Document 2 AR.pdf

Document 2
TGA Pre-Submission Meeting to discuss applications for orphan
designation and registration for Xyrem in the treatment of
narcolepsy.
Briefing Document

UCB
February 2018

1

  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package

  UCB Pharma (Australia) Pty Ltd (UCB) is the Australian Sponsor for sodium oxybate (Xyrem)
which is currently being supplied under Category B of the special access scheme (SAS) to
patients with narcolepsy. Although Xyrem is not a core product, since 2015 there has been an
ongoing demand from specialist sleep physicians, patients and carers for this medicine.
  UCB wish to discuss with TGA at a pre-submission meeting the best means to register the
product based on the available EU dossier and orphan designation.

1. Summary
Background information on the disease to be treated
Narcolepsy is a chronic neurological disorder of unknown aetiology that affects the normal
sleep/waking rhythm. The First International Symposium on Narcolepsy (July 1975, France)
(Guilleminault et al. 1976) produced the first consensus definition of narcolepsy: “A syndrome
of unknown origin that is characterized by abnormal sleep tendencies, including excessive
daytime sleepiness (EDS) and often disturbed nocturnal sleep, and pathological manifestations of
Rapid Eye Movement (REM) sleep. The REM sleep abnormalities include sleep-onset REM
(SOREM) periods and the dissociated REM sleep inhibitory processes, cataplexy and sleep
paralysis. EDS and cataplexy and, less often, sleep paralysis and hypnogogic hallucinations are
the major symptoms of the disease.”
  In this definition, narcolepsy is not simply excessive sleep, but rather an inability to maintain
either wakefulness or consolidated sleep. Patients are typically prone to excessive sleepiness and
unwanted episodes of sleep (inadvertent naps) during the daytime and disturbed sleep at night
(fragmented night-time sleep). Shortly after the discovery of REM sleep (Aserinsky and
Kleitman 1953), it was found that narcoleptic patients often enter REM sleep directly at night,
suggesting that narcolepsy might involve abnormal REM sleep (Vogel 1960). In the same year,
Rechtschaffen et al (1963) and Takahashi and Jimbo (1963) independently confirmed that the
night sleep of narcoleptic patients often began with REM sleep and suggested that cataplexy,
sleep paralysis and hypnogogic hallucinations were abnormal manifestations of dissociated REM
sleep. This led to the generally accepted model that sleep disturbances seen in narcolepsy are
divided into two distinct categories of disturbance: the sleep/wake distribution (EDS/inadvertent
naps and fragmented night-time sleep) and abnormal REM sleep-related symptoms (cataplexy,
hypnogogic hallucinations and sleep paralysis).
  According to the American Academy of Sleep Medicine, second edition of the International
Classification of Sleep Disorders (ICSD-2, 2005) there are two forms of narcolepsy, narcolepsy
with cataplexy and narcolepsy without cataplexy. According to these definitions:
•  The patient has a complaint of EDS occurring almost daily for at least 3 months.
•  The diagnosis should be confirmed by nocturnal polysomnography (PSG) followed by a
multiple sleep latency test (MSLT); the mean sleep latency on the MSLT is less than or
equal to 8 minutes and two or more SOREM periods are observed following sufficient
nocturnal sleep (minimum 6 hours) during the night prior to the test, for both narcolepsy
with and without cataplexy; alternatively, for patients with narcolepsy with cataplexy,

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  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
hypocretin-1 levels in the cerebrospinal fluid (CSF) are less than or equal to 110 pg/ml,
or one third of mean normal control values.
•  The hypersomnia is not better explained by another sleep disorder, medical or
neurological disorder, mental disorder, medication use, or substance use disorder.
•  Patients with narcolepsy with cataplexy should additionally have a definite history of
cataplexy, defined as sudden and transient episodes of loss of muscle tone triggered by
emotions.
•  For a diagnosis of narcolepsy without cataplexy, typical cataplexy must not be present,
although doubtful or atypical cataplexy-like episodes may be reported.
  Research provides compelling evidence that most cases of narcolepsy with cataplexy are
associated with the loss of hypothalamic neurons containing the neuropeptide hypocretin.
Hypocretin is a neurotransmitter that appears to have important roles in sleep-wake regulation,
neuroendocrine stasis, autonomic regulation and control of feeding behaviour (De Lecea et al.
1998, Sakurai et al. 1998). The cell bodies of hypocretin containing neurones are located in the
postero-lateral hypothalamus and have widespread projections within the CNS (Peyron et al.
1998). Two active peptides - hypocretin-1 and hypocretin-2 - have been identified. With regard
to sleep, the dominant activities of the hypocretin system appear to be maintenance of the waking
state and suppression of entry into REM sleep (Sutcliffe and De Lecea 2002). Animal models
show alterations of hypocretin neurotransmission in narcolepsy (Lin et al. 1998; Chemelli et al.
1998), while analysis of CSF from humans with narcolepsy with cataplexy has demonstrated the
concentration of hypocretin-1 to be very low (Nishino et al. 2000). Post-mortem examinations of
brains from narcoleptic patients have shown a dramatic decrease in hypocretin-containing cells
(85-95%) and greatly diminished hypocretin messenger ribonucleic acid (mRNA) (Peyron et al.
2000; Thannickal et al. 2000). Genetic factors are also involved (first-degree relatives of
narcolepsy patients have a higher risk of developing narcolepsy) and the higher incidence of the
human leukocyte antigen (HLA) DQB1 *0602 subtype in narcoleptic individuals compared with
the general population suggests a possible autoimmune effect. On the basis of the HLA
association, loss of hypocretin neurons and age of disease onset, it has been hypothesized that
narcolepsy results from an autoimmune effect in genetically susceptible individuals. However,
no autoimmune triggers or antibodies have yet been identified (Mignot et al 1995).
  In a minority of cases of narcolepsy without cataplexy, the disease is associated with the loss of
hypothalamic neurons containing the neuropeptide hypocretin, as described for narcolepsy with
cataplexy. In most other cases the hypocretin-1 level in the CSF is normal, suggesting another
cause for the disorder.
  Symptomatology
Narcolepsy with cataplexy may be referred to as narcolepsy type 1 and narcolepsy without
cataplexy is referred to as narcolepsy type 2. However described, narcolepsy with or without
cataplexy (hereafter ‘narcolepsy’) remains a clinically diagnosed disease with a constellation of
symptoms:
  Excessive Daytime Sleepiness (EDS)
EDS is the most common and disabling symptom of narcolepsy and is present in all patients with
the disease. Sleepiness in narcolepsy is usually more severe than in other sleep disorders.

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  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
Sleepiness often becomes irresistible, resulting in inadvertent naps, even during activities such as
talking, eating, standing, walking and driving in traffic, thus putting a heavy social burden on
these patients (Dement et al. 1966, Dement 1976).
  Cataplexy
Cataplexy is pathognomonic of the disease. It presents as a sudden but progressive, short lived,
bilateral loss of muscle tone elicited by emotions such as laughter, elation, anger and surprise
(Guilleminault 1976). It is usually associated with normal consciousness and awareness;
respiratory and extra ocular muscles remain unaffected. Cataplexy probably represents the
muscle atonia which normally occurs during REM sleep
  Fragmented night-time sleep
In narcolepsy, a damaged sleep structure with abnormal, disrupted sleep patterns is manifested.
Patients experience abnormal intrusions of SOREM periods and sometimes a greatly increased
proportion of transitional Stage 1 sleep, while Stages 3 and 4 sleep may be significantly
diminished. In addition, they suffer from frequent awakenings and frequent shifts between
different sleep stages (Montplaisir et al. 1978). Typically, narcoleptic patients fall asleep almost
instantly when they go to bed but their sleep is interrupted by frequent awakenings. Many
patients report dreaming as soon as they fall asleep. Disturbed nocturnal sleep is present in
approximately 50% of patients and can be very disabling. The recurrent night-time awakenings
are associated with a feeling of restlessness during the night.
  Ancillary symptoms
Sleep paralysis is an inability to move that occurs at sleep onset or upon awakening. Hypnogogic
and hypnopompic hallucinations are dream-like visual or auditory perceptions that occur at sleep
onset and upon awakening respectively. Automatic behaviours may occur without full awareness
or memory, because of sleepiness or micro sleep. It is merely an indication of the severity of
daytime sleepiness (Guilleminault et al. 1975)
  Narcolepsy affects the social, mental and physical health of patients and has a significant
negative impact on their physical and emotional wellbeing. It can be physically and socially
disabling for patients.
  Current Treatment of Narcolepsy
The current treatment of narcolepsy is aimed at alleviating the individual components of the
symptom pentad of the narcoleptic disease: excessive daytime sleepiness, fragmented night-time
sleep, cataplexy, sleep paralysis and hypnogogic hallucinations. There is however, no single
treatment that has demonstrated ability to bridge all of the contributors to the condition and
improve all the narcolepsy related symptoms, with the exception of sodium oxybate.
  Pharmacotherapy for EDS has consisted primarily of the daytime administration of
sympathomimetic stimulants, such as methylphenidate, and d-amphetamine to increase alertness
and improve daytime performance. Unfortunately, tolerance to these agents develops in as many
as 30% of patients, sometimes necessitating periodic “drug holidays.” Adverse events commonly
include headaches, nervousness, irritability, tremor, insomnia, anorexia, gastrointestinal
disturbances and palpitations. At high doses, the use of stimulants may be associated with

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  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
hypertension, myocardial ischemia and psychosis (Guilleminault 1993). The only recent
advancement for the treatment of EDS in narcolepsy patients is modafinil (and its R- racemate
armodafinil), chemically and pharmacologically unrelated to other stimulants, it has an improved
adverse event profile and decreased abuse potential; however, its use rarely results in normal
measures of EDS (U.S. Modafinil in Narcolepsy Multicenter Study Group 1998). Importantly,
for modafinil, there are only data to support the use for narcoleptic patients demonstrating EDS;
there are no effects on patients with cataplexy or for those experiencing problems with sleep
continuity and architecture. The stimulants registered in Australia are summarised in Table 1.
  Prior to the approval of sodium oxybate, the available treatment for the REM-related symptoms
of narcolepsy were insufficiently tested (class III and class IV evidence studies only) and
unapproved despite their widespread use. Pharmacotherapy consisted primarily of tricyclic
antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). These medications
suppress REM sleep and this property extends, to a limited extent, to the REM related symptoms
of narcolepsy. They provided little, if any, benefit for disrupted night-time sleep. With respect to
TCAs, adverse events are often related to their anticholinergic activity, resulting in dry mouth,
tachycardia, blurred vision, constipation and urinary retention as well as non-anticholinergic
effects, such as sexual dysfunction. Although the newer SSRIs demonstrate an improved adverse
event profile, they are less efficacious than the TCAs. The abrupt discontinuation of agents in
both drug classes may result in rebound cataplexy, representing a serious safety concern.
  The availability of sodium oxybate represents a significant improvement over the REM-
suppressing TCAs and SSRIs, providing significant reductions in cataplexy as well as trends
suggesting important improvements in hypnogogic hallucinations and sleep paralysis. In
addition, it provides significant improvements in EDS and fragmented night-time sleep, as well
as other narcolepsy symptoms, without the development of tolerance.
  Traditional pharmacotherapy for narcolepsy has not provided substantial benefit for disrupted
nocturnal sleep (Rogers et al 1994).
  In Australia no TCA or SSRI is approved for narcolepsy or any of the individual component
symptoms of narcolepsy.

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Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
  Table 1: The registered indications for stimulants
  Class
Drug
Registered Indication
Effectiveness
Sympathomimetic
Methylphenidate
[Tradename] are also indicated for the treatment of
Treatment of EDS - in
stimulants
AUST  R
narcolepsy. The symptoms include daytime sleepiness,
narcolepsy type 2
inappropriate sleep episodes and rapidly occurring loss of
voluntary muscle tone.
No benefit in cataplexy –
[Tradename] is effective for symptoms of sleepiness but not  stipulated in the indication.
for loss of voluntary muscle tone.
Dexamfetamine
Narcolepsy and hyperkinetic behaviour disorders in
Narcolepsy type 2
AUST  R
children
Pemoline
Not registered in Australia

Other
Modafinil
To improve wakefulness in patients with excessive daytime  Treatment of EDS – in
psychostimulants
AUST  R
sleepiness associated with narcolepsy;
narcolepsy type 2
To treat excessive sleepiness associated with moderate to

severe chronic shift work sleep disorder where
No benefit in cataplexy,
nonpharmacological interventions are unsuccessful or
fragmented night-time sleep
inappropriate;
As an adjunct to continuous positive airways pressure
(CPAP) in obstructive sleep apnoea/hypopnoea syndrome
in order to improve wakefulness.
Armodafinil
To improve wakefulness in patients with excessive daytime  Treatment of EDS – in
AUST  R
sleepiness associated with narcolepsy;
narcolepsy type 2
To treat excessive sleepiness associated with moderate to

severe chronic shift work sleep disorder where
No benefit in cataplexy,
nonpharmacological interventions are unsuccessful or
fragmented night-time sleep
inappropriate;
As an adjunct to continuous positive airways pressure
(CPAP) in obstructive sleep apnoea/hypopnoea syndrome
in order to improve wakefulness.

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  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
The proposed orphan condition narcolepsy is intended to include patients with and without
cataplexy (both narcolepsy type 1 and type 2), patients with EDS, sleep fragmentation and
ancillary symptoms. Therefore the broadest patient population is proposed and no consideration
of the plausibility of a sub-set of patients is required.

Background information on the product
The rationale for the use of sodium oxybate in the proposed indication is described in terms of
the active ingredient, its pharmacological class and mechanism of action, as well as the scientific
background on its use in narcolepsy.
  Active, pharmacological class, mechanism of action
Sodium oxybate is the non-proprietary name for the sodium salt of gamma-hydroxybutyrate
(GHB). Sodium oxybate is a central nervous system (CNS) depressant, pharmacotherapeutic
group: Other Nervous System Drugs, ATC code: NO7XX.
  Sodium oxybate is a central nervous system depressant which reduces EDS and cataplexy in
patients with narcolepsy and modifies sleep architecture. The precise mechanism by which
sodium oxybate produces an effect on narcolepsy is unknown, however sodium oxybate is
thought to act by promoting slow (delta) wave sleep and consolidating night-time sleep. Sodium
oxybate administered before nocturnal sleep increases Stages 3 and 4 sleep and increases sleep
latency, whilst reducing the frequency of sleep onset REM periods (SOREMs). Other
mechanisms, which have yet to be elucidated, may also be involved.
Scientific Background on the Use of Sodium Oxybate in Patients with Narcolepsy
Sodium oxybate has been investigated for nearly 40 years and has been studied clinically for the
treatment of narcolepsy with cataplexy for approximately 25 years. Experimental work with
GHB in humans began soon after its discovery. Its pronounced CNS depressant actions
combined with relatively rapid onset, and short duration of action with low toxicity led to its use
initially as an intravenous anaesthetic agent in the 1960s in Europe. However, due to its weak
analgesic and poor muscle relaxant properties, and the emergence of agents with much shorter
duration of action, sodium oxybate never achieved widespread usage as a general or adjunctive
anaesthetic outside Europe. It remains on the market today in France, Germany, and Austria as
an anaesthetic agent and sedative, and in Italy as an oral solution for the treatment of alcohol
withdrawal and maintenance of abstinence. GHB was previously marketed in France between
1969 and 1975 by Cernep Synthelabo Laboratory as an over-the-counter (OTC) agent for
insomnia. It was taken off the OTC market primarily because of the side effects: “gastric
intolerance, effects on the nervous system and too sudden sleep induction.”
  Later research examined sodium oxybate as a potential hypnotic for the treatment of insomnia.
Electroencephalogram (EEG) studies documented changes in sleep architecture that occurred
during sodium oxybate-induced sleep in normal individuals (Yamada et al. 1967, Metcalf et al.
1966, Liberson et al. 1969).

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  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
In humans, sodium oxybate consistently increased delta wave sleep without suppression of REM
sleep, and reported increased REM efficiency while decreasing REM latency. A pilot study of
sodium oxybate in five patients with insomnia (one of whom had narcolepsy) concluded sodium
oxybate induced sleep, which was subjectively and indistinguishable from natural sleep based on
EEG recordings (Mamelak et al. 1973). The authors stated that the only clinical limitation of this
treatment was the short duration of action of sodium oxybate (approximately 2 to 3 hours).
  The effects of sodium oxybate on sleep continuity and architecture were eventually applied to a
group of narcolepsy patients. The night-time oral administration of sodium oxybate in three
small uncontrolled trials demonstrated the same EEG patterns accompanied by substantial
improvements in daytime narcolepsy symptoms (Broughton and Mamelak 1979, 1980; Mamelak
and Webster 1981).
  These improvements were shown to continue in patients treated with nightly sodium oxybate
from 30 weeks (Scharf et al. 1985) to 9 years (Mamelak et al. 1986). In these early trials, sodium
oxybate was well-tolerated. The ease of titrating sodium oxybate as a liquid formulation led to
the development of individualized dosing that maximized therapeutic benefit while minimizing
side effects. Furthermore, Mamelak anecdotally noted that divided doses were required for the
treatment of narcolepsy symptoms. Discontinuation of dosing or taking only one dose resulted in
the gradual recurrence of symptoms (Mamelak et al. 1986).
  The apparent beneficial effects of nightly sodium oxybate administration to narcolepsy with
cataplexy patients were subsequently supported by two randomized placebo-controlled studies.
Collectively, these trials demonstrated that the nightly administration of sodium oxybate
significantly increased combined Stages 3 and 4 sleep, and decreased sleep stage shifts and the
number of night-time awakenings (Scrima et al 1990; Lammers et al. 1993). In addition, they
produced varying degrees of improvement in daytime symptoms including a significant decrease
in cataplexy attacks, hypnogogic hallucinations, inadvertent naps and the severity of subjective
daytime sleepiness (Scrima et al. 1989; 1990; Lammers et al 1993). It was proposed (Scrima et
al. 1990) that the therapeutic effect of sodium oxybate in the treatment of narcolepsy may result
from a consolidation of nocturnal sleep, in part because the short half-life of the drug
(approximately 1 hour) is too short to explain the significant effects seen on daytime symptoms.
  In addition to subjective improvements in the severity of narcolepsy symptoms, there were other
benefits as evidenced from studies where polysomography analysis was performed on patients
before and after sodium oxybate treatment (Scharf et al 1985; Montplaisir et al 1986 Bedard et al
1989). These authors demonstrated decreased REM latency and increased REM efficiency from
baseline to endpoint. The Montplaisir and Scharf studies showed that sodium oxybate increased
the percentage of Stages 3 and 4 sleep. In addition, Montplaisir and Godbout (1986) showed a
decrease in REM fragmentation and an increase in the percentage of REM sleep. Taken together,
these studies indicate that sodium oxybate consolidates sleep architecture. The effective dose
range in these trials was approximately 3 g to 9 g.
  Clinical development
Sodium oxybate has been fully developed as a prescription/controlled medicine.

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  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
In addition to studies of pharmacokinetics (bioavailability, interaction studies, CYP450 effects),
dose-proportionality and a taste test a full clinical program has been developed in narcoleptic
patients.
  Six randomized, double-blind placebo controlled trials have been carried out to support the
effectiveness of sodium oxybate in the treatment of narcolepsy: OMC-SXB-22, OMC-SXB-15,
OMC-GHB-2, OMC-SXB-21, Scrima, and Lammers. Additionally, five uncontrolled studies
have been conducted: OMC-GHB-3, OMC-SXB-6, OMC-SXB-7, OMC-SXB-20 and OMC-
SXB-19.
  Of these trials, 4 controlled (OMC-GHB-2, OMC-SXB-21, Scrima, and Lammers) and 3 open
non-comparative label trials (OMC-GHB-3, OMC-SXB-6, OMC-SXB-20) form the studies
which support of the treatment of cataplexy in narcolepsy patients while 2 additional controlled
trials (OMC-SXB-15, OMC-SXB-22) particularly support the treatment of EDS.
  Sleep continuity and architecture variables were recorded and analyzed in all these trials and
results are detailed to support beneficial effect of sodium oxybate on fragmented night-time
sleep, another important symptom in narcolepsy.
  Results from these trials demonstrate that sodium oxybate, at dosages between 3.0 g and 9.0 g
per day is effective in improving subjectively (Epworth Sleepiness Scale (ESS) and objectively
(Maintenance of Wakefulness Test (MWT)) measured EDS, the number of inadvertent naps
during the day, reducing the frequency of cataplexy attacks, the subjectively and objectively PSG
measured number of nocturnal awakenings, the patients quality of life (Functional Outcomes of
Sleep Questionnaire (FOSQ), SF-36, Pittsburgh Sleep Quality Index (PSQI) as well as the
investigator's overall impression of change in severity of disease (Clinical Global Impression of
change (CGI-c).
  A tabular summary of the trials is provided in Appendix 1.

Regulatory status
Sodium oxybate has not been registered, nor has orphan designation previously been applied for
in Australia.
  Orphan drug designation was sought and approved for the treatment of narcolepsy in both the
EU (February 2003) and in the USA (November 1994).
  Following orphan designation in the EU, UCB decided to submit a marketing authorisation
application for a sub-population – “Treatment of cataplexy in patients with narcolepsy” as the
initial submission in March 2004. A major (Type II) variation to extend the indication to
“Treatment of narcolepsy with cataplexy in adult patients” was submitted and approved in 2007.
  Currently sodium oxybate is registered throughout Europe (including Switzerland), the USA,
Canada and Turkey.

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  Xyrem (sodium oxybate)
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Pre-Submission Briefing Package

Rationale for seeking a pre-submission meeting
The seriously debilitating nature of the condition is based on the serious impact that the disease
can have on a patient’s life. The deleterious impact of narcolepsy on quality of life is well
established (Goswami, 1998; Daniels et al, 2001). Before and after diagnosis, narcoleptics
experience unrelenting psychosocial stress, with different stresses affecting each decade of life.
  Adolescents commonly report embarrassment, academic decline and loss of self-worth.
Hypnagogic hallucination may lead individuals to question their own sanity and may be
mistakenly diagnosed as schizophrenia. Adults face major concerns in the workplace and in
interpersonal relationships. The effects of sleepiness and cataplexy have major effects on
personal and public safety. Of particular concern is the risk of serious accidents at work or while
driving. Severe cataplexy, resulting in immediate and sudden body collapse, can be dangerous
and can occur so quickly that there is not time to prepare. Unless cataplexy can be controlled,
many normal activities must be avoided.
  Quality of life
Narcolepsy affects the social, mental and physical health of patients and has a significant
negative impact on their physical and emotional well being (Goswami 1998). A postal survey of
305 patients in the UK reported that median scores in all eight domains of the Short Form 36
(SF-36) quality of life questionnaire were significantly lower than normative data (Daniels et al.
2001). In considering the quality of life of 481 narcoleptic patients as measured by the SF-36
questionnaire, these patients suffered quality of life domains that were as bad, or worse, than
Parkinson's disease and epilepsy (Beusterien et al. 1999).
  Socioeconomic impact
In a study evaluating the socioeconomic impact of narcolepsy in 75 German patients (54 with
cataplexy, 21 without), 59% were unemployed and 43% of patients stated that their condition
was the main reason for being out of work (Dodel et al. 2004). It is therefore clear that
narcolepsy is physically and socially disabling for patients.
  Existing therapies
The existing therapeutic goods with registered indication including narcolepsy (with or without
cataplexy) include the sympathomimetic stimulants methylphenidate and dexamphetamine,
which are primarily used to manage EDS. It is noted in the product information of
methylphenidate (refer to Table 1) that the product is not effective for ‘the loss of voluntary
muscle tone’, presumably cataplexy. Both modafinil and armodafinil (also psychostimulants,
with a different mechanism) are indicated for EDS associated with narcolepsy.
  Although antidepressants have been used to manage the REM-related symptoms of narcolepsy
they are not registered for use in narcolepsy in Australia.
  Therefore while only dexamphetamine and methylphenidate are indicated for ‘narcolepsy’ as
first line treatments these medications are recognised as often being be inadequate to control
EDS, not to be effective in cataplexy and do not influence sleep fragmentation. Furthermore

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  Xyrem (sodium oxybate)
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these agents have a range of potential side effects which at times make specific therapy
intolerable. There remains an unmet need for patients to adequately control their condition.
  Unment need
This unmet need has been identified by the ASA who in 2014 took it upon themselves to submit
an application to have sodium oxybate rescheduled, and made several contacts with UCB
Australia to explore the mechanisms to make Xyrem available to Australian patients.
  UCB has been providing Xyrem under the Special Access Scheme (SAS) as a Category B
medicine since month year.
  Xyrem is not a core product to UCB, however, with the interest generated by the ASA and
patients (some of whom have engaged with media and with the Department of Health) UCB
wishes to explore orphan designation for the product and available means to facilitate
registration.

2. Questions and Sponsor’s Position
  Prevalence data for narcolepsy
As there are no Australian prevalence data published for narcolepsy UCB have asked the ASA to
provide information on the prevalence of narcolepsy in Australia. ASA reviewed the published
epidemiology and prevalence publications for other countries and confirmed that the both the
demographic details and diagnostic criteria used were in line with the Australian population and
practices.
  In addition the ASA provided information on audits of two large specialist sleep centres which
support the prevalence of narcolepsy in Australia and being similar to that internationally
(published data from USA, Europe, Hong Kong). Their data estimate that the prevalence of
narcolepsy is 31.25 per 100,000 (or approximately 3 per 10,000; thus within the TGA orphan
designation limit). This figure is the mean of prevalence rates across studies (where prevalence
rates were provided for with or without cataplexy, a mid point of these 2 figures was used).
  The ASA statement is attached as an Appendix to this briefing package.

  Question 1:
Does the TGA agree that this approach to source confirmation that the international prevalence is
appropriate, and that the Australian prevalence is consistent with international data?
TGA’s response: The TGA does not believe that Narcolepsy represents a truly orphan indication given
that, there are other drugs [Dexamphetamine,  Modafinil, Armodafinil] on the Australia market
already indicated for Narcolepsy (a chronic neurological disorder of excessive daytime sleepiness (EDS).
It may or may not occur with other symptoms such as cataplexy, sleep paralysis, fragmented night-
time sleep and hal ucinations).


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  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
Given that:
  the cohort of patients in the clinical dossiers evaluated for Dexamphetamine,
Modafinil and Armodafinil experienced Narcolepsy, Cataplexy, disturbed nocturnal
sleep patterns plus other paranormal sleep behaviours;

   al  three drugs only had unqualified Narcolepsy ( EDS ) indication, despite the above;

  Narcolepsy indication for Dexamphetamine,  Modafinil and Armodafinil was based
on  Category  1 Applications

The TGA  believes that:

  a  “head to head” trial assessing the superiority of  UCB Xyrem over those already
registered products for narcolepsy, wil  be more appropriate in terms of clinical
evidence to justify  UCB’s implicit claim, that the effective treatment of the other
“possible symptoms” associated with narcolepsy, such as catalepsy and fragmented
night-time sleep, can only be provided by Xyrem.

  procedural fairness also needs to prevail in that, both the sponsors of
Dexamphetamine, Modafinil and Armodafinil submitted Category 1 Applications to
register the indication of Narcolepsy. Based on that, it is advisable and only fair that
UCB also submits a Category 1 Application to register Xyrem in the treatment of
Narcolepsy indication.

Identification of existing therapeutic goods
Only 4 registered products have been identified which are indicated for ‘narcolepsy’ or for the
treatment of EDS in narcolepsy. These are: methylphenidate, dexamphetamine, modafinil and
armodafinil.

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  Xyrem (sodium oxybate)
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Pre-Submission Briefing Package

However, in the broadest understanding of narcolepsy, none of these 4 registered products is
acknowledged to provide effective treatment of all of the symptoms, most particularly catalepsy
and fragmented night-time sleep. Therefore the current treatment armamentarium is at times
inadequate to control even EDS in the setting of maximal dosage and the range of potential side
effects, which at times make therapy intolerable with existing agents.
  In contrast, clinical trials with sodium oxybate have demonstrated efficacy in each of the three
main symptoms of narcolepsy, and importantly the evidence of efficacy is as both a monotherapy
and an adjunctive therapy (to eg modafinil) for patients with severe cases (including children)
who may be on maximal doses of several conventional medications, and still have significant
symptoms.
  In comparison with other agents indicated for narcolepsy, sodium oxybate offers improved
efficacy. In addition to its proven therapeutic effect on cataplexy (a component of the disease
which is not effectively managed by other therapies), sodium oxybate is effective at alleviating
the individual components of the narcoleptic disease. Sodium oxybate has been shown to
significantly reduce the EDS associated with narcolepsy (both alone and in conjunction with
stimulants), improve the overall clinical status of patients with narcolepsy, and improve the
fragmented night-time nocturnal sleep associated with this disease.
  Question 2:
Does the TGA agree that sodium oxybate offers a significant benefit – in improved efficacy for
patients with narcolepsy, and that the proposed orphan indication ‘treatment of narcolepsy’ is
intended to encompass a broader patient group than the existing products are registered for ?

TGA’s response:  NO. The TGA requires properly conducted and well-designed,
randomised clinical trial with active arm, demonstrating that only Xyrem has proven
therapeutic effect on cataplexy (a possible component of the narcolepsy) which is not
effectively managed by other registered drugs for narcolepsy.

  Availability of EU dossier and evaluation reports to facilitate orphan registration
The EU submissions for sodium oxybate – both the initial MAA for treatment of cataplexy in
patients with narcolepsy and the variation submitted to extend the indications to treatment of
narcolepsy with cataplexy, would be the basis of an eCTD submission to the TGA. UCB will
also try to identify the evaluation reports for these submissions.
  The only differences between the original submissions [MAA (2003) and variation 2007] are:
•  An updated Quality module (Module 3) – to include minor variations since the original
MAA was approved
•  Consolidation of the Clinical Overview and summaries (Module 2.5 and 2.7) with final
reports in place of previously interim reports
•  Conversion to an eCTD submission
  Question 3:

7

Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
Does the TGA consider that submission of the eCTD with the updates as presented would be
acceptable and would there be benefits in providing the EU evaluation reports to facilitate
evaluation ?
TGA response: Submission of the eCTD with the updates as presented would be
acceptable. Provision of EU evaluation reports to facilitate a Category 1 application
evaluation (NOT ORPHAN REGISTRATION) could be useful.

8

  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package

Appendix 1: Tabular listing of al  clinical studies with sodium oxybate oral solution
Type of  Study
Objectives
Study design
Test product;
Number
Healthy subjects
Duration of  Study
Study
Identifier
and control
regimen;route of  of subjects  or diagnosis
treatment
status;
administration
report type
BA
OMC-SXB-11  To assess the effect of  Open,
Sodium oxybate
36 (34
Healthy subjects
Single dose
Complete
a high fat meal on the  randomised,
oral solution 4.5 g  evaluable)
full
BA of sodium
crossover study  as a single oral
oxybate oral solution
dose; fasting vs
high fat meal
IV
Covance
To characterize the in  N/A
Sodium oxybate  N/A
N/A
N/A

6627-129
vivo inhibitory
at concentrations
potential of sodium
of 3, 10, 30, 100
oxybate on CYP450
and 300 µM
isoenzymes.
IV
Covance
To characterize the in  N/A
Sodium oxybate  N/A
N/A
N/A

6627-150
vivo inhibitory
at concentrations
potential of sodium
of 300, 1000 and
oxybate on CYP450
3000 µM
isoenzymes.
PK
OMC-SXB-9
To assess PK<
Open,
Sodium oxybate
13 (12
Healthy subjects
Single dose
Complete
including dose
randomised,
oral solution 4.5 g  evaluable)
full
proportionality
two-period
(2 x 2.25 g) and 9
crossover study  g (2 x 4.5 g)
PK
OMC-SXB-8
To assess PK in males  Open label
Sodium oxybate
36
Healthy subjects
Single dose
Complete
and females
oral solution 4.5 g
full
Taste
OMC-SXB-16  To compare placebo
Blinded,
Sodium oxybate
12
Healthy subjects
Single dose
Complete
solutions with active
placebo
oral solution – 3 g
full
solution with regard
controlled
swilled in mouth
to taste

7

  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package

   Type of  Study
Objectives
Study design
Test product;
Number
Healthy subjects
Duration of  Study
Study
Identifier
and control
regimen; route
of subjects  or diagnosis
treatment
status;
of administration
report type
PK
OMC-GHB-4  To assess PK in
Open
Sodium oxybate
6
Narcoleptic patients  Single dose
Complete
patients on chronic
oral solution at
full
treatment
total dose 6 g (2 x
3 g)
PK
OMC-SXB-10  To assess PK after
Opel label, two  Sodium oxybate
13
Narcoleptic patients  Single dose
Complete
single dose and 8
period study
oral solution at
full
weeks of treatment in
4.5 g
narcoleptic patients
who had not
previously received
sodium oxybate
PK Int
OMC-SXB-12  To assess any PK
Open-label,
Sodium oxybate
15
Healthy subjects
Single dose
Complete
interaction between
three period,
oral solution 3 g
full
sodium oxybate and
three treatment
and 5 g zolpidem,
zolpidem
randomised
alone and together
crossover study
PK Int
OMC-SXB-14  To assess any PK
Open-label,
Sodium oxybate
12 (11
Healthy subjects
Single dose
Complete
interaction between
three period,
oral solution 3 g
evaluable)
full
sodium oxybate and
three treatment
and 5 g
protriptyline
randomised
protriptyline,
crossover study  alone and together
PK Int
OMC-SXB-17  To assess any PK
Open-label,
Sodium oxybate
13 (12
Healthy subjects
Single dose
Complete
interaction between
three period,
oral solution 3 g
evaluable)
full
sodium oxybate and
three treatment
and 5 g modafinil,
modafinil
randomised
alone and together
crossover study
PK Int
OMC-SXB-24  To determine the
Open-label,
Sodium oxybate
44 (42
Healthy subjects
Single dose
Complete
effect of sub-chronic
three period,
oral solution 3 g
evaluable)
full
omeprazole on BA of  three treatment
alone or after
sodium oxybate
randomised
omeprazole 40
crossover study  mg once daily for
5 days

8

  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package

   Type of  Study
Objectives
Study design
Test product;
Number
Healthy subjects
Duration of  Study
Study
Identifier
and control
regimen; route
of subjects  or diagnosis
treatment
status;
of administration
report type
Efficacy  OMC-GHB-2  To compare the
Double-blind,
Sodium oxybate
136
Narcoleptic patients  4 weeks
Complete
/ safety
efficacy and safety of  randomised,
oral solution at
full
three doses of sodium  parallel group,
total doses of 3, 6
oxybate and placebo
placebo
and 9 g (as 2
in the treatment of the  controlled
divided doses)
symptoms of
and placebo taken
narcolepsy
nightly
Efficacy  Scrima
To compare the
Randomised,
Sodium oxybate
20
Narcoleptic patients  29 days
Complete
/ safety
efficacy and safety of  double-blind,
oral solution at 2
full
sodium oxybate and
placebo
x 25 mg/kg at
placebo in the
controlled
night, and
treatment of the
crossover study  matching placebo
symptoms of
cataplexy and with
regard to effects on
the PSG
Efficacy  Lammers
To compare the
Randomised,
Sodium oxybate
25
Narcoleptic patients  4 weeks
Complete
/ safety
efficacy and safety of  double-blind,
oral solution at 2
full
sodium oxybate and
placebo
x 30 mg/kg at
placebo in the
controlled
night, and
treatment of the
crossover study  matching placebo
symptoms of
cataplexy and with
regard to effects on
the PSG
Efficacy  OMC-SXB-21  To provide evidence
Double-blind,
Sodium oxybate
55
Narcoleptic patients  4 weeks
Complete
/ safety
for long-term efficacy  placebo
oral solution at 3,
full
of sodium oxybate
controlled study  4.5, 6, 7.5 or 9
based upon return of
g/day (in 2
cataplexy symptoms
divided doses) at
on cessation of a
night, and
minimum of 6 months
matching placebo
of open label
treatment

9

  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package

   Type of  Study
Objectives
Study design
Test product;
Number
Healthy subjects
Duration of  Study
Study
Identifier
and control
regimen; route
of subjects  or diagnosis
treatment
status;
of administration
report type
Efficacy  OMC-GHB-3  To evaluate the safety  Long-term,
Sodium oxybate
117
Narcoleptic patients  24 months
Complete
/ safety
and efficacy of
open label non-  oral solution at
full
sodium oxybate in
randomised
starting dose of 6
chronic use
extension study  g at night, titrated
(extension of
to effect at 3, 4.5,
OMC-GHB-2)
6 or 9 g/day
Efficacy  OMC-SXB-6
To evaluate the safety  Open label
Sodium oxybate
185
Narcoleptic patients  6 month
Complete
/ safety
and efficacy of
study
oral solution at
full
sodium oxybate in
starting dose of
long-term use
4.5 g at night,
titrated to effect
at 3, 4.5, 6, 7.5 or
9 g/day
Efficacy  OMC-SXB-7
To evaluate the safety  Long-term,
Sodium oxybate
145
Narcoleptic patients  24 months
Not
/ safety
and efficacy of
open label non-  oral solution at
(interim)
complete,
sodium oxybate in
randomised
continued dose of
full (interim)
long-term use
extension study  3, 4.5, 6 or 9
and safety
(extension of
g/day
update
OMC-GHB-3,
reports
OMC-SXB-6 or
Scharf study)
Safety
Scharf
To assess the safety of  Retrospective
Sodium oxybate  143
Narcoleptic patients  Up to 16
Complete,
sodium oxybate in
compilation of
oral solution at 3
years
safety
very long-term use
safety data
to 9 g/night
(up to 16 y)
PD/
OMC-SXB-20  To assess the effects
Open label
Sodium oxybate
25
Narcoleptic patients  10 weeks
Complete,
efficacy/
of sodium oxybate on  study in which
oral solution at
full
safety
sleep architecture (by  patients
total doses of 4.5,
PSG) and narcolepsy
received
6, 7.5 and 9 g/day
symptoms and to
increasing
(in 2 divided
assess safety
doses of sodium  doses) at night
oxybate

10

  Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package

  Type of  Study
Objectives
Study design
Test product;
Number
Healthy subjects
Duration of  Study
Study
Identifier
and control
regimen; route
of subjects  or diagnosis
treatment
status;
of administration
report type
Efficacy  OMC-SXB-15  To compare the
Randomised,
Sodium oxybate
353
Narcoleptic patients  8 weeks
Complete
/ safety
effects and safety of
double-blind,
oral solution at
enrolled,

full

sodium oxybate to
placebo
4.5, 6 or 9 g/day,
285

placebo in the
controlled,
(divided dose)
randomise

treatment of excessive  parallel group
and matching
d, 228 ITT,

daytime sleepiness
multicenter
placebo
206

(EDS) in narcolepsy
study

completed

Efficacy  OMC-SXB-22  To compare the
Randomised,
Sodium oxybate
278
Narcoleptic patients  8 weeks
Complete
/ safety
effects and safety of
double-blind,
oral solution (or
enrolled,

full

sodium oxybate and
double-dummy,  placebo) at 6 or 9  231

modafinil with
placebo
g/day, (divided
randomise

placebo in the
controlled,
dose)
d, 201

treatment of EDS in
parallel group
completed

narcolepsy
multicenter
Modafinil (or

study
placebo) tablet

200, 400 and 600

mg.day

Efficacy  OMC-SXB-19  To evaluate the
Open-label
Sodium oxybate
185

12 weeks
Not
/ safety
efficacy and safety of  multicenter
oral solution at
enrolled

complete;

sodium oxybate in
study
4.5, 6 or 9 g/day,

Safety

patients with

(divided dose)

update

narcolepsy

report.

11

Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
Appendix 2: Australasian Sleep Association position statement and guidelines,
regarding the use of sodium oxybate in the treatment of narcolepsy
  John Swieca, Hailey Meaklim, Arthur Teng, Margot Davey, Yasaman Djavadkhani, Ron
Grunstein, Dev Banerjee & Garun Hamilton

Prevalence of Narcolepsy
Narcolepsy is a rare but serious disorder. This sleep-wake condition causes profound
disturbance to sleep quality, daytime alertness, quality of life and mental health.

The estimated prevalence rate of narcolepsy in Western countries is approximately 30-
50 per 100,000 people, but this rate varies according to study methodology, geography,
and diagnostic criteria used (1-5). To our knowledge, there are no published
epidemiologic studies describing prevalence rates of narcolepsy in Australia. Therefore,
a review of prevalence rates of narcolepsy in countries with similar demographic
profiles and diagnostic procedures to Australia was conducted (Table 1). The average
prevalence rate of narcolepsy from these studies is 31.25 per 100,000 (or
approximately 3 per 10,000; thus within the TGA orphan designation limit). This figure
is the mean of prevalence rates across studies and where prevalence rates were
provided for with or without cataplexy, a mid point of these two figures was used. These
data provide evidence that narcolepsy is a rare disorder, in countries that have similar
demographics to those found in Australia.

Within Australian specialist sleep centres; the prevalence rate of narcolepsy is more
common than in the general population, as would be expected with a filtered
population. Australian studies suggest a prevalence rate 3.05% (5/168) for new
referrals to a busy specialist metropolitan sleep disorder centre in 2015 (
,
personal communication). This is consistent with a 1991 study suggesting a rate of
diagnosis of narcolepsy of 2.5% (5/200) for new patient referrals to another private
sleep disorder centre in Melbourne, Australia (6). Although narcolepsy is common in a
specialist referral population, the general unfiltered population prevalence rate is
substantially lower, as outlined above.

Table 1. Studies on the prevalence of narcolepsy with similar demographic and
diagnostic method to Australia
Study Year  Location and
Diagnosis
Number
Prevalence  Comments
and Author  Population
method
diagnosed/
per
Number
100,000
screened
(95% CI if
available)
1982
Italy
Questionnaire
1/2518
40 (1-221)  Only
(7)
Unselected
and sleep study
inpatients
patients
admitted over
1 year to
hospital aged
6-92 y

12

Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package

1994
Finland
Screen,
3/11,354
26 (5-77)
Finnish Twin
(8)
White twins
interview, sleep
Registry.
aged 33-60 y
study, HLA
White
population. All
three cases
were dizygotic
and
discordant. All
had cataplexy
1996
United
Telephone
2/4927
40 (5-145)  Computerised
(9)
Kingdom.
system
expert system
Random
All with
sample aged 15  cataplexy
Y and over
2002
Minnesota, USA  Medical
1.  35/37,667  1.  36
Study based
(10)
All ages
Records
2.  55/97,667
(25-
on medial care
1.  Narcolepsy
50)
in a defined
with
2.  56
population,
Cataplexy
(42-
Olmsted
2.  Narcolepsy
73)
County, MN,
with or
for 1960-1989
without
cataplexy
2002 (11)
Hong Kong,
Phone screen,
3/9851
30 (6 - 89)  All had
China
interview, sleep
cataplexy.
Residents aged  study, HLA
HLA negative
18 – 68 y
in one case
who had
atypical
cataplexy
2002# (12)  Five European
Telephone
9/18980
47 (22-90)  Computerised
Countries
system
expert system
All with
(Sleep EVAL
cataplexy
Expert
system,
utilising ICSD
diagnostic
criteria for
narcolepsy)
2017
Catalunya
Narcolepsy
381/7424754
5.2
Denominator
(13)
(Spain)
diagnosis on
is the
Patients of 13
patient record,
population of
specialist
validated
Catalunya.
centres and
against
Note the
screening of
Brighton
prevalence
the public
Collaboration
rate 3 – 14
health care
Case Definitions
times lower
system
than those
found in other
countries
2016
United States of  Narcolepsy was  1675 cases/
14.6 – 27.3  Investigated
(5)
America
defined in 3
1685398 non
narcolepsy
Population
ways: (1) 2
cases
increased
based
diagnoses of
incidence
epidemiologica  narcolepsy
before and
l study of active  within 6
after novel
duty military
months of each
pandemic
personal
other, one made

13

Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package

between 2004-  by a sleep

influence in
2013
expert; (2) 2
2009
diagnoses by
any provider
followed by a
narcolepsy
prescription
within 14 days
of last visit; and
(3) procedure
code for a sleep
study followed
by a narcolepsy
diagnosis by a
sleep expert
within 6
months.

Used (ICD-9-CM

criteria)
2009
King County,
1) Required
425/1,366,417  1)
Denominator
(14)
Washington DC  physician

With
was the
18 years and
diagnoses of
cataplexy
population of

older
narcolepsy

= 21.8
King County.

(with and

(18.8 to
Multiple

without

24.8)
methods

cataplexy).

Without
overlapping

2) Then

cataplexy
methods of

patients had an
30.6(27.6-  diagnosis

interview and

33.5)
identification

buccal

2)
targeting both

scrapings for

15.3 (12.8
clinicians and

HLA

to 17.9)
patients.

confirmation

Note: This table extends on the work of (4); HLA = hypocretin levels assessed in
cerebrospinal fluid

The Australian experience with sodium oxybate for narcolepsy – Data from a
single Australian centre
Sodium oxybate was included in Schedule 8 of the Poisons Standard in 2014 with
specialist sleep disorder centres able to provide access to sodium oxybate for
narcolepsy under specific circumstances (the Special Access Scheme, Category B). One
of the largest private sleep clinics in Melbourne, Australia, started prescribing sodium
oxybate under these strict regulations in 2015. A retrospective chart review of patients
at this centre was conducted on patients commencing on sodium oxybate between April
2015-April 2016 to understand their experience (15).

Fourteen patients were commenced on sodium oxybate, and patients were diagnosed
with narcolepsy with cataplexy (Narcolepsy Type 1)(n=6); narcolepsy without
cataplexy (n = 6) (Narcolepsy Type 2) and idiopathic hypersomnia (n=2). The mean
daily starting dose was 3 g. The mean daily dose at week 12 was 5.5 g. For those with
Narcolepsy Type 1 and difficult cataplexy symptoms (n = 6), the mean number of
cataplexy episodes per week reduced from 15.5 to 2. For a subset with paired Epworth

14

Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
Sleepiness Score (ESS), mean ESS reduced from 16 to 10.5 – a very large reduction
noting that the minimum clinically important difference is a reduction of 2 points (16).
Thirteen of fourteen patients (93%) elected to continue sodium oxybate beyond 12
weeks, despite the high cost of the medication. It is important to note, the most
common side effects were nausea and anxiety. 1 patient had to be started on anti-
emetics and 2 needed adjustment of anxiolytic medications. 1 patient had to discontinue
sodium oxybate due to lack of efficacy. To date, 31 patients have commenced on sodium
oxybate at this practice (personal communication,
)

This Australian series indicates that sodium oxybate is a helpful adjunct treatment for
people with narcolepsy, for reducing mean number of cataplexy attacks and
significantly improving excessive daytime sleepiness. Its utility is reflected in the
ongoing usage of sodium oxybate in the majority of people commenced despite its
expense

To date there has not been any Australian experience with using sodium oxybate in
paediatric sleep medicine practice. Despite this, overseas experience suggests it is
equally as effective as in adults.

References

1. Wijnans L, Lecomte C, de Vries C, Weibel D, Sammon C, Hviid A, et al. The incidence of
narcolepsy in europe: Before, during, and after the influenza A(H1N1)pdm09 pandemic
and vaccination campaigns. Vaccine 2013, Feb 6;31(8):1246-54.
2. Overeem S, Black JL, Lammers GJ. Narcolepsy: Immunological aspects. Sleep Med Rev
2008, Apr;12(2):95-107.
3. Ahmed I, Thorpy M. Clinical features, diagnosis and treatment of narcolepsy. Clin
Chest Med 2010, Jun;31(2):371-81.
4. Longstreth WT, Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology
of narcolepsy. Sleep 2007, Jan;30(1):13-26.
5. Lee RU, Radin JM. A population-based epidemiologic study of adult-onset narcolepsy
incidence and associated risk factors, 2004-2013. J Neurol Sci 2016, Nov 15;370:29-34.
6. Johns MW. Polysomnography at a sleep disorders unit in melbourne. Med J Aust 1991,
Sep 2;155(5):303-8.
7. Franceschi M, Zamproni P, Crippa D, Smirne S. Excessive daytime sleepiness: A 1-year
study in an unselected inpatient population. Sleep 1982;5(3):239-47.
8. Hublin C, Kaprio J, Partinen M, Koskenvuo M, Heikkila K, Koskimies S, Guilleminault C.
The prevalence of narcolepsy: An epidemiological study of the finnish twin cohort. Ann
Neurol 1994, Jun;35(6):709-16.
9. Ohayon MM, Priest RG, Caulet M, Guilleminault C. Hypnagogic and hypnopompic
hallucinations: Pathological phenomena? Br J Psychiatry 1996, Oct;169(4):459-67.
10. Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in
olmsted county, minnesota: A population-based study. Sleep 2002, Mar 15;25(2):197-
202.
11. Wing Y-K, Li RH-Y, Lam C-W, Ho CK-W, Fong SY-Y, Leung T. The prevalence of
narcolepsy among chinese in hong kong. Ann Neurol 2002, May;51(5):578-84.

15

Xyrem (sodium oxybate)
Oral solution 500 mg/mL
UCB
Pre-Submission Briefing Package
12. Ohayon MM, Priest RG, Zulley J, Smirne S, Paiva T. Prevalence of narcolepsy
symptomatology and diagnosis in the european general population. Neurology 2002,
Jun 25;58(12):1826-33.
13. Tió E, Gaig C, Giner-Soriano M, Romero O, Jurado M-J, Sansa G, et al. The prevalence
of narcolepsy in catalunya (spain). J Sleep Res 2017, Nov 24.
14. Longstreth WT, Ton TGN, Koepsell T, Gersuk VH, Hendrickson A, Velde S. Prevalence
of narcolepsy in king county, washington, USA. Sleep Med 2009, Apr;10(4):422-6.
15. Khoo J, Cunnington D, Swieca J, Ellender C. Retrospectiv cohort review of people
with narcolepsy treqtment with sodium oxybate: An Australian experience. Journal of
Sleep Research 2016 Oct 1; 25: 38-38.
16. Patel S, Kon SSC, Nolan CM, Barker RE, Simonds AK, Morrell MJ, Man WD-C. The
epworth sleepiness scale: Minimum clinically important difference in obstructive sleep
apnea. Am J Respir Crit Care Med 2017, Sep 29.

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