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.

XERMELO (NDA-208794)

(TELOTRISTAT ETIPRATE)

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

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09/26/2022 (SUPPL-4)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined

Xermelo is contraindicated in patients with a history of a hypersensitivity reaction to telotristat. Reactions have included angioedema, rash and pruritis.

5 Warnings and Precautions

5.1 Constipation

Additions and/or revisions underlined

Xermelo reduces bowel movement frequency and may lead to constipation. Serious complications of constipation have been reported during clinical trials and postmarketing.

… During the 36-week extension period with higher than the recommended dosage of Xermelo, 10 of 115 patients reported constipation, with individual reports of intestinal perforation, obstruction, and fecaloma. In another 12-week, placebo-controlled trial in which patients had less than 4 bowel movements per day, 4 out of 25 patients treated with the recommended dosage of Xermelo reported constipation.

Serious complications of constipation in patients treated with Xermelo at the recommended dosage (e.g., intestinal obstruction) have also been reported in the postmarket setting. Most patients had additional risk factors, including underlying disease and concomitant constipating medications.

…

6 Adverse Reactions

6.2 Postmarketing Experience

New subsection added

The following adverse reactions have been identified during post approval use of Xermelo. 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.

Gastrointesinal: intestinal obstruction [see Warnings and Precautions (5.1)

Immune system disorders: angioedema

Skin and subcutaneious tissue disorders: pruritis, rash

10/26/2020 (SUPPL-1)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 CYP3A4 Substrates

(Additions and/or revisions underlined)

Concomitant use of Xermelo may decrease the efficacy of drugs that are CYP3A4 substrates (e.g., midazolam) by decreasing their systemic exposure. Monitor patients’ response to CYP3A4 substrates when co-administered with Xermelo and consider increasing the dosage of the interacting drug, if necessary [see Clinical Pharmacology (12.3)].

7.2 CYP2B6 Substrates

(Newly added subsection)

Concomitant use of Xermelo may decrease the efficacy of drugs that are CYP2B6 substrates (e.g., bupropion, efavirenz) by decreasing their systemic exposure. Monitor patients’ response to CYP2B6 substrates when co-administered with Xermelo and consider increasing the dosage of the interacting drug, if necessary [see Clinical Pharmacology (12.3)].

8 Use in Specific Populations

8.6 Renal Impairment

(Newly added subsection)

No dosage adjustment of Xermelo is necessary in patients with mild, moderate or severe renal impairment who are not requiring dialysis.

There is no information on Xermelo in patients with end-stage renal disease who require dialysis (eGFR <15 mL/min/1.73 m²).

8.7 Hepatic Impairment

(Newly added subsection)

Systemic exposure of telotristat ethyl and its active metabolite, telotristat, were substantially increased in patients with moderate hepatic impairment (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh C) (3.2- and 5.0-fold, respectively) compared to patients with normal hepatic function [see Clinical Pharmacology (12.3)]. Xermelo is not recommended in patients with moderate and severe hepatic impairment.

No dosage adjustment of Xermelo is necessary in patients with mild hepatic impairment (Child- Pugh A); however, additional monitoring of Xermelo-associated adverse reactions (e.g., constipation) is recommended in these patients [see Warnings and Precautions (5.1)].