorrhage including concurrent anticoagulant therapy.
Postmarketing Experience The following adverse reactions have been identified during post
approval 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.
Cardiovascular Events In postmarketing experience with sildenafil at doses indicated for 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, to sexual activity, to the patient’s underlying cardiovascular
disease, or to a combination of these or other factors.
Nervous system Seizure, seizure recurrence.
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.