Livmarli

Package leaflet: Information for the user

Livmarli 9.5 mg/mL oral solution

maralixibat
This medicinal product is subject to additional monitoring. This will allow rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read this leaflet carefully before you or your child 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, pharmacist, or nurse.
• This medicine has been prescribed for you or your child only. Do not give it to other people, even if they have the same symptoms as you, because it may be harmful.
• If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet

1. What Livmarli is and what it is used for
2. What you need to know before you or your child take Livmarli
3. How to take Livmarli
4. Possible side effects
5. How to store Livmarli
6. Contents of the pack and other information

1. What Livmarli is and what it is used for

What Livmarli is
Livmarli contains the active substance maralixibat (as chloride), which helps remove certain substances called bile acids from the body.
Bile acids are found in a digestive fluid called bile, which is produced by the liver. Bile acids travel from the liver to the intestine to help digest food. After aiding digestion, they return to the liver.

What Livmarli is used for
Livmarli is used to treat cholestatic pruritus in patients aged 2 months and older with Alagille syndrome (ALGS). Livmarli is also used to treat progressive familial intrahepatic cholestasis (PFIC) in patients aged 3 months and older.
ALGS and PFIC are rare genetic diseases that can cause bile acids to accumulate in the liver, a condition known as cholestasis. Cholestasis may worsen over time and can lead to severe itching, fat deposits under the skin (xanthomas), poor growth, and feelings of fatigue.

How Livmarli (maralixibat) works
Maralixibat works by reducing the accumulation of bile acids in the liver. It achieves this by blocking the return of bile acids to the liver after they have performed their function in the intestine. This allows bile acids to be excreted from the body through the faeces.

2. What you should know before you or your child take Livmarli

Do not use Livmarli

• if you or your child are allergic to maralixibat or to any of the other ingredients of this medicine (listed in section 6).
• if you or your child have severe renal and/or hepatic impairment.

Warnings and precautions
If diarrhoea worsens while taking Livmarli, contact your doctor. If you develop diarrhoea, drink plenty of fluids to avoid dehydration.
During treatment with Livmarli, an increase in liver enzyme levels may be observed in liver function tests. Before you start taking Livmarli, your doctor will perform liver function tests to check that your liver is working properly. Your doctor will carry out regular monitoring of your liver function.
Before and during treatment with Livmarli, your doctor may perform blood tests to monitor your INR (international normalized ratio, a laboratory test to assess bleeding risk) and levels of certain fat-soluble vitamins (vitamins A, D, E, and K). If your vitamin levels are low, your doctor may recommend taking vitamin supplements.
Certain diseases, medicines, and surgical procedures may alter the speed at which food passes through the intestine and may also affect how bile acids move between the liver and intestine. This may influence the activity of maralixibat. Make sure your doctor knows if you have had any diseases, are taking any medicines, or have undergone any surgical procedures.
Taking Livmarli with medicines containing alcohol may cause adverse effects in children under 5 years of age or in those with impaired liver and/or kidney function. If you or your child have impaired liver and/or kidney function or if the child is under 5 years of age, speak with your doctor or pharmacist before using this medicine, especially if you or your child are taking other medicines or dietary supplements containing propylene glycol or alcohol.

Children
Livmarli is not recommended in children with Alagille syndrome under 2 months of age or in children with PFIC under 3 months of age. This is because it is not yet known whether it is safe and effective in these age groups.

Other medicines and Livmarli
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. This includes medicines purchased without a prescription and herbal products.
Inform your doctor if you are taking any of the following medicines:

• Fluvastatin, rosuvastatin, or simvastatin (medicines used to treat high blood cholesterol levels)
• Midazolam (a medicine used for sedation or to induce sleep)
• Ursodeoxycholic acid (a medicine used to treat liver diseases)

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, are planning to become pregnant, or are breastfeeding, ask your doctor or pharmacist for advice before taking this medicine. If you are pregnant, it is preferable to avoid using Livmarli.
Livmarli does not enter the bloodstream and therefore should not pass into breast milk. Nevertheless, always follow your doctor’s advice.

Driving and using machines
Livmarli does not affect or affects only slightly the ability to drive and use machines.

Livmarli contains propylene glycol and sodium
This medicine contains 364.5 mg of propylene glycol per mL. When taken at the recommended dose for ALGS, exposure to propylene glycol corresponds to a maximum of 17 mg/kg/day. When taken at the recommended dose for PFIC, exposure to propylene glycol corresponds to a maximum of 50 mg/kg/day.
If the child is under 5 years of age, speak with your doctor or pharmacist before administering this medicine, particularly if the child is taking other medicines containing propylene glycol or alcohol. If you are pregnant or breastfeeding, or if you have liver or kidney disease, do not take this medicine unless otherwise advised by your doctor. Your doctor may perform additional monitoring during treatment.
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially ‘sodium-free’.

3. How to take Livmarli

Take this medicine exactly as instructed by your doctor or pharmacist. If you have any doubts, consult your doctor or pharmacist.

What dose to take

• The dose of Livmarli you will receive depends on your body weight. Your doctor will calculate the appropriate dose for you, tell you how much medicine to take, and which size of oral dosing syringe to use. Your doctor will also record these and other relevant information (e.g., your body weight) in a dedicated patient booklet. Always carry this patient booklet with you when visiting your doctor. Do not calculate the dose yourself and take only the dose calculated for you by your doctor. The doses of maralixibat administered to patients with ALGS and PFIC differ. Your doctor will ensure the correct dose is selected based on your condition and body weight.
• For ALGS: The recommended dose is 380 micrograms of maralixibat per kilogram of body weight once daily.
  o The initial dose is 190 micrograms per kilogram of body weight once daily.
  o After one week, this dose will be increased to 380 micrograms per kilogram of body weight once daily. Your doctor will inform you when to increase the dose. They will also tell you how much medicine to take and which size of oral dosing syringe to use for the higher dose.
• For PFIC: The initial dose is 285 micrograms per kilogram of body weight once daily in the morning.
  o This dose may be increased to 285 micrograms per kilogram of body weight twice daily, and then to 570 micrograms per kilogram of body weight twice daily, if tolerated.
  o Patients under 5 years of age and patients with moderate hepatic or renal impairment must not take doses higher than 285 micrograms per kilogram of body weight twice daily. Your doctor will inform you if this dose restriction applies to you or to the child.

How to take this medicine
Livmarli may be taken with or without food, up to 30 minutes before a meal.
Take or administer the dose orally using the oral dosing syringe; then swallow it (see Figure M).
Do not mix the oral solution with food or drinks.
Use the table below to ensure you are using the correct size of oral dosing syringe for the prescribed dose.

Make sure you measure the volume accurately to avoid overdose.
How to take a dose of the medicine
Step 1: Draw up the dose
1.1 To open the bottle, remove the child-resistant cap by pressing down firmly and turning to the left (counterclockwise) (see Figure A). Do not discard the child-resistant cap, as you will need to replace it after drawing up the required dose.

Figure A
1.2 Make sure you use the oral dosing syringe of the correct size for the dose prescribed to you (see previous table). Your doctor will tell you which syringe size to use.

• If you are using a new oral dosing syringe, remove it from the packaging (see Figure B). Discard the packaging in household waste.
• If you are reusing an oral dosing syringe previously used, make sure it has been cleaned and is dry (see step 2.4 for cleaning instructions).

Figure B

• If the oral dosing syringe has a cap, remove and discard it in household waste (see Figure C).

Figure C
The syringe has dose markings on the barrel. One end of the syringe has a tip that is inserted into the medicine bottle. The other end has a flange and a plunger used to push the medicine out of the syringe for administration (see Figure D).

Figure D
1.3 Push the plunger fully down to remove air from the syringe (see Figure E).

Figure E
1.4 Make sure you have removed the cap from the bottle, and insert the tip of the syringe into the bottle while keeping it upright. The tip of the syringe must be securely inserted into the opening of the bottle (see Figure F).

Figure F
1.5 While keeping the syringe inserted, turn the bottle upside down (see Figure G).

Figure G
1.6 To draw up a dose from the bottle, slowly pull back the plunger until the plunger tip aligns with the marking on the syringe barrel corresponding to the prescribed dose (see Figure H). There are two types of plungers that may come with the syringe: a flat-top plunger or a pointed-top plunger (see Figure I, step 1.6). To determine how to align the plunger with the prescribed dose, see Figure I. For a flat-top plunger, the flat end of the plunger must align with the marking on the syringe barrel corresponding to the prescribed dose (Figure I.a). For a transparent pointed-top plunger, ensure the flat, wide part beneath the tip aligns with the correct marking (Figure I.b.).

Figure H Figure I.a. Figure I.b.
1.7 Check for air bubbles in the syringe. If you see air bubbles:

• Push the plunger to return the air bubbles into the bottle (see Figure J).
• Then draw up the prescribed dose again, following the instructions in step 1.6.

Figure J.a. Figure J.b.
Check for air bubbles Press the plunger in the syringe to remove air bubbles
1.8 After drawing up the correct dose without air bubbles, keep the syringe inserted in the bottle and turn the bottle right-side up (see Figure K).

Figure K
1.9 Gently remove the syringe from the bottle (see Figure L), holding the bottle firmly with one hand and gripping the syringe barrel with the other hand.

• Do not press the plunger of the syringe during this step.

Figure L
Step 2: Administer the dose
Note: You or the child must remain in an upright position during dose administration and for several minutes afterwards.
2.1 Place the tip of the oral dosing syringe against the inside of the cheek (see Figure M).
Gently push the plunger until it is fully depressed, to release the oral solution into the mouth (see Figure N).

Figure M Figure N
2.2 Make sure you or the child swallows the dose. If you are not certain the full dose was swallowed, do not administer another dose. Wait until the next scheduled dose.
2.3 To close the bottle, screw the child-resistant cap back onto the bottle, turning to the right (clockwise) (see Figure O).

Figure O
2.4 Remove the plunger from the syringe barrel (see Figure P) and rinse it with water after each use. Allow the plunger to air-dry before reuse.

Figure P

• Oral dosing syringes may be rinsed with water, air-dried, and reused for up to 130 days.

If you take more Livmarli than you should
If you take more Livmarli than you should, inform your doctor.
If you forget to take Livmarli

• If a dose is missed, take the next dose at the usual time.

If you stop taking Livmarli
Do not stop treatment with Livmarli without first talking to your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
The following side effects may occur with this medicine.
Very common (may affect more than 1 in 10 people)

• diarrhoea
• stomach (abdominal) pain (ALGS)

Common (may affect up to 1 in 10 people)

• stomach (abdominal) pain (PFIC)
• increased liver enzymes (ALT, AST)

These side effects are usually mild or moderate and may improve during continued treatment with Livmarli.
If you experience any side effect, contact your doctor.
Reporting of side effects
If you get any side effect, talk to your doctor, pharmacist, or nurse. This includes any side effect not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Livmarli

Keep this medicine out of the sight and reach of children.
This medicine does not require any special storage temperature. Store in the
original packaging to protect the medicine from light.
Do not use this medicine after the expiry date stated on the carton and on the bottle after
"Exp.". The expiry date refers to the last day of that month.
Once the bottle has been opened, store it at a temperature below 30 °C and use the medicine within
130 days of opening. After 130 days, the bottle must be discarded even if it is not empty. Record the opening date on the Livmarli bottle.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Livmarli contains

• The active substance is maralixibat (as chloride).
• Each mL of solution contains maralixibat chloride, equivalent to 9.5 mg of maralixibat.
• The other components are propylene glycol (E1520) (see section 2 “Livmarli contains propylene glycol and sodium”), edetate sodium (see section 2 “Livmarli contains propylene glycol and sodium”), sucralose, grape flavour, and purified water.

Description of the appearance of Livmarli and contents of the pack
Livmarli is a clear, colourless to pale yellow oral solution. It is contained in a 30 mL amber plastic bottle with a pre-installed adapter and a child-resistant closure.
The package includes three oral administration syringes of different sizes (0.5 mL, 1 mL and 3 mL), compatible with the pre-installed adapter and the reusable closure cap of the bottle.
To ensure an accurate dose of Livmarli, refer to the table in section 3 (“How to take Livmarli”) to select the correct size of oral administration syringe.
Pack:
1 bottle containing 30 mL and 3 oral administration syringes (0.5 mL, 1 mL and 3 mL).

Marketing Authorisation Holder
Mirum Pharmaceuticals International B.V.
Kingsfordweg 151
1043 GR Amsterdam,
The Netherlands

Manufacturer
Millmount Healthcare Limited
Block 7 City North Business Campus
Stamullen, Co. Meath, K32 YD60
Ireland

This medicinal product has been authorised under “exceptional circumstances”. This means that, due to the rarity of the disease, it has not been possible to obtain complete information about this medicine.

Further information
More detailed information on this medicine is available on the website of the European Medicines Agency: http://www.ema.europa.eu/. In addition, links to other websites on rare diseases and their therapeutic treatments are provided.