Revatio Drug Information
Generic name: SILDENAFIL CITRATE
Uses of Revatio
Adults REVATIO is indicated for the treatment of pulmonary arterial hypertension (PAH) (World Health Organization Group I) in adults to improve exercise ability and delay clinical worsening. 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.
Dosage & Administration of Revatio
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. 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.
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. A maximum dose in pediatric patients has not been identified.
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.
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.
Side Effects of Revatio
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. In a 12-week, placebo-controlled clinical study and an open-label extension study (SUPER-1) in 277 REVATIO-treated adults with PAH (WHO Group I) the adverse reactions that were reported by at least 10% of REVATIO-treated patients in any dosing group, 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.
The overall frequency of discontinuation for placebo was 3%. Table 1. Most Common Adverse Reactions in Patients Treated with REVATIO 20 mg, 40 mg, 80 mg and Placebo Three Times Per Day in SUPER-1 (More Frequent in REVATIO-Treated Patients than Placebo-Treated Patients) In a placebo-controlled fixed dose titration study (PACES-1) 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, no new safety issues were identified except for edema, which occurred in 25% of subjects in the combined REVATIO + epoprostenol group compared with 13% of subjects in the epoprostenol group.
In a study to assess the effects of multiple doses of REVATIO on mortality in adults with PAH (StudyA1481324), the lower dose 5 mg TID group showed a higher observed number of deaths (all related to underlying disease/disease under study), serious adverse events, and severe adverse events than the 20 mg and 80 mg TID groups. Overall, the safety data for sildenafil 80 mg TID dose in Study A1481324 was consistent with the established safety profile of sildenafil in previous adult PAH studies. Pediatric Patients REVATIO was studied in a total of 234 PAH pediatric patients 1 to 17 years of age in a 16‑week, double-blind placebo‑controlled study (STARTS-1); 220 patients continued in a long-term extension study (STARTS-2).
Erection increased was observed in 9% of patients treated with sildenafil in STARTS-1. No other new adverse reactions were identified in pediatric patients. REVATIO Injection Adverse events with REVATIO injection were similar to those seen with oral tablets.
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.
| REVATIO 20 mg (n = 69) | REVATIO 40 mg (n = 67) | REVATIO 80 mg (n = 71) | Placebo (n = 70) | |
|---|---|---|---|---|
| Headache | 46% | 42% | 49% | 39% |
| Flushing | 10% | 9% | 16% | 4% |
| Pain in Limb | 7% | 15% | 9% | 6% |
| Myalgia | 7% | 6% | 14% | 4% |
| Back Pain | 13% | 13% | 9% | 11% |
| Dyspepsia | 13% | 8% | 13% | 7% |
| Diarrhea | 9% | 12% | 10% | 6% |
Warnings & Cautions for Revatio
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, 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.
Drug Interactions with Revatio
- Nitrates Concomitant use of REVATIO with nitrates in any form is contraindicated. Strong CYP3A Inhibitors Concomitant use of REVATIO with strong CYP3A inhibitors is not recommended. Moderate-to-Strong CYP3A Inducers Concomitant use of REVATIO with moderate-to-strong CYP3A inducers (such as bosentan) decreases the sildenafil exposure. Dose up-titration of REVATIO may be needed when initiating treatment with moderate-to-strong CYP3A inducers. Reduce the dose of REVATIO to 20 mg three times a day when discontinuing treatment with moderate-to-strong CYP3A inducers.
- Use with strong CYP3A inhibitors: Not recommended.
- Concomitant PDE-5 inhibitors: Avoid use with Viagra ® or other PDE-5 inhibitors.
Pregnancy Safety for Revatio
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/m 2 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/m 2 basis).
Pediatric Use of Revatio
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. 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), an imbalance in the number of deaths was noted: 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.
Contraindications for Revatio
- 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.
- 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.
- Use with organic nitrates or riociguat.
- History of hypersensitivity reaction to sildenafil or any component of the tablet, injection, or oral suspension.
Overdosage Information for Revatio
In studies with healthy volunteers of single doses up to 800 mg, adverse events were similar to those seen at lower doses but rates and severities were increased. In cases of overdose, standard supportive measures should be adopted as required. Renal dialysis is not expected to accelerate clearance as sildenafil is highly bound to plasma proteins and it is not eliminated in the urine.
Clinical Studies of Revatio
SUPER-1 (NCT00644605) - REVATIO Monotherapy A randomized, double-blind, placebo-controlled study of REVATIO (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure ≥ 25 mmHg at rest with a pulmonary capillary wedge pressure < 15 mmHg). Patients were predominantly WHO Functional Classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen.
The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Patients who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.
They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45-50 meters were observed with all doses of REVATIO.
These increases were significantly different from placebo, but the REVATIO dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at Week 8 and Week 12. Figure 3.
Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in SUPER-1: Mean (95% Confidence Interval) Figure 4 displays subgroup efficacy analyses in SUPER-1 for the change from baseline in 6-Minute Walk Distance at Week 12 including baseline walk distance, disease etiology, functional class, gender, age, and hemodynamic parameters. Figure 4. Placebo-Corrected Change from Baseline in 6-Minute Walk Distance (meters) at Week 12 by Study Subpopulation in SUPER-1: Mean (95% Confidence Interval) Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.
These uncontrolled observations do not allow comparison with a group not given sildenafil and cannot be used to determine the long term-effect of sildenafil on mortality. PACES-1 (NCT00159861) - REVATIO Co-Administered with Epoprostenol A randomized, double-blind, placebo‑controlled study (PACES-1) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters).
Patients were randomized to placebo or REVATIO (in a fixed titration starting from 20 mg to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy. There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the REVATIO group compared with the placebo group. Patients on REVATIO achieved a statistically significant reduction in mPAP compared to those on placebo.
Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in PACES-1. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than REVATIO-treated patients and that REVATIO-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074).
Kaplan‑Meier plot of time to clinical worsening is presented in Figure 5. Table 4. Clinical Worsening Events in PACES-1 Figure 5.
Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1 Improvements in WHO Functional Class for PAH were also demonstrated in patients on REVATIO compared to placebo. More than twice as many REVATIO-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH. Study A1481243 (NCT00323297) - REVATIO Added to Bosentan Therapy – Lack of Effect on Exercise Capacity A randomized, double-blind, placebo‑controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of 3 months.
The PAH patients included those with primary PAH and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The results indicate that there is no significant difference in mean change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone.
In this trial, 27% of patients were < 7 years old. The primary objective of the study was to assess the effect of REVATIO on percent change from baseline in PVO 2, normalized to body weight, from baseline to week 16 as measured by the Cardiopulmonary Exercise Test (CPET) (patients who were developmentally able to perform the test, n = 115). Secondary endpoints included hemodynamic monitoring, symptom assessment, WHO Functional Class, change in background treatment, and quality of life measurements (n = 234).
Patients were allocated to one of three sildenafil treatment groups (low, medium, or high) or placebo. Actual doses administered were dependent on body weight (see Table 5). Table 5.
Treatment Allocation by The proportion of patients receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channel blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (48%) and the placebo treatment group (42%). The primary endpoint was a percentage change in VO 2peak from baseline to week 16 assessed by CPET. See Figure 6.
A total of 45% of patients were evaluable for CPET, which comprised those children ≥ 7 years old and developmentally able to perform the test. Children < 7 years were evaluable only for the secondary endpoints. Figure 6.
Percentage Change from Baseline in VO 2Peak: Mean (95% Confidence Intervals) The estimated difference between the combined sildenafil doses and placebo was The results of the main analysis (combined dose groups versus placebo) were not statistically significant (p = 0.056). The estimated difference between the sildenafil medium dose group and placebo was Impact on Hemodynamic Parameters Dose related improvements were observed with PVRI and mPAP. Statistically significant PVRI reductions compared to placebo were seen with the sildenafil medium and high dose groups (18% and 27%, respectively) but not the low dose group The sildenafil medium and high dose groups displayed mPAP changes from baseline compared to placebo, of respectively; while the low dose group showed little difference from placebo (difference of 1.6 mmHg ).
Improvements were observed with cardiac index with all three sildenafil groups over placebo, 10%, 4%, and 15% for the low, medium, and high dose groups, respectively. STARTS-2 (NCT00159874) - Long-Term Survival with Oral Sildenafil Monotherapy in Treatment-Naïve Pediatric Pulmonary Arterial Hypertension Of the 234 pediatric patients treated in the short-term, placebo-controlled study, 220 patients entered the long-term extension study. Patients who had been in the placebo group in the short-term study were randomly reassigned to sildenafil treatment; patients weighing ≤ 20 kg entered the medium or high dose groups (1:2), while patients weighing > 20 kg entered the low, medium, or high dose groups (1:1:1).
Across the short-term and long-term studies, the overall duration of treatment from start of double-blind for individual patients ranged from 3 to 3,129 days. By sildenafil treatment group, median duration of sildenafil treatment was 1,696 days (excluding the 5 patients who received placebo in double-blind and were not treated in the long-term extension study). Peak VO 2 was assessed 1 year after the start of the placebo-controlled study.
Of sildenafil-treated patients developmentally able to perform the CPET 59/114 patients (52%) had not shown any deterioration in PVO 2 from start of sildenafil. Study A1481324 (NCT02060487) - Study to Assess the Effects of REVATIO on Mortality in Adults with PAH A study to assess the effects of multiple doses of sildenafil on mortality in adults with PAH was conducted following the observation of a higher risk of mortality in pediatric patients taking a high dose of REVATIO TID, based on body weight, compared to those taking a lower dose of REVATIO in the long-term extension of the pediatric clinical trial. The study was a randomized, double-blind, parallel-group study in 385 adults with PAH.
Most patients were PAH treatment naïve (83%). For most patients the etiology of PAH was idiopathic (72%). The most common WHO Functional Class was Class III (58% of patients).
Treatment groups were well balanced with respect to baseline demographics of strata history of PAH treatment and etiology of PAH, as well as the WHO Functional Class categories. The primary objective of the study was to compare sildenafil 80 mg TID versus 5 mg TID for mortality, with success defined by ruling out twice the mortality at 80 mg. The key secondary efficacy endpoint was time to first event of clinical worsening, defined as a composite endpoint of all-cause mortality, hospitalization for worsening PAH or disease progression.
An additional secondary endpoint was 6MWD at Months 6 and 12. Overall Survival At the time of a planned interim analysis (50% deaths) it was identified that the primary efficacy objective of this protocol was met and therefore the study was stopped. Based on the primary efficacy endpoint (mortality), the non-inferiority of sildenafil 80 mg TID arm versus 5 mg TID arm was met using a 2-sided significance level of 0.003 for the interim analysis.
Table 6. Table 7. Hazard Ratios for Time to First Event of Clinical Worsening – Intent To Treat Population 6MWD at Months 6 and 12 At baseline, the median of 6MWD for the intent‑to‑treat (ITT) population was 332 to 352 m.
Overall, the safety data for sildenafil 20 mg TID and for the higher sildenafil 80 mg TID dose were consistent with the established safety profile of sildenafil in previous adult PAH studies. Figure 3. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1 Figure 6.
| Placebo (N = 131) | REVATIO (N = 134) | |||
|---|---|---|---|---|
| Number of patients with clinical worsening first event | 23 | 8 | ||
| First Event | All Events | First Event | All Events | |
| Death, n | 3 | 4 | 0 | 0 |
| Lung transplantation, n | 1 | 1 | 0 | 0 |
| Hospitalization due to PAH, n | 9 | 11 | 8 | 8 |
| Clinical deterioration resulting in: Change of Epoprostenol Dose, n Initiation of Bosentan, n | 9 1 | 16 1 | 0 0 | 2 0 |
| Proportion worsened 95% Confidence Interval | 0.187 (0.12-0.26) | 0.062 (0.02-0.10) | ||
| Placebo | Low Dose | Medium Dose | High Dose | ||||
|---|---|---|---|---|---|---|---|
| Body Weight (kg) | N | Dose | N | Dose | N | Dose | N |
| ≥ 8-20 | 18 | na | 10 mg | 15 | 20 mg | 35 | |
| > 20-45 | 32 | 10 mg | 31 | 20 mg | 30 | 40 mg | 31 |
| > 45 | 10 | 10 mg | 11 | 40 mg | 10 | 80 mg | 11 |
| Sildenafil 5 mg N = 129 | Sildenafil 20 mg N = 128 | Sildenafil 80 mg N = 128 | |
|---|---|---|---|
| Patient‑years of follow‑up | 329.8 | 340.5 | 356.7 |
| Number of deaths (%) | 34 (26) | 25 (20) | 19 (15) |
| On treatment deaths On treatment deaths: Any death within 7 days of last dose was regarded as “On treatment”, thus might include deaths occurred after discontinuation from study treatment. (%) | 22 (17) | 13 (10) | 15 (12) |
| Off treatment deaths (%) | 12 (9) | 12 (9) | 4 (3) |
| Hazard ratio relative to sildenafil 5 mg | |||
| Hazard ratio estimate Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. | 0.68 | 0.51 | |
| 99.7% CI | 0.31, 1.49 | 0.22, 1.21 | |
| Hazard ratio relative to sildenafil 20 mg | |||
| Hazard ratio estimate | 0.74 | ||
| 99.7% CI | 0.30, 1.84 |
| Sildenafil 5 mg N = 129 | Sildenafil 20 mg N = 128 | Sildenafil 80 mg N = 128 | |
|---|---|---|---|
| Note: Sildenafil 5 mg is not an approved dosage. Abbreviations: 6MWD = 6‑minute walk distance; CI = confidence interval; PAH = pulmonary arterial hypertension. | |||
| Patient‑years of follow‑up | 249.6 | 276.4 | 306.5 |
| Number of patients with clinical worsening | 52 | 36 | 28 |
| First Event of clinical worsening Clinical worsening events were defined as reduction from baseline in the 6MWD test by at least 15% and worsening functional class from baseline, both confirmed by a second test/evaluation within 2 weeks. n (%) | |||
| Disease progression Count of cases of disease progression as the first event of clinical worsening. | 8 (6) | 2 (2) | 6 (5) |
| Hospitalization for PAH Count of non-elective hospital stays for worsening PAH as the first event of clinical worsening. | 28 (22) | 23 (18) | 11 (9) |
| Death Count of deaths as the first event of clinical worsening. | 16 (12) | 11 (9) | 11 (9) |
| Hazard ratio relative to sildenafil 5 mg | |||
| Hazard ratio estimate | 0.63 | 0.44 | |
| 99.7% CI | 0.33, 1.21 | 0.22, 0.89 | |
| p-value | 0.035 | < 0.001 | |
| Hazard ratio relative to sildenafil 20 mg | |||
| Hazard ratio estimate Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. P-value from the Wald test. | 0.72 | ||
| 99.7% CI | 0.34, 1.52 | ||
| p‑value | 0.195 | ||
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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