Consumer medicine information

Fingolis

Fingolimod

BRAND INFORMATION

Brand name

Fingolis

Active ingredient

Fingolimod

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Fingolis.

What is in this leaflet

This leaflet answers some common questions about FINGOLIS. As this leaflet does not contain all the available information, it is important that you talk to your doctor or pharmacist. All medicines have risks and benefits. Your doctor has weighed the risks of you receiving FINGOLIS against the benefits this medicine is expected to have for you.

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

Keep this leaflet. You may need to read it again.

What FINGOLIS is used for

FINGOLIS contains the active substance fingolimod, which belongs to a group of medicines known as sphingosine 1-phosphate (S1-P) receptor modulators. FINGOLIS can alter the way the body's immune system works and is used to treat relapsing remitting multiple sclerosis (MS) and relapses in patients with secondary progressive 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.

This medicine slows down the progression of physical disability and decreases the number of flare-ups (relapses) in patients with relapsing MS. Fingolimod helps to fight against attacks on myelin by the immune system by affecting the ability of some white blood cells to move freely within the body and by stopping the cells that cause inflammation from reaching the brain. This reduces nerve damage caused by MS. Fingolimod 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 FINGOLIS works or why this medicine has been prescribed for you. This medicine is only available with a doctor's prescription. It is not addictive.

There is not enough information to recommend this medicine for children or adolescents under 18 years of age. Experience with FINGOLIS in older people (more than 65 years old) is limited. Talk to your doctor if you have any concerns.

Before you take FINGOLIS

When you must not take it:

Do not take FINGOLIS if 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).
  • 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).

Do not take FINGOLIS if you are allergic to fingolimod (the active ingredient)or to any of the other ingredients listed at the end of this leaflet.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In these cases, return it to your pharmacist.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, dyes or preservatives. Your doctor will want to know if you are prone to allergies.

Tell your doctor if you are pregnant, think you might be pregnant soon, or are trying to become pregnant. You should avoid becoming pregnant while taking FINGOLIS or in the two months after you stop taking it because FINGOLIS may harm your unborn baby.

If you become pregnant while taking FINGOLIS, 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 FINGOLIS. FINGOLIS can pass into breast milk and there is a risk of serious side effects for a breast-fed baby.

Checking the health of your heart is important. Tell your doctor if any of the following applies to you:

  • 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 may decide not to use FINGOLIS or may refer you first to a cardiologist for further advice before commencing your first dose of FINGOLIS.

Your doctor may decide not to use FINGOLIS. However, if your doctor thinks that FINGOLIS is appropriate for you, he/she may refer you first to a cardiologist (doctor specialised in heart disease). You may also be monitored overnight by a health care professional after taking the first dose of FINGOLIS.

Tell your doctor before taking FINGOLIS if the following applies to you:

  • no history of previous chickenpox infection or no record of vaccination against chickenpox. 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 FINGOLIS treatment one month after the full course of the vaccination is completed.
  • 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.
  • an infection. Any infection that you already have may get worse. Infections could be serious and sometimes life threatening. Before you start taking FINGOLIS, your doctor will confirm whether you have enough white blood cells in your blood.
  • problems with your liver. You will have a blood test to check your liver function before you start taking FINGOLIS. It may affect your liver function.

Tell your doctor 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

Your doctor may want you to have an eye examination before you start treatment and at regular intervals afterwards.

Tell your doctor if you 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 FINGOLIS (see "Taking other medicines").

A skin examination is recommended before you start treatment and at regular intervals during treatment. Your doctor will decide what to do if skin problems are noticed.

If you are not sure whether any of the above conditions apply to you, your doctor can advise you.

Taking other medicines

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

Some medicines may interfere with this medicine. Tell your doctor if you are taking any of the following:

  • medicines for an irregular or abnormal heartbeat such as quinidine, procainamide, amiodarone or sotalol. Your doctor may decide not to use FINGOLIS if you take these medicines due to a possible added effect on irregular heartbeat
  • 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 FINGOLIS 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 FINGOLIS
  • 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 betainterferon, 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 FINGOLIS, 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 FINGOLIS. Your doctor and pharmacist can provide you with more information.

If you have not told your doctor about any of these things, tell him/ her before you start taking this medicine.

How to take FINGOLIS

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

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

First dose precaution

Because FINGOLIS may have a short term effect on your heart rate when you take the first dose, you will be required to have the health of your heart checked:

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

You will need to stay at the doctor's office or clinic for 6 hours after taking the first dose of FINGOLIS 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 FINGOLIS will also apply for your second dose.

At the beginning of treatment, FINGOLIS 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.

FINGOLIS 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

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

Do not exceed the recommended dose.

How to take it

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

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it. It does not matter if you take this medicine before or after food.

How long to take it

Continue taking 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 FINGOLIS unless your doctor tells you to. FINGOLIS 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. The initial effect on your heart rate may occur again if you stop taking FINGOLIS for 1 day or more during your first month of FINGOLIS treatment, or if you stop taking FINGOLIS for more than 2 weeks after your first month of FINGOLIS treatment.

If you restart FINGOLIS 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.

If you forget to take it

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 that you missed.

If you have been taking FINGOLIS for less than 2 weeks and you forget to take a dose for one day, call your doctor right away. 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 take too much (overdose) or if you have taken a first dose by mistake

Immediately telephone your doctor or Poisons Information Centre (telephone number: 13 11 26), or go to Accident and Emergency at your nearest hospital if you think that you or anyone else may have accidentally taken too much FINGOLIS or taken a first dose of FINGOLIS by mistake. Do this even if there are no signs of discomfort or poisoning. Keep the telephone numbers for these places handy. You may need urgent medical attention. 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.

While you are taking FINGOLIS

Things you must do:

You should avoid becoming pregnant while taking FINGOLIS or in the two months after you stop taking it because FINGOLIS 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.

If you become pregnant while taking this medicine, tell your doctor immediately. FINGOLIS should not be taken if you are pregnant.

Tell your doctor about 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.

FINGOLIS may cause swelling of a small area at the back of the eye (macular oedema). 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).

Tell your doctor straight away if you think you have an infection, have fever, or feel like you have the flu. FINGOLIS lowers the white blood cell count because it prevents certain white blood cells from moving freely in your body (particularly the lymphocyte count). White blood cells fight infection. You may get infections more easily while you are taking FINGOLIS (and for up to 2 months after you stop taking it). Any infection that you already have may get worse. Infections could be serious and sometimes life-threatening.

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.

Skin cancers have been reported in MS patients treated with FINGOLIS. 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 FINGOLIS.

Limit your exposure to the sun and UV rays by wearing appropriate clothing and regularly applying sunscreen. This will help minimise your risk of developing skin cancers.

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

  • If you believe your MS is getting worse (e.g. weakness or visual change) or if you notice any new or unusual symptoms, talk to your doctor as soon as possible, because these may be the symptoms of a rare brain disorder caused by infection and called progressive multifocal leukoencephalopathy (PML).
  • 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. These may be symptoms of meningitis.
  • Sudden onset of severe headache, confusion, seizures and vision changes. These may be symptoms of a condition called posterior reversible encephalopathy syndrome (PRES) that has been rarely reported in MS patients treated with FINGOLIS.
  • External red, purple, pink or brown skin lesions on your skin or in your mouth. A type of very rare cancer related to infection with human herpes virus 8 called Kaposi’s sarcoma may develop.

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.

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

Tell any other doctor, dentist or pharmacist who treats you that you are taking FINGOLIS.

Things you must 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 (see "Taking other medicines").

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.

Things to be careful of :

Your doctor will tell you whether your illness allows you to drive vehicles and use machines safely. FINGOLIS is not expected to have an influence on your ability to drive and use machines.

Side Effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking FINGOLIS even if you do not think it is connected with the medicine.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by these lists of possible side effects. You may not experience any of them.

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

Tell your doctor if you notice any of the following side effects and they worry you:

  • infection from flu virus with symptoms such as tiredness, chills, sore throat, joint or muscles aching, fever
  • feeling of pressure or pain in the cheeks and forehead (sinusitis)
  • headache
  • diarrhoea
  • back pain
  • cough.

The above side effects are very common and non-serious. If any of these affects you severely, tell your doctor.

Tell your doctor if you observe any of the following side effects (common and usually not serious) and they affect you severely:

  • ringworm, a fungal infection affecting the skin (tinea versicolour)
  • dizziness
  • severe headache often together with nausea, vomiting and sensitivity to light (signs of migraine)
  • weakness
  • itchy, red, burning rash (eczema)
  • itchy skin
  • breathlessness
  • abnormal lung function test results starting after one month of treatment, remaining stable after that and reversible after treatment discontinuation.
  • blurred vision (see also information on macular oedema below)
  • nausea
  • muscle pain
  • joint pain

Tell your doctor straight away if you notice any of the following:

  • coughing with phlegm, chest pain or fever. These may be symptoms of bronchitis.
  • blisters, burning, itching or pain of the skin, typically on the upper body or face. These may be symptoms of shingles or herpes zoster virus. Other symptoms may be fever and weakness in the early stages of infection, followed by numbness, itching, and red patches with severe pain.
  • fever, cough, difficulty breathing, tiredness, aching joints and muscles which are signs of infections. While you are taking FINGOLIS (and for up to 2 months after you stop taking it), you may get infections more easily. Any infection that you already have may get worse. Infections could be serious and life-threatening.
  • slow heartbeat (bradycardia)
  • fever, cough, difficulty breathing which may be symptoms of pneumonia.
  • 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)
  • moles which may change size, shape, elevation or colour over time, or new moles. The moles may itch, bleed or ulcerate. These may be symptoms of melanoma, a type of skin cancer usually developing from an unusual mole (naevus).
  • convulsion, fits
  • bleeding or bruising more easily than normal. This may be due to low level of platelets (thrombocytopenia)

These side effects can be serious.

Tell your doctor immediately or go to Accident and Emergency if you notice any of the following:

  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing sudden onset of rash or hives
  • yellowing of your skin or the whites of your eyes, abnormally dark urine, unexplained nausea, vomiting and tiredness. Your doctor may carry out blood tests to check your liver function and may consider stopping FINGOLIS treatment if your liver problem is serious
  • sudden onset of severe headache, confusion, seizures and/or vision changes, which are symptoms of a condition called posterior reversible encephalopathy (PRES).
  • an infection, fever, feel like you have the flu, or have a headache accompanied by stiff neck, sensitivity to light, nausea, and/or confusion which are symptoms of a condition called cryptococcal infections (a type of fungal infection), including cryptococcal meningitis.
  • 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.

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

  • hypertension (FINGOLIS may cause a mild increase in blood pressure)
  • higher levels of liver enzymes
  • increased level of blood fat (triglycerides)
  • low level of white blood cells (lymphopenia, leucopenia).

Tell your doctor if you notice anything else that is making you feel unwell. Some people may have other side effects not yet known or mentioned in this leaflet.

After taking FINGOLIS

Storage

  • Keep your medicine in the original container until it is time to take it.
  • Store it in a cool dry place where the temperature stays below 25°C.
  • Do not store FINGOLIS or any other medicine in the bathroom or near a sink.
  • Do not leave it in the car or on window sills.

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

Disposal

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

Product description

What it looks like

FINGOLIS hard capsules are white to off white powder in hard gelatin capsules. Capsules comprise a white opaque body imprinted in black ink with ‘MF’ and white opaque cap imprinted in black ink with ‘0.5mg’.

FINGOLIS are available in packs of 7, 28 and 84. Not all pack sizes may be marketed in Australia.

Ingredients

Each FINGOLIS capsule contains 0.56 mg of fingolimod hydrochloride (equivalent to 0.5 mg of fingolimod) as the active ingredient. The capsule also contains the following inactive ingredients: pregelatinized maize starch, fumaric acid, stearic acid, titanium dioxide, black ink (TekPrint SW-9008) and gelatin.

Sponsor

FINGOLIS is sponsored in Australia by:

Cipla Australia Pty Ltd
Level-1, 132-136 Albert Road, South Melbourne, VIC 3205
www.cipla.com
[email protected]
03 9696 4413

AUSTR 302761

This leaflet was revised in January 2019.

Published by MIMS August 2023

BRAND INFORMATION

Brand name

Fingolis

Active ingredient

Fingolimod

Schedule

S4

 

1 Name of Medicine

Fingolimod.

2 Qualitative and Quantitative Composition

Each fingolimod capsule contains 0.56 mg fingolimod hydrochloride (equivalent to 0.5 mg fingolimod).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White to off white powder in size 3 hard gelatin capsules. Capsules comprise a white opaque body imprinted in black ink with 'MF' and white opaque cap imprinted in black ink with '0.5 mg'.

4 Clinical Particulars

4.1 Therapeutic Indications

Fingolis is indicated for the treatment of relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis with superimposed relapses to delay the progression of physical disability and reduce the frequency of relapse.

4.2 Dose and Method of Administration

The recommended dose of fingolimod is one 0.5 mg capsule taken orally once daily, which 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 fingolimod 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).

Switching patients from other disease modifying therapies.

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

Children.

Fingolimod is not indicated for use in paediatric patients (see Section 5 Pharmacological Properties).

The elderly (≥ 65 years).

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

Patients with renal impairment.

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

Patients with hepatic impairment.

No fingolimod dose adjustments are needed in patients with mild or moderate hepatic impairment. Fingolimod 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 fingolimod dose adjustments based on ethnic origin are needed (see Section 5 Pharmacological Properties).

Gender.

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

Diabetic patients.

Fingolimod 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 (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker.
Baseline QTc interval ≥ 500 ms.
Concomitant treatment with Class Ia or Class III anti-arrhythmic drugs during fingolimod initiation.
See Section 4.4 Special Warnings and Precautions for Use for further information.
Further, fingolimod 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.

Fingolimod 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). Fingolimod may therefore increase the risk of infections, including opportunistic infections, some serious in nature. Before initiating treatment with fingolimod (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.
Anti-neoplastic, immune-modulating or immunosuppressive therapies (including corticosteroids) should be co-administered 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 fingolimod to report symptoms of infections to a physician. Suspension of treatment with fingolimod 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 post-marketing 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 post-marketing 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 cases 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, fingolimod treatment should be suspended until PML has been excluded. Early diagnosis and stopping therapy are important factors in management of PML in patients on fingolimod. 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 fingolimod. 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 fingolimod 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 fingolimod (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 fingolimod 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 fingolimod therapy. A full course of VZV vaccination of antibody-negative patients should be considered prior to commencing treatment with fingolimod, following which initiation of treatment with fingolimod should be postponed for 1 month to allow full effect of vaccination to occur.
For paediatric patients, please also see Paediatric use.

Macular oedema.

Macular oedema can occur with or without visual symptoms. An ophthalmologic evaluation should be performed before starting fingolimod 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). Fingolimod 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 fingolimod therapy and should have regular follow-up ophthalmologic evaluations.
If patients report visual disturbances at any time while on fingolimod therapy, evaluation of the fundus, including the macula, should be carried out.
Continuation of fingolimod in patients with macular oedema has not been evaluated. A decision on whether or not fingolimod therapy should be discontinued needs to take into account the potential benefits and risks for the individual patient.

Bradyarrhythmia.

Initiation of fingolimod 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 5.1 Pharmacodynamic Properties, Pharmacodynamics, Heart rate and rhythm). In patients receiving fingolimod 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 fingolimod treatment has been associated with atrio-ventricular conduction delays, usually as first-degree atrio-ventricular blocks (prolonged PR interval on electrocardiogram). Second-degree atrio-ventricular blocks, usually Mobitz type I (Wenckebach) have been observed in less than 0.5% of patients receiving fingolimod 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 AV block have been reported during post-marketing use of fingolimod (see Section 4.8 Adverse Effects (Undesirable Effects)).

First dose monitoring.

Therefore on initiation of fingolimod 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 post-dose 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 fingolimod.
Additional observation until the finding has resolved is also required:
if the heart rate at 6 hours post-dose is < 45 bpm 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 AV block.
If the ECG at 6 hours after the first dose shows a QTc interval > 470 msec (females) or > 450 msec (males) the patient should be monitored overnight in a medical facility.
Due to the risk of serious cardiac rhythm disturbances, fingolimod 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 fingolimod treatment results in decreased heart rate and therefore a prolongation of the QT interval, fingolimod 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)). Fingolimod 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, fingolimod should not be used in these patients. In patients for whom fingolimod 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.
Fingolimod has not been studied in patients with arrhythmias requiring treatment with Class Ia (e.g. quinidine, procainamide) or Class III anti-arrhythmic drugs (e.g. amiodarone, sotalol). Class Ia and Class III anti-arrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of fingolimod treatment results in decreased heart rate, fingolimod must not be used concomitantly with these drugs during fingolimod initiation (see Section 4.3 Contraindications).
Experience with fingolimod 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 fingolimod 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 fingolimod initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment with fingolimod should generally not be initiated in patients who are concurrently treated with these substances. If treatment with fingolimod 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 fingolimod therapy is discontinued for more than 2 weeks after the first month of treatment the effects on heart rate and atrio-ventricular conduction may recur on reintroduction of fingolimod 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 fingolimod. During clinical trials, 3-fold or greater elevation in liver transaminases occurred in 8.5% of patients treated with fingolimod 0.5 mg and drug was discontinued if the elevation exceeded 5-fold increase. Recurrence of liver transaminase elevations occurred upon re-challenge 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 fingolimod.
Clinically significant liver injury has been reported in patients treated with fingolimod in the postmarket 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 fingolimod. Patients should be monitored periodically while on treatment and until two months after fingolimod 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 fingolimod 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 fingolimod, caution in the use of fingolimod should be exercised in patients with a history of significant liver disease.
Fingolimod 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 post-marketing 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, fingolimod 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 fingolimod, 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.

Fingolimod 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 fingolimod.
A careful case-by-case assessment regarding the timing of the initiation of fingolimod treatment is recommended.
Elimination of natalizumab usually takes up to 2-3 months following discontinuation.
In MS patients the teriflunomide median t1/2z 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 terifluomide product information.

Alemtuzumab.

Due to the characteristics and duration of alemtuzumab immune suppressive effects described in its product information, initiating treatment with fingolimod after alemtuzumab is not recommended unless the benefits of fingolimod 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 fingolimod (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 fingolimod. Healthcare professionals and patients are advised to monitor for suspicious skin lesions before initiating treatment and regularly during treatment with fingolimod. 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 fingolimod discontinuation.

Cases of severe exacerbation of disease have been reported after stopping fingolimod in the post-marketing setting. This was generally observed within 12 weeks after stopping fingolimod, but was also reported up to and beyond 24 weeks after fingolimod discontinuation. Therefore, caution is indicated when stopping fingolimod therapy. If discontinuation of fingolimod 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 fingolimod 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 fingolimod, 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 fingolimod may lead to an additive effect on the immune system and therefore caution should be applied.
Also see section above: Return of disease activity (rebound) after fingolimod discontinuation.

Use in hepatic impairment.

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 fingolimod, caution in the use of fingolimod should be exercised in patients with a history of significant liver disease.

Use in the elderly.

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

Paediatric use.

Safety and efficacy of fingolimod in paediatric patients below the age of 18 have not been studied. Fingolimod is not indicated for use in paediatric patients.

Effects on laboratory tests.

Since fingolimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient treated with fingolimod.
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.

Anti-neoplastic, immunosuppressive or immune modulating therapies (including corticosteroids) should be co-administered 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 fingolimod 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 fingolimod 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 fingolimod vaccination may be less effective. The use of live attenuated vaccines may carry the risk of infection and should also therefore be avoided during fingolimod treatment and for up to 2 months after treatment with fingolimod (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 co-medications and/or biologics transported by the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1, OATP1B3) or the sodium taurocholate co-transporting polypeptide (NTCP). Similarly, they are not expected to inhibit the efflux of co-medications 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 co-administration 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 co-administration 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 fingolimod 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 co-administered 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 co-administration of the latter two drugs with fingolimod.

Carbamazepine.

The co-administration 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 very limited data from the use of fingolimod in pregnant women. The use of fingolimod in women who are or may become pregnant should only be considered if the potential benefit justifies the potential risk to the foetus.
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 post-implantation 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.
Before initiation of fingolimod treatment, women of childbearing potential should be counselled on the potential for serious risk to the foetus and the need for effective contraception during treatment with fingolimod and for at least 2 months following discontinuation of therapy, as it will take approximately 2 months to eliminate the compound from the body upon stopping treatment.
 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 fingolimod on the breastfed child or the effects of fingolimod 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 fingolimod 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)

The safety population of fingolimod 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 fingolimod (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 edema and transient atrio-ventricular 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 fingolimod 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 (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); 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 fingolimod 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. Co-administration 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 fingolimod in the post-marketing setting (see Section 4.4 Special Warnings and Precautions for Use).
Cases of opportunistic infections, have been reported in the post-marketing 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 fingolimod 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 re-challenge 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).
Fingolimod 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 fingolimod 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 fingolimod treatment results in a transient decrease in heart rate and may also be associated with atrio-ventricular conduction delays (see Section 4.4 Special Warnings and Precautions for Use).
In multiple sclerosis clinical trials the mean maximal decrease in heart rate after the first dose intake was seen 4 - 5 hours post-dose, with declines in mean heart rate, as measured by pulse, of 8 beats per minute for fingolimod 0.5 mg. The second dose may result in a slight further decrease. Heart rates below 40 beats per minute were rarely observed in patients on fingolimod 0.5 mg. Heart rate returned to baseline within 1 month of chronic dosing.
In the multiple sclerosis clinical program first-degree atrio-ventricular block (prolonged PR interval on electrocardiogram) was detected following drug initiation in 4.7% of patients on fingolimod 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 fingolimod 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 atrio-ventricular block.

Blood pressure.

In multiple sclerosis clinical trials fingolimod 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 fingolimod 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 fingolimod (see Section 4.4 Special Warnings and Precautions for Use). In multiple sclerosis clinical trials, 8.5% and 1.9% of patients treated with fingolimod 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 fingolimod within approximately 2 months. In a small number of patients, 10 patients on fingolimod 1.25 mg and 2 patients on fingolimod 0.5 mg, who experienced liver transaminase elevations ≥ 5 x ULN and who continued on fingolimod 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 fingolimod 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 fingolimod, 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 fingolimod 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 post-marketing 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.

Post-marketing experience.

See Table 2.

Bradyarrhythmia.

Isolated events of transient, spontaneously resolving complete AV block have been observed during the six hour observation period following the first dose of fingolimod. 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 fingolimod is uncertain.

Reporting suspected adverse effects.

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

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 5.1 Pharmacodynamic 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 AV 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 fingolimod 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 atrio-ventricular 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 post-dose, 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 fingolimod has been demonstrated in two studies which evaluated once daily doses of fingolimod 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.
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 fingolimod 0.5 mg (n=425) or fingolimod 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 fingolimod 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 fingolimod 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 microgram, 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 fingolimod 0.5 mg (n=431) or 1.25 mg (n=426) or interferon beta-1a 30 microgram 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 fingolimod than in patients who received interferon beta-1a IM. There was no significant difference between the fingolimod 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 fingolimod than in patients who received interferon beta-1a IM. There was no significant difference in the time to 3-month confirmed disability progression between fingolimod 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.

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 fingolimod 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 CYP 4F2 and possibly other CYP4F isoenzymes and subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive non-polar 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 post dose 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.

Pharmacokinetics in special patient groups.

Pharmacokinetics in children.

Safety and efficacy of fingolimod in paediatric patients below the age of 18 have not been studied. Fingolimod is not indicated for use in paediatric patients.

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 fingolimod 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 or 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

Pregelatinized maize starch, fumaric acid, stearic acid, titanium dioxide, black ink (TekPrint SW-9008), gelatin.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25 degrees Celsius.

6.5 Nature and Contents of Container

PVC/ACLAR or Alu/Alu 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

Fingolimod hydrochloride is a white to off white crystalline powder which is freely soluble in water. Fingolimod is a base with pKa of 6.70. 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.

Chemical structure.

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

CAS number.

162359-56-0.

7 Medicine Schedule (Poisons Standard)

Poison Schedule: S4.

Summary Table of Changes