Consumer medicine information

Evrysdi

Risdiplam

BRAND INFORMATION

Brand name

Evrysdi

Active ingredient

Risdiplam

Schedule

SUMMARY CMI

Evrysdi^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using Evrysdi?

Evrysdi contains the active ingredient risdiplam. Evrysdi is used to treat spinal muscular atrophy (SMA). For more information, see Section 1. Why am I using Evrysdi? in the full CMI.

2. What should I know before I use Evrysdi?

Do not use if you have ever had an allergic reaction to risdiplam or any of the ingredients listed at the end of the CMI.
Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant, or are breastfeeding. If you are female, your doctor may do a pregnancy test to confirm you are not pregnant.
If you are male and planning to donate sperm or have children, talk to your doctor. For more information, see Section 2. What should I know before I use Evrysdi? in the full CMI.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop. For more information, see Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Evrysdi?

Take Evrysdi orally (by mouth or through a feeding tube) once a day, at approximately the same time each day, after a meal, using only the oral syringes provided in the pack.
The recommended dose in adults and adolescents is 5 mg (6.6 mL) a day. Your doctor will decide the dose for infants and children based on their age and body weight.

More information can be found in Section 4. How do I use Evrysdi? in the full CMI and in the Instructions for use leaflet provided in the pack.

5. What should I know while using Evrysdi?

Things you should do	Men and women should use contraception during treatment and for at least 1 month (women) or for at least 4 months (men) after stopping treatment (women). If you do become pregnant during treatment with Evrysdi, tell your doctor straight away.
Things you should not do	Do not stop treatment with Evrysdi unless your doctor tells you to. Avoid getting Evrysdi on your skin. If Evrysdi gets on your skin, wash the area with soap and water.
Driving or using machines	Evrysdi is unlikely to affect your ability to drive and use machines.
Looking after your medicine	Store the oral solution at 2°C to 8°C (refrigerate, do not freeze) in the original bottle. Discard the medicine after the expiry date printed on the bottle label or after 64 days (refer to the “Discard contents after” date written on the bottle label). If necessary, you or your caregiver may store the oral solution at room temperature (below 40°C) for no more than a total combined time of 5 days. Keep the bottle closed tightly and in an upright position. Once transferred to the oral syringe, use right away. Do not store the solution in the syringe.

For more information, see Section 5. What should I know while using Evrysdi? in the full CMI.

6. Are there any side effects?

Serious side effects include difficulty breathing, rapid breathing or shortness of breath; increased heart rate; blue lips, fingertips or skin; watery or bloody diarrhea; bleeding into the skin; skin hives or skin ulcers; joint dislocation.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

Evrysdi^®

Active ingredient: risdiplam

Consumer Medicine Information (CMI)

This leaflet provides important information about using Evrysdi. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Evrysdi.

Where to find information in this leaflet:

1. Why am I using Evrysdi?
2. What should I know before I use Evrysdi?
3. What if I am taking other medicines?
4. How do I use Evrysdi?
5. What should I know while using Evrysdi?
6. Are there any side effects?
7. Product details

1. Why am I using Evrysdi?

Evrysdi contains the active ingredient risdiplam.
Risdiplam is a selective survival of motor neuron 2 (SMN2) gene splicing modifier.

Evrysdi is used to treat spinal muscular atrophy (SMA).

SMA is a genetic condition people can be born with, that is caused by a shortage of a protein called “survival of motor neuron” (SMN) in the body. The SMN protein is needed for nerves to function properly. Not having enough SMN protein results in the loss of motor neurons, leading to muscle weakness and muscle wasting. Basic activities such as head and neck control, sitting, crawling and walking may be affected. The muscles used for breathing and swallowing may also be affected.

Evrysdi works by helping the body make more SMN protein and maintain SMN protein levels throughout the body with continued use. This reduces the loss of nerve cells and may improve muscle strength and function in a broad range of ages and SMA types.

In infants with SMA, Evrysdi improves survival, preserves swallowing, improves likelihood of achieving motor milestones, and reduces the need for hospitalisation and ventilator supported breathing. In children (infants to adolescents) and adults, Evrysdi may maintain or improve motor function over time.

2. What should I know before I use Evrysdi?

Warnings

Do not take Evrysdi if:

you are allergic to risdiplam, or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have any other medical conditions
have a kidney or liver disorder
take any medicines for any other condition
are female and pregnant or plan to become pregnant, or are breastfeeding or plan to breastfeed (see Pregnancy)
are male and planning to donate sperm or have children (see Male fertility)
have any issues with the structure of your eye
have been diagnosed with Type 0 or IV SMA
are older than 60 years

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Contraception

For women: You should use highly effective contraception during treatment and for at least 1 month after you stop treatment with Evrysdi.

For men: If your female partner is of childbearing potential, you and your partner should both use highly effective contraception during treatment and for at least 4 months after you stop taking Evrysdi.

Talk to your healthcare provider about reliable methods of contraception that should be used.

Pregnancy

Evrysdi could harm your unborn baby. If you are pregnant, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine. Your doctor will consider the benefit of you taking Evrysdi against the risk to your baby.
Before you start treatment with Evrysdi, your doctor may do a pregnancy test to confirm you are not pregnant.
If you do become pregnant during treatment with Evrysdi, tell your healthcare provider doctor straight away. You and your doctor will decide what is best for you and your unborn baby.

Breastfeeding

Do not breastfeed while taking this medicine. This is because Evrysdi may pass into breast milk and may harm your baby.

Discuss with your doctor if you should stop breastfeeding or if you should stop taking Evrysdi.

Male fertility

Evrysdi may affect fertility in men.

Do not donate sperm during your treatment and for at least 4 months after you stop taking Evrysdi.

For your family planning, ask your doctor for advice.

3. What if I am taking other medicines?

Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these could affect Evrysdi.

Evrysdi may increase the effect of:

metformin
fexofenadine

Evrysdi may affect your eye. Tell your doctor if you are taking other medicines that affect the eye while taking Evrysdi.

4. How do I use Evrysdi?

Evrysdi is a liquid, and is referred to as a ‘solution’ or ‘medicine’ in this leaflet.

How much to take

Adolescents and adults: The daily dose of Evrysdi is 5 mg (6.6 mL of the 750 microgram/mL oral solution).
Infants and children: Your doctor will determine the daily dose of Evrysdi based on your child's age and weight.

You must take your daily dose as instructed by your doctor. Do not change the dose without speaking to your doctor.

If you do not swallow the full dose, or vomit after taking a dose of Evrysdi, do not take an extra dose. Instead, just take the next dose at the usual time the next day.

When to take Evrysdi

Take Evrysdi once daily at approximately the same time each day. This will help you remember when to take your medicine.
You should take Evrysdi after a meal.
If your baby is being breastfed, you can give your baby Evrysdi after breastfeeding.

How to take Evrysdi

Always take this medicine exactly as your healthcare provider has told you. Check with your healthcare provider if you are not sure.

Read carefully and follow the “Instructions for use” leaflet enclosed in the pack on how to take or give Evrysdi.

You should receive Evrysdi from your healthcare provider as a liquid for oral administration that can be given by mouth or through a feeding tube. Do not mix Evrysdi with formula or milk.

Use only oral syringes provided.

It is important that you only use the oral syringe provided in the pack to measure your or your child's dose of Evrysdi as they are specially designed to protect the medicine from light.

If your oral syringes are lost or damaged, contact your healthcare provider and they will advise you on how to continue to take your medicine.

If you forget to take Evrysdi

Evrysdi should be used regularly at the same time each day. If you miss your dose at the usual time:

If it is within 6 hours of when you normally take Evrysdi, take the missed dose as soon as you remember.
If it is over 6 hours from when you normally take Evrysdi, skip the missed dose and then take your next dose at the usual time.

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

If you use too much Evrysdi

If you think that you have taken too much Evrysdi, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

Take the medicine pack and this leaflet with you.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Evrysdi?

Things you should do

Use contraception during treatment (men and women) and for at least 1 month after stopping treatment (women), or for at least 4 months after stopping treatment (men) (see Contraception).
If you do become pregnant during treatment with Evrysdi, tell your healthcare provider doctor straight away (see Pregnancy).
Inform any other doctor or health professional you visit that you are using Evrysdi.

Things you should not do

Do not stop treatment with Evrysdi unless your doctor tells you to.
Avoid getting Evrysdi on your skin. If Evrysdi gets on your skin, wash the area with soap and water.

Driving or using machines

Evrysdi is unlikely to affect your ability to drive and use machines.

Looking after your medicine

Store the oral solution in the refrigerator at 2°C to 8°C (refrigerate, do not freeze).
If necessary, you or your caregiver may store the oral solution at room temperature (below 40°C) for no more than a total combined time of 5 days.
Keep the oral solution in the original amber bottle to protect from light.
Keep the oral solution bottle in an upright position with the cap closed tightly.
Keep it where young children cannot reach it.

Once transferred from the bottle to the oral syringe, use Evrysdi right away. Do not store the Evrysdi solution in the syringe.

Wash the syringes as described in the “Instructions for use” leaflet. Do not throw them away.

When to discard your medicine (as relevant)

Evrysdi oral solution can be used for up to 64 days after reconstitution by your pharmacist when stored in the refrigerator at 2°C to 8°C. Your pharmacist will write the "Discard contents after" date on the bottle label.

Discard the medicine:

after the expiry date printed on the bottle label or after the “Discard contents after” date written on the bottle label,
or if the medicine has been stored at room temperature (below 40°C) for more than a total combined time of 5 days,
or if the medicine has been stored at above 40°C.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to a pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects include

Less serious side effects

What to do

Stomach related:

constipation or
diarrhea
nausea
vomiting
pain in the upper region of the stomach
heartburn, difficulty swallowing, a chronic cough

Skin related

rash
ulcers in the mouth and the inside of the lip and cheek
eczema

General

fever
teething
headache

Muscle and joint related

swelling and pain in the joints

Infections

urinary tract infection, symptoms include strong and frequent urge to urinate, cloudy, bloody or strong-smelling urine, pain or a burning sensation when urinating
infection of the airways, symptoms include runny nose, stuffy nose, cough, sore throat
ear infection, symptoms include pain in the ear, fever, loss of balance, difficulty hearing
infection and inflammation of the digestive system (gastroenteritis), symptoms include watery and possibly bloody diarrhea, stomach cramps, nausea, vomiting, fever

Speak to your doctor if you have any of these side effects and they worry you.

Serious side effects include

Serious side effects

What to do

Lung related

difficulty breathing, rapid breathing or shortness of breath, shallow breaths or flaring of the nostrils
your skin, fingernails or lips look blue or pale
wheezing
increased heart rate
tiredness or loss of consciousness
pneumonia or bronchitis, symptoms include fever, chills, shortness of breath, cough, phlegm and occasionally blood in the phlegm

Skin related

cutaneous vasculitis, inflammation of the blood vessels of the skin, causing them to be narrowed or blocked. Symptoms include areas if flat and red skin, raised skin, bleeding into the skin causing small red or reddishblue to purple spots or net-like patterns on the skin, skin hives ((raised red patches of skin that are often very itchy) or skin ulcers (round open sores in the skin)

Muscle and joint related

dislocation of a joint

Related to the reproductive system

undescended testicle or testis

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Evrysdi contains

Active ingredient (main ingredient)	Risdiplam
Other ingredients (inactive ingredients)	Mannitol Isomalt Strawberry flavour Tartaric acid Sodium benzoate Macrogol 6000 Sucralose Ascorbic acid Disodium edetate

Do not take this medicine if you are allergic to any of these ingredients.

When prepared by your healthcare provider, the volume of the solution is 80 mL. Each mL of the reconstituted oral solution contains 750 micrograms of risdiplam.

Each Evrysdi pack contains 1 bottle of the medicine and press-in bottle adapter, 2 plastic 1mL re-usable oral syringes, 2 plastic 6 mL re-usable oral syringes and 1 plastic 12 mL reusable oral syringe.

What Evrysdi looks like

You should receive Evrysdi from your healthcare provider as a greenish yellow to yellow, strawberry flavoured oral solution. The liquid solution must be prepared by your healthcare provider. If the medicine in the bottle is a powder, do not use it. Contact your healthcare provider for a replacement.

Evrysdi is a powder for oral solution (AUST R 340350).

Who distributes Evrysdi

Evrysdi is distributed in Australia by:

Roche Products Pty Ltd
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
Medical enquiries: 1800 233 950

Please check with your pharmacist for the latest Consumer Medicine Information.

This leaflet was prepared in August 2024.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Evrysdi

Active ingredient

Risdiplam

Schedule

1 Name of Medicine

Risdiplam.

2 Qualitative and Quantitative Composition

Evrysdi is available as a powder for oral solution. Each bottle is filled with 2.0 g of powder containing 60 mg of risdiplam. The powder is reconstituted to form an oral solution containing risdiplam 0.75 mg/mL.

Excipients with known effect.

Evrysdi contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.
Evrysdi contains sodium benzoate and sucralose.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Powder for oral solution.
Evrysdi is supplied as a powder in an amber glass bottle.
The powder is reconstituted with purified water or water for injections to yield an oral solution containing 0.75 mg/mL of risdiplam (see Section 4.2, Preparation of the powder for oral solution by a healthcare professional). The reconstituted solution is clear, greenish yellow to yellow in colour.

4 Clinical Particulars

4.1 Therapeutic Indications

Evrysdi is indicated for the treatment of 5q spinal muscular atrophy (SMA).

4.2 Dose and Method of Administration

Evrysdi oral solution must be reconstituted by a healthcare professional prior to being dispensed.
SMA treatment should be initiated as early as possible after diagnosis.
Treatment with Evrysdi should be initiated and monitored by a specialist medical practitioner experienced in the diagnosis and management of SMA.
Evrysdi is taken orally once daily after a meal using the oral syringe provided, at approximately the same time each day.
In infants who are breastfed, Evrysdi should be administered after breastfeeding. Evrysdi cannot be mixed with formula or milk.

Dose.

The recommended once daily dose of Evrysdi for SMA patients is determined by age and body weight (see Table 1).

Dose changes must be made under the supervision of a healthcare professional. Treatment with a daily dose above 5 mg has not been studied.

Delayed or missed doses.

Evrysdi is taken orally once daily at approximately the same time each day. If a dose of Evrysdi is missed, administer as soon as possible if still within 6 hours of the scheduled dose. Otherwise, skip the missed dose and take the next dose at the regularly scheduled time the next day.
If a dose is not fully swallowed or vomiting occurs after taking a dose of Evrysdi, do not administer another dose to make up for the incomplete dose. Wait until the next day to administer the next dose at the regularly scheduled time.

Preparation of the powder for oral solution by a healthcare professional.

Refer to the "Instructions for Reconstitution" provided in the pack.
Caution should be exercised during handling. Avoid inhalation and avoid direct contact with skin or mucous membranes with the dry powder and the reconstituted solution.
Wear disposable gloves during reconstitution and while wiping the outer surface of the bottle/cap and cleaning the working surface after reconstitution. If contact occurs, wash thoroughly with soap and water; rinse eyes with water.
Instructions for reconstitution:
1. Gently tap the bottom of the closed glass bottle to loosen the powder.
2. Remove the cap. Do not throw away the cap.
3. Carefully pour 79 mL of purified water or sterile water for injections into the bottle to yield the 0.75 mg/mL oral solution.
4. Hold the medicine bottle on the table with one hand. Insert the press-in bottle adapter into the opening by pushing it down with the other hand. Ensure the adapter is completely pressed against the bottle lip.
5. Put the cap back on the bottle and close the bottle tightly. Ensure it is completely closed and then shake well for 15 seconds. Wait for 10 minutes. You should have obtained a clear solution. If not, shake well again for after 15 seconds.
6. Write the "Discard after" date of the solution on the bottle label. (The "Discard after" date is calculated as 64 days after reconstitution, the day of reconstitution is counted as day 0). Put the bottle back in its original carton with syringes (in pouches) and "Instructions for Use - Administration" booklet.

Method of administration.

Refer to the "Instructions for Use - Administration" provided in the pack.
Use the re-usable oral syringe provided to deliver the daily dose of Evrysdi. It is recommended that a healthcare professional discuss with the patient or caregiver how to prepare the prescribed daily dose prior to administration of the first dose.
For the calculation of dosing volume, the syringe markings need to be considered. Round up or round down the dose volume to the nearest graduation mark on the selected oral syringe (see Table 2).

Select the correct oral syringes (1 mL, 6 mL or 12 mL) based on the patient's dosage and remove the other oral syringes from the carton/dispensing pack.
Patients should take Evrysdi immediately after it is drawn up into the oral syringe. If it is not taken within 5 minutes, the dose should be discarded and a new dose should be prepared.
The patient should drink some water after taking Evrysdi to ensure the drug has been completely swallowed. If the patient is unable to swallow and has a nasogastric or gastrostomy tube, administer Evrysdi via the tube. The tube should be flushed with water after delivering Evrysdi.

Special populations.

Hepatic impairment.

No dose adjustment is required in patients with mild or moderate hepatic impairment (see Section 5.2, Pharmacokinetics in special populations, Hepatic impairment). Evrysdi has not been studied in patients with severe hepatic impairment.

Renal impairment.

The safety and efficacy of Evrysdi in patients with renal impairment have not been studied. No dose adjustment is expected to be required in patients with renal impairment (see Section 5.2, Pharmacokinetics in special populations, Renal impairment).

Elderly.

Evrysdi has not been studied in patients with SMA above 60 years of age (see Section 5.2, Pharmacokinetics in special populations, Elderly).

Paediatric populations.

The safety and efficacy of Evrysdi in patients 2 months of age and younger is supported by pharmacokinetic and safety data from paediatric patients 16 days and older (see Section 4.8, Clinical trials; Section 5.1, Clinical trials; Section 5.3 Preclinical Safety Data, Juvenile animal studies). No data on risdiplam pharmacokinetics are available in patients less than 16 days of age. The safety and efficacy of Evrysdi in preterm infants before reaching the corrected age of 16 days have not been established.

4.3 Contraindications

Evrysdi is contraindicated in patients with a known hypersensitivity to risdiplam or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Embryo-fetal toxicity.

Embryo-fetal toxicity has been observed in animal studies (see Section 4.6, Use in pregnancy). Patients of reproductive potential should be informed of the risks and must use highly effective contraception during treatment and until at least 1 month after the last dose of Evrysdi in female patients, and 4 months after the last dose of Evrysdi in male patients (see Section 4.6, Contraception in males and females).

Potential effects on male fertility.

Male patients should not donate sperm while on treatment and for 4 months after the last dose of Evrysdi due to reversible effects of Evrysdi on male fertility, based on observations from animal studies (see Section 4.6, Effects on fertility).

Retinal toxicity.

The effects of Evrysdi on retinal structure observed in the non-clinical safety studies have not been observed in clinical studies with SMA patients. However, long-term data are still limited. The clinical relevance of these nonclinical findings in the long-term has therefore not been established (see Section 5.3 Preclinical Safety Data, Retinal toxicity).

Type 0 or IV SMA.

Patients most likely to develop type 0 or IV SMA have not been included in the clinical development program for Evrysdi. The decision to treat should be based on individualised expert evaluation of the expected benefits of treatment for that individual, balanced against the potential risk of treatment with Evrysdi. The full benefits and risks are unknown among patients diagnosed with type 0 or IV SMA.

Use in hepatic impairment.

The PK, safety and tolerability of a single dose of 5 mg risdiplam were evaluated in subjects with mild or moderate hepatic impairment in a dedicated clinical study. Mild or moderate hepatic impairment had no impact on the PK of risdiplam. No dose adjustment is therefore required in patients with mild or moderate hepatic impairment. Evrysdi has not been studied in patients with severe hepatic impairment (see Section 4.2, Dose, Special populations, Hepatic impairment; Section 5.2, Pharmacokinetics in special populations, Hepatic impairment).

Use in renal impairment.

The safety and efficacy of Evrysdi in patients with renal impairment have not been studied. A change in dose is not expected to be required for patients with renal impairment (see Section 4.2, Dose, Special populations, Renal impairment; Section 5.2, Pharmacokinetics in special populations, Renal impairment).

Use in the elderly.

Evrysdi has not been studied in patients with SMA above 60 years of age (see Section 4.2, Dose, Special populations, Elderly; Section 5.2, Pharmacokinetics in special populations, Elderly).

Paediatric use.

Evrysdi has not been studied in paediatric patients below the age of 16 days. The safety and efficacy of Evrysdi in preterm infants before reaching the corrected age of 16 days have not been established (see Section 5.1, Clinical trials; Section 5.3 Preclinical Safety Data, Juvenile animal studies).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Risdiplam is primarily metabolised by flavin monooxygenase 1 and 3 (FMO1 and 3), and also by cytochrome P450 (CYP)1A1, 2J2, 3A4 and 3A7. Risdiplam is not a substrate of human multidrug resistance protein 1 (MDR1).

Effects of other medicines on Evrysdi.

Co-administration of 200 mg itraconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of 6 mg risdiplam did not exhibit a clinically relevant effect on the PK of risdiplam (11% increase in AUC, 9% decrease in C_max). No dose adjustments are required when Evrysdi is co-administered with a CYP3A inhibitor.
The potential of co-administered FMO1/3 inducers or inhibitors to affect risdiplam or M1 metabolite exposure was not investigated.

Effects of Evrysdi on other medicines.

In vitro risdiplam and its major circulating metabolite M1 did not induce CYP1A2, 2B6, 2C8, 2C9, 2C19 or 3A4. In vitro risdiplam and M1 did not inhibit (reversible or Time-Dependent Inhibition) any of the CYP enzymes tested (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6) with the exception of CYP3A.
Evrysdi is a weak inhibitor of CYP3A. In healthy adult subjects, administration of Evrysdi once daily for 2 weeks slightly increased the exposure of midazolam, a sensitive CYP3A substrate (AUC 11%; C_max 16%). The extent of the interaction is not considered clinically relevant and therefore no dose adjustment is required for CYP3A substrates. Based on physiologically based pharmacokinetic (PBPK) modelling, a similar magnitude of the effect is expected in children and infants as young as 2 months old.
In vitro studies have shown that risdiplam and its major metabolite are not significant inhibitors of human MDR1, organic anion-transporting polypeptide (OATP)1B1, OATP1B3, organic anion transporter 1 and 3 (OAT 1 and 3) or organic cation transporter 2 (OCT2). Risdiplam and its metabolite are, however, in vitro inhibitors of the multidrug and toxin extrusion (MATE)1 and MATE2-K transporters. The effect of coadministration of risdiplam on the pharmacokinetics of MATE1 and MATE2-K substrates in humans is unknown. Based on in vitro data, Evrysdi may increase plasma concentrations of drugs eliminated via MATE1 or MATE2-K, such as metformin and fexofenadine. If co-administration cannot be avoided, monitor for drug-related toxicities and consider dosage reduction of the co-administered drug (based on the labelling of that drug) if needed.

Concomitant administration with other SMA therapies.

There is no efficacy or safety data to support the concomitant use of risdiplam and nusinersen. Efficacy data for Evrysdi treatment when used in patients that previously received SMN1 gene therapy is not available.

Concomitant use with retinotoxic drugs.

The potential for synergistic effects of concomitant administration of risdiplam with retinotoxic drugs has not been studied. Therefore, caution in using concomitant medications with known or suspected retinal toxicity is recommended.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Male patients.

Based on nonclinical findings, male fertility may be compromised while on treatment with Evrysdi. Based on observations from animal studies, the effects on sperm cells are expected to be reversible upon discontinuation of risdiplam.
Oral administration of risdiplam to rats for 4 (0, 1, 3, or 9 mg/kg/day) or 26 (0, 1, 3, or 7.5 mg/kg/day) weeks resulted in histopathological effects in the testis (degenerated spermatocytes, degeneration/atrophy of the seminiferous tubules) and epididymis (degeneration/necrosis of ductular epithelium) at the mid and/or high doses. At the high dose in the 26-week study, the testicular lesions persisted to the end of the recovery period, which corresponds, in rat, to approximately one spermatogenic cycle. The no-effect dose for adverse reproductive system effects in adult male rats (1 mg/kg/day) was associated with plasma drug exposures (unbound AUC) similar to that in humans at the Maximum Recommended Human Dose (MRHD) of 5 mg/day.
Adverse effects of risdiplam on the testis could not be fully evaluated in the monkey because the majority of monkeys tested were sexually immature. However, oral administration of risdiplam (0, 2, 4, or 6 mg/kg/day) for 2 weeks resulted in histopathological changes in the testis (increases in multinucleate cells, germ cell degeneration) at the highest dose. At the no-effect dose for testicular toxicity in monkeys, plasma exposures were approximately 1.6 times (unbound AUC) that in humans at the MRHD. Oral administration of risdiplam to post-weaning juvenile rats resulted in male reproductive toxicity (degeneration/necrosis of the testis seminiferous epithelium with associated oligo/aspermia in the epididymis and abnormal sperm parameters). The no-effect dose for adverse reproductive effects in post-weaning male juvenile rats was associated with plasma exposures approximately 2.4 times (unbound AUC) that in humans at the MRHD.
Prior to initiating treatment with Evrysdi, fertility preservation strategies should be discussed with male patients receiving Evrysdi. Male patients may consider sperm preservation, prior to treatment initiation or after a treatment-free period of at least 4 months. Male patients who wish to father a child should stop treatment with Evrysdi for a minimum of 4 months. Treatment may be re-started after conception.

Female patients.

Based on nonclinical data, an impact of Evrysdi on female fertility is not expected. No effects were seen on female reproductive organs in rats and monkeys after treatment with risdiplam.

Patients of reproductive potential.

Contraception in males and females.

Male and female patients of reproductive potential should adhere to the following contraception requirements:
Female patients of childbearing potential should use highly effective contraception during treatment with Evrysdi and for at least 1 month after the last dose.
Male patients and their female partners of childbearing potential should both use highly effective contraception during treatment with Evrysdi and for at least 4 months after his last dose.

Pregnancy testing.

The pregnancy status of females of reproductive potential should be verified prior to initiating Evrysdi therapy. Pregnant women should be clearly advised of the potential risk to the fetus.
(Category D)
There are no clinical data from the use of Evrysdi in pregnant women. Risdiplam has been shown to be embryo-fetotoxic and teratogenic in animals. Based on the findings from animal studies, risdiplam crosses the placental barrier and may cause fetal harm.
Oral administration of risdiplam (0, 1, 3, or 7.5 mg/kg) to pregnant rats throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal structural variations at the highest dose tested, which was not associated with maternal toxicity. The no-effect level for adverse effects on embryofetal development (3 mg/kg/day) was associated with maternal plasma exposure (unbound AUC) approximately 3 times that in humans at the maximum recommended human dose (MRHD) of 5 mg.
Oral administration of risdiplam (0, 1, 4, or 12 mg/kg) to pregnant rabbits throughout organogenesis resulted in embryofetal mortality, fetal malformations (hydrocephaly), and structural variations at the highest dose tested, which was associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development (4 mg/kg/day) was associated with maternal plasma exposure (unbound AUC) approximately 3 times that in humans at the MRHD.
In a pre- and post-natal study in rats treated daily with risdiplam, risdiplam caused a slight delay in gestation length. No adverse effects were recorded on the survival, growth, functional (behavioural or reproductive) performance of the offspring. There were no effects on female germ cells, as assessed by primordial follicle counts and ovarian histopathology.
Studies in pregnant rats showed that risdiplam crosses the placenta barrier.
Evrysdi should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the fetus. If a pregnant woman needs to be treated with Evrysdi, she should be clearly advised on the potential risk to the fetus.

Labour and delivery.

The safe use of Evrysdi during labour and delivery has not been established.
It is not known whether Evrysdi is excreted in human breast milk. Studies in rats show that risdiplam is excreted into milk. As the potential for harm to the nursing infant is unknown, a decision must be made with the treating physician. It is recommended not to breastfeed during treatment with Evrysdi.

4.7 Effects on Ability to Drive and Use Machines

Evrysdi has no influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The safety profile of Evrysdi is based on four clinical trials FIREFISH, SUNFISH, RAINBOWFISH and JEWELFISH (see Section 5.1, Clinical trials).
The safety profile for infantile-onset SMA patients is based on the pooled analysis of 62 patients from the FIREFISH study Part 1 and 2. FIREFISH is a two-part, open-label study that enrolled 62 patients with infantile-onset SMA between 2.2 and 6.9 months of age. The median exposure duration was 27.8 months (range: 0.6 to 46.5 months). The adverse events observed in clinical trials for infantile-onset SMA are based on the pooled analysis of patients from FIREFISH Part 1 and 2 (see Table 3).
The safety profile for later-onset SMA patients is based on the SUNFISH Part 2 study. The SUNFISH study is a two-part study with later-onset SMA between 2-25 years of age. The adverse events observed in clinical trials for later-onset SMA are based on SUNFISH Part 2 (n = 180), the randomised double-blind, placebo-controlled portion of the study with a follow-up duration of at least 12 months (see Table 4). Adverse events occurring in ≥ 5% of Evrysdi treated patients which occurred ≥ 5% more frequently, or at least 2 times as frequently, as in placebo control patients, is provided in Table 4.
Tables 3 and 4 summarise the adverse events that have been reported with the use of Evrysdi in FIREFISH Part 1 and 2 and SUNFISH Part 2, regardless of causality.
The corresponding frequency category for each adverse events is based on the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Adverse events from clinical trials are listed by MedDRA system organ class.

The RAINBOWFISH study is an open-label, single-arm study that enrolled 26 patients with pre-symptomatic SMA between 16 and 41 days of age at first dose. At the primary analysis, the median exposure duration was 20.4 months (range: 10.6 to 41.9 months) (see Section 5.1, Clinical trials). The safety profile of Evrysdi in pre-symptomatic patients in the RAINBOWFISH study is consistent with the safety profile for symptomatic SMA patients treated with Evrysdi in clinical trials.

Safety profile in patients treated previously with other SMA modifying therapies.

Based on the primary analysis of the JEWELFISH study, the safety profile of Evrysdi in the treatment of non-naive patients who received for up to 59 months (including those previously on treatment with nusinersen (n=76) or with onasemnogene abeparvovec (n=14)) is consistent with the safety profile for treatment naive SMA patients treated with Evrysdi in the FIREFISH, SUNFISH and RAINBOWFISH studies.

Post-marketing experience.

The following adverse drug reaction has been identified from post-marketing experience with Evrysdi (Table 5). Adverse drug reaction is listed according to system organ classes in MedDRA.

Cutaneous vasculitis was identified during post-marketing experience. Symptoms recovered after permanent discontinuation of Evrysdi.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no experience with overdose of Evrysdi in clinical trials. There is no known antidote for overdose of Evrysdi. In case of overdose, the patient should be closely supervised and supportive care instituted.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Evrysdi is a survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier designed to treat SMA caused by mutations in chromosome 5q that lead to SMN protein deficiency. Functional SMN protein deficiency is the pathophysiological mechanism of all SMA types. Evrysdi corrects the splicing of SMN2 to shift the balance from exon 7 exclusion to exon 7 inclusion into the mRNA transcript leading to an increased production in functional and stable SMN protein. Thus, Evrysdi treats SMA by increasing and sustaining functional SMN protein levels.
In vitro and in vivo data indicate that risdiplam may cause alternative splicing of additional genes, including FOXM1 and MADD. FOXM1 and MADD are thought to be involved in cell cycle regulation and apoptosis, respectively, and have been identified as possible contributors to adverse effects seen in animals.
Risdiplam distributes evenly to all parts of the body, including the central nervous system (CNS) by crossing the blood brain barrier, and thereby leading to SMN protein increase in the CNS and throughout the body. Concentrations of risdiplam in plasma and SMN protein in blood reflect its distribution and pharmacodynamic effects in tissues such as brain and muscle.
In all clinical trials for infantile-onset SMA and later-onset SMA patients, Evrysdi led to a consistent and durable increase in SMN protein with a greater than 2-fold median change from baseline within 4 weeks of treatment initiation as measured in blood. This increase in SMN protein was sustained throughout the treatment period of at least 24 months (see Section 5.1, Clinical trials).

Cardiac electrophysiology.

The effect of Evrysdi on the QTc interval was evaluated in a study in 47 healthy adult subjects. At the therapeutic exposure, Evrysdi did not prolong the QTc interval.

Clinical trials.

The efficacy of Evrysdi for the treatment of SMA patients with infantile-onset and later-onset SMA was evaluated in 2 pivotal clinical studies, FIREFISH and SUNFISH. The efficacy of Evrysdi for the treatment of pre-symptomatic SMA patients was evaluated in the RAINBOWFISH study. The overall findings of these studies support the efficacy of Evrysdi for SMA patients. Patients with a clinical diagnosis of Type 0 and Type 4 SMA have not been studied in clinical trials.
Infantile-onset SMA. Study BP39056 (FIREFISH) is an open-label, 2-part study to investigate the efficacy, safety, PK and pharmacodynamics (PD) of Evrysdi in symptomatic Type 1 SMA patients (all patients had genetically confirmed disease with 2 copies of the SMN2 gene). Part 1 of FIREFISH was designed as the dose-finding part of the study. The confirmatory Part 2 of the FIREFISH study assessed the efficacy of Evrysdi at the therapeutic dose selected based on the results from Part 1 (see Section 4.2 Dose and Method of Administration). Patients from Part 1 did not take part in Part 2.
A total of 62 patients with symptomatic Type 1 SMA were enrolled in FIREFISH part 1 (n = 21) and Part 2 (n = 41), of which 58 patients received the therapeutic dose. The median age of onset of clinical signs and symptoms was 1.5 months (range: 0.9 to 3.0 months). The median age at enrolment was 5.6 months (range: 2.2 to 6.9 months), and the median time between onset of symptoms and the first dose was 3.7 months (range 1.0 to 6.0 months). Of these patients, 60% were female, 57% were Caucasian, and 29% were Asian. At baseline the median CHOP-INTEND score was 23 (range: 8 to 37), and the median HINE-2 score was 1 (range: 0 to 5). The baseline demographics and disease characteristics of those enrolled in part 1 were comparable to those in part 2.
The primary endpoint was the proportion of patients with the ability to sit without support for at least 5 seconds (BSID-III gross motor scale, Item 22) after 12 months of treatment in part 2; 29% of patients (n = 12/41, 90% CI: 17.8%, 43.1%, p < 0.0001) achieved this milestone.
The key efficacy endpoints of Evrysdi treated patients in FIREFISH part 1 and part 2 are shown in Table 6 and displayed in Figure 1 and Figure 2.

At month 24, 40% (23/58) of patients who received the therapeutic dose achieved sitting without support for 30 seconds (BSID-III, Item 26). In addition, patients continued to achieve additional motor milestones as measured by the HINE-2 at month 24; 78% of patients were able to roll (31% of patients could roll to the side, 7% could roll from prone to supine and 40% could roll from supine to prone), and 28% of patients achieved a standing measure (16% supporting weight and 12% standing with support).
The proportion of patients alive without permanent ventilation (event-free survival) was 84% for all patients at month 24, see Figure 1. Six infants died (4 within the first 3 months following study enrolment) and one additional patient withdrew from treatment and died 3.5 months later. Four patients required permanent ventilation by month 24. These results indicate a clinically meaningful deviation from the natural history of untreated infantile-onset SMA. Untreated patients with infantile-onset SMA would never be able to sit without support and only 25% would be expected to survive without permanent ventilation beyond 14 months of age.

Later-onset SMA. Study BP39055 (SUNFISH), is a 2-part, multicentre trial to investigate the efficacy, safety, PK and PD of Evrysdi in SMA Type 2 or Type 3 patients between 2-25 years of age. Part 1 was the dose-finding portion and Part 2 was the randomised, double-blind, placebo-controlled confirmatory portion. Patients from Part 1 did not take part in Part 2.
The primary endpoint was the change from baseline score at Month 12 on the Motor Function Measure-32 (MFM32). The MFM32 has the ability to assess a wide range of motor function across a broad range of SMA patients. The total MFM32 score is expressed as a percentage (range: 0 to 100) of the maximum possible score, with higher scores indicating greater motor function. The MFM32 measures motor function abilities, which relate to important daily functions. Small changes in motor function can result in meaningful gain or loss of daily function(s).

SUNFISH part 2.

SUNFISH Part 2 is the randomised, double-blind, placebo-controlled portion of the SUNFISH study in 180 non-ambulant patients with Type 2 (71%) or Type 3 (29%) SMA. Patients were randomised 2:1 to receive either Evrysdi at the therapeutic dose (see Section 4.2 Dose and Method of Administration) or placebo. Randomisation was stratified by age group (2 to 5, 6 to 11, 12 to 17, 18 to 25 years old).
The median age of patients at the start of treatment was 9.0 years old (range 2-25 years old) and the median time between onset of initial SMA symptoms to first treatment was 102.6 (1-275) months. Of the 180 patients included in the trial, 51% were female, 67% Caucasian and 19% Asian. At baseline, 67% of patients had scoliosis (32% of patients with severe scoliosis). Patients had a mean baseline MFM32 score of 46.1 and a Revised Upper Limb Module (RULM) score of 20.1. The overall baseline demographic characteristics were well balanced between Evrysdi and placebo groups with the exception of an imbalance of patients with scoliosis (63.3% of patients in the Evrysdi arm and 73.3% of patients in the placebo control).
The primary analysis for SUNFISH Part 2, the change from baseline in MFM32 total score at Month 12, showed a clinically meaningful and statistically significant difference between patients treated with Evrysdi and placebo. The results of the primary analysis and key secondary endpoints are shown in Table 7 and Figures 3 and 4.

When compared to placebo, patients treated with Evrysdi demonstrated significant improvements in motor function assessed by the MFM32 after 12 months of treatment (mean difference 1.55 points; p = 0.0156). Patients 2-5 years old treated with Evrysdi demonstrated the greatest improvement on MFM32 compared to placebo control (≥ 3 points increase: 78.1% vs 52.9%). Patients ≥ 18 years old treated with Evrysdi achieved stabilisation of disease (change from baseline MFM32 total score ≥ 0 point(s): 57.1% vs. 37.5%). Consistent improvement compared to baseline MFM32 was observed in both Type 2 and 3 SMA patients treated with Evrysdi compared to placebo control (1.54 points [95% CI: 0.06, 3.02]; 1.49 points [95% CI: -0.94, 3.93], respectively).
The study also met a secondary independent motor function outcome, RULM. On the RULM, statistically significant and clinically meaningful improvements in motor function were observed after 12 months of treatment compared to baseline. The patients 2-5 years old treated with Evrysdi demonstrated the greatest improvement on the RULM (3.41 points [95% CI: 1.55, 5.26]) and improvement was also observed in the patients ≥ 18 years old (1.74 points [95% CI: -1.06, 4.53]).

Upon completion of 12 months of treatment, 117 patients continued to receive Evrysdi. At the time of the 24 month analysis, these patients who were treated with Evrysdi for 24 months overall experienced maintenance of improvement in motor function between month 12 and month 24. The mean change from baseline for MFM32 was 1.83 (95% CI: 0.74, 2.92) and for RULM was 2.79 (95% CI: 1.94, 3.64) at month 24.

SUNFISH part 1.

The efficacy of Evrysdi in later-onset SMA patients was also supported by results from Part 1, the dose-finding part of SUNFISH. In Part 1, 51 patients with Type 2 and 3 SMA (including 7 ambulatory patients) between 2 to 25 years old were enrolled. After 1 year of treatment at the therapeutic dose (the dose selected for Part 2), there was a clinically meaningful improvement in motor function as measured by MFM32 with a mean change from baseline of 2.7 points (95% CI: 1.5, 3.8). The improvement in MFM32 was maintained up to 2 years on Evrysdi treatment (mean change of 2.7 points [95% CI: 1.2, 4.2]).
Pre-symptomatic SMA. Study BN40703 (RAINBOWFISH) is an open-label, single-arm, multicenter clinical study to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of Evrysdi in infants from birth to 6 weeks of age (at first dose) who have been genetically diagnosed with SMA but do not yet present with symptoms.
The efficacy in pre-symptomatic SMA patients was evaluated at Month 12 in 26 patients [intent-to-treat (ITT) population] who had been treated with Evrysdi. The median age of these patients at first dose was 25 days (range: 16 to 41 days), 62% were female and 85% were Caucasian. Eight patients, 13 patients and 5 patients had 2, 3 and ≥ 4 copies of the SMN2 gene, respectively. At baseline the median CHOP-INTEND score was 51.5 (range: 35 to 62), the median HINE-2 score was 2.5 (range: 0 to 6) and the median ulnar nerve compound muscle action potential (CMAP) amplitude was 3.6 mV (range: 0.5 to 6.7 mV).
The primary efficacy population (N = 5) included patients with 2 SMN2 copies and a baseline CMAP amplitude ≥ 1.5 mV. In these patients, the median CHOP-INTEND score was 48.0 (range: 36.0 to 52.0), the median HINE-2 score was 2.0 (range 1.0 to 3.0), and the median CMAP amplitude was 2.6 mV (range: 1.6 to 3.8 mV) at baseline.
The primary endpoint was the proportion of patients in the primary efficacy population with the ability to sit without support for at least 5 seconds (BSID-III gross motor scale, Item 22) at Month 12; a statistically significant and clinically meaningful proportion of patients achieved this milestone compared to the predefined performance criterion of 5%.
The key efficacy endpoints of Evrysdi treated patients are shown in Tables 8 and 9, and Figure 5.

Additionally, 80% (4/5) of the primary efficacy population, 87.5% (7/8) of patients with 2 SMN2 copies, and 80.8% (21/26) of patients in the ITT population achieved sitting without support for 30 seconds (BSID-III, Item 26).
Patients in the ITT population also achieved motor milestones as measured by the HINE-2 at month 12 (N = 25). In this population 96.0% of patients could sit [1 patient (1/8 patients with 2 SMN2 copies) achieved stable sit and 23 patients (6/8, 13/13, 4/4 of patients with 2, 3, and ≥ 4 SMN2 copies, respectively) could pivot/rotate]. In addition, 84% of patients could stand; 32% (N = 8) patients could stand with support (3/8, 3/13 and 2/4 patients with 2, 3, and ≥ 4 SMN2 copies, respectively) and 52% (N = 13) patients could stand unaided (1/8, 10/13 and 2/4 of patients with 2, 3, and ≥ 4 SMN2 copies, respectively). Furthermore, 72% of patients could bounce, cruise or walk; 8% (N = 2) patients could bounce (2/8 patients with 2 SMN2 copies), 16% (N = 4) could cruise (3/13 and 1/4 patients with 3 and ≥ 4 SMN2 copies, respectively) and 48% (N = 12) could walk independently (1/8, 9/13 and 2/4 patients with 2, 3, and ≥ 4 SMN2 copies, respectively). Seven patients were not tested for walking at month 12.

Use in patients previously treated with other SMA modifying therapies. Study BP39054 (JEWELFISH, n = 174) is a single arm, open-label study to investigate the safety, tolerability, PK and PD of Evrysdi in patients with infantile-onset and later-onset SMA (median age 14 years [range 1-60 years]), who had previously received treatment with other approved (nusinersen n = 76, onasemnogene abeparvovec n = 14) or investigational SMA modifying therapies.
Patients had a greater than 2-fold median increase in SMN protein levels in blood compared to baseline after 4 weeks of Evrysdi treatment. The increase in SMN protein was maintained throughout the treatment period of at least 2 years.
At the analysis at month 24 of treatment, patients 2-60 years of age showed overall stabilisation in motor function in MFM-32 and RULM (n = 137 and n = 133, respectively). Patients less than 2 years (n = 6) maintained or gained motor milestones such as head control, rolling and sitting independently. All ambulatory patients (aged 5-46 years, n = 15) retained their ability to walk.

5.2 Pharmacokinetic Properties

Pharmacokinetic parameters for Evrysdi have been characterised in healthy adult subjects and in patients with SMA.
After administration of Evrysdi as an oral solution, the PK of risdiplam were approximately linear between 0.6 and 18 mg. Risdiplam's PK was best described by a population PK model with three-transit-compartment absorption, two-compartment disposition and first-order elimination. Body weight and age were found to have significant effect on the PK.
The estimated exposure (mean AUC_0-24h) for infantile-onset SMA patients (age 2-7 months at enrolment) at the therapeutic dose of 0.2 mg/kg once daily was 1930 nanogram/mL. For pre-symptomatic infants (16 days to ≤ 2 months) in the RAINBOWFISH study, the estimated exposure is 2020 nanogram/mL at 0.15 mg/kg after 2 weeks once daily administration. The estimated exposure for later-onset SMA patients (2-25 years old at enrolment) in the SUNFISH study (Part 2) at the therapeutic dose (0.25 mg/kg once daily for patients with a body weight < 20 kg; 5 mg once daily for patients with a body weight ≥ 20 kg) was 2070 nanogram/mL. The estimated exposure (mean AUC_0-24h) for SMA treatment non-naive patients (age 1-60 years at enrolment) was 1700 nanogram.h/mL at the therapeutic dose of 0.25 mg/kg or 5 mg. The observed maximum concentration (mean C_max) was 194 nanogram/mL at 0.2 mg/kg in FIREFISH and 120 nanogram/mL in SUNFISH Part 2, the estimated maximum concentration at 0.15 mg/kg in RAINBOWFISH is 111 nanogram/mL, and 129 nanogram/mL in JEWELFISH.

Absorption.

Risdiplam was rapidly absorbed in the fasted state with a plasma t_max ranging from 1 to 4 hours after oral administration. In the clinical efficacy studies, risdiplam was administered with a morning meal or after breastfeeding.

Distribution.

The population PK parameter estimates were 98 L for the apparent central volume of distribution, 93 L for the peripheral volume, and 0.68 L/hour for the inter-compartment clearance.
Risdiplam is predominantly bound to serum albumin, without any binding to alpha-1 acid glycoprotein, with a free fraction of 11%.

Metabolism.

Risdiplam is metabolised primarily by flavin monooxygenase 1 and 3 (FMO1 and FMO3), and also by CYPs 1A1, 2J2, 3A4 and 3A7.
Co-administration of 200 mg itraconazole twice daily, a strong CYP3A inhibitor, with a single oral dose of Evrysdi 6 mg showed no clinically relevant effect on the PK of risdiplam (11% increase in AUC, 9% decrease in C_max).

Excretion.

Population PK analyses estimated an apparent clearance (CL/F) of 2.6 L/h for risdiplam.
The effective half-life of risdiplam was approximately 50 hours in SMA patients.
Risdiplam is not a substrate of human multidrug resistance protein 1 (MDR1).
Approximately 53% of the dose (14% unchanged risdiplam) was excreted in the faeces and 28% in urine (8% unchanged risdiplam). Parent drug was the major component found in plasma, accounting for 83% of drug related material in circulation. The pharmacologically inactive metabolite M1 was identified as the major circulating metabolite.