Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

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-207947)

(SELEXIPAG)

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

Download Data

Expand all

10/25/2021 (SUPPL-9)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

Hypersensitivity to the active substance or to any of the excipients.

Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil) [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

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

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

PATIENT INFORMATION

(Additions and/or revisions underlined)

…

Do not take UPTRAVI if you:

take gemfibrozil because this medicine may affect how UPTRAVI works and cause side effects.
are allergic to selexipag or any of the other ingredients of this medicine (listed under Inactive ingredients).

…

08/19/2021 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Pulmonary Edema with Pulmonary Veno-Occlusive Disease

(Section title revised)

(Additions and/or revisions underlined)

Should signs of pulmonary edema occur, consider the possibility of associated pulmonary veno- occlusive disease. If confirmed, discontinue UPTRAVI.

6 Adverse Reactions

6.1 Clinical Trial Experience

(Newly added information)

UPTRAVI for Injection

Infusion-site reactions (infusion site erythema/redness, pain and swelling) were reported with UPTRAVI for Injection.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

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.

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 1600 mcg twice daily on an area under the curve [AUC] 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 1600 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 1600 mcg twice daily on an AUC basis). Treatment with selexipag did not cause adverse developmental effects in this study at any dose.

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

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.

Patient Information

(Extensive changes; please refer to label)

09/04/2019 (SUPPL-7)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 CYP2C8 Inhibitors

(Additions and/or revisions are underlined)

Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled 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 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 patients on a moderate CYP2C8 inhibitor.

12/20/2017 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Newly added subsection)

The following adverse reactions have been identified during postapproval 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.

Symptomatic hypotension

07/21/2017 (SUPPL-1)

Approved Drug Label (PDF)

4 Contraindications

Addition of the following:

Concomitant use of strong inhibitors of CYP2C8 (e.g., gemfibrozil)

7 Drug Interactions

7.1 CYO2C8 Inhibitors

Additions and/or revisions underlined:

Concomitant administration with gemfibrozil, a strong inhibitor of CYP2C8, doubled 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.

Although not studied, use of UPTRAVI with moderate CYP2C8 inhibitors (e.g., teriflunomide and deferasirox) can be expected to increase exposure to the active metabolite of selexipag. Consider a less frequent dosing regimen, e.g., once-daily, when initiating UPTRAVI in patients on a moderate CYP2C8 inhibitor. Reduce UPTRAVI when a moderate CYP2C8 inhibitor is initiated.

Newly added subsection:

7.2 CYP2C8 Inducers

Concomitant administration with an inducer of CYP2C8 and UGT 1A3 and 2B7 enzymes (rifampin) halved exposure to the active metabolite. Increase dose up to twice of UPTRAVI when co-administered with rifampin. Reduce UPTRAVI when rifampin is stopped.