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.

HETLIOZ (NDA-205677)

(TASIMELTEON)

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

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12/01/2020 (SUPPL-7)

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 clinical practice.

More than 2080 subjects have been treated with at least one dose of HETLIOZ, of which more than 380 have been treated for > 26 weeks and more than 170 have been treated for > 1 year.

Nighttime Sleep Disturbances in Smith-Magenis Syndrome (SMS)

A 9-week, double-blind, randomized, placebo-controlled, two-period crossover study evaluated HETLIOZ (capsules and oral suspension; n=25) compared to placebo (n=26) in the treatment of nighttime sleep disturbances in patients with Smith-Magenis Syndrome. Pediatric patients (n=11, age 3 to 15 years) received HETLIOZ LQ oral suspension, and patients ?16 years of age (n=14) received HETLIOZ capsules.

Adverse reactions were similar in patients treated for Non-24 and patients with Smith-Magenis syndrome treated for nighttime sleep disturbances. Adverse reactions were also similar in pediatric patients (3 years to 15 years) who received HETLIOZ LQ oral suspension, and patients greater than or equal to 16 years of age who received HETLIOZ capsules.

7 Drug Interactions

7.3 Beta-adrenergic Receptor Antagonists (e.g., ace butolol, metoprolol)

(Newly added subsection)

Beta-adrenergic receptor antagonists have been shown to reduce the production of melatonin via specific inhibition of beta-1 adrenergic receptors. Nighttime administration of beta-adrenergic receptor antagonists may reduce the efficacy of HETLIOZ.

8 Use in Specific Populations

8.4 Pediatric Use

(Additions and/or revisions underlined)

Safety and effectiveness of HETLIOZ for the treatment of Non-24 in pediatric patients have not been established.

Safety and effectiveness of HETLIOZ LQ oral suspension for the treatment of nighttime sleep disturbances in Smith-Magenis Syndrome (SMS) have been established in pediatric patients 3 years and older. Use is based on a placebo-controlled crossover study of pediatric and adult patients [see Clinical Studies (14.2)].

Safety and effectiveness of HETLIOZ for the treatment of nighttime sleep disturbances in SMS have not been established in patients younger than 3 years old.

Juvenile Animal Toxicity Data

Juvenile rats received oral doses of tasimelteon at 50, 150, or 450 mg/kg from weaning (day 21) through adulthood (day 90). These doses are approximately 12 to 108 times the maximum recommended human dose (MRHD) of 20 mg based on a mg/m2 body surface area. Toxicity was observed mainly at the highest dose and included mortality (females only), tremors, unsteady gait, decrease in growth and development compared to controls. The former reflected as decreases in bone growth, bone mineral content, bone ossification, and a delay in attainment of sexual maturation. Tasimelteon had no effect on fertility, reproduction, or learning and memory. The No Observed Adverse Effect Level (NOAEL) is 150 mg/kg/day, which is approximately 178 times the MRHD based on AUC.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling for HETLIOZ LQ oral suspension, if appropriate (Instructions for Use).

Advise patients to limit their activities to preparing for going to bed after taking HETLIOZ capsules or HETLIOZ LQ oral suspension because HETLIOZ can potentially impair the performance of activities requiring complete mental alertness [see Warnings and Precautions (5.1)].

Administration Information for HETLIOZ capsules and HETLIOZ LQ oral suspension [see Dosage and Administration (2.1, 2.2, 2.3, 2.4)].

Advise patients to take HETLIOZ without food.
Advise patients to take HETLIOZ before bedtime at the same time every night.
Advise patients to skip the dose that night if they cannot take HETLIOZ at approximately the same time on a given night.
Advise patients to swallow HETLIOZ capsules whole.
HETLIOZ LQ oral suspension:

Advise patients to shake the bottle for at least 30 seconds before each administration; use the press-in bottle adapter included in the package; leave the adapter in place on the

bottle neck; replace the cap; and refrigerate after each use. After opening, discard after 5 weeks (for the 48 mL bottle) and after 8 weeks (for the 158 mL bottle).

Non-24 (HETLIOZ capsules)

Advise patients that because of individual differences in circadian rhythms, daily use for several weeks or months may be necessary before benefit from HETLIOZ is observed [see Dosage and Administration (2.2)].

10/07/2019 (SUPPL-6)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; please refer to label for complete information.

8.2 Lactation

PLLR conversion; additions as below:

Risk Summary

There are no data on the presence of tasimelteon or its metabolites in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HETLIOZ and any potential adverse effects on the breastfed infant from HETLIOZ or from the underlying maternal condition.