Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

UPTRAVI (NDA-214275)

(SELEXIPAG)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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05/23/2026 (SUPPL-2)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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) [see Clinical Studies (14.1)]. 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

…

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 greater than or equal to 2 to <18 years of age were randomized 1:1 to receive either UPTRAVI or placebo [see Clinical Studies (14.2)]. 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 ?0.3 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.

7 Drug Interactions

7.1 CYP2C8 Inhibitors

Additions and/or revisions underlined:

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 [see Contraindications (4) and Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)]. Reduce the dosing of UPTRAVI to once daily in adult and pediatric patients on a moderate CYP2C8 inhibitor [see Dosage and Administration (2.7)].

7.2 CYP2C8 Inducers

Additions and/or revisions underlined:

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 [see Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

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.

…

8.4 Pediatric Use

Additions and/or revisions underlined:

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) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14.2)].

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 [see Adverse Reactions (6.1)].

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.

8.6 Patients with Hepatic Impairment

Additions and/or revisions underlined:

No adjustment to the dosing regimen is needed in patients with mild hepatic impairment (Child-Pugh class A).

A once-daily regimen is recommended in adult and pediatric patients with moderate hepatic impairment (Child-Pugh class B) due to the increased exposure to selexipag and its active metabolite. There is no experience with UPTRAVI in patients with severe hepatic impairment (Child-Pugh class C). Avoid use of UPTRAVI in patients with severe hepatic impairment [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

8.7 Patients with Renal Impairment

Additions and/or revisions underlined:

No adjustment to the dosing regimen is needed in patients with estimated glomerular filtration rate greater than or equal to 15 mL/min.

There is no clinical experience with UPTRAVI in patients undergoing dialysis or in patients with glomerular filtration rates <15 mL/min [see Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Extensive changes; please refer to label for complete information

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Inform Patients

To take a missed dose as soon as possible, unless the next dose is within the next 6 hours.
Not to split or crush tablets.
To follow the instructions for alternate methods of administration for patients who cannot swallow tablets whole [see Dosage and Administration (2.1)].