Revatio
(sildenafil)Dosage & Administration
Revatio Prescribing Information
Adults
REVATIO is indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group I) in adults to improve exercise ability and delay clinical worsening [see Clinical Studies (14)].
Pediatric Patients (1 to 17 Years old)
REVATIO is indicated in pediatric patients 1 to 17 years old for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) to improve exercise ability and, in pediatric patients too young to perform standardized exercise testing, pulmonary hemodynamics thought to underlie improvements in exercise [see Clinical Studies (14)].
Recommended Dosage in Adults
Oral Dosage
The recommended dosage of REVATIO is 20 mg three times a day. Dose may be titrated to a maximum of 80 mg three times a day, if required, based on symptoms and tolerability [see Clinical Studies (14)].
Although dose-response improvement in exercise ability was not observed in short-term studies in adults with PAH, the delay in clinical worsening with long-term use of sildenafil in Study A1481324 supports dosing up to a maximum of 80 mg three times a day [see Clinical Studies (14)].
Intravenous Dosage
The recommended dose is 10 mg administered as an intravenous bolus injection three times a day. The dose of REVATIO injection does not need to be adjusted for body weight.
A 10-mg dose of REVATIO injection is predicted to provide pharmacological effect of sildenafil and its N-desmethyl metabolite equivalent to that of a 20-mg oral dose.
Recommended Dosage in Pediatric Patients
Oral Dosage
The recommended dosage in patients ≤20 kg is 10 mg three times a day.
For pediatric patients 20 kg to 45 kg, the recommended dosage is 20 mg three times a day.
For pediatric patients 45 kg and greater, the recommended dosage is 20 mg three times a day. A maximum dose in pediatric patients has not been identified. Based on the experience in adults, dose may be titrated to a maximum of 40 mg three times a day for pediatric patients >45 kg, if required, based on symptoms and tolerability [see Clinical Studies (14)].
Reconstitution of the Powder for Oral Suspension
Note: Reconstitute the contents of the bottle with a total volume of 90 mL (60 mL followed by 30 mL). Refer to the detailed instructions below.
- 1.
- Tap the bottle to loosen the powder.
- 2.
- Add 60 mL of water to the bottle.
- 3.
- Replace the cap and shake the bottle vigorously for a minimum of 30 seconds.
- 4.
- Add another 30 mL of water to the bottle.
- 5.
- Replace the cap and shake the bottle vigorously for a minimum of 30 seconds.
- 6.
- Remove cap and press the bottle adaptor into the neck of the bottle. Replace the cap on the bottle.
- 7.
- Write the expiration date of the reconstituted oral suspension on the bottle label (the expiration date of the reconstituted oral suspension is 60 days from the date of reconstitution).
Incompatibilities
Do not mix with any other medication or additional flavoring agent.
REVATIO Tablets
White, film-coated, round tablets engraved with “RVT20” containing sildenafil citrate equivalent to 20 mg of sildenafil.
REVATIO for Oral Suspension
White to off-white powders containing 1.57 g of sildenafil citrate (equivalent to 1.12 g of sildenafil) in a bottle for reconstitution to 10 mg/mL. Following reconstitution with 90 mL of water, the total volume of the oral suspension is 112 mL. A 2-mL oral dosing syringe (with 0.5 mL and 2 mL dose markings) and a press-in bottle adaptor are also provided.
REVATIO Injection
Single use vial containing 10 mg/12.5 mL of sildenafil.
Pregnancy
Risk Summary
Limited published data from randomized controlled trials, case-controlled trials, and case series do not report a clear association with sildenafil and major birth defects, miscarriage, or adverse maternal or fetal outcomes when sildenafil is used during pregnancy. There are risks to the mother and fetus from untreated pulmonary arterial hypertension (see Clinical Considerations). Animal reproduction studies conducted with sildenafil showed no evidence of embryo-fetal toxicity or teratogenicity at doses up to 32- and 65-times the recommended human dose (RHD) of 20 mg three times a day in rats and rabbits, respectively (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Pregnant women with untreated pulmonary arterial hypertension are at risk for heart failure, stroke, preterm delivery, and maternal and fetal death.
Data
Animal Data
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 65-times, respectively, the recommended human dose (RHD) of 20 mg three times a day. 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).
Lactation
Risk Summary
Limited published data from a case report describe the presence of sildenafil and its active metabolite in human milk. There is insufficient information about the effects of sildenafil on the breastfed infant and no information on the effects of sildenafil on milk production. Limited clinical data during lactation preclude a clear determination of the risk of REVATIO to an infant during lactation.
Pediatric Use
The safety and efficacy of REVATIO have been established in pediatric patients 1 to 17 years old, for the treatment of PAH (WHO Group I) to improve exercise ability and, in patients too young to perform standard exercising testing, pulmonary hemodynamics thought to underlie improvements in exercise Use of REVATIO for this indication is supported by evidence from adequate and well-controlled studies in adults with additional PK and safety data in pediatric patients aged 1 year and older [see Adverse Reactions (6.1), Clinical Studies (14)]. The safety and effectiveness of REVATIO have not been established in pediatric patients younger than 1 year of age.
During the conduct of the pediatric studies (STARTS-1 and STARTS-2) [see Clinical Studies (14)], an imbalance in the number of deaths was noted: 5/55 (9.1%), 10/74 (13.5%), and 22/100 (22%) in the sildenafil low, medium, and high dose groups, respectively. The causes of death were related to the progression of PAH. This safety observation in pediatrics was not confirmed in a study conducted in adults designed to evaluate this risk (Study A1481324).Given the beneficial effects on clinical worsening and death observed in adults with increasing doses (Study A1481324) and the expected similarity of disease in pediatrics and adults, a causal association for the observed dose-related effect on mortality in pediatric patients is unlikely, and therefore, the available data support dosing in pediatric patients >45 kg up to a maximum of 40 mg three times a day.
Geriatric Use
Clinical studies of REVATIO did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 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 (12.3)].
Patients with Hepatic Impairment
No dose adjustment for mild to moderate impairment is required. Severe impairment has not been studied [see Clinical Pharmacology (12.3)].
Patients with Renal Impairment
No dose adjustment is required (including severe impairment CLcr <30 mL/min) [see Clinical Pharmacology (12.3)].
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 (5.1)].
- •
- Concomitant use of riociguat, a guanylate cyclase stimulator. Phosphodiesterase-5 (PDE-5) inhibitors, including sildenafil, may potentiate the hypotensive effects of riociguat.
- •
- 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.
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 [blood pressure less than 90/50], fluid depletion, severe left ventricular outflow obstruction, or autonomic dysfunction). Monitor blood pressure when co‑administering 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%) patients. 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 post marketing in temporal association with the use of PDE-5 inhibitors, including sildenafil. Most patients had underlying anatomic or vascular risk factors for developing NAION, including low cup to disc ratio (“crowded disc”).
Advise patients to seek immediate medical attention in the event of a sudden loss of vision in one or both eyes while taking REVATIO.
There are no controlled clinical data on the safety or efficacy of REVATIO in patients with retinitis pigmentosa, a minority of whom have genetic disorders of retinal phosphodiesterases. Therefore, use of REVATIO in patients with retinitis pigmentosa is not recommended.
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 Disease
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 PH secondary to sickle cell disease has not been established.