Page 2 of 11

 This correspondence is intended to share the results of new research with OOPD 

regarding a serious safety risk associated with both IR oxybate formulations to further support 

the clinical superiority of LUMRYZ over XYREM and XYWAV. 

Inappropriate Schedule of Dosing Administration and Accidental Overdose with 

Twice-Nightly IR Oxybate Products

 Pursuant to the approved Prescribing Information (“PI”) for XYREM and XYWAV, the 

total nightly dosage of each respective drug is divided into two doses, and patients are instructed 

to prepare both doses prior to bedtime.1

 Prior to ingestion, patients are instructed to withdraw 

the appropriate dose of the oral solution via syringe and dilute it with water; patients are then 

instructed to take the first nightly dose at bedtime (at least 2 hours after eating) and take the 

second nightly dose at least 2.5 hours but no more than 4 hours after the first dose. The PI states 

that patients should take both doses while in bed, lie down immediately after dosing, and remain 

in bed following ingestion of each dose. The PI also states that patients may need to set an alarm 

to awaken for the second dose, and if the second dose is missed, that dose should be skipped and 

XYREM or XYWAV should not be taken again until the next night. The PI warns that two 

doses should never be taken at one time. 

 In the pivotal trial for XYWAV (n=201), a serious adverse drug reaction was reported 

after a patient inadvertently took the second dose of XYWAV shortly after the first dose.2 Both 

doses were 4.5 g, totaling the maximum approved total nightly dosage of 9 g. The participant 

experienced confusion and hallucinations and was hospitalized, with discharge after symptom 

resolution. Similarly, in a post-market study in Europe, an 18-year-old female also experienced 

accidental overdose due to an inappropriate schedule of drug administration, where the patient 

took the second dose of XYREM immediately after the first.3 The patient was hospitalized 

overnight. 

 Because of the inherent potential for accidental dosing administration errors of this type 

with an IR oxybate formulation that must be administered twice-nightly, once in the middle of 

the night, Avadel undertook to examine FDA’s Adverse Event Reporting System (“FAERS”) 

database to better assess this safety risk and further underscore the benefit of a once-nightly ER 

oxybate product. 

1 XYWAV is also approved for treatment of idiopathic hypersomnia via once-nightly dosing of a maximum dosage 

of 6 g; however, the labeling instructions for dosing and administration of XYREM and XYWAV for the treatment 

of narcolepsy are the same. See XYREM PI (Rev. Mar. 2022), http://pp.jazzpharma.com/pi/xyrem.en.USPI.pdf; 

XYWAV PI (Rev. Mar. 2022), https://www.xywav.com/pdf/xywav.en.USPI.pdf. 

2 Bogan, et al., Efficacy and Safety of Calcium, Magnesium, Potassium, and Sodium Oxybates (Lower-Sodium 

Oxybate [LXB]; JZP-258) in a Placebo-Controlled, Double-Blind, Randomized Withdrawal Study in Adults with 

Narcolepsy with Cataplexy, Sleep (2021): 44(3), 1-13, 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953213/pdf/zsaa206.pdf. 

3 Mayer, et al., Long-Term Compliance, Safety, and Tolerability of Sodium Oxybate Treatment in Patients with 

Narcolepsy Type 1: A Postauthorization, Noninterventional Surveillance Study, Sleep (2018): 41(9), 1-8, 

https://academic.oup.com/sleep/article-pdf/41/9/zsy128/25714959/zsy128.pdf. 
Page 3 of 11

The FAERS Public Dashboard was searched via the “Search by Product” feature using 

product names “Xyrem,” “Xywav,” “sodium oxybate,” and “calcium oxybate\magnesium 

oxybate\potassium oxybate\sodium oxybate.” The list of reported reactions was reviewed to 

identify the term most likely to capture incidents of patients taking an IR oxybate not according 

to the instructions in the PI. The Medical Dictionary for Regulatory Activities (“MedDRA”) 

preferred term “inappropriate schedule of product administration” was used to identify reports in 

which the second dose may not have been taken as required. The search criteria were further 

refined to only include reports in which the IR oxybate product was the “Suspect Product” and 

for which the case outcome was classified as “serious,” (i.e., death, life-threatening, 

hospitalization, disability or permanent damage, congenital anomaly/birth defect, or other serious 

or important medical event that may jeopardize the patient). The identified FAERS reports were 

then requested from FDA under the Freedom of Information Act (“FOIA”). All FAERS reports 

were analyzed by two separate reviewers to adjudicate relevant reports for inclusion in the 

analysis, i.e., those in which the patient took the second dose of IR oxybate less than 2.5 hours 

after the first dose and experienced an adverse event.

 For the FAERS data available through March 31, 2022, there were a total of 541 reports 

that included the preferred term of “inappropriate schedule of product administration” as a 

reaction with either IR oxybate product. Of the 541 reports identified, there were 178 reports in 

which IR oxybate was the suspect product and the patient had a serious outcome. During the 

timeframe from July 2021 through July 2022, the 178 reports meeting the search criteria were 

requested under FOIA and reviewed. Upon review, one report was identified as a duplicate and 

removed from the analysis. Forty-one reports, all classified as serious, described patients 

accidentally taking their second dose of IR oxybate less than 2.5 hours after the first dose and 

experiencing one or more adverse events as a result (Figure 1). All 41 reports of interest were 

submitted to FDA by the manufacturer, Jazz, between August 2011 and November 2020. 
Page 4 of 11

Figure 1: Flow Chart of FAERS Reports Identified and Included in Analysis

 A brief description of the 41 reports is attached (Appendix 1). Twenty-six (63%) reports 

involved female patients, and the age of the affected patients ranged from 7-65 years old with an 

average of 42 years. Nine (22%) reports described incidents involving emergency medical 

services or emergency department visits, and eleven (27%) reports described incidents resulting 

in hospitalization. Ten (24%) reports were initially reported by the American Association of 

Poison Control Centers (“AAPCC”). One report involved a patient who had a tendency to take 

her second dose 30 minutes to 1.5 hours after the first dose; upon her death, XYREM was noted 

as possibly contributing. 

 Timing of dosing errors varied: eight (20%) took their two doses at the same or almost 

the exact same time; eight (20%) took their second dose less than 1 hour after the first dose; and 

twenty-five (61%) took the second dose between 1 and 2.5 hours after the first dose. Harm to 

patients was described more frequently when patient took their second dose 1 hour or less after 

their first dose. Adverse events reported with accidentally taking the second dose too early 

included central nervous system (“CNS”) depression, bradycardia, respiratory depression, 

dizziness, seizure, confusion, delirium, difficulty awakening, drowsiness, falls, nausea, vomiting, 

and enuresis. 

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By providing a once-nightly dosing option, Avadel’s LUMRYZ stands to eliminate the 

need for a second middle-of-the-night dose, greatly reducing the risk of dosing errors, accidental 

overdose, and associated patient harm. This significant improvement in patient safety further 

supports Avadel’s demonstration of clinical superiority of LUMRYZ over XYREM and 

XYWAV for purposes of orphan drug exclusivity upon approval. 

Avadel thanks OOPD for its consideration of the information and data discussed in this 

correspondence. Please do not hesitate to contact me with any questions at (314) 750-2751 or 

jgudeman@avadel.com. 

 Sincerely,

 Jennifer Gudeman, PharmD 

 Vice President, Clinical & Medical Affairs

Avadel CNS Pharmaceuticals, LLC

Attachments
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Appendix 1

Line Listing of FAERS Reports of Interest

FAERS 

Report 

Number

Report Priority 

for FDA

Initial FDA 

Receipt Date

Patient 

Sex

Patient 

Age 

(years) 

Dosing Error 

8086716 Expedited 02-AUG-2011 Male 63 Took by error 2nd dose 10 

minutes after 1st dose

8148479 Expedited 07-SEP-2011 Female 63 Inadvertently took 2nd dose 

before 2.5 hours after 1st

dose 

9407996 Expedited 22-APR-2013 Female 43 Took 2nd dose 1.5 hours 

early

10172732 Expedited 13-MAY2014 Female 53 Took 1st dose, began nightly 

routine and accidentally took 

2nd dose after just having 

taken the 1st 

10229851 Expedited 09-JUN-2014 Male 23 Took 2nd dose 1.5 hours after 

1st dose 

10645638 Expedited 09-DEC-2014 Male 7 Patient’s mother 

administered 2 doses within 

a too short period between 

doses (2 hours)

10836059* Expedited 19-FEB-2015 Male 52 Took 1st dose and 1 hour 

later without thinking 

accidentally took 2nd dose 

12442374 Expedited 07-JUN-2016 Female 34 Ingested 2 doses close to the 

same time; patient's son did 

not know that she had taken 

her 1st dose and accidentally 

gave her 2nd dose

12497430 Expedited 24-JUN-2016 Female Not 

provided 

Took 2nd dose immediately 

after 1st dose because forgot 

had taken 1st dose 

12581349 Expedited 21-JUL-2016 Female 63 Inadvertently took 2nd dose 

when awoke and thought it 

was time to take but it was 

too early 

12620152 Expedited 03-AUG-2016 Male Unknown Took doses 2 hours apart 

13052535 Expedited 21-DEC-2016 Female 49 Took 2nd dose too early 

while sleepwalking
Page 8 of 11

FAERS 

Report 

Number

Report Priority 

for FDA

Initial FDA 

Receipt Date

Patient 

Sex

Patient 

Age 

(years) 

Dosing Error 

13156675 Non-Expedited 26-JAN-2017 Female 18 Took doses too close 

together 

13441020 Expedited 13-APR-2017 Female 38 Accidentally took 2nd dose 1 

hour after 1st dose 

13500013 Expedited 01-MAY2017 Female 53 Took 1st dose and 

accidentally took 2nd dose 

right after 1st without 

thinking 

14074197 Expedited 11-OCT-2017 Female 54 Took 2nd dose 2 hours after 

1st dose; didn’t realize had 

taken doses too close 

together 

14080329 Expedited 12-OCT-2017 Female 61 Accidentally took 2nd dose 

approximately 1 hour after 

taking 1st dose

14442031 Expedited 25-JAN-2018 Female 62 Woke up in the middle of 

the night and did not pay 

attention to alarm clock and 

overlapped doses; was about 

1.5 hours after 1st dose 

14650306 Expedited 16-MAR-2018 Male 17 Patient was given 2nd dose 2 

hours after 1st dose

14800123 Expedited 24-APR-2018 Male 65 Accidentally took a double 

dose; tired when preparing 

doses and ran out of 

medication in current bottle, 

got new bottle to finish 

drawing up doses and got 

distracted and put both doses 

into one dosing container 

14844046 Non-Expedited 03-MAY2018 Male 34 Took 2nd dose about 2 hours 

after 1st dose instead of 4 

hours because thought it was 

time to take 2nd dose 

14854175 Expedited 07-MAY2018 Male 65 Accidentally took 2nd dose 

30 minutes after 1st dose 

14914500 Expedited 18-MAY2018 Male 15 Accidentally took doses 

about 30 minutes apart

14914593 Non-Expedited 18-MAY2018 Female 48 Inadvertently took 2 doses 

too close together 
Page 9 of 11

FAERS 

Report 

Number

Report Priority 

for FDA

Initial FDA 

Receipt Date

Patient 

Sex

Patient 

Age 

(years) 

Dosing Error 

14923710 Expedited 22-MAY2018 Male 44 Unintentionally took 2nd

dose 30 minutes after 1st

dose 

14927962 Expedited 23-MAY2018 Female 57 Inadvertently took 2 doses, 

one shortly after the other; 

took dose, went to the 

bathroom and when came 

back, forgot had already 

taken 1st dose and took 2nd

dose 

15588213 Non-Expedited 05-NOV-2018 Female 40 Accidentally took double 

dose 

15608982 Expedited 12-NOV-2018 Female 41 Woke up 1 hour and 45 

minutes after taking 1st dose 

and took 2nd dose at that 

time 

15992034 Expedited 21-FEB-2019 Female 55 Took 1st dose and then got 

distracted; went back to bed, 

forgot already took 1st dose 

and took 2nd dose about 15 

minutes apart 

16171676 Non-Expedited 08-APR-2019 Male 33 Accidentally took 2nd dose 

approximately 1 hour after 

taking 1st dose 

16882499 Non-Expedited 03-OCT-2019 Female 46 Inadvertently took a double 

dose 1 hour apart 

17000238 Expedited 06-NOV-2019 Female 26 Accidentally took 2 doses 

together 

17422250 Expedited 14-FEB-2020 Male 30 Unintentionally took both 

doses at the same time

17503945 Expedited 05-MAR-2020 Male 14 Given doses too close 

together by mistake by 

parents

17547622 Expedited 16-MAR-2020 Female 33 Unintentionally took doses 

too close together 

17758591 Expedited 07-MAY2020 Female 26 Took 1st dose, forgot about 

it, and took 2nd dose 

approximately 30 minutes 

after 1st dose 
Page 10 of 11

FAERS 

Report 

Number

Report Priority 

for FDA

Initial FDA 

Receipt Date

Patient 

Sex

Patient 

Age 

(years) 

Dosing Error 

17965625 Non-Expedited 30-JUN-2020 Female 23 Doses unintentionally taken 

too close together 

18108233 Expedited 03-AUG-2020 Male 60 Took 2nd dose 1.5 hours after 

1st dose because of 

misreading the clock

18377576 Expedited 13-OCT-2020 Female 50 Tendency to take 2nd dose 

before 2.5 hours 

18491354 Expedited 11-NOV-2020 Female 24 Unintentionally took 2nd

dose 2 hours later 

18491355 Expedited 11-NOV-2020 Female 57 Unintentionally took 2nd

dose 30 minutes after 1st

dose 

*FAERS Report Number 10996114 identified to be a duplicate of 10836059.
Page 11 of 11

Appendix 2

 Report

(b) (4)


(b) (4) 



(





(b) (

(b) (4)