Consumer medicine information

Mayzent

Siponimod

BRAND INFORMATION

Brand name

Mayzent

Active ingredient

Siponimod

Schedule

SUMMARY CMI

Mayzent™

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 Mayzent?

Mayzent contains the active ingredient siponimod. Mayzent is used for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS).

For more information, see Section 1. Why am I using Mayzent? in the full CMI.

2. What should I know before I use Mayzent?

Do not use if you have ever had an allergic reaction to Mayzent 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.

For more information, see Section 2. What should I know before I use Mayzent? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Mayzent and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Mayzent?

You start Mayzent treatment with a starter titration pack that lasts for 5 days.
On Day 6, you take your prescribed dose. The usual dose is one 2mg tablet taken once a day.

More instructions can be found in Section 4. How do I use Mayzent? in the full CMI.

5. What should I know while using Mayzent?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Mayzent. Have a blood test to check genotype and for complete blood count before starting Mayzent Have an eye check up before starting Mayzent Tell your doctor if you plan to receive a vaccine Have regular skin checks and protect your skin from sun exposure Avoid becoming pregnant while using Mayzent and for 10 days after you stop using it
Things you should not do	Do not stop using this medicine suddenly.
Driving or using machines	It is not known if Mayzent will influence your ability to drive and use machines.
Drinking alcohol	There are no known interactions between Mayzent and alcohol
Looking after your medicine	Refrigerate, do not freeze. Store between 2°C – 8°C for the 0.25mg, 1mg and 2mg tablets. After opening, only the 1mg and 2mg tablets can be stored below 30°C for up to 3 months. Keep out of reach of children

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

6. Are there any side effects?

Common side effects include headache, dizziness, diarrhoea, feeling unwell, pain in arms/legs, weakness, shaking.

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

Mayzent™

Active ingredient(s): siponimod

Consumer Medicine Information (CMI)

This leaflet provides important information about using Mayzent. 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 Mayzent.

Where to find information in this leaflet:

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

1. Why am I using Mayzent?

Mayzent contains the active ingredient siponimod. Mayzent belongs to a group of medicines called sphingosine-1-phosphate (S1P) receptor modulators. Mayzent helps to slow down the effects of multiple sclerosis (MS) such as worsening disability and decline in thinking. It may also slow down the nerve damage caused by MS and increase your time without relapse.

Mayzent is used for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS).

2. What should I know before I use Mayzent?

Warnings

Do not use Mayzent if:

you are allergic to siponimod, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
you have the CYP2C9 *3*3 genotype
in the last 6 months, you have had a heart attack, angina, stroke or certain types of heart failure.
you have irregular or abnormal heartbeat (arrhythmia) and you do not have a pacemaker.

Check with your doctor if you:

have CYP2C9 *3*3 genotype (less than 0.4 to 0.5% of the population). Your doctor will do a blood test to check this before you start Mayzent.
have not had a recent blood test. A complete blood count should be done before starting Mayzent.
have an infection
have a lowered immune system (due to a disease or take medicines that lower your immune system) and may get infections more easily
have not had chickenpox or have not been vaccinated against chicken pox
plan to receive a vaccine. You should not receive certain vaccines (called live attenuated vaccines) during treatment with Mayzent and for up to 4 weeks after stopping treatment with Mayzent.
have or have had eye problems or vision problems. Your doctor will organise an eye check up before you start Mayzent and then regular eye check ups.
have uncontrolled high blood pressure
have a slow heartbeat or are taking medicines that can slow your heartbeat
have severe breathing problems or asthma
have liver problems. Your doctor will do a blood test to check your liver function before you start Mayzent.
have any other medical conditions
take any medicines for any other condition.

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?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Your doctor will discuss with you what is best for you and your baby.

If you become pregnant or think you are pregnant, tell your doctor right away.

You should not take Mayzent while you are breastfeeding. Talk to your doctor if you are breastfeeding or intend to breastfeed.

Contraception

You should avoid becoming pregnant while using Mayzent and for at least 10 days after you stop using it. Ask your doctor or pharmacist for options of effective birth control.

Use in children

Mayzent has not been studied in patients below 18 years old.

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.

Some medicines may interfere with Mayzent and affect how it works.

Medicines for an irregular heartbeat such as quinidine, procainamide, amiodarone or sotalol.
Medicines that slow down your heartbeat such as verapamil or diltiazem, ivabradine or digoxin.
Medicines that affect the immune system such as other medicines used to treat multiple sclerosis, or corticosteroids.
Certain types of vaccines (called live attenuated vaccines).
A medicine called carbamazepine.
Medicines such as modafinil and fluconazole if you have a certain genotype.

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

4. How do I use Mayzent?

How much to take

Your Mayzent treatment will start with a titration pack that lasts for 5 days. You take the following tablets:

Titration	Titration dose	Titration regimen
Day 1	0.25 mg	1 tablet of 0.25 mg Mayzent
Day 2	0.25 mg	1 tablet of 0.25 mg Mayzent
Day 3	0.5 mg	2 tablets of 0.25 mg Mayzent
Day 4	0.75 mg	3 tablets of 0.25 mg Mayzent
Day 5	1.25 mg	5 tablets of 0.25 mg Mayzent

On Day 6, you take your prescribed dose. The usual dose is one 2mg tablet taken once a day.
For some patients that have a CYP2C9 *2*3 or CYP2C9 *1*3 genotype, the usual dose is 1 mg once daily.

Follow the instructions provided, and take Mayzent until your doctor tells you to stop.

When and how to take Mayzent

Take Mayzent once a day at about the same time each day.
Swallow the tablets with half a glass of water. You can take Mayzent with or without food.

If you forget to take Mayzent

Mayzent should be taken regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, and then take the next tablet as usual.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

If you missed a dose on one day during first 6 days of treatment, call your doctor before you take the next dose. Your doctor will need to prescribe a new starter titration pack. You will have to restart at Day 1 with a new starter titration pack.

Do not stop taking Mayzent or change your dose without talking with your doctor.

If you stop taking Mayzent for 4 or more repeated daily doses, you need to re-start treatment with the starter titration pack.

If you take too much Mayzent

If you think that you have taken too much Mayzent, 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.

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

5. What should I know while using Mayzent?

Things you should do

Have regular eye check ups
Have regular skin checks and protect your skin from sun exposure
Tell your doctor if you plan to receive a vaccine
Avoid becoming pregnant while using Mayzent and for 10 days after you stop using it.

Call your doctor straight away if you:

develop any type of infection
notice any skin changes or sores
believe your multiple sclerosis is getting worse (e.g. weakness or eye changes) or if you notice any new or unusual symptoms – this can be serious.
get a fever, feel like you have a flu, or have a headache with a stiff neck, sensitivity to light, feel sick, and feel confused (as these may be caused by a viral or fungal infection).

Remind any doctor, dentist or pharmacist you visit that you are taking Mayzent.

Things you should not do

Do not stop using this medicine suddenly.

If you stop taking Mayzent, symptoms of multiple sclerosis can return and may become worse compared to before or during treatment. Keep taking Mayzent unless your doctor tells you to stop.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Mayzent affects you.

Mayzent may cause dizziness in some people.

Looking after your medicine

Store the tablets in a refrigerator (between 2 to 8°C). Do not freeze.
After opening, only the 1mg and 2mg tablets can be stored below 30°C for up to 3 months (in a cool dry place away from moisture, heat or sunlight). Keep in the original package.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any 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

Less serious side effects	What to do
General such as: Headache Dizziness Diarrhoea Feeling unwell Pain in legs or arms Swollen hands, ankles, legs or feet Weakness Skin changes such as small spots or lumps of colours ranging from blue/dark to brown, pink to skin coloured.	Speak to your doctor if you have any of these less serious side effects and they worry you. If these side effects become severe, please tell your doctor, pharmacist or healthcare provider

Serious side effects

Serious side effects

What to do

Infections such as:

Shingles - a painful rash of small fluid-filled blisters appearing on reddened skin, tingling burning sensation
Fever, sore throat or mouth ulcers.
Fungal or viral - headaches with a stiff neck, sensitivity to light, feeling sick, and feeling confused
Weakness or visual changes, memory loss, trouble thinking or difficulty walking (signs of a rare brain infection called progressive multifocal leukoencephalopathy).

Heart issues such as:

Slow heartbeat
Irregular heartbeat.

Skin cancer:

Raised, smooth, shiny pink or pearly bump on the skin (basal cell carcinoma).
Scaly or red raised patch, or wart like sore, or a new sore on an existing scar (squamous cell carcinoma).

Worsening of multiple sclerosis symptoms such as:

muscle weakness, muscle stiffness, muscle spasms
eye changes such as blurred vision, double vision
tremor
general weakness or
any unusual or different symptoms.

General:

Difficulty breathing
Convulsions, uncontrolled shaking of the body
Blurred vision, trouble seeing colours
Unexplained nausea, vomiting with abdominal pain, fatigue, yellowing of the skins or eyes, dark urine.

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.

Some side effects can only be found when your doctor does tests from time to time to check your progress. These include:

Higher levels of liver enzymes
Changes to your blood cell counts
Changes to the health of your eyes
Abnormal changes to your skin.

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 Mayzent contains

Active ingredient (main ingredient)	siponimod
Other ingredients (inactive ingredients)	Tablet core: Lactose monohydrate microcrystalline cellulose crospovidone colloidal anhydrous silica glycerol dibehenate. Tablet coating: Polyvinyl alcohol titanium dioxide iron oxide yellow (2 mg tablet) iron oxide red black iron oxide (0.25 mg and 1mg tablet) purified talc lecithin (soya) xanthan gum.
Potential allergens	Lactose Sugars as lactose

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

What Mayzent looks like

Mayzent is supplied as film-coated tablets in blister packs.

Mayzent 0.25 mg tablets are: pale red, round, biconvex-beveled edged film-coated tablet with Novartis logo on one side and T on other side (AUST R 310498). Each pack contains 12 tablets (titration pack) or 120 tablets.

Mayzent 1 mg tablets are: violet white, round biconvex-beveled edged film-coated tablet with Novartis logo on one side and L on other side. (AUST R 395451). Each pack contains 28 tablets.

Mayzent 2 mg tablets are: pale yellow, round, biconvex-beveled edged film-coated tablet with Novartis logo on one side and II on other side (AUST R 310499). Each pack contains 28 tablets.

Who distributes Mayzent

Mayzent is supplied in Australia by:

Novartis Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone 1 800 671 203
Web site: www.novartis.com.au

Mayzent is supplied in New Zealand by:

NOVARTIS New Zealand Ltd
PO Box 99102, Newmarket
Auckland 1149, New Zealand
Telephone: 0800 354 335

™ = Registered Trademark

This leaflet was prepared in July 2023.

(may140723c.doc based on PI may140723i.doc)

Published by MIMS September 2023

BRAND INFORMATION

Brand name

Mayzent

Active ingredient

Siponimod

Schedule

1 Name of Medicine

The active ingredient of Mayzent is siponimod.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 0.25 mg, 1 mg or 2 mg siponimod (as siponimod hemifumarate).

Excipients with a known effect.

Sugars as lactose (0.25 mg and 1 mg tablet) and lactose (2 mg tablet). For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablets.

Mayzent 0.25 mg.

Pale red, round, biconvex, beveled-edged film-coated tablet with Novartis logo on one side and T on other side.

Mayzent 1 mg.

Violet white, round, biconvex, beveled-edged film-coated tablet with Novartis logo on one side and L on other side.

Mayzent 2 mg.

Pale yellow, round, biconvex, beveled-edged film-coated tablet with Novartis logo on one side and II on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Mayzent is indicated for the treatment of adult patients with secondary progressive multiple sclerosis (SPMS).

4.2 Dose and Method of Administration

Dosage regimen.

Patient selection.

Before initiation of treatment with Mayzent the CYP2C9 genotype of the patient should be determined. Mayzent is contraindicated in patients with a CYP2C9*3*3 genotype (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Pharmacogenomics; Section 5.2 Pharmacokinetic Properties, Pharmacogenomics).
For recommendations related to switching treatment from other disease modifying therapies to Mayzent, see Section 4.4 Special Warnings and Precautions for Use, Prior treatment with immunosuppressive or immune-modulating therapies.

Treatment initiation.

Treatment has to be initiated with a titration pack that lasts for 5 days (see Section 5 Pharmacological Properties). The dose titration starts with 0.25 mg once daily on day 1 and 2, followed by once daily doses of 0.5 mg on day 3 (two tablets of 0.25 mg), 0.75 mg on day 4 (three tablets of 0.25 mg), and 1.25 mg on day 5 (five tablets of 0.25 mg), to reach the maintenance dose of 2 mg* Mayzent starting on day 6. See Table 1.

During the first 6 days of treatment initiation the recommended daily dose should be taken once daily in the morning with or without food.
If a titration dose is missed on one day during the first 6 days of treatment, treatment needs to be re-initiated with a new titration pack.

General target population.

The recommended maintenance dose of Mayzent is 2 mg taken once daily with or without food. In patients with a CYP2C9 *2*3 or *1*3 genotype, the recommended maintenance dose is 1 mg taken once daily (see Special populations, Pharmacogenomics). For treatment initiation in these patients the same titration pack should be used (see Treatment initiation).

Re-initiation of maintenance therapy after treatment interruption.

If Mayzent maintenance treatment is interrupted for 4 or more consecutive daily doses, treatment has to be re-initiated with a new titration pack (see Treatment initiation above). Treatment interruptions for up to 3 missed consecutive daily doses do not require re-titration and treatment should be continued at the maintenance dose level.

Special populations.

Pharmacogenomics.

Mayzent is contraindicated in patients with a CYP2C9*3*3 genotype (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use, Pharmacogenomics; Section 5.2 Pharmacokinetic Properties, Pharmacogenomics).
The recommended maintenance dose of Mayzent in patients with a CYP2C9 *2*3 or *1*3 genotype is 1 mg once daily (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties, Pharmacogenomics).

Renal impairment.

No Mayzent dose adjustments are needed in patients with renal impairment (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

No Mayzent dose adjustments are needed in patients with hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric patients (below 18 years).

No studies have been performed in paediatric patients.

Geriatric patients (65 years or above).

No Mayzent dose adjustment is needed in patients aged 65 years and over.

Method of administration.

Mayzent tablets should be taken orally with or without food and swallowed whole with water.

4.3 Contraindications

Mayzent should not be administered to patients:
With known hypersensitivity to siponimod or any of the excipients.
With a CYP2C9*3/*3 genotype (see Section 4.4 Special Warnings and Precautions for Use, Pharmacogenomics).
Who in the last 6 months had myocardial infarction (MI), unstable angina pectoris, stroke/transient ischemic attack (TIA), decompensated heart failure (requiring inpatient treatment), or New York Heart Association Class III/IV heart failure.
With second-degree Mobitz type II atrioventricular (AV) block, third-degree AV block, sino-atrial heart block or sick-sinus syndrome, if they do not have a pacemaker (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Infections.

A core pharmacodynamic effect of Mayzent is a dose dependent reduction of peripheral lymphocyte count to 20 to 30% of baseline values. This is due to the reversible sequestration of lymphocytes in lymphoid tissues (see Section 5 Pharmacological Properties).
The immune system effects of Mayzent may increase the risk of infections (see Section 5 Pharmacological Properties).
Before initiating treatment with Mayzent, a recent complete blood count (CBC) (i.e. within last 6 months or after discontinuation of prior therapy) should be available.
Initiation of treatment with Mayzent should be delayed in patients with severe active infection until resolution. Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3 to 4 weeks after discontinuation of Mayzent, vigilance for infection should be continued throughout this period (see Stopping Mayzent therapy below).
Patients receiving Mayzent should be instructed to report symptoms of infections to their physician. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. Suspension of treatment with Mayzent, should be considered if a patient develops a serious infection.
Cases of cryptococcal meningitis (CM) have been reported with Mayzent. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with such symptoms and signs should undergo prompt diagnostic evaluation. Mayzent treatment should be suspended until CM has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
Cases of progressive multifocal leukoencephalopathy (PML) have been reported for S1P receptor modulators, including Mayzent, and other therapies for MS (see Section 4.8 Adverse Effects (Undesirable Effects)). Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. If PML is suspected, Mayzent treatment should be suspended until PML has been excluded.
Cases of herpes viral infection, including cases of meningitis or meningoencephalitis caused by varicella zoster virus, have been reported with Mayzent. Patients without a healthcare professional confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before initiating Mayzent (see subsection Vaccination).
Anti-neoplastic, immune-modulating or immunosuppressive therapies (including corticosteroids) should be co-administered with caution due to the risk of additive immune system effects during such therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Vaccination.

A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with Mayzent, following which initiation of treatment with Mayzent should be postponed for 1 month to allow the full effect of vaccination to occur (see Section 4.8 Adverse Effects (Undesirable Effects)).

Live attenuated vaccines.

The use of live attenuated vaccines should be avoided while patients are taking Mayzent. Mayzent treatment discontinuation is recommended 1 week prior to vaccination until 4 weeks after vaccination (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Non-live attenuated vaccines.

Non-live attenuated vaccines may be less effective if administered during Mayzent treatment. The decision whether to continue or pause the treatment with Mayzent should be based on the benefit-risk assessment of the individual patient (see Stopping Mayzent therapy below; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Macular oedema.

Macular oedema (see Section 4.8 Adverse Effects (Undesirable Effects)) with or without visual symptoms was more frequently reported on siponimod (1.8%) than on placebo (0.2%) in the phase 3 clinical study. The majority of cases occurred within the first 3 to 4 months of therapy. An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients before starting treatment and at any time if there is any change in vision while taking Mayzent.
Patients with a history of diabetes mellitus, uveitis or underlying/co-existing retinal diseases are at increased risk of macular oedema. In addition to the examination of the fundus, including the macula, prior to treatment, MS patients with diabetes mellitus, uveitis or a history of retinal disorders should have follow-up evaluations while receiving Mayzent therapy.
Continuation of Mayzent therapy in patients with macular oedema has not been evaluated. A decision on whether or not Mayzent should be discontinued needs to take into account the potential benefits and risks for the individual patient.

Bradyarrhythmia.

Heart rate.

Since initiation of Mayzent treatment results in a transient decrease in heart rate (see Section 5 Pharmacological Properties), an up-titration scheme to reach the maintenance dose of Mayzent on day 6 is applied at treatment start (see Section 4.2 Dose and Method of Administration).
After the first titration dose, the heart rate decrease starts within an hour and the day 1 decline is maximal at approximately 3 to 4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days with maximal decrease from day 1-baseline reached on day 5 to 6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on day 1 with the pulse declining on average 5 to 6 beats per minute (bpm). Post-dose declines on the following days are less pronounced. With continued dosing, heart rate starts increasing after day 6 and reaches placebo levels within 10 days after treatment initiation.
Heart rates below 40 bpm were rarely observed. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced mild to moderate symptoms including dizziness or fatigue which resolved within 24 hours without intervention (see Section 4.8 Adverse Effects (Undesirable Effects)).

Atrioventricular conduction.

Initiation of Mayzent treatment has been associated with transient atrioventricular conduction delays that follow a similar temporal pattern as the observed decrease in heart rate during dose titration. The atrioventricular conduction delays manifested in most of the cases as first-degree atrioventricular (AV) blocks (prolonged PR interval on electrocardiogram). Second-degree AV blocks, usually Mobitz type I (Wenckebach), have been observed in less than 1.7% of patients in clinical trials at the time of treatment initiation with Mayzent. The conduction abnormalities typically were transient, asymptomatic, resolved within 24 hours and did not require discontinuation of Mayzent treatment.

Treatment initiation recommendations.

Mayzent treatment initiation with a dose titration is usually well tolerated (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications).
As a precautionary measure, patients with sinus bradycardia (heart rate (HR) < 55 bpm), first or second-degree [Mobitz type I] atrioventricular block (AV block), or a history of myocardial infarction or heart failure, if not contraindicated should be observed for a period of 6 hours after the first dose of Mayzent for signs and symptoms of bradycardia. Obtaining an electrocardiogram (ECG) prior to dosing, and at the end of the observation period is recommended in these patients. Should post-dose bradyarrhythmia or conduction related symptoms occur or if ECG 6 hours post-dose show new onset second degree or higher AV block or QTc ≥ 500 msec, appropriate management should be initiated and observation should be continued until the symptoms/findings have resolved. If pharmacological treatment is required, monitoring should be continued overnight and 6-hour monitoring should be repeated after the second dose.
Due to the risk of serious cardiac rhythm disturbances, Mayzent should not be used in patients with sino-atrial heart block.
Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest with onset > 6 months prior to Mayzent treatment initiation, cerebrovascular disease, uncontrolled hypertension or severe untreated sleep apnea, Mayzent should not be used in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy.
Use of Mayzent in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring.
A thorough QT study demonstrated no significant direct QT prolonging effect of Mayzent and Mayzent is not associated with an arrhythmogenic potential related to QT prolongation. Initiation of Mayzent treatment may result in decreased heart rate and indirect prolongation of the QT interval during the titration phase. Mayzent was not studied in patients with significant QT prolongation (QTc > 500 msec) or who were treated with QT prolonging drugs. If treatment with Mayzent is considered in patients with pre-existing significant QT prolongation or who are treated with QT prolonging drugs with known arrhythmogenic properties, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy during treatment initiation.
Mayzent has not been studied in patients with arrhythmias requiring treatment with Class Ia (e.g. quinidine, procainamide) or Class III anti-arrhythmic drugs (e.g. amiodarone, sotalol). Class Ia and Class III anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. Since initiation of Mayzent treatment results in decreased heart rate, Mayzent should not be used concomitantly with these drugs during treatment initiation.
Experience with Mayzent is limited in patients receiving concurrent therapy with heart-rate lowering calcium channel blockers (such as verapamil or diltiazem), or other substances that may decrease heart rate (e.g. ivabradine or digoxin). Concomitant use of these substances during Mayzent initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment with Mayzent should generally not be initiated in patients who are concurrently treated with these substances.
If concomitant treatment with Mayzent and the above mentioned substances is considered during initiation of treatment with Mayzent, advice from a cardiologist should be sought regarding the switch to non-heart-rate lowering drugs or appropriate monitoring for treatment initiation.
Bradyarrhythmic effects are more pronounced when Mayzent is added to beta-blocker therapy. For patients receiving a stable dose of beta-blocker, the resting heart rate should be considered before introducing Mayzent treatment. If the resting heart rate is > 50 bpm under chronic beta-blocker treatment, Mayzent can be introduced. If resting heart rate is ≤ 50 bpm, then beta-blocker treatment should be interrupted until the baseline heart-rate is > 50 bpm. Treatment with Mayzent can then be initiated and treatment with beta-blocker can be re-initiated after Mayzent has been up-titrated to the target maintenance dose.

Missed dose during treatment initiation and re-initiation of therapy following treatment interruption.

If a titration dose is missed on one day during the first 6 days of treatment or if 4 or more consecutive daily doses are missed during maintenance therapy, the same initial dose titration and monitoring recommendations should apply (see Treatment initiation recommendations above; see Section 4.2 Dose and Method of Administration).

Liver function.

Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with Mayzent. In study A2304, Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) three times upper limit of normal (ULN) were observed in 5.6% of patients treated with Mayzent 2 mg compared to 1.5% of patients receiving placebo (see Section 4.8 Adverse Effects (Undesirable Effects)). In clinical trials, Mayzent was discontinued if the elevation exceeded a 3-fold increase and the patient showed symptoms related to hepatic function.
Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, rash with eosinophilia or jaundice and/or dark urine during treatment, should have liver enzymes checked and Mayzent should be discontinued if significant liver injury is confirmed.
Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function test (LFT) values when taking Mayzent, caution should be exercised when using Mayzent in patients with a history of significant liver disease.

Cutaneous neoplasms.

In study A2304, the incidence of basal cell carcinoma (BCC) was 1.1% in Mayzent-treated patients and 1.3% in patients receiving placebo. For squamous cell carcinoma (SCC), the incidence in study A2304 was the same for Mayzent-treated patients and placebo (0.2%). However, additional cases of BCC and SCC in Mayzent-treated patients have been reported with longer exposure (see Section 4.8 Adverse Effects (Undesirable Effects)). Cases of other skin malignancies, including melanoma, have also been reported in patients treated with Mayzent and in patients on another S1P modulator.
Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer and patients with suspicious skin lesions. Patients should be advised to report any suspicious skin lesions to their physician for prompt evaluation. Patients treated with Mayzent should be cautioned against exposure to sunlight without protection. These patients should not receive concomitant phototherapy with UV-B radiation or PUVA-photochemotherapy.

Blood pressure effect.

Hypertension was more frequently reported in patients on siponimod (12.6%) than on placebo (9.0%) in the phase 3 clinical trial in patients with SPMS. Treatment with siponimod resulted in an increase of systolic and diastolic blood pressure starting early after treatment initiation, reaching maximum effect after approximately 6 months of treatment (systolic 3 mmHg, diastolic 1.2 mmHg) and staying stable thereafter. The effect persisted with continued treatment. Blood pressure should be monitored during treatment with Mayzent and managed appropriately.

Unexpected neurological or psychiatric symptoms/signs.

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported for another sphingosine 1-phosphate (S1P) receptor modulator. Such events have not been reported for Mayzent in the development program. However, should a patient on Mayzent treatment develop any unexpected neurological or psychiatric symptoms/signs (e.g. cognitive deficits, behavioral changes, cortical visual disturbances or any other neurological cortical symptoms/signs or any symptom/sign suggestive of an increase of intracranial pressure) or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider a magnetic resonance imaging (MRI).

Prior treatment with immunosuppressive or immune-modulating therapies.

When switching from other disease modifying therapies, the half-life and mode of action of the other therapy must be considered to avoid an additive immune effect whilst at the same time minimizing risk of disease reactivation.
Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its product information, initiating treatment with Mayzent after alemtuzumab is not recommended unless the benefits of Mayzent treatment clearly outweigh the risks for the individual patient.

Pharmacogenomics.

Before initiation of treatment with Mayzent, patients should be genotyped (as tested and confirmed by NATA/RCPA accredited Pathology Lab) for CYP2C9 to determine the CYP2C9 genotype (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties, Pharmacogenomics).

Stopping Mayzent therapy.

Severe exacerbation of disease including disease rebound has been rarely reported after discontinuation of another S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping siponimod treatment. Patients should be observed for relevant signs of possible severe exacerbation or return of high disease activity upon siponimod discontinuation and appropriate treatment should be instituted as required.
After stopping Mayzent therapy siponimod remains in the blood for up to 10 days. Starting other therapies during this interval will result in concomitant exposure to siponimod.
Lymphocyte counts typically return to the normal range in the vast majority (90%) of SPMS patients within 10 days of stopping therapy. However, residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count may persist for up to 3 to 4 weeks after the last dose. Use of immunosuppressants within this period may lead to an additive effect on the immune system and therefore caution should be applied 3 to 4 weeks after the last dose.

Use in patients with asthma.

In the phase 3 clinical study in patients with SPMS, mean reductions from baseline in FEV₁ in the siponimod group were 0.1 L with no change in the placebo group (see Section 4.8 Adverse Effects (Undesirable Effects), Respiratory effects). These reductions were greater (approximately 0.15 L mean change from baseline in FEV₁) in patients with respiratory disorders such as asthma or chronic obstructive pulmonary disease (COPD) treated with siponimod. Mayzent may be used with caution in patients with asthma. However, asthma status should be reviewed and medications (including preventers) should be optimised before Mayzent treatment is considered.

Use in hepatic impairment.

No dose adjustments for siponimod are needed in patients with hepatic impairment. The unbound siponimod pharmacokinetics AUC is 15% and 50% higher in subjects with moderate and severe hepatic impairment, respectively, in comparison with healthy subjects for the 0.25 mg single dose studied. The mean half-life of siponimod was unchanged in hepatic impairment.

Use in renal impairment.

No siponimod dose adjustments are needed in patients with mild, moderate or severe renal impairment. Mean siponimod half-life and C_max (total and unbound) were comparable between subject with severe renal impairment and healthy subjects. Total and unbound AUCs were only slightly increased (by 23 to 33%), compared to healthy subjects. The effects of end-stage renal disease or hemodialysis on the pharmacokinetics of siponimod has not been studied. Due to the high plasma protein binding (> 99.9%) of siponimod, hemodialysis is not expected to alter the total and unbound siponimod concentration and no dose adjustments are anticipated based on these considerations.

Use in the elderly.

Results from population pharmacokinetics suggest that dose adjustment would not be necessary in elderly patients. However, to date clinical experience in patients aged above 65 years is limited.

Paediatric use.

No studies have been performed in paediatric patients.

Effects on laboratory tests.

Since siponimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilised to evaluate the lymphocyte subset status of a patient treated with Mayzent.
Laboratory tests requiring the use of circulating mononuclear cells require large blood volumes due to reduction in the number of circulating lymphocytes.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic interactions.

Anti-neoplastic, immune-modulating or immunosuppressive therapies. Mayzent has not been studied in combination with anti-neoplastic, immune-modulating or immunosuppressive therapies. Caution should be used during concomitant administration due to the risk of additive immune effects during such therapy and in the weeks following stopping administration of any of these drugs (see Section 4.4 Special Warnings and Precautions for Use).
When switching from other disease modifying therapies, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimizing risk of disease reactivation.
Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its product information, initiating treatment with Mayzent after alemtuzumab is not recommended unless the benefits of Mayzent treatment clearly outweigh the risks for the individual patient.
Mayzent can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.
Anti-arrhythmic drugs, QT prolonging drugs, drugs that may decrease heart rate. During treatment initiation Mayzent should not be concomitantly used in patients receiving Class Ia (e.g. quinidine, procainamide), Class III anti-arrhythmic drugs (e.g. amiodarone, sotalol), QT prolonging drugs with known arrhythmogenic properties, heart rate lowering calcium channel blockers (such as verapamil or diltiazem) or other substances which may decrease heart rate (e.g. ivabradine or digoxin) because of the potential additive effects on heart rate. If treatment with Mayzent is considered, advice from a cardiologist should be sought (see Section 4.4 Special Warnings and Precautions for Use, Treatment initiation recommendations).
Beta-blockers. Caution should be applied when Mayzent is initiated in patients receiving beta-blockers due to the additive effects on lowering heart rate (see Section 4.4 Special Warnings and Precautions for Use, Treatment initiation recommendations). Beta-blocker treatment can be initiated in patients receiving stable doses of Mayzent.
The negative chronotropic effect of co-administration of siponimod and propranolol was evaluated in a dedicated PD/safety study. The addition of propranolol on top of siponimod PK/PD steady-state had less pronounced negative chronotropic effects (less than additive) in comparison to addition of siponimod on top of propranolol PK/PD steady state (additive HR effect).
Vaccination.

Live attenuated vaccines.

The use of live attenuated vaccines may carry the risk of infection and should therefore be avoided during Mayzent treatment. Mayzent treatment discontinuation is recommended 1 week prior to vaccination until 4 weeks after vaccination (see Section 4.4 Special Warnings and Precautions for Use, Vaccination).

Non-live attenuated vaccines.

Potential effects of siponimod on the immune response/immunogenicity of selected non-live attenuated vaccines were investigated in a dedicated study with two representative vaccines, a PPV-23 vaccine (T cell-independent vaccine) and a quadrivalent influenza vaccine (T cell-dependent vaccine). The study demonstrated that concomitant Mayzent treatment does not compromise the efficacy of a PPV-23 vaccination and therefore no Mayzent treatment pause is necessary. The efficacy of the influenza vaccination is not compromised if Mayzent treatment is paused 1 week prior and until 4 weeks after vaccination. Shorter treatment pause from 10 days prior to 14 days after vaccination and concomitant Mayzent treatment showed only modest impact on influenza vaccination efficacy with responder rates approximately 15% to 30% lower than on placebo (see Section 4.4 Special Warnings and Precautions for Use, Vaccination).

Pharmacokinetic interactions.

Potential of other drugs to affect siponimod pharmacokinetics (PK) (siponimod as a substrate). Siponimod is primarily metabolized by cytochrome P450 CYP2C9 (79.3%) and to a lesser extent by CYP3A4 (18.5%). CYP2C9 is a polymorphic enzyme and the drug-drug interaction (DDI) effect in presence of CYP3A or CYP2C9 perpetrator drugs is predicted to be dependent on the CYP2C9 genotype (see Section 5.2 Pharmacokinetic Properties, Pharmacogenomics).
CYP2C9 and CYP3A4 inhibitors. Caution should be applied with concomitant use of Mayzent with drugs that cause moderate CYP2C9 and moderate or strong CYP3A4 inhibition due to a clinically relevant increase in exposure to siponimod. This concomitant drug regimen can consist of moderate CYP2C9/CYP3A4 dual inhibitors (e.g. fluconazole) or a moderate CYP2C9 inhibitor in combination with a separate moderate or strong CYP3A4 inhibitor.
Moderate CYP2C9/CYP3A4 dual inhibitors (e.g. fluconazole) are expected to increase siponimod exposure by 1.78 to 2.73-fold according to clinical drug-drug interaction studies and in silico (physiologically based pharmacokinetics) evaluation of the drug interaction potential.
CYP2C9 and CYP3A4 inducers. Caution should be applied with concomitant use of Mayzent with drugs that cause moderate CYP2C9 and strong CYP3A4 induction in all patients regardless of genotype because of a clinically relevant decrease in siponimod exposure. This concomitant drug regimen can consist of moderate CYP2C9/strong CYP3A4 dual inducers (e.g. rifampin or carbamazepine) or a moderate CYP2C9 inducer in combination with a separate strong CYP3A4 inducer.
Caution is also needed with concomitant use of Mayzent with moderate CYP3A4 inducers (e.g. modafinil) in patients with CYP2C9*1*3 or *2*3 genotypes.
Strong CYP3A4/moderate CYP2C9 inducers (e.g. carbamazepine) and moderate CYP3A4 inducers (e.g. modafinil) are expected to significantly reduce siponimod exposure by up to 76% and up to 51%, respectively, according to clinical drug-drug interaction studies and in silico evaluation of the drug interaction potential.
Potential of siponimod to affect the PK or PD of other drugs.

Oral contraceptives.

Co-administration with siponimod did not reveal clinically relevant effects on the PK and PD of the combined ethinylestradiol and levonorgestrel oral contraceptive. Therefore, the efficacy of the investigated oral contraceptive was maintained under siponimod treatment. No interaction studies have been performed with oral contraceptives containing other progestagens, however an effect of siponimod on the efficacy of oral contraceptives is not expected.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Contraception.

Females of reproductive potential should be advised that animal studies have been performed showing siponimod to be harmful to the developing fetus. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using Mayzent and for at least ten days after stopping treatment with Mayzent (also see Section 4.4 Special Warnings and Precautions for Use, Stopping Mayzent therapy).

Fertility.

There are no data with Mayzent on fertility in humans.
Siponimod had no effect on male reproductive organs in rats and monkeys or fertility parameters in rats.
In fertility studies in male and female rats, animals received oral doses of siponimod up to 200 mg/kg/day and 1 mg/kg/day, respectively, before mating and until 2 weeks post mating for male, and until gestation day 6 for females.
There was no effect on mating or sperm parameters in males and on mating and early embryonal development until implantation in female rats, indicating that siponimod is not associated with an increased risk of effect on fertility.
Changes in reproductive organs were only seen in rats exposed to high levels of siponimod.
(Category D)

Risk summary.

There are no available data on Mayzent use in pregnant women to inform a drug associated risk of adverse developmental outcomes. Based on animal data and its mechanism of action Mayzent can cause fetal harm when administered to a pregnant woman. Reproductive and developmental studies in pregnant rats and rabbits have demonstrated siponimod induced embryotoxicity and fetotoxicity in rats and rabbits and teratogenicity in rats. Increased incidences of post-implantation loss and fetal abnormalities (external, urogenital and skeletal) in rat and of embryo-fetal deaths, abortions and fetal variations (skeletal and visceral) in rabbit were observed following prenatal exposure to siponimod at levels similar to those in humans at the highest recommended dose of 2 mg/day.
Pregnant women should be advised of a potential risk to the fetus if Mayzent is used during pregnancy or if the patient becomes pregnant while taking this medicinal product.
The use of Mayzent in women who are or may become pregnant should only be considered if the potential benefit justifies the potential risk to the fetus.
Epidemiologic studies from USA, Canada, major EU countries and South American countries have shown that the risk of birth defects in MS population is similar to that in the general population. For spontaneous abortions and stillbirths, the background risk in the MS population in the US appears to be similar to that in the general US population.

Animal data.

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of siponimod up to 40 mg/kg/day and 5 mg/kg/day, respectively, during the period of organogenesis. A significant increase in embryo-fetal mortality occurred at dose levels that did not produce maternal toxicity.
In rats, fetal resorption and teratogenicity (skeletal malformations, e.g. cleft palate and misshapen clavicles, cardiomegaly and edema) were noted at ≥ 1 mg/kg/day. No maternal reproductive and fetal no observed adverse effects levels (NOAELs) were established. At 1 mg/kg/day (lowest observed adverse effect level) the maternal exposure (area under the curve, AUC) was approximately 19 times the exposure in humans at the highest recommended dose (2 mg).
In rabbits, siponimod resulted in a significant increase in embryo-fetal deaths and skeletal variations at doses ≥ 1 mg/kg/day, and abortions and increased skeletal or visceral variations at 5 mg/kg/day. The maternal reproductive NOAEL was 1 mg/kg/day and the NOAEL for embryo-fetal development was 0.1 mg/kg/day. At 0.1 mg/kg/day (NOAEL), the maternal exposure (AUC) was estimated to be approximately 0.2 times the exposure in humans at the highest recommended dose (2 mg).
In a pre- and post-natal development study in rats, pregnant animals received oral doses of siponimod up to 0.5 mg/kg/day during the period of organogenesis and until weaning. In the F0 generation dams, ≥ 0.15 mg/kg/day resulted in effects on body weight and food consumption as well as an increased gestation length. At 0.5 mg/kg/day, the numbers of dead and malformed pups were increased.
In F1 generation pups, adverse clinical signs, decreased body weights and decreased postnatal survival were observed at ≥ 0.15 mg/kg/day. Increased abnormalities including external, urogenital and skeletal findings were observed at ≥ 0.15 mg/kg/day. In F1 generation adults, delayed sexual maturation, but no effects on reproductive function or behavioral performance, were noted at 0.5 mg/kg/day. At 0.05 mg/kg/day (NOAEL) in rat, the maternal exposure (AUC) was approximately 0.9 times the exposure in humans at the highest recommended dose (2 mg).
Malformations and/or embryofetal mortality identified in rat and rabbit reproductive and developmental studies may be related to the modulation of the S1P receptor. The receptor affected by siponimod is known to be involved in vascular formation and skeletal development during embryogenesis in rodents.

Risk summary.

It is not known if siponimod is present in human milk. There are no data on the effects of siponimod on the breast-fed child or on milk production.
Since many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from Mayzent, a nursing woman should be advised on the potential risks to the child. Women receiving Mayzent should not breastfeed.

Animal data.

In lactating rats dosed with a single oral dose of 10 mg/kg, siponimod and its metabolites passed into the milk.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

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.

Summary of the safety profile.

A total of 1,737 multiple sclerosis (MS) patients have been treated with siponimod in doses of at least 2 mg daily. These were included in study A2304, a phase 3, multicenter, randomized, double-blind, placebo-controlled study in patients with SPMS and study A2201, a phase 2, double-blind, randomized, multi-center, adaptive dose-ranging, placebo-controlled study in patients with relapsing-remitting MS (RRMS). Study A2304 randomized 1,651 SPMS patients 2:1 to receive either Mayzent 2 mg once daily or placebo. Median treatment duration was 18 months (range 0 to 37 months). Study A2201 randomized a total of 297 RRMS patients to receive Mayzent at once daily doses ranging from 0.25 mg to 10 mg or placebo for up to 6 months.
In study A2304 a higher percentage of siponimod than placebo patients completed the double-blinded part of the study drug treatment (66.7% and 59.0%, respectively). The most common reasons for discontinuations in the siponimod and placebo groups were subject/guardian decisions (10.3% siponimod vs. 13.0% placebo), disease progression (9.1% for siponimod vs. 14.8% for placebo) and adverse events (8.5% siponimod vs 5.1% placebo). The most common adverse drug reactions in the siponimod 2 mg group (incidence ≥ 10%) in study A2304 were headache and hypertension.

Tabulated summary of adverse drug reactions from clinical trials.

Adverse drug reactions from clinical trials have been defined primarily on the basis of the experience in study A2304 (Table 2) and are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): 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).

Description of selected adverse drug reactions.

Infections.

In the phase 3 clinical trial in patients with SPMS the overall rate of infections was comparable between the patients on siponimod and those on placebo (49.0% vs. 49.1%, respectively). However, an increase in the rate of herpes zoster infections was reported on siponimod (2.5%) compared to placebo (0.7%). Cases of herpes viral infection, including cases of meningitis or meningoencephalitis caused by varicella zoster virus, have been reported with Mayzent (see Section 4.4 Special Warnings and Precautions for Use).
Cases of progressive multifocal leukoencephalopathy and cryptococcal meningitis have been reported for Mayzent (see Section 4.4 Special Warnings and Precautions for Use).

Macular oedema.

Macular oedema was more frequently reported in patients receiving siponimod (1.8%) than placebo (0.2%). Although the majority of cases occurred within 3 to 4 months of commencing siponimod, cases were also reported in patients treated with siponimod for more than 6 to 12 months (see Section 4.4 Special Warnings and Precautions for Use). Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine ophthalmic examination. The macular oedema generally improved or resolved spontaneously after drug discontinuation. The risk of recurrence after re-challenge has not been evaluated.

Bradyarrhythmia.

Initiation of siponimod treatment results in a transient decrease in heart rate and may also be associated with atrio-ventricular conduction delays (see Section 4.4 Special Warnings and Precautions for Use).

Liver function tests.

Increased hepatic enzymes (mostly ALT elevation) have been reported in MS patients treated with siponimod. In the phase 3 trial in patients with SPMS, liver function test increase were more frequently observed in patients on siponimod (11.3%) than in those on placebo (3.1%), mainly due to liver transaminase (ALT/AST/GGT) elevations. The majority of elevations occurred within 6 months of starting treatment. ALT levels returned to normal within approximately 1 month after discontinuation of siponimod (see Section 4.4 Special Warnings and Precautions for Use).

Seizures.

Cases of seizures were reported in 1.7% of patients treated with siponimod compared to 0.4% on placebo in the phase 3 clinical trial in patients with SPMS. It is not known whether these events were related to the effects of MS, to siponimod, or to a combination of both.

Respiratory effects.

Minor reductions in forced expiratory volume in 1 second (FEV₁) and in the diffusing capacity of the lung for carbon monoxide (DLCO) values were observed with siponimod treatment. At month 3 and month 6 of treatment in the phase 3 clinical trial in patients with SPMS, mean changes from baseline in the siponimod group were -0.1 L at each time point, with no change in the placebo group. On chronic treatment, this reduction did not translate into clinically significant adverse events and was not associated with an increase in reports of cough or dyspnea.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
Healthy subjects received siponimod as single doses (0.1 to 75 mg) or as multiple doses (0.25 to 20 mg). The single maximum tolerated dose was determined to be 25 mg based upon the occurrence of symptomatic bradycardia after single doses of 75 mg. The highest investigated multiple dose of 20 mg over 28 days was well tolerated (9 subjects receiving 100 mg on the last day of dosing and 5 subjects receiving up to 200 mg daily for a duration of 3 to 4 days). Some of the 9 subjects had asymptomatic mild to moderate transient elevations of liver function tests.
One patient (with a history of depression) took 84 mg siponimod. Aside from a slight elevation in liver transaminases, the patient did not experience any other adverse events from the overdose.
If the overdose constitutes first exposure to Mayzent or occurs during the dose titration phase of Mayzent it is important to observe for signs and symptoms of bradycardia, which could include overnight monitoring. Regular measurements of pulse rate and blood pressure are required and electrocardiograms should be performed (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).
There is no specific antidote to siponimod available. Neither dialysis nor plasma exchange would result in meaningful removal of siponimod from the body.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group, ATC code.

Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA42.

Mechanism of action.

Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds selectively on two out of five G-protein-coupled receptors (GPCRs) for S1P, namely S1P₁ and S1P₅. By acting as a functional antagonist on S1P1 receptors on lymphocytes, siponimod prevents egress from lymph nodes. This reduces the recirculation of T-cells into the central nervous system (CNS) to limit central inflammation. Siponimod spares effector memory T-cells in peripheral tissues and blood and does not impair lymphocyte activation.
Siponimod readily crosses the blood brain barrier.
In animal studies direct effects have been demonstrated for siponimod on neural cells, via S1P₁ on astrocytes and S1P₅ on oligodendrocytes. In a mouse model of experimental autoimmune encephalomyelitis a direct neuroprotective effect, independent from effects on lymphocytes, was also demonstrated for siponimod applied centrally (via intracerebroventricular infusions).

Pharmacodynamics (PD).

Immune system. Mayzent induces a dose-dependent reduction of the peripheral blood lymphocyte count within 6 hours of the first dose, due to the reversible sequestration of lymphocytes in lymphoid tissues.
With continued daily dosing, the lymphocyte count continues to decrease, reaching a nadir median (90% CI) lymphocyte count of approximately 0.560 (0.271 to 1.08) cells/nanoL in a typical CYP2C9*1*1 or *1*2, non-Japanese SPMS patient, corresponding to 20 to 30% of baseline. Low lymphocyte counts are maintained with chronic daily dosing.
Lymphocyte counts typically return to the normal range in the vast majority (90%) of SPMS patients within 10 days of stopping therapy. After stopping Mayzent treatment residual lowering effects on peripheral lymphocyte count may persist for up to 3 to 4 weeks after the last dose.
Cardiac electrophysiology.

Heart rate and rhythm.

Mayzent causes a transient reduction in heart rate and atrioventricular conduction upon treatment initiation (see Section 4.8 Adverse Effects (Undesirable Effects)). The maximum decline in heart rate is seen in the first 6 hours post-dose. Autonomic responses of the heart, including diurnal variation of heart rate and response to physical exercise, are not affected by siponimod treatment.
A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase of Mayzent, that plateaued at doses ≥ 5 mg and bradyarrhythmic events (AV Blocks and sinus pauses) were detected at a higher incidence under Mayzent treatment compared to placebo.
No second degree AV blocks of Mobitz type II or higher degree were observed. Most AV blocks and sinus pauses occurred above the therapeutic dose of 2 mg with notably higher incidence under non titrated conditions compared to dose titration conditions.
The decrease in heart rate induced by Mayzent can be reversed by atropine or isoprenaline.

Potential to prolong the QT interval.

The effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod on cardiac repolarization were investigated in a thorough QT study. The results did not suggest an arrhythmogenic potential related to QT prolongation with siponimod. Siponimod increased the placebo-corrected baseline-adjusted mean QTcF (ΔΔQTcF) by more than 5 ms with a maximum mean effect of 7.8 ms (2 mg) and 7.2 ms (10 mg), respectively, at 3 h post-dose. The upper bound of the one-sided 95% CI for the ΔΔQTcF at all time points remained below 10 ms. Categorical analysis revealed no treatment-emergent QTc values above 480 ms, no QTc increases from baseline of more than 60 ms and no corrected or uncorrected QT/QTc value exceeded 500 ms.
Pulmonary function. Mayzent treatment with single doses or multiple doses for 28 days is not associated with clinically relevant increases in airway resistance as measured by forced expiratory volume in 1 second (FEV₁) and forced expiratory flow (FEF) during expiration of 25 to 75% of the forced vital capacity (FEF25-75%). A slight trend of reduced FEV₁ was detected at non-therapeutic single doses (> 10 mg). Multiple doses of Mayzent were associated with mild to moderate changes in FEV₁ and FEF 25-75% which were not dose and daytime dependent and were not associated with any clinical signs of increased airway resistance.
Concomitant treatment of Mayzent with propranolol resulted in minimal decrease of FEV₁ in comparison to propranolol alone. The changes with the individual drugs or with the combination were within the physiological variability of FEV₁ and not clinically significant.

Clinical trials.

The efficacy of Mayzent was demonstrated in a phase 3 study that evaluated once-daily doses of Mayzent 2 mg in patients with SPMS. A dose-ranging phase 2 study in patients with RRMS demonstrated dose-dependent reduction in inflammatory lesions on MRI and found Mayzent 2 mg to provide a near maximum effect.

Study A2304 (EXPAND) in SPMS.

Study A2304 was a randomized, double-blind, placebo-controlled, event and follow-up duration-driven, phase 3 study in patients with SPMS who had documented evidence of progression in the prior 2 years in the absence or independent of relapses, no evidence of relapse in 3 months prior to study enrollment and with Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5 at study entry.
Patients were randomized 2:1 to receive either once daily Mayzent 2 mg or placebo. Evaluations were performed at screening and every 3 months and at the time of relapse. MRI evaluations were performed at screening and every 12 months.
The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP) determined as at least a 1-point increase from baseline in EDSS (0.5 point increase for patients with baseline EDSS of 5.5 or more) sustained for 3 months. Key secondary endpoints were time to 3-month confirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25FW) and change from baseline in T2 lesion volume. Additional secondary endpoints included time to 6-month CDP, percent brain volume change, measures of inflammatory disease activity (annualized relapse rate, MRI lesions). Change in cognitive processing speed on Symbol Digit Modality Test oral score was an exploratory endpoint.
Study duration was variable for individual patients (median study duration was 18 months, range 11 to 37 months).
The study randomized 1,651 patients to either Mayzent 2 mg (N = 1,105) or placebo (N = 546); 82% of Mayzent-treated patients and 78% of placebo-treated patients completed the study. Median age was 49.0 years, median disease duration was 16.0 years and median EDSS score was 6.0 at baseline; 63.9% of patients had no relapses in the 2 years prior to study entry and 78% had no gadolinium (Gd)-enhancing lesions on their baseline MRI scan; 78.3% of patients had been previously treated with a therapy for their MS.
Time to onset of 3-month confirmed disability progression (primary endpoint) was significantly delayed for Mayzent with a 21.2% risk reduction compared to placebo (hazard ratio (HR) 0.79, p < 0.0134).
The results for this study are summarized in Table 3 and Figure 1.

Mayzent did not significantly delay time to 3-month confirmed ≥ 20% deterioration in the T25FW compared to placebo (a numerical 6.2% risk reduction was observed).
Results from the study showed a consistent risk reduction in the time to 3-month CDP with Mayzent compared to placebo in subgroups defined based on gender, age, prior multiple sclerosis therapy, pre-study relapse activity, baseline MRI disease activity and disability levels at baseline.

Study A2201 (BOLD) in RRMS.

Study A2201 was a randomized, double-blind, placebo-controlled, adaptive dose-ranging, phase 2 study in patients with RRMS who had experienced at least 2 documented relapses in the past 2 years, or 1 relapse in the past 1 year, or had a positive Gd-enhanced MRI scan at study entry and with an EDSS score of 0 to 5.0.
The primary endpoint of the study was the dose-response relationship among 5 doses of Mayzent and placebo based on the number of combined unique active inflammatory lesions (CUALs) on 3 monthly MRI scans. Other measures included the number of Gd-enhancing lesions and number of new T2 lesions on MRI and MS relapses over 3 and 6 months.
The study randomized 297 patients with RRMS to 2 cohorts to receive once daily Mayzent at doses of 0.5 mg, 2 mg or 10 mg or placebo for up to 6 months in cohort 1 (N = 188) and 0.25 mg, 1.25 mg or placebo for up to 3 months in cohort 2 (N = 109). MRI evaluations were performed monthly, neurological evaluations every 3 months and at the time of relapse.
Mean age was 36 years, mean disease duration was 7 years; mean number of 2 relapses in the past 2 years and 45% of patients had Gd-enhancing lesions on their baseline MRI scan.
Treatment with Mayzent resulted in a dose-related up to 80% reduction in the number of CUALs compared to placebo (p=0.0001). The model-predicted MRI dose-response curve indicated near-maximal efficacy at 2 mg.
The annualized relapse rate over 6 months was reduced vs placebo by 48% (p=0.148) with 10 mg and 66% (p=0.041) with 2 mg; the ARRs were similar for the 0.5 mg and placebo groups.

5.2 Pharmacokinetic Properties

Absorption.

The time (T_max) to reach maximum plasma concentrations (C_max) after multiple oral administration of siponimod was about 4 hours (range 2 to 12 hours). Siponimod absorption is extensive (≥ 70%, based on the amount of radioactivity excreted in urine and the amount of metabolites in feces extrapolated to infinity). The absolute oral bioavailability of siponimod is approximately 84%. For 2 mg siponimod given once daily over 10 days, a mean C_max of 30.4 nanogram/mL and mean AUC_tau of 558 h*nanogram/mL were observed on day 10. Steady state was reached after approximately 6 days of multiple once daily administration of siponimod.

Food effect.

Food intake had no effect on the systemic exposure of siponimod (C_max and AUC). Therefore, Mayzent may be taken without regard to meals (see Section 4.2 Dose and Method of Administration).

Distribution.

Siponimod is distributed to body tissues with a moderate mean volume of distribution of 124 L. Siponimod fraction found in plasma is 68% in humans. Animal studies show that siponimod readily crosses the blood-brain-barrier. Protein binding of siponimod is > 99.9% in healthy subjects and in hepatic and renal impaired patients.

Metabolism.

Siponimod is extensively metabolized, mainly via CYP2C9 (79.3%), followed by CYP3A4 (18.5%).
The pharmacological activity of the main metabolites M3 and M17 is not expected to contribute to the clinical effect and the safety of siponimod in humans.

Excretion.

An apparent systemic clearance (CL/F) of 3.11 L/h was estimated in MS patients (see Pharmacogenomics). The apparent elimination half-life is approximately 30 hours.
Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion.

Linearity.

Siponimod concentration showed a linear dependence on dose over the range 0.3 mg to 20 mg.
Steady-state-plasma concentrations are reached after approximately 6 days of once daily dosing and steady-state levels are approximately 2 to 3-fold greater than the initial dose. An up-titration regimen is used to stepwise reach the clinical therapeutic dose of siponimod of 2 mg after 6 days and 4 additional days of dosing are required to reach the steady-state-plasma concentrations.

In vitro and in vivo evaluation of drug interaction potential.

Siponimod (and metabolites M3, M17) as a causative agent of interaction. In vitro investigations indicated that siponimod and its major systemic metabolites M3 and M17 do not show any clinically relevant drug-drug interaction potential at the therapeutic dose of 2 mg once daily for all investigated CYP enzymes and transporters, and do not necessitate clinical investigation.
Siponimod as an object of interaction. CYP2C9 is polymorphic and the genotype influences the fractional contributions of the two oxidative metabolism pathways to overall elimination. Physiologically based pharmacokinetic modeling indicates a differential CYP2C9 genotype-dependent inhibition and induction of CYP3A4 pathways. With decreased CYP2C9 metabolic activity in the respective genotypes, a larger effect of the CYP3A4 perpetrators on siponimod exposure is anticipated.

Co-administration of siponimod with CYP2C9 and CYP3A4 inhibitors.

The co-administration of fluconazole (moderate CYP2C9 (/CYP3A4) dual inhibitor) 200 mg daily at steady-state and a single dose of siponimod 4 mg in CYP2C9*1*1 healthy volunteers led to a two-fold increase in the AUC of siponimod. Mean siponimod terminal half-life was increased by 50%.

Co-administration of siponimod with CYP2C9 and CYP3A4 inducers.

Strong CYP3A4/moderate 2C9 inducers (e.g. carbamazepine) and moderate CYP3A4 inducers (e.g. modafinil) significantly reduced siponimod AUC by up to 76% and up to 51%, respectively, according to clinical drug-drug interaction studies and in silico evaluation of the drug interaction potential. The co-administration of siponimod 2 mg daily in the presence of 600 mg daily doses of rifampin (strong CYP3A4 and moderate CYP2C9 inducer) decreased siponimod AUC_tau,ss and C_max,ss by 57% and 45%, respectively, in CY2C9*1*1 subjects.
Gender. Gender has no influence on siponimod pharmacokinetics.
Race/ethnicity. The single dose PK parameters were not different between Japanese and Caucasians healthy subjects, indicating absence of ethnic sensitivity on the pharmacokinetics of siponimod.
Pharmacogenomics. The CYP2C9 genotype has a significant impact on siponimod metabolism. Patients homozygous for CYP2C9*3 (CYP2C9*3*3 genotype: approximately 0.3 to 0.4% of Caucasians and less in others) are contraindicated with Mayzent (see Section 4.3 Contraindications). Use of Mayzent in these patients results in substantially elevated siponimod plasma levels. The recommended maintenance dose of Mayzent is 1 mg daily in patients with CYP2C9 *2*3 or *1*3 genotype to avoid an increased exposure to siponimod (see Section 4.2 Dose and Method of Administration).
There are other less frequent occurring polymorphisms for CYP2C9. The pharmacokinetics of siponimod have not been evaluated in such subjects. Some polymorphisms such as *5, *6, *8 and *11 are associated with decreased or loss of enzyme function. It is estimated that CYP2C9 *5, *6, *8 and *11 alleles have a combined frequency of approximately 10% in populations with African ancestry, 2% in Latinos/Hispanics and < 0.4% in Caucasians and Asians.
After a single dose of 0.25 mg siponimod, both AUC_inf and AUC_last were approximately 2- and 4-fold higher in subjects with the CYP2C9*2*3 and CYP2C9*3*3 genotypes, respectively, while there was only a minor increase of C_max by 21% and 16%, respectively, compared to extensive metabolizers (CYP2C9*1*1). The mean half-life was prolonged in CYP2C9*2*3 and CYP2C9*3*3 carriers (51 and 126 h).
An apparent systemic clearance (CL/F) of about 3.11 L/h was estimated in CYP2C9 extensive metabolizer (CYP2C9*1*1 and CYP2C9*1*2) SPMS patients after multiple oral administrations of siponimod. Cl/F is 2.5, 1.9, 1.6, and 0.9 L/h in subjects with the CYP2C9*2*2, CYP2C9*1*3, CYP2C9*2*3 and CYP2C9*3*3 genotypes, respectively. As the apparent clearance estimated for subjects with the CYP2C9*1*2 genotype was comparable to that for subjects of the CYP2C9*1*1 genotype, similar siponimod exposure is expected for both genotypes. The resultant increase in siponimod AUC was 25, 61, 91, 285% in subjects with the CYP2C9*2*2, CYP2C9*1*3, CYP2C9*2*3 and CYP2C9*3*3 genotypes, respectively, as compared to those with the CYP2C9*1*1 genotype.

5.3 Preclinical Safety Data

Genotoxicity.

In vitro genotoxicity tests (bacterial mutation, micronucleus test including human cell line and chromosome aberration test using normal human lymphocytes) and in vivo micronucleus studies using mice and rats did not reveal genotoxic potential of siponimod.

Carcinogenicity.

Consistent with an immunomodulatory effect, siponimod induced increased incidences of malignant lymphoma in mice; the human relevance is unknown.
In a carcinogenicity study in mice increased incidences of hemangiosarcomas and hemangiomas were observed at all dose levels doses in both sexes. Mechanistic studies showed activation of vascular endothelial cells, leading to induction of abnormal angiogenesis and finally hemangiosarcomas. No sustained vascular endothelial cell activation and no increased incidences of hemangiosarcomas were found in rats. Mouse, rat and human endothelial cell cultures demonstrated different responses upon siponimod treatment. Human and rat cells showed no proliferative responses as opposed to mouse cells. Therefore, the siponimod-induced hemangiosarcomas in mice are considered species-specific and there is no evidence to suggest an associated risk to humans.
In rats, siponimod-related neoplastic changes (follicular cell adenoma/carcinoma) in the thyroid gland in males only and non-neoplastic, proliferative changes in the thyroid gland (males only) and in the liver (both sexes) are considered to be due to a well-known rodent specific effect ('liver-thyroid-axis'). These changes are considered to represent adaptive effects in rodents with limited human relevance.

6 Pharmaceutical Particulars

6.1 List of Excipients

Tablet core.

Lactose monohydrate, microcrystalline cellulose, crospovidone, glyceryl dibehenate and colloidal anhydrous silica.
Each 0.25 mg tablet contains 62.2 mg lactose monohydrate.
Each 1 mg tablet contains 61.4 mg lactose monohydrate.
Each 2 mg tablet contains 60.3 mg lactose monohydrate.

Tablet coating.

Polyvinyl alcohol, titanium dioxide, iron oxide yellow (2 mg only), iron oxide red, black iron oxide (0.25 mg and 1 mg only), purified talc, lecithin (soya), xanthan gum.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.