Consumer medicine information

Zeposia

Ozanimod

BRAND INFORMATION

Brand name

Zeposia

Active ingredient

Ozanimod

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Zeposia.

What is in this leaflet

This leaflet answers some common questions about Zeposia. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Zeposia 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 Zeposia is used for

Zeposia is used to treat adult patients with Relapsing forms of Multiple Sclerosis. Zeposia contains an active substance called ozanimod, which belongs to a group of medicines called sphingosine-1-phosphate (S1P) receptor modulators.

Multiple Sclerosis (MS) is a disease in which inflammation in the body attacks and destroys the protective coating around your nerves (called myelin). This stops the nerves from working properly. The symptoms of MS can vary from person to person. In relapsing MS, patients will experience relapse or flare-ups from time to time, followed by a period of recovery and stability, where symptoms may disappear or some symptoms may remain.

Zeposia can affect the ability of some white blood cells to move freely within the body and stops them from reaching the central nervous system (the brain, spine and optic nerve), where they can cause inflammation and damage. In doing so, Zeposia may help protect against attacks on the nerves, reduce inflammation and damage to the nerves’ protective coating and slow down the progression of disability.

Ask your doctor if you have any questions about how Zeposia works, or 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.

Safety and effectiveness of Zeposia in children younger than 18 years have not been established.

Before you take Zeposia

When you must not take it

Do not take Zeposia if you have an allergy to:

  • any medicine containing ozanimod
  • any of the ingredients listed at the end of this leaflet.

Some of the general 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 Zeposia if you:

  • have had a heart attack, angina, stroke or warning of a stroke or certain types of heart failure in the last 6 months
  • have certain types of irregular or abnormal heartbeats (arrhythmia)
  • have untreated severe breathing problems when you sleep (severe sleep apnoea)

Do not take this medicine/it 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.

Follow your doctor’s instructions carefully. If you have not fully understood these instructions, ask your doctor again before taking Zeposia.

Before you start taking Zeposia, your doctor will conduct liver and blood tests prior to starting you on Zeposia. You will also have an electrocardiogram (also called an ECG), which measures and records the heart’s rhythm and activity.

Tell your doctor before taking Zeposia if you have or have had any of the following:

  • a slow heart rate
  • high blood pressure
  • problems with your liver
  • infection
  • low levels of a type of white blood cell - called lymphocytes
  • you have never had, or are not sure if you have had chickenpox or you have not been vaccinated against varicella zoster virus (VZV). Your doctor can do a blood test to check if you need VZV vaccination.
  • recently had or are planning to have a vaccination. Some vaccines (called “live attenuated vaccines”) should not be given whilst taking Zeposia and for 3 months after stopping treatment with Zeposia. Your doctor will check if you should have any vaccines before you receive Zeposia.
  • problems with your vision or other symptoms of swelling in the central vision area at the back of the eye (a condition called macular oedema)
  • inflammation of the eye (uveitis), diabetes (which can cause problems with your eyes) or history of problems with your retina (the thin layer of tissue on the inside wall at the back of the eye). These may increase your risk of macular oedema. Your doctor will organise an eye examination before you start Zeposia and follow up examinations whilst you are on Zeposia.

While you are taking Zeposia (and for up to 3 months after you stop taking it), you may get infections more easily. Any infection that you already have may get worse.

Tell your doctor if you are taking or have taken any of the following medicines:

  • medicines that affect the immune system (e.g. ciclosporin)
  • other medicines used to treat MS
    - beta interferon
    - glatiramer acetate
    - corticosteroids
    - natalizumab
    - mitoxantrone
    - teriflunomide
    - dimethyl fumarate
    - alemtuzumab
    - fingolimod
    - siponimod
    - cladribine
    - ocrelizumab

Taking Zeposia with these medicines may increase the risk of infection.

Tell your doctor if you or others notice worsening of your MS symptoms as well as any new or unfamiliar symptoms. These may be due to a rare infection of the brain called ‘Progressive Multifocal Leukoencephalopathy’ (PML), which has been reported in patients receiving medicine for MS.

Tell your doctor if you have a headache, fever, neck pain, nausea and/or vomiting, sensitivity to light, confusion or others notices changes in your behaviour. These symptoms may be due to a type of fungal (cryptococcal) infection in the brain.

Tell your doctor straight away if you develop a severe headache, feel confused, or have seizures and vision loss during treatment with Zeposia. These symptoms may be due to a syndrome called ‘Posterior Reversible Encephalopathy Syndrome’ (PRES).

Limit your exposure to sunlight and UV light There may be an increased risk of skin cancer with medicines such as Zeposia. You should limit your exposure to sunlight and UV light, by wearing protective clothing and applying regular sunscreen (with high sun protection factor). Tell your doctor if you are receiving phototherapy with UV-B radiation or PUVA-photochemotherapy as they should not be used with Zeposia.

Do not give this medicine to a child or adolescent under the age of 18 years. Safety and effectiveness of Zeposia in children younger than 18 years have not been established.

Tell your doctor if you are or may be pregnant or plan to become pregnant. You should avoid becoming pregnant while taking Zeposia or in the three months after you stop taking it, because there is a risk of harm to your unborn baby.

You should have a pregnancy test to confirm that you are not pregnant before starting Zeposia and you should use an effective method of contraception during treatment and for 3 months after stopping Zeposia.

If you become pregnant while taking Zeposia, tell your doctor without delay. You and your doctor will decide what is best for you and your baby.

Tell your doctor if you are breastfeeding. You should not breastfeed while taking Zeposia. This is because it is not known if this medicine passes into human milk.

If you have not told your doctor about any of the above, tell them before you start taking Zeposia.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines or have recently taken any other medicines, including any medicines that you buy without a prescription from a pharmacy, supermarket or health food shop. Some medicines and Zeposia may interfere with each other.

Before taking Zeposia, tell your doctor or pharmacist if you are taking or have recently taken any of the following medicines:

  • medicines that suppress or modulate the immune system, including other medicines used to treat MS, and drugs such as ciclosporin or eltrombopag
  • gemfibrozil for fats or cholesterol in the blood
  • rifampicin, an antibiotic for treating tuberculosis and other serious infections
  • monoamine oxidase (MAO) inhibitors, such as phenelzine for depression or selegiline for Parkinson’s disease
  • medicines that slow your heart rate
  • certain type of vaccines

These medicines may be affected by Zeposia 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 Zeposia

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

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

How much to take

  • When you first start taking Zeposia, you will receive an ‘initiation pack’ which contains the doses as listed in the table below.
  • Take one capsule each day as indicated on the ‘initiation pack’.
  • Your treatment will start at a lower dose and will gradually be increased over the first 7 days of treatment. This is to minimise the risk of heart rate reductions.

  • On Day 8 and thereafter, once you have completed the ‘initiation pack’, you will move on to a ‘maintenance pack’ with orange capsules each containing the recommended dose of 920 microgram of Zeposia. You will continue regular treatment with one 920 microgram capsule daily.

Do not exceed the recommended dose

How to take it

Swallow the capsules whole with a full glass of water, once a day as directed by your doctor. Zeposia can be taken with or without food.

When to take it

Take your medicine at about the same time each day.

How long to take it

Continue taking Zeposia until your doctor asks you to stop.

Your doctor will monitor your condition to check the medicine is working. This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

During the first 14 days of treatment
If you have missed a dose of Zeposia on one day, call your doctor before you take the next dose. Your doctor will need to prescribe a new initiation pack and you will have to restart at Day 1.

After treatment for 14 consecutive days
If you miss a dose, take a tablet as soon as possible on the same day. However, if it is nearly time for your next dose, skip the missed dose. Then take the next dose at your usual time. Do not take a double dose to make up for a forgotten dose.

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

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

If you stop taking Zeposia

Do not stop taking Zeposia without talking to your doctor first. Your doctor will tell you if you need to stop taking Zeposia. Your symptoms may return or become worse if you stop Zeposia. Tell your doctor straight away if you have worsening of your MS symptoms after you have stopped Zeposia.

If you stop taking Zeposia for more than 7 consecutive days between day 15 and 28 of treatment or more than 14 consecutive days after day 28 of treatment, you will need to start the treatment 'initiation pack’ again.

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

If you take too much (overdose)

In Australia, 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 Zeposia.

Do this even if there are no signs of discomfort or poisoning. Keep the telephone numbers for these places handy.

Take the medicine pack and this leaflet with you.

While you are using Zeposia

Things you must do

  • Tell any other doctors, dentists, and pharmacists who are treating you that you are taking Zeposia.
  • If you are about to be started on any new medicine, remind your doctor, dentist or pharmacist that you are taking Zeposia
  • If you become pregnant while taking this medicine, tell your doctor immediately.
  • Keep all of your doctor’s appointments so that your progress can be checked.
    Your doctor will do tests from time to time to ensure that the medicine is working and to prevent unwanted side effects.

Things you must not do

  • Do not let yourself run out of medicine over the weekend or on holidays.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not take this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not stop taking Zeposia or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how Zeposia affects you.

This medicine is not likely to affect you being able to drive, cycle or use any tools or machines.

Side effects

Tell your doctor or pharmacist as soon as possible if your symptoms worsen while you are taking Zeposia.

Like all medicines, Zeposia can have side effects, although not everybody gets them and some are uncommon. 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 if you notice any of the following:

These are the more common side effects of your medicine

  • infections of the nose or nostrils, nasal cavity, mouth, throat (pharynx), or voice box (larynx) caused by viruses
  • low blood levels of a type of white blood cell – called lymphocytes
  • sore throat (pharyngitis)
  • respiratory (lung) infection

Tell your doctor immediately if you notice any of the following:

  • low heart rate
  • urinary tract infection
  • increase in blood pressure
  • low blood pressure when you stand up from sitting or lying down (orthostatic hypotension)
  • allergic reaction – the signs may include rash or hives, swelling of the face, lips, mouth, tongue or throat, shortness of breath, wheezing or difficulty breathing
  • signs of serious infections such as fever, sore throat, cough, tiredness, aching joints and/or muscles
  • new or worsening breathing problems
  • significant changes in vision including shadows or blind spots in the centre of the vision, blurred vision, problems seeing colours or details
  • increased liver enzyme levels in blood tests or yellow pigmentation of the skin, mucus membrane or eyes (jaundice)
  • rash of small fluid-filled blisters, appearing on reddened skin, signs of viral infection that can be potentially severe (herpes zoster or shingles)

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist immediately if any of the side effects gets worse, or if you notice any other side effects not listed in this leaflet.

After taking Zeposia

Storage

Store the capsules in the original package.

Store in a cool dry place where the temperature stays below 25°C.

Do not store Zeposia 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 this medicine 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

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, take any unused Zeposia capsules to your pharmacist.

Medicines should not be disposed of via wastewater or household waste. These measures will help to protect the environment.

Product description

What it looks like

  • The Zeposia 230 microgram capsule is light grey opaque imprinted in black ink with “OZA” on the cap and “0.23 mg” on the body.
  • The Zeposia 460 microgram capsule is light grey / orange opaque imprinted in black ink with “OZA” on the cap and “0.46 mg” on the body.
  • The Zeposia 920 microgram capsule is orange opaque imprinted in black ink with “OZA” on the cap and “0.92 mg” on the body.

Pack sizes

  • Treatment initiation pack is a wallet pack containing 7 capsules: 4 x 230 microgram capsules and 3 x 460 microgram capsules.
  • Maintenance pack containing 28 x 920 microgram capsules.

Ingredients

The active substance is ozanimod.

  • Zeposia 230 microgram capsules
    Each capsule contains 230 microgram of ozanimod (as hydrochloride).
  • Zeposia 460 microgram capsules
    Each capsule contains 460 microgram of ozanimod (as hydrochloride).
  • Zeposia 920 microgram capsules
    Each hard capsule contains 920 microgram of ozanimod (as hydrochloride).

The other ingredients in the capsules are:

Microcrystalline cellulose, silicon dioxide, croscarmellose sodium, magnesium stearate.

The capsule shells contain:

  • Each 230 microgram capsule contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide and red iron oxide.
  • Each 460 microgram capsule contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide and red iron oxide.
  • Each 920 microgram capsule contains gelatin, titanium dioxide, yellow iron oxide and red iron oxide.

The printing ink on the capsules is black ink.

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

Supplier

Zeposia is supplied in Australia by:

Celgene Pty Limited
Level 2, 4 Nexus Court
Mulgrave VIC 3170
Telephone: 1800 CELGENE (1800 235 4363)

® = Registered Trademark

This leaflet was prepared in February 2022.

Australian Registration Numbers:

Zeposia 230 microgram and 460 microgram capsules initiation pack

AUST R 318801

Zeposia 920 microgram capsules blister pack

AUST R 318800

Published by MIMS March 2022

BRAND INFORMATION

Brand name

Zeposia

Active ingredient

Ozanimod

Schedule

S4

 

1 Name of Medicine

Australian Approved Name: ozanimod.

2 Qualitative and Quantitative Composition

Each 230 microgram capsule contains 230 microgram ozanimod (equivalent to 250 microgram ozanimod hydrochloride).
Each 460 microgram capsule contains 460 microgram ozanimod (equivalent to 500 microgram ozanimod hydrochloride).
Each 920 microgram capsule contains 920 microgram ozanimod (equivalent to 1.00 mg ozanimod hydrochloride).
For the full list of excipients, see Section 6.1 List of Excipients.

Description.

Ozanimod hydrochloride is a white to off-white solid with a melting point of ~240°C. Ozanimod hydrochloride is poorly hygroscopic. The solubility of ozanimod hydrochloride in ethanol and methanol is 1.43 and 2.41 mg/mL and in a pH 5.1 aqueous medium is 3.51 mg/mL. The pKa for ozanimod hydrochloride is 7.90 and the partition coefficient (logP) is 3.28.
Ozanimod hydrochloride exists as the (S) configuration with an enantiomeric purity of not less than 99.0%.

3 Pharmaceutical Form

Capsule.

Zeposia 230 microgram capsules.

Light grey opaque capsule, size 4, imprinted in black ink with "OZA" on the cap and "0.23 mg" on the body.

Zeposia 460 microgram capsules.

Light grey/orange opaque capsule, size 4, imprinted in black ink with "OZA" on the cap and "0.46 mg" on the body.

Zeposia 920 microgram capsules.

Orange opaque capsule, size 4, imprinted with "OZA" on the cap and "0.92 mg" on the body.

4 Clinical Particulars

4.1 Therapeutic Indications

Multiple sclerosis.

Zeposia is indicated for the treatment of adult patients with relapsing forms of multiple sclerosis.

Ulcerative colitis.

Zeposia is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biological therapy.

4.2 Dose and Method of Administration

Treatment should be initiated under the supervision of a physician experienced in the management of multiple sclerosis (MS) or ulcerative colitis (UC).

Dosage.

The recommended dose of Zeposia for adults is 920 microgram once daily taken orally.
Zeposia capsules should be swallowed whole and can be administered with or without food.
If a dose of Zeposia is missed, the next scheduled dose should be taken the following day.
The initial dose escalation regimen of Zeposia from Day 1 to Day 7 is shown in Table 1. Following the 7-day dose escalation, the once daily dosage is 920 microgram taken orally starting on Day 8. Initiation of Zeposia without dose escalation may result in greater reductions in heart rate (see Section 4.4).

Prior to initiation of therapy.

Obtain an electrocardiogram (ECG) to determine whether pre-existing cardiac conduction abnormalities are present (see Section 4.4).
Obtain recent (i.e. within 6 months) liver function tests (see Section 4.4).
Obtain a recent (i.e. within 6 months or after discontinuation of prior MS or UC therapy) complete blood count (CBC, including lymphocyte count) (see Section 4.4).
Arrange an ophthalmological assessment in patients with risk factors for macular oedema, such as diabetes mellitus, history of uveitis or history of retinal disease (see Section 4.4).

Current or prior medications.

If patients are taking anti-neoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with Zeposia (see Section 4.4).
Determine if patients are taking drugs that could slow heart rate or atrioventricular conduction (see Section 4.5).

Vaccinations.

Test patients for antibodies to varicella zoster virus (VZV) before initiating Zeposia (see Section 4.4). VZV vaccination of antibody-negative patients is recommended at least 1 month prior to commencing treatment with Zeposia.
If live attenuated immunisations are required, administer at least 1 month prior to initiation of Zeposia (see Section 4.4).

Method of administration.

See Table 1.
Re-initiation of therapy following treatment interruption. If a dose of Zeposia is missed during the first 2 weeks of treatment, reinitiate treatment using the dose escalation regimen.
If a dose of Zeposia is missed after the first 2 weeks of treatment, continue with the treatment as planned.
If more than 7 consecutive days are missed between Day 15 and Day 28 of treatment, or more than 14 consecutive days after Day 28 of treatment, reinitiate treatment using the dose escalation regimen.
If the treatment interruption is of shorter duration than the above, the treatment should be continued with the next dose as planned.
Special populations.

Elderly.

No dose adjustment is needed in patients over 65 years of age. Caution should be used in patients over 65 years of age, given the potential for an increased risk of serious adverse reactions (infections) in this population.

Hepatic impairment.

Zeposia may be used with caution in patients with mild or moderate chronic hepatic impairment (Child-Pugh class A or B). Closer monitoring, which may include testing of liver function and lymphocytes count, is recommended. Steady state may take several months to reach (see Section 5.2, Hepatic impairment). In patients with mild or moderate chronic hepatic impairment, the recommended dose is to complete the 7-day dose escalation regimen, and then take 920 microgram once every other day (see Section 5.2, Hepatic impairment).
The pharmacokinetics of Zeposia was not evaluated in subjects with severe hepatic impairment. Use in patients with severe hepatic impairment is not recommended (Child-Pugh class C).

Renal impairment.

No dosage adjustment is necessary for patients with renal impairment.

Paediatric population.

The safety and effectiveness of Zeposia in patients below the age of 18 years have not been established.

4.3 Contraindications

Hypersensitivity to ozanimod or any of the excipients (see Section 6.1).
Treatment should not be initiated in patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischaemic attack (TIA), decompensated heart failure requiring hospitalisation or Class III/IV heart failure.
Treatment should not be initiated in patients who have a history or presence of second-degree atrioventricular (AV) block Type II or third-degree AV block or sick sinus syndrome unless the patient has a functioning pacemaker.
Treatment should not be initiated in patients with severe untreated sleep apnoea.

4.4 Special Warnings and Precautions for Use

Bradycardia - reduction in heart rate.

Initiation of Zeposia may result in transient reductions in heart rate (HR) (see Section 4.8). After the initial dose of Zeposia 230 microgram, the greatest mean reduction from baseline in HR was 1.2 beats per minute (bpm) in active-controlled MS clinical trials and 0.7 bpm in controlled UC clinical trials at Hour 5 on Day 1, returning to near baseline at Hour 6. HR below 40 bpm were not observed. Initiation of Zeposia without dose escalation may result in greater reductions in HR (see Section 4.2).
If treatment with Zeposia is considered, advice from a cardiologist should be sought for those individuals:
With significant QT prolongation (QTcF > 450 msec in males, > 470 msec in females).
With arrhythmias requiring treatment with Class 1a or Class III antiarrhythmic drugs.

Liver injury.

Clinically significant liver injury has occurred in patients treated with Zeposia in the post-marketing setting (see Section 4.8). Signs of liver injury, including elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as ten days after the first dose. Severe liver injury may result in the need for a liver transplant.
Obtain liver function tests if not recently available (i.e. within 6 months), before initiation of Zeposia (see Section 4.2, Dosage).
Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have liver function tests checked and Zeposia should be discontinued if significant liver injury is confirmed.
Resumption of therapy will be dependent on whether another cause of liver enzyme elevation is determined and on the benefits to patient of resuming therapy versus the risks of recurrence of liver dysfunction.
Patients with pre-existing liver disease may be at increased risk of developing elevated hepatic enzymes when taking Zeposia.

Return of MS disease activity (rebound) after Zeposia discontinuation.

In MS, severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of another sphingosine 1-phosphate (S1P) receptor modulator. The possibility of severe exacerbation of disease after stopping Zeposia treatment should be considered. Patients should be observed for relevant signs of possible severe exacerbation or return of high disease activity upon Zeposia discontinuation and appropriate treatment should be instituted as required.
After stopping Zeposia in the setting of progressive multifocal leukoencephalopathy (PML), monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS).

Infections.

Risk of infections.

Zeposia causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline values because of reversible retention of lymphocytes in lymphoid tissues. Zeposia may therefore increase the susceptibility to infections.
Obtain a recent (i.e. within 6 months or after discontinuation of prior MS or UC therapy) complete blood count (CBC) including lymphocyte count before initiation of Zeposia (see Section 4.2, Dosage).
Delay initiation of Zeposia in patients with an active infection until the infection is resolved. After discontinuing Zeposia 920 microgram, the median time to recovery of peripheral blood lymphocytes to the normal range was 30 days, with approximately 90% of patients recovering within 3 months.
Consider interruption of treatment with Zeposia if a patient develops a serious infection.
Because the elimination of Zeposia after discontinuation may take up to 3 months, continue monitoring for infections throughout this period.

Prior and concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies.

In the MS and UC clinical trials, patients who received Zeposia were not to receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS and UC. Concomitant use of Zeposia with any of these therapies would be expected to increase the risk of immunosuppression.
In UC clinical trials, concomitant use of corticosteroids was allowed and did not appear to influence the safety or efficacy of Zeposia.
When switching to Zeposia from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects (see Section 4.5, Effects of other drugs on ozanimod).
Zeposia can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.

Progressive multifocal leukoencephalopathy (PML).

PML is an opportunistic viral infection of the brain caused by the John Cunningham Virus (JCV) that typically occurs in patients who are immunocompromised and may lead to death or severe disability.
PML has been reported in patients treated with S1P receptor modulators, including Zeposia, and other MS and UC therapies.
Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. If PML is suspected, treatment with Zeposia should be suspended until PML has been excluded. If confirmed, treatment with Zeposia should be discontinued.
Immune reconstitution inflammatory syndrome (IRIS) has been reported in MS patients treated with S1P receptor modulators 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.

Herpes viral infection.

Cases of localised herpes virus infection (e.g. herpes zoster and herpes simplex) were seen in clinical trials of Zeposia (see Section 4.8).
Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against VZV, should be tested for antibodies to VZV before initiating Zeposia (see Vaccinations below).

Cryptococcal infection.

Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. Zeposia treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

Vaccinations.

Patients without a healthcare professional-confirmed history of chickenpox or without documentation of a full course of vaccination against VZV should be tested for antibodies to VZV before initiating Zeposia. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with Zeposia.
No clinical data are available on the efficacy and safety of vaccinations in patients taking Zeposia. Avoid the use of live attenuated vaccines during and for 3 months after treatment with Zeposia.
If live attenuated vaccine immunisations are required, administer at least 1 month prior to initiation of Zeposia. VZV vaccination of patients without documented immunity to VZV is recommended at least 1 month prior to initiating treatment with Zeposia.

Macular oedema.

Patients observed to have macular oedema with Zeposia had pre-existing risk factors (see Section 4.8). Patients with risk factors for macular oedema, such as a history of uveitis, diabetes mellitus or history of retinal disease, should have an ophthalmologic evaluation prior to treatment with Zeposia and have follow up evaluations while receiving therapy.
Patients who present with visual symptoms of macular oedema should be evaluated and, if confirmed, treatment with Zeposia should be discontinued.

Posterior reversible encephalopathy syndrome (PRES).

PRES is a syndrome characterised by sudden onset of severe headache, confusion, seizures and visual loss. Symptoms of PRES are usually reversible but may evolve into ischaemic stroke or cerebral haemorrhage.
In MS controlled clinical trials with Zeposia, one case of PRES was reported in a patient with Guillain-Barré syndrome.
If PRES is suspected, treatment with Zeposia should be discontinued.

Increased blood pressure.

Hypertension was more frequently reported in patients treated with Zeposia than in patients treated with IFN beta-1a IM (see Section 4.8) and in patients receiving concomitant Zeposia and SSRIs or SNRIs.
Blood pressure should be regularly monitored during treatment with Zeposia.

Fetal risk.

There are no adequate and well-controlled studies in pregnant women. In animals, findings at similar exposure levels included embryo-fetal death, abnormal/delayed ossification, and abnormalities of the viscera and large blood vessels.
Before initiation of treatment, women of childbearing potential must be informed of this risk to the fetus, should have a negative pregnancy test and should use effective contraception during treatment and for 3 months after stopping Zeposia (see Section 4.6, Use in pregnancy).

Malignancies.

Given the immunomodulatory/immunosuppressive properties of ozanimod a potential risk for increased malignancy cannot be ruled out.

Cutaneous neoplasms.

An increased risk of cutaneous malignancies has been reported with S1P receptor modulators.
Half of the neoplasms reported with ozanimod in active controlled MS clinical trials consisted of skin malignancies, with basal cell carcinoma presenting as the most common skin neoplasm and reported with a similar incidence in the combined ozanimod (0.2%, 3 patients) and IFN beta-1a (0.1%, 1 patient) group.
In patients treated with ozanimod in controlled UC clinical trials, one patient (0.2%) had squamous cell carcinoma of the skin in the induction period, and one patient (0.4%) had basal cell carcinoma in the maintenance period. There were no cases in patients who received placebo.
Since there is a potential risk of malignant skin growths, patients treated with Zeposia should be cautioned against exposure to sunlight without protection. These patients should not receive concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Ozanimod is extensively metabolised in humans to form a number of circulating active metabolites, including two major active metabolites, CC112273 and CC1084037 and several minor active metabolites including RP101988 and RP101075.

Effects of other drugs on ozanimod.

Caution should be applied when switching patients from long-acting therapies with immune effects (see Section 4.4, Return of MS disease activity (rebound) after Zeposia discontinuation).

Inhibitors of breast cancer resistance protein (BCRP).

Co-administration of ozanimod with ciclosporin (BCRP inhibitor) had no effect on the exposure of ozanimod or the major active metabolites CC112273 and CC1084037.

Strong inhibitors of CYP2C8.

The co-administration of gemfibrozil (a strong inhibitor of CYP2C8) 600 mg twice daily at steady state and a single dose of ozanimod 460 microgram increased exposure (AUC) of the major active metabolites CC112273 and CC1084037 by approximately 47% and 69%, respectively. Caution should be exercised for concomitant use of ozanimod with strong CYP2C8 inhibitors (e.g. gemfibrozil, clopidogrel).

Strong CYP3A and P-gp inhibitors.

Co-administration of itraconazole (a strong inhibitor of CYP3A and P-gp) 200 mg once daily at steady state and a single dose of Zeposia 920 microgram resulted in no clinically meaningful changes in exposure of ozanimod, CC112273 and CC1084037.

Strong CYP3A/P-gp and moderate CYP2C8 inducers.

Co-administration of rifampicin (a strong inducer of CYP3A and P-gp, and a moderate inducer of CYP2C8) 600 mg once daily at steady state and a single dose of Zeposia 920 microgram resulted in no clinically meaningful changes in exposure (AUC) of ozanimod and reduced exposure (AUC) for CC112273 and CC1084037 by approximately 60% and 55%, respectively. The effect of rifampicin on CC112273 and CC1084037 was due to CYP2C8 induction. The co-administration of CYP2C8 inducers (i.e. rifampicin) with Zeposia is not recommended.

Monoamine oxidase (MAO) inhibitors.

Co-administration with MAO-B inhibitors may decrease exposure of CC112273 and consequently CC1084037. The potential for clinical interaction with MAO inhibitors has not been studied. Co-administration of MAO inhibitors (e.g. selegiline, phenelzine) with Zeposia is not recommended.

Prednisone and prednisolone.

Population pharmacokinetic analyses showed that concomitant administration of prednisone or prednisolone in patients with UC did not alter the steady state exposure (AUC) of CC112273.

Effect of ozanimod on other drugs.

Drugs that slow heart rate or atrioventricular conduction (e.g. beta blockers or calcium channel blockers).

In healthy subjects, initiating ozanimod 230 microgram with steady-state propranolol long acting 80 mg once daily or diltiazem extended release 240 mg once daily did not result in any additional clinically meaningful changes in HR and PR interval compared to either propranolol or diltiazem alone.
The effect of co-administration of the maintenance dosage of Zeposia, propranolol, or diltiazem, or administration with both a beta-blocker and a calcium channel blocker taken together has not been studied.

Adrenergic agents.

A placebo-controlled crossover study was conducted to assess the potential of Zeposia to enhance pressor responses to pseudoephedrine in healthy subjects. Co-administration of Zeposia with pseudoephedrine did not potentiate the pseudoephedrine-induced blood pressure response. Zeposia increased the pseudoephedrine-induced heart rate response by approximately 3 bpm.

Oral contraceptives.

Co-administration of ozanimod 920 microgram once daily and a single dose of oral contraceptive containing ethinyl estradiol (EE) 35 microgram and norethindrone (NE) 1 mg resulted in no change in EE or NE exposure. Dosing duration of ozanimod was not long enough to attain steady state for the major active metabolites; however, CC112273 and CC1084037 have no in vitro effect on CYP enzymes and therefore are not expected to have any effect on EE and NE exposure.

MAO activity.

CC112273 and CC1084037 inhibited MAO-B with more than 1000-fold selectivity over monoamine oxidase A (MAO-A) (IC50 > 10000 nanoM) with IC50 values of 5.72 nanoM and 58 nanoM, respectively. In a serotonergic mouse model study, CC112273 concentrations up to 84 nanoM (approximately 4-fold higher than the mean steady-state Cmax of CC112273 [19.4 nanoM] in RMS patients receiving ozanimod 920 microgram QD for 12 weeks) did not induce signs of serotonin syndrome in normal mice or exacerbate mild serotonin syndrome in mice induced by 5-hydroxytryptophan. In a clinical study with Zeposia, CC112273 and CC1084037 had no inhibition effect on human platelet MAO-B activity. In active-controlled MS clinical trials, the use of serotonergic agents including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) was not excluded and no patients with serotonin syndrome were identified.

CYP enzymes.

Ozanimod, CC112273, CC1084037 and other metabolites have no inhibitory effect on CYPs 1A2, 2B6, 2C19, 2C8, 2C9, 2D6, and 3A and no induction effect on CYPs 1A2, 2B6, and 3A.

Drug transporters.

Ozanimod, CC112273, CC1084037 and other metabolites have no inhibitory effect on P-glycoprotein, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, and MATE2-K. CC112273 and CC1084037 inhibit BCRP with IC50 values of 25.2 nanoM and 22.8 nanoM, respectively. At clinically relevant concentrations of CC112273 and CC1084037, inhibition of BCRP is not expected.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No fertility data are available in humans. No effects on fertility were observed in animal studies. Ozanimod had no effect on fertility in rats up to 30 mg/kg/day (estimated systemic exposure more than 2000 times the anticipated clinical exposure) in a study in which both male and female animals were treated orally and mated. There was no apparent effect on sperm count/motility. Data from animals does not suggest that ozanimod would be associated with an increased risk of reduced fertility.
(Category D)
There are no adequate data on the developmental risk associated with the use of Zeposia in pregnant women. If the patient becomes pregnant or plans to become pregnant while taking Zeposia, she should be informed of the potential hazards and discontinuation of therapy should be considered.
Ozanimod and/or its metabolites crossed the placental barrier in pregnant rats and rabbits. When administered during organogenesis, ozanimod was teratogenic in the rat at oral doses of 5 mg/kg/day or higher (426 times the clinical exposure on an AUC basis) with a no effect dose of 1 mg/kg/day (63.7 times the clinical exposure). The most common findings were anasarca, malpositioned testes and delayed/incomplete ossification. Rabbits showed an increase in malformation of great blood vessels, incomplete ossification and malpositioned vertebrae at oral doses of 0.6 mg/kg/day or higher (8 times the clinical exposure on an AUC basis) with a no effect dose of 0.2 mg/kg/day (2.4 times the clinical exposure).
The vascular effects, as well as an increased incidence of post-implantation loss and resorptions seen in rats (5 mg/kg/day, 426 times the clinical exposure) and rabbits (2 mg/kg/day; 27.6 times the clinical exposure) are consistent with the pharmacological mechanism of ozanimod, since the sphingosine-1-phosphate receptor is involved in vascular formation during embryogenesis.
Women of childbearing potential should use effective contraception during Zeposia treatment and for 3 months after stopping Zeposia.
 There are no data on the presence of ozanimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Ozanimod and its metabolites are present in rat milk. Reduced immunocompetence was evident in juvenile rats following oral administration.
Due to the potential for serious adverse reactions to ozanimod/metabolites in nursing infants, women receiving ozanimod should not breastfeed.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and the use of machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Tabulated summary of adverse events.

Multiple sclerosis.

The Safety Population for the two active-controlled phase 3 MS clinical trials included 2659 subjects, of whom 882 subjects received at least 1 dose of ozanimod 920 microgram, 892 subjects received at least 1 dose of ozanimod 460 microgram, and 885 subjects received at least 1 dose of IFN beta-1a.
The system organ classes with the highest proportions of subjects reporting AEs were Infections and Infestations, Nervous System Disorders, and Investigations. Adverse events reported by ≥ 2% of subjects in any treatment group are provided in Table 2.

Ulcerative colitis.

The safety of Zeposia was evaluated in two randomised, double-blind, placebo-controlled clinical trials, UC Study 1 (TRUENORTH-I, n=429) and in UC Study 2 (TRUENORTH-M, n =230), in adult subjects with moderately to severely active ulcerative colitis (see Section 5.1, Clinical trials). Additional data from the induction period of a Phase 2, UC Study 3 (TOUCHSTONE) randomised, double-blind, placebo-controlled trial included 67 patients who received Zeposia 920 microgram. The system organ classes with the highest proportions of subjects reporting AEs were infections and infestations and gastrointestinal disorders. Adverse events reported by ≥ 2% of subjects in any treatment group during the induction (UC Study 1 and 3) and maintenance period (UC Study 2) are provided in Table 3 and Table 4, respectively.

Tabulated summary of adverse drug reactions.

The adverse drug reactions were determined based on data from the ozanimod clinical development programme. The frequencies of adverse drug reactions are those reported in the ozanimod arms of the two active-controlled MS clinical trials and three placebo-controlled UC clinical trials. In MS trials, 1774 patients received Zeposia with an overall exposure of 2641 person-years. In UC Study 1 and 3, 496 patients had 97.5 person-years of exposure to Zeposia during the induction period. In UC Study 2, 230 patients had 165.5 person-years of exposure to Zeposia during the maintenance period.
The most commonly reported adverse reaction in these MS and UC clinical trials were nasopharyngitis, alanine aminotransferase increased, and gamma-glutamyl transferase increased. The most common adverse reactions leading to discontinuation were related to liver enzyme elevations in the MS clinical trials. The overall safety profile was similar with MS and UC.
The adverse reactions observed in patients treated with ozanimod are listed in Tables 5 and 6 by system organ class (SOC) and frequency for all adverse reactions. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100).

Description of selected adverse reactions.

Bradycardia - reduction in heart rate.

After the initial dose of Zeposia 230 microgram, the greatest mean reduction from baseline in heart rate was 1.2 beats per minute (bpm) in active-controlled MS clinical trials and 0.7 bpm in controlled UC induction clinical trials at Hour 5 on Day 1 returning to near baseline at Hour 6.
In active-controlled MS clinical trials, bradycardia was reported in 0.5% on Zeposia versus 0% on IFN beta-1a on the day of treatment initiation. After Day 1, the incidence of bradycardia was 0.8% on Zeposia versus 0.7% on IFN beta-1a. Patients who experienced bradycardia were generally asymptomatic.
In MS clinical trials, first-degree atrioventricular block was reported in 0.6% (5/882) of patients treated with Zeposia versus 0.2% (2/885) treated with IFN beta-1a IM. Of the cases reported with Zeposia, 0.2% were reported on Day 1 and 0.3% were reported after Day 1.
In UC induction clinical trials, bradycardia was reported on the day of treatment initiation in 1 patient (0.2%) treated with Zeposia compared to none in patients who received placebo. After Day 1, bradycardia was reported in 1 patient (0.2%) treated with Zeposia. In UC Study 2, bradycardia was not reported.
In controlled MS and UC clinical trials with dose escalation, second-or third-degree atrioventricular blocks were not reported with Zeposia.

Increased blood pressure.

In active-controlled MS clinical trials, patients treated with Zeposia had an average increase of approximately 1 to 2 mm Hg in systolic pressure over IFN beta-1a, and no effect on diastolic pressure. The increase in systolic pressure was first detected after approximately 3 months of treatment initiation and remained stable throughout treatment. Hypertension-related events (hypertension, essential hypertension, and blood pressure increased) were reported as an adverse reaction in 4.5% of patients treated with Zeposia 920 microgram and in 2.3% of patients treated with IFN beta-1a IM.
The mean increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in UC patients treated with Zeposia is similar to patients with MS.
In UC induction clinical trials, the average increase from baseline in SBP was 3.7 mm Hg in patients treated with Zeposia and 2.3 mm Hg in patients treated with placebo. In UC Study 2, the average increase from baseline in SBP was 5.1 mm Hg in patients treated with Zeposia and 1.5 mm Hg in patients treated with placebo. There was no effect on DBP.
Hypertension events were reported in 1.2% of patients treated with Zeposia 920 microgram and none in patients treated with placebo in UC induction clinical trials, and in 2.2% and 2.2% of patients in UC Study 2, respectively. Hypertensive crisis was reported in one patient receiving Zeposia and one patient receiving placebo.

Elevated hepatic enzymes.

In active-controlled MS clinical trials, elevations of ALT to 5-fold the upper limit of normal (ULN) or greater occurred in 1.6% of patients treated with Zeposia 920 microgram and 1.3% of patients on interferon (IFN) beta-1a. Elevations of 3-fold the ULN or greater occurred in 5.5% of patients on Zeposia and 3.1% of patients on IFN beta-1a. The median time to elevation 3-fold the ULN was 6 months. The majority (79%) continued treatment with Zeposia with values returning to < 3 times the ULN within approximately 2-4 weeks.
In clinical trials, Zeposia was discontinued for a confirmed elevation greater than 5-fold the ULN. Overall, the discontinuation rate due to elevations in hepatic enzymes was 1.1% of patients on Zeposia 920 microgram and 0.8% of patients on IFN beta-1a.
In UC Study 1, elevations of ALT to 5-fold the ULN or greater occurred in 0.9% of patients treated with Zeposia 920 microgram and 0.5% of patients who received placebo, and in UC Study 2, elevations occurred in 0.9% of patients and no patients, respectively. In UC Study 1, elevations of ALT to 3-fold the ULN or greater occurred in 2.6% of UC patients treated with Zeposia 920 microgram and 0.5% of patients who received placebo. In UC Study 2 elevations occurred in 2.3% of patients receiving Zeposia and no patients on placebo.
In controlled and uncontrolled UC trials, the majority of patients with ALT greater than 3 fold the ULN continued treatment with Zeposia with values returning to less than 3 fold the ULN within approximately 2 to 4 weeks.
In clinical trials, Zeposia was discontinued for a confirmed elevation of ALT or AST greater than 5-fold the ULN. Overall, the discontinuation rate due to elevations in hepatic enzymes was 1.1% of MS patients on Zeposia 920 microgram and 0.8% of patients on IFN beta-1a. Overall, the discontinuation rate because of elevations in hepatic enzymes was 0.4% in patients treated with Zeposia 920 microgram, and none in patients who received placebo in the controlled UC trials.

Blood lymphocyte count reduction.

The proportion of patients who experienced lymphocyte counts less than 0.2 x 109/L was 3.3% in MS Study 1 and 2 and less than or equal to 3% in UC controlled trials. These values generally returned to greater than 0.2 x 109/L while patients remained on treatment with Zeposia In the MS and UC clinical trials, after discontinuing Zeposia 920 microgram, the median time to recovery of peripheral blood lymphocytes to the normal range was 30 days, with approximately 80% to 90% of patients recovering within 3 months.

Infections.

In active-controlled MS clinical trials, the overall rate of infections (35%) with Zeposia 920 microgram was similar to IFN beta-1a IM. Zeposia increased the risk of upper respiratory tract infections and urinary tract infection. The overall rate of serious infections was similar between Zeposia (1%) and IFN beta-1a IM (0.8%) in MS clinical trials.
In UC induction clinical trials, the overall rate of infections and rate of serious infections in patients treated with Zeposia were similar to that in patients who received placebo (9.9% vs. 10.7% and 0.8% vs. 0.4%, respectively). In UC Study 2, the overall rate of infections in patients treated with Zeposia was higher than in patients treated with placebo (23% vs. 12%) and the rate of serious infections was similar (0.9% vs. 1.8%).
Progressive multifocal leukoencephalopathy was reported with Zeposia.

Herpetic infections.

Cases of localised herpes virus infection (e.g. herpes zoster and herpes simplex) were seen in clinical trials of Zeposia.
In active-controlled MS trials, herpes zoster was reported as an adverse reaction in 0.6% of patients treated with Zeposia 920 microgram and in 0.2% of patients on IFN beta-1a.
In UC induction clinical trials, herpes zoster was reported in 0.4% of patients who received Zeposia and none in patients who received placebo. In UC Study 2, herpes zoster was reported in 2.2% of patients who received Zeposia and 0.4% of patients who received placebo. None were serious or disseminated.

Macular oedema.

In the active-controlled MS clinical trials, macular oedema was observed in 1 (0.1%) patient with Zeposia 920 microgram, 3 (0.3%) patients with Zeposia 460 microgram and none with IFN beta-1a.
Macular oedema was reported in a total of 1 (0.2%) patient in UC induction clinical trials, 1 (0.4%) patient in UC Study 2 treated with Zeposia, and in no patients who received placebo.

Hypersensitivity.

Hypersensitivity, including rash and urticaria, has been reported with Zeposia in active-controlled MS clinical trials at a frequency of uncommon.

Respiratory system.

Minor dose-dependent reductions in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were observed with Zeposia treatment.
At months 3 and 12 of treatment in MS clinical trials, median changes from baseline in the Zeposia 920 microgram group were as follows: FEV1 -0.07 L and -0.1 L, and FVC -0.05 L and -0.065 L, respectively, with smaller changes from baseline in the IFN beta-1a group (FEV1: -0.01 L and -0.04 L, FVC: 0.00 L and -0.02 L).
Similar to MS clinical trials, in UC induction clinical trials, small mean reductions in pulmonary function tests were observed with Zeposia relative to placebo (FEV1 and FVC). There were no further reductions with longer term treatment with Zeposia in UC Study 2 and these small changes in pulmonary function tests were reversible in patients re-randomised to placebo.

Post-marketing experience.

The following events have been identified during post-marketing use of ozanimod. Because reports are voluntary from a population of unknown size, an estimate of frequency cannot be made.

Hepatobiliary disorders.

Liver injury.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

In the event of overdose, patients should be managed by symptomatic and supportive care.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ozanimod is a potent sphingosine 1-phosphate (S1P) receptor modulator, which binds with a high affinity to S1P receptor subtypes 1 and 5. Ozanimod has minimal or no activity on S1P2, S1P3, and S1P4. In vitro, ozanimod and its major active metabolites demonstrated similar activity and selectivity for S1P1 and S1P5. Ozanimod causes the retention of lymphocytes in lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis and ulcerative colitis is unknown but may involve the reduction of lymphocyte migration into the central nervous system and intestine.

Cardiac electrophysiology.

Ozanimod may cause a transient reduction in heart rate on initiation of dosing. A dose escalation schedule of Zeposia 230 microgram followed by doses of 460 microgram, and 920 microgram attenuates the magnitude of heart rate reductions.
In a randomised, positive- and placebo-controlled thorough QT study using a 14-day dose-escalation regimen of 230 microgram QD for 4 days, 460 microgram QD for 3 days, 920 microgram QD for 3 days, and 1.84 mg QD for 4 days in healthy subjects, no evidence of QTc prolongation was observed as demonstrated by the upper boundary of the 95% one-sided confidence interval (CI) that was below 10 ms. Concentration-QTc analysis for ozanimod and the major active metabolites, CC112273 and CC1084037, using data from another Phase 1 study showed the upper boundary of the 95% CI for model derived QTc (corrected for placebo and baseline) below 10 ms at maximum concentrations achieved with Zeposia doses ≥ 920 microgram once daily.

Reduction in blood lymphocyte counts.

In active-controlled MS and UC clinical trials, mean lymphocyte counts decreased to approximately 45% of baseline at 3 months (approximate mean blood lymphocyte counts 0.8 x 109/L) and remained stable during treatment with Zeposia.
After discontinuing Zeposia 920 microgram, the median time to recovery of peripheral blood lymphocytes to the normal range was approximately 30 days, with approximately 80% to 90% of patients recovering within 3 months.

Reduction in faecal calprotectin.

In patients with UC, treatment with Zeposia resulted in a decrease in the inflammatory marker, faecal calprotectin (FCP) during UC Study 1, which was maintained throughout UC Study 2.

Clinical trials.

Multiple sclerosis. Zeposia was evaluated in two randomised, double-blind, double-dummy, parallel-group, active controlled clinical trials of similar design and endpoints, in patients with relapsing forms of MS (RMS) treated for at least 1 year (Study 1 - SUNBEAM - Treatment continued for all patients until the last enrolled patient completed 1 year) and 2 years (Study 2 - RADIANCE).
The dose of Zeposia was 920 microgram and 460 microgram given orally once daily, with a starting dose of 230 microgram on Days 1-4, followed by an escalation to 460 microgram on Days 5-7, and followed by the assigned dose on Day 8 and thereafter. The dose of IFN beta-1a, the active comparator, was 30 microgram given intramuscularly once weekly. Both studies included patients who had experienced at least one relapse within the prior year, or one relapse within the prior two years with evidence of at least a gadolinium-enhancing (GdE) lesion in the prior year and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.0. Neurological evaluations were performed at baseline, every 3 months, and at the time of a suspected relapse. MRIs were performed at baseline (Studies 1 and 2), 6 months (Study 1), 1 year (Studies 1 and 2), and 2 years (Study 2).
The primary outcome of both Study 1 and Study 2 was the annualised relapse rate (ARR) over 12 months for Study 1 and 24 months for Study 2. The key secondary outcome measures included: 1) the number of new or enlarging MRI T2 hyperintense lesions over 12 and 24 months 2) the number of MRI T1 GdE lesions at 12 and 24 months, and 3) the time to confirmed disability progression, defined as at least a 1-point increase from baseline EDSS sustained for 12 weeks. Confirmed disability progression was prospectively evaluated in a pooled analysis of Studies 1 and 2. An additional MRI outcome measure was the mean percentage change from baseline in normalised brain volume.
In Study 1, 1346 patients were randomised to receive Zeposia 920 microgram (n = 447), Zeposia 460 microgram (n = 451), or IFN beta-1a (n = 448); 94% of Zeposia-treated 920 microgram, 94% of Zeposia-treated 460 microgram, and 92% of IFN beta-1a-treated patients completed the study. Mean (median) age was 35.6 (35) years, 66% were female, mean (median) time since MS symptom onset was 7 (5.2) years. The mean (median) EDSS score at baseline was 2.62 (2.5); 70% had not been treated with a disease-modifying therapy. At baseline, the mean number of relapses in the prior year was 1.3 and 47% of patients had one or more T1 Gd-enhancing lesions (mean 1.7).
The median duration of treatment was 13.6 months.
In Study 2, 1313 patients were randomised to receive Zeposia 920 microgram (n = 433), Zeposia 460 microgram (n = 439), or IFN beta-1a (n = 441); 90% of Zeposia-treated 920 microgram, 85% of Zeposia-treated 460 microgram, and 85% of IFN beta-1a-treated patients completed the study. Mean (median) age was 35.5 (35) years, 67% were female, mean (median) time since MS symptom onset was 6.5 (4.8) years, and mean (median) EDSS score at baseline was 2.51 (2.5); 71% had not been treated with a disease-modifying therapy. At baseline, the mean number of relapses in the prior year was 1.3 and 43% of patients had one or more T1 Gd-enhancing lesions (mean 1.7).
The median duration of treatment was 24 months.
The ARR was significantly lower in patients treated with ozanimod 920 microgram than in patients who received IFN beta-1a 30 microgram IM. The number of new or enlarging T2 lesions and the number of GdE lesions was significantly lower in patients treated with Zeposia than in patients who received IFN beta-1a. Three month confirmed disability progression was low and similar between Zeposia and IFN beta-1a-treated patients over 2 years. The difference was not statistically significant.
A consistent reduction of the ARR compared to IFN beta-1a was observed in subgroups defined by sex, age, prior DMT therapy, and baseline disease activity. See Table 7.
In Studies 1 and 2, treatment with Zeposia 920 microgram resulted in reductions in mean percent change from baseline in normalised brain volume compared to IFN beta-1a (-0.41% versus -0.61%, and -0.71% versus -0.94%, respectively, nominal p-value < 0.0001 for both studies).

Long-term data.

Patients who completed the Phase 3 Studies 1 and 2 could enter an open label extension study (Study 3 - DAYBREAK). Of the 751 patients initially randomised to ozanimod 920 microgram and treated for up to 3 years, the (adjusted) ARR between year 2 and 3 of treatment was 0.124.
Ulcerative colitis. The efficacy and safety of Zeposia were evaluated in two multi-centre, randomised, double-blind, placebo-controlled clinical trials [UC Study 1 (TRUENORTH-I) and UC Study 2 (TRUENORTH-M)] in adult patients with moderately to severely active ulcerative colitis. UC Study 1 included patients who were randomised 2:1 to ozanimod 920 microgram or placebo. The total population included an additional group who received Zeposia 920 microgram open-label. The 10-week induction period was followed by a 42-week, randomised, withdrawal maintenance period (UC Study 2) for a total of 52 weeks of therapy. Patients could have had an inadequate response, loss of response, or intolerance to a biologic (e.g. TNF blocker and/or vedolizumab), corticosteroids, and/or immunomodulators (e.g. 6-mercaptopurine and azathioprine). Patients were to be receiving treatment with oral aminosalicylates and/or corticosteroids.
Disease assessment was based on the Mayo score, which ranges from 0 to 12 and has four subscores from 0 (normal) to 3 (most severe): stool frequency, rectal bleeding, findings on centrally-reviewed endoscopy, and physician global assessment. Moderately to severely active ulcerative colitis was defined at baseline (Week 0) as a Mayo score of 6 to 12, including a Mayo endoscopy subscore ≥ 2. An endoscopy score of 2 was defined by marked erythema, lack of vascular pattern, friability, erosions; and a score of 3 was defined by spontaneous bleeding, ulceration.

UC study 1 (TRUENORTH-I).

In the UC Study 1 (TRUENORTH-I), patients were randomised to either Zeposia 920 microgram given orally once daily (n=429) or placebo (n=216) beginning with a dose titration (see Section 4.2). There were another 361 patients who received open-label Zeposia 920 microgram orally once daily. Patients received concomitant aminosalicylates (e.g. mesalazine 71%; sulfasalazine 13% of the total population) and/or oral corticosteroids (33% of randomised patients) at a stable dose prior to and during the induction period.
There were 30% of patients who had an inadequate response, loss of response or intolerant to TNF blockers. Of these patients, 63% received at least two or more biologics including TNF blockers; 47% received an integrin receptor blocker (e.g. vedolizumab); 36% failed to ever respond to at least one TNF blocker; 65% lost response to a TNF blocker. There were 41% of patients who failed and/or were intolerant to immunomodulators. At baseline, patients had a median Mayo score of 9, with 65% of patients less than or equal to 9 and 35% having greater than 9.
The primary endpoint was clinical remission at Week 10, defined as a Three-component Mayo: Rectal bleeding subscore = 0 and Stool frequency subscore ≤ 1 (and a decrease of ≥ 1 point from the Baseline Stool Frequency subscore) and Endoscopy subscore ≤ 1 without friability.
Key secondary endpoints at Week 10 were clinical response, endoscopic improvement, and mucosal healing. Clinical response with a definition of Three-component Mayo (a reduction from Baseline in the 9-point Mayo score of ≥ 2 points and ≥ 35%, and a reduction from Baseline in the Rectal Bleeding subscore of ≥ 1 point or an absolute Rectal Bleeding subscore of ≤ 1 point), endoscopic improvement with a definition of Endoscopy subscore of ≤ 1 point, and mucosal healing defined as Endoscopy subscore of ≤ 1 point and a Geboes index score < 2.0.
A significantly greater proportion of patients treated with ozanimod achieved clinical remission, clinical response, endoscopic improvement, and mucosal healing compared to placebo at Week 10 as shown in Table 8.

UC study 2 (TRUENORTH-M).

In order to be randomised to treatment in UC Study 2 (TRUENORTH-M), patients had to have received Zeposia 920 microgram and have a clinical response at Week 10 of UC Study 1. Patients could have come from either UC Study 1 (TRUENORTH-I) or from a group who received Zeposia 920 microgram open-label. Patients were re-randomised in a double-blinded fashion (1:1) to receive either Zeposia 920 microgram (n=230) or placebo (n=227) for 42 weeks. The total study duration was 52 weeks, including both studies. Efficacy assessments were at Week 52. Concomitant aminosalicylates were required to remain stable through Week 52. Patients on concomitant corticosteroids were to taper their dose upon entering the maintenance study.
At study entry, 35% of patients were in clinical remission, 29% of patients were on corticosteroids and 31% of patients were previously treated with TNF blockers.
The primary endpoint was the proportion of patients in clinical remission at Week 52. Key secondary endpoints at Week 52 were the proportion of patients with clinical response, endoscopic improvement, endoscopic improvement with histologic remission, corticosteroid-free clinical remission, mucosal healing and maintenance of clinical remission at Week 52 in the subset of patients in remission at Week 10.
The results of the efficacy endpoints in UC Study 2 are shown in Table 9.

Long-term data.

Patients who did not achieve clinical response at the end of UC Study 1, lost response in UC Study 2 or completed the UC studies were eligible to enter an open label extension study (OLE) and received Zeposia 920 microgram. A total of 821 of the 1012 eligible patients entered the OLE. In this open-label extension study, patients were observed for up to 142 weeks.

Additional clinical data.

UC Study 3 (TOUCHSTONE), a 33 week placebo controlled Phase 2 study in patients with moderate to severe ulcerative colitis demonstrated a significant treatment difference for Zeposia 920 microgram (n=67) relative to placebo (n=65) in clinical remission (using the pre-specified 4-component Total Mayo Score) of 16% (p=0.0482) at Week 9 and 21% (p=0.0108) at Week 33.

5.2 Pharmacokinetic Properties

Ozanimod is extensively metabolised in humans to form a number of circulating active metabolites, including two major active metabolites, CC112273 and CC1084037, with similar activity and selectivity for S1P1 and S1P5 to the parent drug. Approximately 94% of circulating total active drug exposure is represented by ozanimod (6%), CC112273 (73%), and CC1084037 (15%) in humans. The maximum plasma concentration (Cmax) and area under the curve (AUC) for ozanimod, CC112273, and CC1084037 increased proportionally over the dose range of Zeposia 460 microgram to 920 microgram (0.5 to 1 time the recommended dose). At a dose of 920 microgram orally once daily in RMS, the geometric mean [coefficient of variation (CV%)] Cmax and AUC0-24h at steady state were 231.6 picogram/mL (37.2%) and 4223 picogram*h/mL (37.7%), respectively, for ozanimod, and 6378 picogram/mL (48.4%) and 132861 picogram*h/mL (45.6%), respectively, for CC112273. Cmax and AUC0-24h for CC1084037 are approximately 20% of that for CC112273. Factors affecting CC112273 are applicable for CC1084037 as they are interconverting metabolites.
Population pharmacokinetic analysis indicated that there were no meaningful differences in these pharmacokinetic parameters in patients with relapsing MS or UC.

Absorption.

The Tmax of ozanimod is approximately 6-8 hours. Administration of Zeposia with a high-fat, high-calorie meal (approximately 900 to 1100 calories with 150, 250 to 360, and 500 to 600 calories from protein, carbohydrate, and fat, respectively) had no effect on ozanimod exposure (Cmax and AUC). Ozanimod may be taken without regard to meals.
In a study of female rats, absolute oral bioavailability of ozanimod was 64% with an oral capsule formulation.

Distribution.

The mean (CV%) apparent volume of distribution of ozanimod (Vz/F) was 5590 L (27%), indicating extensive tissue distribution. Binding of ozanimod to human plasma proteins is approximately 98.2%. Binding of CC112273 and CC1084037 to human plasma proteins is approximately 99.8% and 99.3%, respectively. Ozanimod and its metabolites do not bind extensively to whole blood components, such as red blood cells.

Metabolism.

Ozanimod was extensively metabolised in humans with a number of metabolites identified in plasma, urine and faeces. Multiple enzyme systems play an important role in the metabolism of ozanimod and no single enzyme system predominates in the overall metabolism of ozanimod. The oxidative pathway to formation of carboxylate metabolite RP101988 is mediated by ALDH/ADH while formation of RP101075 by dealkylation is predominantly carried out by CYP3A4. RP101075 is N-acetylated by NAT-2 to form RP101442 or deaminated by MAO-B to form the major metabolite CC112273.
CC112273 is either reduced to form CC1084037 or undergoes CYP2C8 mediated oxidation to form RP101509. CC1084037 is oxidised rapidly to form CC112273 by AKR 1C1/1C2, and/or 3β- and 11β-HSD and undergoes reversible metabolism to CC112273. The oxido-reduction interconversion between CC112273 and CC1084037 favours CC112273 and there are no direct metabolites of CC1084037 other than its metabolism to CC112273 and subsequent elimination via that pathway. Gut microbial flora plays an important role in vivo, via anaerobic reductive metabolism of the oxadiazole ring system in the formation of many inactive metabolites.

Excretion.

Following a single oral 920 microgram dose of [14C]-ozanimod, approximately 26% and 37% of the radioactivity was recovered from urine and faeces, respectively, primarily composed of inactive metabolites. Ozanimod, CC112273, and CC1084037 concentrations in urine were negligible, indicating that renal clearance is not an important excretion pathway for ozanimod, CC112273 and CC1084037.
The mean (CV%) apparent oral clearance for ozanimod was approximately 192 L/h (37%). The mean (CV%) plasma half-life (t1/2) of ozanimod was approximately 21 hours (15%). Steady state for ozanimod was achieved within 7 days, with the estimated accumulation ratio following repeated oral administration of 920 microgram once daily of approximately 2.
The model-based mean (CV%) effective half-life (t1/2) of CC112273 was approximately 11 days (104%) in RMS patients, with mean (CV%) time to steady state of approximately 45 days (45%) and accumulation ratio of approximately 16 (101%). Plasma levels of CC112273 and its direct, interconverting metabolite CC1084037 declined in parallel in the terminal phase, yielding similar t1/2 for both metabolites. Steady state attainment and accumulation ratio for CC1084037 are expected to be similar to CC112273.

Renal impairment.

In a dedicated renal impairment trial, following a single oral dose of 230 microgram Zeposia, exposures (AUClast) for ozanimod and CC112273 were approximately 27% higher and 23% lower, respectively, in subjects with end stage renal disease (N=8) compared to subjects with normal renal function (N=8).
Based on this trial, renal impairment had no clinically important effects on pharmacokinetics of ozanimod or CC112273.
No dose adjustment is needed in patients with renal impairment.

Hepatic impairment.

Two studies were conducted with subjects with chronic liver disease, a single dose study, and an 8-day multiple dose study evaluating the 7-day dose escalation followed by a single 920 microgram on Day 8. In both studies, there was no meaningful impact of mild or moderate chronic hepatic impairment (Child-Pugh A or B) on the concentrations of ozanimod or the major metabolite CC112273 after the first dose on Day 1. In the 8-day multiple dose hepatic impairment trial, there was also no meaningful impact on ozanimod or CC112273 concentrations on Day 5 or Day 8 of dosing. After dose escalation in the 8-day multiple dose hepatic impairment trial, administration of 920 microgram ozanimod resulted in increased CC112273 and CC1084037 mean unbound AUC0-last (measured up to 64 days post-dose) in subjects with mild or moderate chronic hepatic impairment of 99.64% to 129.74% relative to healthy control subjects. This study did not reach steady state exposure, and the terminal half-life of CC112273 in mild and moderate hepatic impairment was approximately 28 and 64 days, respectively.
The pharmacokinetics of ozanimod were not evaluated in subjects with severe hepatic impairment.
Patients with mild or moderate chronic hepatic impairment (Child-Pugh class A or B) are recommended to complete the 7-day dose escalation regimen, and then take 920 microgram once every other day. Use in patients with severe hepatic impairment is not recommended (Child-Pugh class C).

Pharmacokinetics in children.

No PK data are available on administration of Zeposia to paediatric or adolescent patients (< 18 years of age).

Pharmacokinetics in elderly.

Population pharmacokinetic analyses showed that steady state exposure (AUC) of CC112273 in patients over 65 years of age was approximately 3% to 4% greater than patients over 45 to 65 years of age and 27% greater than adult patients under 45 years of age. There is not a meaningful difference in the pharmacokinetics in elderly patients.

Pharmacokinetics in smokers.

Population PK results showed that CC112273 steady-state exposure (AUC) was approximately 50% lower in smokers than in non-smokers, although for smokers this reduction in exposure did not result in meaningful differences in ALC reduction or an apparent impact on clinical efficacy.

Gender.

While population PK of ozanimod are not affected by gender, CC112273 steady-state exposure (AUC) was lower in males than in females. The effect of gender on CC112273 systemic exposure was not deemed clinically meaningful.

Ethnicity.

In a dedicated Japanese PK bridging study, following repeated dosing of 920 microgram, ozanimod exposure (Cmax and AUCtau) were unchanged and CC112273 exposure (Cmax and AUCtau) were approximately 28% and 43% higher, respectively, in Japanese subjects (N=10) compared to Caucasian subjects (N=12). These differences were not considered clinically meaningful.

5.3 Preclinical Safety Data

Genotoxicity.

Ozanimod and multiple metabolites were evaluated for bacterial mutagenicity. These mutagenicity assays examined ozanimod, CC112273, CC1084037, RP101124, RP101988, RP101075, and RP101442, which were all negative for mutagenicity. In vitro aneugenicity/clastogenicity assessment included ozanimod (negative in the mouse lymphoma), CC112273 (negative in the human peripheral blood lymphocyte assay), and CC1084037 (positive in the TK6 assay). The positive in vitro TK6 result with CC1084037 was assessed using a two-organ in vivo study (negative bone marrow micronucleus assay and a negative hepatic comet assay at doses up to 1000 mg/kg/day for 3 days in mice). Ozanimod was also negative in the in vivo bone marrow micronucleus assay (at doses up to 800 mg/kg/day for 2 days in rats).
Overall, ozanimod and metabolites did not exhibit any in vitro or in vivo genotoxicity concerns.

Carcinogenicity.

Ozanimod was evaluated for carcinogenicity in the 6-month Tg.rasH2 mouse bioassay and the two-year rat bioassay. In the 6-month Tg.rasH2 mouse study, a statistically significant increased incidence of hemangiosarcomas was seen at the mid and high dose (25 mg/kg/day and 80 mg/kg/day) across multiple organs. At the low dose (8 mg/kg/day), the hemangiosarcoma incidence was lower and remained within laboratory background levels.
Hemangiosarcomas in mice have been postulated to be a result of chronic stimulation of endothelial cells through the S1P1 receptor (also known as the endothelial differentiation gene (EDG) 1 receptor). This receptor is abundant on vascular endothelial cells and is important in endothelial cell migration, differentiation, and survival. In mice, S1P1 agonism results in sustained production of placental growth factor 2 (PlGF2) and subsequently, persistent vascular endothelial cell mitoses. In contrast, rat and human vascular endothelial cells do not release PlGF2 or only transiently release PlGF2 in response to S1P1 agonism, and subsequently, sustained stimulation and hemangiosarcoma formation are not observed in these species.
Based upon the evidence that hemangiosarcomas formation by S1P1 agonism is specific to mice and not relevant to humans, the Tg.rasH2 mouse exposure margin for human risk with the top dose of oral ozanimod at 80 mg/kg/day is 17364x. The metabolite exposure margin is 17.3x for CC112273 and is 15.5x for CC1084037. At the NOAEL dose in mice of 8 mg/kg/day, the exposure margins are 1795x for ozanimod, 1.4x for CC112273, and 1.40x for CC1084037.
In the two-year rat bioassay, no incidence of any tumour type was increased at any ozanimod dose (top dose of 2 mg/kg/day).
In rats, the exposure margin at the highest dose tested (2 mg/kg/day), which was the NOAEL, was 135x for ozanimod, 0.29x for CC112273, and 0.176x for CC1084037.

6 Pharmaceutical Particulars

6.1 List of Excipients

Capsule content.

Microcrystalline cellulose, silicon dioxide, croscarmellose sodium, and magnesium stearate.

Capsule shell.

230 microgram capsule contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide and red iron oxide.
460 microgram capsule contains gelatin, titanium dioxide, yellow iron oxide, black iron oxide and red iron oxide.
920 microgram capsule contains gelatin, titanium dioxide, yellow iron oxide and red iron oxide.

Black ink.

TekPrint SW-9008 or TekPrint SW-9049.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the ARTG. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Store in the original package.

6.5 Nature and Contents of Container

Polyvinyl chloride (PVC)/ polychlorotrifluoroethylene (PCTFE)/ aluminium foil blisters.

Zeposia initiation pack.

Pack size of 7 capsules (4 x 230 microgram, 3 x 460 microgram).

Zeposia 920 microgram capsules.

Pack size of 28 capsules.

6.6 Special Precautions for Disposal

None.

6.7 Physicochemical Properties

Molecular formula: C23H24N4O3.HCl.
Molecular weight: 440.92.
Chemical name: 5-(3-{(1S)-1-[(2-hydroxyethyl)amino]-2,3-dihydro-1H-inden-4- yl}-1,2,4-oxadiazol-5-yl)-2-[(propan-2-yl)oxy]benzonitrile monohydrochloride.

CAS number.

Chemical abstract service (CAS) registry number: 1618636-37-5.

Chemical structure.


7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine.

Summary Table of Changes