Xyrem

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 

 

 



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1. NAME OF THE MEDICINAL PRODUCT 

 
Xyrem 500 mg/mL oral solution 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 
Each mL of solution contains 500 mg of sodium oxybate. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 

 
Oral solution. 
 
The oral solution is clear to slightly opalescent. 
 
 
4. CLINICAL PARTICULARS 

 
4.1 Therapeutic indications 

 
Treatment of narcolepsy with cataplexy in adult patients, adolescents and children from the age of 7 
years.  
 
4.2 Posology and method of administration 
 
Treatment should be initiated by and remain under the guidance of a physician experienced in the 
treatment of narcolepsy. Physicians should strictly adhere to the contraindications, warnings and 
precautions. 
 
Posology  
Adult 
The recommended starting dose is 4.5 g/day sodium oxybate divided into two equal doses of 
2.25 g/dose. The dose should be titrated to effect based on efficacy and tolerability (see section 4.4) up 
to a maximum of 9 g/day divided into two equal doses of 4.5 g/dose by adjusting up or down in dose 
increments of 1.5 g/day (i.e. 0.75 g/dose). A minimum of one to two weeks is recommended between 
dose increments. The dose of 9 g/day should not be exceeded due to the possible occurrence of severe 
symptoms at doses of 18 g/day or above (see section 4.4). 
 

Single doses of 4.5 g should not be given unless the patient has been titrated previously to that dose 
level. 
 
If sodium oxybate and valproate are used concomitantly (see section 4.5), a decrease in sodium 
oxybate dose by 20% is recommended. The recommended starting dose for sodium oxybate, when 
used concomitantly with valproate, is 3.6 g per day  administered orally in two equal divided doses of 
approximately 1.8 g. If concomitant use is warranted, patient response and tolerability should be 
monitored and dose should be adapted accordingly (see section 4.4).  
 
Discontinuation of Xyrem 

The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled 
clinical trials (see section 4.4). 
 
If the patient stops taking the medicinal product for more than 14 consecutive days, titration should be 
restarted from the lowest dose. 



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Special populations 

 

Elderly 

Elderly patients should be monitored closely for impaired motor and/or cognitive function when 
taking sodium oxybate (see section 4.4). 
 

Hepatic impairment 

The starting dose should be halved in all patients with hepatic impairment, and response to dose 
increments monitored closely (see section 4.4 and 5.2). 
 
Renal impairment 

All patients with impaired renal function should consider a recommendation to reduce sodium intake 
(see section 4.4). 
 
Paediatric population 

 
Adolescents and children from 7 years of age with a minimum body weight of 15kg: 
 
Xyrem is administered orally twice nightly. Dosing recommendations are provided in Table 1. 
 
Table 1  Sodium Oxybate Recommended Dose Initiation and Titration for Paediatric Patients 

 
Patient weight Initial total daily 

dose  
(taken in 2 

divided doses)* 

Titration regimen (to clinical 
effect) 

Recommended maximum 
total daily dose 

15kg - <20kg ≤ 1g/day ≤ 0.5g/day/week 0.2g/kg/day 
 20kg - <30kg ≤ 2g/day ≤ 1g/day/week 

30kg - <45kg ≤ 3g/day ≤ 1g/day/week 
≥45kg ≤ 4.5g/day ≤ 1.5g/day/week 9g/day 

*At bedtime and 2.5 to 4 hours later. For children who sleep more than 8 hours per night, sodium oxybate may be 
given after bedtime, while the child is in bed, in two equally divided doses 2.5 to 4 hours apart. 
 
The dose should be gradually titrated to effect based on efficacy and tolerability (see section 4.4). A 
minimum of one to two weeks is recommended between dosage increments. Sodium oxybate dose 
recommendations (initial dose, titration regimen and maximum dose) for paediatric patients are based 
on body weight. Therefore, patients should have their body weight checked at regular intervals 
especially during titration to ensure that the appropriate dose of sodium oxybate is administered.  
 
The recommended maximum total daily dose is 0.2g/kg/day in paediatric patients weighing less than 
45kg. For paediatric patients weighing 45kg or more the maximum total daily dose is 9g/day.  
 
If sodium oxybate and valproate are used concomitantly (see section 4.5), a decrease in sodium 
oxybate dose by 20% is recommended e.g. 4.8g/day instead of 6g/day. 
 
The safety and efficacy of sodium oxybate in children below 7 years of age has not been established 
and therefore sodium oxybate is not recommended below 7 years of age. Children below 15kg should 
not receive sodium oxybate.   
 
 



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Method of administration 
Xyrem should be taken orally upon getting into bed and again between 2.5 to 4 hours later. It is 
recommended that both doses of Xyrem should be made up at the same time upon retiring to bed. 
Xyrem is provided for use with a graduated measuring syringe and two 90 mL dosing cups with child 
resistant caps. Each measured dose of Xyrem must be dispensed into the dosing cup and diluted with 
60 mL of water prior to ingestion. Because food significantly reduces the bioavailability of sodium 
oxybate, both adult and paediatric patients should eat at least several (2-3) hours before taking the 
first dose of Xyrem at bedtime. Adult and paediatric patients should always observe the same timing 
of dosing in relation to meals. Doses should be taken within 24 hours after preparation, or else 
discarded. 
 

4.3 Contraindications 

 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Patients with major depression. 
 
Patients with succinic semialdehyde dehydrogenase deficiency. 
 
Patients being treated with opioids or barbiturates. 
 
4.4 Special warnings and precautions for use 

 

Xyrem has the potential to induce respiratory depression  
 
Respiratory and CNS depression 
Sodium oxybate also has the potential to induce respiratory depression. Patients should be assessed 
before treatment for sleep apnoea and caution should be exercised when considering treatment. 
Apnoea and respiratory depression have been observed in a fasting healthy subject after a single 
intake of 4.5g (twice the recommended starting dose). During post-marketing surveillance, it has been 
observed that the use of sodium oxybate may predispose the patients to choking sensation during 
sleep. Patients should be questioned regarding signs of Central Nervous System (CNS) or respiratory 
depression.  Special caution should be observed in patients with an underlying respiratory disorder. 
Patients should be monitored for signs of respiratory depression during treatment. Because of the 
higher risk of sleep apnoea, patients with a BMI ≥40 kg/m2 should be monitored closely when taking 
sodium oxybate. 
 
Approximately 80% of patients who received sodium oxybate during clinical trials maintained CNS 
stimulant use. Whether this affected respiration during the night is unknown. Before increasing the 
sodium oxybate dose (see section 4.2), prescribers should be aware that sleep apnoea occurs in up to 
50% of patients with narcolepsy. 
 

 Benzodiazepines 

Given the possibility of increasing the risk of respiratory depression, the concomitant use of 
benzodiazepines and sodium oxybate should be avoided. 
 

 Alcohol and CNS depressants 

The combined use of alcohol, or any CNS -depressant medicinal product, with sodium 
oxybate may result in potentiation of the CNS-depressant effects of sodium oxybate as well as 
increased risk of respiratory depression. Therefore, patients should be warned against the use 
of alcohol in conjunction with sodium oxybate. 

 
 Gamma hydroxybutyrate (GHB) dehydrogenase inhibitors 

Caution is required in patients who are treated concomitantly with valproate or other GHB 
dehydrogenase inhibitors as pharmacokinetic and pharmacodynamic interactions have been 



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observed when sodium oxybate is co-administered with valproate (see section 4.5). If 
concomitant use is warranted, dose adjustment is to be considered (see section 4.2). 
Additionally, patient response and tolerability should be carefully monitored and dose should 
be adapted accordingly. 
 

 Topiramate 

There have been clinical observation(s) of coma and increased plasma GHB concentration 
after co-administration of sodium oxybate with topiramate. Therefore, patients should be 
warned against the use of topiramate in conjunction with sodium oxybate (section 4.5).  
 

Abuse potential and dependence 
Sodium oxybate, which is as the sodium salt of GHB, is a CNS depressant active substance with well-
known abuse potential. Prior to treatment physicians should evaluate patients for a history of or 
susceptibility to drug abuse. Patients should be routinely monitored and in the case of suspected 
abuse, treatment with sodium oxybate should be discontinued. 
 
There have been case reports of dependence after illicit use of GHB at frequent repeated doses (18 to 
250 g/day) in excess of the therapeutic dose range. Whilst there is no clear evidence of emergence of 
dependence in patients taking sodium oxybate at therapeutic doses, this possibility cannot be 
excluded. 
 
Patients with porphyria 
Sodium oxybate is considered to be unsafe in patients with porphyria because it has been shown to be 
porphyrogenic in animals or in vitro systems.  
 
Neuropsychiatric events 
Patients may become confused while being treated with sodium oxybate. If this occurs, they should be 
evaluated fully, and appropriate intervention considered on an individual basis. Other 
neuropsychiatric events include anxiety, psychosis, paranoia, hallucinations, and agitation. The 
emergence of thought disorders including thoughts of committing violent acts (including harming 
others) and/or behavioural abnormalities when patients are treated with sodium oxybate requires 
careful and immediate evaluation. 
 
The emergence of depression when patients are treated with sodium oxybate requires careful and 
immediate evaluation. Patients with a previous history of affective disorders (including depressive 
illness, anxiety and bipolar disorder),   suicide attempt and psychosis should be monitored especially 
carefully for the emergence of depressive symptoms and/or suicidal ideation while taking sodium 
oxybate. Major depression is contraindicated for use with sodium oxybate.(see section 4.3). 
 

If a patient experiences urinary or faecal incontinence during sodium oxybate therapy, the prescriber 
should consider pursuing investigations to rule out underlying aetiologies. 
 
Sleepwalking has been reported in patients treated in clinical trials with sodium oxybate.  It is unclear 
if some or all of these episodes correspond to true somnambulism (a parasomnia occurring during 
non-REM sleep) or to any other specific medical disorder. The risk of injury or self-harm should be 
borne in mind in any patient with sleepwalking. Therefore, episodes of sleepwalking should be fully 
evaluated and appropriate interventions considered. 
 
Paediatric Population: 
 
Monitoring during titration phase 
The patient’s tolerability, especially with regards to potential signs of central nervous system and 
respiratory depression, should be carefully monitored with each dose increase during titration. Careful 
monitoring should include that the parent/caregivers observe the child’s breath after sodium oxybate 
intake to assess if there is any abnormality in breathing during the first two hours, for example rude 
breathing, sleep apnoea, cyanosis of lips/face. If abnormality in breathing is observed medical support 



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should be sought. If any abnormality is noted after the first dose, the second dose should not be 
administered. If no abnormality is noted the second dose can be administered. The second dose should 
not be given earlier than 2.5 hours or later than 4 hours after the first dose. In individual cases, e.g. if 
it is uncertain that the parent/caregivers can manage careful monitoring as described, sodium oxybate 
is not recommended unless medical supervision of treatment can be organized.   
If in doubt about administration of a dose, do not re-administer the dose to reduce the risk of 
overdose. 
 
Weight Loss 

Weight decrease is common amongst patients treated with sodium oxybate (see section 4.8). For 
paediatric patients it is important that their weight is checked at regular intervals especially during 
dose titration to ensure that the appropriate dose of sodium oxybate is being administered (see section 
4.2). 
 

Neuropsychiatric events 

For children and adolescents extra care should be taken to assess any potential suicidal or depressive 
conditions before starting treatment with sodium oxybate (see section 4.8) and to monitor any 
treatment-emergent events. 
 

Alcohol and CNS depressants 

Given the risk of alcohol intake among adolescents, it is noted that alcohol may further increase the 
CNS and respiratory depressant effects of sodium oxybate in children – adolescents taking sodium 
oxybate (see section 4.5). 
 
Sodium intake 
Patients taking sodium oxybate will have an additional daily intake of 0.18g of sodium per 1 gram of 
sodium oxybate dose. A recommendation to reduce sodium intake should be carefully considered in 
the management of patients with heart failure, hypertension or compromised renal function (see 
section 4.2 and 4.9) 
 
Elderly 
There is very limited experience with sodium oxybate in the elderly.  Therefore, elderly patients 
should be monitored closely for impaired motor and/or cognitive function when taking sodium 
oxybate. 
 
Epileptic patients 
Seizures have been observed in patients treated with sodium oxybate. In patients with epilepsy, the 
safety and efficacy of sodium oxybate has not been established, therefore use is not recommended. 
 
Rebound effects and withdrawal syndrome 
The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled 
clinical trials.  In some patients, cataplexy may return at a higher frequency on cessation of sodium 
oxybate therapy, however this may be due to the normal variability of the disease. Although the 
clinical trial experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses 
does not show clear evidence of a withdrawal syndrome, in rare cases, events such as insomnia, 
headache, anxiety, dizziness, sleep disorder, somnolence, hallucination, and psychotic disorders were 
observed after GHB discontinuation. 
 
Educational Materials 
In order to assist prescribers, and patients/caregivers about the important information for Xyrem  
educational materials will be provided to them. In particular the materials will reinforce that 
for  paediatric patients, an initial assessment of the patient should be performed with regard to growth 
and learning ability and that in addition to any side effects, any behaviour changes (social and 
learning), should be reported to the child’s healthcare provider.  
 



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4.5 Interaction with other medicinal products and other forms of interaction 

 
The combined use of alcohol with sodium oxybate may result in potentiation of the central nervous 
system-depressant effects of sodium oxybate.  Patients should be warned against the use of any 
alcoholic beverages in conjunction with sodium oxybate. 
 
Sodium oxybate should not be used in combination with sedative hypnotics or other CNS depressants. 
 
Sedative hypnotics 

Drug interaction studies in healthy adults with sodium oxybate (single dose of 2.25 g) and lorazepam 
(single dose of 2 mg) and zolpidem tartrate (single dose of 5 mg) demonstrated no pharmacokinetic 
interactions. Increased sleepiness was observed after concomitant administration of sodium oxybate 
(2.25 g) and lorazepam (2 mg). The pharmacodynamic interaction with zolpidem has not been 
assessed. When higher doses up to 9 g/d of sodium oxybate are combined with higher doses of 
hypnotics (within the recommended dose range) pharmacodynamic interactions associated with 
symptoms of CNS depression and/or respiratory depression cannot be excluded (see section 4.3). 
 
Tramadol 

A drug interaction study in healthy adults with sodium oxybate (single dose of 2.25 g) and tramadol 
(single dose of 100 mg) demonstrated no pharmacokinetic/pharmacodynamic interaction. When 
higher doses up to 9 g/day of sodium oxybate are combined with higher doses of opioids (within the 
recommended dose range) pharmacodynamic interactions associated with symptoms of CNS 
depression and/or respiratory depression cannot be excluded (see sections 4.3). 
 

Antidepressants 

Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between 
sodium oxybate (single dose of 2.25 g) and the antidepressants protriptyline hydrochloride (single 
dose of 10 mg) and duloxetine (60 mg at steady state). No additional effect on sleepiness was 
observed when comparing single doses of sodium oxybate alone (2.25 g) and sodium oxybate (2.25 g) 
in combination with duloxetine (60 mg at steady state). Antidepressants have been used in the 
treatment of cataplexy. A possible additive effect of antidepressants and sodium oxybate cannot be 
excluded. The rate of adverse reactions has increased when sodium oxybate is co-administered with 
tricyclic antidepressants. 
 
Modafinil 

A drug interaction study in healthy adults demonstrated no pharmacokinetic interactions between 
sodium oxybate (single dose of 4.5 g) and modafinil (single dose of 200 mg). Sodium oxybate has 
been administered concomitantly with CNS stimulant agents in approximately 80% of patients in 
clinical studies in narcolepsy. Whether this affected respiration during the night is unknown. 
 

Omeprazole 

The co-administration of omeprazole has no clinically significant effect on the pharmacokinetics of 
sodium oxybate.  The dose of sodium oxybate therefore does not require adjustment when given 
concomitantly with proton pump inhibitors. 
 
Ibuprofen 

Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between 
sodium oxybate and ibuprofen. 
 
Diclofenac 

Drug interaction studies in healthy adults demonstrated no pharmacokinetic interactions between 
sodium oxybate and diclofenac.  Co-administration of sodium oxybate and diclofenac in healthy 
volunteers reduced the attention deficit caused by the administration of sodium oxybate alone as 
measured by psychometric tests.  
 



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GHB dehydrogenase inhibitors 

Since sodium oxybate is metabolised by GHB dehydrogenase there is a potential risk of an interaction 
with medicinal products that stimulate or inhibit this enzyme (e.g. valproate, phenytoin or 
ethosuximide) (see section 4.4).  
 

The co-administration of sodium oxybate (6 g per day) with valproate (1250 mg per day) resulted in 
an increase in systemic exposure to sodium oxybate by approximately 25% and no significant change 
in Cmax. No effect on the pharmacokinetics of valproate was observed. The resulting 
pharmacodynamic effects, including increased impairment in cognitive function and sleepiness, were 
greater with co-administration than those observed with either drug alone. If concomitant use is 
warranted, patient response and tolerability should be monitored and dose adjustments made if 
required (see section 4.2). 
 

Topiramate 

Possible pharmacodynamic and pharmacokinetic interactions when sodium oxybate is used 
concomitantly with topiramate cannot be excluded as clinical observation(s) of coma, and increased 
plasma GHB concentration were reported in a patient(s) under concomitant use of sodium oxybate 
and topiramate (section 4.4).  
 

Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does not 

significantly inhibit the activities of the human isoenzymes (see section 5.2). 

 

4.6 Fertility, pregnancy and lactation 

 
Pregnancy 
Animal studies have shown no evidence of teratogenicity but embryo lethality was seen in both rat 
and rabbit studies (see section 5.3). 
 
Data from a limited number of pregnant women exposed in the first trimester indicate a possible 
increased risk of spontaneous abortions. To date no other relevant epidemiological data are available. 
Limited data from pregnant patients during second and third trimester indicate no malformative or 
foeto/neonatal toxicity of sodium oxybate. 
 
Sodium oxybate is not recommended during pregnancy. 
 
Breast-feeding 
Sodium oxybate and/or its metabolites are excreted into breast milk. Changes in sleep patterns have 
been observed in breastfed infants from exposed mothers, which may be consistent with the effects of 
sodium oxybate on the nervous system. Sodium Oxybate should not be used during breastfeeding. 
 
Fertility 
There is no clinical data available on the effect of sodium oxybate on fertility. Studies in male and 
female rats at doses up to 1,000 mg/kg/day GHB have shown no evidence of an adverse effect on 
fertility.  
 
4.7 Effects on ability to drive and use machines 

 
Sodium oxybate has major influence on the ability to drive and use machines. 
For at least 6 hours after taking sodium oxybate, patients must not undertake activities requiring 
complete mental alertness or motor co-ordination, such as operating machinery or driving.  
When patients first start taking sodium oxybate, until they know whether this medicinal product will 
still have some carryover effect on them the next day, they should use extreme care while driving a 
car, operating heavy machines, or performing any other task that could be dangerous or require full 
mental alertness.  
 



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For paediatric patients, physicians and parents or caregivers are advised that if the daily dose to body 
weight ratio exceeds 0.1g/kg/day, the waiting time may be longer than 6 hours depending on 
individual sensitivity. 
 

4.8 Undesirable effects 

 

Summary of the safety profile 
 
Clinical Studies 
The safety profile was qualitatively the same in adult and paediatric studies. 
 
In adults the most commonly reported adverse reactions were  dizziness, nausea, and headache, all 
occurring in 10% to 20% of patients. The most serious adverse reactions are suicidal attempt, 
psychosis, respiratory depression and convulsion. 
 
In adults the efficacy and safety  of sodium oxybate for the treatment of narcolepsy symptoms was 
established in four multicentre, randomised, double-blind, placebo-controlled, parallel-group trials in 
patients with narcolepsy with cataplexy except for one trial where cataplexy was not required for 
enrolment. Two Phase 3 and one Phase 2 double-blind, parallel-group, placebo-controlled studies were 
performed to assess the indication of sodium oxybate for fibromyalgia in adults. Additionally, 
randomised, double-blind, placebo-controlled, crossover drug-drug interaction studies with ibuprofen, 
diclofenac and valproate were performed in healthy adult subjects and are summarised in section 4.5. 
 
Post-marketing experience  
In addition to the adverse reactions reported during clinical studies, adverse reactions have been 
reported in post-marketing experience. It is not always possible to reliably estimate the frequency of 
their incidence in the population to be treated. 
 
Tabulated summary of adverse reactions 
Undesirable effects are listed according to MedDRA System Organ Class. 
 
Frequency estimate: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 
1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from 
the available data). 
 
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 
 
Infections and infestations 
Common: nasopharyngitis, sinusitis  
 
Immune system disorders 
Uncommon: hypersensitivity 
 
Metabolism and nutrition disorders 
Common: anorexia, decreased appetite 
Not known: Dehydration, increased appetite 
 
Psychiatric disorders 
Common: depression, cataplexy, anxiety, abnormal dreams, confusional state, disorientation, 
nightmares, sleepwalking, sleep disorder, insomnia, middle insomnia, nervousness 
Uncommon: suicide attempt, psychosis, paranoia, hallucination, abnormal thinking, agitation, initial 
insomnia 
Not known: suicidal ideation, homicidal ideation, aggression, euphoric mood, sleep-related eating 
disorder, panic attack, mania / bipolar disorder, delusion, bruxism, irritability and increased libido 
 



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Nervous system disorders 
Very common: dizziness, headache 
Common: sleep paralysis, somnolence, tremor, balance disorder, disturbance in attention, 
hypoaesthesia, paraesthesia, sedation, dysgeusia 
Uncommon:  myoclonus, amnesia, restless legs syndrome 
Not known: convulsion, loss of consciousness, dyskinesia 
 
Eye disorders 
Common: blurred vision 
 
Ear and labyrinth disorders 
Common: vertigo 
Not known tinnitus 
 
Cardiac disorders 
Common: palpitations 
 
Vascular disorders 
Common: hypertension 
 
Respiratory, thoracic and mediastinal disorders 
Common: dyspnoea, snoring, nasal congestion 
Not known: respiratory depression, sleep apnoea, choking sensation  
 
Gastrointestinal disorders 
Very common: nausea (the frequency of nausea is higher in women than men) 
Common: vomiting, diarrhoea, abdominal pain upper, 
Uncommon: faecal incontinence 
Not known: dry mouth  
 
Skin and subcutaneous tissue disorders 
Common: hyperhidrosis, rash 
Not known: urticaria, angioedema, seborrhea 
 
Musculoskeletal and connective tissue disorders 
Common: arthralgia, muscle, spasms, back pain 
 
Renal and urinary disorders 
Common: enuresis nocturna, urinary incontinence 
Not known: pollakiuria / micturition urgency, nocturia 
 
General disorders and administration site conditions 
Common: asthenia, fatigue, feeling drunk, oedema peripheral 
 
Investigations 
Common: blood pressure increased, weight decreased  
 
Injury, poisoning and procedural complications 
Common: fall 
 
Description of selected adverse reactions 
In some patients, cataplexy may return at a higher frequency on cessation of sodium oxybate therapy, 
however this may be due to the normal variability of the disease.  Although the clinical trial 
experience with sodium oxybate in narcolepsy/cataplexy patients at therapeutic doses does not show 
clear evidence of a withdrawal syndrome, in rare cases, adverse reactions such as insomnia, headache, 



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anxiety, dizziness, sleep disorder, somnolence, hallucination, and psychotic disorders were observed 
after GHB discontinuation. 
 
Special Populations 
 
Paediatric population 
In the paediatric population the efficacy and safety of sodium oxybate for the treatment of narcolepsy 
with cataplexy symptoms was established in a phase 2/3 double-blind, placebo-controlled, 
randomized-withdrawal multicenter study.  
 
In a study in children and adolescents the most frequently reported related TEAEs were enuresis 
(18.3%), nausea (12.5%), vomiting (8.7%), and weight decreased (8.7%), decreased appetite (6.7%), 
headache (5.8%), dizziness (5.8%). Adverse drug reactions of suicidal ideation (1%) and of acute 
psychosis (1%) were also reported. (see section 4.4 and section 6).   
 
In some children between 7 and < 18 years, postmarketing surveillance has shown that sodium 
oxybate was discontinued due to abnormal behaviour, aggression and mood alteration. 
 
Reporting of suspected adverse reactions 
Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 

 
4.9 Overdose 

 
Information about signs and symptoms associated with overdose with sodium oxybate is limited.  
Most data derives from the illicit use of GHB. Sodium oxybate is the sodium salt of GHB.  Events 
associated with withdrawal syndrome have been observed outside the therapeutic range. 
 
Symptoms 
Patients have exhibited varying degrees of depressed consciousness that may fluctuate rapidly 
between a confusional, agitated combative state with ataxia and coma.  Emesis (even with impaired 
consciousness), diaphoresis, headache, and impaired psychomotor skills may be observed.  Blurred 
vision has been reported.  An increasing depth of coma has been observed at higher doses.  
Myoclonus and tonic-clonic seizures have been reported.  There are reports of compromise in the rate 
and depth of respiration and of life-threatening respiratory depression, necessitating intubation and 
ventilation. Cheyne-Stokes respiration and apnoea have been observed.  Bradycardia and hypothermia 
may accompany unconsciousness, as well as muscular hypotonia, but tendon reflexes remain intact. 
Bradycardia has been responsive to atropine intravenous administration. Events of hypernatremia with 
metabolic alkalosis have been reported in the context of concomitant use of NaCl infusion.  
 
Management 
Gastric lavage may be considered if co-ingestants are suspected. Because emesis may occur in the 
presence of impaired consciousness, appropriate posture (left lateral recumbent position) and 
protection of the airway by intubation may be warranted.  Although gag reflex may be absent in 
deeply comatose patients, even unconscious patients may become combative to intubation, and rapid 
sequence induction (without the use of sedative) should be considered. 
 
No reversal of the central depressant effects of sodium oxybate can be expected from flumazenil 
administration. There is insufficient evidence to recommend the use of naloxone in the treatment of 
overdose with GHB. The use of haemodialysis and other forms of extracorporeal medicinal product 
removal have not been studied in sodium oxybate overdose.  However, due to the rapid metabolism of 
sodium oxybate, these measures are not warranted. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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5. PHARMACOLOGICAL PROPERTIES 

 
5.1 Pharmacodynamic properties 

 
Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX04.  

Mechanism of action 

Sodium oxybate is a central nervous system depressant which reduces excessive daytime sleepiness 
and cataplexy in patients with narcolepsy and modifies sleep architecture reducing fragmented 
nighttime sleep. The precise mechanism by which sodium oxybate produces an effect 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 (SOREMPs). 
Other mechanisms, which have yet to be elucidated, may also be involved. In the clinical trial 
database, greater than 80 % of patients maintained concomitant stimulant use. 
 
Adults 
 
The effectiveness of sodium oxybate for the treatment of narcolepsy symptoms was established in 
four multicentre, randomised, double-blind, placebo-controlled, parallel-group trials (Trial 1, 2, 3 and 
4) in patients with narcolepsy with cataplexy except for trial 2 where cataplexy was not required for 
enrolment  Concomitant stimulant use was permitted in all trials (except for the active-treatment 
phase of Trial 2); antidepressants were withdrawn prior to active treatment in all trials with the 
exception of Trial 2. In each trial, the daily dose was divided into two equal doses. The first dose each 
night was taken at bedtime and the second dose was taken 2.5 to 4 hours later. 
 
 
Table 2 Summary of clinical trials performed using sodium oxybate for the treatment of 

narcolepsy 

 
Trial Primary 

Efficacy 

N Secondary Efficacy Duration Active 

treatment 

and Dose 

(g/d) 

Trial 
1 

EDS (ESS); 
CGIc 

246 MWT/Sleep 
Architecture/ 

Cataplexy/Naps/FOSQ 

8 weeks Sodium 
oxybate4.5 - 9 

Trial 
2 

EDS (MWT) 231 Sleep Architecture/ 
ESS/CGIc/Naps 

8 weeks Sodium 
oxybate 6 – 9 

Modafinil 
200-600 mg 

Trial 
3 

Cataplexy 136 EDS (ESS)/CGIc/Naps 4 weeks Sodium 
oxybate 3 - 9 

Trial 
4 

Cataplexy 55 None 4 weeks Sodium 
oxybate 3 - 9 

EDS – Excessive daytime sleepiness; ESS – Epworth Sleepiness Scale; MWT – Maintenance of 
Wakefulness Test; Naps – Number of inadvertent daytime naps; CGIc – Clinical Global Impression of 
Change; FOSQ – Functional Outcomes of Sleep Questionnaire 
 



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Trial 1 enrolled 246 patients with narcolepsy and incorporated a 1 week up-titration period.  The 
primary measures of efficacy were changes in excessive daytime sleepiness as measured by the 
Epworth Sleepiness Scale (ESS), and the change in the overall severity of the patient’s narcolepsy 
symptoms as assessed by the investigator using the Clinical Global Impressions of Change (CGI-c) 
measure. 
 

Table 3 Summary of ESS in Trial 1 

 

Epworth Sleepiness Scale (ESS; range 0-24) 
Dose Group [g/d 

(n)] 
Baseline Endpoint Median Change 

from Baseline 
Change from Baseline 
Compared to Placebo 

(p-value) 
Placebo (60) 17.3 16.7 -0.5 - 
4.5 (68) 17.5 15.7 -1.0 0.119 
6 (63) 17.9 15.3 -2.0  0.001 
9 (55) 17.9 13.1 -2.0 < 0.001 

 
Table 4 Summary of CGI-c in Trial 1 

 
Clinical Global Impressions of Change (CGI-c) 

Dose Group [g/d (n)] Responders* 
N (%) 

Change from Baseline Compared 
to Placebo 
(p-value) 

Placebo (60) 13 (21.7) - 
4.5 (68) 32 (47.1) 0.002 
6 (63) 30 (47.6) < 0.001 
9 (55) 30 (54.4) < 0.001 

 
* The CGI-c data were analysed by defining responders as those patients who were very much 
improved or much improved.   
 
Trial 2 compared the effects of orally administered sodium oxybate, modafinil and sodium oxybate + 
modafinil, with placebo in the treatment of daytime sleepiness in narcolepsy.  During the 8 week 
double-blind period, patients took modafinil at their established dose or placebo equivalent.  The 
sodium oxybate or placebo equivalent dose was 6 g/day for the first 4 weeks and was increased to 
9 g/day for the remaining 4 weeks.  The primary measure of efficacy was excessive daytime 
sleepiness as measured by objective response in MWT.   
 
Table 5 Summary of MWT in Trial 2 

 
TRIAL 2 

Dose Group Baseline Endpoint Mean Change from 
Baseline 

Endpoint 
Compared to 

Placebo 
Placebo (56) 9.9 6.9 -2.7 - 
Sodium Oxybate 
(55) 

11.5 11.3 0.16 <0.001 

Modafinil (63) 10.5 9.8 -0.6 0.004 
Sodium Oxybate + 
Modafinil (57) 

10.4 12.7 2.3 <0.001 

 
Trial 3 enrolled 136 narcoleptic patients with moderate to severe cataplexy (median of 21 cataplexy 
attacks per week) at baseline.  The primary efficacy measure in this trial was the frequency of 
cataplexy attacks. 



14 

 
 
Table 6 Summary of outcomes in Trial 3 

 
Dosage Number of 

Subjects 

Cataplexy Attacks 

Trial 3 Baseline Median Change 
from Baseline 

Change from 
Baseline 

Compared to 
Placebo (p-value) 

 Median attacks/week 
Placebo 33 20.5 -4 - 
3.0 g/day 33 20.0 -7 0.5235 
6.0 g/day 31 23.0 -10 0.0529 
9.0 g/day 33 23.5 -16 0.0008 

 
Trial 4 enrolled 55 narcoleptic patients who had been taking open-label sodium oxybate for 7 to 
44 months. Patients were randomised to continued treatment with sodium oxybate at their stable dose 
or to placebo. Trial 4 was designed specifically to evaluate the continued efficacy of sodium oxybate 
after long-term use. The primary efficacy measure in this trial was the frequency of cataplexy attacks. 
 
Table 7 Summary of outcome in Trial 4 

 

Treatment 

Group 

Number of 

Subjects 

Cataplexy Attacks 

Trial 4 Baseline Median Change 
from Baseline 

Change from 
Baseline 

Compared to 
Placebo (p-value) 

 Median attacks/two weeks 
Placebo 
 

29 4.0 21.0 - 

Sodium oxybate 26 1.9 0 p <0.001 
 
In Trial 4, the response was numerically similar for patients treated with doses of 6 to 9 g/day, but 
there was no effect seen in patients treated with doses less than 6 g/day. 
 
Paediatric population 
 
The effectiveness of sodium oxybate in paediatric patients with narcolepsy with cataplexy, was 
established in a double-blind, placebo-controlled, randomized-withdrawal, multicentre trial.  
 
This study demonstrated the clinical efficacy of sodium oxybate in the treatment of cataplexy and 
Excess Daytime Sleepiness (EDS) in narcolepsy in pediatric subjects. 
63 patients were randomized in the efficacy population where the primary efficacy endpoint in this 
trial was the change in number of weekly cataplexy attacks between the last two weeks of the stable 
dose period and the double-blind period. 
 
During the double-blind period, the median (Q1, Q3) change from baseline (i.e. the last 2 weeks of the 
stable dose period) in the weekly number of cataplexy attacks was 12.71 (3.44, 19.77) for patients 
randomized to placebo and 0.27 (-1.00, 2.50) for patients randomized to sodium oxybate.  
 
 



15 

Table 8 Summary of outcome in study 13-005 in children / adolescents  

 

Treatment Group Number of 

Patients 

      

Weekly Number of Cataplexy Attacks (median) 

Baseline                      

(i.e. Last 2 weeks 
of stable dose 
period) 

Double-blind 

period 

Change from 

Baseline 

                       
Placebo 
 

32 4.67 21.25 12.71 

Sodium oxybate 31 3.50 3.77 0.27 
p-value < 0.0001 
 
When subgroup analyses by age group (7-11 years and 12-17 years) were conducted for the primary 
endpoint, similar results were observed. During the Double-blind Treatment Period, among subjects 
aged 7 to 11 years, the median (Q1, Q3) change from baseline in the weekly number of cataplexy 
attacks was 18.32 (7.58, 35.75) for subjects randomized to Placebo and 0.13 (-1.15, 2.05) for subjects 
randomized to sodium oxybate (p < 0.0001). During the Double-blind Treatment Period, among 
subjects aged 12 to 17 years, the median (Q1, Q3) change from baseline in the weekly number of 
cataplexy attacks was 9.39 (1.08, 16.12) for subjects randomized to Placebo and 0.58 (-0.88, 2.58) for 
subjects randomized to sodium oxybate (p = 0.0044) 
 
During the Double-blind Treatment Period, the median (Q1, Q3) change of the secondary endpoint 
(change in ESS scores) from baseline (which occurred at Visit 3 – the end of the Stable Dose Period) 
in Epworth Sleepiness Scale for Children and Adolescent (ESS-CHAD) score was 3.0 (1.0, 5.0) for 
subjects randomized to Placebo and 0.0 (-1.0, 2.0) for subjects randomized to sodium oxybate. The 
comparison of the rank change from baseline between treatments was statistically significant (p = 
0.0004) when analyzed by ANCOVA modeling containing treatment as a factor and rank baseline 
value as a covariate. Subjects randomized to Placebo had, on average, higher ESS (CHAD) scores at 
baseline compared to those on sodium oxybate. 
 

Table 9 Summary of ESS (CHAD) Score during the Double-blind Treatment Period (Efficacy  

Population)             

 
 Treatment Group  Number of 

Patients 

      

Change in ESS (CHAD) Score (median) 

Baseline                      

(Visit 3-End of 
Stable Dose 
Period) 

End of Double-

blind Treatment 

Period (Visit 4) 

Change from 

Baseline 

                       
Placebo 
 

32 11.0 12.0 3.0 

Sodium oxybate 31 8.0 9.0 0.0 
p-value 0.0004 
Abbreviations: ESS (CHAD) = Epworth Sleepiness Scale for Children and Adolescents  
 
 
5.2 Pharmacokinetic properties 

 
Sodium oxybate is rapidly and almost completely absorbed after oral administration; absorption is 
delayed and decreased by a high fat meal.  It is eliminated mainly by metabolism with a half-life of 
0.5 to 1 hour.  Pharmacokinetics is nonlinear with the area under the plasma concentration curve 
(AUC) versus time curve increasing 3.8-fold as dose is doubled from 4.5 g to 9 g. The 
pharmacokinetics is not altered with repeat dosing. 
 



16 

 
Absorption  
Sodium oxybate is absorbed rapidly following oral administration with an absolute bioavailability of 
about 88 %.  The average peak plasma concentrations (1st and 2nd peak) following administration of 
a 9 g daily dose divided into two equivalent doses given four hours apart were 78 and 142 µg/mL, 
respectively.  The average time to peak plasma concentration (Tmax) ranged from 0.5 to 2 hours in 
eight pharmacokinetic studies.  Following oral administration, the plasma levels of sodium oxybate 
increase more than proportionally with increasing dose.  Single doses greater than 4.5 g have not been 
studied.  Administration of sodium oxybate immediately after a high fat meal resulted in delayed 
absorption (average Tmax increased from 0.75 hr to 2.0 hr) and a reduction in peak plasma level 
(Cmax) by a mean of 58 and of systemic exposure (AUC) by 37

 
Distribution  
Sodium oxybate is a hydrophilic compound with an apparent volume of distribution averaging 190-
384 mL/kg.  At sodium oxybate concentrations ranging from 3 to 300 µg/mL, less than 1% is bound 
to plasma proteins. 
 
Biotransformation  
Animal studies indicate that metabolism is the major elimination pathway for sodium oxybate, 
producing carbon dioxide and water via the tricarboxylic acid (Krebs) cycle and secondarily by -
oxidation.  The primary pathway involves a cytosolic NADP+-linked enzyme, GHB dehydrogenase, 
that catalyses the conversion of sodium oxybate to succinic semialdehyde, which is then 
biotransformed to succinic acid by the enzyme succinic semialdehyde dehydrogenase.  Succinic acid 
enters the Krebs cycle where it is metabolised to carbon dioxide and water.  A second mitochondrial 
oxidoreductase enzyme, a transhydrogenase, also catalyses the conversion to succinic semialdehyde in 
the presence of -ketoglutarate.  An alternate pathway of biotransformation involves -oxidation via 
3,4-dihydroxybutyrate to Acetyl CoA, which also enters the citric acid cycle to result in the formation 
of carbon dioxide and water.  No active metabolites have been identified. 
 
Studies in vitro with pooled human liver microsomes indicate that sodium oxybate does not 
significantly inhibit the activities of the human isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, 
CYP2E1, or CYP3A up to the concentration of 3 mM (378 µg/mL).  These levels are considerably 
higher than levels achieved with therapeutic doses. 
 
Elimination  
The clearance of sodium oxybate is almost entirely by biotransformation to carbon dioxide, which is 
then eliminated by expiration.  On average, less than 5% of unchanged medicinal product appears in 
human urine within 6 to 8 hours after dosing. Faecal excretion is negligible. 
 
Special populations 
 
Elderly 
In a limited number of patients greater than the age of 65 years the pharmacokinetics of sodium 
oxybate was not different compared to patients younger than 65 years of age. 
 
Paediatric population 
The major pharmacokinetic characteristics of sodium oxybate in paediatric subjects are the same as 
those reported in pharmacokinetic studies of sodium oxybate in adults 
 
Paediatric and adult subjects receiving the same mg/kg dose have similar plasma concentration-time 
profiles. (see section 4.2)  
 
Renal impairment 
Because the kidney does not have a significant role in the excretion of sodium oxybate, no 
pharmacokinetic study in patients with renal dysfunction has been conducted; no effect of renal 
function on sodium oxybate pharmacokinetics would be expected. 



17 

 
Hepatic impairment 
Sodium oxybate undergoes significant presystemic (hepatic first-pass) metabolism.  After a single oral 
dose of 25 mg/kg, AUC values were double in cirrhotic patients, with apparent oral clearance reduced 
from 9.1 in healthy adults to 4.5 and 4.1 mL/min/kg in Class A (without ascites) and Class C (with 
ascites) patients, respectively.  Elimination half-life was significantly longer in Class C and Class A 
patients than in control subjects (mean t1/2 of 59 and 32 versus 22 minutes).  The starting dose should 
be halved in all patients with hepatic impairment, and response to dose increments monitored closely 
(see section 4.2). 
 
Race 
The effect of race on metabolism of sodium oxybate has not been evaluated. 
 
5.3 Preclinical safety data 

 
Repeat administration of sodium oxybate to rats (90 days and 26 weeks) and dogs (52 weeks) did not 
result in any significant findings in clinical chemistry and micro- and macro pathology. Treatment-
related clinical signs were mainly related to sedation, reduced food consumption and secondary 
changes in body weight, body weight gain and organ weights. The rat and dog exposures at the NOEL 
were lower (~50%) than that in humans.  Sodium oxybate was non-mutagenic and non-clastogenic in 
in vitro and in vivo assays.  
 

Gamma Butyrolactone (GBL), a pro-drug of GHB tested at exposures similar to the expected in man 
(1.21-1.64 times) has been classified by NTP as non-carcinogenic in rats and equivocal carcinogen in 
mice, due to slight increase of pheochromocytomas which was difficult to interpret due to high 
mortality in the high dose group. In a rat carcinogenicity study with oxybate no compound-related 
tumours were identified.  
 
GHB had no effect on mating, general fertility or sperm parameters and did not produce embryo-
foetal toxicity in rats exposed to up 1000 mg/kg/day GHB (1.64 times the human exposure calculated 
in nonpregnant animals). Perinatal mortality was increased and mean pup weight was decreased 
during the lactation period in high-dose F1 animals. The association of these developmental effects 
with maternal toxicity could not be established. In rabbits, slight foetotoxicity was observed. 
 
In a 10-week repeat dose toxicity study conducted in juvenile rats treated from postnatal day 21 to 90, 
sodium oxybate produced adverse effects including mortalities during the first week of treatment, 
when animals were 21 to 27 days old, corresponding to an approximate age of 3-4 years in children. 
Acute toxicity appeared at exposures below those expected in paediatric patients and mortality was 
preceded by sodium oxybate-related clinical signs (bradypnea, deep breathing, decreased activity, 
uncoordinated gait, impaired righting reflex), in line with its expected pharmacology. The reason for 
this relatively stronger toxicity during the first week of treatment is not fully clear. It could be related 
to the fact that young animals appear to exhibit higher systemic exposure than older juvenile rats. It 
could also be due to higher sensitivity of pups to sodium oxybate compared to older juvenile and adult 
rats and/or to a tolerance development phenomenon.  Reduced body weight and food consumption 
similarly as in adults were also observed, with additional respiratory signs (deep and slow breathing). 
Sodium oxybate did not produce adverse effects on growth and development up to exposure levels 2- 
to 4-fold higher than the exposure expected at the maximum recommended dose in paediatric subjects 
(200mg/kg/day in paediatric patients with body weight less than 45kg or 9g/day for paediatric patients 
with body weight ≥45kg).   
 
Drug discrimination studies show that GHB produces a unique discriminative stimulus that in some 
respects is similar to that of alcohol, morphine and certain GABA-mimetic medicinal products. Self-
administration studies in rats, mice and monkeys have produced conflicting results, whereas tolerance 
to GHB as well as cross-tolerance to alcohol and baclofen has been clearly demonstrated in rodents. 
 

 



18 

6. PHARMACEUTICAL PARTICULARS 

 
6.1 List of excipients 

 
Purified water 
Malic acid for pH adjustment 
Sodium hydroxide for pH adjustment 
 
6.2 Incompatibilities 

 
This medicinal product must not be mixed with other medicinal products. 
 
6.3 Shelf life 

 
5 years 
 
After first opening: 90 days 
 
After dilution in the dosing cups, the preparation should be used within 24 hours. 
 
6.4 Special precautions for storage 

 
This medicinal product does not require any special storage conditions. 
For storage conditions after first opening of the medicinal product, see section 6.3 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container and special equipment for use 

 
180 mL solution in an amber oval 240 mL PET bottle which is delivered with a plastic/foil seal and 
closed with a child resistant closure composed of HDPE/polypropylene with a pulpboard inner liner. 
 
Each carton contains one bottle, a press-in bottle adaptor, a graduated measuring device 
(polypropylene syringe), two polypropylene dosing cups and two HDPE child resistant screw 
closures. 
 
6.6 Special precautions for disposal  

 
No special requirements 
 

 

7. MARKETING AUTHORISATION HOLDER 

 

UCB Pharma SA  
Allée de la Recherche 60   
B-1070 Brussels  
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER 

 
EU/1/05/312/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION 

 

Date for first authorisation: 13 October 2005 



19 

Date of latest renewal: 08 September 2015 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/ 
 

 



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 

 
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 



21 

A MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer responsible for batch release 
 
UCB Pharma Ltd                    or                    UCB Pharma S.A., 
208 Bath Road,     Chemin du Foriest, 
Slough,      B-1420 Braine l'Alleud, 
Berkshire SL1 3WE,    Belgium 
United Kingdom 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to special and restricted medical prescription (See Annex I: Summary of 
Product Characteristics, section 4.2). 
 
 
C OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 
 Periodic Safety Update Reports 

 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
 Risk Management Plan (RMP) 

 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted:  

 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 
 Additional risk minimisation measures 

The Marketing Authorisation Holder (MAH) shall develop an educational programme for Xyrem to 
ensure that physicians who intend to prescribe Xyrem are aware about the posology of Xyrem and the 
important risks. The five components of this comprehensive program are: 

 Healthcare Professional Checklist (i.e. forms for treatment initiation and follow-up visits) : to 
remind physicians to check the following:   



22 

a. contraindications, warnings, and precautions in the SmPC and specifically 
highlighting that Xyrem can cause CNS and respiratory depression, that alcohol may 
result in the potentiation of CNS depression and that Xyrem has an abuse potential. 

b. For pediatric patients: height, weight, learning, social and psychiatric behaviour   
 Frequently Asked Questions (FAQ) for patients (to be given to the patient): to provide 

patients with responses to some questions they might have about taking Xyrem. 
 Patient instructions for administration of sodium oxybate (to be given to the patient): to 

provide patients with information related to the use of Xyrem. 
 Xyrem guide for pediatric patients and their caregivers to provide information about the safe 

use and handling of sodium oxybate. 
 Patient Alert Card (to be given to the patient): to remind patients, caregivers, and physicians 

of the important safety information related to the use of Xyrem. 
 
The MAH has established a controlled distribution program that enhances existing controls for Xyrem 
to allow reaching the intended population of narcolepsy patients while minimizing the risk of Xyrem 
being diverted by those seeking to misuse it. 
 



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



25 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 

OUTER PACKAGING  

 

Carton and bottle 

 
 
1. NAME OF THE MEDICINAL PRODUCT 

 
Xyrem 500 mg/mL oral solution 
Sodium oxybate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE 

 
Each mL of solution contains 500 mg sodium oxybate 
 
 
3. LIST OF EXCIPIENTS 

 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 

 
One bottle of 180 mL oral solution 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 
Read the package leaflet before use. 
Oral use.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 
 
 
8. EXPIRY DATE 

 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
The medicinal product should be used within 90 days after the first opening. 
After dilution in the dosing cups the preparation should be used within 24 hours. 
 
 
 



26 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 
 
UCB Pharma SA  
Allée de la Recherche 60  
B-1070 Brussels  
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER 

 
EU/1/05/312/001 
 
 
13. BATCH NUMBER 

 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 

 
Medicinal product subject to medical prescription 
 
15. INSTRUCTIONS ON USE 

 
 
16. INFORMATION IN BRAILLE 

 
Xyrem 500 mg/mL (applies to carton only) 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 

 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 
PC:  
SN:  
NN:  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



28 

Package leaflet: Information for the user 
 

Xyrem 500 mg/mL oral solution 

Sodium oxybate 
 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or your pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet:  
1. What Xyrem is and what it is used for 
2. What you need to know before you take Xyrem 
3. How to take Xyrem 
4. Possible side effects 
5 How to store Xyrem 
6. Contents of the pack and other information 
 
 
1. What Xyrem is and what it is used for 
 
Xyrem contains the active substance sodium oxybate. Xyrem works by consolidating night-time sleep, 
though its exact mechanism of action is unknown. 
 
Xyrem is used to treat narcolepsy with cataplexy in adults, adolescents and children from 7 years of 
age.  
 
Narcolepsy is a sleep disorder that may include attacks of sleep during normal waking hours, as well 
as cataplexy, sleep paralysis, hallucinations and poor sleep.  Cataplexy is the onset of sudden muscle 
weakness or paralysis without losing consciousness, in response to a sudden emotional reaction such 
as anger, fear, joy, laughter or surprise. 
 
 
2. What you need to know before you take Xyrem 
 
Do not take Xyrem 
- if you are allergic to sodium oxybate or any of the other ingredients of this medicine (listed in 

section 6); 
- if you have succinic semialdehyde dehydrogenase deficiency (a rare metabolic disorder); 
- if you suffer from major depression; 
- if you are being treated with opioid or barbiturate medicines. 

 
 
Warnings and precautions 

Talk to your doctor or pharmacist before taking Xyrem: 
- if you have breathing or lung problems (and especially if you are obese), because Xyrem has 

the potential to cause difficulty in breathing; 
- if you have or have previously had depressive illness, suicidal thoughts, anxiety, psychosis (a 

mental disorder that may involve hallucinations, incoherent speech, or disorganized and 
agitated behaviour) or bipolar disorder  

- if you have heart failure, hypertension (high blood pressure), liver or kidney problems as your 
dose may need to be adjusted; 



29 

- if you have previously abused drugs; 
- if you suffer from epilepsy as the use of Xyrem is not recommended in this condition; 
- if you have porphyria (an uncommon metabolic disorder). 
 
If any of these apply to you, tell your doctor before you take Xyrem. 
 
While you are taking Xyrem, if you experience bed wetting and incontinence (both urine and faeces), 
confusion, hallucinations, episodes of sleepwalking or abnormal thinking you should tell your doctor 
straight away. Whilst these effects are uncommon, if they do occur they are usually mild-to-moderate 
in nature. 
 
If you are elderly, your doctor will monitor your condition carefully to check whether Xyrem is 
having the desired effects. 
 
Xyrem has a well-known abuse potential. Cases of dependency have occurred after the illicit use of 
sodium oxybate. 
 
Your doctor will ask if you have ever abused any drugs before you start taking Xyrem and whilst you 
are using the medicine. 
 
Children and adolescents 

Xyrem can be taken by adolescents and children from 7 years of age when they are over 15 kg in 
weight. 
 
Xyrem cannot be taken by children below 7 years of age or below 15 kg in weight.   
 
If you are a child or adolescent, your doctor will monitor your body weight regularly. 
 
Whilst the doctor is adjusting the dose which may take a number of weeks, parent/caregivers should 
carefully monitor the child’s breath during the first 2 hours after sodium oxybate intake to assess if 
there is any abnormality in breathing, for example stoppage of breathing for short periods while 
sleeping, noisy breathing and bluish colour of the lips and face. If abnormality in breathing is 
observed medical support should be sought and the doctor should be informed as soon as possible. If 
any abnormality is noted after the first dose, the second dose should not be administered. If no 
abnormality is noted the second dose can be administered. The second dose should not be given 
earlier than 2.5 hours or later than 4 hours after the first dose.  
 
If you have had or are having upsetting feelings particularly if you are feeling very sad or have lost 
interest in life it is important that you tell the doctor or caregiver. 
 
 

Other medicines and Xyrem 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
In particular Xyrem should not be taken together with sleep inducing medicines and medicines that 
reduce central nervous system activity (the central nervous system is the part of the body related to the 
brain and spinal cord).  
 
Also tell your doctor or pharmacist if you are taking any of the following types of medicines: 

 medicines that increase central nervous system activity  
 antidepressants 
 medicines that may be processed in a similar way by the body (e.g., valproate, phenytoin or 

ethosuximide which are used for the treatment of fits) 
 topiramate (used for treatment of epilepsy) 



30 

 
If you are taking Valproate, your daily dose of Xyrem will need to be adjusted (see section 3) as it 
may lead to interactions with Valproate 
 

Xyrem with alcohol 
You must not drink alcohol while taking Xyrem, as its effects can be increased. 
 
Pregnancy and breast-feeding  

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. 
There have been very few women who have taken Xyrem sometime during their pregnancy and a few 
of them had spontaneous abortions. The risk of taking Xyrem during pregnancy is unknown, and, 
therefore, the use of Xyrem in pregnant women or women trying to become pregnant is not 
recommended.  
 
Patients taking Xyrem should not breast feed since it is known that Xyrem passes into breast milk. 
Changes in sleep patterns have been observed in breastfed infants from exposed mothers. 
 

Driving and using machines 
Xyrem will affect you if you drive or operate tools or machines. Do not drive a car, operate heavy 
machinery, or perform any activity that is dangerous or that requires mental alertness for at least 6 
hours after taking Xyrem. When you first start taking Xyrem, until you know whether it makes you 
sleepy the next day, use extreme care while driving a car, operating heavy machinery or doing 
anything else that could be dangerous or needs you to be fully mentally alert.  
 
For paediatric patients, physicians, parents or caregivers are advised that the waiting time for 
performing activities that require mental alertness, motor co-ordination or any activities that may have 
a physical risk may have to be longer than 6 hours, depending on individual sensitivity.  
 
Xyrem contains sodium 

You need to monitor the amount of salt you take as Xyrem contains sodium (which is found in table 
salt) which may affect you if you have had high blood pressure, heart or kidney problems in the past.. 
In every 1 g dose of sodium oxybate (Xyrem), there is 0.18 g of sodium. You may need to moderate 
your intake of salt. 
 
 
3. How to take Xyrem 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.   
 
It is important that you only use the syringe provided in the box when preparing doses of Xyrem. The 
Xyrem syringe has two different measurement scales, one scale may be more helpful for you than the 
other depending on which dose your doctor has prescribed. By looking at each scale you will see 
which one provides the exact mark for your dose. 
 
Adults – taking Xyrem on its own  

 For adults the recommended starting dose is 4.5 g each day, given as two seperate doses of 
2.25 g. 

 Your doctor may gradually increase your dose up to a maximum of 9 g each day given as two 
separate doses of 4.5 g. 

 Take Xyrem orally two times each night:  
- Take the first dose upon getting into bed and the second dose  2½ to 4 hours later. You 

may need to set an alarm clock to make sure you wake up to take the second dose.   
- Food decreases the amount of Xyrem that is absorbed by your body. Therefore, it is best 

to take Xyrem at set times 2 to 3 hours after a meal.  



31 

- Prepare both doses before bedtime.   
- Take doses within 24 hours after preparation. 

Adolescents and children aged 7 years and over who weigh 15 kg or more - taking Xyrem on its 

own  

For those aged 7 years and over who weigh 15 kg or more, a doctor will work out the right dose based 
on your body weight.  
 
Your doctor will work out the right dose for you. Do not exceed the dose prescribed for you. 
 
 
Adults - taking Xyrem with Valproate  
If you are taking valproate together with Xyrem, the dose of Xyrem will be adapted by your doctor.  
 

 For adults the recommended starting dose for Xyrem, when used together with Valproate, is 
3.6 g each day, given as two separate doses of 1.8 g.  

 Take the first dose when getting into bed and the second dose 2½ to 4 hours later.   
 
Adolescents and children aged 7 years and older who weigh 15 kg or more - taking Xyrem with 

Valproate  

If you are taking Valproate together with Xyrem, the dose of Xyrem will be adapted by your doctor.  
 
Kidney or liver problems  

 If you have kidney problems, you should consider a dietary recommendation to reduce sodium 
(salt) intake.If you have liver problems, the starting dose should be halved. Your doctor may 
gradually increase your dose. 

 
Instructions on how to dilute Xyrem 
 

The following instructions explain how to prepare Xyrem. Please read the instructions carefully and 
follow them step by step. Do not allow children to prepare Xyrem.  
 
To help you, the Xyrem carton contains 1 bottle of medicine, a measuring syringe (with two different 
measurement scales) and two dosing cups with child-resistant caps. 
 
 

Step 1  

 Remove the bottle cap by pushing down while turning the cap 
anticlockwise (to the left).  

 After removing the cap, set the bottle upright on a table-top.  
 There is a plastic covered foil seal on the top of the bottle, which must be 

removed before using the bottle for the first time.  
 While holding the bottle in its upright position, insert the press-in-bottle-

adaptor into the neck of the bottle. This needs only to be done the first 
time that the bottle is opened. The adaptor can then be left in the bottle 
for all subsequent uses 
 
 
 
 
 
 
 
 
 
 



32 

 
Step 2 

 Next, insert the tip of the measuring syringe into the centre opening 
of the bottle and press down firmly  

 While holding the bottle and syringe with one hand, draw up the 
prescribed dose with the other hand by pulling on the plunger.  
NOTE: Medicine will not flow into the syringe unless you keep the 
bottle in its upright position  

 
 
 
 
Step 3                                                                                                                                                                                    

 Remove the syringe from the centre opening of the bottle.  
 Empty the medicine from the syringe into one of the dosing cups 

provided by pushing on the plunger Repeat this step for the second 
dosing cup.  

 Then add about 60 ml of water to each dosing cup (60 mL is about 
4 tablespoons).  

 
      
Step 4 

 Place the caps provided on the dosing cups and turn each cap clockwise 
(to the right) until it clicks and locks into its child-resistant position  

 Rinse out the syringe with water.  
 

 
 
 

 
 

 Just before going to sleep:  
- Adult patients should place the second dose near their bed .  
- The parent or caregiver of adolescents and children aged 7 years and over should not leave the 

second dose near the child’s bed or within easy reach of the child. 
- You may need to set an alarm so you wake up to take your second dose no earlier than 2½ 

hours and no later than 4 hours after your first dose.   
 

Then: 
o Remove the cap from the first dosing cup by pressing down on the child-resistant locking tab 

and turning the cap anticlockwise (to the left).   
o Drink all of the first dose while sitting in bed, recap the cup, and then lie down right away. For 

children who sleep longer than 8 hours but less than 12 hours, the first dose may be given after 
the child has been sleeping for 1 to 2 hours.  

-   
 

 When you wake up or wake up the child  2 ½ to 4 hours later, remove the cap from the second 
dosing cup. While sitting in bed, drink all of the second dose right before lying down to 
continue sleeping. Recap the second cup. 

 
If you have the impression that the effect of Xyrem is too strong or too weak, talk to your doctor or 
pharmacist. 
 
 

 



33 

If you take more Xyrem than you should 

Symptoms of Xyrem overdose may include agitation, confusion, impaired movement, impaired 
breathing, blurred vision, profuse sweating, headache, vomiting, decreased consciousness leading to 
coma and seizures, excessive thirst, muscle cramps and weakness. If you take more Xyrem than you 
were told to take, or take it by accident, get emergency medical help right away. You should take the 
labelled medicine bottle with you, even if it is empty. 
 

If you forget to take Xyrem 
If you forget to take the first dose, take it as soon as you remember and then continue as before.  If 
you miss the second dose, skip that dose and do not take Xyrem again until the next night. Do not take 
a double dose to make up for a forgotten dose. 
 
If unsure if you took Xyrem 

If in doubt about administration of a dose, do not re-administer the dose to reduce the risk of overdose  
 
If you stop taking Xyrem 

You should continue to take Xyrem for as long as instructed by your doctor. You may find that your 
cataplexy attacks return if your medicine is stopped and you may experience insomnia, headache, 
anxiety, dizziness, sleeping problems, sleepiness, hallucination and abnormal thinking. 
If you stop taking Xyrem for more than 14 consecutive days, you should consult your doctor as you 
should restart taking Xyrem at a reduced dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. These are 
usually mild to moderate.. 
 
 
Adults - most common side effects observed in clinical studies (occurring in 10% to 20% of 
patients): 
 dizziness 
 nausea 
 headache. 

 
If you experience any of these side effects, tell your doctor straight away. 

  

Children and adolescents - most common side effects observed in a clinical study: 

 bed wetting (18.3%) 
 nausea (12.5%) 
 vomiting (8.7%) 
 weight decrease (8.7%) 
 decreased appetite (6.7%) 
 headache (5.8%)  
 dizziness (5.8%) 
 suicidal thoughts (1%)  
 feeling mentally unwell (loss of contact with reality) (1%) 

 
If you experience any of these side effects, tell your doctor straight away 

 

 



34 

The side effects in adults and children are the same.  If you experience any of the side effects listed 
below, tell your doctor straight away:  
 
Very common (may affect more than 1 in 10 people): 

  nausea 
 dizziness 
 headache 
  
Common (may affect up to 1 in 10 people): 
  sleeping problems including insomnia, abnormal dreams, sleep paralysis, sleepiness, nightmares, 

sleep walking, bed wetting, excessive daytime sleepiness, difficulty in falling asleep in the middle 
of the night 

 feeling drunk, trembling, confusion/ disorientation, blurred vision, balance disorder, fall, feeling of 
“spinning” (vertigo), 

 feeling the heart beat, increased blood pressure, shortness of breath 
 vomiting, stomach pains, diarrhoea 
 anorexia, decreased appetite, weight loss 
 weakness, tiredness, sedation 
 sweating  
 depression 
 muscle cramps, swelling  
 joint pain, back pain  
 disturbance in attention, disturbed sensitivity particularly to touch, abnormal touch sensation, 

abnormal taste 
 anxiety, nervousness 
 urinary incontinence 
 snoring, congestion of the nose 
 rash 
 inflammation of the sinuses,inflammation of nose and throat  
 

Uncommon (may affect up to 1 in 100 people): 
  psychosis (a mental disorder that may involve hallucinations, incoherent speech, or disorganized 

and agitated behaviour)  
 paranoia, abnormal thinking, hallucination, agitation, suicide attempt  
 difficulty in falling asleep, restless legs 
 forgetfulness  
 myoclonus (involuntary contractions of muscles) 
 involuntary passage of faeces 
 hypersensitivity 
 

Not known (cannot be estimated from the available data): 

  convulsion 
 decreased breathing depth or rate, short cessation of breathing during sleep 
 hives 
 suicidal thoughts, delusion, thoughts of committing violent acts (including harming others)  
 irritability, aggression 
 euphoric mood 
 panic attack 
 mania / bipolar disorder  
 dry mouth, dehydration 
 swelling face (angioedema)  
 bruxism (teeth grinding and jaw clenching) 
 pollakiuria / micturition urgency (increase need to urinate)  
 tinnitus (noise in the ears such as ringing or buzzing)  
 sleep-related eating disorder 
 increased appetite  



35 

 loss of consciousness 
 dyskinesia (e.g. abnormal, uncontrolled movements of the limbs)  
 dandruff 
 increased sexual desire 
 nocturia (excessive urination at night) 
 choking sensation 

 
 
If you experience any of the side effects listed above, tell your doctor straight away.  

 

 

Reporting of side effects  
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety 
of this medicine.  
 
 
5. How to store Xyrem 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date stated on the bottle after (EXP). The expiry date refers 
to the last day of that month. 
 
After dilution in the dosing cups, the preparation should be used within 24 hours. 
 
Once you open a bottle of Xyrem, any contents that you have not used with 90 days of opening should 
be disposed of. 
 
Do not throw away any medicines via wastewater or household waste.  Ask your pharmacist how to 
dispose of medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 

 
What Xyrem contains 

- The active substance is sodium oxybate. Each mL contains 500 mg of sodium oxybate. 
- The other ingredients are purified water, malic acid and sodium hydroxyde.  
 
What Xyrem looks like and contents of the pack 

Xyrem is supplied in a 240 mL amber plastic bottle containing 180 mL of oral solution and closed 
with a child-resistant cap. When the bottle is delivered, there is a plastic covered foil seal which is on 
the top of the bottle, underneath the cap. Each pack contains one bottle, a press-in-bottle-adaptor 
(PIBA), a plastic measuring syringe and two dosing cups with child-resistant caps. 
Xyrem is a clear to slightly opalescent solution.  
 
Marketing Authorisation Holder  

UCB Pharma SA, Allée de la Recherche 60, B-1070 Brussels, Belgium 
 

Manufacturer 

UCB Pharma S.A., Chemin du Foriest, B-1420 Braine l'Alleud, Belgium 
                                                         or 
UCB Pharma Ltd, 208 Bath Road, Slough, Berkshire, SL1 3WE, United Kingdom. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


36 

You should have received a Xyrem Information Pack from your physician, which includes a booklet 
on how to take the medicine, a Frequently Asked Questions patient information sheet and a patient 
alert card.  
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
UCB Pharma SA/NV 
Tel/Tél: +32 / (0)2 559 92 00 
 

Lietuva 
UCB Pharma Oy Finland 
Tel: + 358 9 2514 4221 (Suomija) 
 

България 

Ю СИ БИ България ЕООД 
Teл.: + 359 (0) 2 962 30 49 

Luxembourg/Luxemburg 
UCB Pharma SA/NV 
Tél/Tel: +32 / (0)2 559 92 00 
 

Česká republika 
UCB s.r.o. 
Tel: + 420 221 773 411 
 

Magyarország 

UCB Magyarország Kft. 
Tel.: + 36-(1) 391 0060 
 

Danmark 
UCB Nordic A/S 
Tlf: + 45 / 32 46 24 00 
 

Malta 

Pharmasud Ltd. 
Tel: +356 / 21 37 64 36 
 

Deutschland 
UCB Pharma GmbH 
Tel: + 49 /(0) 2173 48 4848 
 

Nederland 
UCB Pharma B.V. 
Tel.: +31 / (0)76-573 11 40 
 

Eesti 

UCB Pharma Oy Finland 
Tel: + 358 9 2514 4221 (Soome) 
 

Norge 

UCB Nordic A/S 
Tel: +45 / 32 46 24 00 
 

Ελλάδα 

UCB Α.Ε.  
Τηλ: +30 / 2109974000 
 

Österreich 

UCB Pharma GmbH 
Tel: +43 (0) 1 291 80 00 

España 

UCB Pharma, S.A. 
Tel: + 34 / 91 570 34 44 
 

Polska 

UCB Pharma Sp. z o.o. 
Tel.: + 48 22 696 99 20 
 

France 

UCB Pharma S.A. 
Tél: + 33 / (0)1 47 29 44 66 

Portugal 

UCB Pharma (Produtos Farmacêuticos), Lda 
Tel: + 351 / 21 302 5300 
 

Hrvatska 

Medis Adria d.o.o. 
Tel: +385 (0) 1 230 34 46 
 

România 

UCB Pharma Romania S.R.L. 
Tel: +40 21 300 29 04 
 

Ireland 

UCB (Pharma) Ireland Ltd. 
Tel: + 353 / (0)1-46 37 395  
 

Slovenija 
Medis, d.o.o. 
Tel: + 386 1 589 69 00 
 

Ísland 

Vistor hf. 
Tel: +354 535 7000 
 

Slovenská republika 

UCB s.r.o., organizačná zložka 
Tel: + 421 (0) 2 5920 2020 
 



37 

Italia 

UCB Pharma S.p.A. 
Tel: + 39 / 02 300 791 

Suomi/Finland 

UCB Pharma Oy Finland 
Puh/ Tel: + 358 9 2514 4221 
 

Κύπρος 

Lifepharma (Z.A.M.) Ltd 
Τηλ: + 357 22 34 74 40  
 

Sverige 

UCB Nordic A/S 
Tel: + 46 / (0) 40 29 49 00 

Latvija 

UCB Pharma Oy Finland 
Tel: + 358 9 2514 4221 (Somija) 
 

United Kingdom 

UCB Pharma Ltd. 
Tel : +44 / (0)1753 534 655 

 
 
This leaflet was last revised in  
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/ 
<------------------------------------------------------------------------------------------------------------------------------ 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET