Oxybatin® For Healthcare Professionals

Oxybatin® contains the active substance sodium oxybate. Oxybatin® acts by stabilising nocturnal sleep, although its exact mechanism of action is not known.

Treatment of narcolepsy with cataplexy in adult patients, adolescents and children from 7 years of age.

Treatment initiation and continuation should be under the guidance of a physician experienced in the treatment of narcolepsy. Physicians should strictly observe the contraindications, warnings and precautions.

Dosage:

Adults

The recommended starting dose of sodium oxybate is 4.5g daily divided into two equal doses of 2.25g. The dose should be titrated on the basis of efficacy and tolerability (see section 4.4) up to a maximum of 9g per day, divided into two equal doses of 4.5g per dose, adjusting up or down in increments of 1.5g per day (i.e. 0.75g per dose). A minimum interval of one to two weeks is recommended before each stepwise dose change. The dose of 9g daily must not be exceeded, because of the possible occurrence of serious symptoms at doses of 18g per day or greater (see section 4.4).

Doses of 4.5g are administered only if the patient has previously been titrated to this dose level.

Discontinuation of Oxybatin

The effects of discontinuing sodium oxybate have not been systematically evaluated in controlled clinical trials.

If the patient stops taking the medicinal product for more than 14 consecutive days, titration must be restarted from the lowest dose.

Special Populations:

Elderly

Elderly patients should be closely monitored for impairment of motor and/or cognitive function when taking sodium oxybate.

Hepatic Impairment

The starting dose should be halved in all patients with hepatic impairment and the response to each stepwise dose increase should be carefully monitored.

Renal Impairment

All patients with impaired renal function should take into account the recommendation to reduce sodium intake.

Paediatric Population

Adolescents and children from 7 years of age with a minimum body weight of 15 kg:

Oxybatin is administered orally twice at night. Dosing recommendations are provided in the table below:

Patient Weight	Starting total daily dose (taken in 2 divided doses)*	Titration regimen (until 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	0.2g/kg/day
30kg – <45kg	≤ 3g/day	≤ 1g/day/week	0.2g/kg/day
≥45kg	≤ 4.5g/day	≤ 1.5g/day/week	9g/day

Summary of the safety profile

Clinical Studies

The safety profile was qualitatively the same in adult and paediatric studies.

In adults, the most frequently reported adverse reactions are dizziness, nausea and headache, all of which occur in 10% to 20% of patients. The most serious adverse reactions are suicide attempt, psychosis, respiratory depression and convulsions.

In adults, the safety and efficacy of sodium oxybate for the management of narcolepsy symptoms were established in four multicentre, randomised, double-blind, placebo-controlled, parallel-group studies in patients with narcolepsy with cataplexy, except for one study in which patients were not required to have narcolepsy in order to be enrolled. Two Phase 3 and one Phase 2, double-blind, parallel-group, placebo-controlled studies were conducted to evaluate the indication of sodium oxybate for fibromyalgia in adults. In addition, randomised, double-blind, placebo-controlled, crossover drug interaction studies were conducted with ibuprofen, diclofenac and valproate in healthy subjects.

Post-marketing experience

In addition to the adverse reactions reported during clinical studies, adverse reactions have been reported during post-marketing experience. It is not always possible to reliably estimate their frequency in the population to be treated.

Tabulated list of adverse reactions

Adverse reactions are listed by System Organ Class according to the MedDRA database.

Frequency estimation: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (frequency cannot be estimated from the available data).

Within each frequency category, adverse reactions are presented in order of decreasing seriousness.

Infections and infestations

Common: nasopharyngitis, vaginitis

Immune system disorders

Uncommon: hypersensitivity

Metabolism and nutrition disorders

Common: anorexia, decreased appetite

Frequency not known: dehydration, increased appetite

Psychiatric disorders

Common: depression, cataplexy, anxiety, abnormal dreams, abnormal thinking, confusional state, disorientation, nightmares, sleepwalking, sleep disorder, insomnia, middle insomnia, nervousness.

Uncommon: suicide attempt, psychosis, paranoia, hallucinations, abnormal thinking, agitation, initial insomnia

Frequency not known: suicidal ideation, homicidal ideation, aggression, euphoric mood, sleep-related eating disorder, panic attack, mania / bipolar disorder, delusion, bruxism, irritability and increased libido

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

Frequency not known: convulsions, loss of consciousness, dyskinesia

Eye disorders

Common: blurred vision

Ear and labyrinth disorders

Common: vertigo

Frequency not known: tinnitus

Cardiac disorders

Common: palpitations

Vascular disorders

Common: hypertension

Respiratory, thoracic and mediastinal disorders

Common: dyspnoea, snoring, nasal congestion

Frequency not known: respiratory depression, sleep apnoea

Gastrointestinal disorders

Very common: nausea (the frequency of nausea is higher in women than in men)

Common: vomiting, diarrhoea, upper abdominal pain

Uncommon: faecal incontinence

Frequency not known: dry mouth

Skin and subcutaneous tissue disorders

Common: hyperhidrosis, rash

Frequency not known: urticaria, angioedema, seborrhoea.

Musculoskeletal and connective tissue disorders

Common: arthralgia, muscle spasms, back pain

Renal and urinary disorders

Common: nocturnal enuresis, urinary incontinence

Frequency not known: pollakiuria / urgency, nocturia

General disorders and administration site conditions

Common: asthenia, fatigue, feeling drunk, peripheral oedema

Investigations

Common: blood pressure increased, weight decreased

Injury, poisoning and procedural complications

Common: fall

Description of selected adverse reactions

In some patients, a relapse of cataplexy is observed with greater frequency upon discontinuation of sodium oxybate treatment; however, the greater frequency may be due to the usual fluctuations of the disease. Although the experience from clinical trials of sodium oxybate in patients with narcolepsy/cataplexy at therapeutic doses does not clearly demonstrate the induction of a withdrawal syndrome, in rare cases adverse reactions such as insomnia, headache, anxiety, dizziness, sleep disorders, somnolence, hallucinations and psychotic disorders have been observed following discontinuation of GHB.

Special Populations

Paediatric Population

In the paediatric population, the efficacy and safety of sodium oxybate for the treatment of narcolepsy with symptoms of cataplexy were established in a phase 2/3 double-blind, placebo-controlled, multicentre, randomised-withdrawal study.

In a study in children and adolescents the most frequently reported related adverse reactions 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 reactions of suicidal ideation (1%) and acute psychosis (1%) were also reported. (see section 4.4 and section 6).

In some children between 7 and < 18 years of age, post-marketing surveillance showed that sodium oxybate was discontinued because of abnormal behaviour, aggression and mood change.

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Hellenic Association of Patients with Narcolepsy and Idiopathic Hypersomnia