Fingolimod

Overdose

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

Fingolimod can induce bradycardia upon treatment initiation. The decline in heart rate usually starts within 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. There have been reports of slow atrioventricular conduction, with isolated reports of transient, spontaneously resolving complete AV block.

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

Additionally, if after 6 hours the heart rate is <45 bpm or if the ECG at 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 monitoring including overnight monitoring.

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

Fingolimod price

Contraindications

Known immunodeficiency syndrome.

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

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

Known active malignancies.

Severe liver impairment (Child-Pugh class C).

Patients with myocardial infarction (MI), unstable angina pectoris, stroke/transient ischaemic attack (TIA), decompensated heart failure (requiring inpatient treatment), or New York Heart Association (NYHA) class III/IV heart failure in the previous 6 months.

Patients with severe cardiac arrhythmias requiring anti-arrhythmic treatment with class Ia or class III anti-arrhythmic drugs.

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

Patients with a baseline QTc interval >500 msec.

Incompatibilities

Not applicable.

Undesirable effects

Summary of the safety profile

The safety population of Gilenya is derived from two Phase III placebo-controlled clinical studies and one Phase III active-controlled clinical study in patients with relapsing remitting multiple sclerosis. It includes a total of 2,431 patients on Gilenya (0.5 or 1.25 mg). Study D2301 (FREEDOMS) was a 2-year placebo-controlled clinical study in 854 patients treated with fingolimod (placebo: 418). Study D2309 (FREEDOMS II) was a 2-year placebo-controlled clinical study in 728 multiple sclerosis patients treated with fingolimod (placebo: 355). In the pooled data from these two studies the most serious adverse reactions on Gilenya 0.5 mg were infections, macular oedema and transient atrioventricular block at treatment initiation. The most frequent adverse reactions (incidence >10%) on Gilenya 0.5 mg were influenza, sinusitis, headache, diarrhoea, back pain, hepatic enzyme increased and cough. The most frequent adverse reaction reported for Gilenya 0.5 mg leading to treatment interruption was ALT elevations (2.2%). The adverse reactions in Study D2302 (TRANSFORMS), a 1-year study in 849 patients treated with fingolimod which used interferon beta-1a as comparator, were generally similar to placebo-controlled studies, taking into account the differences in study duration.

Adverse reactions reported with Gilenya 0.5 mg in Studies D2301 (FREEDOMS) and D2309 (FREEDOMS II) are shown below. Frequencies were defined using the following 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 the available data).

Tabulated list of adverse reactions

* Not reported in Studies FREEDOMS, FREEDOMS II and TRANSFORMS. The frequency category was based on an estimated exposure of approximately 10, 000 patients to fingolimod in all clinical trials.

** PML and cryptococcal infections (including cases of cryptococcal meningitis) have been reported in the post-marketing setting.

*** Adverse drug reactions from spontaneous reports and literature.

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

Description of selected adverse reactions

Infections

In multiple sclerosis clinical studies the overall rate of infections (65.1%) at the 0.5 mg dose was similar to placebo. However, lower respiratory tract infections, primarily bronchitis and to a lesser extent herpes infection and pneumonia were more common in Gilenya-treated patients.

Some cases of 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 cryptococcal meningitis) or bacterial (e.g. atypical mycobacterium), have been reported, some of which have been fatal.

Macular oedema

In multiple sclerosis clinical studies macular oedema occurred in 0.5% of patients treated with the recommended dose of 0.5 mg and 1.1% of patients treated with the higher dose of 1.25 mg. The majority of cases occurred within the first 3-4 months of therapy. Some patients presented with blurred vision or decreased visual acuity, but others were asymptomatic and diagnosed on routine ophthalmological examination. The macular oedema generally improved or resolved spontaneously after discontinuation of Gilenya. 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 in multiple sclerosis patients with diabetes mellitus, a disease which is associated with an increased risk for macular oedema. In renal transplant clinical studies in which patients with diabetes mellitus were included, therapy with fingolimod 2.5 mg and 5 mg resulted in a 2-fold increase in the incidence of macular oedema.

Bradyarrhythmia

Initiation of Gilenya treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays.1).

In multiple sclerosis clinical studies first-degree atrioventricular block (prolonged PR interval on ECG) was detected after treatment initiation in 4.7% of patients on fingolimod 0.5 mg, in 2.8% of patients on intramuscular interferon beta-1a, and in 1.6% of patients on placebo. Second-degree atrioventricular block was detected in less than 0.2% patients on Gilenya 0.5 mg. In the post-marketing setting, isolated reports of transient, spontaneously resolving complete AV block have been observed during the six hour monitoring period following the first dose of Gilenya. The patients recovered spontaneously. The conduction 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 patients did not require medical intervention, one patient on Gilenya 0.5 mg received isoprenaline for asymptomatic second-degree Mobitz I atrioventricular block.

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

Blood pressure

In multiple sclerosis clinical studies Gilenya 0.5 mg was associated with an average increase of approximately 3 mmHg in systolic pressure and approximately 1 mmHg in diastolic pressure, manifesting approximately 1 month after treatment initiation.).

Liver function

Increased hepatic enzymes have been reported in multiple sclerosis patients treated with Gilenya.).

Nervous system disorders

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

Vascular disorders

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

Respiratory system

Minor dose-dependent reductions in values for forced expiratory volume (FEV1) and diffusion capacity for carbon monoxide (DLCO) were observed with Gilenya treatment starting at Month 1 and remaining 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 treatment discontinuation. For DLCO the reductions at Month 24 were 3.3% for fingolimod 0.5 mg and 2.7% for placebo.

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. The incidence of lymphoma (B-cell and T-cell) cases was higher in clinical trials than expected in the general population. Some T-cell lymphoma cases were also reported in the post-marketing setting.

Haemophagocytic syndrome

Very rare cases of haemophagocytic syndrome (HPS) with fatal outcome have been reported 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 suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Preclinical safety data

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

No evidence of carcinogenicity was observed in a 2-year bioassay in rats at oral doses of fingolimod up to the maximally tolerated dose of 2.5 mg/kg, representing an approximate 50-fold margin based on human systemic exposure (AUC) at the 0.5 mg dose. However, in a 2-year mouse study, an increased incidence of malignant lymphoma was seen at doses of 0.25 mg/kg and higher, representing an approximate 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 the highest dose tested (10 mg/kg), representing an approximate 150-fold margin based on human systemic 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 in rats at this dose was similar to that in patients at the therapeutic dose (0.5 mg). The most common foetal visceral malformations included persistent truncus arteriosus and ventricular septum defect. The teratogenic potential in rabbits could not be fully assessed, however an increased embryo-foetal mortality was seen at doses of 1.5 mg/kg and higher, and a decrease in viable foetuses as well as foetal growth retardation was seen at 5 mg/kg. Drug exposure in rabbits at these doses was similar to that in patients.

In rats, F1 generation pup survival was decreased in the early postpartum period at doses that did not cause maternal toxicity. However, F1 body weights, development, behaviour, and fertility were not affected by treatment with fingolimod.

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

Environmental Risk Assessment (ERA)

A risk for the environment due to use of Gilenya by patients with relapsing multiple sclerosis is not expected.

Therapeutic indications

Gilenya is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following adult patient groups:

- Patients with highly active disease despite a full and adequate course of treatment with at least one disease modifying therapy.

or

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

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Selective immunosuppressants, ATC code: L04AA27

Mechanism of action

Fingolimod is a sphingosine 1-phosphate receptor modulator. Fingolimod is metabolised by sphingosine kinase to the active metabolite fingolimod phosphate. Fingolimod phosphate binds at low nanomolar concentrations to sphingosine 1-phosphate (S1P) receptor 1 located on lymphocytes, and readily crosses the blood-brain barrier to bind to S1P receptor 1 located on neural cells in the central nervous 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 a redistribution, rather than depletion, of lymphocytes. Animal studies have shown that this redistribution reduces the infiltration of pathogenic lymphocytes, including pro-inflammatory Th17 cells, 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 S1P receptors on neural cells.

Pharmacodynamic effects

Within 4-6 hours after the first dose of fingolimod 0.5 mg, the lymphocyte count decreases to approximately 75% of baseline in peripheral blood. With continued daily dosing, the lymphocyte count continues to decrease over a two-week period, reaching a minimal count of approximately 500 cells/microlitre or approximately 30% of baseline. Eighteen percent of patients reached a minimal count below 200 cells/microlitre on at least one occasion. Low lymphocyte counts are maintained with chronic daily dosing. The majority of T and B lymphocytes regularly traffic through lymphoid organs and these are the cells mainly affected by fingolimod. Approximately 15-20% of T lymphocytes have an effector memory phenotype, cells that are important for peripheral immune surveillance. Since this lymphocyte subset typically does not traffic to lymphoid organs it is not affected by fingolimod. Peripheral lymphocyte count increases are evident within days of stopping fingolimod treatment and typically normal counts are reached within one to two months. Chronic fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of baseline. Monocytes are unaffected by fingolimod.

Fingolimod causes a transient reduction in heart rate and decrease in atrioventricular conduction at treatment initiation. The maximal decline in heart rate is seen within 6 hours post dose, with 70% of the negative chronotropic effect achieved on the first day. With continued administration heart rate returns to baseline within one month. The decrease in heart rate induced by fingolimod can be reversed by parenteral doses of atropine or isoprenaline. Inhaled salmeterol has also been shown to have a modest positive chronotropic effect. With initiation of fingolimod treatment there is an increase in atrial premature contractions, but there is no increased rate of atrial fibrillation/flutter or ventricular arrhythmias or ectopy. Fingolimod treatment is not associated with a decrease in cardiac output. Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise are not affected by fingolimod treatment.

Fingolimod treatment with single or multiple doses of 0.5 and 1.25 mg for two weeks is not associated with a detectable increase in airway resistance as measured by FEV1 and forced expiratory flow rate (FEF) 25-75. However, single fingolimod doses >5 mg (10-fold the recommended dose) are associated with a dose-dependent increase in airway resistance. Fingolimod treatment with multiple doses of 0.5, 1.25, or 5 mg is not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in airway responsiveness to methacholine. Subjects on fingolimod treatment have a normal bronchodilator response to inhaled beta-agonists.

Clinical efficacy and safety

The efficacy of Gilenya has been demonstrated in two studies which evaluated once-daily doses of fingolimod 0.5 mg and 1.25 mg in patients with relapsing-remitting multiple sclerosis (RRMS). Both studies included patients who had experienced >2 relapses in the prior 2 years or >1 relapse during the prior year. Expanded Disability Status Score (EDSS) was between 0 and 5.5. A third study targeting the same patient population was completed after registration of Gilenya.

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

Table 1: Study D2301 (FREEDOMS): Main results

Patients who completed the 24-month core FREEDOMS study could enter a dose-blinded extension study (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 to 1.25 mg). After 12 months (month 36), 856 patients (93%) were still enrolled. Between months 24 and 36, the annualised relapse rate (ARR) for patients on fingolimod 0.5 mg in the core study who remained on 0.5 mg was 0.17 (0.21 in the core study). The ARR for patients who switched from placebo 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

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 baseline characteristics were: age 36 years, disease duration 5.9 years, and EDSS score 2.0. Outcome results are shown in Table 3. There were no significant differences between the 0.5 mg and the 1.25 mg doses as regards study endpoints.

Table 3: Study D2302 (TRANSFORMS): Main results

Patients who completed the 12-month core TRANSFORMS study could enter a dose-blinded extension (D2302E1) and receive fingolimod. In total, 1,030 patients entered, however, 3 of these patients did not receive treatment (n=356 continued on 0.5 mg, 330 continued on 1.25 mg, 167 switched from interferon beta-1a to 0.5 mg and 174 from interferon beta-1a to 1.25 mg). After 12 months (month 24), 882 patients (86%) were still enrolled. Between months 12 and 24, the ARR for patients on fingolimod 0.5 mg in the core study who remained on 0.5 mg was 0.20 (0.19 in the core study). 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 reduction in annualised relapse rate compared to comparator in subgroups defined by gender, age, prior multiple sclerosis therapy, disease activity or disability levels at baseline.

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

).

Pharmacokinetic properties

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

The pharmacologically active metabolite responsible for efficacy is fingolimod phosphate.

Absorption

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

Food intake does not alter Cmax or exposure (AUC) of fingolimod. Fingolimod phosphate Cmax was slightly decreased by 34% but AUC was unchanged. Therefore, Gilenya may be taken without regard to meals.

Distribution

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

Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1,200±260 litres. A study in four healthy subjects who received a single intravenous dose of a radioiodolabelled analogue of fingolimod demonstrated that fingolimod penetrates into the brain. In a study in 13 male multiple sclerosis patients who received Gilenya 0.5 mg/day, the mean amount of fingolimod (and fingolimod phosphate) in seminal ejaculate, at steady-state, was approximately 10,000 times lower than the oral dose administered (0.5 mg).

Biotransformation

Fingolimod is transformed in humans by reversible stereoselective phosphorylation to the pharmacologically active (S)-enantiomer of fingolimod phosphate. Fingolimod is eliminated by oxidative biotransformation catalysed mainly via CYP4F2 and possibly other isoenzymes and subsequent fatty acid-like degradation to inactive metabolites. Formation of pharmacologically inactive non-polar ceramide analogues of fingolimod was also observed. The main enzyme involved in the 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 in blood, as judged from their contribution to the AUC up to 34 days post dose of total radiolabelled components, are fingolimod itself (23%), fingolimod phosphate (10%), and inactive metabolites (M3 carboxylic acid metabolite (8%), M29 ceramide metabolite (9%) and M30 ceramide metabolite (7%)).

Elimination

Fingolimod blood clearance is 6.3±2.3 l/h, and the average apparent terminal half-life (t1/2) is 6-9 days. Blood levels of fingolimod and fingolimod phosphate decline in parallel in the terminal phase, leading to similar half-lives for both.

After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingolimod and fingolimod phosphate are not excreted intact in urine but are the major components in the faeces, with amounts representing less than 2.5% of the dose each. After 34 days, the recovery of the administered dose is 89%.

Linearity

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

Characteristics in specific groups of patients

The pharmacokinetics of fingolimod and fingolimod phosphate do not differ in males and females, in patients 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), no change 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 pharmacokinetics of 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 hepatic impairment, 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). Fingolimod should be introduced cautiously in mild and moderate hepatic impaired patients.

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.

Paediatric population

There are limited data available from a renal transplant study that included 7 children above 11 years of age (study FTY720A0115). The comparison of these data to those in adult healthy volunteers is of limited relevance and no valid conclusions can be drawn regarding the pharmacokinetic properties of fingolimod in children.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Bradyarrhythmia

Initiation of Gilenya treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays, including the occurrence of isolated reports of transient, spontaneously resolving complete AV block.

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 usually abates over the next weeks. With continued administration, the average heart rate returns towards baseline within one month. However individual patients may not return to baseline heart rate by the end of the first month. Conduction abnormalities were typically transient and asymptomatic. They usually did not require treatment and resolved within the first 24 hours on treatment. If necessary, the decrease in heart rate induced by fingolimod can be reversed by parenteral doses of atropine or isoprenaline.

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

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

If the heart rate at 6 hours is the lowest since the first dose was administered (suggesting that the maximum pharmacodynamic effect on the heart may not yet be manifest), monitoring should be extended by at least 2 hours and until heart rate increases again. Additionally, if after 6 hours, the heart rate is <45 bpm, or the ECG shows new onset second degree or higher grade 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).

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

Due to the risk of serious rhythm disturbances, Gilenya should not be used in patients with sino-atrial heart block, a history of symptomatic bradycardia or recurrent syncope, or in patients with significant QT prolongation (QTc>470msec (female) or >450msec (male)).).).

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) antiarrhythmic medicinal products. Class Ia and class III antiarrhythmic medicinal products have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of Gilenya treatment results in decreased heart rate, Gilenya should not be used concomitantly with these medicinal products.

Experience with Gilenya is limited in patients receiving concurrent therapy with beta blockers, heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem), or other substances which may decrease heart rate (e.g. ivabradine, digoxin, anticholinesteratic agents or pilocarpine).), concomitant use of these substances during Gilenya initiation may be associated with severe bradycardia and heart block.).).

The effects on heart rate and atrioventricular conduction may recur on re-introduction of Gilenya treatment depending on duration of the interruption and time since start of Gilenya treatment. The same first dose monitoring as for treatment initiation is recommended when treatment is interrupted 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 continued with the next dose as planned.

QT interval

In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTcI, with the upper limit of the 90% CI ≤13.0 ms. There is no dose- or exposure-response relationship of fingolimod and QTcI prolongation. There is no consistent signal of increased incidence of QTcI outliers, either absolute or change from baseline, associated with fingolimod treatment.

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

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

Immunosuppressive effects

Fingolimod has an immunosuppressive effect that predisposes patients to an infection risk, including opportunistic infections that can be fatal, and increases the risk of developing lymphomas and other malignancies, particularly those of the skin.“Infections” and “Cutaneous neoplasms” and section 4.8 “Lymphomas”).

Infections

A core pharmacodynamic effect of Gilenya is a dose-dependent reduction of the peripheral lymphocyte count to 20-30% of baseline values. This is due to the reversible sequestration of lymphocytes in lymphoid tissues.

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

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

Patients need to be assessed for their immunity to varicella (chickenpox) prior to Gilenya treatment. It is recommended that patients without a health care professional confirmed history of chickenpox or documentation of a full course of vaccination with varicella vaccine undergo antibody testing to varicella zoster virus (VZV) before initiating Gilenya therapy. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with Gilenya. Initiation of treatment with Gilenya should be postponed for 1 month to allow full effect of vaccination to occur.

The immune system effects of Gilenya may increase the risk of infections, including opportunistic infections. Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy. When evaluating a patient with a suspected infection that could be serious, referral to a physician experienced in treating infections should be considered. During treatment, patients receiving Gilenya should be instructed to report promptly symptoms of infection to their physician.

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

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 the duration of treatment is unknown. Patients with symptoms and signs consistent with cryptococcal meningitis (e.g. headache accompanied by mental changes such as confusion, hallucinations, and/or personality changes) should undergo prompt diagnostic evaluation. If cryptococcal meningitis is diagnosed, fingolimod should be suspended and appropriate treatment should be initiated. A multidisciplinary consultation (i.e. infectious disease specialist) should be undertaken if re-initiation of fingolimod is warranted.

Progressive multifocal leukoencephalopathy (PML) has been reported under fingolimod treatment since marketing authorisation. PML is an opportunistic infection caused by John Cunningham virus (JCV), which may be fatal or result in severe disability. Cases of PML have occurred after approximately 2-3 years of monotherapy treatment without previous exposure to natalizumab, although an exact relationship with the duration of treatment is unknown. Additional PML cases have occurred in patients who had been treated previously with natalizumab, which has a known association with PML. PML can only occur in the presence of a JCV infection. If JCV testing is undertaken, it should be considered that the influence of lymphopenia on the accuracy of anti-JCV antibody testing has not been studied in fingolimod-treated patients. It should also be noted that a negative anti-JCV antibody test does not preclude the possibility of subsequent JCV infection. Before initiating treatment with fingolimod, a baseline MRI should be available (usually within 3 months) as a reference. During routine MRI (in accordance with national and local recommendations), physicians should pay attention to PML suggestive lesions. MRI may be considered as part of increased vigilance in patients considered at increased risk of PML. If PML is suspected, MRI should be performed immediately for diagnostic purposes and treatment with fingolimod should be suspended until PML has been excluded.

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

Macular oedema

Macular oedema with or without visual symptoms has been reported in 0.5% of patients treated with fingolimod 0.5 mg, occurring predominantly in the first 3-4 months of therapy. An ophthalmological evaluation is therefore recommended at 3-4 months after treatment initiation. If patients report visual disturbances at any time while on therapy, evaluation of the fundus, including the macula, should be carried out.

Patients with history of uveitis and patients with diabetes mellitus are at increased risk of macular oedema. Gilenya has not been studied in multiple sclerosis patients with concomitant diabetes mellitus. It is recommended that multiple sclerosis patients with diabetes mellitus or a history of uveitis undergo an ophthalmological evaluation prior to initiating therapy and have follow-up evaluations while receiving therapy.

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

Liver function

Increased hepatic enzymes, in particular alanine aminotransaminase (ALT) but also gamma glutamyltransferase (GGT) and aspartate transaminase (AST) have been reported in multiple sclerosis patients treated with Gilenya. In clinical trials, elevations 3-fold the upper limit of normal (ULN) or greater in ALT occurred in 8.0% of patients treated with fingolimod 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 was discontinued if the elevation exceeded 5 times the ULN. Recurrence of liver transaminase elevations occurred 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 within the first 12 months. Serum transaminase levels returned to normal within approximately 2 months after discontinuation of fingolimod.

Gilenya has not been studied in patients with severe pre-existing hepatic injury (Child-Pugh class C) and should not be used in these patients.

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

Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with Gilenya. In the absence of clinical symptoms, liver transaminases should be monitored at Months 1, 3, 6, 9 and 12 on therapy and periodically thereafter. If liver transaminases rise above 5 times the ULN, more frequent monitoring should be instituted, including serum bilirubin and alkaline phosphatase (ALP) measurement. With repeated confirmation of liver transaminases above 5 times the ULN, treatment with Gilenya should be interrupted and only re-commenced once liver transaminase values have normalised.

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 enzymes checked and Gilenya should be discontinued if significant liver injury is confirmed (for example liver transaminase levels greater than 5-fold the ULN and/or serum bilirubin elevations). Resumption of therapy will be dependent on whether or not another cause of liver injury is determined and on the benefits to patient of resuming therapy versus the risks of recurrence of liver dysfunction.

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

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 a patient treated with Gilenya. Laboratory tests involving the use of circulating mononuclear cells require larger blood volumes due to reduction in the number of circulating lymphocytes.

Blood pressure effects

Patients with hypertension uncontrolled by medication were excluded from participation in premarketing clinical trials and special care is indicated if patients with uncontrolled hypertension are treated with Gilenya.

In MS clinical trials, patients treated with fingolimod 0.5 mg had an average increase of approximately 3 mmHg in systolic pressure, and approximately 1 mmHg in diastolic pressure, first detected approximately 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 on fingolimod 0.5 mg and in 3.3% of patients on placebo. Therefore, blood pressure should be regularly monitored during treatment with Gilenya.

Respiratory effects

Minor dose-dependent reductions in values for forced expiratory volume (FEV1) and diffusion capacity for carbon monoxide (DLCO) were observed with Gilenya treatment starting at Month 1 and remaining stable thereafter.).

Posterior reversible encephalopathy syndrome

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

Prior treatment with immunosuppressive or immunomodulatory therapies

There have been no studies performed to evaluate the efficacy and safety of Gilenya when switching patients from teriflunomide, dimethyl fumarate or alemtuzumab treatment to Gilenya. When switching patients from another disease modifying therapy to Gilenya, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimising the risk of disease reactivation. A CBC is recommended prior to initiating 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 treatment with Gilenya is started.

Due to the long half-life of natalizumab, elimination usually takes up to 2-3 months following discontinuation. Teriflunomide is also eliminated slowly from the plasma. Without an accelerated elimination procedure, clearance of teriflunomide from plasma can take from several months up to 2 years. An accelerated elimination procedure as defined in the teriflunomide summary of product characteristics is recommended or alternatively washout period should not be shorter than 3.5 months. Caution regarding potential concomitant immune effects is required when switching patients from natalizumab or teriflunomide to Gilenya.

Alemtuzumab has profound and prolonged immunosuppressive effects. As the actual duration of these effects is unknown, initiating treatment with Gilenya after alemtuzumab is not recommended unless the 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 careful consideration.

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.

Cutaneous neoplasms

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 patients receiving Gilenya. Vigilance for skin lesions is warranted and a medical evaluation of the skin is recommended at initiation, and then every 6 to 12 months taking into consideration clinical judgement. 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 be cautioned against exposure to sunlight without protection. These patients should not receive concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy.

Return of disease activity (rebound)

In the post-marketing setting, severe exacerbation of disease has been observed rarely in some patients stopping fingolimod. The possibility of recurrence of exceptionally high disease activity should be considered (see "Stopping therapy" below).

Stopping therapy

If a decision is made to stop treatment with Gilenya a 6 week interval without therapy is needed, based on half-life, to clear fingolimod from the circulation. Lymphocyte counts progressively return to normal range within 1-2 months of stopping therapy in most patients although full recovery can take significantly longer in some patients. Starting other therapies during this interval will result in concomitant exposure to fingolimod. Use of immunosuppressants soon after the discontinuation of Gilenya may lead to an additive effect on the immune system and caution is therefore indicated.

Caution is also indicated when stopping fingolimod therapy due to the risk of a rebound (see "Return of disease activity (rebound)" above). If discontinuation of Gilenya is deemed necessary, patients should be monitored during this time for relevant signs of a possible rebound.

Effects on ability to drive and use machines

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

However, dizziness or drowsiness may occasionally occur when initiating therapy with Gilenya. On initiation of Gilenya treatment it is recommended that patients be observed for a period of 6 hours.

Dosage (Posology) and method of administration

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

Posology

The recommended dose of Gilenya is one 0.5 mg capsule taken orally once daily. Gilenya can be taken with or without food.

The same first dose monitoring as for treatment initiation is recommended when treatment is interrupted 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 continued with the next dose as planned.

Special populations

Elderly population

Gilenya should be used with caution in patients aged 65 years and over due to insufficient data on safety and efficacy.

Renal impairment

Gilenya 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 to severe renal impairment.

Hepatic impairment

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

Diabetic patients

Gilenya has not been studied in multiple sclerosis patients with concomitant diabetes mellitus. Gilenya should be used with caution in these patients due to a potential increase in the risk of macular oedema. Regular ophthalmological examinations should be conducted in these patients to detect macular oedema.

Paediatric population

The safety and efficacy of Gilenya in children aged 0 to 18 years have not yet been established.

Special precautions for disposal and other handling

No special requirements.