XYREM Oral solution Ref.[115197] Active ingredients: Sodium oxybate

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.

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:

^* 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.

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.

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 as well as acidosis. 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, but has been reported in cases of acidosis due to GHB overdose. However, due to the rapid metabolism of sodium oxybate, these measures may not be warranted.

5 years.

After first opening: 90 days.

After dilution in the dosing cups, the preparation should be used within 24 hours.

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.

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.

No special requirements.