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.

XENAZINE (NDA-021894)

(TETRABENAZINE)

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

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09/13/2017 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

XENAZINE is contraindicated in patients:

Addition of the following:

Taking deutetrabenazine or valbenazine

5 Warnings and Precautions

Additions and/or revisions underlined:

5.1 Depression and Suicidality

… six had suicidal ideation.

When considering the use of XENAZINE, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with XENAZINE …

5.2 Clinical Worsening and Adverse Effects

… Whether these effects persist, resolve, or worsen with continued treatment is unknown.

Prescribers should periodically re-evaluate the need for XENAZINE in their patients by assessing the effect on chorea and possible adverse effects, including depression and suicidality, cognitive decline, parkinsonism, dysphagia, sedation/somnolence, akathisia, restlessness, and disability. It may be difficult to distinguish between adverse reactions and progression of the underlying disease …

5.4 Neuroleptic Malignant Syndrome

… There is no general agreement about specific pharmacological treatment regimens for NMS.

Recurrence of NMS has been reported with resumption of drug therapy. If treatment with …

5.5 Akathisia, Restlessness, and Agitation

XENAZINE may increase the risk of akathisia, restlessness, and agitation.

In a 12-week, double-blind, placebo-controlled study in patients …

5.11 Binding to Melanin-Containing Tissues

… conducted in the chronic toxicity studies in a pigmented species, such as dogs …

6 Adverse Reactions

The following serious adverse reactions are described below and elsewhere in the labeling:

Additions and/or revisions underlined:

Depression and Suicidality
Neuroleptic Malignant Syndrome (NMS)
Akathisia, Restlessness, and Agitation

Parkinsonism

Sedation and Somnolence
QTc Prolongation
Hypotension and Orthostatic Hypotension
Hyperprolactinemia
Binding to Melanin-Containing Tissues
6.1 Clinical Trials Experience
… The most common adverse reactions (over 10%, and at least 5% greater than placebo) were sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety/anxiety aggravated, and nausea.
Dysphagia
… Dysphagia may be associated with aspiration pneumonia. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, dysphagia was observed in 4% of XENAZINE-treated patients and 3% of placebo-treated patients. In 48-week and 80-week, open-label studies, dysphagia was observed in 10% …

7 Drug Interactions

Newly added subsection:

7.7 Concomitant Deutetrabenazine or Valbenazine

XENAZINE is contraindicated in patients currently taking deutetrabenazine or valbenazine.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; as below:

Risk Summary

There are no adequate data on the developmental risk associated with the use of XENAZINE in pregnant women. Administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspring mortality. Administration of a major human metabolite of tetrabenazine to rats during pregnancy or during pregnancy and lactation produced adverse effects on the developing fetus and offspring (increased mortality, decreased growth, and neurobehavioral and reproductive impairment). The adverse developmental effects of tetrabenazine and a major human metabolite of tetrabenazine in rats occurred at clinically relevant doses.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data

Animal Data

Tetrabenazine had no clear effects on embryofetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or 3 times the maximum recommended human dose [MRHD] of 100 mg/day on a mg/m2 basis). Tetrabenazine had no effects on embryofetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the MRHD on a mg/m2 basis).

When tetrabenazine (5, 15, and 30 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day and delayed pup maturation was observed at all doses. A no-effect dose for pre- and postnatal developmental toxicity in rats was not identified. The lowest dose tested (5 mg/kg/day) was less than the MRHD on a mg/m2 basis.

Because rats dosed orally with tetrabenazine do not produce 9-desmethyl-?-DHTBZ, a major human metabolite of tetrabenazine, the metabolite was directly administered to pregnant and lactating rats. Oral administration of 9-desmethyl-?-DHTBZ (8, 15, and 40 mg/kg/day) throughout the period of organogenesis produced increases in embryofetal mortality at 15 and 40 mg/kg/day and reductions in fetal body weights at 40 mg/kg/day, which was also maternally toxic. When 9-desmethyl-?-DHTBZ (8, 15, and 40 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, increases in gestation duration, stillbirths, and offspring postnatal mortality (40 mg/kg/day); decreases in pup weights (40 mg/kg/day); and neurobehavioral (increased activity, learning and memory deficits) and reproductive (decreased litter size) impairment (15 and 40 mg/kg/day) were observed. Maternal toxicity was seen at the highest dose. The no-effect dose for developmental toxicity in rats (8 mg/kg/day) was associated with plasma exposures (AUC) of 9-desmethyl-?-DHTBZ in pregnant rats lower than that in humans at the MRHD.

8.2 Lactation

PLLR conversion; as below:

Risk Summary

There are no data on the presence of tetrabenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XENAZINE and any potential adverse effects on the breastfed infant from XENAZINE or from the underlying maternal condition.