Active ingredients: Fingolimod
GILENYA 0.5 mg hard capsules
Indications Why is Gilenya used? What is it for?
What is Gilenya
The active ingredient in Gilenya is fingolimod.
What Gilenya is for
Gilenya is used in adults for the treatment of relapsing-remitting multiple sclerosis (MS), particularly in:
Patients who have not responded to therapy with MS treatment.
or
Patients with rapidly evolving severe MS.
Gilenya does not cure MS, but it helps reduce the number of relapses and slow the progression of physical disability caused by MS.
What is multiple sclerosis
MS is a chronic disease that affects the central nervous system (CNS), which includes the brain and spinal cord. In MS, inflammation destroys the protective sheath (called myelin) that lines the nerves in the CNS and prevents the nerves from functioning as they should. This process is called demyelination.
Relapsing-remitting MS is characterized by relapsing attacks (relapses) of neurological symptoms that reflect an inflammatory state of the central nervous system. Symptoms vary from patient to patient, but usually involve difficulty walking, numbness, vision or balance disturbances. The symptoms of a relapse may disappear completely when the relapse is over, but some complaints may persist.
How Gilenya works
Gilenya helps protect the nervous system from immune system attacks by reducing the ability of some white blood cells (lymphocytes) to circulate freely within the body and preventing them from reaching the brain and spinal cord. This limits the nerve damage caused. from the MS.
Contraindications When Gilenya should not be used
Do not take Gilenya
- if you have a reduced immune response (due to an immunodeficiency syndrome, a disease or medicines that depress the immune system).
- if you have a severe ongoing infection or a chronic ongoing infection such as hepatitis or tuberculosis.
- if you have active cancer (except if it is a type of skin cancer called basal cell skin cancer).
- if you have severe liver problems.
- if you are allergic to fingolimod or any of the other ingredients of this medicine.
If any of these apply to you, tell your doctor before taking Gilenya.
Precautions for use What you need to know before taking Gilenya
Talk to your doctor before taking Gilenya:
- if you have an irregular, abnormal heartbeat.
- if you experience symptoms of low heart rate (e.g. dizziness, nausea or palpitations).
- if you have any heart problems, blockage of the blood vessels in your heart, have had a heart attack or cardiac arrest in the past, or have angina.
- if you have had a stroke in the past.
- if you suffer from heart failure.
- if you have severe breathing problems while sleeping (severe sleep apnea).
- if you have been told that you have an abnormal EKG.
- if you are taking or have recently taken medicines for irregular heartbeat such as quinidine, disopyramide, amiodarone or sotalol.
- if you are taking or have recently taken medicines that slow the heartbeat (such as beta blockers, verapamil, diltiazem or ivabradine, digoxin, anticholinesterase drugs or pilocarpine).
- if you have ever had episodes of sudden loss of consciousness or fainting (syncope).
- if you intend to get vaccinated.
- if you have never had chickenpox.
- if you have or have had visual disturbances or other signs of swelling in the central vision area (macula) at the back of the eye (a condition known as macular edema, see below), if you have or have had an "inflammation or" infection of the eye (uveitis), or if you have diabetes (which can cause eye problems).
- if you have liver problems.
- if you have high blood pressure which cannot be controlled by medicines.
- if you have severe lung problems or if you have a cough from smoking.
If any of these apply to you, tell your doctor before taking Gilenya.
Slow heartbeat (bradycardia) and irregular heartbeat: At the start of treatment, Gilenya causes a slowing of the heart rate. As a result you may experience dizziness or tiredness, awareness of your heartbeat or a drop in blood pressure. If these effects are pronounced, contact your doctor, as you may need immediate treatment. Gilenya can also cause an irregular heartbeat, especially after the first dose. Irregular heartbeat usually returns to normal in less than a day. Slow heart rate usually returns. back to normal within a month.
Your doctor will ask you to stay in the clinic or hospital for at least 6 hours after administering the first dose of Gilenya, during which your pulse and blood pressure will be measured at any time: in this way, appropriate measures can be taken in case of side effects that occur at the start of treatment. You must have an electrocardiogram available before the first dose of Gilenya and at the end of the 6 hours of monitoring. Your doctor may check your electrocardiogram continuously during this period. If after 6 hours hours your heart rate is very low or decreases, or if your EKG shows abnormalities, you may need to be observed for a longer period (at least another 2 hours and possibly until the next morning), until these problems are resolved.The same can happen if she takes G again ilenya after an interruption of treatment, depending on how long the interruption was and how long you have been taking Gilenya before the interruption.
If you have or are at risk of having an irregular or abnormal heartbeat, if your EKG is abnormal, or if you have heart disease or heart failure, Gilenya may not be suitable for you.
If you have ever had episodes of sudden loss of consciousness or a reduced heart rate, Gilenya may not be suitable for you. You will be seen by a cardiologist (heart specialist) who will advise you on how to start your treatment with Gilenya, including monitoring until the next morning.
If you are taking medicines that can cause a decrease in heart rate, Gilenya may not be suitable for you. You will be seen by a cardiologist who will assess whether you can take medicines that do not decrease your heart rate as an alternative, allowing you to start treatment with Gilenya. If this change in therapy is not possible, your cardiologist will advise you on how to start treatment with Gilenya, including monitoring until the next morning.
If you have never had chickenpox: If you have never had chickenpox, your doctor will check your immunity against the virus that causes it (varicella zoster virus). If you are not protected against the virus, you may need a vaccination before starting treatment with Gilenya. If this occurs, your doctor will postpone the start of Gilenya treatment for up to one month after completing the full vaccination course.
Infections: Gilenya reduces the number of white blood cells (especially lymphocytes). White blood cells fight infections. While taking Gilenya (and up to 2 months after stopping treatment), you may get infections more easily. Any existing infection could get worse. Infections can be serious and life-threatening. If you think you have an infection, if you have fever, if you have flu symptoms, or if you have a headache accompanied by stiff neck, sensitivity to light, nausea and / or confusion (these can be symptoms of meningitis), contact your doctor right away. .
Macular edema: Before starting treatment with Gilenya, if you have or have had visual disturbances or other signs of swelling in the central vision area (macula) at the back of the eye, if you have or have had an "inflammation or" infection eye (uveitis) or if you have diabetes, your doctor may ask you to have an eye examination.
Your doctor may ask you to have an eye examination 3-4 months after starting treatment with Gilenya.
The macula is a small area of the retina located in the back of the eye that allows you to see shapes, colors and details clearly and sharply. Gilenya can cause swelling of the macula, a condition that is known as macular edema. The swelling occurs. usually in the first 4 months of treatment with Gilenya.
Macular edema is more likely to occur if you have diabetes or have had an "inflammation of the eye" called uveitis. In these cases, your doctor will want to check you regularly for the first signs of macular edema.
If you have suffered from macular edema, talk to your doctor before restarting treatment with Gilenya.
Macular edema can cause some of the visual symptoms (optic neuritis) that also occur during MS attacks. In the initial stage there may be no symptoms. Be sure to tell your doctor about any vision changes. Your doctor may ask you to refer to them. undergo an eye examination, especially if:
- the central viewing area is out of focus or has shadows;
- a blind spot develops in the central vision area;
- have trouble distinguishing colors or fine details.
Liver function tests: If you have severe liver problems, you should not take Gilenya. Treatment with Gilenya can affect your liver function. You will likely not notice any symptoms, but if you notice yellowing of your skin or whites of your eyes, abnormal dark urine or unexplained nausea and vomiting, tell your doctor immediately.
If you get any of these symptoms after starting Gilenya treatment, please tell your doctor immediately.
During the first twelve months of treatment, your doctor will ask you to have blood tests to check your liver function. If the results indicate that there is a liver problem, treatment with Gilenya may need to be stopped.
High pressure
Because Gilenya causes a slight increase in blood pressure, your doctor may have your blood pressure checked regularly. Lung problems Gilenya has a weak effect on lung function. In patients with severe lung problems or cough from smoking, side effects may occur more easily.
Blood count The desired effect of treatment with Gilenya is to reduce the amount of white blood cells in the blood. These usually return to normal within 2 months of stopping treatment. If you need to have blood tests, please tell your doctor you are taking Gilenya.
Before starting treatment with Gilenya, your doctor will confirm if your white blood cell count is sufficient, and may ask you to repeat the count regularly. If you do not have enough white blood cells, you may need to stop taking Gilenya.
Posterior reversible encephalopathy syndrome (PRES)
A syndrome called posterior reversible encephalopathy (PRES) has been reported rarely in patients with multiple sclerosis treated with Gilenya. Symptoms can include sudden onset of severe headache, confusion, seizures, and changes in vision. Tell your doctor if any of these symptoms occur during treatment with Gilenya.
Use in the elderly
Experience with Gilenya in elderly patients over the age of 65 is limited. If you have any further questions, ask your doctor.
Children and adolescents
Gilenya is not intended for use in children and adolescents under 18 years of age as it has not been studied in MS patients under the age of 18.
Interactions Which drugs or foods can change the effect of Gilenya
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Tell your doctor if you are taking any of the following medications:
- Medicines that suppress or modify the immune system, including other medicines used to treat MS, such as interferon beta, glatiramer acetate, natalizumab, mitoxantrone, teriflunomide, dimethyl fumarate or alemtuzumab. You should not use Gilenya with these medicines as they may intensify the effect on the immune system (see also "Do not take Gilenya").
- Corticosteroids, due to the possible additive effect on the immune system.
- Vaccines. If you need to have a vaccination, ask your doctor for advice first. During and up to 2 months after treatment with Gilenya, you should not receive some types of vaccines (live attenuated vaccines) as they may trigger the infection they were supposed to prevent. Other vaccines may not work as well as usual if given at this time. .
- Medicines that slow the heartbeat (such as beta-blockers, such as atenolol). Concomitant use of Gilenya with these medicines could intensify the effect on heart rate in the first days of Gilenya treatment.
- Medicines for irregular heartbeat, such as quinidine, disopyramide, amiodarone or sotalol. Your doctor may decide not to prescribe Gilenya if you are taking these types of medicines as they may intensify the effect on irregular heartbeat.
- Other Medicines:
- protease inhibitors, anti-infectives such as ketoconazole, azole antifungals, clarithromycin or telithromycin.
- carbamazepine, rifampicin, phenobarbital, phenytoin, efavirenz or St. John's wort (potential risk of reduced efficacy).
Warnings It is important to know that:
Pregnancy and breastfeeding
Before starting treatment with Gilenya, your doctor may ask you to have a pregnancy test to make sure you are not pregnant. While taking Gilenya or for two months after stopping treatment, you should avoid becoming pregnant as there is a risk of harm to the baby. Talk to your doctor about reliable methods of contraception to use during treatment. with Gilenya and for 2 months after stopping treatment.
If you become pregnant while taking Gilenya, stop the treatment and tell your doctor immediately. Your doctor will decide with you what is best for you and your baby.
Do not breast-feed while taking Gilenya. Gilenya is excreted in breast milk with the risk of serious side effects for the newborn.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Your doctor will tell you if your illness allows you to drive and use machines safely. Gilenya is not expected to affect the ability to drive and use machines.
However, at the start of treatment you will need to stay in your doctor's office or hospital for 6 hours after taking the first dose of Gilenya. The ability to drive and use machines may be impaired during this time and potentially beyond.
Dosage and method of use How to use Gilenya: Dosage
Treatment with Gilenya will be supervised by a doctor experienced in the treatment of multiple sclerosis.
Always take this medicine exactly as your doctor has told you.
If in doubt, consult your doctor. The dose is one capsule once a day. Take Gilenya once a day with a glass of water. Gilenya can be taken with or without food.
Taking Gilenya at the same time each day will help you remember when to take the medicine.
Do not exceed the recommended dose.
Your doctor can switch you directly from treatment with interferon beta, glatiramer acetate or dimethyl fumarate to Gilenya if there are no signs of abnormalities caused by previous treatment. Your doctor may have you do a blood test to rule out these abnormalities. After stopping natalizumab it may be necessary to wait 2-3 months before starting treatment with Gilenya. For switching from teriflunomide, your doctor may advise you to wait for a certain amount of time or to proceed with an accelerated elimination procedure. If you have been treated with alemtuzumab, careful evaluation and discussion with your doctor is required to decide whether Gilenya is suitable for you.
If you are unsure of how long you will be taking Gilenya, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Gilenya
If you take more Gilenya than you should
If you have taken too many Gilenya capsules, tell your doctor immediately.
If you forget to take Gilenya
If you have been taking Gilenya for less than 1 month and forget to take 1 dose for a full day, talk to your doctor before taking the next dose. Your doctor may decide to observe you when you take your next dose.
If you have been taking Gilenya for at least 1 month and have forgotten to take your medicine for more than 2 weeks, talk to your doctor before taking your next dose. Your doctor may decide to observe you when you take your next dose.However, if you have forgotten to take your medicine for 2 weeks or less, you can take your next dose as planned.
Never take a double dose to make up for a forgotten dose.
If you stop taking Gilenya
Do not stop taking Gilenya or change your dose without first contacting your doctor.
Gilenya will remain in the body for up to 2 months after stopping treatment. The number of white blood cells (lymphocytes) may remain low during this time and the side effects described in this leaflet may still occur. After stopping Gilenya treatment it may be necessary to wait 6-8 weeks before starting a new treatment for multiple sclerosis.
If you need to restart Gilenya after more than 2 weeks of stopping treatment, the effect on heart rate that normally occurs at the start of treatment may occur again. hospital under observation Do not restart Gilenya after stopping it for more than two weeks without consulting your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist
Side Effects What are the side effects of Gilenya
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Some side effects can be or become serious
Common (may affect up to 1 in 10 people):
- Cough with phlegm, chest discomfort, fever (signs of lung disorders)
- Herpes virus infection (St. Anthony's fire or herpes zoster), with symptoms such as blistering, burning, itching, or pain in the skin, usually in the upper body or on the face. Other symptoms may be fever and weakness in the early stages. infection, followed by numbness, itching, or red spots with severe pain
- Slow heartbeat (bradycardia), irregular heart rhythm
Uncommon (may affect up to 1 in 100 people):
- Pneumonia with symptoms such as fever, cough, difficulty breathing
- Macular edema (swelling in the central vision area of the retina at the back of the eye) with symptoms such as shadows or blind spots in the center of vision, blurred vision, problems distinguishing colors or details
Rare (may affect up to 1 in 1000 people):
- A syndrome called posterior reversible encephalopathy. Symptoms may include sudden onset of severe headache, confusion, seizures and / or visual disturbances
Isolated cases:
- Cryptococcal infections (a type of fungal infection), including cryptococcal meningitis with symptoms such as headache accompanied by neck stiffness, sensitivity to light, nausea and / or confusion.
If you get any of these side effects, tell your doctor right away.
Other side effects
Very common (may affect more than 1 in 10 people):
- Influenza virus infection with symptoms such as fatigue, chills, sore throat, joint or muscle pain, fever
- Feeling of pressure or pain in the cheeks and forehead (sinusitis)
- Headache
- Diarrhea
- Back pain
- Blood tests showing higher levels of liver enzymes
- Cough
Common (may affect up to 1 in 10 people):
- Ringworm, a "fungal infection of the skin (pityriasis versicolor)
- Dizziness
- Severe headache often accompanied by nausea, vomiting and sensitivity to light (migraine)
- Low levels of white blood cells (lymphocytes, leukocytes)
- Weakness
- Skin rash with itching, redness and burning (eczema)
- Itching
- Increased levels of fats (triglycerides) in the blood
- Hair loss
- Wheezing
- Depression
- Blurred vision (see also section on "macular edema" Some side effects may be or become serious ")
- Hypertension (Gilenya may cause a slight increase in blood pressure)
Uncommon (may affect up to 1 in 100 people):
- Low levels of some white blood cells (neutrophils)
- Depressed mood
Rare (may affect up to 1 in 1000 people):
- Blood vessel disorders
- Disorders of the nervous system
- Cancer of the lymphatic system (lymphoma)
Not known (frequency cannot be estimated from the available data):
- Allergic reaction and skin rash
If any of these side effects occur severely, please tell your doctor.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after "EXP" / "EXP". The expiry date refers to the last day of that month.
Do not store above 25ºC.
Store in the original package to protect the medicine from moisture.
Do not use packages that are damaged or show signs of tampering.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Gilenya contains
- The active ingredient is fingolimod. Each capsule contains 0.5 mg of fingolimod (as hydrochloride).
- The other ingredients are: Capsule contents: magnesium stearate, mannitol Capsule shell: yellow iron oxide (E172), titanium dioxide (E171), gelatin Ink: lacquer (E904), dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol , purified water, concentrated ammonia solution, potassium hydroxide, black iron oxide (E172), yellow iron oxide (E172), titanium dioxide (E171), dimethicone
Description of what Gilenya looks like and contents of the pack
Gilenya 0.5 mg hard capsules have an opaque white opaque body and a deep yellow opaque cap. The black writing "FTY0,5mg" is engraved on the head and two yellow bands are engraved on the body.
Gilenya is available in packs containing 7, 28 or 98 capsules, or in multipacks containing 84 capsules (3 packs of 28 capsules). Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
GILENYA 0.5 MG HARD CAPSULES
▼ Medicinal product subject to additional monitoring. This will allow the rapid identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 0.5 mg of fingolimod (as hydrochloride).
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsule.
16 mm capsule with intense yellow opaque cap and white opaque body; black "FTY0.5 mg" engraving on the head and two yellow circular bands engraved on the body.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Gilenya is indicated on its own, as a disease-modifying drug, in highly active relapsing-remitting multiple sclerosis in the following adult patient groups:
- Patients with high disease activity despite treatment with at least one therapy disease modifying (see sections 4.4 and 5.1 for exceptions and information on washout).
These patients can be defined as those who have not responded to a complete and adequate course of therapy (usually at least one year of treatment) with at least one therapy disease modifying. Patients must have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2 hyperintense lesions on brain MRI or at least 1 gadolinium-enhancing lesion. One patient non-responder it can also be defined as a patient who has an unchanged or increased relapse rate compared to the previous year or who has severe relapses.
or
- Patients with rapidly evolving severe relapsing-remitting multiple sclerosis, defined by two or more disabling relapses in a year, and with 1 or more gadolinium-enhancing lesions on brain MRI or with a significant increase in T2 lesion load compared to a previous MRI recently carried out.
04.2 Posology and method of administration
Treatment should be initiated and supervised by a physician experienced in multiple sclerosis.
Dosage
The recommended dose of Gilenya is one 0.5 mg capsule taken orally once a day. Gilenya can be taken both during and away from meals.
It is recommended to perform the same monitoring as at the start of treatment after the first dose if treatment is stopped for:
• 1 or more days during the first two weeks of treatment
• more than 7 days during the third and fourth week of treatment
• more than 2 weeks after one month of treatment.
If the interruption of treatment is of shorter duration than described above, treatment should continue with the administration of the next dose as planned (see section 4.4).
Special populations
Senior citizens
Gilenya should be used with caution in patients 65 years of age and older as there are insufficient data on safety and efficacy available (see section 5.2).
Impaired renal function
In the main pivotal studies conducted in multiple sclerosis, Gilenya has not been studied in patients with impaired renal function. Based on clinical pharmacology studies, no dose adjustment is required in patients with mild to severe renal impairment.
Impaired liver function
Gilenya must not be used in patients with severe hepatic impairment (Child-Pugh class C) (see section 4.3). Although no dose adjustment is required in patients with mild or moderate hepatic impairment, caution is recommended when initiating treatment in these patients (see sections 4.4 and 5.2).
Diabetic patients
Gilenya has not been studied in patients with multiple sclerosis and diabetes mellitus. Gilenya should be used with caution in these patients due to a possible increased risk of macular edema (see sections 4.4 and 4.8). These patients should undergo regular ophthalmological examinations for signs of macular edema.
Pediatric population
The safety and efficacy of Gilenya in children aged 0-18 years have not yet been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.
04.3 Contraindications
- Diagnosed immunodeficiency syndrome.
- Patients who have an increased risk of opportunistic infections, including immunocompromised patients (including those treated with concomitant immunosuppressive therapies or those immunocompromised by previous therapies).
- Severe active infections, chronic active infections (hepatitis, tuberculosis).
- Diagnosed active malignant tumors, with the exception of patients with basal cell skin cancer.
- Severe hepatic impairment (Child-Pugh class C).
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Bradyarrhythmia
Initiation of Gilenya treatment results in a transient decrease in heart rate and may also be associated with delays in atrioventricular conduction, including isolated episodes of complete, transient and spontaneously resolving atrioventricular block (see sections 4.8 and 5.1).
After the administration of the first dose, the decrease in heart rate begins within one hour and is maximal within the first 6 hours. In the following days this post-dose effect persists, although generally of lesser intensity, and usually decreases over the following weeks. . With continued administration, the mean heart rate returns to baseline within one month. However, in particular patients, heart rate may not return to baseline by the end of the first month. Conduction abnormalities have usually been transient and asymptomatic. generally required no treatment and resolved within the first 24 hours of starting treatment. If necessary, the decrease in heart rate induced by fingolimod can be reversed by parenteral administration of doses of atropine or isoprenaline.
All patients should have an electrocardiogram and blood pressure measurement before the first dose of Gilenya and after 6 hours. All patients should be monitored for 6 hours for signs and symptoms of bradycardia, with hourly heart rate and blood pressure measurement. Continuous (real-time) ECG monitoring is recommended during these 6 hours. .
If symptoms of bradyarrhythmia occur after administration, appropriate clinical patient management procedures should be initiated and monitoring continued until symptoms have resolved. Should a patient require pharmacological intervention during monitoring after the first dose, monitoring should be done until the next morning in a hospital setting and should be repeated after the second dose of Gilenya.
If, at the end of 6 hours, the heart rate value is the lowest after the first dose (suggesting that the maximum pharmacodynamic effect on the heart may not yet be manifest), monitoring should be continued for at least 2 hours and until the heart rate increases again. Additional monitoring is also required (at least until the next morning and in any case until the symptoms are resolved) if, after 6 hours from the administration of the first dose, the heart rate is beats per minute , or if the electrocardiogram shows new onset second degree or higher atrioventricular block, or if the QTc interval is ≥500 msec. The onset of third degree atrioventricular block at any time must also lead to an extension of the monitoring (at least until the following morning).
Due to the risk of severe rhythm disturbances, Gilenya should not be used in patients with second degree Mobitz type II or higher atrioventricular block, in patients with sick sinus syndrome or sino-atrial block, history of symptomatic bradycardia or recurrent syncope, or in patients with significant QT prolongation (QTc> 470 msec (women) or> 450 msec (men)). Since significant bradycardia may be poorly tolerated in patients with known ischemic heart disease (including angina pectoris), cerebrovascular disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, uncontrolled hypertension or severe sleep apnea, Gilenya should not be used in these patients. Treatment with Gilenya should only be considered in these patients if the expected benefits outweigh the potential risks; if it is decided to start therapy with Gilenya, a cardiologist should be consulted before starting treatment to define the most appropriate monitoring. Monitoring is recommended at least until the next morning for the initiation of treatment (see also section 4.5).
Gilenya has not been studied in patients with arrhythmias requiring treatment with class Ia (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol) antiarrhythmics.Class Ia and class III antiarrhythmics have been associated with cases of torsades de pointes in patients with bradycardia. As the initiation of treatment with Gilenya results in a decrease in heart rate, Gilenya should not be used concomitantly with these medicines.
Experience with Gilenya in patients on concomitant treatment with beta-blockers, calcium channel blockers that cause a decrease in heart rate (such as verapamil, diltiazem or ivabradine), or with other drugs that may decrease heart rate (eg digoxin, anticholinesterase drugs or pilocarpine) is limited. Since initiation of Gilenya treatment is also associated with decreased heart rate (see also section 4.8 Bradyarrhythmia), concomitant use of these drugs at initiation of Gilenya treatment may be associated with severe bradycardia and heart block. Due to the potential additive effects on heart rate, treatment with Gilenya should not be initiated in patients receiving these drugs (see also section 4.5). In these patients, treatment with Gilenya should only be considered if the expected benefits outweigh the potential risks. If therapy with Gilenya is considered, it is recommended that a cardiologist be consulted before starting treatment to consider switching to other medicinal products that do not cause a decrease in heart rate. If it is not possible to stop treatment with these drugs, a cardiologist should be consulted to define adequate monitoring at the start of treatment. Monitoring at least until the next morning is recommended (see also section 4.5).
Depending on the duration of the interruption and the duration of treatment (time between the start of treatment and its discontinuation), the effects on heart rate and atrioventricular conduction may recur when treatment with Gilenya is restarted. It is recommended to perform the same monitoring as at the start of treatment after the first dose if treatment is stopped for:
• 1 or more days during the first two weeks of treatment
• more than 7 days during the third and fourth week of treatment
• more than 2 weeks after one month of treatment.
If the interruption of treatment is of shorter duration than described above, treatment should continue with the administration of the next dose as planned.
QT interval
In a thorough QT interval study conducted with fingolimod doses of 1.25 mg or 2.5 mg, at steady state (when the negative chronotropic effect of fingolimod was still present), treatment with fingolimod induced prolongation of the dose. corrected QT interval (QTc), with the upper limit of 90% confidence interval ≤ 13.0 ms. No dose-response or exposure-response correlation was observed between fingolimod and QTc interval prolongation. , neither as an absolute value nor as a change from baseline.
The clinical significance of these findings is unknown. No clinically significant prolongation of the QT interval was observed in studies in patients with multiple sclerosis, but patients at risk of developing QT interval prolongation were not included in clinical trials.
Medicines that can prolong the QTc interval should be avoided in patients with significant risk factors, such as hypokalaemia or congenital prolongation of the QT interval.
Infections
A relevant pharmacodynamic effect of Gilenya is the dose-dependent reduction in peripheral lymphocyte counts to 20-30% of baseline values. This is due to the reversible sequestration of lymphocytes in lymphoid tissues (see section 5.1).
A recent complete blood count (ie taken within 6 months before or after stopping previous therapy) should be available prior to initiation of treatment with Gilenya. It is also recommended during treatment to evaluate blood counts periodically after 3 months and at least annually thereafter, and in case of onset of signs of infection. An absolute lymphocyte count of less than 0.2x109 / l, if confirmed, should lead to discontinuation. treatment until return to normal, as fingolimod was discontinued in clinical trials in patients with absolute lymphocyte counts below 0.2x109 / l.
The initiation of treatment with Gilenya should be postponed in patients with ongoing severe infections until recovery.
Patients should be evaluated for their immunity status for chickenpox before starting treatment with Gilenya. In the absence of a physician-confirmed history of chickenpox or evidence of a complete varicella vaccination course, it is recommended that patients be tested for antibodies to varicella-zoster virus (VZV) before starting Gilenya therapy. For patients with a negative antibody titre, a complete vaccination course against varicella is recommended before starting treatment with Gilenya (see section 4.8). The initiation of treatment with Gilenya should be postponed by 1 month for the vaccination to be fully effective.
The effects of Gilenya on the immune system may increase the risk of infections (see section 4.8). Effective diagnostic and therapeutic strategies should be implemented in patients treated with Gilenya who present with symptoms of infections. Patients should be instructed to report symptoms of infection to their physician during treatment with Gilenya.
If a severe infection develops in a patient, discontinuation of Gilenya therapy should be considered and the benefit-risk balance should be assessed before resuming treatment.
Elimination of fingolimod after discontinuation of therapy may take up to two months and therefore infection control should be persisted during this period. Patients should be instructed to report symptoms of infection within two months of stopping fingolimod.
Macular edema
Macular edema with or without visual disturbances has been reported in 0.5% of patients treated with 0.5 mg fingolimod, mainly in the first 3-4 months of therapy (see section 4.8). An ophthalmological evaluation is therefore recommended 3-4 months after the start of treatment. If patients report visual disturbances at any time during treatment, a fundus examination, including the macula, should be performed.
Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of developing macular edema (see section 4.8). Gilenya has not been studied in patients with multiple sclerosis and concomitant diabetes mellitus. It is recommended that patients with multiple sclerosis and concomitant diabetes mellitus or with a history of uveitis undergo an ophthalmological evaluation before starting therapy and follow-up checks during treatment.
Continuation of Gilenya treatment in patients with macular edema has not been studied. It is recommended that Gilenya treatment be discontinued if macular edema occurs in a patient. In deciding whether or not Gilenya therapy should be resumed after healing, the potential benefits and risks for the individual patient should be considered.
Liver function
Elevations of liver enzymes, particularly alanine aminotransferase (ALT) but also gamma glutamyltranspeptidase (GGT) and aspartate transaminase (AST) have been reported in patients with multiple sclerosis treated with Gilenya. In clinical trials, ALT elevations ≥3 times the upper limit of normal range (ULN) occurred in 8.0% of patients treated with fingolimod 0.5 mg compared with 1.9% of patients treated with placebo. . Increases of 5 times the upper limit of normal range occurred in 1.8% of patients treated with fingolimod and in 0.9% of patients treated with placebo. In clinical trials, treatment with fingolimod was discontinued if the increase was> 5 times the upper limit of the normal range. In some patients re-treatment after discontinuation, hepatic transaminase elevations reoccurred, confirming a relationship between this increase and the drug. In clinical studies, elevations in hepatic transaminases occurred at any time during treatment, although most occurred in the first 12 months. Blood transaminase levels returned to normal approximately 2 months after discontinuation of fingolimod.
Gilenya has not been studied in patients with pre-existing severe hepatic impairment (Child-Pugh class C) and therefore should not be used in these patients (see section 4.3).
Due to the immunosuppressive properties of fingolimod, initiation of treatment should be delayed in patients with ongoing active viral hepatitis until resolution of the active phase.
Recent analyzes (ie within the previous 6 months) of transaminase and bilirubin levels should be available prior to initiation of treatment with Gilenya. In the absence of clinical symptoms, liver transaminase levels should be checked after 1, 3, 6, 9 and 12 months of treatment and periodically thereafter. If hepatic transaminase levels reach values greater than 5 times the limit of normal (ULN), more frequent checks should be arranged, including checks of serum bilirubin and alkaline phosphatase ( ALP) If after repeated checks the liver transaminase values remain more than 5 times the limit of normal (ULN), treatment with Gilenya should be stopped and restarted only when the liver transaminase values have returned to normal.
In patients presenting with symptoms of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice and / or dark urine, liver enzyme levels should be evaluated; if significant hepatic injury is confirmed (e.g. hepatic transaminase levels exceeding the upper limit of the normal range by more than 5 times and / or increases in serum bilirubin levels), treatment with Gilenya should be discontinued. Resumption of therapy will depend on whether or not another cause of liver damage is identified and the patient's benefit in resuming therapy versus the risk of liver dysfunction recurring.
Although there are no data to establish that patients with pre-existing liver disease have an increased risk of developing elevated liver function tests, caution should be exercised when administering Gilenya to patients with a history of significant liver disease.
Interference with serological assays
As fingolimod reduces blood lymphocyte counts by redistribution to secondary lymphoid organs, it cannot be used to assess the lymphocyte status of a patient treated with Gilenya. Laboratory tests involving the use of circulating mononuclear cells require higher blood volumes due to the reduction in the number of circulating lymphocytes.
Effects on blood pressure
Patients with non-drug controlled hypertension were excluded from clinical trials conducted prior to marketing of Gilenya; therefore, special attention is recommended if patients with uncontrolled hypertension are treated with Gilenya.
In clinical studies in patients with multiple sclerosis, treatment with fingolimod 0.5 mg was associated with a mean increase of approximately 3 mmHg in systolic blood pressure and approximately 1 mmHg of diastolic blood pressure: these increases occurred approximately 1 month later. treatment initiation and persisted with continued treatment. In a two-year placebo-controlled study, hypertension was reported as an adverse event in 6.5% of patients treated with Gilenya 0.5 mg and in 3.3% of patients treated with placebo. Therefore your blood pressure should be checked regularly during treatment with Gilenya.
Effects on the respiratory system
Slight dose-dependent decreases in forced expiratory volume (FEV1) and diffusion capacity for carbon monoxide (Dlco) were observed during treatment with Gilenya, decreases that occurred in the first month and remained stable over the course of the treatment. Gilenya should be used with caution in patients with severe respiratory disorders, pulmonary fibrosis and chronic obstructive pulmonary disease (see section 4.8).
Posterior reversible encephalopathy syndrome
Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in clinical trials and post-marketing experience with the 0.5 mg dose (see section 4.8). Symptoms reported included sudden onset of severe headache, nausea, vomiting, altered mental status, visual disturbances and seizures. Symptoms of PRES are usually reversible but can progress to ischemic stroke or cerebral haemorrhage. Delay in diagnosis and treatment can lead to permanent neurological consequences. If presence is suspected. of PRES, treatment with Gilenya should be discontinued.
Previous treatment with immunosuppressive or immunomodulatory therapies
No studies have been performed to evaluate the efficacy and safety of Gilenya when patients switch from teriflunomide, dimethyl fumarate or alemtuzumab to Gilenya. When patients switch from another therapy. disease modifying in Gilenya, the half-life and mechanism of action of the other therapy must be taken into account to avoid an additive effect on the immune system and, at the same time, minimize the risk of reactivation of the disease. It is recommended to evaluate a complete blood count before starting treatment with Gilenya to ensure that the effects on the immune system induced by previous therapy (e.g. cytopenia) have resolved.
Treatment with Gilenya can generally be started immediately after discontinuation of interferon or glatiramer acetate therapy.
In the case of dimethyl fumarate, the period of washout it must be sufficient to restore adequate blood counts before starting treatment with Gilenya.
Due to natalizumab's long half-life, elimination generally takes up to 2-3 months after stopping treatment. Teriflumonide is also slowly eliminated from plasma. Without an accelerated elimination procedure, clearance of teriflunomide from plasma can take from several months to 2 years. It is recommended to perform an accelerated elimination procedure as described in the summary of product characteristics for teriflunomide, or alternatively the washout period should not be less than 3.5 months. Caution should be exercised when switching patients from natalizumab or teriflunomide therapy to Gilenya regarding potential concomitant effects on the immune system.
Alemtuzumab has intense and prolonged immunosuppressive effects. As the true duration of these effects is unknown, it is recommended not to initiate treatment with Gilenya following alemtuzumab unless the benefits of treatment for the individual patient clearly outweigh the risks.
The decision to co-administer prolonged corticosteroid treatments must be made after careful consideration.
Concomitant administration with potent CYP450 inducers
Fingolimod should be used with caution in combination with potent CYP450 inducers. It is recommended not to administer St. John's wort concomitantly (see section 4.5).
Discontinuation of therapy
Based on the half-life of the drug, if a decision is made to discontinue treatment with Gilenya, an interval of 6 weeks without therapy should be left to allow fingolimod to be cleared from the blood (see section 5.2). The lymphocyte count progressively returns to normal values within 1-2 months after discontinuation of therapy (see section 5.1). Starting other therapies during this time interval results in concomitant exposure to fingolimod. The use of immunosuppressive drugs soon after the discontinuation of Gilenya administration may have an additional effect on the immune system and therefore caution is recommended.
04.5 Interactions with other medicinal products and other forms of interaction
Antineoplastic, immunomodulatory or immunosuppressive therapies
Antineoplastic, immunomodulatory or immunosuppressive therapies should not be administered concomitantly due to the risk of additive effects on the immune system (see sections 4.3 and 4.4).
Caution should also be exercised when patients initiate Gilenya therapy after discontinuing treatment with long-acting therapies with effects on the immune system, such as natalizumab or mitoxantrone (see section 4.4). In clinical trials in sclerosis. Multiple concomitant relapse treatment with a short course of corticosteroids was not associated with an increased rate of infections.
Vaccinations
Vaccinations may be less effective during treatment and up to two months after stopping treatment with Gilenya. The use of live attenuated vaccines may pose a risk of infections and should therefore be avoided (see sections 4.4 and 4.8).
Substances that induce bradycardia
Fingolimod was studied in combination with atenolol and diltiazem.When fingolimod was administered with atenolol in an interaction study in healthy volunteers, an additional 15% reduction in heart rate occurred upon initiation of treatment; this effect was not observed with diltiazem. Due to the potential additive effect. heart rate, Gilenya treatment should not be initiated in patients taking beta-blockers or other drugs that may decrease heart rate, such as class Ia and III antiarrhythmics, calcium channel blockers (such as ivabradine, verapamil or diltiazem), digoxin, anticholinesterases or pilocarpine (see sections 4.4 and 4.8). If treatment with Gilenya is considered for these patients, a cardiologist should be consulted to consider switching to other medicinal products that do not cause decreased heart rate or to define adequate monitoring at the start of treatment. If it is not possible to stop treatment with drugs that decrease heart rate, monitoring is recommended at least until the next morning.
Changes in the pharmacokinetics of fingolimod induced by other substances
Fingolimod is mainly metabolised by CYP4F2. Other enzymes such as CYP3A4 may also be involved in its metabolization, particularly in the case of potent induction of CYP3A4. Potent carrier protein inhibitors are not expected to affect the behavior of fingolimod. Co-administration of fingolimod with ketoconazole resulted in a 1.7-fold increase in exposure (AUC) to fingolimod and fingolimod phosphate via inhibition of CYP4F2. Caution should be exercised when administering fingolimod with substances that may inhibit CYP3A4 ( protease inhibitors, azole antifungals, some macrolides such as clarithromycin or telithromycin).
Concomitant administration of carbamazepine 600 mg twice daily, reached steady state, and a single dose of fingolimod 2 mg reduced the AUC of fingolimod and its metabolite by approximately 40%. Other potent inducers of the CYP3A4 enzyme, such as rifampicin, phenobarbital, phenytoin, efavirenz and St. John's wort, can induce a reduction in the AUC of fingolimod and its metabolite by at least this magnitude. As this could potentially compromise their efficacy, caution should be exercised when administering in combination. Concomitant administration with St John's wort is however not recommended (see section 4.4).
Changes in the pharmacology of other substances induced by fingolimod
Fingolimod is unlikely to interact with substances metabolised primarily by CYP450 enzymes or substrates of major carrier proteins.
Co-administration of fingolimod with cyclosporine did not result in any change in exposure to cyclosporine or fingolimod. Therefore, fingolimod is not expected to alter the pharmacokinetics of medicinal products that are substrates of CYP3A4.
Co-administration of fingolimod with oral contraceptives (ethinyl estradiol and levonorgestrel) did not result in any change in oral contraceptive exposure. exposure to such drugs.
04.6 Pregnancy and lactation
Women of childbearing potential / Contraception in women
Before initiating treatment with Gilenya, women of childbearing potential should be informed of the possible serious risks to the fetus and of the need to use effective contraceptive measures during treatment with Gilenya. Since it takes approximately two months after stopping treatment to clear fingolimod from the body (see section 4.4), the potential risk to the fetus may exist and therefore contraceptive measures must continue during that time.
Pregnancy
A negative pregnancy test must be available before starting treatment in women of childbearing potential. Women should not become pregnant during treatment and effective contraception is recommended. If a woman becomes pregnant while taking Gilenya, discontinuation of treatment is recommended.
Animal studies have shown reproductive toxicity, including fetal loss and organ defects, particularly persistent arterial trunk and ventricular septal defect (see section 5.3). The receptor on which fingolimod acts (sphingosine 1-phosphate ) is involved in vascular formation during embryogenesis. There are very limited data from the use of fingolimod in pregnant women.
There are no data on the effects of fingolimod on labor and delivery.
Feeding time
Fingolimod is excreted in the milk of lactating animals at concentrations 2-3 times higher than those found in the mother's plasma (see section 5.3). Due to the potential for serious adverse reactions to fingolimod in breastfed infants, women in treatment with Gilenya should not breastfeed.
Fertility
Data from preclinical studies do not indicate that fingolimod is associated with an increased risk of impaired fertility (see section 5.3).
04.7 Effects on ability to drive and use machines
Gilenya has no or negligible influence on the ability to drive or use machines.
However, sometimes dizziness or somnolence may occur upon initiation of treatment with Gilenya. It is recommended that patients be observed for 6 hours when initiating treatment with Gilenya (see section 4.4 Bradyarrhythmia).
04.8 Undesirable effects
Summary of the safety profile
The safety population of Gilenya is derived from two phase III placebo-controlled clinical trials and one active-controlled phase III clinical trial conducted in patients with relapsing-remitting multiple sclerosis. It includes a total of 2,431 patients treated with Gilenya (0.5 or 1.25 mg). In the 2-year placebo-controlled clinical study D2301 (FREEDOMS), 854 patients (placebo: 418 patients) were treated with fingolimod. In the 2-year, placebo-controlled study D2309 (FREEDOMS II), 728 patients with multiple sclerosis (placebo: 355 patients) were treated with fingolimod. Pooled results from these two studies indicate that the most serious adverse reactions that occurred with Gilenya 0.5 mg were infections, macular edema and transient atrioventricular block at the start of treatment. The most frequent adverse reactions (incidence ≥ 10%) that occurred with Gilenya 0.5 mg were flu, sinusitis, headache, diarrhea, back pain, elevated liver enzymes and cough. The most frequent adverse reaction with Gilenya 0.5 mg leading to "discontinuation of treatment was" increased blood ALT levels (2.2%). In 1-year study D2302 (TRANSFORMS) involving 849 patients treated with fingolimod and using interferon beta-1α as a control , the adverse reactions that occurred were generally similar to those in the placebo-controlled studies, taking into account the different study duration.
Adverse reactions reported for Gilenya 0.5 mg in studies D2301 (FREEDOMS) and D2309 (FREEDOMS II) are listed below. Frequency categories are defined using the following convention: very common (≥1 / 10); common (≥1 / 100,
Summary table of adverse reactions
* Not reported in FREEDOMS, FREEDOMS II, and TRANSFORMS studies. Event frequency categorization was based on an estimated "fingolimod exposure of approximately 10,000 patients across all clinical trials."
Description of some specific adverse reactions
Infections
In clinical trials in patients with multiple sclerosis, the overall rate of infections (65.1%) reported with the 0.5 mg dose was similar to that seen with placebo. However, lower respiratory tract infections, mainly bronchitis and, to a lesser extent, herpetic infections and pneumonia, were more frequent in patients treated with Gilenya.
A few cases of disseminated herpetic infection, including fatal cases, have been reported even with the 0.5 mg dose.
Macular edema
In clinical studies in patients with multiple sclerosis macular edema occurred in 0.5% of patients treated with the recommended dose of 0.5 mg and in 1.1% of patients treated with the higher dose (1, 25 mg). Most cases occurred within the first 3-4 months of therapy. Some patients reported blurred vision and decreased visual acuity; others were asymptomatic and the diagnosis was made during a routine ophthalmological visit. Macular edema generally improved or resolved spontaneously after discontinuation of treatment. The risk of recurrence after re-exposure to treatment has not been studied.
The incidence of macular edema is increased in multiple sclerosis patients with a history of uveitis (17% with a history of uveitis vs. 0.6% without a history of uveitis). Gilenya has not been studied in patients with multiple sclerosis and diabetes mellitus. a disease associated with an increased risk of macular edema (see section 4.4). In clinical studies in renal transplant patients including patients with diabetes mellitus, treatment with fingolimod 2.5 mg and 5 mg resulted in increased twice the incidence of macular edema.
Bradyarrhythmia
Initiation of treatment with Gilenya results in a transient decrease in heart rate and may also be associated with delays in atrioventricular conduction. In clinical trials in patients with multiple sclerosis, the maximum decrease in heart rate was observed within the first 6 hours after surgery. "initiation of treatment, with decreases in frequency by an average of 12-13 beats per minute during treatment with Gilenya 0.5 mg. A decrease in heart rate below 40 beats per minute has been observed rarely in patients treated with Gilenya 0.5 mg. Mean heart rate returned to baseline within 1 month of continued treatment. Bradycardia was generally asymptomatic, but some patients experienced mild to moderate symptoms, including hypotension, dizziness, fatigue and / or palpitations, which resolved within the first 24 hours after initiation of treatment (see also sections 4.4 and 5.1. ).
In clinical studies in patients with multiple sclerosis, first degree atrioventricular block (prolongation of the PR interval to ECG) was observed in 4.7% of patients treated with fingolimod 0.5 mg, in 2.8% of patients. patients treated with intramuscular interferon beta-1α and in 1.6% of patients treated with placebo. Second degree atrioventricular block has been reported in less than 0.2% of patients treated with Gilenya 0.5 mg. In post-marketing experience, isolated episodes of transient, spontaneously resolving complete atrio-ventricular block have been reported during 6 hours of monitoring after the first dose of Gilenya. post-marketing experience, were usually transient, asymptomatic, and resolved within the first 24 hours of starting treatment. Although no medical intervention was required for most patients, one patient being treated with Gilenya 0, 5 mg was given isoprenaline following an asymptomatic second-degree Mobitz type 1 atrioventricular block.
In post-marketing experience, isolated events with late onset, including transient asystole and unexplained death, occurred within 24 hours following the administration of the first dose. Evaluation of these cases is complicated by the presence of concomitant medications and / or pre-existing conditions The correlation of these events with Gilenya is uncertain.
Blood pressure
In clinical studies in patients with multiple sclerosis, treatment with Gilenya 0.5 mg was associated with an average increase in systolic blood pressure of approximately 3 mmHg and diastolic blood pressure of approximately 1 mmHg: these increases occurred approximately 1 month later. treatment initiation and were maintained with continued treatment. Hypertension was reported in 6.5% of patients treated with fingolimod 0.5 mg and in 3.3% of patients treated with placebo. cases of hypertension which may require treatment with antihypertensive drugs or discontinuation of Gilenya have been reported within the first month and on the first day of treatment (see also section 4.4 Effects on blood pressure).
Liver function
Elevations of liver enzymes have been reported in patients with multiple sclerosis treated with Gilenya. In clinical studies, asymptomatic elevation of blood ALT levels ≥3 times and ≥5 times the upper limit of normal range (ULN) was observed in 8.0% and 1.8% of patients treated with Gilenya, respectively. 0.5 mg. In some patients re-treatment after discontinuation, hepatic transaminase elevations reoccurred, confirming a relationship between this increase and the drug. In clinical trials elevations in hepatic transaminases occurred at any time during treatment, although most occurred in the first 12 months. ALT levels returned to normal approximately 2 months after stopping treatment with Gilenya. In a small number of patients (N = 10 at the 1.25 mg dose, N = 2 at the 0.5 mg dose), who experienced ALT elevations ≥5 times the upper limit of normal range and who continued therapy with Gilenya, ALT values returned to normal within approximately 5 months (see also section 4.4 Hepatic function).
Nervous system disorders
In clinical studies, rare events involving the nervous system, including ischemic and haemorrhagic stroke and atypical neurological disorders, such as eg events similar to acute disseminated encephalomyelitis (EAD).
Vascular pathologies
Rare cases of peripheral arterial disease have occurred in patients treated with fingolimod at the higher doses (1.25 mg).
Respiratory System
Slight dose-dependent decreases in forced expiratory volume (FEV1) and diffusion capacity for carbon monoxide (Dlco) were observed during treatment with Gilenya, decreases that occurred in the first month and remained stable over the course of the treatment. At month 24, the percentage reduction from baseline in predicted FEV1 was 2.7% for fingolimod 0.5 mg and 1.2% for placebo, a difference that resolved after treatment was stopped. the Dlco reductions at month 24 were 3.3% for fingolimod 0.5 mg and 2.7% for placebo.
Lymphomas
Cases of various types of lymphoma have been reported in both clinical trials and post-marketing experience, including one fatal case of Epstein-Barr virus (EBV) positive B-cell lymphoma. The incidence of lymphoma cases (B-cell and T-cell) was higher in clinical studies than expected in the general population.
Hemophagocytic syndrome
Very rare cases of haemophagocytic syndrome have been reported (Haemophagocytic syndrome, HPS) with fatal outcome in patients treated with fingolimod in the context of an "infection." HPS is a rare condition that has been described in association with infections, immunosuppression and a variety of autoimmune diseases.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. in "Annex V.
04.9 Overdose
Single doses up to 80 times the recommended dose (0.5 mg) were well tolerated in healthy volunteers. At the 40 mg dose, 5 of the 6 subjects reported weak chest tightness or malaise clinically related to airway reactivity.
Fingolimod can induce bradycardia at the start of treatment. The decrease in heart rate usually occurs within one hour of the first dose and is maximal within the first 6 hours. The negative chronotropic effect of Gilenya persists beyond 6 hours and progressively subsides over the subsequent days of treatment (see section 4.4 for further details). There have been reports of atrioventricular conduction slowing, with isolated reports of atrioventricular block. complete, transient and spontaneous resolution (see sections 4.4 and 4.8).
If the overdose coincides with the first exposure to Gilenya, it is important to have the patient continuously (real-time) electrocardiographic monitoring with hourly heart rate and blood pressure measurements, at least during the first 6 hours (see section 4.4).
Additional monitoring is also required (at least until the next morning and in any case until the symptoms are resolved) if, after 6 hours from the administration of the first dose, the heart rate is
Fingolimod is not eliminated by either dialysis or plasmapheresis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: selective immunosuppressants.
ATC code: L04AA27.
Mechanism of action
Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator. By means of the sphingosine kinase fingolimod is transformed into the active metabolite fingolimod phosphate which binds, at low nanomolar concentrations, to the S1P1 receptor located on the lymphocyte surface, and easily crosses the blood-brain barrier to bind to the receptor in the central nervous system S1P1 placed on the cells of the central nervous system. Fingolimod phosphate, acting as a functional antagonist of S1P receptors expressed on lymphocytes, inhibits the ability of lymphocytes to escape from the lymph nodes, resulting in redistribution rather than destruction of the lymphocytes. This redistribution reduces the infiltration of pathogenic lymphocytes into the central nervous system, where they are involved in nerve inflammation and tissue damage. Animal studies and experiments in vitro indicate that fingolimod can also act by interacting with S1P receptors expressed on cells of the central nervous system.
Pharmacodynamic effects
Within 4-6 hours after the first administration of fingolimod 0.5 mg, the number of lymphocytes in the peripheral blood decreases to approximately 75% of the baseline value. Continuing with the daily administration, the number of lymphocytes continues to decrease for two weeks, reaching a minimum value of about 500 cells / microliter, or about 30% of the baseline value. 18% of patients reached a minimum value below 200 cells / microliter at least once. With continuous daily treatment, the number of lymphocytes remains low. Most T and B lymphocytes regularly migrate through the lymphoid organs: fingolimod acts mainly on these cells. About 15-20% of T lymphocytes have a TEM (memory effector) phenotype: these cells are important for peripheral immune surveillance. Since this type of lymphocytes generally do not migrate to the lymphoid organs, fingolimod does not act on these cells. The increase in the number of peripheral lymphocytes is evident in the days following the discontinuation of treatment with fingolimod; lymphocyte counts usually return to normal within one to two months. Chronic administration of fingolimod results in a slight decrease in the number of neutrophils equal to approximately 80% of the baseline value. Fingolimod does not act on monocytes.
Fingolimod causes a transient reduction in heart rate and decreased atrioventricular conduction upon initiation of treatment (see sections 4.4 and 4.8). 70% of the negative chronotropic effect. With subsequent administrations, the heart rate returns to baseline within one month. The reduction in heart rate induced by fingolimod can be reversed by parenteral administration of atropine or isoprenaline. Inhaled salmeterol has also been shown to have a modest positive chronotropic effect. When initiating treatment with fingolimod there is an increase in premature atrial contractions, but there is no increased rate of atrial fibrillation / flutter or ventricular arrhythmias or ectopia. Treatment with fingolimod does not result in decreased cardiac output, and does not affect sympathomimetic responses of the heart, including diurnal heart rate variation and response to exertion.
Treatment with fingolimod, single or repeated doses of 0.5 mg and 1.25 mg for two weeks, does not result in a perceptible increase in airway resistance measured as FEV1 and Forced Expiratory Flow (FEF) 25-75. However, with single doses of fingolimod ≥5 mg (10 times the recommended dose), a dose-dependent increase in airway resistance occurs. Treatment with repeated doses of fingolimod of 0.5 mg, 1.25 mg, or 5 mg does not result in impaired oxygenation or oxygen desaturation under exercise or an increase in airway response to methacholine. Subjects treated with fingolimod respond with normal bronchodilation to inhaled beta-agonists.
Clinical efficacy and safety
The efficacy of Gilenya was demonstrated in two studies evaluating the once daily administration of fingolimod 0.5 mg and 1.25 mg in patients with relapsing-remitting multiple sclerosis (RRMS). Both studies were enrolled patients who had had ≥ 2 relapses in the previous 2 years or ≥1 relapses in the previous year. The score on the Expanded Disability Status Scale (EDSS) was 0-5.5. A third study conducted in the same patient population was completed after Gilenya's registration.
In the 2-year, randomized double-blind controlled placebo-controlled study D2301 (FREEDOMS), 1272 patients were included (n = 425 treated with fingolimod 0.5 mg, 429 with fingolimod 1.25 mg, 418 with placebo). Median values of baseline characteristics were: age 37 years, disease duration 6.7 years, EDSS score of 2.0. The results are presented in Table 1. There were no significant differences between the 0.5 mg and 1.25 mg doses for all endpoints.
Table 1: Study D2301 (FREEDOMS): Main results
† Disability progression defined as 1-point increase in EDSS confirmed at 3 months
** p
All clinical endpoints were evaluated by analysis intent-to-treat. Analyzes related to MRI data used evaluable datasets.
Patients who had completed the phase core of the 24-month FREEDOMS study were able to enter the dose-blind extension phase (D2301E1) and receive fingolimod. A total of 920 patients entered (n = 331 continued at the 0.5 mg dose, 289 at the 1.25 mg dose, 155 switched from placebo to 0.5 mg and 145 from placebo to 1.25 mg). After 12 months (month 36), 856 patients (93%) were still enrolled. Between month 24 and month 36, the annualized relapse rate (ARR) for patients receiving fingolimod 0.5 mg in phase core of the study and who had continued at the same dose (0.5 mg) was 0.17 (0.21 in phase core of study). The annualized relapse rate for patients who switched from placebo to fingolimod 0.5 mg was 0.22 (0.42 in phase core of study).
Similar results were obtained in a Phase III, 2-year, randomized, double-blind placebo controlled study (D2309; FREEDOMS 2) conducted in 1,083 patients with relapsing-remitting multiple sclerosis (n = 358 treated with fingolimod 0 , 5 mg, 370 with fingolimod 1.25 mg, 355 with placebo). Median values of baseline characteristics were: age 41 years, disease duration 8.9 years, EDSS score of 2.5.
Table 2: Study D2309 (FREEDOMS 2): Main results
† Disability progression defined as 1-point increase in EDSS confirmed at 3 months
** p
All clinical endpoints were evaluated by analysis intent-to-treat. Analyzes related to MRI data used evaluable datasets.
In study D2302 (TRANSFORMS), phase III, lasting 1 year, randomized, double-blind controlled and double-dummy versus active drug (interferon beta-1α) 1280 patients were included (n = 429 treated with fingolimod 0.5 mg, 420 with fingolimod 1.25 mg, 431 with intramuscular injection of interferon beta-1α at a dose of 30 micrograms once per week). Median values of baseline characteristics were: age 36 years, disease duration 5.9 years, EDSS score of 2.0. The results of the study are presented in Table 3. There was no significant difference between the doses of 0.5 mg and 1.25 mg with respect to the study endpoints.
Table 3: Study D2302 (TRANSFORMS): Main results
† Disability progression defined as 1-point increase in EDSS confirmed at 3 months
** p
All clinical endpoints were evaluated by analysis intent-to-treat. Analyzes related to MRI data used evaluable datasets.
Patients who had completed the phase core of the 12-month TRANSFORMS study were able to enter the dose-blind extension phase (D2302E1) and receive fingolimod. A total of 1,030 patients entered, however 3 of these did not receive treatment (n = 356 continued at the 0.5 mg dose, 330 at the 1.25 mg dose, 167 switched from interferon beta-1α to 0, 5 mg and 174 from interferon beta-1α at 1.25 mg). After 12 months (month 24), 882 patients (86%) were still enrolled. Between months 12 and 24, the annualized relapse rate (ARR) for patients receiving fingolimod 0.5 mg in phase core of the study and who had continued at the same dose (0.5 mg) was 0.20 (0.19 in phase core of study). The annualized relapse rate for patients who switched from interferon beta-1α to fingolimod 0.5 mg was 0.33 (0.48 in phase core of study).
Pooled results from studies D2301 and D2302 showed a consistent and statistically significant reduction from control of the annualized relapse rate in subgroups defined by gender, age, previous MS therapy, disease activity or disability at baseline.
Further analysis of clinical trial results demonstrates significant treatment effects in subgroups of patients with highly active relapsing-remitting multiple sclerosis.
The European Medicines Agency has deferred the obligation to submit the results of studies with Gilenya in one or more subsets of the pediatric population in multiple sclerosis (see section 4.2 for information on pediatric use).
05.2 "Pharmacokinetic properties
Pharmacokinetic data were obtained in healthy volunteers, renal transplant patients and patients with multiple sclerosis.
The pharmacologically active metabolite responsible for efficacy is fingolimod phosphate.
Absorption
Absorption of fingolimod occurs slowly (Tmax of 12-16 hours) and is extensive (≥85%). The apparent absolute bioavailability following oral administration is 93% (confidence interval: 79-111%). Concentrations blood at steady-state are achieved within 1 to 2 months after administration of single daily doses of fingolimod and allo levels steady-state they are about 10 times higher than those seen with the starting dose.
Food intake does not change the peak concentration (Cmax) or systemic exposure (AUC) value of fingolimod. Fingolimod phosphate Cmax was slightly increased by 34% while AUC was unchanged. Therefore Gilenya can be taken either on a full or empty stomach (see section 4.2).
Distribution
Fingolimod distributes rapidly in red blood cells, and is present in 86% of blood cells. Fingolimod phosphate has a 17% lower distribution in red blood cells. Plasma protein binding of fingolimod and fingolimod phosphate is high (> 99%) .
Fingolimod is extensively distributed in tissues with a volume of distribution of approximately 1,200 ± 260 liters.
Biotransformation
In humans, fingolimod is metabolised by reversible stereoselective phosphorylation with formation of the pharmacologically active (S) -enantiomer of fingolimod phosphate. Fingolimod is eliminated by oxidative biotransformation, catalysed mainly by CYP4F2 and possibly other isoenzymes, and subsequent degradation to inactive metabolites, similar to that of fatty acids. Formation of pharmacologically inactive non-polar ceramide analogues of fingolimod was also observed. The major enzyme involved in the metabolism of fingolimod is partially identified and could be CYP4F2 or CYP3A4.
Following a single oral administration of fingolimod [14C], the major components related to fingolimod, detected in the blood by their contribution to AUC up to 34 days after administration of the total radiolabelled components, are fingolimod itself (23%), fingolimod phosphate (10%) and some inactive metabolites (M3 carboxylic acid metabolite (8%), M29 ceramide metabolite (9%) and M30 ceramide metabolite (7%)).
Elimination
Blood clearance of fingolimod is 6.3 ± 2.3 L / h and the mean terminal elimination half-life (t1 / 2) is 6-9 days. Blood levels of fingolimod and fingolimod phosphate decrease in parallel in the terminal phase , thus resulting in similar half-lives for both molecules.
After oral administration approximately 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod phosphate are not excreted unchanged in the urine but are present as major components in the faeces, with amounts each representing less than 2.5 % of dose. After 34 days the recovery of the administered dose is 89%.
Linearity
Concentrations of fingolimod and fingolimod phosphate increase in an apparently dose-proportional manner after repeated administration of single daily doses of 0.5 mg or 1.25 mg.
Characteristics in specific populations
The pharmacokinetics of fingolimod and fingolimod phosphate are not differentiated between males and females, in patients of different ethnic origins or in patients with mild to severe renal impairment.
In subjects with mild, moderate or severe hepatic impairment (Child-Pugh classes A, B and C) no change in fingolimod Cmax was observed, while fingolimod AUC increased by 12%, 44% and 103%. In patients with severe hepatic impairment (Child-Pugh class C), fingolimod phosphate Cmax was decreased by 22% and AUC was not substantially changed. The pharmacokinetics of fingolimod phosphate have not been evaluated in patients with mild to moderate hepatic impairment. The apparent elimination half-life of fingolimod was unchanged in subjects with mild hepatic impairment, while it was increased by approximately 50% in patients with moderate or severe hepatic impairment.
Fingolimod must not be used in patients with severe hepatic impairment (Child-Pugh class C) (see section 4.3). Fingolimod therapy should be initiated with caution in patients with mild and moderate hepatic impairment (see section 4.2).
Clinical experience and pharmacokinetic data in patients over 65 years of age are limited. Gilenya should be used with caution in patients aged 65 years and over (see section 4.2).
Pediatric population
Data from a kidney transplant study including 7 children over 11 years of age are limited (study FTY720A0115). Comparison of these data with those of healthy adult volunteers is of little relevance and no meaningful conclusions can be drawn regarding the pharmacokinetic properties of fingolimod in children.
05.3 Preclinical safety data
The preclinical safety profile of fingolimod was evaluated in mice, rats, dogs and monkeys.The main target organs were the lymphoid system (lymphopenia and lymphoid atrophy), the lungs (weight gain, smooth muscle hypertrophy at the bronchioloalveolar junction), and in various species the heart (negative chronotropic effect, increased blood pressure blood, perivascular changes and myocardial degeneration); in a 2-year study, fingolimod was active on blood vessels (vasculopathy) only in rats at doses of 0.15 mg / kg and above, equivalent to approximately 4 times the human systemic exposure (AUC) at a daily dose of 0. , 5 mg.
No evidence of carcinogenicity was observed in a 2-year study in rats with oral doses of fingolimod up to the maximum tolerated dose of 2.5 mg / kg, which represents a margin of approximately 50 times the human systemic exposure ( AUC) at a dose of 0.5 mg. However, in a 2-year study in mice, a higher incidence of malignant lymphoma was observed at doses of 0.25 mg / kg and higher, equivalent to approximately 6 times the human exposure. systemic (AUC) at a daily dose of 0.5 mg.
In animal studies, fingolimod was not found to be mutagenic or clastogenic.
Fingolimod had no effect on sperm count / motility or fertility of male and female rats up to the maximum tested dose (10 mg / kg), which represents a margin of approximately 150 times the human systemic exposure (AUC) at a daily dose of 0.5 mg.
Fingolimod was shown to be teratogenic in rats when administered at doses of 0.1 mg / kg or higher. The most common fetal visceral malformations include persistent arterial trunk and ventricular septal defect. The teratogenic potential in rabbits cannot be fully assessed, however increased embryo-fetal mortality was observed at doses of 1.5 mg / kg and above, and decreased viable fetuses as well as fetal growth retardation at doses of 5 mg / kg. kg.
In rats, the survival of the F1 generation of pups was decreased in the early post partum period at doses that did not cause maternal toxicity. However, the F1 generation was unaffected by fingolimod treatment with respect to body weight, development, behavior and fertility.
Fingolimod was excreted in the milk of treated lactating animals. Fingolimod and its metabolites crossed the placental barrier in pregnant rabbits.
Environmental Risk Assessment (Environmental Risk Assessment, WAS)
No environmental risk is anticipated from the use of Gilenya by patients with relapsing multiple sclerosis.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Capsule contents:
Magnesium stearate
Mannitol
Capsule shell:
Yellow iron oxide (E172)
Titanium dioxide (E171)
Jelly
Ink:
Lacquer (E904)
Dehydrated alcohol
Isopropyl alcohol
Butyl alcohol
Propylene glycol
Purified water
Concentrated ammonia solution
Potassium hydroxide
Black iron oxide (E172)
Yellow iron oxide (E172)
Titanium dioxide (E171)
Dimethicone
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Do not store above 25 ° C.
Store in the original package to protect the medicine from moisture.
06.5 Nature of the immediate packaging and contents of the package
Packs containing 7, 28 or 98 hard capsules or multipacks containing 84 (3 packs of 28) in PVC / PVDC / aluminum blisters.
Packs containing 7 x 1 hard capsules in PVC / PVDC / aluminum perforated unit dose blisters.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/11/677 / 001-006
040949012
040949024
040949036
040949048
040949051
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
17.03.2011
10.0 DATE OF REVISION OF THE TEXT
June 2014
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