XYREM 500 mg/mL ORAL SOLUTION

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 a deficiency of succinic semialdehyde dehydrogenase (a rare metabolic disorder);
• if you have severe depression;
• if you are receiving treatment with opioid or barbiturate medicines.

Warnings and precautions

Talk to your doctor or pharmacist before you start taking Xyrem.

• if you have respiratory or pulmonary problems (and especially if you are obese), as Xyrem has the potential to cause breathing difficulties;
• if you have or have had depression, suicidal thoughts, anxiety, psychosis (a mental disorder that

can involve hallucinations, incoherent speech, or disorganized and agitated behavior) or bipolar disorder;

• if you have heart failure, high blood pressure, liver or kidney problems, you may need to have your dose adjusted;
• if you have previously used drugs or abused medicines;
• if you have epilepsy, as the use of Xyrem is not recommended in this disease;
• if you have porphyria (a rare metabolic disorder).

If you have any of these problems, tell your doctor before taking Xyrem.

If, while taking Xyrem, you experience nocturnal urine loss and incontinence (both urinary and fecal), confusion, hallucinations, sleepwalking episodes, or abnormal thinking, you should immediately inform your doctor. Although these effects are rare, if they appear, they are usually mild to moderate in nature.

In elderly people, the doctor will carefully monitor your progress to check if Xyrem is producing the desired effects.

Xyrem has a well-known potential for abuse. There have been cases of dependence after illicit use of sodium oxybate.

Your doctor will ask you if you have used any drugs before starting to take Xyrem and while you are taking this medicine.

Children and adolescents

Xyrem can be taken by adolescents and children from 7 years of age who weigh more than 15 kg.

Xyrem must not be taken by children under 7 years of age or who weigh less than 15 kg.

If you are a child or adolescent, your doctor will regularly check your body weight.

While the doctor is adjusting the dose, which can take several weeks, parents/caregivers must carefully monitor the child's breathing during the first 2 hours after taking sodium oxybate to assess if there is any breathing abnormality; for example, interruption of breathing during short periods while sleeping, noisy breathing, and a bluish color in the lips and face. If breathing abnormalities are observed, medical assistance should be sought and the doctor should be informed as soon as possible. If any abnormality is observed after the first dose, the second dose should not be administered. If no abnormality is observed, the second dose can be administered. The second dose should not be administered before 2.5 hours or after 4 hours after the administration of the first dose.

If you have had or are having unpleasant feelings, especially if you feel very sad or have lost interest in life, it is important that you inform your doctor or caregiver.

Using Xyrem with other medicines

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines.

In particular, Xyrem must not be used with medicines that induce sleep and medicines that reduce the activity of the Central Nervous System (the Central Nervous System is the part of the body made up of the brain and spinal cord):

You should also inform your doctor or pharmacist if you are using any of the following types of medicines:

• medicines that increase the activity of the central nervous system
• antidepressants
• medicines that can be metabolized in a similar way by the body (e.g., valproate, phenytoin, or ethosuximide, which are used to treat epileptic seizures)
• topiramate (used to treat epilepsy)

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

Taking Xyrem with alcohol

Do not drink alcohol while taking Xyrem, as its effects may be increased.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

There have been very few women who have taken Xyrem during pregnancy, and some of them had miscarriages. The risk of taking Xyrem during pregnancy is not known, so it is not recommended for use in pregnant women or women who are trying to become pregnant.

Patients taking Xyrem must stop breastfeeding, as Xyrem passes into breast milk. Changes in sleep have been observed in breastfed infants of mothers exposed to Xyrem.

Driving and using machines

Xyrem may affect you if you drive or use machines. Do not drive, do not use heavy machinery, or do not perform any activity that may be hazardous or requires mental alertness for at least 6 hours after taking Xyrem. When you first start taking Xyrem and until you know if it makes you sleepy the next day, be extra careful when driving, operating heavy machinery, or doing any other activity that could be dangerous or requires complete mental alertness.

In pediatric patients, doctors, parents, or caregivers are warned that the waiting time for performing activities that require a state of mental alertness, motor coordination, or activities that may have a physical risk may be more than 6 hours, depending on individual sensitivity.

Xyrem contains sodium

This medicine contains 182.24 mg of sodium (the main component of table/cooking salt) per gram. This is equivalent to 9.11% of the maximum recommended daily intake of sodium for an adult.

Consult your doctor or pharmacist if you need to take 2 grams of sodium oxybate (Xyrem) or more per day for a prolonged period, especially if you have been advised to follow a low-salt diet.

3. How to take Xyrem

Follow the instructions for administration of this medicine exactly as indicated by your doctor or pharmacist. If you are unsure, consult your doctor or pharmacist again.

It is important that you only use the syringe included in the box when preparing Xyrem doses. The Xyrem syringe has two different measurement scales: one scale may be more useful for you than the other, depending on the dose your doctor has prescribed. When looking at each scale, you will see which one has the exact mark for your dose.

Adults: taking Xyrem alone

• The recommended initial dose for adults is 4.5 grams per day, divided into two separate doses of 2.25 grams.
• Your doctor may gradually increase your dose up to a maximum of 9 grams per day, divided into two separate doses of 4.5 grams.
• Take Xyrem orally twice each night:

• Take the first dose when going to bed and the second dose 2½ to 4 hours later. You may need an alarm clock to make sure you wake up to take the second dose.
• Food reduces the amount of Xyrem absorbed by your body. Therefore, it is best to take Xyrem at a fixed time, 2 or 3 hours after meals.
• Prepare both doses before going to bed.
• Take the doses within 24 hours after preparation.

Adolescents and children from 7 years of age who weigh 15 kg or more: taking Xyrem alone

For children from 7 years of age who weigh 15 kg or more, the doctor will calculate the suitable dose based on body weight.

The doctor will calculate the suitable dose for you. Do not exceed the dose that has been prescribed for you.

Adults: taking Xyrem with valproate

If you are taking valproate with Xyrem, your doctor will adjust your Xyrem dose.

• The recommended initial dose of Xyrem when used with valproate is 3.6 grams per day, divided into two separate doses of 1.8 grams.
• Take the first dose when going to bed and the second dose 2½ to 4 hours later.

Adolescents and children from 7 years of age who weigh 15 kg or more: taking Xyrem with valproate

If you are taking valproate with Xyrem, your doctor will adjust your Xyrem dose.

Liver or kidney problems

If you have kidney problems, you should follow the dietary recommendations to reduce sodium intake.

If you have liver problems, the initial dose should be reduced by half. Your doctor may gradually increase your dose.

Instructions for diluting Xyrem

The following instructions explain how to prepare Xyrem. Read the instructions carefully and follow them step by step. Do not allow children to prepare Xyrem.

To help you, the Xyrem pack contains 1 bottle of medicine, a graduated syringe (with two different measurement scales), and two dosing cups with child-resistant caps.

Step 1

• Remove the cap from the bottle by pressing down,

and unscrew it counterclockwise (to the left).

• After removing the cap, place the bottle vertically

on a table.

• The plastic seal film should be removed from the

bottle mouth before using it for the first time.

• Keeping the bottle in a vertical position, insert

the pressure adapter into the bottle neck. This should only be done the first time the bottle is opened.

The adapter can be left on the bottle for subsequent uses.

Figure 1

Step 2

• Next, insert the tip of the graduated syringe

into the center of the bottle opening and press firmly.

• Keeping the bottle and syringe in one hand,

prepare the prescribed dose with the other hand by pulling the plunger.

NOTE: The medicine will not flow into the syringe unless you keep the bottle in a vertical position.

Figure 2

Step 3

• Remove the syringe from the center of the bottle opening.
• Empty the medicine from the syringe into one of the provided dosing cups by pushing the plunger. Repeat this step for the second dosing cup.
• Then add approximately 60 ml of water to each dosing cup (60 ml is approximately 4 tablespoons).

Figure 3

Step 4

• Put the caps on the dosing cups

and turn each cap clockwise (to the right) until it clicks

and is locked in the child-resistant position (caution: as the dosing cup cap is reversible, only after hearing the click sound can you be sure that the cap is securely closed for children).

• Rinse the syringe with water.

Figure 4

Just before going to bed:

• Adult patients should place their second dose near their bed.
• Parents or caregivers of adolescents and children from 7 years of age should not leave the second dose near the child's bed or within their reach.
• You may need an alarm clock to make sure you wake up to take your second dose, no earlier than 2.5 hours and no later than 4 hours after your first dose.

Then:

• Remove the cap from the first dosing cup by pressing the child-resistant cap and turning it counterclockwise (to the left).
• Drink the first dose sitting in bed, cover the cup, and then lie down immediately. In the case of children who sleep more than 8 hours but less than 12, the first dose can be administered after the child has slept for 1 to 2 hours.

• When you wake up or wake the child between 2 ½ and 4 hours later, remove the cap from the second dosing cup. Sitting in bed, drink the second dose just before lying down again to continue sleeping. Cover the second cup.

If you think that the effect of Xyrem is too strong or too weak, tell your doctor or pharmacist.

If you take more Xyrem than you should

The symptoms of overdose with Xyrem can include agitation, confusion, altered mobility, breathing difficulties, blurred vision, excessive sweating, headache, vomiting, decreased consciousness that can lead to coma, and epileptic seizure, excessive thirst, muscle cramps, and weakness. If you take more Xyrem than you should, or take it by accident, seek immediate emergency medical help. You should take the medicine box 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 continue with the procedure described previously. 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 the missed doses.

If you are not sure if you have taken Xyrem

In case of doubt about the administration of a dose, do not administer the dose again to reduce the risk of overdose.

If you stop taking Xyrem

You should continue taking Xyrem as long as your doctor prescribes it for you. If the medication is stopped, cataplexy attacks may return, and you may experience insomnia, headache, anxiety, dizziness, sleep disorders, somnolence, hallucinations, and abnormal thinking.

If you stop treatment with Xyrem for more than 14 days, you should consult your doctor, as you may need to restart treatment with Xyrem from a lower dose.

If you have any other questions about the use of this medicine, ask your doctor or pharmacist.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them. These are often of mild to moderate intensity.

Adults: most frequent adverse effects observed in clinical studies(occurring in 10% to 20% of patients):

• dizziness
• nausea
• headache.

If you experience any of these adverse effects, inform your doctor immediately.

Children and adolescents: most frequent adverse effects observed in a clinical study:

• bedwetting (18.3%)
• nausea (12.5%)
• vomiting (8.7%)
• weight loss (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 adverse effects, inform your doctor immediately.

The adverse effects in adults and children are the same. If you experience any of these adverse effects, inform your doctor immediately:

Very common (may affect more than 1 in 10 people):

• nausea

• dizziness
• headache.

Common (may affect up to 1 in 10 people):

• sleep problems such as insomnia, abnormal dreams, sleep paralysis, somnolence, nightmares, sleepwalking, bedwetting, excessive daytime sleepiness, difficulty falling asleep in the middle of the night,
• feeling of intoxication, tremors, confusion or disorientation, blurred vision, balance disorder, falls, feeling of "dizziness" (vertigo),
• feeling heartbeats, increased blood pressure, shortness of breath
• vomiting, stomach pain, diarrhea
• anorexia, decreased appetite, weight loss
• weakness, fatigue, sedation
• sweating
• depression
• muscle cramps, swelling
• joint pain, back pain
• attention disorder, sensitivity disorder especially to touch, abnormal touch sensation, abnormal taste
• anxiety, nervousness
• urinary incontinence
• snoring, nasal congestion
• rash
• breast inflammation, nasal and throat inflammation

Uncommon (may affect up to 1 in 100 people):

• psychosis (a mental disorder that may include hallucinations, incoherent speech or disorganized and agitated behavior)
• paranoia, abnormal thinking, hallucinations, agitation, attempted suicide
• difficulty falling asleep, restless legs
• memory loss
• myoclonus (involuntary muscle contractions)
• involuntary bowel movements
• hypersensitivity

Frequency not known (cannot be estimated from the available data):

• seizure
• decrease in depth or frequency of breathing, short cessation of breathing during sleep
• urticaria
• suicidal thoughts, delirium, thoughts of committing violent acts (including harming others)
• irritability, aggression
• euphoric mood
• panic attack
• mania/bipolar disorder
• dry mouth, dehydration
• facial swelling (angioedema)
• bruxism (bruxism and jaw clenching)
• pollakiuria/urinary urgency (increased need to urinate)
• tinnitus (noise in the ears, such as ringing or buzzing)
• sleep-related eating disorder
• increased appetite
• loss of consciousness
• dykinesia (e.g., abnormal and uncontrolled movements of the limbs)
• dandruff
• increased sexual desire
• nocturia (excessive urination at night)
• feeling of suffocation

If you experience any of these side effects, inform your doctor immediately.

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that is not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Xyrem

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiration date that appears on the bottle after (EXP). The expiration date is the last day of the month indicated.

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

Once the Xyrem bottle is opened, any unused content must be discarded after 90 days.

Medicines should not be thrown away through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines that are no longer needed. This will help protect the environment.

6. Package Contents and Additional Information

Xyrem Composition

Xyrem Composition

• The active ingredient is sodium oxybate. Each ml contains 500 mg of sodium oxybate.
• The other ingredients are purified water, malic acid, and sodium hydroxide.

Product Appearance and Package Contents

Xyrem is presented in a 240 ml amber plastic bottle containing 180 ml of oral solution, closed with a child-resistant cap. The bottle has a plastic seal layer on the mouth of the bottle, under the cap. Each package contains a bottle, a press-in bottle adapter (PIBA), a graduated plastic syringe, and two dosing cups with child-resistant caps.

Xyrem is a clear to slightly opalescent solution.

Marketing Authorization Holder

UCB Pharma S.A., Allée de la Recherche 60, B-1070 Brussels, Belgium

Manufacturer

UCB Pharma S.A., Chemin du Foriest, B-1420 Braine l'Alleud, Belgium

Your doctor should have given you a package of information about Xyrem, which includes a brochure on how to take the medicine, a patient information leaflet with Frequently Asked Questions, and a patient alert card.

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of Last Revision of this Leaflet(MM/YYYY)

Other Sources of Information

Detailed information about this medicine is available on the European Medicines Agency website: http://www.ema.europa.eu/