UPTRAVI®
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UPTRAVI® (selexipag)
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UPTRAVI - Transitioning From Epoprostenol for Infusion
Last Updated: 08/07/2024
SUMMARY
- A search of scientific literature for information on the transitioning from intravenous (IV) epoprostenol (all marketed formulations) to UPTRAVI in the treatment of pulmonary arterial hypertension (PAH) retrieved 3 research articles1
- 3 , 1
single-center cohort study4, and 4 singlecenter case series5 -8 published as congress abstracts. In these publications, patients were selected to undergo transition from IV epoprostenol to UPTRAVI based on consideration of clinical status, patient request, and complications related to ongoing IV treatment. Details from these publications are summarized in this letter. - In addition, 12 case reports9
-20 were identified and included as citations in the REFERENCES section for your review.
CLINICAL DATA
| Author, Year, and Reference | Patient Characteristics | Transitioning Methodology | Reported Efficacy and Safety Outcomes |
|---|---|---|---|
| Research Articles | |||
| Tamura et al (2022)1 | Overall, 37 patients with IPAH/HPAH receiving triple combination therapy, including parenteral prostanoids were enrolled in the study. The mean (±SD) duration from diagnosis to transition was 2400 (±747) days. Four of 37 patients (10.8%; all females) attempted the transition from parenteral prostanoids to UPTRAVI and were successful. | Epoprostenol and treprostinil doses were reduced by 1 ng/kg/min and 2 ng/kg/min every 2-3 weeks to achieve the target doses of 10 ng/kg/min and 20 ng/kg/min, respectively, in patients showing favorable hemodynamic and symptomatic improvements while on upfront triple combination therapy (mPAP <30 mmHg; WHO FC I or II). The mean maximum prostanoid dose was 43.3±2.4 ng/kg/min. Patients withdrew parenteral therapy and transitioned to UPTRAVI 3.2 mg/day when they reached their target doses. | mPAP and PVR at the time of diagnosis and transition showed significant improvements, from 60.0±4.7 to 23.8±1.7 mmHg (P<0.05) and 21.9±3.4 to 4.5±0.5 WU (P<0.05), respectively. The mean (±SD) post transition evaluation and observation periods were 110 (±10) days and 628 (±247) days, respectively, during which the exercise tolerance and hemodynamics of all the 4 patients showed long-term stability. Patients continued to receive an ERA and a PDE-5 inhibitor along with UPTRAVI in the follow-up period. |
| Parikh et al (2020)2 | Fourteen patients (11 female) with PAH (WHO group I) FC II symptoms who were on constant dose of any parenteral prostanoid (ie, IV epoprostenol, IV treprostinil, or SC treprostinil). Patients were selected based on specific eligibility criteria and were transitioned from parenteral prostanoid therapy to UPTRAVI using a protocol that included clinic visits and RHC assessments. At the time of the transition, patients had a median (Q1-Q3) age of 53.5 (48.5-59.0) years and BMI of 30.1 kg/m2. The median (Q1-Q3) time from diagnosis of PAH to initiation of parenteral therapy was 1.3 (014.5) months and from initiation of parenteral therapy to initiation of UPTRAVI was 5.6 (3.08.8) years. Over 80% of patients were on combination therapy (no details reported). | The transition occurred over a median (Q1-Q3) time of 5.5 (4.1-6.4) months from the start of UPTRAVI to post RHC assessment. Conversion was individualized for each participant but followed the same general principles: initiation with UPTRAVI 200 mcg BID followed by weekly dose increases in twice-daily increments of 200 mcg. Dose of the parenteral drug was decreased by ≥1 ng/kg/min with initiation of UPTRAVI based on the patients’ prior tolerability with prostanoid titration. With every up titration of UPTRAVI, 3 days were allowed to reach the steady state and then the dose of parenteral therapy was reduced by 1/8 over that week. In case of increased PAH symptoms prior to the next scheduled increase of UPTRAVI, the dose of parenteral prostanoid therapy was increased by 1-3 ng/kg/min per day. If the patient was still experiencing PAH symptoms at a dose of UPTRAVI 1600 mcg BID, further titration up to 3200 mcg BIDa | The median total daily UPTRAVI dose achieved was 3200 mcg and 6/15 patients were taking >3200 mcga total daily dose. Two patients required an additional oral agent (PDE-5 inhibitor and/or ERA) during the transition period. Repeat assessments of PAH severity and functional capacity revealed stability in hemodynamics, NT-proBNP levels, and functional capacity. RV function remained stable except in 1 patient who could only tolerate 1200 mcg total daily dose of UPTRAVI. This patient’s RV function worsened from normal to mild dysfunction in the setting of stable symptoms and other assessed surrogate markers. All but 1 subject remained on UPTRAVI and none required reinitiation of parenteral therapy (median [Q1-Q3], 23.7 [20.328.6] months. Death occurred in 1 patient with PoPHb |
| Yanaka et al (2020)3 | Eight patients with PAH (IPAH, n=5; HPAH, n=2; PAH-CTD, n=1) who were transitioned from IV epoprostenol to UPTRAVI (6 females; median [Q1-Q3] age, 39.4 [34.1-52.7] years). All had a severe form of PAH at the time of diagnosis and at least 1 evaluation, including RHC, while on UPTRAVI. Patients were in a stable condition, and most were at "lowrisk" category according to the French invasive and non-invasive approaches and the SPAHR/COMPERA method. Transition was decided either because of the patient's refusal to continue IV epoprostenol (n=2) or due to recurrent catheter-related infections (n=6). All patients were also receiving an ERA and a PDE-5 inhibitor in combination with IV epoprostenol. | At the time of transition, patients had been receiving IV epoprostenol for a median (Q1-Q3) of 5.1 (2.0-8.3) years. The median (Q1-Q3) dose of epoprostenol was 17.5 (15.029.5) ng/kg/min. UPTRAVI dosage was up titrated from 200 mcg BID to the maximal tolerated dose stepwise over 2-5 days, while parallel perfusion of epoprostenol was tapered off. After transition and during follow up, patients still received an ERA and a PDE 5 inhibitor together with a stable dose of UPTRAVI (1600 mcg BID in all cases). | After transition to UPTRAVI, although clinical criteria (such as 6MWD) remained stable, hemodynamic parameters (such as cardiac index) and risk assessment significantly worsened. Please consult the publication for outcome details. |
| Congress Abstracts | |||
| Spence et al (2023)4 | Five patients with PAH who transitioned from parenteral prostacyclin therapy to UPTRAVI were enrolled in the study. All patients were treated with baseline triple therapy, which included IV epoprostenol and 2 oral agents. Transition was decided due to line infections (n=4) and patient preference (n=1). | UPTRAVI was up-titrated over 13-18 days to a mean total daily dose of 2640 mcg (range: 1200-3200 mcg), and epoprostenol was weaned over 10-56 days. Post-transition follow-up period was between 24 and 71 months. | UPTRAVI side effects included headache and nausea. No side effects were transition-limiting. Twenty-four months after transition, 1 patient (baseline high-risk REVEAL 2.0 score) died of right heart failure. Supplemental oxygen was initiated in 1 patient (baseline high-risk REVEAL 2.0 score) who remained alive 28 months after the transition. No morbidity events were observed in 2 patients (baseline low-risk and intermediate-risk REVEAL 2.0 scores) at 34 and 71 months of follow up, respectively. |
| Shah et al (2019)5 | A total of 12 female patients underwent transition from epoprostenol or prostacyclin analogs (no details provided) to UPTRAVI. Patients were considered for transition based on hemodynamics and overall risk profile (PVR <5 WU and no sign of RV failure by RHC or echocardiogram). Eleven out of 12 were planned transitions and followed a defined protocol (see transitioning methodology) whereas 1 patient discontinued SC treprostinil treatment 2 weeks prior to transition. | The dose for patients undergoing planned transition was tapered down to epoprostenol 10 ng/kg/min or treprostinil 20 ng/kg/min over several weeks. Thereafter, patients were reevaluated in clinic for worsening of symptoms and by RHC or echocardiogram. Stable patients were initiated on UPTRAVI at 200 mcg BID and up titrated while simultaneously tapering down parenteral treatment per protocol. | Nine patients were deemed to have undergone a successful transition to UPTRAVI, while 3 patients failed to transition. Out of the 3 patients who failed to transition, 2 needed hospitalization for worsening of PAH and were restarted on parenteral prostacyclin treatment, whereas 1 had worsening symptoms when epoprostenol was decreased, needing up titration. |
| Mims et al (2017)6 | Fourteen patients with PAH (86% female) receiving either IV epoprostenol (N=9; dose range: 5.5-38 ng/kg/min) or SC treprostinil (N=5; dose range: 1848 ng/kg/min). Mean age: 55.6±11 years. Mean duration of IV or SC therapy before transition: 30.1±18.3 months. All patients were on additional background PAH therapy (N=8 on combined ERA/NO pathway medications; N=5 on NO alone; and N=1 on ERA alone). | Not described. Rationale for transition was individualized and included hemodynamic profile, patient preference, and complications related to ongoing IV or SC treatment. NYHA FC was assessed before and after (average time: 6.6 months) transition to UPTRAVI. Eight patients had follow-up hemodynamics at the time of publication of the poster. | After transitioning to UPTRAVI: Eleven of 14 patients maintained their FC. Three patients had clinical worsening after transitioning, of whom: One patient required re-initiation of parenteral therapy. One FC IV patient with SSc-PAH and features of PVOD was considered ineligible for lung transplantation and transitioned to UPTRAVI for difficulty in maintaining IV therapy. She had clinical worsening after transition due to right heart failure and was restarted on IV therapy prior to supportive care and death. |
| Miller (2017)7 | Six patients with IPAH or PAH-CTD (WHO FC II or III symptoms and presenting normalized to mildly depressed RV function by echocardiogram) were transitioned from parenteral treprostinil (median dose: 45 ng/kg/min) or epoprostenol (median dose: 30 ng/kg/min). All patients were on additional background PAH therapy with 2 oral agents (an ERA and riociguat or tadalafil). | UPTRAVI was started at a dose of 400 mcg BID and was increased every 12 hours by 400 mcg BID in conjunction with decreases in parenteral prostacyclin dose by 25%. Patients were titrated to a maximum possible dose of 1600 mcg BID of UPTRAVI. Hemodynamic monitoring was performed at baseline and at ≥12 hours after transition. Echocardiogram was repeated at 3 months following transition. | All 6 patients underwent successful transition to UPTRAVI at a dose of 1600 mcg BID. There were no significant changes in hemodynamics. Echocardiogram at 3 months after transition did not show any significant changes in RV size or function. |
| Safdar et al (2017)8 | Four female patients (mean age, 48±7 years) with PAH (IPAH, n=2; PAH-CTD, n=2) underwent transition from IV epoprostenol to UPTRAVI. Transition was considered in clinically stable PAH patients with repeated line infection and/or at patient’s request. | UPTRAVI was started at 200 mcg BID and the IV epoprostenol dose was decreased while simultaneously increasing the UPTRAVI dose weekly to the maximum dose of 1600 mcg BID. The duration of transition was 2-3 months. Clinical assessment during the transition included echocardiogram, WHO FC assessment, BNP, and 6MWT. Hemodynamic monitoring was performed at baseline and continued for an additional 30 minutes after stopping IV epoprostenol. | Two patients were successfully weaned off IV epoprostenol and transitioned to UPTRAVI 1600 mcg BID. Prior to stopping IV epoprostenol, the echocardiogram showed a normal right atrium and ventricle, no pericardial effusion, and a cardiac index of 3.0±0.5 L/min/m2 Mean PA (27.5±2 mmHg) and CO (6.55±0.21 L/min) remained unchanged from baseline. |
| Abbreviations: 6MWD/6MWT, 6-minute walk distance/test; BNP, B-type natriuretic peptide; BID, twice daily; BMI, body mass index; CO, cardiac output; COMPERA, comparative, prospective registry of newly initiated therapies for pulmonary hypertension; CTD, connective tissue disease; ERA, endothelin receptor antagonist; FC, functional class; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; mPAP, mean pulmonary arterial pressure; NO, nitric oxide; NT-proBNP, N-terminal pro b-type natriuretic peptide; NYHA, New York Heart Association; PA, pulmonary artery; PAH, pulmonary arterial hypertension; PDE-5, phosphodiesterase nitric oxide; PAH-CTD, pulmonary arterial hypertension associated with connective tissue disease; PoPH, portopulmonary hypertension; PVOD, pulmonary veno-occlusive disease; PVR, pulmonary vascular resistance; Q, quartile; REVEAL, Registry to Evaluate Early and Long-Term PAH Disease Management risk calculator; RHC, right heart catheterization; RV, right ventricle; SC, subcutaneous; SD, standard deviation; SPAHR, Swedish pulmonary arterial hypertension registry; SSc-PAH, systemic sclerosis-associated pulmonary arterial hypertension; WHO, World Health Organization; WU, woods units.Data are given as number of patients (n) or mean±SD, unless otherwise stated. aThis dose is unapproved and not recommended; UPTRAVI is approved at doses up to 1600 mcg BID.bOff-label usage of UPTRAVI for PoPH is not recommended. | |||
Literature Search
A literature search of MEDLINE®
References
| 1 | Tamura Y, Furukawa A, Tamura Y, et al. Long‐term safety of a structured transition protocol from parenteral prostanoids to selexipag in pulmonary arterial hypertension. Pulm Circ. 2022;12(1):e12058. |
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