Xyrem 500 mg/ml oral solution

 

What is it and how is it used?

Xyrem works by consolidating night-time sleep, though its exact mechanism of action is unknown.

Xyrem is used to treat narcolepsy with cataplexy in adult patients.

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.

What do you have to consider before using it?

Do not take Xyrem

  • if you are allergic (hypersensitive) to sodium oxybate or any of the other ingredients of Xyrem
  • 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

Take special care with Xyrem

  • if you have breathing or lung problems (and especially if you are obese), because Xyrem has the potential to cause respiratory depression
  • if you have or have previously had depressive illness
  • if you have heart failure, hypertension (high blood pressure), liver or kidney problems as your dose may need to be adjusted
  • if you are taking other central nervous system depressants or alcohol
  • if you have previously had experience with drug abuse
  • 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 should not be taken by children and adolescents.

When you discontinue taking Xyrem you need to follow your doctor’s instructions as it may result in side effects e.g. headache, lack of sleep, mood changes and hallucinations.

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

Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

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 care should be taken to tell your doctor and pharmacist if your are taking any of the following types of medicines:

  • medicines that increase central nervous system activity and antidepressants
  • medicines that may be processed in a similar way by the body (eg valporate, phenytoin or ethosuximide)

Taking Xyrem with food and drink
You must not drink alcohol while taking Xyrem, as its effects can be increased.

Xyrem is to be taken at a set time well after a meal (two - three hours) as food decreases the amount of Xyrem that is absorbed by your body.

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. If you take two 2.25 g doses of sodium oxybate each night you will take 0.82 g of sodium, or if you take two 4.5 g doses of sodium oxybate each night you will take in 1.6 g sodium. You may need to moderate your intake of salt.

Pregnancy and breast-feeding
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. Tell your doctor if you are pregnant or are planning to become pregnant.

It is not known whether Xyrem passes into breast milk. Patients taking Xyrem should stop breast feeding.

Ask your doctor or pharmacist for advice before taking any medicine.

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.

How is it used?

Always take Xyrem exactly as your doctor has told you to. You should check with your doctor or pharmacist if you are not sure.

The usual starting dose is 4.5 g/day, given as two equally divided doses of 2.25 g/dose. Your doctor may gradually increase your dose up to a maximum of 9 g/day given as two equally divided doses of 4.5 g/dose.

Take Xyrem orally two times each night. Take the first dose upon getting into bed and the second dose 2.5 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 well after a meal (two-three hours). Prepare both doses before bedtime.

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.

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.

To help you, the Xyrem carton contains 1 bottle of medicine, a measuring syringe and two dosing cups with child-resistant caps.

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

2. Next, insert the tip of the measuring syringe into the centre opening of the bottle and press down firmly (See Figure 1).

Figure 1

3. 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 (See Figure 2).

Figure 2

4. 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 (See Figure 3). 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).

Figure 3

5. 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 (See Figure 4). Rinse out the syringe with water.

Figure 4

6. Just before going to sleep, place your second dose near your bed. You may need to set an alarm so you wake up to take your second dose no earlier than 2.5 hours and no later than 4 hours after your first dose. 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). Drink all of the first dose while sitting in bed, recap the cup, and then lie down right away.

7. When you wake up 2.5 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.

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. 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 forgotten individual doses.

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 have any further questions on the use of this product, ask your doctor or pharmacist.

What are possible side effects?

Like all medicines, Xyrem can have side effects. These are usually mild to moderate. If you experience any of these, tell your doctor straight away.

The frequency of possible side effects listed below is defined using the following convention: very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
not known (frequency cannot be estimated from the available data)

Very common side effects (affects more than 1 user in 10) include:
Nausea, dizziness, headache

Common side effects (affects 1 to 10 users in 100) include:
Sleeping problems including insomnia, blurred vision, feeling the heart beat, vomiting, stomach pains, diarrhoea, anorexia, decreased appetite, weight loss, weakness, abnormal dreams, tiredness, feeling drunk, sleep paralysis, sleepiness, trembling, confusion/ disorientation, nightmares, sleep walking, bed wetting, sweating, depression, muscle cramps, swelling, fall, joint pain, back pain, cataplexy, balance disorder, disturbance in attention, disturbed sensitivity particularly to touch, abnormal touch sensation, sedation, abnormal taste, anxiety, difficulty in falling asleep in the middle of the night, nervousness, feeling of “spinning” (vertigo), urinary incontinence, shortness of breath, snoring, congestion of the nose, rash, inflammation of the sinuses, inflammation of nose and throat, increased blood pressure

Uncommon side effects (affects 1 to 10 users in 1,000) include:
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

Side effects with unknown frequency (cannot be estimated from the available data) include: Convulsion, decreased breathing depth or rate, hives, , suicidal thoughts, short cessation of breathing during sleep.

If any of these affect you severely, tell your doctor.
If you are concerned about any side effect, or if you notice any side effects not mentioned in this leaflet, please tell your doctor or pharmacist.

How should it be stored?

Keep out of the reach and sight of children.

Do not use Xyrem after the expiry date stated on the bottle (EXP). The expiry date refers to the last day of that month.

Store in the original container.
Do not store Xyrem solutions diluted with water for more than 24 hours.

Once you open a bottle of Xyrem, any contents that you have not used with 40 days of opening should be disposed of.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What is it?

Xyrem is an oral solution that contains the active substance sodium oxybate (500 mg/ml).

What is it used for?

Xyrem is used to treat adults who have narcolepsy with cataplexy. Narcolepsy is a sleep disorder that causes excessive daytime sleepiness. Cataplexy is a symptom of narcolepsy involving sudden muscle weakness in response to an emotional reaction such as anger, fear, joy, laughter or surprise. Cataplexy can sometimes cause a patient to collapse.

The medicine can only be obtained with a special prescription.

How is it used?

Xyrem treatment should be started and given under the guidance of a doctor who has experience in the treatment of sleep disorders. Because sodium oxybate can be abused, doctors should check for a history of or susceptibility to drug abuse before treatment, and monitor for misuse and abuse during treatment.

Xyrem is given at a dose of 4.5 to 9 g per day in two equally divided doses. The maximum daily dose is 9 g. Patients should usually start with two doses of 2.25 g (4.5 ml) per day. The dose is then adjusted at one- to two-week intervals depending on the patient’s response. The starting dose should be halved in patients who have problems with their liver. Patients who have problems with their kidneys should consider a low sodium diet. Patients taking Xyrem should avoid alcohol, as it can increase Xyrem’s effects.

Xyrem is supplied with a measuring device and a cup. Before taking the medicine, the patient should dissolve the dose in water to make up a drink. The first dose of the day is taken at bedtime, at least two to three hours after food. The second dose is taken 2.5 to 4 hours later. Both doses should be prepared at the same time before the patient goes to bed. For more information, see the package leaflet.

How does it work?

The active substance in Xyrem, sodium oxybate, is a central nervous system depressant. The precise way in which it works is not known, but it is thought to attach to receptor molecules on the surface of some cells in the brain. This leads to changes in the activity of the brain, bringing about ‘delta’ (slow) brain waves and night-time sleep. When taken at bedtime, Xyrem increases deep sleep and increases the amount of time spent asleep at night, whilst reducing the number of sleeping periods during the day. This improves the symptoms of narcolepsy.

How has it been studied?

The effects of Xyrem in narcolepsy and cataplexy have been studied in 707 patients in four studies. In all of the studies, Xyrem was given at a daily dose between 3 and 9 g and was compared with placebo (a dummy treatment). The first study (136 patients) examined the effects of Xyrem on the number of cataplexy attacks over four weeks of treatment. The second study, including 56 patients who had been taking Xyrem for at least six months, compared the effects of continuing to take Xyrem at the same dose as before, with the effects of switching to placebo. The study measured the number of cataplexy attacks over two weeks. The other two studies (516 patients) examined the effects of Xyrem on excessive daytime sleepiness and other symptoms of narcolepsy, either taken alone or as an add-on to the patient’s existing dose of modafinil (a stimulant medicine used to treat narcolepsy). The main measure of effectiveness was the change in daytime sleepiness.

The effects of Xyrem have also been studied in fibromyalgia patients with moderate to severe symptoms in two short-term (12-week) studies in 1,121 patients, and one long-term (up to nine months) study in 560 patients. Fibromyalgia is a disease of unknown origin causing long-lasting, widespread pain and painful responses to touch. The main measure of effectiveness was based on reduction of pain severity and improvement in function.

What benefits has it shown during the studies?

Xyrem was more effective than placebo in reducing symptoms. In the first study, a daily dose of 9 g reduced the number of cataplexy attacks by 16.1 (from 23.5 to 8.7) per week, compared with a fall of 4.3 per week in the patients taking placebo. The second study showed that Xyrem continued to prevent cataplexy attacks after long-term treatment: there was no change over two weeks in the number of attacks in the patients continuing to take Xyrem, compared to an increase of 21.0 attacks in those switching to placebo. Xyrem also reduced excessive daytime sleepiness in patients who continued to take modafinil, as well as in those who took Xyrem alone.

The data obtained in the fibromyalgia studies did not support the use of Xyrem in this condition in the European population.

What is the risk associated?

The most common side effects with Xyrem (seen in more than 1 patient in 10) are dizziness, headache and nausea (feeling sick). Nausea is more common in women than in men. Xyrem can also cause respiratory depression (inhibition of breathing). For the full list of all side effects reported with Xyrem, see the package leaflet.

Xyrem should not be used in people who may be hypersensitive (allergic) to sodium oxybate or any of the other ingredients. It must not be used in patients with major depression, in patients with ‘succinic semialdehyde dehydrogenase deficiency’ (a rare metabolic disease), or in patients being treated with opioids (such as some painkillers) or barbiturates (such as some anaesthetics and medicines used to prevent seizures). Because sodium oxybate can be abused, doctors must carefully monitor patients using Xyrem.

Why has it been approved?

The CHMP decided that Xyrem’s benefits are greater than its risks. Although the 9-g dose was the most effective, it was linked to high levels of side effects, so the Committee recommended a starting dose of 4.5 g per day. Since the effective dose is close to the dose at which side effects become serious, increases in dose must be carried out strictly and under the supervision of a doctor specialised in the treatment of sleep disorders. The Committee recommended that Xyrem be given marketing authorisation.

How has it been studied?

The company that makes Xyrem will minimise the risk of abuse of Xyrem by providing educational materials to healthcare workers and patients, strictly controlling the distribution of the medicine, and monitoring its use.

Further information

The European Commission granted a marketing authorisation valid throughout the European Union for Xyrem to UCB Pharma Ltd on 13 October 2005. After five years, the marketing authorisation was renewed for a further five years. europa.eu/Find medicine/Human medicines/European Public Assessment Reports. For more information about treatment with Xyrem, read the Package Leaflet (also part of the EPAR) or contact your doctor or pharmacist.

This summary was last updated in 04-2011.