Ravicti

Package leaflet: Information for the patient

RAVICTI 1.1 g/ml oral liquid

phenylbutyrate glycerol
Please read all of this leaflet carefully before you take this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you. Do not give it to other people, even if their symptoms are the same as yours, because it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4. Contents of this leaflet:
  1. What RAVICTI is and what it is used for
  2. What you need to know before taking RAVICTI
  3. How to take RAVICTI
  4. Possible side effects
  5. How to store RAVICTI
  6. Contents of the pack and other information

1. What RAVICTI is and what it is used for

RAVICTI contains the active substance "glycerol phenylbutyrate", which is used to treat six known "urea cycle disorders" (UCD) in adults and children. Urea cycle disorders include deficiencies of certain liver enzymes such as carbamoyl phosphate synthetase I (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), arginase I (ARG), and ornithine translocase (hyperammonaemia-hyperornithinaemia-homocitrullinuria [HHH] syndrome).
RAVICTI should be used in combination with a protein-restricted diet and, in some cases, with additional dietary supplements such as essential amino acids (arginine, citrulline) and protein-free caloric supplements.

Urea cycle disorders

• In urea cycle disorders, the body is unable to remove nitrogen from the proteins we eat.
• Normally, the body converts excess nitrogen from proteins into a waste compound called "ammonia". Liver enzymes then remove ammonia from the body through a process known as the "urea cycle".
• In urea cycle disorders, the body cannot produce sufficient amounts of liver enzymes to eliminate the ammonia generated from excess nitrogen.
• This means that ammonia accumulates in the body. If ammonia is not removed, it can damage the brain and may lead to unconsciousness or coma.
• Urea cycle disorders are rare.

How RAVICTI works
RAVICTI helps the body eliminate waste nitrogen. This reduces the amount of ammonia in the body.

2. What you should know before taking RAVICTI

Do not take RAVICTI:

• if you are allergic to glycerol phenylbutyrate
• if you have acute hyperammonemia (high levels of ammonia in the blood), which requires faster intervention (see section “Warnings and precautions”).

If you are unsure whether the above applies to you, speak to your doctor or pharmacist before
taking RAVICTI.
Warnings and precautions
Talk to your doctor or pharmacist before taking RAVICTI:

• if you have kidney or liver problems – because RAVICTI is eliminated from the body through the kidneys and liver
• if you have pancreas, stomach or intestinal problems – these organs are responsible for the absorption of RAVICTI into the body.

If any of the above conditions apply to you (or if you are unsure), speak to your doctor or pharmacist
before taking RAVICTI.
In certain situations, such as during infections or after surgery, ammonia levels may rise despite
treatment with this medicine and may damage the brain (hyperammonaemic encephalopathy).
In other cases, ammonia levels in the blood may rise rapidly. In such cases, RAVICTI may not be able
to lower blood ammonia levels, which could become severely elevated.
High ammonia levels can cause nausea, vomiting, or confusion.
Contact your doctor or go to hospital promptly if you notice any of these symptoms.
Laboratory tests should be performed so that your doctor can determine and maintain the correct dose for you.
Other medicines and RAVICTI
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other
medicines.
In particular, inform your doctor or pharmacist if you are taking any of the following medicines,
which may be less effective when used with RAVICTI. If you are taking these medicines, you may need
regular blood tests:

• midazolam and barbiturates – sedatives used to treat sleep disorders or epilepsy
• contraceptives

Additionally, inform your doctor if you are taking any of the following medicines, as they may increase ammonia levels in the body or alter the action of RAVICTI:

• corticosteroids – used to treat inflamed areas of the body
• valproate – used to treat epilepsy
• haloperidol – used to treat certain mental disorders
• probenecid – used to treat high levels of uric acid in the blood, which can cause gout ("hyperuricaemia")
• lipase inhibitors (such as orlistat) – used to treat obesity
• lipases – used in pancreatic replacement therapies

If any of the above apply to you (or if you are unsure), speak to your doctor before taking RAVICTI.
Pregnancy, contraception and breastfeeding

• If you are pregnant, inform your doctor before starting RAVICTI. If you become pregnant while taking RAVICTI, contact your doctor. RAVICTI should not be used during pregnancy, as risk to the unborn child cannot be excluded.
• If you are a woman of childbearing age, you must use an effective method of contraception during treatment with RAVICTI. Discuss with your doctor which contraceptive method is best for you.
• You must talk to your doctor before breastfeeding while taking RAVICTI. A decision must be made whether to breastfeed or discontinue RAVICTI, taking into account the benefit of treatment for you and the benefit of breastfeeding for the child. This is because RAVICTI may pass into breast milk and harm to the newborn/child cannot be excluded.

Driving and using machines
RAVICTI may impair your ability to drive or operate machinery. While taking RAVICTI, you may
experience dizziness or headache. Do not drive or operate machinery if you experience these side effects.

3. How to take RAVICTI

Take this medicine exactly as directed by your doctor. If you have any doubts, consult your doctor or pharmacist.
You must follow a special low-protein diet during treatment with RAVICTI.

• This diet will be planned for you by your doctor or dietitian.
• You must follow the diet carefully.
• You may need to take amino acid supplements.
• You will need to remain on treatment and follow the diet for life, unless you receive a successful liver transplant.

Dosage
Your doctor will tell you how much RAVICTI to take each day.

• Your dose will depend on your height and weight, the amount of protein in your diet, and the severity of your urea cycle disorder.
• Your doctor may prescribe a lower dose if you have liver or kidney problems.
• You will need regular blood tests so your doctor can determine the correct dose for you.
• Your doctor may instruct you to take RAVICTI more than 3 times a day. In young children, it may be taken 4 to 6 times a day. At least 3 hours should pass between doses.

How to take this medicine
Your doctor will instruct you on how to take oral RAVICTI liquid. It can be taken:

• by mouth
• through a tube that goes through the abdomen ("abdomen") into the stomach – called a "gastrostomy tube"
• through a tube that goes through the nose into the stomach – called a "nasogastric tube"

Take RAVICTI by mouth unless otherwise directed by your doctor.

RAVICTI and meals
Take RAVICTI with or immediately after a meal. In young children, the medicine should be given during or immediately after feeding.

Measuring the dose

• Use an oral syringe (without needle) to measure the dose.
• To ensure the correct amount of RAVICTI is taken, use the RAVICTI bottle together with an oral syringe.

1. Open the RAVICTI bottle by pressing the cap down and turning it to the left.

2. Insert the tip of the oral syringe into the syringe adapter built into the bottle.

3. Invert the bottle with the syringe still inserted.

4. Fill the oral syringe by pulling back the plunger until the syringe contains the amount of RAVICTI liquid prescribed by your doctor.
   • Note: If possible, use the oral syringe size in ml closest to (but not smaller than) the recommended dose (for example, if the dose is 0.8 ml, use a 1 ml oral syringe).

5. Tap the oral syringe to remove air bubbles, ensuring it is filled with the correct amount of liquid.

6. Swallow the liquid from the oral syringe or attach the oral syringe to the gastrostomy or nasogastric tube.

7. Important note: Do not mix or dilute RAVICTI in large volumes of liquid such as water or juice, as RAVICTI is heavier than most liquids. Mixing RAVICTI with large volumes of liquid may prevent you from receiving the full dose.
8. RAVICTI may be mixed with a small amount of semi-liquid food such as ketchup, medical foods, apple puree, or pumpkin puree.
9. If the volume of the oral syringe is less than the prescribed dose, repeat these steps to obtain the full dose. Use an oral syringe for all doses taken each day.
10. After taking the full dose, drink some water to ensure no medicine remains in the mouth, or flush the gastrostomy or nasogastric tube with 10 ml of water using a new oral syringe. The syringe used to flush the tube must not be reused for measuring RAVICTI to avoid introducing water into the medicine.

11. Close the bottle by screwing the cap back on.

12. Important note: Do not wash the oral syringe between doses during the day, as contact with water causes degradation of RAVICTI. If RAVICTI comes into contact with water, the liquid may become cloudy. Between doses, store the bottle and oral syringe in a clean, dry place.
13. After the last dose of the day, dispose of the oral syringe. Do not reuse the oral syringe to measure RAVICTI on another day.
14. Unused syringes should be stored and used with another bottle. Each opened bottle must be discarded after 14 days.

If you take more RAVICTI than you should
If you take more medicine than prescribed, contact your doctor.
If you experience any of the following signs, contact a doctor or go to hospital immediately, as these may be signs of overdose or high ammonia levels:

• drowsiness, fatigue, dizziness, or confusion
• headache
• altered taste
• hearing problems
• disorientation
• difficulty remembering things
• worsening of existing neurological conditions

If you forget to take RAVICTI
If you miss a dose, take it as soon as you remember. However, for adults, if the next dose is less than 2 hours away, skip the missed dose and take the next dose at the usual time.
For children: if the next dose is less than 30 minutes away, skip the missed dose and administer the next dose at the usual time.

• Do not take a double dose to make up for a missed dose.

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

If you stop taking RAVICTI
You must take this medicine and follow a special low-protein diet for life. Do not stop taking RAVICTI without first discussing it with your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Tell your doctor or pharmacist if you notice any of the following side effects.
The following side effects may occur with this medicine:
Common: may affect up to 1 in 10 people

• stomach swelling or pain, constipation, diarrhoea, heartburn, flatulence, vomiting, malaise (nausea), mouth pain, retching
• swelling of hands or feet, feeling tired
• dizziness, headache, or tremor
• increased or decreased appetite
• loss of desire to eat certain foods
• bleeding between periods
• acne, unusual skin odour
• tests show increased levels of liver enzymes, imbalance of salts in the blood, low levels of a type of white blood cells ("lymphocytes"), or low levels of vitamin D

Uncommon: may affect up to 1 in 100 people

• dry mouth
• burping, stomach ache or discomfort, changes in stools such as oily appearance, urgency to defecate, painful bowel movements, inflammation of mouth and lips
• feeling hungry
• increased body temperature
• hot flushes
• gallbladder pain
• bladder pain
• back pain, joint swelling, muscle spasms, pain in arms and legs, heel spur
• viral intestinal infection
• pins and needles sensation, restlessness, drowsiness, feeling of dizziness, speech problems, confusion, feeling of depression, altered taste
• interruption or irregularity of menstruation
• voice disorder, nosebleeds, stuffy nose, sore throat
• hair loss, excessive sweating
• irregular heartbeat
• reduced thyroid function
• weight loss or weight gain
• tests show higher or lower potassium levels in the blood
• blood tests show higher levels of triglycerides, low-density lipoproteins, or white blood cells
• tests show abnormal electrocardiogram (ECG)
• tests show prolonged prothrombin time
• tests show low albumin levels in the blood

Side effects in children under 2 months of age

The following side effects were observed in a clinical study involving 16 patients under 2 months of age:

• diarrhoea, constipation, flatulence, gastroesophageal reflux, poor feeding
• rash
• reduced number of red blood cells
• increased number of platelets (may lead to blood clots)
• increased liver enzymes
• decreased levels of amino acids

Side effects in children from 2 months to less than 2 years of age

• diarrhoea, constipation
• eczema, nail ridging, rash

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V. Reporting side effects can help provide more information on the safety of this medicine.

5. How to store RAVICTI

Keep this medicine out of the sight and reach of children.
Do not use RAVICTI after the expiry date stated on the label of the bottle and the carton following the abbreviation "Exp.". The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions. After opening the bottle, the medicine must be used within 14 days of opening. The bottle must be disposed of even if it is not completely empty.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What RAVICTI contains

• The active substance is glycerol phenylbutyrate.
• Each ml of liquid contains 1.1 g of glycerol phenylbutyrate. This corresponds to a density of 1.1 g/ml.
• It contains no other ingredients.

Description of the appearance of RAVICTI and contents of the pack
The liquid is contained in a 25 ml transparent bottle closed with a child-resistant plastic cap.
To ensure accurate dosing of RAVICTI, additional oral syringes with CE marking, appropriately sized for the prescribed dose and compatible with the syringe adapter, are available from any pharmacy. Ask your doctor or pharmacist which type of syringe you should use, based on the prescribed dose volume.
Marketing Authorisation Holder
Immedica Pharma AB
SE-113 63 Stockholm
Sweden
Manufacturer
Unimedic AB
Storjordenvägen 2
SE-864 31 Matfors
Sweden
Patheon France
40 Boulevard de Champaret
38300 Bourgoin Jallieu
France
Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu. Links to other websites on rare diseases and their therapeutic treatments are also provided.