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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

UPTRAVI® (selexipag)

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Treatment of Eisenmenger Syndrome With UPTRAVI

Last Updated: 11/20/2024

SUMMARY

UPTRAVI is not approved by the regulatory agencies for the treatment of patients with Eisenmenger syndrome (ES). Johnson & Johnson does not recommend the use of UPTRAVI in a manner that is inconsistent with the approved labeling.
Studies specifically designed to investigate the safety and/or efficacy of UPTRAVI for the treatment of patients with ES have not been performed.
A search of the scientific literature retrieved limited information from few case series and case reports describing the administration of UPTRAVI to patients with ES; relevant information from these publications is summarized in this letter.¹^-⁸
Please note that this document does not contain any references to local prescribing information. For complete prescribing recommendations about UPTRAVI in your country, please refer to your local product information.

CLINICAL DATA

Relevant information from scientific literature is summarized in Table: Case Series/Reports Describing Administration of UPTRAVI to Patients With ES.

In addition, Van Dissel et al (2020)⁹, in a congress abstract, have described the data of a multicenter, prospective study involving 34 adult patients with pulmonary arterial hypertension associated with congenital heart disease who were treated with UPTRAVI. A total of 60% of these patients had ES; however, the study results refer to the entire cohort, and no safety or efficacy outcomes specific to the subgroup of patients with ES are included.

The reader is referred to the full text of each study for full details.

Case Series/Reports Describing Administration of UPTRAVI to Patients With ES

Reference	Patient(s)	UPTRAVI Treatment	Efficacy Outcomes	Safety Outcomes
Kanai et al (2021)¹ Case study	A 41-year-old female patient was diagnosed with VSD and suspected to have ES complicated by severe PAH.	PAB was performed to control the increased PA flow due to intensive PAH treatment. After PAB, UPTRAVI (1600 mcg/day) was added to macitentan^a and tadalafil and later switched to epoprostenol.	After treatment with UPTRAVI, the patient’s 6MWD improved with increased oxygenation (1.5-2 L/min). After 1 year, mPAP and mRAP were 51 mmHg and 8 mmHg, respectively. Catheter examination showed substantial reduction in PVRi (11.3 WUm²). After 1.5 years, mPAP and mRAP were 52 mmHg and 4 mmHg, respectively. Catheter examination showed a reduction in PVR by 45.6% from baseline.	Not reported
Ekhomu et al (2021)² Case report (Congress abstract)	A 25-year-old pregnant female patient had ES and pulmonary hypertension (group 1 and grade 2; WHO FC II) secondary to ASD.	The patient received UPTRAVI and sildenafil.	Before treatment with UPTRAVI, initial ECHO (performed 2 years prior) showed an LVEF and RVEF of 35% and 20%, respectively. After treatment with UPTRAVI, at 5 months GA, LVEF and RVEF were 55% and 25%, respectively; the estimated RV pressure was 70 mmHg, and EDV was 365 mL.	Not reported
Demerouti et al (2021)³ Case series	Three patients had ES-associated PAH, an unsatisfactory clinical condition, and progressive clinical worsening. Patient 1: A 48-year-old woman had an aortopulmonary window with recurrent hemoptysis necessitating frequent blood transfusions. Patient 2: A 38-year-old woman had a history of patent ductus arteriosus surgical ligation, with a remaining large VSD. Patient 3: A 33-year-old woman had a large ASD. All 3 patients were treated with specific PAH combination therapies with PDE-5i and ERA and were stable for more than 6 years before UPTRAVI initiation.	Patients started UPTRAVI 200 mcg BID, which was uptitrated weekly to their maximum tolerated dose (patient 1, 1200 mcg BID; patient 2, 800 mcg BID; and patient 3, 1000 mcg BID).	Patient symptoms (FC), exercise capacity according to 6MWD, and NT-proBNP levels were improved. Patient 1: Severe hemoptysis resolved completely 6 months after UPTRAVI initiation. Patient 3: UPTRAVI induced pulmonary vasodilation; the pulmonary cardiac index, pressure, and resistance improved, with an 11% decrease in the pulmonary-to-systemic resistance ratio. It induced systemic vasodilation to a lesser degree, with an improved systemic cardiac index and resistance.	No significant side effects or adverse events, such as disease progression or need for drug-therapy escalation, were noted during follow-up.
Blisset et al (2020)⁴ Case series of 5 patients with CHD-PAH	Patient 1, patient 2, and patient 3 had Eisenmenger physiology Patient 1: A 31-year-old woman had a large unrepaired ASD, normal pulmonary venous drainage, severe PA dilation, WHO FC II, and Eisenmenger physiology. She was initially treated with macitentan^a and tadalafil. UPTRAVI was subsequently added to improve hemodynamics and perform ASD closure. Patient 2: A 29-year-old woman had a large aortopulmonary window and Eisenmenger physiology and had been treated with tadalafil 20 mg daily for years. Macitentan^a 10 mg daily was started and UPTRAVI was added as part of a treat-to-close strategy. Patient 3: A 48-year-old woman had unrepaired patent ductus arteriosus associated with Eisenmenger physiology and experienced WHO FC III symptoms on tadalafil 20 mg daily and macitentan 10 mg daily. Patient was started on UPTRAVI.	Patient 1: UPTRAVI was uptitrated to the maximally tolerated dose of 1600 mcg BID. Patient 2: UPTRAVI was uptitrated to a maximum dose of 1600 mcg BID. Patient 3: UPTRAVI was initiated at 200 mcg BID and increased by 400 mcg a day every week. However, due to side effects and upon interruption (see Safety Outcomes), the dosage was then resumed at 200 mcg BID and uptitrated to 600/800 mcg BID, which was tolerated.	Patient 1: Repeat hemodynamics after 3 months of therapy were suitable for ASD closure. Starting 4 months following closure, the patient underwent serial RHCs to guide downtitration of oral pulmonary vasodilators. UPTRAVI was weaned first, followed by macitentan and then tadalafil over the course of 12 months. mPAP was borderline elevated with a normal PVR following discontinuation of all pulmonary vasodilators. Improvements in the functional capacity and 6MWD were also observed. Patient 2: After 3 months of oral triple therapy, RHC revealed improvements, with hemodynamics suitable for a fenestrated closure. The patient made an informed decision not to proceed with surgical repair. Patient 3: Although her hemodynamics on oral triple therapy remained consistent with Eisenmenger physiology, subjective and objective improvements in symptoms, FC, and exercise capacity were noted.	Patient 1: During UPTRAVI treatment, myalgias, headaches, jaw pain, nausea, vomiting, and diarrhea were reported as bothersome yet tolerable side effects. Patient 2: The patient transiently experienced tolerable nausea, vomiting, and headaches during dosing increase. Patient 3: The patient intermittently stopped taking UPTRAVI for a week when the dose was increased from 600 to 800 mcg BID due to intolerable headaches and nausea.
Akagi et al (2020)⁵ Case report	A 32-year-old woman had unrepaired complex congenital heart disease as well as severe PAH and ES and was administered PAH-specific drugs including UPTRAVI during the perioperative period and immediately after surgery.	At 2 months after the surgery, the UPTRAVI^b dose was 3600 mcg/day and was gradually reduced during the postoperative period.	The patient underwent surgery to repair coarctation of the aorta, patent ductus arteriosus, and VSD; no pulmonary hypertension crisis occurred after the surgery. The therapy improved the patient’s symptoms and 6MWD and decreased mPAP and PVR. mPAP was 22 mmHg and PVR was 4.7 WU at the 1-year follow-up. Although combination therapy with 4 PAH-specific drugs was required immediately after surgery, the number and doses of these medications were reduced over time.	Not reported
El-Kersh et al (2018)⁶ Case series (Letter to the editor)	Four female patients (ASD, n=1; VSD, n=2; and AVSD, n=1), aged 20-66 years, had PAH and ES (NYHA FC III; mPAP, 49-66 mmHg). Three patients had associated Down syndrome or cerebral palsy, which complicated initiation of parenteral prostacyclin. All patients had background PDE-5i and ERA therapy.	Final dose range: 200-1600 mcg BID (treatment period not specified).	NYHA FC improved from III to II after initiation of UPTRAVI (time frame to improvement not specified). All patients were maintained on triple therapy with stable FC (NYHA FC II) at the last clinic visit.	Not reported
Xia et al (2018)⁷ Case report (Congress abstract)	A 51-year-old female patient had severe PAH and ES (unrepaired ASD; PAP, 125/30 mmHg; oxygen saturation, 60%-70%) and presented with shortness of breath and lower extremity edema.	PAH regimen at admission: UPTRAVI (no dose details provided), ERA, and sGC stimulator.	Due to continued hemodynamic deterioration, the patient was transitioned from UPTRAVI to IV epoprostenol using a conservative cross-titration regimen (see full text of the abstract for details).	No significant adverse events or hemodynamic instability were noted during the cross-titration process, and oxygen saturation improved to 80%-90%.
Davis et al (2018)⁸ Case series, including 1 relevant patient (patient 3) (Congress abstract)	A 6-year-old^c female patient had ES and background PDE-5i therapy.	UPTRAVI^b was initiated at 100 mcg BID and titrated by 100 mcg weekly to 300 mcg BID.	At the 5-month follow-up, oxygen saturation and endurance had improved (no details provided in the abstract).	The patient experienced diarrhea during treatment with UPTRAVI.
Abbreviations: 6MWD, 6-minute walk distance; ASD, atrial septal defect; AVSD, atrioventricular septal defect; BID, 2 times daily; CHD-PAH, pulmonary arterial hypertension associated with congenital heart disease; ECHO, echocardiogram; EDV, end-diastolic volume; ERA, endothelin receptor antagonist; ES, Eisenmenger syndrome; FC, functional class; GA, gestational age; IV, intravenous; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; mRAP, mean right arterial pressure; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association; PA, pulmonary artery; PAB, pulmonary artery banding; PAH, pulmonary arterial hypertension; PAP, pulmonary artery pressure; PDE-5i, phosphodiesterase-5 inhibitor; PVR, pulmonary vascular resistance; PVRi, pulmonary vascular resistance index; RHC, right heart catheterization; RV, right ventricle; RVEF, right ventricular ejection fraction; sGC, soluble guanylate cyclase; VSD, ventricular septal defect; WHO, World Health Organization; WU, Wood units. Data are presented as number of patients (n) or mean±standard deviation, unless stated otherwise. ^aAdministration of macitentan for the treatment of ES is unapproved and not recommended.^bThe publication describes an unapproved method of UPTRAVI administration that is not recommended. ^cAdministration of UPTRAVI to pediatric patients is unapproved and not recommended.

LITERATURE SEARCH

A literature search of MEDLINE®, EMBASE®, BIOSIS Previews®, DERWENT® (and/or other resources, including internal/external databases) was conducted on 06 November 2024.

References

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1	Kanai A, Koitabashi N, Akagi S, et al. A case of a middle-aged patient with a ventricular septal defect complicated by severe pulmonary hypertension-stepwise surgical repair with pulmonary vasodilators. J Cardiol Cases. 2021;24(3):131-135.
2	Ekhomu O, Murphy J, Bokowski J. An atrial septal defect, Eisenmenger’s and a baby; the conundrum of care [abstract]. J Am Coll Cardiol. 2021;77(18, Suppl. 1). 2765.
3	Demerouti EA, Karyofyllis P, Apostolopoulou SC. Use of the prostacyclin-receptor agonist selexipag in pulmonary arterial hypertension associated with Eisenmenger syndrome. Can J Cardiol. 2021;37(8):1286-1288.
4	Blissett S, Blusztein D, Mahadevan VS. Contemporary use of Selexipag in pulmonary arterial hypertension associated with congenital heart disease: a case series. Eur Hear J - Case Rep. 2020;4(6):1-7.
5	Akagi S, Kasahara S, Akagi T, et al. Medical and surgical management of a pulmonary hypertensive adult patient with unrepaired complex congenital heart disease: a case report. J Congenit Cardiol. 2020;4(1):2.
6	El-Kersh K, Suliman S, Smith JS. Selexipag in congenital heart disease-associated pulmonary arterial hypertension and Eisenmenger syndrome. Am J Ther. 2018;25(6):e714-e715.
7	Xia R, Guha A, Donahue K. Transition of oral selexipag to parenteral prostacyclin in patient with Eisenmenger’s syndrome case report [abstract]. J Am Coll Clin Pharm. 2018;1(Suppl. 2). 352.
8	Davis A, Yung D. Selexipag in three pediatric patients [abstract]. Pulm Circ. 2018;8(Suppl. 3). 12.
9	Dissel AV, Post M, Sieswerda GT, et al. Early experience with selexipag for the treatment of adults with pulmonary arterial hypertension associated with congenital heart disease. Eur Heart J. 2020;41(Suppl. 2):2191.