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.

WAKIX (NDA-211150)

(PITOLISANT HYDROCHLORIDE)

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

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02/13/2026 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

…

Pediatric Patients (6 years and older) with Narcolepsy

In a clinical trial for narcolepsy, 73 pediatric patients 6 years and older were treated with WAKIX in the placebo-controlled phase for up to 8 weeks and 105 patients in the open-label extension phase for up to 8 years.

…

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of WAKIX have been established for the treatment of excessive daytime sleepiness or cataplexy in pediatric patients 6 years of age and older with narcolepsy. Use of WAKIX in this age group is supported by one adequate and well-controlled study in 110 pediatric patients with narcolepsy ages 6 to less than 18 years of age [see Clinical Studies (14.1)].

The safety and effectiveness of WAKIX have not been established for the treatment of excessive daytime sleepiness or cataplexy in pediatric patients less than 6 years of age with narcolepsy.

…

8.8 Use in Genomic Subgroups

Subsection title revised.

Additions and/or revisions underlined:

The maximum recommended dosage is lower in patients who are CYP2D6 poor metabolizers because these patients have higher pitolisant concentrations than CYP2D6 normal metabolizers and may have increased risk of adverse events [see Dosage and Administration (2.7), Warnings and Precautions (5.1), Clinical Pharmacology (12.5)].

The prevalence of CYP2D6 poor metabolizers is approximately 7% in White populations, 2% in Asian populations, and 2% in Black or African American populations.

06/21/2024 (SUPPL-5)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information:

Pediatric Patients (6 years and older) with Narcolepsy

Most Common Adverse Reactions

In the placebo-controlled phase of the study, the most common adverse reactions (occurring in ?5% of patients and greater than the rate of placebo) with the use of WAKIX were headache (19%) and insomnia (7%).

The overall adverse reaction profile of WAKIX in the pediatric clinical trial was similar to that seen in the adult clinical trial program.

6.2 Postmarketing Experience

Additions and revisions underlined:

The following adverse reactions have been identified during post-approval use of WAKIX. 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:

. . .

Nervous system disorders: dizziness, epilepsy

. . .

8 Use in Specific Populations

8.4 Pediatric Use

Additions and revisions underlined:

The safety and effectiveness of WAKIX have been established for the treatment of excessive daytime sleepiness in pediatric patients 6 years of age and older with narcolepsy. Use of WAKIX in this age group is supported by one adequate and well-controlled study in 110 pediatric patients with narcolepsy ages 6 to less than 18 years of age [see Clinical Studies (14.1)].

The safety and effectiveness of WAKIX have not been established for treatment of excessive daytime sleepiness in pediatric patients less than 6 years of age with narcolepsy.

The safety and effectiveness of WAKIX have not been established for treatment of cataplexy in pediatric patients with narcolepsy.

Juvenile Animal Toxicity Data

In a juvenile animal study, male and female rats were administered pitolisant at 9, 21, or 48 mg/kg/day by oral gavage from postnatal day (PND) 7 to PND 70. Mortality occurred at the highest dose of 48 mg/kg/day; however, death was primarily related to aspiration/inhalation of food material. No adverse effects on growth and development up to the high dose were observed; however, plasma exposures at this dose were lower than those predicted to occur in pediatric patients at the maximum recommended human dose (MRHD) of 35.6 mg due to low oral bioavailability in juvenile rats.

In a second juvenile animal study, male and female rats were administered pitolisant at 15 or 30 mg/kg/day or 30 mg/kg/twice daily (60 mg/kg/day) by intraperitoneal injection from PND 7 to PND 70. Mortality and convulsions were observed at the top two doses of 30 and 60 mg/kg/day. Similar findings of convulsions and mortality were also observed in studies in adult rats at comparable doses. The no observed adverse effect level (NOAEL) is 15 mg/kg/day in juvenile animals administered pitolisant by intraperitoneal injection, which corresponds to plasma exposures that are approximately 4 times and 1 times the predicted pediatric exposures at the MRHD of 35.6 mg, based on Cmax and AUC, respectively.

8.7 Renal Impairment

Additions and revisions underlined:

The pharmacokinetics of WAKIX in patients with end-stage renal disease (ESRD) (eGFR of <15 mL/minute/1.73 m2) is unknown [see Clinical Pharmacology (12.3)]. Therefore, WAKIX is not recommended in patients with ESRD [see Dosage and Administration (2.4), Warnings and Precautions (5.1)].

Dosage adjustment of WAKIX is recommended in patients with eGFR <60 mL/minute/1.73 m2 [see Dosage and Administration (2.4)].

12/22/2022 (SUPPL-3)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.2 Lactation

Additions and revisions underlined:

Risk Summary

The transfer of pitolisant into breastmilk is low based on data from a lactation study. The mean infant dose was 0.009 mg/day, and the relative infant dose was less than 1% of the maternal weight-adjusted dose (see Data). There are no data on the effects of pitolisant on the breastfed infant, or the effect of this drug on milk production.

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

Data

An open-label study in 8 healthy lactating women who were 11 to 96 weeks post-partum evaluated the concentration of pitolisant in breast milk samples collected over 24 hours and serum samples collected over 120 hours after a single dose administration of 35.6 mg of pitolisant. Pitolisant was present in breast milk with a mean Cmax of 47.5 ng/mL, while the mean Cmax of pitolisant in serum was

61.4 ng/mL. Following a single dose of pitolisant 35.6 mg, approximately 50% of the amount of pitolisant measured in breast milk occurred during the first 4 hours post dose. Based on single dose data, the mean infant dosage of pitolisant was calculated to be 0.009 mg/day, which represented a mean of 0.564% of the maternal dose received.