MEMORANDUM 

DEPARTMENT OF HEALTH AND HUMAN SERVICES 

PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION

Division of Neurology 1

Office of Neuroscience 

Center for Drug Evaluation and Research

Date: November 27, 2020

From: Eric Bastings, MD

Division Director

Subject: Orphan Products Consult Request #2020-00029-EC

NDA 212690

XywavTM

Request for Orphan Drug Exclusivity 

To: Director

Office of Orphan Products Development

 

Document Type: Consult 

Enclosed is the Division’s response to your request
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NDA 212690, Xywav (JZP-258), Jazz Pharmaceuticals, Inc 11/27/20

Review and Evaluation of Clinical Data

NDA (Serial Number) 212690

Sponsor: Jazz Pharmaceuticals, Inc

Drug: Xywav (JZP-258)

Approved Indication: Narcolepsy

Material Received: Consultation Request

Consultation Request Date: 10/26/20

Date Received By Reviewer: 10/26/20

Date Review Completed 11/27/20

Reviewer: Ranjit B. Mani, M.D.

1. Introduction

This consultation request has been received from the Office of Orphan Products 

Development, and follows a request to that office for the grant of orphan drug 

exclusivity for XywavTM.

Currently, XywavTM (a low-sodium oxybate oral solution formulation containing a 

mixture of calcium, magnesium, potassium, and sodium oxybates) is approved 

for the treatment of cataplexy or excessive daytime sleepiness, in patients 7 

years or older with narcolepsy. Another product approved for the same indication

is Xyrem® (sodium oxybate oral solution). Xyrem® was initially approved, under 

NDA 21196, on July 17, 2002, whereas XywavTM was initially approved, under 

NDA 212690, on July 21, 2020. One or more generic formulations of sodium 

oxybate oral solution have also been approved for the treatment of narcolepsy. 

All the aforementioned oxybate formulations are administered twice nightly, with 

the two nightly doses separated by an interval of 2.5 to 4 hours.

The active moiety in both XywavTM and Xyrem® is oxybate (gammahydroxybutyric acid). The sponsor of both products is the same: Jazz 

Pharmaceuticals, Inc.

Orphan drug designation was originally granted to sodium oxybate by the Office 

of Orphan Products Development on November 7, 1994.

2. Text Of Consultation Request

The following section headings and text are copied from the consultation request

from the Office of Orphan Products Development, dated October 26, 2020.

2.1 Background: 

The Office of Orphan Products Development (OOPD) granted orphan drug designation 

to sodium oxybate on 11/07/94 for the treatment of narcolepsy. Sodium oxybate was 

originally approved for use in the treatment of narcolepsy on 7/17/02 under the trade 

name Xyrem. Xywav (calcium, magnesium, potassium, and sodium oxybates) was 
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approved on 7/21/20 for treatment of cataplexy or excessive daytime sleepiness (EDS) 

in patients 7 years of age and older with narcolepsy. At the time of this approval, the 

indication for Xyrem was identical. Since the active moiety in both Xyrem and Xywav is 

oxybate (gamma-hydroxybutyrate), the orphan drug designation granted in 1994 also 

applies to Xywav. The purpose of this consult request is to obtain the review division’s 

input in order to help the OOPD determine eligibility for orphan drug exclusivity for 

Xywav. 

Per the orphan drug regulations, since the active moiety, oxybate, was already approved 

for the same use or indication, in order to receive orphan drug exclusivity, Xywav must 

be clinically superiority to all previously approved oxybate products for the same 

indication, i.e. Xyrem. For the purpose of orphan drug exclusivity, clinical superiority 

can be based on greater effectiveness, greater safety in a substantial portion of the 

target population, or a major contribution to patient care (MCTPC), with all else being 

equal (see definition below). Please note that for orphan drug exclusivity purposes we 

apply the definition of clinical superiority from the regulations below and do not apply 

the substantial evidence standard as is required for a labeling claim. 

 

The sponsor for Xywav submitted a request to the OOPD on 4/24/20 for orphan drug 

exclusivity based on clinical superiority with regard to safety over Xyrem. The same 

request was also submitted to the NDA on the same date (see NDA 212690 eCTD 

Sequence Number 0009). In this document, the sponsor makes a case that Xywav 

provides greater safety because it provides a greatly reduced chronic sodium burden 

compared to Xyrem. To support their position, the sponsor has provided various 

references regarding a link between excess sodium intake and poor cardiovascular 

outcomes, as well as references to public health initiatives to decrease sodium 

intake. In addition, the sponsor notes that patients with narcolepsy often experience 

comorbidities such as metabolic disorders and obesity, hypertension, coronary heart 

failure, and myocardial infarction, which puts them at higher cardiovascular risk than 

the general population.

Furthermore, the sponsor notes that Xyrem’s labeling has included warnings about 

Xyrem’s high salt content and associated instructions for prescribers and patients since 

its initial approval. According to the sponsor, the recommended effective nightly dose 

of Xywav contains between 87 to 131 mg of sodium compared to 1,100 to 1,638 mg of 

sodium contained in a nightly dose of Xyrem. This equates to a sodium reduction of 

1,013 to 1,507 mg per day relative to a patient started or maintained on oxybate 

therapy with Xyrem. To support that this reduction is clinically meaningful, the sponsor 

references several published meta-analyses of randomized controlled trials that 

reported lower systolic and diastolic blood pressure in patients with mean or median 

reductions in exposure to sodium that were similar to the reduction in sodium exposure 

associated with the use of Xywav instead of Xyrem. Other publications are referenced 

to support that a sodium reduction in this range is associated with a reduced risk of 

cardiovascular disease and hypertension. 
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The approved labeling for Xywav and Xyrem suggests to the OOPD that the reduction in 

sodium content in Xywav is expected to be clinically meaningful. First, we note that the 

approved labeling for both Xyrem and Xywav indicate that fluid retention and 

hypertension have been observed in postmarketing experience with Xyrem. We also 

note that the approved labeling for Xyrem contains a Warning and Precaution regarding 

its use in patients with conditions such as heart failure, hypertension, or renal 

impairment due to the drug’s high salt content. The approved labeling for Xywav does 

not contain a similar warning. In addition, we note that the orphan drug regulations use 

the specific example of the elimination of an ingredient that is associated with adverse 

effects as a way to adequately support clinical superiority by means of safety (see 

definitions below). Overall, the OOPD thinks the sponsor’s argument for clinical 

superiority for Xywav may have merit. 

2.2 Consult Questions 

Question 1 

Is there any evidence to suggest that the efficacy of Xywav may be substantially 

different from Xyrem? If so, please elaborate.

 

Question 2 

Does the review division agree that Xywav provides greater safety in a substantial 

portion of the target population when compared to Xyrem? Please explain. (As a 

reminder, the orphan drug regulations do not require head-to-head studies for clinical 

superiority based on safety.) 

 

Question 3 

Is the review division aware of any other possible advantages or disadvantages of Xywav 

compared to Xyrem? If so, please elaborate. 

2.3 Designation Statutes and Regulations: 

21 CFR 316.3(b)(3) defines clinical superiority as follows: 

3. Clinically superior means that a drug is shown to provide a significant therapeutic 

advantage over and above that provided by an approved drug (that is otherwise the 

same drug) in one or more of the following ways:

(i) Greater effectiveness than an approved drug (as assessed by effect on a 

clinically meaningful endpoint in adequate and well controlled clinical trials). 

Generally, this would represent the same kind of evidence needed to support 

a comparative effectiveness claim for two different drugs; in most cases, 

direct comparative clinical trials would be necessary; or 
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(ii) Greater safety in a substantial portion of the target populations, for example, 

by the elimination of an ingredient or contaminant that is associated with 

relatively frequent adverse effects. In some cases, direct comparative clinical 

trials will be necessary; or 

(iii) In unusual cases, where neither greater safety nor greater effectiveness has 

been shown, a demonstration that the drug otherwise makes a major 

contribution to patient care. 

4. Summary Of Sponsor Request For Orphan Drug Exclusivity

As stated in the previous section, the sponsor (i.e., Jazz Pharmaceuticals, Inc.) 

submitted a package containing a request for orphan drug exclusivity for 

XywavTM, also referred to as “JZP-258,” to the Office of Orphan Products 

Development on April 24, 2020. A copy of that request package was submitted to 

NDA 212690 on the same day (the initial submission under that NDA was under 

review by the Agency at that time).

The following is a summary list of the key arguments and assertions by the 

sponsor in that request. Please see the full text of that request for more details.

An excess sodium intake in human subjects is associated with an increase

in blood pressure which, in turn, is a predictor of cardiovascular disease in 

the general population.

The National Academies of Science, Engineering, and Medicine have 

concluded in an assessment entitled “Dietary Reference Intakes for 

Sodium and Potassium at 65,” (2019) that “there is moderate to high 

strength of evidence for both a causal relationship and intake-response 

relationship between sodium and several interrelated chronic disease 

indicators: cardiovascular disease, hypertension, systolic blood pressure, 

and diastolic blood pressure.”

Many professional organizations have recommended a reduction of 

sodium intake as a public health goal. Health authorities, including this 

Agency, have made efforts to reduce the sodium content of consumer 

products including pharmaceutical products in an effort to reduce the daily 

intake of sodium. The upper limit for daily sodium consumption has been 

set at 2300 mg, with an optimal consumption limit of 1500 mg/day

(however, a typical American diet already has a sodium content exceeding 

those limits).

Narcolepsy may be associated with a higher risk of hypertension and 

other cardiovascular conditions.
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Xyrem® has a high salt content, as depicted in a table included in the 

Prescribing Information for that product (this table is also in the next 

section of this review). 

The recommended total nightly doses of both Xyrem® and XywavTM range 

from 6 grams to 9 grams: that range encompasses a range of 1100 to 

1638 mg of sodium for Xyrem® versus 87 to 131 mg of sodium for 

XywavTM. Thus for patients taking a total Xyrem® dose or 6 to 9 grams 

nightly, a change to XywavTM would result in a reduction in nightly sodium 

intake ranging from 1013 mg (for the 6 g dose) to 1507 mg (for the 9 g 

dose).

Meta-analyses of randomized, controlled trials investigating the effects of 

dietary sodium restriction on blood pressure and cardiovascular morbidity,

and publications interpreting the results of those trials indicate that a

change in daily sodium intake similar to that which will occur if XywavTM

(JZP-258) is substituted for Xyrem® at the 6-9 gram nightly dose is likely to

be associated with a reduction in cardiovascular morbidity.

Given the differences in sodium content between XywavTM and Xyrem®,

XywavTM is safer and thus clinically superior to Xyrem® in the following: all 

patients with narcolepsy; the substantial proportion of the narcolepsy 

population that is salt-sensitive (i.e., individuals who have greater changes 

in blood pressure with changes in salt intake than those who are not salt 

sensitive, representing about 50% of the general population); the 

substantial proportion of the narcolepsy population that is hypertensive 

(about 30% of the general population is hypertensive); and the substantial 

proportion of the narcolepsy population (39%) who cannot be prescribed 

Xyrem® due to co-existing medical conditions that can be made worse as 

a result of the high sodium content of Xyrem®.

 

 

 
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5. Efficacy And Safety Of XywavTM Compared With Xyrem® As 

Described In Prescribing Information

There are no head-to-head comparisons of the efficacy and safety of XywavTM

with that of Xyrem® described in the Prescribing Information for the products.

To supplement what is stated in this consultative review, I have provided links to 

the current approved Prescribing Information for both products.

The current Prescribing Information for XywavTM is available at:

https://www.accessdata.fda.gov/drugsatfda docs/label/2020/212690s000lbl.pdf

The current Prescribing Information for Xyrem® is available at:

https://www.accessdata.fda.gov/drugsatfda docs/label/2020/021196s032lbl.pdf

The comparative efficacy and safety of the two products to the extent that is 

apparent from the Prescribing Information for each will be summarized next.

5.1 Comparative Efficacy Of XywavTM and Xyrem®

No prospectively-designed head-to-head comparisons of the efficacy of Xyrem®

and XywavTM have been performed.

Retrospective comparisons of the efficacy of the two products using data from 

the pre-approval clinical trials described in the product label are confounded by 

many factors. Nonetheless the efficacy of the two products, XywavTM and

Xyrem®, in treating cataplexy and excessive daytime sleepiness in narcolepsy 

appears to be broadly similar.

5.2 Comparative Safety Of XywavTM and Xyrem®

As already stated, no head-to-head comparisons of the safety and tolerability of 

XywavTM and Xyrem® have been conducted. Neither have the effects on 

cardiovascular morbidity of a change in regimen from Xyrem® to XywavTM (for the 

treatment of cataplexy or excessive daytime sleepiness in patients with 

narcolepsy, 7 years and older), been investigated in a prospectively-designed 

clinical trial.

However, the observed safety profiles of the two products as described in the 

Prescribing Information and in prior clinical reviews, for each, do not have 

substantial differences. 


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hypertension, may constitute a significant proportion of those with cataplexy and

excessive daytime sleepiness in narcolepsy. The difference in sodium content 

between XywavTM and Xyrem® is also very likely to be clinically meaningful in all 

patients with narcolepsy, including those who are salt sensitive. 

Adequate support for this view is provided in the request for orphan exclusivity 

submitted by the sponsor on April 24, 2020, which discusses the above in much 

greater detail. 

7. Consult Questions From Office Of Orphan Products 

Development And Division Of Neurology 1 Responses

7.1 Question 1

Is there any evidence to suggest that the efficacy of Xywav may be substantially 

different from Xyrem? If so, please elaborate.

Division of Neurology 1 Response:

There is no evidence available to suggest that the efficacy of XywavTM may be 

substantially different from that of Xyrem®.

7.2 Question 2

Does the review division agree that Xywav provides greater safety in a substantial 

portion of the target population when compared to Xyrem? Please explain. (As a 

reminder, the orphan drug regulations do not require head-to-head studies for clinical 

superiority based on safety.)

Division of Neurology 1 Response:

We agree that XywavTM provides greater safety than Xyrem® in a substantial 

proportion of patients for whom both XywavTM and Xyrem® are indicated. The 

sodium content of XywavTM at the recommended doses of 6 to 9 grams nightly is 

much less than the sodium content of Xyrem® at the same doses. Although the 

safety of Xyrem® and XywavTM have not been compared head-to-head in clinical 

trials, the available evidence from other sources, including the data that has been 

submitted by the sponsor, indicates that 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. This view is explained further above in this review. 

7.3 Question 3

Is the review division aware of any other possible advantages or disadvantages of Xywav 

compared to Xyrem? If so, please elaborate.

Division of Neurology 1 Response:

MEMORANDUM 

DEPARTMENT OF HEALTH AND HUMAN SERVICES 

PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION

Division of Neurology 1

Office of Neuroscience 

Center for Drug Evaluation and Research

Date: March 8, 2021

From: Eric Bastings, MD

Division Director

Subject: Orphan Products Consult Request #2020-00029-EC

NDA 212690

XywavTM

Request for Orphan Drug Exclusivity 

To: Director

Office of Orphan Products Development

 

Document Type: Consult 

Enclosed is the Division’s response to your request
Ranjit B. Mani, MD, HFD-120 Medical Review Page 2 of 12

NDA 212690, Xywav (JZP-258), Jazz Pharmaceuticals, Inc. 3/8/21

Review and Evaluation of Clinical Data

NDA (Serial Number) 212690

Sponsor: Jazz Pharmaceuticals, Inc.

Product: Xywav (JZP-258)

Proposed Indication: Narcolepsy

Material Submitted: Consultation Request

Consultation Request Date: 1/8/21

Date Received By Reviewer: 1/11/21

Date Review Completed: 3/8/21

Reviewer: Ranjit B. Mani, M.D.

1. Background

This consultation request has been received from the Office of Orphan Products 

Development, and is related to a letter to that office requesting that the Agency 

refrain from granting orphan drug exclusivity for XywavTM.

Currently, XywavTM (a low-sodium oxybate oral solution formulation containing a 

mixture of calcium, magnesium, potassium, and sodium oxybates) is approved 

for the treatment of cataplexy or excessive daytime sleepiness, in patients 7 

years or older with narcolepsy. Another product approved for the same indication 

is Xyrem® (sodium oxybate oral solution). Xyrem® was initially approved, under 

NDA 21196, on July 17, 2002, whereas XywavTM was initially approved, under 

NDA 212690, on July 21, 2020. One or more generic formulations of sodium 

oxybate oral solution have also been approved for the treatment of narcolepsy. 

All the aforementioned oxybate formulations are administered twice nightly, with 

the two nightly doses separated by an interval of 2.5 to 4 hours.

The active moiety in both XywavTM and Xyrem® is oxybate (gammahydroxybutyric acid). The sponsor of both products is the same: Jazz 

Pharmaceuticals, Inc.

Orphan drug designation was originally granted to sodium oxybate by the Office 

of Orphan Products Development on November 7, 1994.

An earlier consultation was completed by this Division (in response to a request 

from the Office of Orphan Products Development), that was related to the current 

request for orphan drug exclusivity for XywavTM. That consultation request was 

made on October 26, 2020, and was completed on November 27, 2020. Please 

see the text of that consultation request for further details.

(b) (4)
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2. Text Of Consultation Request

The full text of the consultation request is copied verbatim below.

(b) (4)

(b) (4)
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(b) (4)
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Regulations: 

21 CFR 316.3(b)(3) defines clinical superiority as follows: 

(3) Clinically superior means that a drug is shown to provide a significant therapeutic advantage 

over and above that provided by an approved drug (that is otherwise the same drug) in one or 

more of the following ways: 

(i) Greater effectiveness than an approved drug (as assessed by effect on a clinically meaningful 

endpoint in adequate and well controlled clinical trials). Generally, this would represent the same 

kind of evidence needed to support a comparative effectiveness claim for two different drugs; in 

most cases, direct comparative clinical trials would be necessary; or 

(ii) Greater safety in a substantial portion of the target populations, for example, by the 

elimination of an ingredient or contaminant that is associated with relatively frequent adverse 

effects. In some cases, direct comparative clinical trials will be necessary; or 

(iii) In unusual cases, where neither greater safety nor greater effectiveness has been shown, a 

demonstration that the drug otherwise makes a major contribution to patient care. 

3. Reviewer’s Background Comments

In this section, this reviewer has summarized several subjects that are pertinent 

to this consultation request.

The current approved Prescribing Information for Xyrem® and XywavTM have 

been referenced in this section. I have therefore provided links to the current 

approved Prescribing Information for both products.

The current approved Prescribing Information for Xyrem® is available at the 

following link.

https://www.accessdata.fda.gov/drugsatfda docs/label/2020/021196s032lbl.p

df

The current approved Prescribing Information for XywavTM is available at the 

next link.

https://www.accessdata.fda.gov/drugsatfda docs/label/2021/021196s035,212

690s001s002lbl.pdf

(b) (4)

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3.1.2 XywavTM

3.1.2.1 Dosage Forms And Strengths

The following text has been extracted from Section 3 (DOSAGE FORMS AND 

STRENGTHS) of the Prescribing Information.

Please also see Section 11 (DESCRIPTION) of the Prescribing Information for 

XywavTM for additional information regarding the composition of this product.

3.1.2.2 Dosage And Administration

As stated in Section 2 of the current Prescribing Information for XywavTM, the 

recommended dose range for XywavTM is 6 to 9 grams per night in 2 divided 

doses.

Based on data previously made available to this reviewer, XywavTM doses of 6 to 

9 grams per night would have a sodium content that ranges from 87 to 131 mg.

Thus for patients already taking a total Xyrem® dose of 6 grams or 9 grams 

nightly, a change to XywavTM at the same total nightly dose, 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). 

3.1.2.3 Warnings and Precautions

Unlike the corresponding section of Prescribing Information for Xyrem®, this

section of the XywavTM label contains no text pertaining to its use in patients who 

are sensitive to a high sodium intake, which is unsurprising given the sodium 

content of XywavTM.

3.2 Xyrem® And Adverse Cardiovascular Outcomes

There are no studies that have been prospectively designed to specifically 

investigate whether the administration of Xyrem® at doses recommended in the 

Prescribing Information 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 (e.g., hypertension or

obesity) that may predispose to such outcomes. Moreover, the controlled clinical 

trials of Xyrem® that are described in the Prescribing Information for that drug 

have been of too short a duration and have exposed too few patients to Xyrem®

to enable such outcomes to be investigated.
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3.3 Salt Intake And Cardiovascular Disease

Please refer to the publication by the US Department of Agriculture entitled 

“Dietary Guidelines for Americans 2020-2025” published in December 2020,

which is available at the following link.

https://www.dietaryguidelines.gov/sites/default/files/2020-

12/Dietary Guidelines for Americans 2020-2025.pdf

The following is stated on Page 46 (of 159) of the above guidelines.

“Sodium is an essential nutrient primarily consumed as salt (sodium chloride). 

Healthy eating patterns limit sodium to the Chronic Disease Risk Reduction 

(CDRR) levels defined by the National Academies—1,200 mg/day for ages 1 

through 3; 1,500 mg/day for ages 4 through 8; 1,800 mg/day for ages 9 through 

13; and 2,300 mg/day for all other age groups. The CDRR for sodium was 

established using evidence of the benefit of reducing sodium intake on 

cardiovascular risk and hypertension risk.”

The publication by the National Academies cited above is summarized in a news 

release dated March 5, 2019, which is available at the link below.

https://www.nationalacademies.org/news/2019/03/sodium-and-potassiumdietary-reference-intake-values-updated-in-new-report

A link to the same publication in full is available in the body of that news release.

The following text is extracted from the above news release.

“There is sufficient evidence to characterize the relationship between sodium 

intake and risk of chronic disease. Therefore, the committee established a 

chronic Disease Risk Reduction Intake (CDRR) for sodium using evidence of the 

beneficial effect of reducing sodium intake on cardiovascular disease risk, 

hypertension risk, systolic blood pressure, and diastolic blood pressure. 

Reductions in intakes that exceed the sodium CDRR are expected to reduce 

chronic disease risk within the apparently healthy population. For individuals 

ages 14 and older, the CDRR recommendation is to reduce sodium intakes if 

above 2,300 mg per day.”

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

official publication that daily salt intake in individuals 14 years and older be 

restricted to 2300 mg or less. The National Academies have also stated that 

there is evidence that a reduction is 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.
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3.4 Co-Morbidities Associated With Narcolepsy

A higher prevalence of hypertension, obesity, hyperlipidemia, and glucose 

intolerance has been reported in association with narcolepsy, in addition to other 

medical and psychiatric disorders. An example of a publication describing such 

co-morbidities is available at the link below.

https://www.sciencedirect.com/science/article/abs/pii/S1389945717315587

4. Consult Questions From Office Of Orphan Products 

Development And Division Of Neurology 1 Responses

 

(b) (4)

(b) (4)
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(b) (4)

(b) (4)


1

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.
Jazz Pharmaceuticals Ireland Limited

2

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
Nicole Wolanski

Digitally signed by Nicole Wolanski

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

GUID: 13313
Page | 1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

 Food and Drug Administration

 Office of Orphan Products Development

Exclusivity Memorandum

Date: 6/23/21

From: Theodore Garnett, PhD, Health Science Administrator

Roberta Szydlo, RPh, MBA, Senior Program Management Officer

Through:

Henry Startzman III, MD, Director, Orphan Drug Designation Program

Aaron Friedman, JD, Senior Regulatory Counsel

Nicole Wolanski, Acting Director, Office of Orphan Products Development

To File #: DRU-1994-858

Name of drug or 

biologic: Xywav (calcium, magnesium, potassium, and sodium oxybates)

Orphan 

designation: Treatment of narcolepsy

Designation date: 11/7/1994

Sponsor name: Jazz Pharmaceuticals

NDA, sNDA, 

BLA, or sBLA #: NDA 212690 

Approval date: 7/21/2020

Henry H. 

Startzman -S

Digitally signed by 

Henry H Startzman S 

Date: 2021 09 30 

12:31:49 04'00'

Aaron R. 

Friedman -S

Digita ly signed by Aaron R 

Friedman S 

Da e 2021 09 30 17 07 19 

04 00'

Roberta T. 

Szydlo -S3

Digitally signed by 

Roberta T Szyd o 

S3 

Date: 2021 09 30 

17:12:31 04'00'
Page | 2 

Approved 

indication: 

XYWAV is indicated for the treatment of cataplexy or excessive daytime sleepiness 

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

Is the approval 

within scope of 

designation? 

Yes ց No տ

Comments: 

The approval of XYWAV (calcium, magnesium, potassium, and sodium oxybates) for 

the indication above is within the scope of orphan drug designation #1994-858 for the 

treatment of narcolepsy. 

Has the same 

drug or biologic 

been previously 

approved? 

Yes ց No տ 

Is the 

drug or 

biologic a 

New 

Molecular 

Entity 

(NME) or 

New 

Biological 

Entity 

(NBE)? 

Yes տ No ց

Comments: 

According to the Clinical Review for Xywav dated July 21, 2020, the sponsor 

developed Xywav to be a low-sodium alternative to their other drug, Xyrem (sodium 

oxybate), which was originally approved by the Agency on July 17, 2002 under NDA 

21196 (see page 7). Xywav and Xyrem both contain the same active moiety which is 

oxybate (also known as gamma hydroxybutyrate) (see page 6 and 7 of the Clinical 

Review). Therefore, Xywav is not a new molecular entity. 

Has the same 

drug or biologic 

already been 

approved for the 

same indication? 

Yes ց No տ 

Comments: 

As noted above, Xyrem and Xywav contain the same active moiety. Xyrem was 

originally approved on July 17, 2002, for the treatment of cataplexy in narcolepsy. 

Subsequent efficacy supplements approved on November 18, 2005, and October 26, 

2018, respectively, expanded the approved use of Xyrem to include the treatment of 

cataplexy or excessive daytime sleepiness (EDS) in patients 7 years of age and older 

with narcolepsy (see page 7 of the Clinical Review). Therefore, the indications for 

Xyrem and Xywav are currently identical which means that the same drug has been 

previously approved for the same indication. 

Has clinical 

superiority been 

demonstrated?

Yes ց No տ Not Applicable տ 

Comments: 

Since the same drug has been previously approved for the same indication, Xywav must 

be clinically superior to Xyrem in order to be eligible for orphan drug exclusivity. Sec. 

527(c)(1) of the FD&C Act; 21 CFR 316.34(c). Clinical superiority means that a drug is 

shown to provide a significant therapeutic advantage over and above that provided by 

an approved drug (that is otherwise the same drug) through greater effectiveness, 

greater safety in a substantial portion of the target population, or in unusual cases, by 

making a major contribution to patient care. Sec. 527 (c)(2) of the FD&C Act; 21 CFR 
Page | 3 

316.3(b)(3). 

The sponsor for Xywav submitted a request to the OOPD on April 24, 2020 for orphan 

drug exclusivity for Xywav based on clinical superiority with regard to safety over 

Xyrem. The same request was also submitted to the NDA on the same date (NDA 

212690 eCTD Sequence Number 0009). In this document, the sponsor asserted that 

Xywav provides greater safety because it provides a greatly reduced chronic sodium 

burden compared to Xyrem. Specifically, a daily dose of Xyrem adds 1,100 to 1,638 

mg of sodium to each patient’s daily sodium intake. A daily dose of Xywav contains 87 

to 131 mg of sodium, thus reducing the sodium burden by 1.5 grams (92%) at the 

highest dose. The sponsor argues that reducing the sodium burden is important because 

excess sodium intake is associated with poor cadiovascular outcomes. The amount of 

sodium reduction from Xyrem to Xywav is associated with clinically meaningful 

reductions in blood pressure and cardiovasular disease. In addition, the sponsor noted 

that patients with narcolepsy often experience comorbidities such as metabolic 

disorders and obesity, hypertension, coronary heart failure, and myocardial infarction, 

which puts them at higher cardiovascular risk than the general population. 

Furthermore, the sponsor noted that Xyrem’s labeling has included warnings about its 

high salt content and associated instructions for prescribers and patients since its initial 

approval. 

 

The OOPD consulted with the Division of Neurology 1 (DN1) to help determine if 

Xywav is clinically superior to Xyrem. In their consult response dated Nov. 27, 2020, 

DN1 agreed that Xywav is clinically superior because it provides greater safety than 

Xyrem in a substantial proportion of patients for whom both Xywav and Xyrem are 

indicated. DN1 noted that although the safety of Xyrem and Xywav have not been 

compared in a head-to-head manner, "the available evidence from other sources, 

including the data that has been submitted by the sponsor, indicates that 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." Specifically, DN1 stated the following: 

 

"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. The 

difference in sodium content between Xywav and Xyrem® is both substantial and 

clinically meaningful when daily sodium intake requires restriction in patients who 

concomitantly have conditions such as cardiac failure, hypertension, and renal 

impairment. Xywav rather than Xyrem® will be the medication of choice in such 

patients. Such patients, especially those with hypertension, may constitute a significant 

proportion of those with cataplexy and excessive daytime sleepiness in narcolepsy. The 

difference in sodium content between Xywav and Xyrem® is also very likely to be 

clinically meaningful in all patients with narcolepsy, including those who are salt 

sensitive." 

The OOPD concurs with DN1's consult response. The orphan drug regulations, within 

the definition of “clinically superior,” provide that “the elimination of an ingredient or 

contaminant that is associated with relatively frequent adverse effects” is an eample of 

greater safety. 21 CFR 316.3(b)(3)(ii). Although sodium is not eliminated in Xywav, 

the amount is substantially reduced such that it is likely to be clinically meaningful for