Consumer medicine information

Mayzent

Siponimod

BRAND INFORMATION

Brand name

Mayzent

Active ingredient

Siponimod

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mayzent.

What is in this leaflet

This leaflet answers some common questions about Mayzent.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Mayzent against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Mayzent is used for

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

This medicine belongs to a group of medicines called sphingosine-1- phosphate (S1P) receptor modulators.

Mayzent binds selectively on two out of five receptors for S1P, namely S1P1 and S1P5. Mayzent can affect the ability of some white blood cells to move freely within the body and in this alter the way the body’s immune system works. Mayzent stops the cells that cause inflammation from reaching the brain and spinal cord and helps to fight against attacks of the immune system. This reduces nerve damage caused by MS and thus Mayzent helps to slow down the effects of the disease activity (such as worsening disability, brain lesions and relapses). Mayzent may also have a beneficial effect on certain brain cells (neural cells) involved in repairing or slowing down the damage caused by multiple sclerosis (MS).

In studies of patients with SPMS, Mayzent was seen to reduce attacks, disability progression and decline in thinking, and increase time without relapse.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

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

This medicine is not expected to affect your ability to drive a car or operate machinery.

It is not known whether Mayzent is safe and effective in children.

Before you take Mayzent

When you must not take it

Do not take Mayzent if you have an allergy to:

  • any medicine containing siponimod
  • any of the ingredients listed at the end of this leaflet.
  • any other similar medicines (such as medicines of the same class or with a similar structure).

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take Mayzent if:

  • 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 certain types of irregular or abnormal heartbeat (arrhythmia) and you do not have a pacemaker.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Before initiation of treatment with Mayzent

Before initiation of treatment with Mayzent your CYP2C9 genotype should be determined. Your doctor will find this out with a blood test.

  • If you have a CYP2C9 *3*3 genotype (less than 0.4 to 0.5% of the population), you should not take Mayzent.

Before you start taking Mayzent, you will have a blood test to check your white blood cells and to check your liver function unless your doctor has the results of a recent blood test.

Tell your doctor if you have or have had any of the following medical conditions:

  • if you have an infection. Any infection that you already have may get worse. Infections could be serious and sometimes life-threatening. Before you start taking Mayzent, your doctor will confirm whether you have enough white blood cells in your blood.
  • if you have a lowered immune response (due to a disease or medicines that suppress the immune system, see "Taking other medicines"). You may get infections more easily or an infection you already have may get worse. Mayzent lowers the white blood cell count (particularly the lymphocyte count). White blood cells fight infection. While you are taking Mayzent (and for up to 3 to 4 weeks after you stop taking it), you may get infections more easily.
  • if you have no history of chickenpox or have not been vaccinated against varicella zoster virus.
    Your doctor will test your status of the antibody against this virus and may decide to vaccinate you if you do not have antibodies to this virus. In this case, you will start Mayzent treatment one month after the full course of the vaccination is completed.
  • if you plan to receive a vaccine. You should not receive certain types of vaccines (called "live attenuated vaccines") during treatment with Mayzent and for up to 4 weeks after stopping treatment with Mayzent (see "Taking other medicines"). For the other vaccines, they can be less effective and your doctor may want you to stop Mayzent one week before the vaccination and for up to 4 weeks after vaccination.
  • if you have or have had visual disturbances or other signs of swelling in the central vision area at the back of the eye (a condition known as macular oedema), if you have or have had inflammation or infection of the eye (uveitis) or diabetes. Your doctor will organise an eye examination before you start Mayzent and at regular intervals after the start of Mayzent treatment. The macula is a small area of the retina at the back of the eye which enables you to see shapes, colours, and details clearly and sharply (central vision). Mayzent may cause swelling in the macula and it usually happens during the first 3 to 4 months of Mayzent treatment. Your chance of developing macular oedema is higher if you have diabetes or have had an inflammation of the eye called uveitis. Macular oedema can cause some of the same vision symptoms as an MS attack (optic neuritis). Be sure to tell your doctor about any changes in your vision. This includes blurred vision or seeing shadows, or if you develop a blind spot in the centre of your vision, or if you have problems seeing colours or fine detail.
  • if you have uncontrolled high blood pressure, if you have certain types of diseases related to blood vessels in the brain, if when you sleep you are severely affected by an inability to breathe (sleep apnoea that is not treated), if you are at risk for, or if you have heart rhythm disturbances (called abnormal ECG heart tracing). Your doctor may decide not to prescribe Mayzent if you have or have had one of these conditions or may refer you first to a cardiologist.
  • if you are taking medicines for an irregular heartbeat such as quinidine, procainamide, amiodarone or sotalol, your doctor may decide not to prescribe Mayzent (see "Taking other medicines").
  • if you suffer from a slow heart rate, if at the start of treatment with Mayzent you are taking medicines that slow your heart rate or if you have a history of sudden loss of consciousness (fainting). Your doctor may decide not to prescribe Mayzent or may refer you first to a cardiologist to switch you to medicines that do not slow your heart rate.
    At the beginning of treatment, Mayzent can cause the heart rate to slow down. It cannot be excluded that Mayzent can also cause indirectly an irregular heartbeat, during the titration phase (first 5 days of treatment when the dose is gradually increased). Slow heart rate usually returns to normal within 10 days after treatment initiation. Irregular heartbeat usually returns to normal in less than one day. If your heart rate slows down during the titration phase, you may not feel anything or you may feel dizzy or tired.
  • if you have severe respiratory or breathing problems. Your asthma medicines will be checked by your doctor.
  • if you have liver problems. Mayzent may affect your liver function. You will probably not notice any symptoms but if you notice yellowing of your skin or the whites of your eyes, abnormally dark urine or unexplained nausea, vomiting and tiredness during your treatment, tell your doctor straight away. Your doctor may carry out blood tests to check your liver function and may consider stopping Mayzent treatment if your liver problem is serious.
  • If you have high blood pressure, your blood pressure will need to be checked regularly.

Tell your doctor straight away, if you get any of following symptoms or diseases during your treatment with Mayzent, because it could be serious:

  • If you get an infection.
  • If you believe your MS is getting worse (e.g. weakness or visual changes) or if you notice any new or unusual symptoms, because these may be the symptoms of a rare brain infection called progressive multifocal leukoencephalopathy (PML).
  • If you get a fever, feel like you have a flu, or have a headache accompanied by stiff neck, sensitivity to light, nausea, and/or confusion as these may be symptoms of cryptococcal meningitis (caused by a fungal infection).
  • If you have symptoms such as sudden onset of severe headache, confusion, seizures and vision changes, a condition called posterior reversible encephalopathy syndrome (PRES).
  • If you develop a type of skin cancer called basal cell carcinoma (BCC) and other cutaneous neoplasms such as malignant melanoma. Symptoms of BCC may include skin nodules (e.g. shiny pearly nodules), patches or open sores that do not heal within weeks. Symptoms of other cutaneous neoplasms may include abnormal growth or changes of skin tissue (e.g. unusual moles) which may present as a change in colour, shape or size over time. Long-term exposure to the sun and a weak immune system can affect the risk of developing BCC or other cutaneous neoplasms. You should limit your exposure to the sun and UV rays by wearing appropriate protective clothing and regularly applying sunscreen with a high degree of UV protection. Phototherapy with UV radiation or PUVA photochemotherapy should be avoided during Mayzent treatment (it may increase your risk of developing skin cancer).
  • If your MS is getting worse after you have stopped your treatment with Mayzent.

Children and adolescents (below 18 years)
Mayzent has not been studied in patients below 18 years.

Older people (65 years or above)
You can use Mayzent if you are aged 65 years or over at the same dose as for other adults.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks involved. Mayzent may harm your unborn baby.

You should not breast-feed while you are taking Mayzent. Mayzent can pass into breast milk and there is a risk of serious side effects for a breast-fed baby. Talk with your doctor before breastfeeding while you take Mayzent.

Ask your doctor or pharmacist for advice before taking any medicine, if you are pregnant or breast-feeding.

You should avoid becoming pregnant while taking Mayzent and for at least 10 days after you stop taking it. Mayzent may harm your unborn baby. Female patients who might become pregnant should use effective birth control during treatment and for at least 10 days after stopping Mayzent. Ask your doctor about options of effective birth control.

If you become pregnant or think you are pregnant, tell your doctor right away. You and your doctor will decide what is best for you and your baby.

If you have not told your doctor about any of the above, tell him/ her before you start taking Mayzent.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Mayzent may interfere with each other. These include:

  • Medicines for an irregular heartbeat
    such as, quinidine, procainamide, amiodarone or sotalol. Your doctor may decide not to prescribe Mayzent if you take these medicines due to a possible added effect on irregular heartbeat.
  • Medicines that slow down heartbeat
    such as verapamil or diltiazem (called calcium channel blockers), ivabradine or digoxin. Your doctor may decide to refer you to a cardiologist to change your medicines due to a possible added effect on slowing down heartbeat during the first days you start Mayzent. For medicines such as atenolol or propranol (called beta-blockers), if your heart rate at rest is above 50 beats per minute, your doctor may ask you to start treatment with Mayzent without stopping your beta-blocker treatment. However if your heart rate at rest is below 50 beats per minute, your doctor may ask you to stop your beta-blocker treatment first for the heart rate to return above 50, then to start treatment with Mayzent. In this case, it is only after you have reached the usual daily dose of Mayzent that your doctor will ask you to restart your beta-blocker treatment.
  • Medicines that suppress or modulate the immune system including other medicines used to treat MS
    such as beta-interferon, glatiramer acetate, natalizumab, mitoxantrone, dimethyl fumarate, teriflunomide, alemtuzumab or corticosteroids due to a possible added effect on the immune system.
  • Vaccines.
    If you need to receive a vaccine, seek your doctor’s advice first. During treatment and for up to 4 weeks after stopping treatment with Mayzent, administration of some vaccines containing live virus (live attenuated vaccines) may result in infection.
  • Treatment with medicines such as carbamazepine
    can lower the level of Mayzent.in your blood. Your doctor may give you further instruction or change your other medicines.
  • If you have the CYP2C9 *1*3 or *2*3 genotype,
    treatment with medicines such as modafinil can lower the level of Mayzent in your blood. Your doctor may give you further instruction or change your other medicines.
  • If you have the CYP2C9 *2*2 genotype,
    treatment with medicines such as fluconazole, can increase the level of Mayzent in your blood. Your doctor may give you further instruction, decide to reduce your daily dose to 1 mg Mayzent or change your other medicines.

Tell your doctor or a pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

These medicines may be affected by Mayzent or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take Mayzent

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

Do not exceed the recommended dose prescribed by your doctor.

Your doctor will give you a Patient Reminder Card. Read it carefully and follow the instructions on it.

Always show the Patient Reminder Card to your doctor, pharmacist, or dentist when you see them or if you need to go to hospital.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

Treatment initiation with a starter pack:

On day 6 switch to your prescribed treatment dose.

During the first 6 days of treatment the recommended daily dose should be taken once daily in the morning with or without food. If you missed a dose for more than one day during the first 6 days of treatment, the treatment should be re-started with a new starter pack.

The usual daily dose after the titration phase is 2 mg (one tablet of 2 mg Mayzent).

For some patients that have a CYP2C9 *2*3 or CYP2C9 *1*3 genotype the usual daily dose is 1 mg once daily. The same treatment initiation schedule (with a starter pack) applies as well for these patients.

How to take it

Take Mayzent once a day, with half a glass of water. You can take Mayzent with or without food.

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

It does not matter if you take this medicine before or after food.

How long to take it

Continue taking Mayzent every day for as long as your doctor tells you.

This is a long-term treatment, possibly lasting for months or years. Your doctor will regularly monitor your condition to check that the treatment is having the desired effect.

If you have questions about how long to take Mayzent, talk to your doctor or your pharmacist or healthcare provider.

If you forget to take it

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 pack. You will have to restart at Day 1 with a new starter pack.

Subsequently if you miss a dose, 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 missed dose and continue as usual.

Do not take a double dose to make up for a forgotten tablet. Instead, wait until it is time for your next tablet.

Do not stop taking Mayzent or change your dose without talking with your doctor. If you stop taking Mayzent for 4 or more consecutive daily doses, treatment has to be re-started with the starter pack.

After Mayzent is stopped, symptoms of MS can return and may become worse compared to before or during treatment. Tell your doctor if you have worsening of MS symptoms after stopping Mayzent.

If you are a woman, see "Pregnancy and breast-feeding".

Mayzent will stay in your body for up to 10 days after you stop taking it. Your white blood cell count (lymphocyte count) may also remain low during this time and for up to 3 to 4 weeks and the side effects described in this leaflet may still occur.

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

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Mayzent. Do this even if there are no signs of discomfort or poisoning.

Your doctor may decide to observe you with heart rate and blood pressure measurements, to run electrocardiograms (ECGs) and he may decide to monitor you overnight.

While you are taking Mayzent

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Mayzent.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take Mayzent to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Mayzent.

This medicine helps most people with SPMS, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • Headache.
  • High blood pressure with sometimes signs such as headache and dizziness (hypertension).
  • Moles or nevi that appear recently: small spots or lumps of colours ranging from blue/dark to brown, pink to skin coloured (melanocytic naevus).
  • Dizziness.
  • Involuntary shaking of the body (tremor).
  • Diarrhoea.
  • Nausea.
  • Pain in extremity.
  • Swollen hands, ankles, legs or feet (peripheral oedema).
  • Weakness (asthenia).
  • Breathing difficulty.

The above list includes the more common side effects of your medicine. They are usually mild to moderate and will generally disappear after a few days to a week of treatment.

Tell your doctor as soon as possible if you notice any of the following:

  • Rash of small fluid-filled blisters, appearing on reddened skin, signs of viral infection that can be potentially severe (herpes zoster).
  • A type of skin cancer called basal cell carcinoma (BCC) which often appears as a pearly nodule, though it can also appear in other forms.
  • Fever, sore throat or mouth ulcers due to infections (lymphopenia).
  • Convulsion, fits (seizures).
  • Shadows or blind spot in the centre of the vision, blurred vision, problems seeing colors or details (signs of swelling in the macular area of the retina at the back of the eye: macular oedema).
  • Irregular heartbeat (atrioventricular block).
  • Slow heartbeat (bradycardia).

Some side effects can only be found when your doctor does tests from time to time to check your progress. These include abnormal liver function test results that give information about the health of the liver (liver function test increased): high level of an enzyme called alanine aminotransferase (ALT), high level of an enzyme called gammaglutamyltransferase (GGT), high level of aspartate aminotransferase (AST).

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Storage

Keep your tablets in the pack until it is time to take them. If you take the tablets out of the pack they may not keep well.

Keep your tablets in a refrigerator (2°C – 8°C). Do not freeze.

Do not store Mayzent or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Do not take this medicine after the expiry date, which is stated on the (carton)

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it 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.

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.

Ingredients

Mayzent contains 0.25 mg or 2 mg of siponimod (as siponimod hemifumarate) as the active ingredient.

The other ingredients (excipients) of Mayzent are

Tablet core

  • Lactose monohydrate
  • microcrystalline cellulose
  • crospovidone
  • colloidal anhydrous silica
  • glycerol dibehenate.

Each 0.25 mg tablet contains 62.2 mg lactose monohydrate.

Each 2 mg tablet contains 60.3 mg lactose monohydrate.

Tablet coating

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

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Manufacturer/Distributor/ Supplier

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

™ = Registered Trademark

© Copyright 2021.

This leaflet was prepared in March 2021

MAYZENT 0.25 mg film-coated tablet blister pack AUST R 310498

MAYZENT 2 mg film-coated tablet blister pack AUST R 310499

(may100321c.doc based on PI may100321i.doc)

Published by MIMS May 2021

BRAND INFORMATION

Brand name

Mayzent

Active ingredient

Siponimod

Schedule

S4

 

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.
Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators, including Mayzent, who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient's condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.
Cases of herpes viral infection, including cases of meningitis or meningoencephalitis caused by varicella zoster virus (VZV), 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 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 treated with other S1P receptor modulators (see Section 4.8 Adverse Effects (Undesirable Effects)).
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 in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS).
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 Cmax (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 (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).

Adverse drug reactions from open-label extension part of clinical trials or from spontaneous reports and literature cases (frequency not known).

The following adverse drug reactions have been derived from post-marketing experience with Mayzent via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness. See Table 3.

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%).

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: Immunosuppressants, sphingosine-1-phosphate (S1P) receptor modulators, ATC code: L04AE03.

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 4 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 (Tmax) to reach maximum plasma concentrations (Cmax) 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 Cmax of 30.4 nanogram/mL and mean AUCtau 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 (Cmax 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 AUCtau,ss and Cmax,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 AUCinf and AUClast 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 Cmax 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.

6.4 Special Precautions for Storage

Mayzent 0.25 mg, Mayzent 1 mg and Mayzent 2 mg.

Prior to dispensing: Store 2°C to 8°C (Refrigerate. Do not freeze).
After dispensing:

Mayzent 0.25 mg.

Store 2°C to 8°C (Refrigerate. Do not freeze).

Mayzent 1 mg.

Store below 30°C for up to 3 months.

Mayzent 2 mg.

Store below 30°C for up to 3 months.
Store in the original package.
Information might differ in some countries.
Mayzent must be kept out of the reach and sight of children.

6.5 Nature and Contents of Container

PA/Al/PVC/Al blister packs containing:
0.25 mg strength: 120 film coated tablets and 12 film coated tablets (titration pack);
1 mg strength: 28 film coated tablets;
2 mg strength: 28 film coated tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

The molecular formula for siponimod is C29H35F3N2O3 and the molecular mass is 516.61.

Chemical name (IUPAC).

(2E)-But-2-enedioic acid-1-({4-[(1E)-N-{[4-cyclohexyl-3-(trifluoromethyl) phenyl] methoxy} ethanimidoyl]-2-ethylphenyl} methyl) azetidine-3-carboxylic acid (1/2).

Chemical structure.


CAS number.

CAS registry number: 1230487-00-9.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription medicine.

Summary Table of Changes