Consumer medicine information

Gilenya

Fingolimod

BRAND INFORMATION

Brand name

Gilenya

Active ingredient

Fingolimod

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Gilenya.

SUMMARY CMI

GILENYA®

Consumer Medicine Information (CMI) summary

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

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

1. Why am I using Gilenya?

Gilenya contains the active ingredient fingolimod hydrochloride. Gilenya is used to treat relapsing forms of multiple sclerosis in adults, children and adolescents (10 years of age and above). For more information, see Section 1. Why am I using Gilenya? in the full CMI.

2. What should I know before I use Gilenya?

Do not use if you have ever had an allergic reaction to fingolimod hydrochloride or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Gilenya? in the full CMI.

3. What if I am taking other medicines?

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

4. How do I use Gilenya?

Adults: The usual dose is one 0.5 mg capsule taken once a day. Children and adolescents: The dose is dependent on body weight. More instructions can be found in Section 4. How do I use Gilenya? in the full CMI.

5. What should I know while using Gilenya?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Gilenya.
  • Tell your doctor about any changes in your vision.
  • Tell your doctor straight away if you think you have an infection, fever, or feel like you have the flu.
  • Talk to your doctor straight away if you notice any skin nodules (e.g. shiny pearly nodules), patches or open sores that do not heal within weeks.
Things you should not do
  • You should not receive certain types of vaccines (live attenuated vaccines) during and for up to 2 months after treatment with this medicine.
  • You should avoid becoming pregnant while taking Gilenya or in the two months after you stop taking it because Gilenya may harm your unborn baby.
  • Do not give this medicine to anyone else, even if their condition seems similar to yours.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Gilenya affects you. Your doctor will tell you whether your illness allows you to drive vehicles and use machines safely. Gilenya is not expected to have an influence on your ability to drive or use any machines.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • Store it in a cool dry place where the temperature stays below 30°C (0.5 mg capsule) or below 25°C (0.25 mg capsule).

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

6. Are there any side effects?

Common side effects: flu symptoms, headache, diarrhoea. Serious side effects: coughing with phlegm, chest pain, shingles/ herpes zoster, slow or irregular heartbeat, blurred vision, skin nodules. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

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



FULL CMI

GILENYA®

Active ingredient(s): fingolimod hydrochloride

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I using Gilenya?

Gilenya contains the active ingredient fingolimod. Gilenya belongs to a group of medicines known as sphingosine 1-phosphate (S1-P) receptor modulators.

Gilenya is used to treat adults, children and adolescents (10 years of age and above) with relapsing forms of multiple sclerosis (MS).

This medicine can alter the way the body's immune system works and slows the progression of physical disability and decreases the number of flare-ups (relapses) in patients with relapsing MS.

MS is a long-term condition that affects the central nervous system (CNS), particularly how the brain and spinal cord work. In MS, inflammation destroys the protective cover around the nerves (called myelin) and stops the nerves from working properly.

The cause of MS is unknown, but it is thought that an abnormal response by the body's immune system plays an important part in the process which damages the CNS.

Gilenya helps to fight against attacks on myelin by the immune system and by stopping the cells that cause inflammation from reaching the brain. This reduces nerve damage caused by MS.

Gilenya may also have a direct and beneficial effect on certain brain cells (neural cells) involved in repairing or slowing down the damage of MS.

Ask your doctor if you have any questions about how Gilenya works or why this medicine has been prescribed for you or your child.

2. What should I know before I use Gilenya?

Warnings

Do not use Gilenya if:

  • you are allergic to fingolimod, or any other similar medicines (such as medicines of the same class or with a similar structure), or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
    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.
  • you have had a heart attack, unstable angina, stroke or warning stroke or certain types of heart failure in the last 6 months
  • have certain types of irregular or abnormal heartbeat (arrhythmia)
  • you are taking or have recently taken medicine for irregular heartbeat such as quinidine, disopyramide, amiodarone or sotalol (due to a possible added effect on irregular heartbeat).

Check with your doctor if you:

  • have had heart problems, a stroke or warning of a stroke
    Checking the health of your heart is important. If any of the following applies to you, your doctor may decide not to use Gilenya or may refer you to a cardiologist for further advice before commencing your first dose of Gilenya:
    - irregular or abnormal heartbeat
    - severe heart disease
    - uncontrolled high blood pressure
    - history of stroke or other diseases related to blood vessels in the brain
    - severe breathing difficulties when asleep (sleep apnoea that is not treated)
    - a heart rhythm disturbances (called QTc prolongation or abnormal ECG heart tracing) or the risk of these disturbances
    - slow heart rate or if you have a history of sudden loss of consciousness (fainting).
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 Gilenya treatment one month after the full course of the vaccination is completed.
Children or adolescents (10 years of age and above) need to have completed their vaccination schedule before starting treatment with Gilenya.
  • plan to receive a vaccine
    You should not receive certain types of vaccines (called "live attenuated vaccines") during and up to 2 months after treatment with Gilenya (see Section 3 "What if I am taking other medicines?").
  • have any other medical conditions:
    - 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.
    - problems with your liver. Gilenya may affect your liver function.
  • have an infection as it may get worse
    Infections can be serious and sometimes life-threatening. Before you start taking Gilenya, your doctor will confirm whether you have enough white blood cells (these fight infections) in your blood.
  • take any medicines for any other condition
    If you are not sure whether any of the above conditions apply to you, your doctor can advise you.

Before you start treatment, you will have:

  • a blood test to check your liver function before and during treatment with Gilenya and until two months after stopping treatment. If liver problems are detected your doctor may decide to discontinue treatment.
  • a skin examination is recommended before you start and at regular intervals during treatment. Your doctor will decide what to do if skin problems are noticed.
  • an eye examination before you start treatment and at regular intervals afterwards is recommended if you have or have had one of the following conditions:
    - visual disturbances or other signs of swelling in the central vision area at the back of the eye (a condition known as macular oedema)
    - inflammation or infection of the eye (uveitis)
    - diabetes
  • vaccination against human papilloma virus (HPV) is recommended. If you are female, your doctor will also recommend HPV screening.

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

Pregnancy and breastfeeding

If you are female, a pregnancy test is recommended before starting treatment to check if you are pregnant.

Check with your doctor if you are pregnant or intend to become pregnant.

You should avoid becoming pregnant while taking Gilenya or in the two months after you stop taking it because Gilenya may harm your unborn baby.

If you become pregnant while taking Gilenya, tell your doctor without delay.

You and your doctor will decide what is best for you and your baby.

You should not breast-feed while you are taking Gilenya.

Gilenya can pass into breast milk and there is a risk of serious side effects for a breast-fed baby.

Elderly

Experience with Gilenya in older people (more than 65 years old) is limited.

Children under 10 years

Gilenya has not been studied in children under 10 years of age.

3. What if I am taking other medicines?

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

Some medicines may interfere with Gilenya and affect how it works. These include:

  • medicines for an irregular or abnormal heartbeat such as quinidine, procainamide, amiodarone or sotalol.
  • medicines that slow down heartbeat such as atenolol (a beta-blocker); verapamil, diltiazem or (calcium channel blockers) or ivabradine or digoxin. Your doctor may decide not to use Gilenya or may refer you first to a cardiologist to switch to medicines that do not slow your heart rate or to decide how you should be observed after the first dose of Gilenya
  • medicines that can cause an abnormal heart rhythm called Torsades de Pointes such as citalopram, chlorpromazine, haloperidol, methadone or erythromycin
  • medicines that suppress or modulate the immune system including other medicines used to treat MS such as beta-interferon, glatiramer acetate, natalizumab, mitozantrone, 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 and up to 2 months after treatment with Gilenya, administration of some vaccines containing live virus (live attenuated vaccines) may result in an infection that the vaccination is designed to prevent, while others may not work as well.

You may need to take different amounts of your medicines or to take different medicines while you are taking Gilenya.

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

4. How do I use Gilenya?

First dose precaution

Because Gilenya may have a short-term effect on your heart rate when you take the first dose (or when children/adolescents switch from the 0.25 mg capsule to the 0.5 mg capsule), you will be required to have the health of your heart checked:

  • Before your first dose of Gilenya
  • 6 hours after taking your first dose of Gilenya, and
  • if you start Gilenya again after a break from therapy (depending on how long the break is and how long you have been receiving Gilenya treatment).

You will need to stay at the doctor's office or clinic for 6 hours after taking the first dose of Gilenya (or after taking the first dose of 0.5 mg when your child switches from the 0.25 mg capsule daily dose) so that your heart rate and blood pressure can be checked each hour. Your doctor will also check and record the electrical activity of your heart (using a test called an ECG) and check your heart rhythm.

Tell your doctor if you feel dizzy, tired, or are conscious of your heartbeat.

At the end of the 6-hour observation period, you will be required to have a second ECG.

In case of unusual ECG or slow heart rate at the end of the 6-hour observation period, you may be observed for longer and overnight if necessary. In this case, the same observation process that took place for your first dose of Gilenya will also apply for your second dose.

At the beginning of treatment, Gilenya can cause the heart rate to slow down in some patients. If your heart rate slows down after your first dose, you may feel dizzy or tired or be consciously aware of your heartbeat. If your heart rate slows down too much or your blood pressure drops, you may need treatment without delay. Slow heart rate usually returns to normal within one month.

Gilenya can also cause an irregular heartbeat in some patients, especially after the first dose. Irregular heartbeat usually returns to normal in less than one day.

How much to take

Adults

  • The usual dose is one capsule per day (0.5 mg of fingolimod).

Children and adolescents (10 years of age and above)

  • The dose depends on the body weight:
  • Children and adolescents who weigh 40 kg or less: one 0.25 mg capsule per day.
  • Children and adolescents with a body weight above 40 kg: one 0.5 mg capsule per day.
  • Children and adolescents who started on one 0.25 mg capsule per day and reach a stable body weight above 40 kg will be instructed by their doctor to switch to one 0.5 mg capsule per day. In this case, it is recommended to repeat the first dose observation period.

Do not exceed the recommended dose.

When to take Gilenya

  • Gilenya should be taken 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 to take Gilenya

  • Swallow the Gilenya capsule with a glass of water.
  • Gilenya can be taken with or without food.

How long to take Gilenya

  • Continue taking your medicine for as long as your doctor tells you to.
    Your doctor will check your progress to make sure the medicine is working and will discuss with you how long your treatment should continue.
  • Do not stop taking Gilenya unless your doctor tells you to.
    Your symptoms may return or become worse if you stop the treatment. Tell your doctor if you have worsening of MS symptoms after stopping Gilenya.

Gilenya will stay in your body for up to 2 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 stop taking Gilenya:
    - for 1 day or more during the first 2 weeks of treatment, or
    - for more than 7 days during weeks 3 and 4 of treatment, or
    - for more than 2 weeks after your first month of Gilenya treatment, the initial effect on your heart rate may occur again.

If you restart Gilenya therapy after a break, your doctor may decide to monitor your heart rate and blood pressure every hour, to run ECGs, or to monitor you overnight.

After using Gilenya

  • Tell your doctor straight away, if you believe your MS is getting worse after you have stopped treatment with Gilenya, because it could be serious.
  • Symptoms of MS can return and may become worse compared to before or during treatment.

If you forget to use Gilenya

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

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

Your doctor may decide to observe you at the time you take the next dose.

This may increase the chance of you getting an unwanted side effect.

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 use too much Gilenya

If you think that you have used too much Gilenya or taken a first dose of Gilenya by mistake, you may need urgent medical attention.

You should immediately:

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

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

Your doctor may decide to observe you with hourly heart rate and blood pressure measurements, run ECGs, and he/she may decide to monitor you overnight.

Symptoms of an overdose may include:

  • swelling in hands or feet
  • tingling or numbness in hands or feet
  • muscle pain
  • fever.

5. What should I know while using Gilenya?

Things you should do

  • Avoid becoming pregnant while taking Gilenya or in the two months after you stop taking it because Gilenya may harm your unborn baby.
    - Talk to your doctor about the associated risk. Talk with your doctor about reliable methods of birth control that you should use during treatment and for 2 months after you stop treatment.
  • 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.
    This will help minimise your risk of developing skin cancers.
  • Keep all of your doctor's appointments so that your progress can be checked.
    Your doctor will do regular checks to help prevent you from having side effects from the medicine. This includes blood tests to check your liver function and regular skin checks.
  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Gilenya.
    Remind any doctor, dentist or pharmacist you visit that you are using Gilenya.

Call your doctor straight away if you:

  • become pregnant while taking this medicine.
    Gilenya should not be taken if you are pregnant.
  • think you have an infection, fever or feel like you have the flu.
    You may get infections more easily while you are taking Gilenya and for up to 2 months after you stop taking it. Any infection that you already have may get worse. Infections can be serious and sometimes life-threatening.
  • notice any changes in your vision, especially if:
    - the centre of your vision gets blurry or has shadows
    - if you develop a blind spot in the centre of your vision
    - if you have problems seeing colours or fine detail.
Gilenya may cause macular oedema uncommonly (swelling of a small area at the back of the eye). When this side effect does occur, it usually happens in the first 4 months of treatment. Your chance of developing macular oedema is higher if you have diabetes or have had an inflammation of the eye called uveitis. It can cause some of the same vision symptoms as an MS attack (optic neuritis).
  • notice any skin nodules (e.g., shiny pearly nodules), patches or open sores that do not heal within weeks.
    Skin cancers have been reported in MS patients treated with Gilenya. Symptoms may include abnormal growth or changes of skin tissue (e.g., unusual moles) which may change in colour, shape or size over time. Your doctor should carry out regular skin examinations during your treatment with Gilenya.
  • notice any of following symptoms while you are taking Gilenya because it could be serious:
    - signs that your MS is getting worse (e.g., weakness or visual change) or if you notice any new or unusual symptoms. These may be the symptoms of a rare brain disorder caused by infection, called progressive multifocal leukoencephalopathy (PML) or a condition called tumefactive lesions. Your doctor may organise an MRI scan to decide if you need to stop taking Gilenya.
    - If you think you have an infection; a fever; feel like you have the flu, or have a headache accompanied by stiff neck, sensitivity to light, nausea, and/or confusion, or seizures/fits (these may be symptoms of meningitis and/or encephalitis)
    - sudden onset of severe headache, confusion, seizures and vision changes which are symptoms of a condition called posterior reversible encephalopathy (PRES)
    - swelling in your neck, armpits or groin, persistent tiredness, fever, night sweats, shortness of breath, unexplained weight loss, itchy skin which are symptoms of lymphoma
    - unexplained nausea, vomiting, abdominal pain, tiredness, yellowing of the skin or whites of your eyes, abnormally dark urine. These may be signs of liver injury.

Things you should not do

  • You should not receive certain types of vaccines (live attenuated vaccines) during and for up to 2 months after treatment with this medicine
  • Do not give this medicine to anyone else, even if their condition seems similar to yours.
  • Do not use it to treat any other complaints unless your doctor tells you to.

Driving or using machines

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

Gilenya may cause dizziness in some people.

Your doctor will tell you whether your illness allows you to drive vehicles and use machines safely.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Keep your medicine in the original container until it is time to take it.

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

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Less serious side effects

Less serious side effectsWhat to do
General
  • headache
  • dizziness
  • severe headache often together with nausea, vomiting and sensitivity to light (signs of migraine)
  • weakness
Infection related
  • flu symptoms such as tiredness, chills, sore throat, joint or muscles aching, fever
  • feeling of pressure or pain in the cheeks and forehead (sinusitis)
Skin related
  • ringworm, a fungal infection affecting the skin with ring-like red itchy rash
  • itchy, red, burning rash (eczema)
  • itchy skin
Gut or Gastrointestinal related
  • diarrhoea
  • nausea
  • weight loss
Muscles related
  • back pain
  • muscle or joint pain
Respiratory related
  • cough
  • breathlessness
Eye related
  • blurred vision
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Lungs related
  • bronchitis with symptoms such as coughing with phlegm, chest pain, fever
  • pneumonia with symptoms such as fever, cough, difficulty breathing
Infection related
  • shingles or herpes zoster symptoms such as blisters, burning, itching or pain of the skin, typically on the upper body or face.
  • a headache accompanied by stiff neck, sensitivity to light, nausea, and/or confusion or seizures (fits) which are symptoms of a cryptococcal infection (a type of fungal infection), including cryptococcal meningitis or meningitis/encephalits (caused by herpes or varicella zoster virus).
  • fever, cough, difficulty breathing, tiredness, aching joints and muscles
Heart related
  • slow heartbeat (bradycardia) or irregular heartbeat
Eyes related
  • shadows or blind spot in the centre of your vision, blurred vision, problems seeing colours or details which are symptoms of macular oedema (swelling in the central vision area of the retina at the back of the eye)
Signs of skin cancer
  • moles which may change size, shape, elevation or colour over time, or new moles which may be symptoms of melanoma, a type of skin cancer usually developing from an unusual mole (naevus). The moles may itch, bleed or ulcerate
  • skin nodules (e.g. shiny pearly nodules), patches or open sores
  • skin lesions of unusual colour
  • convulsions, fits (more frequent in children and adolescents than in adults).
Blood related
  • bleeding or bruising more easily than normal. This may be due to low level of platelets
  • (thrombocytopenia).
Liver related
  • yellowing of your skin or the whites of your eyes, abnormally dark urine, unexplained nausea, vomiting, pain on the right side of your stomach area, feeling less hungry than usual and tiredness
Brain related
  • worsening of MS symptoms (e.g. weakness or visual changes) which could be signs of a rare brain disorder caused by infection called progressive multifocal leukoencephalopathy.
  • sudden onset of severe headache, confusion, seizures and/or vision changes, which are symptoms of a condition called posterior reversible encephalopathy (PRES).
Allergy related
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • sudden onset of rash or hives
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Some side effects may not give you any symptoms and can only be found when tests are done. These include:

  • hypertension (increase in blood pressure)
  • higher levels of liver enzymes and/or liver injury
  • increased level of blood fat (triglycerides)
  • changes to blood cell counts
  • abnormal lung function test results.

Reporting side effects

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

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

7. Product details

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

What Gilenya contains

Active ingredient
(main ingredient)		fingolimod
Other ingredients
(inactive ingredients)

0.5 mg capsule:

  • Mannitol
  • magnesium stearate
  • gelatin
  • titanium dioxide
  • iron oxide yellow
  • printing ink - black
  • printing ink - yellow.

0.25 mg capsule:

  • Mannitol
  • magnesium stearate
  • hyprolose
  • hydroxypropylbetadex
  • gelatin
  • titanium dioxide
  • iron oxide yellow
  • printing ink - black.
Potential allergens
  • gelatin may contain residual sulfites.
  • Gilenya does not contain gluten, tartrazine or any other azo dyes.

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

What Gilenya looks like

Gilenya 0.25mg hard capsules - ivory opaque body and cap, with black radial imprint “FTY 0.25mg” on cap and black radial band on body, contains white to almost white powder (Aust R 300029).

GILENYA 0.5mg hard capsules - white opaque body and bright yellow opaque cap; radial imprint with black ink, "FTY 0.5 mg" on cap and two radial bands imprinted on the body with yellow ink, containing white to almost white powder (Aust R 169890).

Gilenya capsules are available in packs containing 28 capsules.

Who distributes Gilenya

NOVARTIS Pharmaceuticals Australia Pty Limited
ABN 18 004 244 160
54 Waterloo Road
Macquarie Park NSW 2113
Telephone: 1 800 671 203

This leaflet was prepared in August 2023.

(gil090221c_v2 based on PI gil090221i)

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Gilenya

Active ingredient

Fingolimod

Schedule

S4

 

1 Name of Medicine

The active ingredient of Gilenya is fingolimod.

2 Qualitative and Quantitative Composition

Fingolimod hydrochloride is a white to almost white crystalline powder which is freely soluble in water. Fingolimod is a base with pKa of 7.82. Therefore, it has high solubility at low pH and very low solubility at high pH (e.g. < 0.01 mg/mL at pH 6.8). Relevant distribution coefficients are 22.3 in n-Octanol/water and 1290 in n-Octanol/hydrochloric acid 0.1 N.

0.25 mg hard capsules.

Each Gilenya capsule contains 0.28 mg fingolimod hydrochloride (equivalent to 0.25 mg fingolimod), mannitol, hyprolose, hydroxypropylbetadex, magnesium stearate, gelatin, titanium dioxide and iron oxide yellow.

0.5 mg hard capsules.

Each Gilenya capsule contains 0.56 mg fingolimod hydrochloride (equivalent to 0.5 mg fingolimod), mannitol, magnesium stearate, titanium dioxide, iron oxide yellow and gelatin.

Excipients with known effect.

Gelatin may contain residual sulfites.

3 Pharmaceutical Form

Gilenya 0.25 mg capsule.

White to almost white powder in ivory opaque (body and cap), size 3, with black radial imprint "FTY 0.25 mg" on cap and black radial band on body.

Gilenya 0.5 mg capsule.

White to almost white powder in white opaque body and bright yellow opaque cap gelatin capsules, size 3, radial imprint with black ink "FTY 0.5 mg" on cap and two radial bands imprinted on body with yellow ink.

4 Clinical Particulars

4.1 Therapeutic Indications

Gilenya is indicated for the treatment of adult and paediatric patients of 10 years of age and above with relapsing forms of multiple sclerosis to reduce the frequency of relapses and to delay the progression of disability.

4.2 Dose and Method of Administration

In adults, the recommended dose of Gilenya is one 0.5 mg capsule taken orally once daily.
In paediatric patients (10 years of age and above), the recommended dose is dependent on body weight:
Paediatric patients with body weight ≤ 40 kg: one 0.25 mg capsule daily taken orally.
Paediatric patients with body weight > 40 kg: one 0.5 mg capsule daily taken orally.
Paediatric patients who start on 0.25 mg capsules and subsequently reach a stable body weight above 40 kg should be switched to 0.5 mg capsules.
Gilenya can be taken with or without food. If a dose is missed, treatment should be continued with the next dose as planned.
On initiation of Gilenya treatment, after the first dose, it is recommended that all patients be observed, with hourly pulse and blood pressure measurement, for a period of 6 hours for signs and symptoms of bradycardia. All patients should have an electrocardiogram performed prior to dosing and at the end of the 6 hour monitoring period (see Section 4.4 Special Warnings and Precautions for Use, Bradyarrhythmia).
When switching from a 0.25 mg to a 0.5 mg daily dose, it is recommended to repeat the observation after first dose.

Switching patients from other disease modifying therapies.

For recommendations related to switching patients from other disease modifying therapies to Gilenya (see Section 4.4 Special Warnings and Precautions for Use, Prior treatment with immunosuppressive or immune modulating therapies).

Children (below 10 years of age).

The safety and efficacy of Gilenya in paediatric patients below 10 years of age have not been studied.

The elderly (≥ 65 years).

Gilenya should be used with caution in patients aged 65 years and over (see Section 5 Pharmacological Properties).

Patients with renal impairment.

No Gilenya dose adjustments are needed (see Section 5 Pharmacological Properties).

Patients with hepatic impairment.

No Gilenya dose adjustments are needed in patients with mild or moderate hepatic impairment. Gilenya is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C) (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in patients with impaired renal or hepatic function).

Ethnicity.

No Gilenya dose adjustments based on ethnic origin are needed (see Section 5 Pharmacological Properties).

Gender.

No Gilenya dose adjustments are needed based on gender (see Section 5 Pharmacological Properties).

Diabetic patients.

Gilenya should be used with caution in patients with diabetes mellitus due to a potential increased risk of macular oedema (see Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or class III/IV heart failure.
History or presence of Mobitz type II second degree or third degree atrioventricular (A-V) block or sick sinus syndrome, unless patient has a functioning pacemaker.
Baseline QTc interval ≥ 500 ms.
Concomitant treatment with class Ia or class III antiarrhythmic drugs during Gilenya initiation.
See Section 4.4 Special Warnings and Precautions for Use for further information.
Further, Gilenya should not be administered to patients with known hypersensitivity to fingolimod or any of the excipients.

4.4 Special Warnings and Precautions for Use

Infections.

Gilenya causes a dose dependent reduction in peripheral lymphocyte count to 20-30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues (see Section 5 Pharmacological Properties). Gilenya may therefore increase the risk of infections, including opportunistic infections, some serious in nature. Before initiating treatment with Gilenya (for switching patients from other disease modifying therapies, see Section 4.4 Special Warnings and Precautions for Use, Prior treatment with immunosuppressive or immune modulating therapies), a recent complete blood count (CBC) should be available.
Because the elimination of fingolimod after discontinuation can take up to two months, continue monitoring for infections throughout this period.
Antineoplastic, immune modulating or immunosuppressive therapies (including corticosteroids) should be coadministered with caution due to the risk of additive immune system effects. Specific decisions as to the dosage and duration of treatment with corticosteroids should be based on clinical judgement (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Instruct patients receiving Gilenya to report symptoms of infections to a physician. Suspension of treatment with Gilenya if a patient develops a serious infection, and consideration of the benefit/ risk should be undertaken.
Cases of cryptococcal infections, including cryptococcal meningitis, have been reported in the postmarketing setting after approximately 2-3 years of treatment, although the exact relationship between the risk of cryptococcal infections and the duration of treatment is unknown (see Section 4.8 Adverse Effects (Undesirable Effects)). Cryptococcal meningitis may be fatal. For this reason, patients with symptoms and signs consistent with cryptococcal infections should undergo prompt diagnostic evaluation. If a cryptococcal infection is diagnosed, appropriate treatment should be initiated.
Human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancer, has been reported in patients treated with fingolimod in the post-marketing setting (see Section 4.8 Adverse Effects (Undesirable Effects)). Due to the immunosuppressive properties of fingolimod, vaccination against HPV should be considered prior to treatment initiation with fingolimod taking into account vaccination recommendations. Cancer screening is recommended as per standard of care.

Progressive multifocal leukoencephalopathy.

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in the postmarketing setting (see Section 4.8 Adverse Effects (Undesirable Effects)). PML is an opportunistic infection caused by JC virus, which may be fatal or result in severe disability. Cases of PML have occurred after approximately 2-3 years of treatment. Although the estimated risk appears to increase with cumulative exposure over time, an exact relationship between the risk of PML and the duration of treatment is unknown. The incidence rate for PML appears to be higher for patients in Japan; the reasons are currently unknown. Cases of PML have occurred in patients who had not been treated previously with natalizumab, which has a known association with PML, and who were not taking any concomitant immunosuppressive or immunomodulatory medications, and who had no other ongoing systemic medical conditions resulting in compromised immune system function.
Physicians should be vigilant for clinical symptoms or MRI findings that may be suggestive of PML. If PML is suspected, Gilenya treatment should be suspended until PML has been excluded. Early diagnosis and stopping therapy are important factors in management of PML in patients on Gilenya. Delay in diagnosis and treatment worsen prognosis which can result in permanent neurological sequelae or death. There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs.
For diagnosis, an evaluation that includes neurological assessment and a gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain is recommended. MRI findings suggestive of PML may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with MS medications associated with PML, including Gilenya. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present.
Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. Appropriate diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. In multiple sclerosis clinical trials, the overall rate of infections (65.1%) at the 0.5 mg dose was similar to placebo. However, bronchitis, herpes zoster and pneumonia, were more common in Gilenya treated patients. Serious infections occurred at a rate of 1.6% in the fingolimod 0.5 mg group versus 1.4% in the placebo group.

Vaccination.

Vaccination may be less effective during and for up to two months after stopping treatment with Gilenya (see Section 4.4 Special Warnings and Precautions for Use, Stopping therapy). The use of live attenuated vaccines should be avoided.
As could be considered for any immune modulating drug, before initiating therapy, patients need to be assessed for their immunity to varicella (chickenpox) prior to Gilenya therapy. It is recommended that patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating Gilenya therapy. A full course of VZV vaccination of antibody negative patients should be considered prior to commencing treatment with Gilenya, following which initiation of treatment with Gilenya should be postponed for 1 month to allow full effect of vaccination to occur.
For paediatric patients, please also see Paediatric use (10 years of age and above).

Macular oedema.

Macular oedema can occur with or without visual symptoms. An ophthalmologic evaluation should be performed before starting Gilenya and at 3-4 months after treatment initiation. Monitor visual acuity at baseline and during routine evaluations of patients.
Patients with diabetes mellitus or a history of uveitis are at increased risk of macular oedema (see Section 4.8 Adverse Effects (Undesirable Effects), Macular oedema). Gilenya has not been studied in multiple sclerosis patients with concomitant diabetes mellitus. It is recommended that multiple sclerosis patients with diabetes mellitus or a history of uveitis undergo an ophthalmologic evaluation prior to initiating Gilenya therapy and should have regular follow-up ophthalmologic evaluations.
If patients report visual disturbances at any time while on Gilenya therapy, evaluation of the fundus, including the macula, should be carried out.
Continuation of Gilenya in patients with macular oedema has not been evaluated. A decision on whether or not Gilenya therapy should be discontinued needs to take into account the potential benefits and risks for the individual patient.

Bradyarrhythmia.

Initiation of Gilenya treatment results in a decrease in heart rate. After the first dose, the heart rate decrease starts within an hour and the day 1 decline is maximal within 6 hours (see Section 5 Pharmacological Properties, Pharmacodynamics, Heart rate and rhythm). In patients receiving Gilenya 0.5 mg, this decrease in heart rate, as measured by pulse, averages approximately 8 beats per minute (bpm) (see Section 4.8 Adverse Effects (Undesirable Effects)). Some patients experienced mild to moderate symptoms, including hypotension, dizziness, fatigue, and/or palpitations.
Initiation of Gilenya treatment has been associated with atrioventricular conduction delays, usually as first degree atrioventricular blocks (prolonged PR interval on electrocardiogram). Second degree atrioventricular blocks, usually Mobitz type I (Wenckebach) have been observed in less than 0.5% of patients receiving Gilenya 0.5 mg in clinical trials. The conduction abnormalities typically were transient, asymptomatic, usually did not require treatment and resolved within the first 24 hours on treatment. Isolated cases of transient, spontaneously resolving complete A-V block have been reported during postmarketing use of Gilenya (see Section 4.8 Adverse Effects (Undesirable Effects)).

First dose monitoring.

Therefore, on initiation of Gilenya treatment, it is recommended that all patients be observed, with hourly pulse and blood pressure measurement, for a period of 6 hours for signs and symptoms of bradycardia. All patients should have an electrocardiogram performed prior to dosing and at the end of the 6 hour monitoring period. Should postdose bradyarrhythmia related symptoms occur, appropriate management should be initiated as necessary and the patient should be observed until the symptoms have resolved. Should a patient require pharmacologic intervention during the first dose observation, overnight monitoring in a medical facility should be instituted and the first dose monitoring strategy should be repeated after the second dose of Gilenya.
The same precautions as for the first dose should be taken when patients are switched from the 0.25 mg to the 0.5 mg daily dose.
Additional observation until the finding has resolved is also required:
if the heart rate at 6 hours post-dose is < 45 bpm in adults, < 55 bpm in paediatric patients aged 12 years and above, or < 60 bpm in paediatric patients aged 10 to below 12 years, or is the lowest value post-dose (suggesting that the maximum pharmacodynamic effect on the heart is not yet manifest);
or if the ECG at 6 hours after the first dose shows new onset second degree or higher A-V block.
If the ECG at 6 hours after the first dose shows a QTc interval > 470 msec (adult females), QTc > 460 msec (paediatric females) or > 450 msec (adult and paediatric males) the patient should be monitored overnight in a medical facility.
Due to the risk of serious cardiac rhythm disturbances, Gilenya is contraindicated in patients with second degree Mobitz type II or higher AV block, or sick-sinus syndrome unless the patient has a functioning pacemaker (see Section 4.3 Contraindications) and should not be used in patients with sino-atrial heart block, a history of recurrent syncope or symptomatic bradycardia. Since initiation of Gilenya treatment results in decreased heart rate and therefore a prolongation of the QT interval, Gilenya must not be used in patients with a baseline QTc interval ≥ 500 msec (see Section 4.3 Contraindications) and should be used with caution in patients with significant QT prolongation (QTc > 470 msec (females) or > 450 msec (males)). Gilenya is best avoided in patients with relevant risk factors for QT prolongation (for example, hypokalaemia, hypomagnesemia or congenital QT prolongation) or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes (e.g. citalopram, chlorpromazine, haloperidol, methadone, erythromycin). Since significant bradycardia may be poorly tolerated in patients with known ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension or severe untreated sleep apnea period, Gilenya should not be used in these patients. In patients for whom Gilenya is not contraindicated, 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, which should last overnight.
Gilenya has not been studied in patients with arrhythmias requiring treatment with class Ia (e.g. quinidine, procainamide) or class III antiarrhythmic drugs (e.g. amiodarone, sotalol). Class Ia and class III antiarrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. Since initiation of Gilenya treatment results in decreased heart rate, Gilenya must not be used concomitantly with these drugs during Gilenya initiation (see Section 4.3 Contraindications).
Experience with Gilenya is limited in patients receiving concurrent therapy with beta-blockers, heart rate lowering calcium channel blockers (such as verapamil or diltiazem), or other substances which may decrease heart rate (e.g. ivabradine or digoxin). Since the initiation of Gilenya treatment is also associated with slowing of the heart rate (see Section 4.8 Adverse Effects (Undesirable Effects), Bradyarrhythmia), concomitant use of these substances during Gilenya initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment with Gilenya should generally not be initiated in patients who are concurrently treated with these substances. If treatment with Gilenya is considered, advice from a cardiologist should be sought regarding the switch to non-heart rate lowering drugs or appropriate monitoring for treatment initiation (should last overnight).
If Gilenya therapy is discontinued for more than 2 weeks after the first month of treatment the effects on heart rate and atrioventricular conduction may recur on reintroduction of Gilenya treatment and the same precautions as for initial dosing should apply. Within the first 2 weeks of treatment, first dose procedures are recommended after interruption of one day or more, during week 3 and 4 of treatment first dose procedures are recommended after treatment interruption of more than 7 days.

Liver function.

Increased liver enzymes, mostly alanine aminotransaminase (ALT) elevation, have been reported in multiple sclerosis patients treated with Gilenya. During clinical trials, 3-fold or greater elevation in liver transaminases occurred in 8.5% of patients treated with Gilenya 0.5 mg and drug was discontinued if the elevation exceeded 5-fold increase. Recurrence of liver transaminase elevations occurred upon rechallenge in some patients, supporting a relationship to the drug. In clinical studies, transaminase elevations occurred at any time during treatment although the majority occurred within 6-9 months. Serum transaminase levels returned to normal within approximately two months after discontinuation of Gilenya.
Clinically significant liver injury has been reported in patients treated with Gilenya in the post-market setting including cases of acute liver failure requiring liver transplant.
Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with Gilenya. Patients should be monitored periodically while on treatment and until two months after Gilenya discontinuation.
Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine during treatment, should have liver enzymes and bilirubin checked and Gilenya should be discontinued if significant liver injury is confirmed (see Section 4.8 Adverse Effects (Undesirable Effects), Liver transaminases). Although there are no data to establish that patients with pre-existing liver disease are at increased risk to develop elevated liver function tests (LFTs) when taking Gilenya, caution in the use of Gilenya should be exercised in patients with a history of significant liver disease.
Gilenya has not been studied in patients with severe pre-existing hepatic injury (Child-Pugh class C) and is not recommended for use in these patients.

Posterior reversible encephalopathy syndrome.

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported at 0.5 mg dose in clinical trials and in the postmarketing setting (see Section 4.8 Adverse Effects (Undesirable Effects)). Symptoms reported included sudden onset of severe headache, nausea, vomiting, altered mental status, visual disturbances and seizure. Symptoms may evolve into ischemic stroke or cerebral haemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, Gilenya should be discontinued.

Prior treatment with immunosuppressive or immune modulating therapies.

When switching patients from other disease modifying therapies, the elimination half-life and mode of action of other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimising the risk of disease reactivation. Before initiating treatment with Gilenya, a recent CBC (i.e. after discontinuation of prior therapy) should be available to ensure any immune effects of such therapy (e.g. cytopenia) have resolved.

Beta interferon, glatiramer acetate or dimethyl fumarate.

Gilenya can generally be started immediately after discontinuation of beta interferon, glatiramer acetate or dimethyl fumarate.

Natalizumab or teriflunomide.

Due to the long elimination half-life of natalizumab or teriflunomide, caution regarding potential additive immune effects is required when switching patients from these therapies to Gilenya. A careful case by case assessment regarding the timing of the initiation of Gilenya treatment is recommended.
Elimination of natalizumab usually takes up to 2-3 months following discontinuation.
In MS patients the teriflunomide median t½z was approximately 19 days after repeated doses of 14 mg. If a decision is made to stop treatment with teriflunomide during the interval of 5 half-lives (approximately 3.5 months although may be longer in some patients), starting other therapies will result in concomitant exposure to teriflunomide. Without an accelerated elimination procedure, it may take up to 2 years to reach teriflunomide concentrations < 0.02 microgram/mL due to individual variation in clearance. The accelerated elimination procedure is described in the teriflunomide product information.

Alemtuzumab.

Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its product information, initiating treatment with Gilenya after alemtuzumab is not recommended unless the benefits of Gilenya treatment clearly outweigh the risks for the individual patient.

Skin cancers.

Skin cancers including basal cell carcinoma (BCC), malignant melanoma, squamous cell carcinoma, Kaposi's sarcoma and Merkel cell carcinoma, have been reported in patients receiving Gilenya (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience).
Since there is a potential risk of malignant skin growths, patients treated with fingolimod should be cautioned against exposure to sunlight without protection. These patients should not receive concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy.
Periodic skin examination is recommended for all patients. Vigilance for cutaneous neoplasms is recommended in patients receiving Gilenya. Healthcare professionals and patients are advised to monitor for suspicious skin lesions before initiating treatment and regularly during treatment with Gilenya. If a suspicious skin lesion is observed, it should be promptly evaluated.

Lymphomas.

There have been cases of lymphoma in clinical studies and the post-marketing setting. The cases reported were heterogeneous in nature, mainly Non-Hodgkin's Lymphoma, including B-cell and T-cell lymphomas. Cases of cutaneous T cell lymphoma (mycosis fungoides) have been observed (see Section 4.8 Adverse Effects (Undesirable Effects)).

Return of disease activity (rebound) after Gilenya discontinuation.

Cases of severe exacerbation of disease have been reported after stopping Gilenya in the postmarketing setting. This was generally observed within 12 weeks after stopping Gilenya, but was also reported up to and beyond 24 weeks after Gilenya discontinuation. Therefore, caution is indicated when stopping Gilenya therapy. If discontinuation of Gilenya is deemed necessary, patients should be monitored for relevant signs and symptoms and appropriate treatment should be initiated as required.

Tumefactive lesions.

Rare cases of tumefactive lesions associated with MS relapse were reported in the post-marketing setting. In case of severe relapses, MRI should be performed to exclude tumefactive lesions. Discontinuation of Gilenya should be considered by the physician on a case-by-case basis taking into account individual benefits and risks.

Stopping therapy.

If a decision is made to stop treatment with Gilenya, the physician needs to be aware that fingolimod remains in the blood and has pharmacodynamic effects, such as decreased lymphocyte counts, for up to two months following the last dose. Lymphocyte counts typically return to normal range within 1-2 months of stopping therapy (see Section 5 Pharmacological Properties). Starting other therapies during this interval will result in a concomitant exposure to fingolimod. Use of immunosuppressants soon after the discontinuation of Gilenya may lead to an additive effect on the immune system and therefore caution should be applied.
See also section above: Return of disease activity (rebound) after Gilenya discontinuation.

Use in hepatic impairment.

Although there are no data to establish that patients with preexisting liver disease are at increased risk to develop elevated liver function tests (LFTs) when taking Gilenya, caution in the use of Gilenya should be exercised in patients with a history of significant liver disease.

Use in the elderly.

Gilenya should be used with caution in patients aged 65 years and over (see Section 5 Pharmacological Properties).

Paediatric use (10 years of age and above).

It is recommended that paediatric patients complete all immunisations in accordance with current immunisation guidelines prior to initiating Gilenya therapy.

Pregnancy, fetal risk, and contraception.

Due to the potential for a serious risk to the fetus, the pregnancy status of females of reproductive potential should be verified prior to starting treatment with Gilenya. Medical advice should be given regarding the risk of harmful effects on the fetus associated with treatment.
While on treatment with Gilenya, females should not become pregnant and effective contraception is recommended during treatment and for 2 months after stopping treatment. If a female becomes pregnant while taking Gilenya, discontinuation of Gilenya should be considered, taking into account the individual benefit risk assessment for both the mother and the fetus. (See Section 4.6, Use in pregnancy; Section 4.4, Return of disease activity (rebound) after Gilenya discontinuation).

Effects on laboratory tests.

Since fingolimod reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient treated with Gilenya.
Laboratory tests requiring the use of circulating mononuclear cells require larger blood volumes due to reduction in the number of circulating lymphocytes.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic interactions.

Antineoplastic, immunosuppressive or immune modulating therapies (including corticosteroids) should be coadministered with caution due to the risk of additive immune system effects (see Section 4.4 Special Warnings and Precautions for Use, Prior treatment with immunosuppressive or immune modulating therapies). Specific decisions as to the dosage and duration of treatment with corticosteroids should be based on clinical judgement (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Caution should also be applied when switching patients from long acting therapies with immune effects such as natalizumab, teriflunomide or mitoxantrone (see Section 4.4 Special Warnings and Precautions for Use, Prior treatment with immunosuppressive or immune modulating therapies). In multiple sclerosis clinical trials the concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased rate of infection.
When fingolimod is used with atenolol, there is an additional 15% reduction of heart rate upon fingolimod initiation, an effect not seen with diltiazem.
Treatment with Gilenya should not be initiated in patients receiving beta-blockers, 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 additive effects on heart rate. If treatment with Gilenya is considered, advice from a cardiologist should be sought regarding the switch to non-heart rate lowering medicinal products or appropriate monitoring for treatment initiation (should last overnight) (see Section 4.4 Special Warnings and Precautions for Use).
During and for up to two months after treatment with Gilenya vaccination may be less effective. The use of live attenuated vaccines may carry the risk of infection and should also therefore be avoided during Gilenya treatment and for up to 2 months after treatment with Gilenya (see Section 4.8 Adverse Effects (Undesirable Effects)).

Pharmacokinetic interactions.

Fingolimod is primarily cleared via cytochrome P450 4F2 (CYP4F2) and possibly other CYP4F isoenzymes. In vitro studies with human hepatocytes indicated that CYP3A4 may contribute to fingolimod metabolism in the case of strong induction of CYP3A4.
Potential of fingolimod and fingolimod-phosphate to inhibit the metabolism of co-medications. In vitro inhibition studies using pooled human liver microsomes and specific metabolic probe substrates demonstrated that fingolimod and fingolimod phosphate have little or no capacity to inhibit the activity of CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11 (fingolimod only). Therefore, fingolimod and fingolimod phosphate are unlikely to reduce the clearance of drugs that are mainly cleared through metabolism by the major CYP isoenzymes.
Potential of fingolimod and fingolimod-phosphate to induce its own and/or the metabolism of co-medications. Fingolimod was examined for its potential to induce human CYP3A4, CYP1A2, CYP4F2, and ABCB1 (P-glycoprotein) mRNA and CYP3A, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP4F2 activity in primary human hepatocytes. Fingolimod did not induce mRNA or activity of the different CYP enzymes and ABCB1 with respect to the vehicle control. Therefore, no clinically relevant induction by fingolimod of the tested CYP450 enzymes or ABCB1 is expected at therapeutic concentrations. In vitro experiments with primary human hepatocytes did not provide an indication of CYP induction by fingolimod phosphate at clinically relevant concentrations.
Potential of fingolimod and fingolimod-phosphate to inhibit the active transport of co-medications. Based on in vitro data, fingolimod as well as fingolimod phosphate are not expected to inhibit the uptake of comedications and/or biologics transported by the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1, OATP1B3) or the sodium taurocholate cotransporting polypeptide (NTCP). Similarly, they are not expected to inhibit the efflux of comedications and/or biologics transported by the breast cancer resistance protein (BCRP), the bile salt export pump (BSEP), the multidrug resistance associated protein 2 (MRP2) or P-glycoprotein (P-gp) at therapeutic concentrations.

Cyclosporin.

The pharmacokinetics of single dose fingolimod were not altered during coadministration with cyclosporine at steady state, nor were cyclosporin steady-state pharmacokinetics altered by single dose, or multi dose (28 days) fingolimod administration. These data indicate that fingolimod is unlikely to reduce or increase the clearance of drugs mainly cleared by CYP3A4 and that inhibition of CYP3A4 is unlikely to reduce the clearance of fingolimod. Potent inhibition of transporters P-gp, MRP2 and OATP1B1 does not influence fingolimod disposition.

Ketoconazole.

The coadministration of oral ketoconazole 200 mg twice daily at steady state and a single dose of fingolimod 5 mg led to a modest increase in the AUC of fingolimod and fingolimod phosphate (1.7-fold increase) by inhibition of CYP4F2. Patients who use Gilenya and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater.

Isoproterenol, atropine, atenolol, and diltiazem.

Single dose fingolimod and fingolimod phosphate exposure was not altered by coadministered isoproterenol or atropine. Likewise, the single dose pharmacokinetics of fingolimod and fingolimod phosphate and the steady-state pharmacokinetics of both atenolol and diltiazem were unchanged during the coadministration of the latter two drugs with fingolimod.

Carbamazepine.

The coadministration of carbamazepine 600 mg twice daily at steady state and a single dose of fingolimod 2 mg significantly decreased the AUC of fingolimod and fingolimod phosphate.
Population pharmacokinetics analysis of potential drug-drug interactions. A population pharmacokinetics evaluation, performed in multiple sclerosis patients, did not provide evidence for a significant effect of fluoxetine and paroxetine (strong CYP2D6 inhibitors) and carbamazepine (potent enzyme inducer) on fingolimod or fingolimod phosphate concentrations. In addition, the following, commonly prescribed substances had no clinically relevant effect (≤ 20%) on fingolimod or fingolimod phosphate concentrations: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, corticosteroids and oral contraceptives.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no human data on the effects of fingolimod on male or female fertility. Fingolimod had no effect on fertility in rats up to the highest dose tested of 10 mg/kg/day (estimated systemic exposure more than 100 times the anticipated clinical exposure) in a study in which both male and female animals were treated and mated. There was no apparent effect on sperm counts. Data from animals do not suggest that fingolimod would be associated with an increased risk of reduced fertility.
(Category D)
There are no adequate and well-controlled studies in pregnant women. Available human data (post-marketing data and pregnancy registry information) suggest that use of Gilenya is associated with an increased prevalence of major congenital malformation in comparison to the general population.
For females planning to become pregnant, Gilenya should be stopped 2 months before conception (see Section 4.4 Special Warnings and Precautions for Use, Pregnancy, fetal risk, and contraception). It will take approximately 2 months to eliminate the compound from the body upon stopping treatment.
If a female becomes pregnant while taking Gilenya, discontinuation of Gilenya should be considered, taking into account the individual benefit risk assessment for both the mother and the fetus.
Medical advice should be given regarding the risk of harmful effects on the fetus associated with treatment and medical follow-up examination should be performed (e.g. ultrasonography examination). If Gilenya is discontinued because of pregnancy or planned pregnancy, the possibility of severe exacerbation of disease should be considered, see Section 4.4 Special Warnings and Precautions for Use, Return of disease activity (rebound) after Gilenya discontinuation, Stopping therapy.
In more than 600 prospective pregnancies with live births, still births or termination of pregnancy due to fetal anomaly with maternal exposure to fingolimod during pregnancy that were reported in post-marketing setting, the proportion of major congenital malformations was approximately 5%. The prevalence of major congenital malformation in the general population is 2 to 4%.
The pattern of malformation reported for Gilenya is similar to that observed in the general population, wherein the common major malformations are:
Congenital heart disease such as atrial and ventricular septal defects, tetralogy of Fallot;
Renal abnormalities;
Musculoskeletal abnormalities;
There is no evidence of clustering of specific birth defects with Gilenya.
Animal studies have shown reproductive toxicity, including fetal loss. Fingolimod and/or its metabolites crossed the placental barrier in pregnant rats and rabbits. When administered during organogenesis, fingolimod was teratogenic in the rat at oral doses of 0.1 mg/kg/day or higher (similar to the clinical dose on a body surface area basis). The most common malformations were persistent truncus arteriosus and ventricular septal defect. At a lower dose (0.03 mg/kg/day), an increased incidence of left umbilical artery was the only finding. A pharmacological mechanism may be responsible as the sphingosine 1-phosphate receptor is involved in vascular formation during embryogenesis. Rabbits showed an increase in skeletal variations at exposures similar to clinical exposure. An increase in postimplantation loss and/or abortion was observed in rat (0.5 mg/kg/day or higher) and rabbit (5 mg/kg/day or higher) studies. Reduced perinatal survival was seen in offspring from rats treated orally from early gestation to weaning with 0.05 mg/kg/day or higher (similar to the clinical dose on a body surface area basis); a no effect dose was not established.
 Fingolimod and/or its metabolites was excreted in the milk of treated rats during lactation. There were no effects on body weight, development, behaviour, or fertility in rat pups from dams treated with oral fingolimod from early gestation to weaning. Reduced immunocompetence was evident in juvenile rats following oral administration.
There are no data on the effects of Gilenya on the breastfed child or the effects of Gilenya on milk production. Since many drugs are excreted in human milk and because of the potential for serious adverse drug reactions from fingolimod in nursing infants, females receiving Gilenya should not breast feed.

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 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.
The safety population of Gilenya is derived from two phase III placebo controlled clinical trials and one phase III active controlled clinical trial in patients with relapsing remitting multiple sclerosis. It includes a total of 2,431 patients on Gilenya (0.5 or 1.25 mg dose).
In the pooled data from the two placebo controlled studies (D2301, FREEDOMS and D2309, FREEDOMS II) the most serious adverse drug reactions (ADRs) for the 0.5 mg recommended therapeutic dose were infections, macular oedema and transient atrioventricular blocks on treatment initiation. The most frequent ADRs (incidence ≥ 10%) at the 0.5 mg dose were headache, hepatic enzyme increased, diarrhoea, cough, influenza, sinusitis and back pain. The most frequent adverse event reported for Gilenya 0.5 mg at an incidence greater than 1% leading to treatment interruption was ALT elevations (2.2%).
The ADRs in study D2302 (TRANSFORMS), a 1 year active controlled study using interferon beta-1a as comparator in 849 patients with multiple sclerosis treated with fingolimod, were generally similar to study D2301, taking into account the differences in study duration.
Table 1 presents the frequency of ADRs reported in the pooled analysis of the placebo controlled studies. ADRs are listed according to MedDRA system organ class. Frequencies were defined as follows: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.

Other adverse reactions reported in clinical trials.

Uncommon: pneumonia, macular oedema, melanoma* and seizure.
Very rare: Kaposi's sarcoma*.
*The frequency category and risk assessment were based on an estimated exposure of more than 24,000 patients to fingolimod 0.5 mg in all clinical trials.

Infections.

In multiple sclerosis clinical trials, the overall rate of infections (65.1%) at the 0.5 mg dose was similar to placebo. However, bronchitis, herpes zoster and pneumonia, were more common in Gilenya treated patients. Serious infections occurred at a rate of 1.6% in the fingolimod 0.5 mg group versus 1.4% in the placebo group.
There have been very rare fatal cases of VZV infections in the context of prolonged concomitant corticosteroid use (more than 5 days) for treatment of multiple sclerosis relapses. Coadministration of a short course of corticosteroids (up to 5 days as per study protocols) did not increase the overall rate of infection in patients treated with fingolimod in the phase III clinical trials, compared to placebo (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
There have been very rare cases of other herpes viral infections with fatal outcome. Two serious cases of disseminated herpes infection which were fatal have occurred on the 1.25 mg dose; a case of herpes encephalitis in a patient in whom initiation of acyclovir therapy was delayed by one week and a case of a primary disseminated varicella zoster infection in a patient not previously exposed to varicella receiving concomitant high dose steroid therapy for a multiple sclerosis relapse.
Human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancer, has been reported under treatment with Gilenya in the post-marketing setting (see Section 4.4 Special Warnings and Precautions for Use).
Cases of opportunistic infections, have been reported in the postmarketing setting, some of which have been fatal. These cases included viral infections such as JCV causing progressive multifocal leukoencephalopathy (PML), herpes simplex or varicella zoster virus which may lead to encephalitis/meningitis, fungal infections including cryptococcal meningitis and atypical mycobacterial skin and lung infections (see Section 4.4 Special Warnings and Precautions for Use).

Macular oedema.

In clinical trials, macular oedema occurred in 0.4% of patients treated with the recommended Gilenya dose of 0.5 mg and in 1.1% of patients treated with the higher 1.25 mg dose. The majority of cases in multiple sclerosis clinical trials occurred within the first 3-4 months of therapy. Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine ophthalmologic examination. The macular oedema generally improved or resolved spontaneously after drug discontinuation. The risk of recurrence after rechallenge has not been evaluated.
Macular oedema incidence is increased in multiple sclerosis patients with a history of uveitis (approximately 20% with a history of uveitis vs 0.6% without a history of uveitis).
Gilenya has not been tested in multiple sclerosis patients with diabetes mellitus. In renal transplant clinical studies where patients with diabetes mellitus were included, therapy with Gilenya 2.5 mg and 5 mg resulted in a 2-fold increase in the incidence of macular oedema. Multiple sclerosis patients with diabetes mellitus are therefore expected to be at a higher risk for macular oedema (see Section 4.4 Special Warnings and Precautions for Use).

Bradyarrhythmia.

Initiation of Gilenya treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays (see Section 4.4 Special Warnings and Precautions for Use).
In multiple sclerosis clinical trials the mean maximal decrease in heart rate after the first dose intake was seen 4-5 hours postdose, with declines in mean heart rate, as measured by pulse, of 8 beats per minute for Gilenya 0.5 mg. The second dose may result in a slight further decrease. Heart rates below 40 beats per minute (bpm) in adults, and below 50 bpm in paediatric patients were rarely observed in patients on Gilenya 0.5 mg. Heart rate returned to baseline within 1 month of chronic dosing.
In the multiple sclerosis clinical program first degree atrioventricular block (prolonged PR interval on electrocardiogram) was detected following drug initiation in 4.7% of patients on Gilenya 0.5 mg, in 2.8% of patients on intramuscular interferon beta-1a and in 1.5% of patients on placebo. Second degree atrioventricular block were detected in less than 0.5% patients on Gilenya 0.5 mg.
The conduction abnormalities were typically transient, asymptomatic and resolved within 24 hours on treatment. Although most patients did not require medical intervention, in clinical trials one patient on the 0.5 mg dose received isoprenaline for an asymptomatic second degree Mobitz I atrioventricular block.

Blood pressure.

In multiple sclerosis clinical trials Gilenya 0.5 mg was associated with a mild increase of approximately 1 mmHg on average in mean arterial pressure manifesting after approximately 2 months of treatment initiation. This increase persisted with continued treatment. Hypertension was reported in 6.1% of patients on Gilenya 0.5 mg and in 3.8% of patients on placebo.

Liver transaminases.

Increased hepatic enzymes (mostly ALT elevation) have been reported in multiple sclerosis patients treated with Gilenya (see Section 4.4 Special Warnings and Precautions for Use). In multiple sclerosis clinical trials, 8.5% and 1.9% of patients treated with Gilenya 0.5 mg experienced asymptomatic elevation in serum levels of hepatic transaminases ≥ 3 x ULN and ≥ 5 x ULN, respectively. The majority of elevations occurred within 6-9 months. Serum transaminase levels returned to normal after discontinuation of Gilenya within approximately 2 months. In a small number of patients, 10 patients on Gilenya 1.25 mg and 2 patients on Gilenya 0.5 mg, who experienced liver transaminase elevations ≥ 5 x ULN and who continued on Gilenya therapy, the elevations returned to normal within approximately 5 months (see Section 4.4 Special Warnings and Precautions for Use).

Respiratory system.

Minor dose dependent reductions in FEV1 and diffusion capacity of the lung for carbon monoxide (DLCO) values were observed with fingolimod treatment starting at month 1 and remaining stable thereafter. At month 24, the reduction from baseline values in percent of predicted FEV1 was 3.1% for fingolimod 0.5 mg and 2.0% for placebo. For DLCO the reductions at month 24 were 3.8% for fingolimod 0.5 mg and 2.7% for placebo. The changes in FEV1 were reversible following treatment discontinuation.

Seizures.

Cases of seizures, including status epilepticus, have been reported with the use of Gilenya in clinical trials and in the post-marketing setting. It is unknown whether these events were related to the effects of multiple sclerosis alone, to Gilenya, or to a combination of both.

Vascular events.

In phase III clinical trials, rare cases of peripheral arterial occlusive disease occurred in patients treated with Gilenya at higher doses (1.25 or 5.0 mg). Rare cases of ischemic and haemorrhagic strokes have also been reported at 0.5 mg dose in clinical trials and in the postmarketing setting although a causal relationship has not been established.

Lymphomas.

There have been cases of lymphoma in clinical studies and the post-marketing setting. The cases reported were heterogeneous in nature, mainly Non-Hodgkin's Lymphoma, including B-cell and T-cell lymphomas. Cases of cutaneous T cell lymphoma (mycosis fungoides) have been observed.

Special populations.

Paediatric patients (10 years of age and above).

In the controlled paediatric trial, the safety profile in paediatric patients (10 to below 18 years of age) receiving Gilenya 0.25 mg or 0.5 mg daily was similar to that seen in adult patients.
In the paediatric study, cases of seizures were reported in 5.6% of fingolimod-treated patients and 0.9% of interferon beta-1a treated patients.

Post-marketing experience.

See Table 2.

Bradyarrhythmia.

Isolated events of transient, spontaneously resolving complete A-V block have been observed during the six hour observation period following the first dose of Gilenya. The patients recovered spontaneously. Isolated delayed onset events, including transient asystole and unexplained death, have occurred within 24 hours of the first dose. These cases have been confounded by concomitant medications and/or pre-existing disease. The relationship of such events to Gilenya is uncertain.

4.9 Overdose

No cases of overdosage have been reported. However, single doses up to 80-fold the recommended dose (0.5 mg) were well tolerated in healthy adult volunteers. At 40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was clinically consistent with small airway reactivity.
Fingolimod can induce bradycardia (see Section 5 Pharmacological Properties, Heart rate and rhythm). Some patients experience mild to moderate symptoms, including hypotension, dizziness, fatigue, and/or palpitations. There have been reports of slow atrioventricular conduction with isolated reports of transient, spontaneously resolving complete A-V block (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
If the overdose constitutes first exposure to Gilenya 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).
Neither dialysis nor plasma exchange would result in meaningful removal of fingolimod from the body.
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.

Fingolimod is a sphingosine 1-phosphate receptor modulator. Fingolimod is metabolized by sphingosine kinase to the active metabolite fingolimod phosphate. Fingolimod phosphate, binds at low nanomolar concentrations to sphingosine 1-phosphate (S1P) receptors 1, 3, and 4 located on lymphocytes, and readily crosses the blood brain barrier to bind to S1P receptors 1, 3, and 5 located on neural cells in the central nervous system. By acting as a functional antagonist of S1P receptors on lymphocytes, fingolimod phosphate blocks the capacity of lymphocytes to egress from lymph nodes, causing a redistribution, rather than depletion, of lymphocytes. This redistribution reduces the infiltration of pathogenic lymphocyte cells into the central nervous system where they would be involved in nerve inflammation and nervous tissue damage.
Animal studies and in vitro experiments indicate that fingolimod may also exert beneficial effects in multiple sclerosis via interaction with S1P receptors on neural cells.

Pharmacodynamics.

Immune system.

Effects on immune cell numbers in the blood.

Within 4-6 hours after the first dose of fingolimod 0.5 mg, the lymphocyte count decreases to approximately 75% of baseline. With continued daily dosing, the lymphocyte count continues to decrease over a two week period, reaching a nadir count of approximately 500 cells/microL or approximately 30% of baseline. Eighteen percent of patients reached a nadir of < 200 cells/microL on at least one occasion.
Low lymphocyte counts are maintained with chronic daily dosing. The majority of T and B lymphocytes regularly traffic through lymphoid organs and these are the cells mainly affected by fingolimod. Approximately 15-20% of T lymphocytes have an effector memory phenotype, cells that are important for peripheral immune surveillance. Since this lymphocyte subset typically does not traffic to lymphoid organs, it is not affected by fingolimod. Peripheral lymphocyte count increases are evident within days of stopping fingolimod treatment and typically normal counts are reached within one to two months. Chronic fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of baseline. Monocytes are unaffected by fingolimod.
Heart rate and rhythm. Fingolimod causes a transient reduction in heart rate and atrioventricular conduction at treatment initiation (see Section 4.4 Special Warnings and Precautions for Use, Bradyarrhythmia; Section 4.8 Adverse Effects (Undesirable Effects)). The maximal decline of heart rate is seen in the first 4-5 hours postdose, with 70% of the negative chronotropic effect achieved on the first day. Heart rate progressively returns to baseline values within one month of chronic treatment.
Pooled analysis of studies with Holter monitoring showed that fingolimod increased the rate of new onset first degree A-V heart block (PR > 200 ms) by 12% on day 1 and that the incidence had reduced to < 1% after 1 week of treatment. Doses ≤ 1.25 mg were associated with a 7% incidence of heart block (cf. 3% in subjects given placebo). These blocks were usually asymptomatic and did not require treatment.
Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise, are not affected by fingolimod treatment.
With initiation of fingolimod treatment there is an increase in atrial premature contractions, but there is no increased rate of atrial fibrillation/ flutter or ventricular arrhythmias or ectopy. Fingolimod treatment is not associated with a decrease in cardiac output.
The decrease in heart rate induced by fingolimod can be reversed by atropine, isoprenaline or salmeterol.
Potential to prolong the QT interval. In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTcI, with the upper bound of the 90% CI ≤ 13.0 ms. There is no dose or exposure response relationship of fingolimod and QTcI prolongation. There is no consistent signal of increased incidence of QTcI outliers, either absolute or change from baseline, associated with fingolimod treatment. In the multiple sclerosis studies, there was no clinically relevant prolongation of QT interval.
Pulmonary function. Persistent pulmonary inflammation and collagenisation with scarring and pulmonary remodelling were observed in association with fingolimod treatment in chronic animal studies (all tested species; mice, rats, dogs and monkeys). Focal pulmonary metaplastic ossification was evident in mice and rats treated for 2 years, but not 6 months, at a dose of 0.25 mg/kg/day and 0.5 mg/kg/day, respectively. Exposure (AUC) at the no effect level was below the clinical exposure in mice and 3 times the clinical exposure in rats. As these pulmonary changes occurred in multiple species, at low relative exposure and were incompletely reversible, adequate pulmonary monitoring should be considered with long-term treatment.
Fingolimod treatment with single or multiple doses of 0.5 and 1.25 mg for two weeks is not associated with a detectable increase in airway resistance as measured by forced expiratory volume in 1 second (FEV1) and forced expiratory flow during expiration of 25 to 75% of the forced vital capacity (FEF25-75). However, single fingolimod doses ≥ 5 mg (10-fold the recommended dose) are associated with a dose dependent increase in airway resistance. Fingolimod treatment with multiple doses of 0.5, 1.25, or 5 mg is not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in airway responsiveness to methacholine. Subjects on fingolimod treatment have a normal bronchodilator response to inhaled β-agonists.

Clinical trials.

The efficacy of Gilenya has been demonstrated in two studies which evaluated once daily doses of Gilenya 0.5 mg and 1.25 mg in patients with relapsing remitting multiple sclerosis. Both studies included patients who had experienced at least 2 clinical relapses during the 2 years prior to randomization or at least 1 clinical relapse during the 1 year prior to randomization, and had an Expanded Disability Status Scale (EDSS) between 0 to 5.5.
The efficacy and safety of once-daily doses of Gilenya 0.25 mg or 0.5 mg (dose selected based on body weight and exposure measurements) have been established in paediatric patients aged 10 to < 18 years old with relapsing-remitting multiple sclerosis.
Patients with the following conditions were excluded from these studies: other chronic disease of the immune system; known immune deficiency syndrome; history of malignancy other than cutaneous BCC or SCC of the skin; active systemic bacterial, viral or fungal infections; AIDS; HBsAg positive or hepatitis C antibody positive; serious psychiatric condition.
Study D2301 (FREEDOMS) was a 2 year randomized, double blind, placebo controlled phase III study in patients with relapsing remitting multiple sclerosis who had not received any interferon beta or glatiramer acetate for at least the previous 3 months and had not received any natalizumab for at least the previous 6 months. Neurological evaluations were performed at screening, every 3 months and at time of suspected relapse. MRI evaluations were performed at screening, month 6, month 12 and month 24. The primary endpoint was the annualised relapse rate.
Median age was 37 years, median disease duration was 6.7 years and median EDSS score at baseline was 2.0. Patients were randomized to receive Gilenya 0.5 mg (n = 425) or Gilenya 1.25 mg (n = 429), or placebo (n = 418) for up to 24 months. Median time on study drug was 717 days on 0.5 mg, 715 days on 1.25 mg and 718.5 days on placebo.
The annualised relapse rate was significantly lower in patients treated with Gilenya than in patients who received placebo. The key secondary endpoint was the time to 3 month confirmed disability progression as measured by at least a 1 point increase from baseline in EDSS (0.5 point increase for patients with baseline EDSS of 5.5) sustained for 3 months. Time to onset of 3 month confirmed disability progression was significantly delayed with Gilenya treatment compared to placebo. There were no significant differences between the 0.5 mg and the 1.25 mg doses on either endpoint.
The results for this study are shown in Table 3 and Figure 1.
Study D2302 (TRANSFORMS) was a 1 year randomized, double blind, double dummy, active (interferon beta-1a 30 micrograms, intramuscular, once weekly) controlled phase III study in patients with RRMS who had not received any natalizumab in the previous 6 months. Prior therapy with interferon-beta or glatiramer acetate up to the time of randomization was permitted.
Neurological evaluations were performed at screening, every 3 months and at the time of suspected relapses. MRI evaluations were performed at screening and at month 12. The primary endpoint was the annualised relapse rate.
Median age was 36 years, median disease duration was 5.9 years and median EDSS score at baseline was 2.0. Patients were randomized to receive Gilenya 0.5 mg (n = 431) or 1.25 mg (n = 426) or interferon beta-1a 30 micrograms via the intramuscular route once weekly (n = 435) for up to 12 months. Median time on study drug was 365 days on 0.5 mg, 354 days on 1.25 mg and 361 days on interferon beta-1a IM.
The annualised relapse rate was significantly lower in patients treated with Gilenya than in patients who received interferon beta-1a IM. There was no significant difference between the Gilenya 0.5 mg and the 1.25 mg doses. The key secondary endpoints were number of new or newly enlarging T2 lesions and time to onset of 3 month confirmed disability progression as measured by at least a 1 point increase from baseline in EDSS (0.5 point increase for those with baseline EDSS of 5.5) sustained for 3 months. The number of new or newly enlarging T2 lesions was significantly lower in patients treated with Gilenya than in patients who received interferon beta-1a IM. There was no significant difference in the time to 3 month confirmed disability progression between Gilenya and interferon beta-1a treated patients at 1 year. There were no significant differences between the 0.5 mg and the 1.25 mg doses on either endpoint.
The results for this study are shown in Table 4 and Figure 2.
Pooled results of studies D2301 and D2302 showed a consistent reduction of annualised relapse rate compared to comparator in subgroups defined by gender, age, prior multiple sclerosis therapy, disease activity or disability levels at baseline.

Study D2311 (PARADIGMS) in paediatric patients 10 years of age and above.

Study D2311 (PARADIGMS) was a double-blind, randomized, active-controlled, parallel-group, multicenter study with flexible duration up to 24 months, to evaluate the efficacy and safety of fingolimod compared to interferon beta-1a in paediatric patients with MS, aged 10 to < 18 years old. Prior therapy with interferon-beta, dimethyl fumarate or glatiramer acetate up to the time of randomization was permitted. Neurological evaluations were performed at screening, every 3 months and at the time of suspected relapses. MRI evaluations were performed at screening, and every 6 months throughout the study. The primary endpoint was the annualized relapse rate.
Median age was 16 years, median disease duration since first symptom was 1.5 years and median EDSS score at baseline was 1.5. Patients were randomized to receive fingolimod or interferon beta-1a via the intramuscular route once weekly for up to 24 months. Median time on study drug was 634 days on fingolimod and 547 days on interferon beta-1a.
The primary endpoint, the annualized relapse rate, was significantly lower in patients treated with fingolimod than in patients who received interferon beta-1a (relative reduction in ARR of 81.9%). The key secondary endpoint, the annualized rate of the number of new or newly enlarged T2 lesions up to Month 24, was also significantly lower in patients treated with fingolimod than in patients who received interferon beta-1a, as was the number of Gd-enhancing T1 lesions per scan up to Month 24. Fingolimod also significantly reduced the annualized rate of brain atrophy from baseline up to month 24. An additional post-hoc analysis confirmed that time to onset of 3-month confirmed disability progression was significantly delayed with fingolimod compared to interferon beta-1a.
The results for this study are shown in Table 5, Figure 3 and Figure 4.

5.2 Pharmacokinetic Properties

Absorption.

Fingolimod absorption is slow (tmax of 12-16 hours) and extensive (≥ 85%, based on the amount of radioactivity excreted in urine and the amount of metabolites in faeces extrapolated to infinity). The apparent absolute oral bioavailability is high (93%).
Food intake does not alter Cmax or exposure (AUC) of fingolimod or fingolimod phosphate. Therefore, Gilenya may be taken without regard to meals (see Section 4.2 Dose and Method of Administration).
Steady-state blood concentrations are reached within 1 to 2 months following once daily administration and steady-state levels are approximately 10-fold greater than with the initial dose.

Distribution.

Fingolimod highly distributes in red blood cells, with the fraction in blood cells of 86%. Fingolimod phosphate has a smaller uptake in blood cells of < 17%. Fingolimod and fingolimod phosphate are highly protein bound (> 99.7%). Fingolimod and fingolimod phosphate protein binding is not altered by renal or hepatic impairment.
Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1200 ± 260 L.

Metabolism.

The biotransformation of fingolimod in humans occurs by three main pathways: by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod phosphate, by oxidative biotransformation catalysed mainly by CYP4F2 and possibly other CYP4F isoenzymes and subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive nonpolar ceramide analogues of fingolimod.
Following single oral administration of [14C]-fingolimod, the major fingolimod related components in blood, as judged from their contribution to the AUC up to 816 hours postdose of total radiolabeled components, are fingolimod itself (23.3%), fingolimod phosphate (10.3%), and inactive metabolites (M3 carboxylic acid metabolite (8.3%), M29 ceramide metabolite (8.9%) and M30 ceramide metabolite (7.3%)).

Excretion.

Fingolimod blood clearance is 6.3 ± 2.3 L/h, and the average apparent terminal elimination half-life (t1/2) is 6-9 days. Blood levels of fingolimod phosphate decline in parallel with fingolimod in the terminal phase yielding similar half-lives for both.
After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod phosphate are not excreted intact in urine but are the major components in the faeces with amounts representing less than 2.5% of the dose each. After 34 days, the recovery of the administered dose is 89%.

Linearity.

Fingolimod and fingolimod phosphate concentrations increase in an apparent dose proportional manner after multiple once daily doses of fingolimod 0.5 mg or 1.25 mg.
In paediatric patients, fingolimod-phosphate concentrations increase in an apparent dose proportional manner after multiple once daily doses of fingolimod 0.25 mg or 0.5 mg.

Pharmacokinetics in special patient groups.

Pharmacokinetics in children.

Fingolimod-phosphate concentration at steady state is similar in adult and paediatric patients. Safety and efficacy of Gilenya in paediatric patients below 10 years of age have not been studied.

Pharmacokinetics in the elderly.

The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in elderly patients. However, clinical experience in patients aged above 65 years is limited.

Pharmacokinetics in patients with impaired renal or hepatic function.

Severe renal impairment increases fingolimod Cmax and AUC by 32% and 43%, respectively, and fingolimod phosphate Cmax and AUC by 25% and 14%, respectively. The apparent elimination half-life is unchanged for both analytes. In severe renal impairment Cmax and AUC for M3, an inactive metabolite, were increased by 805% and 1356% respectively. No Gilenya dose adjustments are needed in patients with renal impairment.
The pharmacokinetics of single dose fingolimod (1 or 5 mg), when assessed in subjects with mild, moderate and severe hepatic impairments, showed no change on fingolimod Cmax, but an increase in AUC by 12%, 44% and 103%, respectively. The apparent elimination half-life is unchanged in mild hepatic impairment but is prolonged by 49-50% in moderate and severe hepatic impairment. Fingolimod phosphate was measured in severe hepatic impairment only, and Cmax, and AUC were decreased by 22% and 29%, respectively. Although hepatic impairment elicited changes in the disposition of fingolimod and fingolimod phosphate, the magnitude of these changes suggests that the fingolimod dose does not need to be adjusted in mild or moderate hepatic impaired patients.
Fingolimod should be used with caution in patients with mild and moderate hepatic impairment. Fingolimod is not recommended for use in patients with severe hepatic impairment (Child-Pugh class C).

Ethnicity.

The effects of ethnic origin on fingolimod and fingolimod phosphate pharmacokinetics are not of clinical relevance.

Gender.

Gender has no influence on fingolimod and fingolimod phosphate pharmacokinetics.

5.3 Preclinical Safety Data

Genotoxicity.

Fingolimod induced numerical chromosomal aberrations (polyploidy) in Chinese hamster cells at concentrations more than three orders of magnitude greater than the clinical steady-state plasma levels, but not in human lymphocytes when tested at similar concentrations. Fingolimod was not clastogenic in the in vivo micronucleus tests in mice and rats at exposures at least 500 times that expected clinically.

Carcinogenicity.

In a 2 year mouse study, an increased incidence of malignant lymphoma was seen at oral doses of fingolimod of 0.25 mg/kg/day and higher, with exposure (plasma AUC) 5-fold the human systemic exposure at a daily dose of 0.5 mg. Exposure at the NOEL (0.025 mg/kg/day) was 0.6-fold human exposure. No evidence of carcinogenicity was observed in a 2 year bioassay in rats at oral doses of fingolimod up to the maximum tolerated dose of 2.5 mg/kg/day, representing a 50-fold margin based on the human systemic exposure (AUC) at the 0.5 mg dose.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

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 ARTG. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Gilenya 0.25 mg: Store below 25 degrees Celsius. Protect from moisture.
Gilenya 0.5 mg: Store below 30 degrees Celsius. Protect from moisture.

6.5 Nature and Contents of Container

Gilenya 0.25 mg: PVC/PVDC/Al blister packs of 7 and 28. Not all pack sizes marketed in Australia.
Gilenya 0.5 mg: PVC/PVDC/Al blister packs of 7, 28 and 84. Not all pack sizes marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical name: 2-amino-2-[2-(4-octylphenyl) ethyl]propan-1,3-diol hydrochloride.
Molecular formula: C19H33NO2.HCl.
Molecular weight: 343.93.

Chemical structure.


CAS number.

162359-56-0.

7 Medicine Schedule (Poisons Standard)

Poison Schedule: S4.

Summary Table of Changes