Uptravi Drug Information
Generic name: SELEXIPAG
Prostacyclin Receptor Agonist [EPC]
Uses of Uptravi
Pulmonary Arterial Hypertension Adult Patients
UPTRAVI is indicated for the treatment of pulmonary arterial hypertension in adults (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Effectiveness of UPTRAVI tablets was established in a long-term study in adult PAH patients with WHO Functional Class II–III symptoms. Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%) . Pediatric Patients UPTRAVI is indicated for the treatment of PAH (WHO Group I) in pediatric patients aged two years and older. UPTRAVI reduces NT-proBNP and is expected to delay disease progression and reduce the risk of hospitalization for PAH.
Dosage & Administration of Uptravi
| 100 mcg orally twice daily | |
| 150 mcg orally twice daily | |
| 150 mcg orally twice daily | |
| 200 mcg orally twice daily |
Side Effects of Uptravi
Clinical Trial 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. UPTRAVI Tablets Adult Patients The safety of UPTRAVI tablets has been evaluated in a long-term, placebo-controlled study enrolling 1,156 adult patients with symptomatic PAH (GRIPHON study) . The exposure to UPTRAVI in this trial was up to 4.2 years with median duration of exposure of 1.4 years. Table 3 presents adverse reactions more frequent on UPTRAVI tablets than on placebo by ≥3%. Table 3: Adverse Reactions UPTRAVI Placebo Adverse Reaction N=575 N=577 Headache 65% 32% Diarrhea 42% 18% Jaw pain 26% 6% Nausea 33% 18% Myalgia 16% 6% Vomiting 18% 9% Pain in extremity 17% 8% Flushing 12% 5% Arthralgia 11% 8% Anemia 8% 5% Decreased appetite 6% 3% Rash 11% 8% These adverse reactions are more frequent during the dose titration phase.
Hyperthyroidism was observed in 1% (n=8) of patients on UPTRAVI tablets and in none of the patients on placebo. Pediatric Patients Two Years and Older The safety of UPTRAVI tablets has been evaluated in a long-term, Phase 3, double-blind, placebo-controlled study (SALTO), where a total of 138 pediatric patients with symptomatic PAH ≥2 to <18 years of age were randomized 1:1 to receive either UPTRAVI or placebo . The exposure to UPTRAVI in this study was up to 4.1 years with a median duration of exposure of 1.5 years. The safety profile in pediatric patients was consistent with that observed in adults with PAH. Compared to adults, a higher frequency of vomiting was observed (39% on UPTRAVI versus 19% on placebo). In addition, abdominal pain was observed in 15% of pediatric patients on UPTRAVI and in 6% on placebo.
UPTRAVI-treated pediatric patients experienced a smaller mean increase in body weight and height compared to the placebo group. The mean change in weight Z-score from baseline at 48 weeks in UPTRAVI-treated pediatric patients (n=54) was –0.31 compared to –0.09 in the placebo group (n=61); and at 96 weeks in UPTRAVI-treated pediatric patients (n=32) was –0.46 compared to –0.12 in the placebo group (n=35). The mean change in height Z-score from baseline at 48 weeks in UPTRAVI-treated pediatric patients (n=54) was –0.16 compared to –0.04 in the placebo group (n=61); and at 96 weeks in the UPTRAVI-treated pediatric patients (n=32) was –0.30 compared to –0.05 in the placebo group (n=35). When treating pediatric patients with UPTRAVI, monitor growth. UPTRAVI for Injection Infusion-site reactions (infusion site erythema/redness, pain and swelling) were reported with UPTRAVI for Injection in adult patients.
Laboratory Test Abnormalities Hemoglobin In a Phase 3 placebo-controlled study in adult patients with PAH, mean absolute changes in hemoglobin at regular visits compared to baseline ranged from −0.34 to −0.02 g/dL in the UPTRAVI group compared to −0.05 to 0.25 g/dL in the placebo group. A decrease in hemoglobin concentration to below 10 g/dL was reported in 8.6% of patients treated with UPTRAVI tablets and 5.0% of placebo-treated patients. Thyroid Function Tests In a Phase 3 placebo-controlled study in adult patients with PAH, a reduction (up to −
MU/L from a baseline median of 2.5 MU/L) in median thyroid-stimulating hormone
(TSH) was observed at most visits in the UPTRAVI group. In the placebo group, little change in median values was apparent. There were no mean changes in triiodothyronine or thyroxine in either group.
Postmarketing Experience
The following adverse reactions have been identified during post approval use of UPTRAVI. 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. Vascular disorders: symptomatic hypotension
Warnings & Cautions for Uptravi
Pulmonary Edema with Pulmonary Veno-Occlusive Disease Should signs of pulmonary edema occur
consider the possibility of associated pulmonary veno-occlusive disease. If confirmed, discontinue UPTRAVI.
Drug Interactions with Uptravi
CYP2C8 Inhibitors
Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled the exposure to selexipag and increased exposure to the active metabolite by approximately 11-fold. Concomitant administration of UPTRAVI with strong inhibitors of CYP2C8 (e.g., gemfibrozil) is contraindicated . Concomitant administration of UPTRAVI tablets with clopidogrel, a moderate inhibitor of CYP2C8, had no relevant effect on the exposure to selexipag and increased the exposure to the active metabolite by approximately 2.7-fold . Reduce the dosing of UPTRAVI to once daily in adult and pediatric patients on a moderate CYP2C8 inhibitor .
CYP2C8 Inducers
Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase UPTRAVI up to twice the dose when co-administered with rifampin. Reduce UPTRAVI when rifampin is stopped .
Pregnancy Safety for Uptravi
Pregnancy Risk Summary There are no adequate and well-controlled studies with UPTRAVI in pregnant women. Animal reproduction studies performed with selexipag showed no clinically relevant effects on embryofetal development and survival. A slight reduction in maternal as well as in fetal body weight was observed when pregnant rats were administered selexipag during organogenesis at a dose producing an exposure to the active metabolite approximately 47 times that in humans at the maximum recommended human dose.
No adverse developmental outcomes were observed with oral administration of selexipag to pregnant rabbits during organogenesis at exposures to the active metabolite up to 50 times the human exposure at the maximum recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 In patients with pulmonary arterial hypertension, pregnancy is associated with an increased rate of maternal and fetal morbidity and mortality, including heart failure, stroke, spontaneous abortion, intrauterine growth restriction, premature labor, and preterm birth. Data Animal Data Pregnant rats were treated with selexipag using oral doses of 2, 6, and 20 mg/kg/day (up to 47 times the exposure to the active metabolite at the maximum recommended human oral dose of 1,600 mcg twice daily on an area under the curve basis) during the period of organogenesis (gestation days 7 to 17). Selexipag did not cause adverse developmental effects to the fetus in this study. A slight reduction in fetal body weight was observed in parallel with a slight reduction in maternal body weight at the high dose.
Pregnant rabbits were treated with selexipag using oral doses of 3, 10, and 30 mg/kg (up to 50 times the exposure to the active metabolite at the maximum recommended human oral dose of 1,600 mcg twice daily on an AUC basis) during the period of organogenesis (gestation days 6 to 18). Selexipag did not cause adverse developmental effects to the fetus in this study. In a pre- and post-natal development study, pregnant rats were treated with selexipag from gestation day 7 through lactation day 20 at oral doses of 2, 6, and 20 mg/kg/day (up to 35 times the exposure to the active metabolite at the maximum recommended human dose of 1,600 mcg twice daily on an AUC basis). Treatment with selexipag did not cause adverse developmental effects in this study at any dose.
Pediatric Use of Uptravi
Pediatric Use Safety and effectiveness of UPTRAVI have been established for the treatment of PAH in pediatric patients aged 2 years and older. Use of UPTRAVI for this indication is supported by evidence from an adequate and well-controlled study in adults with additional pharmacokinetic, pharmacodynamic, and safety data in pediatric patients aged 2 years and older (N=132). The safety profile observed in pediatric patients was consistent with that of adults. A higher frequency of vomiting and abdominal pain was observed in UPTRAVI-treated pediatric patients compared to UPTRAVI-treated adults.
UPTRAVI-treated pediatric patients experienced a smaller mean increase in body weight and height compared to placebo. When treating pediatric patients with UPTRAVI, monitor growth . The safety and effectiveness of UPTRAVI have not been established in pediatric patients younger than 2 years. Due to nonclinical studies demonstrating a risk of intussusception in juvenile dogs and known susceptibility to gastrointestinal intussusception in young children, treatment with UPTRAVI in pediatric patients younger than 2 years of age was not studied.
Juvenile Animal Toxicity Data In juvenile dogs, intussusception due to prostacyclin-related effects on intestinal motility was observed sporadically. Safety margins adapted for prostacyclin receptor potency for the active metabolite were 2-fold (based on total exposure) in relation to human therapeutic exposure. The finding did not occur in mouse or rat toxicity studies.
Contraindications for Uptravi
Hypersensitivity to the active substance or to any of the excipients. Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) . Concomitant use with strong CYP2C8 inhibitors. Hypersensitivity to the active substance or to any of the excipients.
Overdosage Information for Uptravi
Isolated cases of overdose in adults with UPTRAVI tablets up to 3,200 mcg were reported. Mild, transient nausea was the only reported consequence. In the event of overdose, supportive measures must be taken as required.
Dialysis is unlikely to be effective because selexipag and its active metabolite are highly protein-bound.
Clinical Studies of Uptravi
Efficacy of
UPTRAVI Tablets in Adult Patients with Pulmonary Arterial Hypertension The effect of UPTRAVI tablets on progression of PAH was demonstrated in a multi-center, double-blind, placebo-controlled, parallel group, event-driven study (GRIPHON) in 1,156 adult patients with symptomatic (WHO Functional Class I, II, III, and IV ) PAH. Patients were randomized to either placebo (N=582), or UPTRAVI tablets (N=574). The dose was increased in weekly intervals by increments of 200 mcg twice a day to the highest tolerated dose up to 1,600 mcg twice a day. The primary study endpoint was the time to first occurrence up to end-of-treatment of: a) death, b) hospitalization for PAH, c) PAH worsening resulting in need for lung transplantation, or balloon atrial septostomy, d) initiation of parenteral prostanoid therapy or chronic oxygen therapy, or e) other disease progression based on a 15% decrease from baseline in 6-minute walk distance (6MWD) plus worsening of Functional Class or need for additional PAH-specific therapy. The mean age was 48 years, the majority of patients were white (65%) and female (80%). Nearly all patients were in WHO Functional Class II and III at baseline.
Idiopathic or heritable PAH was the most common etiology in the study population (58%) followed by PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%), drugs and toxins (2%), and HIV (1%). At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of an endothelin receptor antagonist (15%), a PDE-5 inhibitor (32%), or both (33%). Patients on UPTRAVI tablets achieved doses within the following groups: 200–400 mcg (23%), 600–1,000 mcg (31%) and 1,200–1,600 mcg (43%). Treatment with UPTRAVI tablets resulted in a 40% reduction (99% CI: 22 to 54%; two-sided log-rank p-value <0.0001) of the occurrence of primary endpoint events compared to placebo (Table 4; Figure 3). The beneficial effect of UPTRAVI was primarily attributable to a reduction in hospitalization for PAH and a reduction in other disease progression events (Table 4). The observed benefit of UPTRAVI was similar regardless of the dose achieved when patients were titrated to their highest tolerated dose . Figure 3 Kaplan-Meier Estimates of the First Morbidity-Mortality Event in GRIPHON Table 4: Primary Endpoints and Related Components in GRIPHON UPTRAVI N=574 Placebo N=582 Hazard Ratio (99% CI) p-value n % n % Primary endpoint events up to the end of treatment All primary endpoint events As first event: 155 27.0 242 41.6 0.60 <0.0001 Hospitalization for PAH 78 13.6 109
Other disease progression (Decrease in 6MWD plus worsening functional class or need
for other therapy) 38 6.6 100
Death 28 4.9 18 3.1 Parenteral prostanoid or chronic oxygen therapy 10
1.7 13
PAH worsening resulting in need for lung transplantation or balloon atrial septostomy
1 0.2 2
It is not known if the excess number of deaths in the
UPTRAVI group is drug-related because there were so few deaths and the imbalance was not observed until 18 months into GRIPHON. Figures 4A, B, and C show time to first event analyses for primary endpoint components of hospitalization for PAH (A), other disease progression (B), and death (C) all censored 7 days after any primary end point event (because many patients on placebo transitioned to open-label UPTRAVI at this point). Figure 4A Hospitalization for PAH as the First Endpoint in GRIPHON Figure 4B Disease Progression as the First Endpoint in GRIPHON Figure 4C Death as the First Endpoint in GRIPHON The treatment effect of UPTRAVI on time to first primary event was consistent irrespective of background PAH therapy (i.e., in combination with an ERA, PDE-5i, both, or without background therapy) (Figure 5). Figure 5 Subgroup Analyses of the Primary Endpoint in GRIPHON Note: Race group "Other" is not displayed in analysis, as the population is less than 30. EU = Number of UPTRAVI patients with events, NU = Number of patients randomized to UPTRAVI, EP = Number of Placebo patients with events, NP = Number of patients randomized to Placebo, HR = Hazard Ratio, CI = Confidence Interval, the size of the squares represent the number of patients in the subgroup. Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all were pre-specified. The 99% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors.
Apparent homogeneity or heterogeneity among groups should not be over-interpreted. Figure 3 Figure 4A Figure 4B Figure 4C Figure 5 6-Minute Walk Distance (6MWD) Exercise capacity was evaluated as a secondary endpoint. Median absolute change from baseline to week 26 in 6MWD measured at trough (i.e., at approximately 12 hours post-dose) was +4 meters with UPTRAVI and -9 meters in the placebo group.
This resulted in a placebo-corrected median treatment effect of 12 meters (99% CI: 1, 24 meters; two-sided p = 0.005). Long-Term Treatment of PAH In long-term follow-up of patients who were treated with UPTRAVI in the pivotal study and the open-label extension (N=574), Kaplan-Meier estimates of survival of these patients across the GRIPHON study and the long-term extension study at 1, 2, 5 and 7 years were 92%, 85%, 71%, and 63%, respectively. The median exposure to UPTRAVI was 3 years. These uncontrolled observations do not allow comparison with a control group not given UPTRAVI and cannot be used to determine the long-term effect of UPTRAVI on mortality.
Efficacy of
UPTRAVI Tablets in Pediatric Patients with Pulmonary Arterial Hypertension The efficacy of UPTRAVI tablets in pediatric patients aged ≥2 to <18 years with PAH was evaluated in a multi-center, randomized, double-blind, placebo-controlled, Phase 3 study (SALTO). A total of 138 patients were randomized 1:1 to receive either UPTRAVI (N=69) or placebo (N=69) twice daily. UPTRAVI doses of 100, 150 or 200 mcg were up-titrated to up to 800, 1,200 or 1,600 mcg twice daily based on weight category and tolerability. The mean age of patients in this study was 11.9 years (range 3.2–17.8 years). The majority of patients had idiopathic PAH (55%), were on background combination therapy (75%) and were WHO FC II (77%). The primary study endpoint, time to first Clinical Events Committee (CEC)-confirmed disease progression event up to 7 days after the last dose of double-blind study treatment, was analyzed only descriptively due to the limited number of events and sample size, which precluded a robust assessment of this endpoint.
With median observation times of 16 and 20 months, CEC-confirmed disease progression events were reported in 22 (32%) patients in the UPTRAVI group and 25 (36%) in the placebo group. Kaplan-Meier estimates for patients free from disease progression at 2 and 3 years were 64% and 55% in the UPTRAVI group and 69% and 45% in placebo group, respectively. The estimated HR was 1.08 (95% CI: 0.61, 1.93). Overall, 44 cumulative recurrent disease progression events up to 7 days after the last dose of study treatment were reported in the UPTRAVI group and 64 in the placebo group.
The average annualized event rate was 0.37 and 0.48 in the UPTRAVI and placebo groups, respectively. NT-proBNP UPTRAVI improved outcomes and reduced NT-proBNP in adults in GRIPHON. Therefore, the effect on NT-proBNP was used to infer a delay in PAH disease progression and reduce the risk of hospitalizations in pediatric patients aged 2 years and older. In pediatric patients aged ≥2 to <18 years (SALTO), NT-proBNP change from baseline to week 24 was evaluated.
The median NT-proBNP concentration at baseline was 231 ng/L in the UPTRAVI group and 168 ng/L in the placebo group. The placebo-adjusted reduction in NT-proBNP for the study population was 7% (geometric mean ratio of 0.93 ). Among patients with baseline levels ≥300 ng/L (n=51), treatment with UPTRAVI resulted in a placebo-adjusted reduction in NT-proBNP of 26% (geometric mean ratio of 0.74 ). Among patients with baseline levels <300 ng/L (n=86) treatment with UPTRAVI resulted in a placebo‑adjusted increase in NT‑proBNP of 5% (geometric mean ratio of 1.05 ).
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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