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Office of Orphan Products Development

Food and Drug Administration

10903 New Hampshire Avenue

WO32-5271

Silver Spring, MD 20993

Jazz Pharmaceuticals, Inc.

2005 Market Street, Suite 2100

Philadelphia, PA 19103

Attention: Arthur Merlin d’Estreux

US Agent for Jazz Pharmaceuticals Ireland Limited

Arthur.MerlindEstreux@jazzpharma.com

 

Re: Orphan-drug designation DRU-1994-858

Dear Mr. Merlin d’Estreux:

This letter refers to your orphan drug calcium, magnesium, potassium, and sodium 

oxybates which was designated pursuant to section 526 of the Federal Food, Drug, and 

Cosmetic Act (21 U.S.C. 360bb) on November 7, 1994, for “treatment of narcolepsy.”

We also refer to the letter from the Center for Drug Evaluation and Research, dated July

21, 2020, granting marketing approval of your New Drug Application for XYWAVTM

(calcium, magnesium, potassium, and sodium oxybates) (hereinafter Xywav). In 

addition, reference is made to the letter dated April 24, 2020 from Jazz Pharmaceuticals, 

Inc. to the Office of Orphan Products Development (OOPD) requesting that orphan-drug 

exclusivity for Xywav be recognized upon marketing approval. Lastly, reference is made 

to the letter dated April 19, 2021 from Jazz Pharmaceuticals to the OOPD requesting to 

expedite recognition of orphan-drug exclusivity for Xywav. 

Jazz Pharmaceuticals Ireland Limited is entitled to seven years of orphan-drug exclusive 

approval pursuant to section 527 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 

360cc) for Xywav (calcium, magnesium, potassium, and sodium oxybates) indicated for 

the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of 

age and older with narcolepsy. The seven-year exclusive approval began on July 21, 

2020, the date of approval of the New Drug Application (NDA #212690). The scope of 

orphan-drug exclusive approval is described under 21 CFR 316.31.

In accordance with section 527(e)(2) of the FD&C Act (21 U.S.C. 360cc(e)(2)), FDA’s 

summary of the clinical superiority finding will be posted at https://www.fda.gov/orphan.

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As the holder of exclusivity, the sponsor is required to assure the availability of sufficient 

quantities of this drug to meet the needs of patients. Failure to do so could result in the 

withdrawal of the drug’s exclusive approval as stipulated under 21 CFR 316.36(b).

Congratulations on obtaining orphan-drug exclusivity. Should you have any questions

regarding this exclusivity, please contact our office at 301-796-8660 or by email at 

orphan@fda.hhs.gov.

Sincerely,

{See appended electronic signature page}

Director

Office of Orphan Products Development

FDA-OOPD-May23-POSTING-000085
Nicole Wolanski

Digitally signed by Nicole Wolanski

Date: 6/24/2021 11:46 AM EDT

GUID: 13313

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Office of Orphan Products Development

Food and Drug Administration

10903 New Hampshire Avenue

WO32-5271

Silver Spring, MD 20993

Avadel CNS Pharmaceuticals, LLC

16640 Chesterfield Grove Road, Suite 200 

Chesterfield, MO 63005 

Attention: Jennifer Gudeman, PharmD 

Vice President, Clinical & Medical Affairs

jgudeman@avadel.com

 

Re: Sodium Oxybate for the Treatment of Narcolepsy 

Dear Dr. Gudeman: 

This letter responds to your letter dated December 8, 2020, about sodium oxybate for the 

treatment of narcolepsy. You requested that the Office of Orphan Products Development 

(OOPD) in the Food and Drug Administration (FDA) refrain from recognizing orphandrug exclusivity for Xywav (calcium, magnesium, potassium, and sodium oxybates), 

approved on July 21, 2020, for the treatment of cataplexy or excessive daytime sleepiness 

(EDS) in patients 7 years of age and older with narcolepsy. 

After careful consideration, OOPD has determined that Xywav is eligible for orphan-drug 

exclusivity,1 because Xywav is clinically superior to the same drug2

 previously approved 

for the same use or indication.3 Specifically, Xywav is clinically superior4 to Xyrem 

(sodium oxybate) by means of greater safety, because Xywav provides a greatly reduced 

chronic sodium burden compared to Xyrem. The differences in the sodium content of the 

two products at the recommended doses will be clinically meaningful in reducing 

cardiovascular morbidity in a substantial proportion of patients for whom the drug is 

indicated. We respond to the arguments in your December 8, 2020, letter below. Please

1 In your December 8, 2020, letter you state, “As of the date of this letter, no such additional period of 

exclusivity is identified for Xywav in the FDA database, indicating an FDA determination that Xywav is 

indeed the ‘same drug’ as Xyrem and, as such, not clinically superior.” This is incorrect. At the time of 

your letter, FDA had not yet determined whether Xywav is clinically superior to Xyrem, and thus had not 

yet determined whether Xywav is eligible for orphan-drug exclusivity. 2 See 21 CFR 316.3(b)(14). 3 See Sec. 527(c)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act); see also 21 CFR 316.34(c). 4 See Sec. 527(c)(2) of the FD&C Act; see also 21 CFR 316.3(b)(3).

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note that this determination is limited to Xywav’s eligibility for orphan-drug exclusivity 

and FDA has not yet evaluated the impact of Xywav’s orphan-drug exclusivity on the 

new drug application (NDA) you submitted for your sodium oxybate product. FDA will 

evaluate the arguments that you submitted in your NDA on December 15, 2020, 

regarding the clinical superiority of your product over any same drug that currently has 

orphan-drug exclusivity for the indication for which you are seeking approval. 

First, your letter argues that there is no clinical or real-world evidence showing that the 

sodium content of Xyrem increases cardiovascular risks in patients with narcolepsy. You 

reference a paper by Avidan and Kushida published in Sleep Medicine in 2020 to support 

that there is no clinical or real-world evidence showing that the sodium content of Xyrem 

increases cardiovascular risks in patients with narcolepsy.5

 That paper is a literature 

review and the authors conclude that exisiting evidence does not support that exposure to 

sodium oxybate leads to increased cardiovascular risk in patients with narcolepsy. 

However, as acknowledged by the authors, this possibility has never been adequately 

investigated since there have been no studies that have been prospectively designed to 

specifically investigate whether the administration of Xyrem at recommended doses is 

associated with adverse cardiovascular outcomes, either in the wider population with 

narcolepsy or in subgroups of patients with narcolepsy who have co-existing medical 

conditions. Nevertheless, the general base of knowledge about the effects of sodium 

support that the amount of sodium in Xyrem would increase cardiovascular risks in 

patients with narcolepsy. The National Academies of Sciences, Engineering and 

Medicine, an authoritative national body in the United States, has recommended in an 

official publication titled “Dietary Reference Intakes for Sodium and Potassium” that 

daily salt intake in individuals 14 years and older be restricted to 2300 mg or less.6 The 

National Academies have also stated that there is evidence that a reduction in sodium 

intake has a beneficial effect on the risk of cardiovascular disease, the risk of 

hypertension, systolic blood pressure and diastolic blood pressure in the general 

population.7 In addition, the US Department of Agriculture’s publication titled “Dietary 

Guidelines for Americans 2020-2025” also supports the recommendations of the National 

Academies.8 

The recommended dose for both Xyrem and Xywav is 6 g to 9 g per night. Xyrem doses 

of 6 g to 9 g per night would have a sodium content that ranges from 1100 mg to 1638 

mg. That led to the labeling for Xyrem to contain a Warning and Precaution regarding 

use in patients that are sensitive to high sodium intake. For patients already taking 

Xyrem at these doses, a change to Xywav at the same total nightly doses would result in a 

reduction in total nightly sodium intake ranging from 1013 mg (for the 6 g dose) to 1507 

mg (for the 9 g dose). The labeling for Xywav does not contain the same Warning and 

5 A.Y. Avidan & C.A. Kushida (2020), The Sodium in Sodium Oxybate: Is There Cause for Concern?,

Sleep Medicine 75:497-501. 6 Available at https://www.nationalacademies.org/our-work/review-of-the-dietary-reference-intakes-forsodium-and-potassium. 7 See https://www.nationalacademies.org/news/2019/03/sodium-and-potassium-dietary-reference-intakevalues-updated-in-new-report. 8 Available at https://www.dietaryguidelines.gov/sites/default/files/2020-

12/Dietary_Guidelines_for_Americans_2020-2025.pdf. 

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Precaution given the reduced sodium content of this drug. Thus, the sodium reduction 

from Xyrem to Xywav is significant under the guidelines referenced above. In addition, 

a higher prevalence of comorbidities such as hypertension, obesity, hyperlipidemia, and 

glucose intolerance has been reported in association with narcolepsy.9 The reduction in 

chronic sodium burden with Xywav would be expected to be beneficial to all patients 

with narcolepsy, especially those with comorbidities that put them at increased risk of 

cardiovascular disease.

Second, your letter argues that the connection between sodium intake and adverse health 

outcomes has been largely disproven. As stated above, the paper by Avidan and Kushida 

published in Sleep Medicine in 2020 does not disprove the connection between sodium 

intake and adverse health outcomes, because the possibility that the sodium content of 

Xyrem increases cardiovascular risks in patients with narcolepsy has not been adequately 

studied to draw that conclusion. You also cite publications by O’Donnell, et al.

10 and 

Moore. et al.

11 to support your argument that the connection between sodium intake and 

adverse health outcomes has been largely disproven. The conclusions by the authors of 

these publications contrast sharply with what is stated in the recent publication by the 

National Academies and with the latest dietary guidelines published by the US 

Department of Agriculture, discussed above. The statements by the National Academies 

and US Department of Agriculture are authoritative and based on the latest consensus 

opinions of experts in the field. The relationship between daily salt intake and 

cardiovascular morbidity is widely accepted, as is the need for salt intake to be generally 

restricted and not only in subjects with conditions such as hypertension, cardiac failure, 

and impaired renal function. 

Third, your letter argues that there is no basis to conclude that reduced sodium in a 

sodium oxybate product will provide greater effectiveness, greater safety, or a major 

contribution to patient care. You point to an article by R.K. Bogan, et al.12 and argue that 

“while the authors identified that the groups already receiving Xyrem had a modest 

increased systolic and diastolic blood pressure at baseline compared to groups not 

receiving Xyrem, no rates of increased blood pressure were reported in the Xywavtreated group after switching, presumably because no difference was observed.” 

However, your presumption that no increases in blood pressure were observed in patients 

after switching to Xwyav because they were not reported is speculative. The authors of 

the paper stated that a rigorous evaluation of changes in blood pressure with Xywav in 

patients previously treated with Xyrem was not performed because it was outside the 

scope of the study. The authors also pointed out that the impact on cardiovascular 

disease risk of the reduction in sodium content in Xywav in patients previously treated 

with Xyrem could not be assessed because the duration of the study was very short. 

9 See https://www.sciencedirect.com/science/article/abs/pii/S1389945717315587. 10 M. O’Donnell, et al., (2020), Salt and Cardiovascular Disease: Insufficient Evidence to Recommend Low 

Sodium Intake, European Heart Journal 41: 3363-73. 11 L.L. Moore, et al. (2018), Low Sodium Intakes are Not Associated with Lower Blood Pressure Levels 

Among Framingham Offspring Study Adults, The FASEB Journal 31(S1). 12 R.K. Bogan, et al. (2020), 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 (electronic publication ahead of print). 

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Finally, we are not responding to your arguments about major contribution to patient 

case, because OOPD will only consider major contribution to patient care “where neither 

greater safety nor greater effectiveness has been shown,”13 and here, greater safety has 

been shown. 

In conclusion, Xywav is clinically superior to Xyrem by means of greater safety, because 

Xywav provides a greatly reduced chronic sodium burden compared to Xyrem. Xywav is 

eligible for orphan-drug exclusivity. Under this exclusivity, with limited exceptions, 

FDA may not approve an application from another sponsor for the same drug for the 

same use or indication for seven years from the date of approval of Xywav.14 If a 

subsequent same drug is clinically superior to Xywav, it will not be considered to be the 

same drug, 15 and not subject to the orphan-drug exclusivity for Xywav. As stated above, 

FDA has not yet evaluated whether your sodium oxybate product is clinically superior to 

any same drug that currently has orphan-drug exclusivity for the indication for which you 

are seeking approval. 

Should you have any questions, please contact our office at 301-796-8660 or by email at 

orphan@fda.hhs.gov. 

Sincerely,

 

Nicole L. Wolanski, CAPT, USPHS 

Acting Director 

Office of Orphan Products Development 

13 21 CFR 316.3(b)(3)(iii). 14 See Sec. 527(a) of the FD&C Act; see also 21 CFR 316.31. 15 See 21 CFR 316.3(b)(14)(i).

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