Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 11 June 2018


1 INDICATIONS 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 [see Clinical Studies (14)]. 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%). REVATIO is a phosphodiesterase-5 (PDE-5) inhibitor indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group I) in adults to improve exercise ability and delay clinical worsening. Studies establishing effectiveness were short-term (12 to 16 weeks), and included predominately patients with NYHA Functional Class II–III symptoms. Etiologies were idiopathic (71%) or associated with connective tissue disease (25%). (1) Limitation of Use: Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity. (1, 14) Limitation of Use : Adding sildenafil to bosentan therapy does not result in any beneficial effect on exercise capacity [see Clinical Studies (14)].

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Advisory information

4 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 (5.2)]. Concomitant use of riociguat, a guanylate cyclase stimulator. 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. Use with organic nitrates or riociguat (4) History of hypersensitivity reaction to sildenafil or any component of the tablet, injection, or oral suspension (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse events are discussed elsewhere in the labeling: Mortality with pediatric use [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)] Hypotension [see Warnings and Precautions (5.2)] Vision loss [see Warnings and Precautions (5.5)] Hearing loss [see Warnings and Precautions (5.6)] Priapism [see Warnings and Precautions (5.8)] Vaso-occlusive crisis [see Warnings and Precautions (5.9)] Most common adverse reactions greater than or equal to 3% and more frequent than placebo were epistaxis, headache, dyspepsia, flushing, insomnia, erythema, dyspnea, and rhinitis. (6.1, 6.2) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at 1-800-438-1985 or FDA at 1-800-FDA-1088 or 6.1 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 [see Clinical Studies (14)]. 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 REVATIO-Treated 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 Insomnia 1 7 6 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 hemorrhage 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. In a placebo-controlled fixed dose titration study (Study 2) of REVATIO (starting with recommended dose of 20 mg and increased to 40 mg and then 80 mg all three times a day) as an adjunct to intravenous epoprostenol in patients with PAH, the adverse reactions that were more frequent in the REVATIO + epoprostenol group than in the epoprostenol group (greater than 6% difference) are shown in Table 2 [see Clinical Studies (14)]. Table 2. Adverse Reactions (%) in patients with PAH in Study 2 (incidence in REVATIO + Epoprostenol group at least 6% greater than Epoprostenol group) REVATIO + Epoprostenol (n = 134) Epoprostenol (n = 131) (REVATIO + Epoprostenol) minus Epoprostenol Headache 57 34 23 Edemaincludes peripheral edema 25 13 14 Dyspepsia 16 2 14 Pain in extremity 17 6 11 Diarrhea 25 18 7 Nausea 25 18 7 Nasal congestion 9 2 7 REVATIO Injection REVATIO injection was studied in a 66-patient, placebo-controlled study in patients with PAH at doses targeting plasma concentrations between 10 and 500 ng/mL (up to 8 times the exposure of the recommended dose). Adverse events with REVATIO injection were similar to those seen with oral tablets. 6.2 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 Ophthalmologic NAION [see Warnings and Precautions (5.5) and Patient Counseling Information (17)].

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Tablet and oral suspension: 5 mg or 20 mg three times a day, 4–6 hours apart (2.1) Injection: 2.5 mg or 10 mg three times a day administered as an intravenous bolus injection (2.2) 2.1 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. 2.2 REVATIO Injection REVATIO injection is for the continued treatment of patients with PAH who are currently prescribed oral REVATIO and who are temporarily unable to take oral medication. The recommended dose is 2.5 mg or 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. 2.3 Reconstitution of the Powder for Oral Suspension Tap the bottle to release the powder. Remove the cap. Accurately measure out 60 mL of water and pour the water into the bottle. (Figure 1) Figure 1 Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. (Figure 2) Figure 2 Remove the cap. 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. (Figure 3) Figure 3 Replace the cap and shake the bottle vigorously for a minimum of 30 seconds. (Figure 4) Figure 4 Remove the cap. Press the bottle adaptor into the neck of the bottle (as shown on Figure 5, below). The adaptor is provided so that you can fill the oral syringe with medicine from the bottle. Replace the cap on the bottle. Figure 5 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). Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Incompatibilities Do not mix with any other medication or additional flavoring agent.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 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). 8.2 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. 8.4 Pediatric Use In a randomized, double-blind, multi-center, placebo-controlled, parallel-group, dose-ranging study, 234 patients with PAH, aged 1 to 17 years, body weight greater than or equal to 8 kg, were randomized, on the basis of body weight, to three dose levels of REVATIO, or placebo, for 16 weeks of treatment. Most patients had mild to moderate symptoms at baseline: WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%). One-third of patients had primary PAH; two-thirds had secondary PAH (systemic-to-pulmonary shunt in 37%; surgical repair in 30%). Sixty-two percent of patients were female. Drug or placebo was administered three times a day. The primary objective of the study was to assess the effect of REVATIO on exercise capacity as measured by cardiopulmonary exercise testing in pediatric patients developmentally able to perform the test (n = 115). Administration of REVATIO did not result in a statistically significant improvement in exercise capacity in those patients. No patients died during the 16-week controlled study. After completing the 16-week controlled study, a patient originally randomized to REVATIO remained on his/her dose of REVATIO or, if originally randomized to placebo, was randomized to low-, medium-, or high-dose REVATIO. After all patients completed 16 weeks of follow-up in the controlled study, the blind was broken and doses were adjusted as clinically indicated. Patients treated with sildenafil were followed for a median of 4.6 years (range 2 days to 8.6 years). Mortality during the long-term study, by originally assigned dose, is shown in Figure 6: Figure 6: Kaplan-Meier Plot of Mortality by REVATIO Dose During the study, there were 42 reported deaths, with 37 of these deaths reported prior to a decision to titrate subjects to a lower dosage because of a finding of increased mortality with increasing REVATIO doses. For the survival analysis which included 37 deaths, the hazard ratio for high dose compared to low dose was 3.9, p=0.007. Causes of death were typical of patients with PAH. Use of REVATIO, particularly chronic use, is not recommended in children. Figure 6 8.5 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 (12.3)]. 8.6 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)]. 8.7 Patients with Renal Impairment No dose adjustment is required (including severe impairment CLcr < 30 mL/min) [see Clinical Pharmacology (12.3)].


7 DRUG INTERACTIONS Concomitant alpha-blockers or amlodipine: Note additive blood pressure lowering effects. (7) Use with ritonavir and other potent CYP3A inhibitors: Not recommended. (7, 12.3) Concomitant PDE-5 inhibitors: Avoid use with Viagra or other PDE-5 inhibitors. (5.7) Nitrates Concomitant use of REVATIO with nitrates in any form is contraindicated [see Contraindications (4)]. Ritonavir and other Potent CYP3A Inhibitors Concomitant use of REVATIO with ritonavir and other potent CYP3A inhibitors is not recommended [see Clinical Pharmacology (12.3)]. Other drugs that reduce blood pressure Alpha blockers. 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. Monitor blood pressure when co-administering blood pressure lowering drugs with REVATIO [see Warnings and Precautions (5.2)].

More information

Category Value
Authorisation number NDA203109
Agency product number BW9B0ZE037
Orphan designation No
Product NDC 0069-0338,0069-0336,0069-4190
Date Last Revised 20-02-2018
RXCUI 1307427
Storage and handling Recommended Storage for REVATIO Tablets: Store at controlled room temperature 20°C – 25°C (68°F – 77°F) ; excursions permitted to 15°C – 30°C (59°F –86°F) [see USP Controlled Room Temperature].
Marketing authorisation holder Pfizer Laboratories Div Pfizer Inc