Evrysdi 0.75 mg/ml powder for oral solution

Patient Information Leaflet

Introduction

Patient Information Leaflet

Evrysdi 0.75 mg/ml powder for oral solution

risdiplam

Read the entire leaflet carefully before you or your child starts taking this medicine, because it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you or your child only, and must not be given to other people, even if they have the same symptoms as you, because it may harm them.
• If you or your child experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are side effects not listed in this leaflet. See section 4.
• The information in this leaflet is intended for you, your caregiver, or your child, but the text refers only to "you".

Leaflet Contents

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

1. What Evrysdi is and what it is used for

Evrysdi contains the active substance risdiplam, which belongs to a group of medicines known as "messenger ribonucleic acid precursor splicing modifiers."

Evrysdi is used to treat spinal muscular atrophy (SMA) in adults and children.

• SMA is an inherited disease: a genetic disorder.
• It is caused by a deficiency in the body of a protein called "survival motor neuron protein" (SMN).

The lack of sufficient SMN protein leads to the loss of motor neurons. Motor neurons are nerve cells that control muscles.

• This causes muscle weakness and loss of muscle mass.
• This can make it more difficult to perform everyday movements, such as head and neck control, sitting, crawling, and walking.
• The muscles used for breathing and swallowing may also become weakened.

How Evrysdi works

Evrysdi works by helping the body produce more SMN protein.

• This means that fewer motor neurons are lost, which may improve muscle function in people with SMA.

In infants with Type 1 SMA, Evrysdi may:

• increase life expectancy,
• reduce the need for a ventilator to assist with breathing,
• help them continue to be fed by mouth.

In children (from infants to adolescents) and adults with Type 2 and Type 3 SMA, Evrysdi may:

• prevent worsening of muscle control,
• improve muscle control.

2. What you need to know before you or your child starts taking Evrysdi

Do not take Evrysdi:

• if you are allergic to risdiplam or to any of the other ingredients of this medicine (listed in section 6).

If in doubt, consult your doctor, pharmacist, or nurse before starting to take Evrysdi.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting to take Evrysdi.

Treatment with Evrysdi may harm an unborn baby or affect male fertility.

See “Pregnancy”, “Contraception”, and “Male fertility” for more information.

Other medicines and Evrysdi

Tell your doctor, pharmacist, or nurse if you are taking, have recently taken, or might need to take any other medicines in the future.

In particular, inform your doctor, pharmacist, or nurse if you are taking or have ever taken any of the following medicines:

• metformin – a medicine used to treat type 2 diabetes
• medicines for the treatment of SMA

Pregnancy

Before starting treatment with this medicine, your doctor must perform a pregnancy test. This is because Evrysdi could harm the unborn baby.

• Do not take this medicine if you are pregnant.

• You must not become pregnant:

• during treatment with Evrysdi and

• for one month after stopping Evrysdi.

If you become pregnant during treatment, inform your doctor immediately. You and your doctor will decide what is best for you and the unborn baby.

Contraception

For women

You must use a highly effective method of contraception:

• while taking this medicine and
• for one month after stopping this medicine.

Talk to your doctor about highly effective contraceptive methods that you and your partner can use.

For men

If your partner is a woman of childbearing age, she must not become pregnant.

You must use a condom:

• while taking this medicine and
• for 4 months after stopping this medicine.

Talk to your doctor about highly effective contraceptive methods that you and your partner can use.

Breastfeeding

Do not breastfeed while taking this medicine. This medicine may pass into breast milk and harm the baby.

Consult your doctor whether you should stop breastfeeding or stop taking Evrysdi.

Male fertility

Evrysdi may reduce male fertility during treatment and for 4 months after the last dose.

• If you are planning to have a child, consult your doctor for advice.
• Do not donate sperm during treatment or for 4 months after the last dose of this medicine.

Driving and using machines

It is unlikely that this medicine will affect your ability to drive or use machines.

Evrysdi contains sodium

Evrysdi contains a small amount of sodium (salt) – less than 1 mmol of sodium (23 mg). This means it is essentially “sodium-free” and can be used by people on a low-sodium diet.

Evrysdi oral solution powder contains 0.375 mg of sodium benzoate per ml. Sodium benzoate may increase the risk of jaundice (yellowing of the skin and eyes) in newborns (up to 4 weeks of age).

Evrysdi contains isomaltose

Evrysdi oral solution powder contains 2.97 mg of isomaltose per ml. If your doctor has told you that you have an intolerance to certain sugars, consult with him before taking this medicine.

3. How to take Evrysdi

Follow exactly the instructions given by your doctor or pharmacist for taking this medicine. If you are unsure, check with your doctor or pharmacist again.

You should have received Evrysdi as an oral solution in liquid form, contained in a bottle. This medicine is a liquid prepared by the pharmacist and referred to in this leaflet as an "oral solution" or "medication". If the contents of the bottle are in powder form, do not use it and contact your pharmacist.

Evrysdi is also available as a film-coated tablet. Your doctor will have helped you choose the appropriate option.

How much Evrysdi to take

Your doctor will determine the correct dose of Evrysdi based on the patient's age and weight.

You must take the daily dose prescribed by your doctor.

• Do not change the dose without first talking to your doctor.

When and how to take Evrysdi

A leaflet titled "Instructions for use" is included in the package, which explains how to draw up the dose using the reusable oral syringe supplied to you. You may take the medicine:

• by mouth,
• through a feeding tube.

You should also read carefully and follow the enclosed leaflet titled "Instructions for use" on how to take or administer Evrysdi.

Take Evrysdi:

• once daily, at approximately the same time each day. This will help you remember when to take the medicine.
• with or without food.
• immediately after drawing up the medicine into the oral syringe. If not taken within 5 minutes, discard the medicine from the oral syringe and draw up a new dose.

Drink water after taking the medicine. Do not mix this medicine with milk or powdered milk.

If Evrysdi comes into contact with the skin, wash the area thoroughly with soap and water.

How long to take Evrysdi

Your doctor will tell you how long you should take Evrysdi. Do not stop treatment with Evrysdi unless instructed by your doctor.

If you take more Evrysdi than you should

If you take more Evrysdi than prescribed, consult a doctor or go to a hospital immediately.

• Bring the medicine packaging and this leaflet with you.

If you forget to take Evrysdi or vomit after taking a dose

If you forget to take a dose:

• If less than 6 hours have passed since your usual dosing time, take the missed dose as soon as you remember.
• If more than 6 hours have passed since your usual dosing time, skip the missed dose and take the next dose at your regular time. Do not take a double dose to make up for a forgotten dose.

If you vomit after taking Evrysdi:

• Do not take an additional dose. Instead, take the next dose the following day at your usual time.

If you spill Evrysdi

If you spill this medicine, wipe the area with a dry paper towel and clean thoroughly with soap and water. Dispose of the paper towel in the trash and wash your hands well with soap and water.

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

4. Possible adverse effects

Like all medicines, this medicine can cause adverse effects, although not everyone will experience them.

Very common: may affect more than 1 in 10 people

• diarrhoea
• rash
• headache
• fever

Common: may affect up to 1 in 10 people

• nausea
• mouth ulcers
• bladder infection
• joint pain

Frequency not known: frequency cannot be estimated from the available data:

• inflamed small blood vessels, mainly in the skin (cutaneous vasculitis).

Reporting of adverse effects

If you experience any adverse effect, talk to your doctor, pharmacist, or nurse, even if it is a possible adverse effect 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 help provide more information on the safety of this medicine.

5. Storage of Evrysdi

• Keep this medicine out of sight and reach of children.
• Store the oral solution in the refrigerator (between 2 °C and 8 °C). If necessary, the oral solution may be kept at room temperature (below 40 °C) for a total of up to 120 hours (5 days). Return the oral solution to the refrigerator when it is no longer necessary to keep it at room temperature.
• Monitor the total time the solution is kept outside the refrigerator (below 40 °C). As indicated above, the cumulative time outside the refrigerator must not exceed 120 hours.
• The oral solution is stable for 64 days after preparation by the pharmacist, provided it is stored in the refrigerator between 2 °C and 8 °C. The pharmacist will record the expiry date on the label of the bottle and on the original packaging under “Discard after”. Do not use this solution after the date indicated under “Discard after”, or discard the medicine if the bottle has been kept at room temperature (below 40 °C) for more than 120 hours (5 days) in total.
• Discard the medicine if at any time the bottle has been stored above 40 °C.
• Keep the medicine in the original bottle to protect it from light.
• Store the medicine bottle in an upright position with the cap securely closed.
• After withdrawing the medicine into the oral syringe, use Evrysdi immediately. Do not store Evrysdi solution in the syringe.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging you no longer need. This will help protect the environment.

6. Package contents and other information

Composition of Evrysdi

• The active substance in the oral solution is risdiplam.
• Each ml of oral solution contains 0.75 mg of risdiplam.
• The other components are mannitol (E 421), isomalt (E 953), strawberry flavour [natural flavouring substances, flavouring preparations, corn maltodextrin, modified waxy corn starch (E1450)], tartaric acid (E 334), sodium benzoate (E 211), macrogol 6000 (E 1521), sucralose, ascorbic acid (E 300) and disodium edetate dihydrate (see Section 2 “Evrysdi contains sodium” and “Evrysdi contains isomalt”).

Appearance of Evrysdi and contents of the pack

• Evrysdi oral powder for solution is supplied as an oral solution after preparation by the pharmacist.
• The oral solution is greenish-yellow to yellow in colour and has a strawberry flavour. The volume of the solution is 80 ml.
• Each pack contains 1 vial, 1 vial adapter, and reusable amber-coloured oral syringes (2 of 1 ml, 2 of 6 ml, and 1 of 12 ml), with graduations to assist in withdrawing the correct dose.

Marketing Authorisation Holder

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

Manufacturer

Roche Pharma AG

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

For further information about this medicinal product, please contact the local representative of the marketing authorisation holder:

Belgium/Belgium/Belgium, Luxembourg/Luxembourg N.V. Roche S.A. Belgium/Belgium/Belgium Tel/Tel: +32 (0) 2 525 82 11	Latvia Roche Latvija SIA Tel: +371 - 6 7039831
	Lithuania UAB “Roche Lietuva” Tel: +370 5 2546799
Czech Republic Roche s. r. o. Tel: +420 - 2 20382111	Hungary Roche (Hungary) Ltd. Tel: +36 1 279 4500
Denmark Roche Pharmaceutical A/S Tlf: +45 - 36 39 99 99	Netherlands Roche Nederland B.V. Tel: +31 (0) 348 438000
Germany Roche Pharma AG Tel: +49 (0) 7624 140	Norway Roche Norge AS Tlf: +47 - 22 78 90 00
Estonia Roche Eesti OÜ Tel: + 372 - 6 177 380	Austria Roche Austria GmbH Tel: +43 (0) 1 27739
Greece Cyprus Roche (Hellas) A.E. Greece Tel: +30 210 61 66 100	Poland Roche Polska Sp.z o.o. Tel: +48 - 22 345 18 88
Spain Roche Farma S.A. Tel: +34 - 91 324 81 00	Portugal Roche Farmacêutica Química, Lda Tel: +351 - 21 425 70 00
France Roche Tél: +33 (0) 1 47 61 40 00	Romania Roche România S.R.L. Tel: +40 21 206 47 01
Croatia Roche d.o.o. Tel: +385 1 4722 333	Slovenia Roche farmacevtska družba d.o.o. Tel: +386 - 1 360 26 00
Ireland, Malta Roche Products (Ireland) Ltd. Ireland/Ireland Tel: +353 (0) 1 469 0700	Slovakia Roche Slovensko, s.r.o. Tel: +421 - 2 52638201
Iceland Roche Pharmaceutical A/S c/o Icepharma hf Tel: +354 540 8000	Finland/Finland Roche Oy Puh/Tel: +358 (0) 10 554 500
Italy Roche S.p.A. Tel: +39 - 039 2471	Sweden Roche AB Tel: +46 (0) 8 726 1200

Date of the most recent review of this leaflet:

Other sources of information

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

DIRECTIONS FOR USE – ADMINISTRATION

Evrysdi 0.75 mg/mL powder for oral solution

risdiplam

Please ensure you read and understand these Directions for use before starting Evrysdi. These instructions show how to prepare and administer Evrysdi using an oral syringe, gastrostomy tube (G-tube), or nasogastric tube (NG-tube).

If you have any doubts about how to use Evrysdi, contact your doctor or pharmacist.

Evrysdi should arrive as a liquid in a vial when you receive it. The pharmacist prepares the oral solution of Evrysdi. If the medication in the vial is a powder, do not use it and contact your pharmacist.

Important information about Evrysdi

• Always use the reusable oral syringes supplied in the package to measure the daily dose.
• See “How to select the correct oral syringe for the Evrysdi dose”.
• Ask your pharmacist if you have any questions about how to select the correct oral syringe from the package and how to measure the prescribed daily dose.
• Contact your doctor or pharmacist if the oral syringe(s) are lost or damaged. They will advise you on how to continue taking the medicine.
• If the vial adapter is not present in the vial, do not use Evrysdi and contact your pharmacist.
• The oral solution can be stored at room temperature (below 40°C) for up to 120 hours (5 days) in total. Monitor the total time the solution is kept outside the refrigerator (below 40°C).
• Do not use Evrysdi after the Discard after date shown on the vial label, or if you or your caregiver have kept the vial at room temperature (below 40°C) for more than 120 hours (5 days) in total. Ask your pharmacist for the Discard after date if it is not written on the vial label.
• Discard the medicine if the vial has ever been stored above 40°C.
• Do not mix Evrysdi with milk or powdered milk.
• Do not use Evrysdi if the vial or oral syringe is damaged.
• Avoid contact of Evrysdi with the skin. If Evrysdi comes into contact with the skin, wash the area with water and soap.
• If Evrysdi is spilled, wipe the area with a clean, dry paper towel and then wash it with water and soap. Dispose of the paper towel in the trash and wash your hands thoroughly with water and soap.
• If there is not enough Evrysdi left in the vial for the prescribed dose, discard the vial with the remaining Evrysdi and the used oral syringe according to local requirements; use a new vial of Evrysdi to obtain a complete dose. Do not mix Evrysdi from the new vial with the vial currently in use.

Each EVRYSDI carton contains (see Figure A): Evrysdi vial with vial adapter and cap 1 oral syringe of 12 ml (in pouch) 6 ml oral syringes (in pouches) 1 ml oral syringes (in pouches) 1 Instructions for Use leaflet (not shown) 1 Package Insert (not shown)

Storage of Evrysdi

Refer to section 5 “Storage of Evrysdi” of the package leaflet for complete information.

• Withdrawal of the dose volume

How to select the correct oral syringe for the Evrysdi dose

If the daily dose of Evrysdi is between 0.3 ml and 1 ml, use a 1 ml oral syringe (yellow label). oral syringe (yellow label).

If the daily dose of Evrysdi is between 1 ml and 6 ml, use a 6 ml oral syringe (grey label). oral syringe (grey label).

If the daily dose of Evrysdi is greater than 6 ml, use a 12 ml oral syringe (brown label).

Consult your doctor or pharmacist on how to round your daily dose, or your child's dose, to the nearest graduation mark.

How to extract the Evrysdi dose

	Step A1 Remove the cap by pressing down and then turn the cap to the left (counterclockwise) (see Figure B). Do not discard the cap.
	Step A2 Push the plunger of the oral syringe fully down to remove air from the oral syringe (see Figure C).
	Step A3 Hold the bottle upright and insert the tip of the syringe into the bottle adapter (see Figure D).
	Step A4 Carefully turn the bottle upside down with the tip of the syringe firmly inserted into the bottle adapter (see Figure E).
	Step A5 Slowly pull back the plunger to withdraw the dose of Evrysdi. The top of the black rubber stopper of the plunger should align with the ml mark on the oral syringe corresponding to the daily dose (see Figure F). Once the correct dose has been withdrawn, keep the plunger in place to prevent it from moving.
	Step A6 Continue to keep the plunger in place to prevent it from moving. Keep the oral syringe in the bottle adapter and turn the bottle upright. Place the bottle on a flat surface. Remove the oral syringe from the bottle adapter by gently pulling the oral syringe upward (see Figure G).
	Step A7 Hold the oral syringe with the tip pointing upward. Inspect the medication inside the oral syringe. If there are large air bubbles in the oral syringe (see Figure H) or if an incorrect dose of Evrysdi has been withdrawn, firmly reinsert the syringe tip into the bottle adapter. Push the plunger fully down to return the medication into the bottle and repeat steps A4 through A7. Take or administer Evrysdi immediately after withdrawing it with the oral syringe. If not taken within 5 minutes, discard the medication from the oral syringe and withdraw a new dose.
	Step A8 Replace the cap on the bottle. Turn the cap to the right (clockwise) to securely close the bottle (see Figure I). Do not remove the bottle adapter from the bottle.

If you are taking the dose of Evrysdi by mouth, follow the instructions given in "B) How to take the dose of Evrysdi by mouth."

If you are taking the dose of Evrysdi through a gastrostomy tube, follow the instructions given in "C) How to administer the dose of Evrysdi through a gastrostomy tube (G-tube)."

If you are taking the dose of Evrysdi through a nasogastric tube, follow the instructions given in "D) How to administer the dose of Evrysdi through a nasogastric tube (NG tube)."

Evrysdi oral syringes are specifically designed to be compatible with the ENFit® system. If the feeding tube is not ENFit® compatible, you may need an ENFit® transition connector to attach the Evrysdi syringe to the G-tube or NG tube.

• How to take the dose of Evrysdi by mouth

Remain seated and upright when taking the dose of Evrysdi by mouth.

	Step B1 Place the oral syringe into the mouth with the tip next to either cheek. Slowly push the plunger all the way down to deliver the full dose of Evrysdi (see Figure J). Administering Evrysdi to the back of the throat or too quickly may cause choking.
	Step B2 Check that no medication remains in the oral syringe (see Figure K).
	Step B3 Drink a small amount of water immediately after taking the dose of Evrysdi (see Figure L). Go to Step E to clean the syringe.

• How to administer the dose of Evrysdi via a gastrostomy tube

If you are administering Evrysdi via a gastrostomy tube, ask your doctor or nurse to show you how to inspect the gastrostomy tube before administering Evrysdi.

	Step C1 Insert the tip of the oral syringe into the gastrostomy tube. Slowly push the plunger all the way down to deliver the complete dose of Evrysdi (see figure M).
	Step C2 Check that no medication remains in the oral syringe (see figure N).
	Step C3 Flush the gastrostomy tube with 10–20 ml of water immediately after administering the dose of Evrysdi (see figure O). Proceed to Step E to clean the syringe.

• How to administer the dose of Evrysdi through a nasogastric tube

If you are going to administer Evrysdi through a nasogastric tube, ask your doctor or nurse to show you how to inspect the nasogastric tube before administering Evrysdi.

	Step D1 Insert the tip of the oral syringe into the nasogastric tube. Slowly push the plunger all the way down to deliver the full dose of Evrysdi (see Figure P).
	Step D2 Check that no medication remains in the oral syringe (see Figure Q).
	Step D3 Flush the nasogastric tube with 10–20 mL of water immediately after administering the dose of Evrysdi (see Figure R). Go to Step E to clean the syringe.

• How to clean the oral syringe after use

	Step E1 Remove the plunger from the oral syringe. Rinse the barrel of the oral syringe thoroughly with clean water (see Figure S).
	Step E2 Rinse the plunger thoroughly with clean water (see Figure T).
	Step E3 Check that the barrel and plunger of the oral syringe are clean. Place the barrel and plunger of the oral syringe on a clean surface in a safe location to air-dry (see Figure U). Wash your hands. Once dry, reassemble the plunger into the barrel of the oral syringe and store the syringe with the medication.

Reconstitution Instructions

Evrysdi 0.75 mg/mL

Oral solution powder

risdiplam

Reconstitution Instructions

(FOR HEALTHCARE PROFESSIONALS ONLY [E.G., PHARMACISTS])

Each box of Evrysdi contains (see Figure A): 1 Cap 1 Evrysdi vial 1 12 ml oral syringe (in pouch) 2 6 ml oral syringes (in pouch) 2 1 ml oral syringes (in pouch) 1 Vial adapter 1 Package insert (not shown) 1 Reconstitution instructions (not shown) 1 Instructions for Use (not shown)

Important information about Evrysdi

• Avoid inhaling Evrysdi powder.

• Use gloves.

• Do not use after the expiration date of the powder. The expiration date of the powder is printed on the label of the vial.

• Do not dispense the reconstituted solution if the “Discard after” date of the solution is later than the expiration date of the original powder.

• Avoid contact between the medication and the skin. If the medication comes into contact with the skin, wash the area with soap and water.

• Do not use the medication if any supplies are missing or damaged.

• Use purified water or water for injection to reconstitute the medication.

• Do not use oral syringes other than those provided within the packaging.

Storage of Evrysdi

• Store the powder (unreconstituted medication) at room temperature (< 25°C) and inside the packaging with the vial tightly closed to protect it from moisture.

• Store the solution (reconstituted medication) in the refrigerator (between 2°C and 8°C) and inside the packaging in an upright position.

• Store the oral solution in the original vial and always keep the vial in an upright position with the cap tightly closed.

Reconstitution

	Step 1 Gently tap the bottom of the vial to loosen the powder (see Figure B).
	Step 2 Remove the stopper by pressing down and then turning it to the left (counterclockwise) (see Figure C). Do not discard the stopper.
	Step 3 Carefully pour 79 mL of purified water or water for preparation of injections into the medicinal vial (see Figure D).
	Step 4 On a flat surface, hold the medicinal vial with one hand. Insert the vial adapter into the opening by pushing down with the other hand. Ensure it is fully pressed against the rim of the vial (see Figure E).
	Step 5 Replace the stopper on the vial. Turn the stopper to the right (clockwise) to close the vial. Make sure it is securely closed and shake vigorously for 15 seconds (see Figure F). Wait 10 minutes. You should have obtained a clear solution. Then, shake again thoroughly for 15 seconds.
	Step 6 Calculate the “Discard after” 64 days after reconstitution (Note: the day of reconstitution is counted as day 0. For example, if reconstitution takes place on April 1, the “Discard after” date will be June 4). Write the “Discard after” date of the solution on the vial label (see Figure G) and on the packaging. Return the vial into its original packaging, together with the syringes (in pouches), the leaflet, and the Instructions for Use booklet. Store the packaging in the refrigerator (between 2 °C and 8 °C).