GILENYA 0.25mg capsules medication leaflet

Gilenya 0.25 mg hard capsules

Gilenya 0.5 mg hard capsules

Gilenya 0.25 mg hard capsules

Each 0.25 mg capsule contains 0.25 mg fingolimod (as hydrochloride).

Gilenya 0.5 mg hard capsules

Each 0.5 mg capsule contains 0.5 mg fingolimod (as hydrochloride).

For the full list of excipients, see section 6.1.

Hard capsule

Gilenya 0.25 mg hard capsules

Capsule of 16 mm with ivory opaque cap and body, with black radial imprint “FTY 0.25mg” on capand black radial band on body.

Gilenya 0.5 mg hard capsules

Capsule of 16 mm with bright yellow opaque cap and white opaque body; imprint with black ink,“FTY0.5 mg” on cap and two radial bands imprinted on the body with yellow ink.

Gilenya is indicated as single disease modifying therapy in highly active relapsing remitting multiplesclerosis for the following groups of adult patients and paediatric patients aged 10 years and older:

- Patients with highly active disease despite a full and adequate course of treatment with at leastone disease modifying therapy (for exceptions and information about washout periods seesections 4.4 and 5.1).

or

- Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or moredisabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRIor a significant increase in T2 lesion load as compared to a previous recent MRI.

The treatment should be initiated and supervised by a physician experienced in multiple sclerosis.

In adults, the recommended dose of fingolimod is one 0.5 mg capsule taken orally once daily.

In paediatric patients (10 years of age and above), the recommended dose is dependent on bodyweight:

- Paediatric patients with body weight ≤40 kg: one 0.25 mg capsule taken orally once daily.

- Paediatric patients with body weight >40 kg: one 0.5 mg capsule taken orally once daily.

Paediatric patients who start on 0.25 mg capsules and subsequently reach a stable body weight above40 kg should be switched to 0.5 mg capsules.

When switching from a 0.25 mg to a 0.5 mg daily dose, it is recommended to repeat the same firstdose monitoring as for treatment initiation.

The same first dose monitoring as for treatment initiation is recommended when treatment isinterrupted for:

- 1 day or more during the first 2 weeks of treatment.

- more than 7 days during weeks 3 and 4 of treatment.

- more than 2 weeks after one month of treatment.

If the treatment interruption is of shorter duration than the above, the treatment should be continuedwith the next dose as planned (see section 4.4).

Gilenya should be used with caution in patients aged 65 years and over due to insufficient data onsafety and efficacy (see section 5.2).

Fingolimod was not studied in patients with renal impairment in the multiple sclerosis pivotal studies.

Based on clinical pharmacology studies, no dose adjustments are needed in patients with mild tosevere renal impairment.

Gilenya must not be used in patients with severe hepatic impairment (Child-Pugh class C) (seesection 4.3). Although no dose adjustments are needed in patients with mild or moderate hepaticimpairment, caution should be exercised when initiating treatment in these patients (see sections 4.4and 5.2).

The safety and efficacy of fingolimod in children aged below 10 years have not yet been established.

No data are available. There are very limited data available in children between 10-12 years old (seesections 4.4, pct. 4.8 and 5.1).

This medicinal product is for oral use.

Gilenya can be taken with or without food (see section 5.2).

The capsules should always be swallowed intact, without opening them.

- Immunodeficiency syndrome.

- Patients with increased risk for opportunistic infections, including immunocompromisedpatients (including those currently receiving immunosuppressive therapies or thoseimmunocompromised by prior therapies).

- Suspected or confirmed progressive multifocal leukoencephalopathy (PML) (see section 4.4).

- Severe active infections, active chronic infections (hepatitis, tuberculosis).

- Active malignancies.

- Severe liver impairment (Child-Pugh class C).

- Patients who in the previous 6 months had myocardial infarction (MI), unstable angina pectoris,stroke/transient ischaemic attack (TIA), decompensated heart failure (requiring inpatienttreatment), or New York Heart Association (NYHA) class III/IV heart failure (see section 4.4).

- Patients with severe cardiac arrhythmias requiring anti-arrhythmic treatment with class Ia orclass III anti-arrhythmic medicinal products (see section 4.4).

- Patients with second-degree Mobitz type II atrioventricular (AV) block or third-degree AVblock, or sick-sinus syndrome, if they do not wear a pacemaker (see section 4.4).

- Patients with a baseline QTc interval ≥ 500 msec (see section 4.4).

- During pregnancy and in women of childbearing potential not using effective contraception (seesections 4.4 and 4.6).

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Bradyarrhythmia

Initiation of treatment results in a transient decrease in heart rate and may also be associated withatrioventricular conduction delays, including the occurrence of isolated reports of transient,spontaneously resolving complete AV block (see sections 4.8 and 5.1).

After the first dose, the decline in heart rate starts within one hour, and is maximal within 6 hours.

This post-dose effect persists over the following days, although usually to a milder extent, and usuallyabates over the next weeks. With continued administration, the average heart rate returns towardsbaseline within one month. However individual patients may not return to baseline heart rate by theend of the first month. Conduction abnormalities were typically transient and asymptomatic. Theyusually did not require treatment and resolved within the first 24 hours on treatment. If necessary, thedecrease in heart rate induced by fingolimod can be reversed by parenteral doses of atropine orisoprenaline.

All patients should have an ECG and blood pressure measurement performed prior to and 6 hours afterthe first dose of Gilenya. All patients should be monitored for a period of 6 hours for signs andsymptoms of bradycardia with hourly heart rate and blood pressure measurement. Continuous (realtime) ECG monitoring during this 6 hour period is recommended.

The same precautions as for the first dose are recommended when patients are switched from the0.25 mg to the 0.5 mg daily dose.

Should post-dose bradyarrhythmia-related symptoms occur, appropriate clinical management shouldbe initiated and monitoring should be continued until the symptoms have resolved. Should a patientrequire pharmacological intervention during the first-dose monitoring, overnight monitoring in amedical facility should be instituted and the first-dose monitoring should be repeated after the seconddose of Gilenya.

If the heart rate at 6 hours is the lowest since the first dose was administered (suggesting that themaximum pharmacodynamic effect on the heart may not yet be manifest), monitoring should beextended by at least 2 hours and until heart rate increases again. Additionally, if after 6 hours, the heartrate is <45 bpm in adults, <55 bpm in paediatric patients aged 12 years and above, or <60 bpm inpaediatric patients aged 10 to below 12 years, or the ECG shows new onset second degree or highergrade AV block or a QTc interval ≥500 msec, extended monitoring (at least overnight monitoring),should be performed, and until the findings have resolved. The occurrence at any time of third degree

AV block should also lead to extended monitoring (at least overnight monitoring).

The effects on heart rate and atrioventricular conduction may recur on re-introduction of fingolimodtreatment depending on duration of the interruption and time since start of treatment. The same firstdose monitoring as for treatment initiation is recommended when treatment is interrupted (seesection 4.2).

Very rare cases of T-wave inversion have been reported in adult patients treated with fingolimod. Incase of T-wave inversion, the prescriber should ensure that there are no associated myocardialischaemia signs or symptoms. If myocardial ischaemia is suspected, it is recommended to seek advicefrom a cardiologist.

Due to the risk of serious rhythm disturbances or significant bradycardia, Gilenya should not be usedin patients with sino-atrial heart block, a history of symptomatic bradycardia, recurrent syncope orcardiac arrest, or in patients with significant QT prolongation (QTc>470 msec [adult female], QTc>460 msec [paediatric female] or >450 msec [adult and paediatric male]), uncontrolled hypertensionor severe sleep apnoea (see also section 4.3). In such patients, treatment with Gilenya should beconsidered only if the anticipated benefits outweigh the potential risks, and advice from a cardiologistsought prior to initiation of treatment in order to determine the most appropriate monitoring. At leastovernight extended monitoring is recommended for treatment initiation (see also section 4.5).

Fingolimod has not been studied in patients with arrhythmias requiring treatment with class Ia (e.g.

quinidine, disopyramide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products.

Class Ia and class III antiarrhythmic medicinal products have been associated with cases of torsades depointes in patients with bradycardia (see section 4.3).

Experience with Gilenya is limited in patients receiving concurrent therapy with beta blockers, heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem), or other substances whichmay decrease heart rate (e.g. ivabradine, digoxin, anticholinesteratic agents or pilocarpine). Since theinitiation of fingolimod treatment is also associated with slowing of the heart rate (see also section 4.8,

Bradyarrhythmia), concomitant use of these substances during treatment initiation may be associatedwith severe bradycardia and heart block. Because of the potential additive effect on heart rate,treatment with Gilenya should not be initiated in patients who are concurrently treated with thesesubstances (see also section 4.5). In such patients, treatment with Gilenya should be considered only ifthe anticipated benefits outweigh the potential risks. If treatment with Gilenya is considered, advicefrom a cardiologist should be sought regarding the switch to non heart-rate lowering medicinalproducts prior to initiation of treatment. If the heart-rate-lowering treatment cannot be stopped,cardiologist’s advice should be sought to determine appropriate first dose monitoring, at leastovernight extended monitoring is recommended (see also section 4.5).

In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negativechronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of

QTcI, with the upper limit of the 90% CI ≤13.0 ms. There is no dose- or exposure-responserelationship of fingolimod and QTcI prolongation. There is no consistent signal of increased incidenceof QTcI outliers, either absolute or change from baseline, associated with fingolimod treatment.

The clinical relevance of this finding is unknown. In the multiple sclerosis studies, clinically relevanteffects on prolongation of the QTc-interval have not been observed but patients at risk for QTprolongation were not included in clinical studies.

Medicinal products that may prolong QTc interval are best avoided in patients with relevant riskfactors, for example, hypokalaemia or congenital QT prolongation.

Immunosuppressive effects

Fingolimod has an immunosuppressive effect that predisposes patients to an infection risk, includingopportunistic infections that can be fatal, and increases the risk of developing lymphomas and othermalignancies, particularly those of the skin. Physicians should carefully monitor patients, especiallythose with concurrent conditions or known factors, such as previous immunosuppressive therapy. Ifthis risk is suspected, discontinuation of treatment should be considered by the physician on a case-by-case basis (see also section 4.4 “Infections” and “Cutaneous malignancies” and section 4.8“Lymphomas”).

A core pharmacodynamic effect of fingolimod is a dose-dependent reduction of the peripherallymphocyte count to 20-30% of baseline values. This is due to the reversible sequestration oflymphocytes in lymphoid tissues (see section 5.1).

Before initiating treatment with Gilenya, a recent complete blood count (CBC) (i.e. within 6 months orafter discontinuation of prior therapy) should be available. Assessments of CBC are alsorecommended periodically during treatment, at month 3 and at least yearly thereafter, and in case ofsigns of infection. Absolute lymphocyte count <0.2x109/l, if confirmed, should lead to treatmentinterruption until recovery, because in clinical studies, fingolimod treatment was interrupted inpatients with absolute lymphocyte count <0.2x109/l.

Initiation of treatment with Gilenya should be delayed in patients with severe active infection untilresolution.

The immune system effects of Gilenya may increase the risk of infections, including opportunisticinfections (see section 4.8). Effective diagnostic and therapeutic strategies should be employed inpatients with symptoms of infection while on therapy. When evaluating a patient with a suspectedinfection that could be serious, referral to a physician experienced in treating infections should beconsidered. During treatment, patients should be instructed to report promptly symptoms of infectionto their physician.

Suspension of Gilenya should be considered if a patient develops a serious infection and considerationof benefit-risk should be undertaken prior to re-initiation of therapy.

Elimination of fingolimod following discontinuation of therapy may take up to two months andvigilance for infection should therefore be continued throughout this period. Patients should beinstructed to report symptoms of infection up to 2 months after discontinuation of fingolimod.

Herpes viral infection

Serious, life-threatening, and sometimes fatal cases of encephalitis, meningitis or meningoencephalitiscaused by herpes simplex and varicella zoster viruses have occurred with Gilenya at any time duringtreatment. If herpes encephalitis, meningitis or meningoencephalitis occur, Gilenya should bediscontinued and appropriate treatment for the respective infection should be administered.

Patients need to be assessed for their immunity to varicella (chickenpox) prior to Gilenya treatment. Itis recommended that patients without a health care professional confirmed history of chickenpox ordocumentation of a full course of vaccination with varicella vaccine undergo antibody testing tovaricella zoster virus (VZV) before initiating fingolimod therapy. A full course of vaccination forantibody-negative patients with varicella vaccine is recommended prior to commencing treatment with

Gilenya (see section 4.8). Initiation of treatment with fingolimod should be postponed for 1 month toallow full effect of vaccination to occur.

Cryptococcal meningitis

Cases of cryptococcal meningitis (a fungal infection), sometimes fatal, have been reported in the post-marketing setting after approximately 2-3 years of treatment, although an exact relationship with theduration of treatment is unknown (see section 4.8). Patients with symptoms and signs consistent withcryptococcal meningitis (e.g. headache accompanied by mental changes such as confusion,hallucinations, and/or personality changes) should undergo prompt diagnostic evaluation. Ifcryptococcal meningitis is diagnosed, fingolimod should be suspended and appropriate treatmentshould be initiated. A multidisciplinary consultation (i.e. infectious disease specialist) should beundertaken if re-initiation of fingolimod is warranted.

PML has been reported under fingolimod treatment since marketing authorisation (see section 4.8).

PML is an opportunistic infection caused by John Cunningham virus (JCV), which may be fatal orresult in severe disability. The majority of PML cases have occurred after 2 or more years offingolimod treatment. In addition to duration of fingolimod exposure, other potential risk factors for

PML include prior therapy with immunosuppressants or immunomodulators, and/or severelymphopenia (<0.5x109/l). Patients at increased risk should be closely monitored for any signs orsymptoms of PML. PML can only occur in the presence of a JCV infection. If JCV testing isundertaken, it should be considered that the influence of lymphopenia on the accuracy of anti-JCVantibody testing has not been studied in fingolimod-treated patients. A negative anti-JCV antibody testdoes not preclude the possibility of subsequent JCV infection. Before initiating treatment withfingolimod, a baseline MRI should be available (usually within 3 months) as a reference. Duringroutine MRI (in accordance with national and local recommendations), physicians should payattention to PML suggestive lesions. MRI findings may be apparent before clinical signs or symptoms.

Annual MRIs may be considered as part of increased vigilance especially in patients at increased riskof PML. Cases of asymptomatic PML based on MRI findings and positive JCV DNA in thecerebrospinal fluid have been reported in patients treated with fingolimod. If PML is suspected, MRIshould be performed immediately for diagnostic purposes and treatment with fingolimod should besuspended until PML has been excluded. If PML is confirmed, treatment with fingolimod must bepermanently discontinued (see also section 4.3).

Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated withsphingosine 1-phosphate (S1P) receptor modulators, including fingolimod, who developed PML andsubsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition thatmay be rapid, can lead to serious neurological complications or death, and is often associated withcharacteristic changes on MRI. The time to onset of IRIS in patients with PML was usually fromweeks to months after S1P receptor modulator discontinuation. Monitoring for development of IRISand appropriate treatment of the associated inflammation should be undertaken.

Human papilloma virus infection

Human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-relatedcancer, has been reported under treatment with fingolimod in the post-marketing setting (seesection 4.8). Due to the immunosuppressive properties of fingolimod, vaccination against HPV shouldbe considered prior to treatment initiation with fingolimod taking into account vaccinationrecommendations. Cancer screening, including Pap test, is recommended as per standard of care.

Macular oedema

Macular oedema with or without visual symptoms has been reported in 0.5% of patients treated withfingolimod 0.5 mg, occurring predominantly in the first 3-4 months of therapy (see section 4.8). Anophthalmological evaluation is therefore recommended at 3-4 months after treatment initiation. Ifpatients report visual disturbances at any time while on therapy, evaluation of the fundus, includingthe macula, should be carried out.

Patients with history of uveitis and patients with diabetes mellitus are at increased risk of macularoedema (see section 4.8). Fingolimod has not been studied in multiple sclerosis patients withconcomitant diabetes mellitus. It is recommended that multiple sclerosis patients with diabetesmellitus or a history of uveitis undergo an ophthalmological evaluation prior to initiating therapy andhave follow-up evaluations while receiving therapy.

Continuation of treatment in patients with macular oedema has not been evaluated. It is recommendedthat Gilenya be discontinued if a patient develops macular oedema. A decision on whether or nottherapy should be re-initiated after resolution of macular oedema needs to take into account thepotential benefits and risks for the individual patient.

Liver injury

Increased hepatic enzymes, in particular alanine aminotransaminase (ALT) but also gammaglutamyltransferase (GGT) and aspartate transaminase (AST) have been reported in multiple sclerosispatients treated with fingolimod. Some cases of acute liver failure requiring liver transplant andclinically significant liver injury have also been reported. Signs of liver injury, including markedlyelevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as ten days afterthe first dose and have also been reported after prolonged use. In clinical trials, elevations 3-fold theupper limit of normal (ULN) or greater in ALT occurred in 8.0% of adult patients treated withfingolimod 0.5 mg compared to 1.9% of placebo patients. Elevations 5-fold the ULN occurred in 1.8%of patients on fingolimod and 0.9% of patients on placebo. In clinical trials, fingolimod wasdiscontinued if the elevation exceeded 5 times the ULN. Recurrence of liver transaminase elevationsoccurred with rechallenge in some patients, supporting a relationship to fingolimod. In clinical studies,transaminase elevations occurred at any time during treatment although the majority occurred withinthe first 12 months. Serum transaminase levels returned to normal within approximately 2 monthsafter discontinuation of fingolimod.

Fingolimod has not been studied in patients with severe pre-existing hepatic injury (Child-Pugh class

C) and should not be used in these patients (see section 4.3).

Due to the immunosuppressive properties of fingolimod, initiation of treatment should be delayed inpatients with active viral hepatitis until resolution.

Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available beforeinitiation of treatment. In the absence of clinical symptoms, liver transaminases and serum bilirubinshould be monitored at months 1, 3, 6, 9 and 12 on therapy and periodically thereafter until 2 monthsafter Gilenya discontinuation. In the absence of clinical symptoms, if liver transaminases are greaterthan 3 but less than 5 times the ULN without increase in serum bilirubin, more frequent monitoringincluding serum bilirubin and alkaline phosphatase (ALP) measurement should be instituted todetermine if further increases occur and in order to discern if an alternative aetiology of hepaticdysfunction is present. If liver transaminases are at least 5 times the ULN or at least 3 times the ULNassociated with any increase in serum bilirubin, Gilenya should be discontinued. Hepatic monitoringshould be continued. If serum levels return to normal (including if an alternative cause of the hepaticdysfunction is discovered), Gilenya may be restarted based on a careful benefit-risk assessment of thepatient.

Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea,vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have liver enzymesand bilirubin checked promptly and treatment should be discontinued if significant liver injury isconfirmed. Treatment should not be resumed unless a plausible alternative aetiology for the signs andsymptoms of liver injury can be established.

Although there are no data to establish that patients with pre-existing liver disease are at increased riskof developing elevated liver function tests when taking Gilenya, caution in the use of Gilenya shouldbe exercised in patients with a history of significant liver disease.

Patients with hypertension uncontrolled by medication were excluded from participation inpremarketing clinical trials and special care is indicated if patients with uncontrolled hypertension aretreated with Gilenya.

In MS clinical trials, patients treated with fingolimod 0.5 mg had an average increase of approximately3 mmHg in systolic pressure, and approximately 1 mmHg in diastolic pressure, first detectedapproximately 1 month after treatment initiation, and persisting with continued treatment. In the two-year placebo-controlled study, hypertension was reported as an adverse event in 6.5% of patients onfingolimod 0.5 mg and in 3.3% of patients on placebo. Therefore, blood pressure should be regularlymonitored during treatment.

Respiratory effects

Minor dose-dependent reductions in values for forced expiratory volume (FEV1) and diffusioncapacity for carbon monoxide (DLCO) were observed with fingolimod treatment starting at month 1and remaining stable thereafter. Gilenya should be used with caution in patients with severerespiratory disease, pulmonary fibrosis and chronic obstructive pulmonary disease (see section 4.8).

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported at the 0.5 mgdose in clinical trials and in the post-marketing setting (see section 4.8). Symptoms reported includedsudden onset of severe headache, nausea, vomiting, altered mental status, visual disturbances andseizure. Symptoms of PRES are usually reversible but may evolve into ischaemic stroke or cerebralhaemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRESis suspected, Gilenya should be discontinued.

There have been no studies performed to evaluate the efficacy and safety of fingolimod whenswitching patients from teriflunomide, dimethyl fumarate or alemtuzumab treatment to Gilenya. Whenswitching patients from another disease modifying therapy to Gilenya, the elimination half-life andmode of action of the other therapy must be considered in order to avoid an additive immune effectwhilst at the same time minimising the risk of disease reactivation. A CBC is recommended prior toinitiating Gilenya to ensure that immune effects of the previous therapy (i.e. cytopenia) have resolved.

Gilenya can generally be started immediately after discontinuation of interferon or glatiramer acetate.

For dimethyl fumarate, the washout period should be sufficient for CBC to recover before treatmentwith Gilenya is started.

Due to the long elimination half-life of natalizumab, elimination usually takes up to 2-3 monthsfollowing discontinuation. Teriflunomide is also eliminated slowly from the plasma. Without anaccelerated elimination procedure, clearance of teriflunomide from plasma can take from severalmonths up to 2 years. An accelerated elimination procedure as defined in the teriflunomide summaryof product characteristics is recommended or alternatively washout period should not be shorter than3.5 months. Caution regarding potential concomitant immune effects is required when switchingpatients from natalizumab or teriflunomide to Gilenya.

Alemtuzumab has profound and prolonged immunosuppressive effects. As the actual duration of theseeffects is unknown, initiating treatment with Gilenya after alemtuzumab is not recommended unlessthe benefits of such treatment clearly outweigh the risks for the individual patient.

A decision to use prolonged concomitant treatment with corticosteroids should be taken after carefulconsideration.

Co-administration with potent CYP450 inducers

The combination of fingolimod with potent CYP450 inducers should be used with caution.

Concomitant administration with St John’s Wort is not recommended (see section 4.5).

Basal cell carcinoma (BCC) and other cutaneous neoplasms, including malignant melanoma,squamous cell carcinoma, Kaposi’s sarcoma and Merkel cell carcinoma, have been reported in patientsreceiving Gilenya (see section 4.8). Vigilance for skin lesions is warranted and a medical evaluation ofthe skin is recommended at initiation, and then every 6 to 12 months taking into consideration clinicaljudgement. The patient should be referred to a dermatologist in case suspicious lesions are detected.

Since there is a potential risk of malignant skin growths, patients treated with fingolimod should becautioned against exposure to sunlight without protection. These patients should not receiveconcomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy.

Lymphomas

There have been cases of lymphoma in clinical studies and the post-marketing setting (seesection 4.8). 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. A fatal case of Epstein-Barr virus (EBV) positive B-cell lymphoma has also beenobserved. If lymphoma is suspected, treatment should be discontinued.

Due to risk to the foetus, fingolimod is contraindicated during pregnancy and in women ofchildbearing potential not using effective contraception. Before initiation of treatment, women ofchildbearing potential must be informed of this risk to the foetus, must have a negative pregnancy testand must use effective contraception during treatment and for 2 months after treatment discontinuation(see sections 4.3 and 4.6 and the information contained in the Physician Information Pack).

Tumefactive lesions

Rare cases of tumefactive lesions associated with MS relapse were reported in the post-marketingsetting. In case of severe relapses, MRI should be performed to exclude tumefactive lesions.

Discontinuation of treatment should be considered by the physician on a case-by-case basis taking intoaccount individual benefits and risks.

Return of disease activity (rebound) after fingolimod discontinuation

In the post-marketing setting, severe exacerbation of disease has been observed rarely in some patientsstopping fingolimod. This has generally been observed within 12 weeks after stopping fingolimod, buthas also been reported up to 24 weeks after fingolimod discontinuation. Caution is therefore indicatedwhen stopping fingolimod therapy. If discontinuation of fingolimod is deemed necessary, thepossibility of recurrence of exceptionally high disease activity should be considered and patientsshould be monitored for relevant signs and symptoms and appropriate treatment initiated as required(see “Stopping therapy” below).

If a decision is made to stop treatment with Gilenya a 6 week interval without therapy is needed, basedon half-life, to clear fingolimod from the circulation (see section 5.2). Lymphocyte countsprogressively return to normal range within 1-2 months of stopping therapy in most patients (seesection 5.1) although full recovery can take significantly longer in some patients. Starting othertherapies during this interval will result in concomitant exposure to fingolimod. Use ofimmunosuppressants soon after the discontinuation of Gilenya may lead to an additive effect on theimmune system and caution is therefore indicated.

After stopping fingolimod in the setting of PML, it is recommended to monitor patients fordevelopment of immune reconstitution inflammatory syndrome (PML-IRIS) (see “Progressivemultifocal leukoencephalopathy” above).

Caution is also indicated when stopping fingolimod therapy due to the risk of a rebound (see “Returnof disease activity (rebound) after fingolimod discontinuation” above). If discontinuation of Gilenya isdeemed necessary, patients should be monitored during this time for relevant signs of a possiblerebound.

Interference with serological testing

Since fingolimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid organs,peripheral blood lymphocyte counts cannot be utilised to evaluate the lymphocyte subset status of apatient treated with Gilenya. Laboratory tests involving the use of circulating mononuclear cellsrequire larger blood volumes due to reduction in the number of circulating lymphocytes.

The safety profile in paediatric patients is similar to that in adults and the warnings and precautions foradults therefore also apply to paediatric patients.

In particular, the following should be noted when prescribing Gilenya to paediatric patients:

- Precautions should be followed at the time of the first dose (see “Bradyarrhythmia” above). Thesame precautions as for the first dose are recommended when patients are switched from the0.25 mg to the 0.5 mg daily dose.

- In the controlled paediatric trial D2311, cases of seizures, anxiety, depressed mood anddepression have been reported with a higher incidence in patients treated with fingolimodcompared to patients treated with interferon beta-1a. Caution is required in this subgrouppopulation (see “Paediatric population” in section 4.8).

- Mild isolated bilirubin increases have been noted in paediatric patients on Gilenya.

- It is recommended that paediatric patients complete all immunisations in accordance withcurrent immunisation guidelines before starting Gilenya therapy (see “Infections” above).

- There are very limited data available in children between 10-12 years old, less than 40 kg or at

Tanner stage <2 (see sections 4.8 and 5.1). Caution is required in these subgroups due to verylimited knowledge available from the clinical study.

- Long-term safety data in the paediatric population are not available.

Anti-neoplastic, immunomodulatory or immunosuppressive therapies

Anti-neoplastic, immunomodulatory or immunosuppressive therapies should not be co-administereddue to the risk of additive immune system effects (see sections 4.3 and 4.4).

Caution should also be exercised when switching patients from long-acting therapies with immuneeffects such as natalizumab, teriflunomide or mitoxantrone (see section 4.4). In multiple sclerosisclinical studies the concomitant treatment of relapses with a short course of corticosteroids was notassociated with an increased rate of infection.

During and for up to two months after treatment with Gilenya vaccination may be less effective. Theuse of live attenuated vaccines may carry a risk of infections and should therefore be avoided (seesections 4.4 and 4.8).

Bradycardia-inducing substances

Fingolimod has been studied in combination with atenolol and diltiazem. When fingolimod was usedwith atenolol in an interaction study in healthy volunteers, there was an additional 15% reduction ofheart rate at fingolimod treatment initiation, an effect not seen with diltiazem. Treatment with Gilenyashould not be initiated in patients receiving beta blockers, or other substances which may decreaseheart rate, such as class Ia and III antiarrhythmics, calcium channel blockers (such as verapamil ordiltiazem), ivabradine, digoxin, anticholinesteratic agents or pilocarpine because of the potentialadditive effects on heart rate (see sections 4.4 and 4.8). If treatment with Gilenya is considered in suchpatients, advice from a cardiologist should be sought regarding the switch to non-heart-rate loweringmedicinal products or appropriate monitoring for treatment initiation, at least overnight monitoring isrecommended, if the heart-rate-lowering medication cannot be stopped.

Pharmacokinetic interactions of other substances on fingolimod

Fingolimod is metabolised mainly by CYP4F2. Other enzymes like CYP3A4 may also contribute toits metabolism, notably in the case of strong induction of CYP3A4. Potent inhibitors of transporterproteins are not expected to influence fingolimod disposition. Co-administration of fingolimod withketoconazole resulted in a 1.7-fold increase in fingolimod and fingolimod phosphate exposure (AUC)by inhibition of CYP4F2. Caution should be exercised with substances that may inhibit CYP3A4(protease inhibitors, azole antifungals, some macrolides such as clarithromycin or telithromycin).

Co-administration of carbamazepine 600 mg twice daily at steady-state and a single dose offingolimod 2 mg reduced the AUC of fingolimod and its metabolite by approximately 40%. Otherstrong CYP3A4 enzyme inducers, for example rifampicin, phenobarbital, phenytoin, efavirenz and St.

John’s Wort, may reduce the AUC of fingolimod and its metabolite at least to this extent. As thiscould potentially impair the efficacy, their co-administration should be used with caution.

Concomitant administration with St. John’s Wort is however not recommended (see section 4.4).

Pharmacokinetic interactions of fingolimod on other substances

Fingolimod is unlikely to interact with substances mainly cleared by the CYP450 enzymes or bysubstrates of the main transporter proteins.

Co-administration of fingolimod with ciclosporin did not elicit any change in the ciclosporin orfingolimod exposure. Therefore, fingolimod is not expected to alter the pharmacokinetics of medicinalproducts that are CYP3A4 substrates.

Co-administration of fingolimod with oral contraceptives (ethinylestradiol and levonorgestrel) did notelicit any change in oral contraceptive exposure. No interaction studies have been performed with oralcontraceptives containing other progestagens, however an effect of fingolimod on their exposure is notexpected.

Fingolimod is contraindicated in women of childbearing potential not using effective contraception(see section 4.3). Therefore, before initiation of treatment in women of childbearing potential, anegative pregnancy test result must be available and counselling should be provided regarding theserious risk to the foetus. Women of childbearing potential must use effective contraception duringtreatment and for 2 months after discontinuation of Gilenya, since fingolimod takes approximately2 months to eliminate from the body after treatment discontinuation (see section 4.4).

Specific measures are also included in the Physician Information Pack. These measures must beimplemented before fingolimod is prescribed to female patients and during treatment.

When stopping fingolimod therapy for planning a pregnancy the possible return of disease activityshould be considered (see section 4.4).

Based on human experience, post-marketing data suggest that use of fingolimod is associated with a2-fold increased risk of major congenital malformations when administered during pregnancycompared with the rate observed in the general population (2-3%; EUROCAT).

The following major malformations were most frequently reported:

- Congenital heart disease such as atrial and ventricular septal defects, tetralogy of Fallot

- Renal abnormalities

- Musculoskeletal abnormalities

There are no data on the effects of fingolimod on labour and delivery.

Animal studies have shown reproductive toxicity including foetal loss and organ defects, notablypersistent truncus arteriosus and ventricular septal defect (see section 5.3). Furthermore, the receptoraffected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascularformation during embryogenesis.

Consequently, fingolimod is contraindicated during pregnancy (see section 4.3). Fingolimod should bestopped 2 months before planning a pregnancy (see section 4.4). If a woman becomes pregnant duringtreatment, fingolimod must be discontinued. Medical advice should be given regarding the risk ofharmful effects to the foetus associated with treatment and ultrasonography examinations should beperformed.

Fingolimod is excreted in milk of treated animals during lactation (see section 5.3). Due to thepotential for serious adverse reactions to fingolimod in nursing infants, women receiving Gilenyashould not breastfeed.

Data from preclinical studies do not suggest that fingolimod would be associated with an increasedrisk of reduced fertility (see section 5.3).

Fingolimod has no or negligible influence on the ability to drive and use machines.

However, dizziness or drowsiness may occasionally occur when initiating treatment. On initiation of

Gilenya it is recommended that patients be observed for a period of 6 hours (see section 4.4,

Bradyarrhythmia).

The most frequent adverse reactions (incidence ≥10%) at the 0.5 mg dose were headache (24.5%),hepatic enzyme increased (15.2%), diarrhoea (12.6%), cough (12.3%), influenza (11.4%), sinusitis(10.9%) and back pain (10.0%).

Adverse reactions reported in clinical trials and derived from post-marketing experience viaspontaneous case reports or literature cases are shown below. Frequencies were defined using thefollowing convention: 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); not known (cannot be estimated from theavailable data). Within each frequency grouping, adverse reactions are presented in the order ofdecreasing seriousness.

Very common: Influenza

Sinusitis

Common: Herpes viral infections

Bronchitis

Tinea versicolor

Uncommon: Pneumonia

Not known: Progressive multifocal leukoencephalopathy (PML)**

Cryptococcal infections**

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Common: Basal cell carcinoma

Uncommon: Malignant melanoma****

Rare: Lymphoma***

Squamous cell carcinoma****

Very rare: Kaposi’s sarcoma****

Not known Merkel cell carcinoma***

Common: Lymphopenia

Leucopenia

Uncommon: Thrombocytopenia

Not known: Autoimmune haemolytic anaemia***

Peripheral oedema***

Not known: Hypersensitivity reactions, including rash, urticaria and angioedemaupon treatment initiation***

Immune reconstitution inflammatory syndrome (IRIS)**

Common: Depression

Uncommon: Depressed mood

Very common: Headache

Common: Dizziness

Migraine

Uncommon: Seizure

Rare: Posterior reversible encephalopathy syndrome (PRES)*

Not known: Severe exacerbation of disease after fingolimod discontinuation***

Common: Vision blurred

Uncommon: Macular oedema

Common: Bradycardia

Atrioventricular block

Very rare: T-wave inversion***

Common: Hypertension

Very common: Cough

Common: Dyspnoea

Very common: Diarrhoea

Uncommon: Nausea***

Not known: Acute hepatic failure***

Common: Eczema

Alopecia

Pruritus

Very common: Back pain

Common: Myalgia

Arthralgia

Common: Asthenia

Very common: Hepatic enzyme increased (increased alanine transaminase, gammaglutamyltransferase, aspartate transaminase)

Common: Weight decreased***

Blood triglycerides increased

Uncommon: Neutrophil count decreased

* The frequency category was based on an estimated exposure of approximately10 000 patients to fingolimod in all clinical trials.

** PML, IRIS and cryptococcal infections (including cases of cryptococcal meningitis) havebeen reported in the post-marketing setting (see section 4.4).

*** Adverse reactions from spontaneous reports and literature

**** The frequency category and risk assessment were based on an estimated exposure of morethan 24 000 patients to fingolimod 0.5 mg in all clinical trials.

In multiple sclerosis clinical studies the overall rate of infections (65.1%) at the 0.5 mg dose wassimilar to placebo. However, lower respiratory tract infections, primarily bronchitis and to a lesserextent herpes infection and pneumonia were more common in fingolimod-treated patients. Some casesof disseminated herpes infection, including fatal cases, have been reported even at the 0.5 mg dose.

In the post-marketing setting, cases of infections with opportunistic pathogens, such as viral (e.g.

varicella zoster virus [VZV], John Cunningham virus [JCV] causing Progressive Multifocal

Leukoencephalopathy, herpes simplex virus [HSV]), fungal (e.g. cryptococci including cryptococcalmeningitis) or bacterial (e.g. atypical mycobacterium), have been reported, some of which have beenfatal (see section 4.4).

Human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-relatedcancer, has been reported under treatment with fingolimod in the post-marketing setting (seesection 4.4). Due to the immunosuppressive properties of fingolimod, vaccination against HPV shouldbe considered prior to treatment initiation with fingolimod taking into account vaccinationrecommendations. Cancer screening, including Pap test, is recommended as per standard of care.

Macular oedema

In multiple sclerosis clinical studies macular oedema occurred in 0.5% of patients treated with therecommended dose of 0.5 mg and 1.1% of patients treated with the higher dose of 1.25 mg. Themajority of cases occurred within the first 3-4 months of therapy. Some patients presented with blurredvision or decreased visual acuity, but others were asymptomatic and diagnosed on routineophthalmological examination. The macular oedema generally improved or resolved spontaneouslyafter discontinuation of treatment. 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 (17%with a history of uveitis vs. 0.6% without a history of uveitis). Gilenya has not been studied inmultiple sclerosis patients with diabetes mellitus, a disease which is associated with an increased riskfor macular oedema (see section 4.4). In renal transplant clinical studies in which patients withdiabetes mellitus were included, therapy with fingolimod 2.5 mg and 5 mg resulted in a 2-fold increasein the incidence of macular oedema.

Bradyarrhythmia

Initiation of treatment results in a transient decrease in heart rate and may also be associated withatrioventricular conduction delays. In multiple sclerosis clinical studies the maximal decline in heartrate was seen within 6 hours after treatment initiation, with declines in mean heart rate of 12-13 beatsper minute for fingolimod 0.5 mg. Heart rate below 40 beats per minute in adults, and below 50 beatsper minute in paediatric patients, was rarely observed in patients on fingolimod 0.5 mg. The averageheart rate returned towards baseline within 1 month of chronic treatment. Bradycardia was generallyasymptomatic but some patients experienced mild to moderate symptoms, including hypotension,dizziness, fatigue and/or palpitations, which resolved within the first 24 hours after treatment initiation(see also sections 4.4 and 5.1).

In multiple sclerosis clinical studies first-degree atrioventricular block (prolonged PR interval on

ECG) was detected after treatment initiation in adult and paediatric patients. In adult clinical trials itoccurred in 4.7% of patients on fingolimod 0.5 mg, in 2.8% of patients on intramuscular interferonbeta-1a, and in 1.6% of patients on placebo. Second-degree atrioventricular block was detected in lessthan 0.2% adult patients on fingolimod 0.5 mg. In the post-marketing setting, isolated reports oftransient, spontaneously resolving complete AV block have been observed during the six hourmonitoring period following the first dose of Gilenya. The patients recovered spontaneously. Theconduction abnormalities observed both in clinical trials and post-marketing were typically transient,asymptomatic and resolved within the first 24 hours after treatment initiation. Although most patientsdid not require medical intervention, one patient on fingolimod 0.5 mg received isoprenaline forasymptomatic second-degree Mobitz I atrioventricular block.

In the post-marketing setting, isolated delayed onset events, including transient asystole andunexplained death, have occurred within 24 hours of the first dose. These cases have been confoundedby concomitant medicinal products and/or pre-existing disease. The relationship of such events to

Gilenya is uncertain.

In multiple sclerosis clinical studies fingolimod 0.5 mg was associated with an average increase ofapproximately 3 mmHg in systolic pressure and approximately 1 mmHg in diastolic pressure,manifesting approximately 1 month after treatment initiation. This increase persisted with continuedtreatment. Hypertension was reported in 6.5% of patients on fingolimod 0.5 mg and in 3.3% ofpatients on placebo. In the post-marketing setting, cases of hypertension have been reported within thefirst month of treatment initiation and on the first day of treatment that may require treatment withantihypertensive agents or discontinuation of Gilenya (see also section 4.4, Blood pressure effects).

Increased hepatic enzymes have been reported in adult and paediatric multiple sclerosis patientstreated with Gilenya. In clinical studies 8.0% and 1.8% of adult patients treated with fingolimod0.5 mg experienced an asymptomatic elevation in serum levels of ALT of ≥3x ULN (upper limit ofnormal) and ≥5x ULN, respectively. Recurrence of liver transaminase elevations has occurred upon re-challenge in some patients, supporting a relationship to the medicinal product. In clinical studies,transaminase elevations occurred at any time during treatment although the majority occurred withinthe first 12 months. ALT levels returned to normal within approximately 2 months afterdiscontinuation of treatment. In a small number of patients (N=10 on 1.25 mg, N=2 on 0.5 mg) whoexperienced ALT elevations ≥5x ULN and who continued on fingolimod therapy, the ALT levelsreturned to normal within approximately 5 months (see also section 4.4, Liver function).

In clinical studies, rare events involving the nervous system occurred in patients treated withfingolimod at higher doses (1.25 or 5.0 mg) including ischaemic and haemorrhagic strokes andneurological atypical disorders, such as acute disseminated encephalomyelitis (ADEM)-like events.

Cases of seizures, including status epilepticus, have been reported with the use of fingolimod inclinical studies and in the post-marketing setting.

Rare cases of peripheral arterial occlusive disease occurred in patients treated with fingolimod athigher doses (1.25 mg).

Minor dose-dependent reductions in values for forced expiratory volume (FEV1) and diffusioncapacity for carbon monoxide (DLCO) were observed with Gilenya treatment starting at month 1 andremaining stable thereafter. At month 24, the reduction from baseline values in percentage of predicted

FEV1 was 2.7% for fingolimod 0.5 mg and 1.2% for placebo, a difference that resolved after treatmentdiscontinuation. For DLCO the reductions at month 24 were 3.3% for fingolimod 0.5 mg and 2.7% forplacebo (see also section 4.4, Respiratory effects).

Lymphomas

There have been cases of lymphoma of different varieties, in both clinical studies and the post-marketing setting, including a fatal case of Epstein-Barr virus (EBV) positive B-cell lymphoma. Theincidence of non-Hodgkin’s lymphoma (B-cell and T-cell) cases was higher in clinical trials thanexpected in the general population. Some T-cell lymphoma cases were also reported in the post-marketing setting, including cases of cutaneous T-cell lymphoma (mycosis fungoides) (see alsosection 4.4, Malignancies).

Haemophagocytic syndrome

Very rare cases of haemophagocytic syndrome (HPS) with fatal outcome have been reported inpatients treated with fingolimod in the context of an infection. HPS is a rare condition that has beendescribed in association with infections, immunosuppression and a variety of autoimmune diseases.

In the controlled paediatric trial D2311 (see section 5.1), the safety profile in paediatric patients (10 tobelow 18 years of age) receiving fingolimod 0.25 mg or 0.5 mg daily was overall similar to that seenin adult patients. There were, nevertheless, more neurological and psychiatric disorders observed inthe study. Caution is needed in this subgroup due to very limited knowledge available from the clinicalstudy.

In the paediatric study, cases of seizures were reported in 5.6% of fingolimod-treated patients and0.9% of interferon beta-1a-treated patients.

Depression and anxiety are known to occur with increased frequency in the multiple sclerosispopulation. Depression and anxiety have also been reported in paediatric patients treated withfingolimod.

Mild isolated bilirubin increases have been noted in paediatric patients on fingolimod.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single doses up to 80 times the recommended dose (0.5 mg) were well tolerated in healthy adultvolunteers. At 40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was clinicallyconsistent with small airway reactivity.

Fingolimod can induce bradycardia upon treatment initiation. The decline in heart rate usually startswithin one hour of the first dose, and is steepest within 6 hours. The negative chronotropic effect of

Gilenya persists beyond 6 hours and progressively attenuates over subsequent days of treatment (seesection 4.4 for details). There have been reports of slow atrioventricular conduction, with isolatedreports of transient, spontaneously resolving complete AV block (see sections 4.4 and 4.8).

If the overdose constitutes first exposure to Gilenya, it is important to monitor patients with acontinuous (real time) ECG and hourly measurement of heart rate and blood pressure, at least duringthe first 6 hours (see section 4.4).

Additionally, if after 6 hours the heart rate is <45 bpm in adults, <55 bpm in paediatric patients aged12 years and above, or <60 bpm in paediatric patients aged 10 years to below 12 years, or if the ECGat 6 hours after the first dose shows second degree or higher AV block, or if it shows a QTc interval≥500 msec, monitoring should be extended at least for overnight and until the findings have resolved.

The occurrence at any time of third degree AV block should also lead to extended monitoringincluding overnight monitoring.

Neither dialysis nor plasma exchange results in removal of fingolimod from the body.

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code:

L04AE01

Fingolimod is a sphingosine 1-phosphate receptor modulator. Fingolimod is metabolised bysphingosine kinase to the active metabolite fingolimod phosphate. Fingolimod phosphate binds at lownanomolar concentrations to sphingosine 1-phosphate (S1P) receptor 1 located on lymphocytes, andreadily crosses the blood-brain barrier to bind to S1P receptor 1 located on neural cells in the centralnervous system (CNS). By acting as a functional antagonist of S1P receptors on lymphocytes,fingolimod phosphate blocks the capacity of lymphocytes to egress from lymph nodes, causing aredistribution, rather than depletion, of lymphocytes. Animal studies have shown that thisredistribution reduces the infiltration of pathogenic lymphocytes, including pro-inflammatory Th17cells, into the CNS, where they would be involved in nerve inflammation and nervous tissue damage.

Animal studies and in vitro experiments indicate that fingolimod may also act via interaction with S1Preceptors on neural cells.

Within 4-6 hours after the first dose of fingolimod 0.5 mg, the lymphocyte count decreases toapproximately 75% of baseline in peripheral blood. With continued daily dosing, the lymphocytecount continues to decrease over a two-week period, reaching a minimal count of approximately500 cells/microlitre or approximately 30% of baseline. Eighteen percent of patients reached a minimalcount below 200 cells/microlitre on at least one occasion. Low lymphocyte counts are maintained withchronic daily dosing. The majority of T and B lymphocytes regularly traffic through lymphoid organsand these are the cells mainly affected by fingolimod. Approximately 15-20% of T lymphocytes havean effector memory phenotype, cells that are important for peripheral immune surveillance. Since thislymphocyte 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 andtypically normal counts are reached within one to two months. Chronic fingolimod dosing leads to amild decrease in the neutrophil count to approximately 80% of baseline. Monocytes are unaffected byfingolimod.

Fingolimod causes a transient reduction in heart rate and decrease in atrioventricular conduction attreatment initiation (see sections 4.4 and 4.8). The maximal decline in heart rate is seen within 6 hourspost dose, with 70% of the negative chronotropic effect achieved on the first day. With continuedadministration heart rate returns to baseline within one month. The decrease in heart rate induced byfingolimod can be reversed by parenteral doses of atropine or isoprenaline. Inhaled salmeterol has alsobeen shown to have a modest positive chronotropic effect. With initiation of fingolimod treatmentthere is an increase in atrial premature contractions, but there is no increased rate of atrialfibrillation/flutter or ventricular arrhythmias or ectopy. Fingolimod treatment is not associated with adecrease in cardiac output. Autonomic responses of the heart, including diurnal variation of heart rateand response to exercise are not affected by fingolimod treatment.

S1P4 could partially contribute to the effect but was not the main receptor responsible for thelymphoid depletion. The mechanism of action of bradycardia and vasoconstriction were also studied invitro in guinea pigs and isolated rabbit aorta and coronary artery. It was concluded that bradycardiacould be mediated primarily by activation of inward-rectifying potassium channel or G-proteinactivated inwardly rectifying K+ channel (IKACh/GIRK) and that vasoconstriction seems to bemediated by a Rho kinase and calcium dependent mechanism.

Fingolimod treatment with single or multiple doses of 0.5 and 1.25 mg for two weeks is not associatedwith a detectable increase in airway resistance as measured by FEV1 and forced expiratory flow rate(FEF) 25-75. However, single fingolimod doses ≥5 mg (10-fold the recommended dose) are associatedwith 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 anincrease in airway responsiveness to methacholine. Subjects on fingolimod treatment have a normalbronchodilator response to inhaled beta-agonists.

The efficacy of fingolimod has been demonstrated in two studies which evaluated once-daily doses offingolimod 0.5 mg and 1.25 mg in adult patients with relapsing-remitting multiple sclerosis (RRMS).

Both studies included adult patients who had experienced ≥2 relapses in the prior 2 years or ≥1 relapseduring the prior year. Expanded Disability Status Score (EDSS) was between 0 and 5.5. A third studytargeting the same adult patient population was completed after registration of Gilenya.

Study D2301 (FREEDOMS) was a 2-year randomised, double-blind, placebo-controlled Phase IIIstudy of 1 272 patients (n=425 on 0.5 mg, 429 on 1.25 mg, 418 on placebo). Median values forbaseline characteristics were: age 37 years, disease duration 6.7 years, and EDSS score 2.0. Outcomeresults are shown in Table 1. There were no significant differences between the 0.5 mg and the1.25 mg doses as regards either endpoint.

Table 1 Study D2301 (FREEDOMS): main results

Fingolimod Placebo0.5 mg

Clinical endpoints

Annualised relapse rate (primary endpoint) 0.18** 0.40

Percentage of patients remaining relapse-free at 70%** 46%24 months

Proportion with 3-month Confirmed Disability 17% 24%

Progression†

Hazard ratio (95% CI) 0.70 (0.52, 0.96)*

MRI endpoints

Median (mean) number of new or enlarging T2 0.0 (2.5)** 5.0 (9.8)lesions over 24 months

Median (mean) number of Gd-enhancing lesions 0.0 (0.2)** 0.0 (1.1)at month 24

Median (mean) % change in brain volume over -0.7 (-0.8)** -1.0 (-1.3)24 months† Disability progression defined as 1-point increase in EDSS confirmed 3 months later

** p<0.001, *p<0.05 compared to placebo

All analyses of clinical endpoints were intent-to-treat. MRI analyses used evaluable dataset.

Patients who completed the 24-month core FREEDOMS study could enter a dose-blinded extensionstudy (D2301E1) and receive fingolimod. In total, 920 patients entered (n=331 continued on 0.5 mg,289 continued on 1.25 mg, 155 switched from placebo to 0.5 mg and 145 switched from placebo to1.25 mg). After 12 months (month 36), 856 patients (93%) were still enrolled. Between months 24 and36, the annualised relapse rate (ARR) for patients on fingolimod 0.5 mg in the core study whoremained on 0.5 mg was 0.17 (0.21 in the core study). The ARR for patients who switched fromplacebo to fingolimod 0.5 mg was 0.22 (0.42 in the core study).

Comparable results were shown in a replicate 2-year randomised, double-blind, placebo-controlled

Phase III study on fingolimod in 1 083 patients (n=358 on 0.5 mg, 370 on 1.25 mg, 355 on placebo)with RRMS (D2309; FREEDOMS 2). Median values for baseline characteristics were: age 41 years,disease duration 8.9 years, EDSS score 2.5.

Table 2 Study D2309 (FREEDOMS 2): main results

Fingolimod Placebo0.5 mg

Clinical endpoints

Annualised relapse rate (primary endpoint) 0.21** 0.40

Percentage of patients remaining relapse-free at 71.5%** 52.7%24 months

Proportion with 3-month Confirmed Disability 25% 29%

Progression†

Hazard ratio (95% CI) 0.83 (0.61, 1.12)

MRI endpoints

Median (mean) number of new or enlarging T2 0.0 (2.3)** 4.0 (8.9)lesions over 24 months

Median (mean) number of Gd-enhancing lesions 0.0 (0.4)** 0.0 (1.2)at month 24

Median (mean) % change in brain volume over -0.71 (-0.86)** -1.02 (-1.28)24 months† Disability progression defined as 1-point increase in EDSS confirmed 3 months later

** p<0.001 compared to placebo

All analyses of clinical endpoints were intent-to-treat. MRI analyses used evaluable dataset.

Study D2302 (TRANSFORMS) was a 1-year randomised, double-blind, double-dummy, active(interferon beta-1a)-controlled Phase III study of 1 280 patients (n=429 on 0.5 mg, 420 on 1.25 mg,431 on interferon beta-1a, 30 µg by intramuscular injection once weekly). Median values for baselinecharacteristics were: age 36 years, disease duration 5.9 years, and EDSS score 2.0. Outcome resultsare shown in Table 3. There were no significant differences between the 0.5 mg and the 1.25 mg dosesas regards study endpoints.

Table 3 Study D2302 (TRANSFORMS): main results

Fingolimod Interferon beta-0.5 mg 1a, 30 μg

Clinical endpoints

Annualised relapse rate (primary endpoint) 0.16** 0.33

Percentage of patients remaining relapse-free at 83%** 71%12 months

Proportion with 3-month Confirmed Disability 6% 8%

Progression†

Hazard ratio (95% CI) 0.71 (0.42, 1.21)

MRI endpoints

Median (mean) number of new or enlarging T2 0.0 (1.7)* 1.0 (2.6)lesions over 12 months

Median (mean) number of Gd-enhancing lesions 0.0 (0.2)** 0.0 (0.5)at 12 months

Median (mean) % change in brain volume over -0.2 (-0.3)** -0.4 (-0.5)12 months† Disability progression defined as 1-point increase in EDSS confirmed 3 months later.

* p<0.01,** p<0.001, compared to interferon beta-1a

All analyses of clinical endpoints were intent-to-treat. MRI analyses used evaluable dataset.

Patients who completed the 12-month core TRANSFORMS study could enter a dose-blindedextension (D2302E1) and receive fingolimod. In total, 1 030 patients entered, however, 3 of thesepatients did not receive treatment (n=356 continued on 0.5 mg, 330 continued on 1.25 mg, 167switched from interferon beta-1a to 0.5 mg and 174 from interferon beta-1a to 1.25 mg). After12 months (month 24), 882 patients (86%) were still enrolled. Between months 12 and 24, the ARRfor patients on fingolimod 0.5 mg in the core study who remained on 0.5 mg was 0.20 (0.19 in the corestudy). The ARR for patients who switched from interferon beta-1a to fingolimod 0.5 mg was 0.33(0.48 in the core study).

Pooled results of Studies D2301 and D2302 showed a consistent and statistically significant reductionin annualised relapse rate compared to comparator in subgroups defined by gender, age, prior multiplesclerosis therapy, disease activity or disability levels at baseline.

Further analyses of clinical trial data demonstrate consistent treatment effects in highly activesubgroups of relapsing remitting multiple sclerosis patients.

The efficacy and safety of once-daily doses of fingolimod 0.25 mg or 0.5 mg (dose selected based onbody weight and exposure measurements) have been established in paediatric patients aged 10 to<18 years with relapsing-remitting multiple sclerosis.

Study D2311 (PARADIGMS) was a double-blind, double-dummy, active-controlled study withflexible duration up to 24 months, with 215 patients 10 to <18 years old (n=107 on fingolimod, 108 oninterferon beta-1a 30 µg by intramuscular injection once weekly).

Median values for baseline characteristics were: age 16 years, median disease duration 1.5 years and

EDSS score 1.5. The majority of patients were Tanner stage 2 or higher (94.4%) and were >40 kg(95.3%). Overall, 180 (84%) of patients completed the core phase on study drug (n=99 [92.5%] onfingolimod, 81 [75%] on interferon beta-1a). Outcome results are shown in Table 4.

Table 4 Study D2311 (PARADIGMS): main results

Fingolimod Interferon beta-1a0.25 mg or 0.5 mg 30 µg

Clinical endpoints N=107 N=107#

Annualised relapse rate (primary endpoint) 0.122** 0.675

Percentage of patients remaining relapse-free at 85.7** 38.824 months

MRI endpoints

Annualised rate of the number of new or newly n=106 n=102enlarging T2 lesions

Adjusted mean 4.393** 9.269

Number of Gd-enhancing T1 lesions per scan up to n=106 n=101month 24

Adjusted mean 0.436** 1.282

Annualised rate of brain atrophy from baseline up to n=96 n=89month 24

Least Square Mean -0.48* -0.80# One patient randomised to receive interferon beta-1a by intramuscular injection was unable toswallow the double-dummy medication and discontinued from study. The patient wasexcluded from the full analysis and safety set.

* p<0.05, ** p<0.001, compared to interferon beta-1a.

All analyses of clinical endpoints were on the full analysis set.

Pharmacokinetic data were obtained in healthy adult volunteers, in renal transplant adult patients andin multiple sclerosis adult patients.

The pharmacologically active metabolite responsible for efficacy is fingolimod phosphate.

Fingolimod absorption is slow (tmax of 12-16 hours) and extensive (≥85%). The apparent absolute oralbioavailability is 93% (95% confidence interval: 79-111%). Steady-state-blood concentrations arereached within 1 to 2 months following once-daily administration and steady-state levels areapproximately 10-fold greater than with the initial dose.

Food intake does not alter Cmax or exposure (AUC) of fingolimod. Fingolimod phosphate Cmax wasslightly decreased by 34% but AUC was unchanged. Therefore, Gilenya may be taken without regardto meals (see section 4.2).

Fingolimod highly distributes in red blood cells, with the fraction in blood cells of 86%. Fingolimodphosphate has a smaller uptake in blood cells of <17%. Fingolimod and fingolimod phosphate arehighly protein bound (>99%).

Fingolimod is extensively distributed to body tissues with a volume of distribution of about1 200260 litres. A study in four healthy subjects who received a single intravenous dose of aradioiodolabelled analogue of fingolimod demonstrated that fingolimod penetrates into the brain. In astudy in 13 male multiple sclerosis patients who received fingolimod 0.5 mg/day, the mean amount offingolimod (and fingolimod phosphate) in seminal ejaculate, at steady-state, was approximately10 000 times lower than the oral dose administered (0.5 mg).

Fingolimod is transformed in humans by reversible stereoselective phosphorylation to thepharmacologically active (S)-enantiomer of fingolimod phosphate. Fingolimod is eliminated byoxidative biotransformation catalysed mainly via CYP4F2 and possibly other isoenzymes andsubsequent fatty acid-like degradation to inactive metabolites. Formation of pharmacologicallyinactive non-polar ceramide analogues of fingolimod was also observed. The main enzyme involved inthe metabolism of fingolimod is partially identified and may be either CYP4F2 or CYP3A4.

Following single oral administration of [14C] fingolimod, the major fingolimod-related components inblood, as judged from their contribution to the AUC up to 34 days post dose of total radiolabelledcomponents, are fingolimod itself (23%), fingolimod phosphate (10%), and inactive metabolites (M3carboxylic acid metabolite (8%), M29 ceramide metabolite (9%) and M30 ceramide metabolite (7%)).

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 and fingolimod phosphate decline in parallel in the terminalphase, leading to similar half-lives for both.

After oral administration, about 81% of the dose is slowly excreted in the urine as inactivemetabolites. Fingolimod and fingolimod phosphate are not excreted intact in urine but are the majorcomponents 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%.

Fingolimod and fingolimod phosphate concentrations increase in an apparently dose proportionalmanner after multiple once-daily doses of 0.5 mg or 1.25 mg.

Characteristics in specific groups of patients

Gender, ethnicity and renal impairment

The pharmacokinetics of fingolimod and fingolimod-phosphate do not differ in males and females, inpatients of different ethnic origin, or in patients with mild to severe renal impairment.

In subjects with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, and C), nochange in fingolimod Cmax was observed, but fingolimod AUC was increased respectively 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 pharmacokineticsof fingolimod-phosphate were not evaluated in patients with mild or moderate hepatic impairment.

The apparent elimination half-life of fingolimod is unchanged in subjects with mild hepaticimpairment, but is prolonged by about 50% in patients with moderate or severe hepatic impairment.

Fingolimod should not be used in patients with severe hepatic impairment (Child-Pugh class C) (seesection 4.3). Fingolimod should be introduced cautiously in mild and moderate hepatic impairedpatients (see section 4.2).

Clinical experience and pharmacokinetic information in patients aged above 65 years are limited.

Gilenya should be used with caution in patients aged 65 years and over (see section 4.2).

In paediatric patients (10 years of age and above), fingolimod-phosphate concentrations increase in anapparent dose proportional manner between 0.25 mg and 0.5 mg.

Fingolimod-phosphate concentration at steady state is approximately 25% lower in paediatric patients(10 years of age and above) following daily administration of 0.25 mg or 0.5 mg fingolimod comparedto the concentration in adult patients treated with fingolimod 0.5 mg once daily.

There are no data available for paediatric patients below 10 years old.

The preclinical safety profile of fingolimod was assessed in mice, rats, dogs and monkeys. The majortarget organs were the lymphoid system (lymphopenia and lymphoid atrophy), lungs (increasedweight, smooth muscle hypertrophy at the bronchio-alveolar junction), and heart (negativechronotropic effect, increase in blood pressure, perivascular changes and myocardial degeneration) inseveral species; blood vessels (vasculopathy) in rats only at doses of 0.15 mg/kg and higher in a 2-yearstudy, representing an approximate 4-fold margin based on the human systemic exposure (AUC) at adaily dose of 0.5 mg.

No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of fingolimodup to the maximally tolerated dose of 2.5 mg/kg, representing an approximate 50-fold margin based onhuman systemic exposure (AUC) at the 0.5 mg dose. However, in a 2-year mouse study, an increasedincidence of malignant lymphoma was seen at doses of 0.25 mg/kg and higher, representing anapproximate 6-fold margin based on the human systemic exposure (AUC) at a daily dose of 0.5 mg.

Fingolimod was neither mutagenic nor clastogenic in animal studies.

Fingolimod had no effect on sperm count/motility or on fertility in male and female rats up to thehighest dose tested (10 mg/kg), representing an approximate 150-fold margin based on humansystemic exposure (AUC) at a daily dose of 0.5 mg.

Fingolimod was teratogenic in the rat when given at doses of 0.1 mg/kg or higher. Drug exposure inrats at this dose was similar to that in patients at the therapeutic dose (0.5 mg). The most commonfoetal visceral malformations included persistent truncus arteriosus and ventricular septum defect. Theteratogenic potential in rabbits could not be fully assessed, however an increased embryo-foetalmortality was seen at doses of 1.5 mg/kg and higher, and a decrease in viable foetuses as well as foetalgrowth retardation was seen at 5 mg/kg. Drug exposure in rabbits at these doses was similar to that inpatients.

In rats, F1 generation pup survival was decreased in the early postpartum period at doses that did notcause maternal toxicity. However, F1 body weights, development, behaviour, and fertility were notaffected by treatment with fingolimod.

Fingolimod was excreted in milk of treated animals during lactation at concentrations 2-fold to 3-foldhigher than that found in maternal plasma. Fingolimod and its metabolites crossed the placental barrierin pregnant rabbits.

Results from two toxicity studies in juvenile rats showed slight effects on neurobehavioural response,delayed sexual maturation and a decreased immune response to repeated stimulations with keyholelimpet haemocyanin (KLH), which were not considered adverse. Overall, the treatment-related effectsof fingolimod in juvenile animals were comparable to those seen in adult rats at similar dose levels,with the exception of changes in bone mineral density and neurobehavioural impairment (reducedauditory startle response) observed at doses of 1.5 mg/kg and higher in juvenile animals and theabsence of smooth muscle hypertrophy in the lungs of the juvenile rats.

Gilenya 0.25 mg hard capsules

Capsule fill

Mannitol

Hydroxypropylcellulose

Hydroxypropylbetadex

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

Shellac (E904)

Black iron oxide (E172)

Propylene glycol (E1520)

Ammonia solution, concentrated (E527)

Gilenya 0.5 mg hard capsules

Capsule fill

Mannitol

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Yellow iron oxide (E172)

Shellac (E904)

Ethanol, anhydrous

Isopropyl alcohol

Butyl alcohol

Propylene glycol (E1520)

Purified water

Ammonia solution, concentrated (E527)

Potassium hydroxide

Black iron oxide (E172)

Yellow iron oxide (E172)

Titanium dioxide (E171)

Dimethicone

Not applicable.

Gilenya 0.25 mg hard capsules2 years

Gilenya 0.5 mg hard capsules2 years

Do not store above 25°C.

Store in the original package in order to protect from moisture.

Gilenya 0.25 mg hard capsules

PVC/PVDC/aluminium blister packs containing 7 or 28 hard capsules.

PVC/PVDC/aluminium perforated unit dose blister packs containing 7x 1 hard capsules.

Gilenya 0.5 mg hard capsules

PVC/PVDC/aluminium blister packs containing 7, 28 or 98 hard capsules.

PVC/PVDC/aluminium blister packs containing 7 or 28 hard capsules presented in wallets ormultipacks containing 84 (3 packs of 28) hard capsules presented in wallets.

PVC/PVDC/aluminium perforated unit dose blister packs containing 7x 1 hard capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Gilenya 0.25 mg hard capsules

EU/1/11/677/007-009

Gilenya 0.5 mg hard capsules

EU/1/11/677/001-006

EU/1/11/677/010

Date of first authorisation: 17 March 2011

Date of latest renewal: 16 November 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu