Fegona is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis
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 least one disease
modifying therapy (for exceptions and information about washout periods see sections 4.4 and 5.1).
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
 

The treatment should be initiated and supervised by a physician experienced in multiple sclerosis.
Posology
In adults, the recommended dose of Fegona is one 0.5 mg capsule taken orally once daily.
In paediatric patients (10 years of age and above), the recommended dose is dependent on body weight:
- Paediatric patients with body weight ≤40 kg: one 0.25 mg capsule 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 above 40 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 first dose
monitoring as for treatment initiation.
Fegona can be taken with or without food.
The capsules should always be swallowed intact, without opening them.
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 (see section 4.4).
SPECIAL POPULATIONS
Elderly population
Fegona should be used with caution in patients aged 65 years and over due to insufficient data on safety and
efficacy (see section 5.2).
Renal impairment
Fegona 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
Fegona must not be used in patients with severe hepatic impairment (Child-Pugh class C) (see section 4.3).
Although no dose adjustments are needed in patients with mild or moderate hepatic impairment, caution should
be exercised when initiating treatment in these patients (see sections 4.4 and 5.2).
Paediatric population
The safety and efficacy of Fegona 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 (see sections 4.4, 4.8 and 5.1).
Method of administration
This medicinal product is for oral use
 

- 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). - 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 inpatient treatment), 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 or class III antiarrhythmic medicinal products (see section 4.4). - Patients with second-degree Mobitz type II atrioventricular (AV) block or third-degree AV block, or sicksinus syndrome, if they do not wear a pacemaker (see section 4.4). - Patients with a baseline QTc interval ≥ 500 msec (see section 4.4). - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Bradyarrhythmia
Initiation of Fegona 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 (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 postdose 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 Fegona. 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.
The same precautions as for the first dose are recommended when patients are switched from the 0.25 mg to the
0.5 mg daily dose.
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 Fegona.
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 in adults, <55
bpm in paediatric patients aged 12 years and above, or <60 bpm in paediatric patients aged 10 to below 12
years, or 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).
The effects on heart rate and atrioventricular conduction may recur on re-introduction of Fegona treatment
depending on duration of the interruption and time since start of Fegona 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.
Very rare cases of T-wave inversion have been reported in adult patients treated with fingolimod. In case of Twave 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 or significant bradycardia, Fegona should not be used in patients
with sino-atrial heart block, a history of symptomatic bradycardia, recurrent syncope or cardiac 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 hypertension or severe sleep apnoea (see also section 4.3).
In such patients, treatment with Fegona should be considered only if the anticipated benefits outweigh the
potential risks, and advice from a cardiologist sought prior to initiation of treatment in order to determine the
most appropriate monitoring. At least overnight extended monitoring is recommended for treatment initiation
(see also section 4.5).
Fegona 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 (see section 4.3).
Experience with Fegona is limited in patients receiving concurrent therapy with beta blockers, heart-ratelowering calcium channel blockers (such as verapamil or diltiazem), or other substances which may decrease
heart rate (e.g. ivabradine, digoxin, anticholinesteratic agents or pilocarpine). Since the initiation of Fegona
treatment is also associated with slowing of the heart rate (see also section 4.8, Bradyarrhythmia), concomitant
use of these substances during Fegona initiation may be associated with severe bradycardia and heart block.
Because of the potential additive effect on heart rate treatment with Fegona should not be initiated in patients
who are concurrently treated with these substances (see also section 4.5). In such patients, treatment with
Fegona should be considered only if the anticipated benefits outweigh the potential risks. If treatment with
Fegona is considered, advice from a cardiologist should be sought regarding the switch to non heart-rate
lowering medicinal products prior to initiation of treatment. If the heart-rate-lowering medication cannot be
stopped, cardiologist's advice should be sought to determine appropriate first dose monitoring, at least overnight
extended monitoring is recommended (see also section 4.5).
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. Physicians should carefully monitor patients, especially those with
concurrent conditions or known factors, such as previous immunosuppressive therapy. If this 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 neoplasms” and section 4.8 “Lymphomas”).
Infections
A core pharmacodynamic effect of Fegona 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 (see
section 5.1).
Before initiating treatment with Fegona, 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 Fegona should be delayed in patients with severe active infection until resolution.
Patients need to be assessed for their immunity to varicella (chickenpox) prior to Fegona 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 Fegona therapy. A full course of vaccination for antibody-negative patients with
varicella vaccine is recommended prior to commencing treatment with Fegona (see section 4.8). Initiation of
treatment with Fegona should be postponed for 1 month to allow full effect of vaccination to occur.
The immune system effects of Fegona may increase the risk of infections, including opportunistic infections
(see section 4.8). 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 Fegona should be instructed to report promptly symptoms of infection to their physician.
Suspension of Fegona 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 (see section 4.8). 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 (see section 4.8). 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.
Human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancer, has
been reported under treatment with fingolimod in the post-marketing setting. Due to the immunosuppressive
properties of fingolimod, vaccination against HPV should be considered prior to treatment initiation with
fingolimod taking into account vaccination recommendations. Cancer screening, including Pap test, is
recommended as per standard of care.
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 (see section 4.8). 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 (see
section 4.8). Fegona 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 Fegona in patients with macular oedema has not been evaluated. It is recommended that Fegona
be discontinued if a patient develops macular oedema. A decision on whether or not Fegona 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 Fegona.
In clinical trials, elevations 3-fold the upper limit of normal (ULN) or greater in ALT occurred in 8.0% of adult
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.
Fegona 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 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 Fegona. 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 Fegona
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
Fegona 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 Fegona, caution in the use of Fegona 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
Fegona. 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 Fegona.
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 Fegona.
Respiratory effects
Minor dose-dependent reductions in values for forced expiratory volume (FEV1) and diffusion capacity for
carbon monoxide (DLCO) were observed with Fegona treatment starting at month 1 and remaining stable
thereafter. Fegona should be used with caution in patients with severe respiratory disease, pulmonary fibrosis
and chronic obstructive pulmonary disease (see also section 4.8).
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 (see section 4.8). 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, Fegona should be discontinued.
Prior treatment with immunosuppressive or immunomodulatory therapies
There have been no studies performed to evaluate the efficacy and safety of Fegona when switching patients
from teriflunomide, dimethyl fumarate or alemtuzumab treatment to Fegona. When switching patients from
another disease modifying therapy to Fegona, 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 Fegona to ensure that immune effects of the previous
therapy (i.e. cytopenia) have resolved.
Fegona 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
Fegona 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 Fegona.
Alemtuzumab has profound and prolonged immunosuppressive effects. As the actual duration of these effects is
unknown, initiating treatment with Fegona 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 (see section 4.5).
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 Fegona (see
section 4.8). 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.
Tumefactive lesions
Rare cases of tumefactive lesions associated with MS relapse were reported in the post-marketing setting. In
case of severe relapses, MRI should be performed to exclude tumefactive lesions. Discontinuation of Fegona
should be considered by the physician on a case-by-case basis taking into account individual benefits and risks.
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 Fegona a 6 week interval without therapy is needed, based on halflife, to clear fingolimod from the circulation (see section 5.2). Lymphocyte counts progressively return to
normal range within 1-2 months of stopping therapy in most patients (see section 5.1) 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 Fegona 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 Fegona is deemed necessary, patients should be monitored
during this time for relevant signs of a possible rebound.
Paediatric population
The safety profile in paediatric patients is similar to that in adults and the warnings and precautions for adults
therefore also apply to paediatric patients.
In particular, the following should be noted when prescribing Fegona to paediatric patients:
- Precautions should be followed at the time of the first dose (see “Bradyarrhythmia” above). The same
precautions as for the first dose are recommended when patients are switched from the 0.25 mg to the 0.5 mg
daily dose.
- In the controlled paediatric trial D2311, cases of seizures, anxiety, depressed mood and depression have been
reported with a higher incidence in patients treated with fingolimod compared to patients treated with interferon
beta-1a. Caution is required in this subgroup population (see “Paediatric population” in section 4.8).
- Mild isolated bilirubin increases have been noted in paediatric patients on Fegona.
- It is recommended that paediatric patients complete all immunisations in accordance with current
immunisation guidelines before starting Fegona 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 very limited 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-administered due 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 immune effects such
as natalizumab, teriflunomide or mitoxantrone (see section 4.4). In multiple sclerosis clinical studies the
concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased
rate of infection.
Vaccination
During and for up to two months after treatment with Fegona vaccination may be less effective. The use of live
attenuated vaccines may carry a risk of infections and should therefore be avoided (see sections 4.4 and 4.8).
Bradycardia-inducing substances
Fingolimod has been studied in combination with atenolol and diltiazem. When fingolimod was used with
atenolol in an interaction study in healthy volunteers, there was an additional 15% reduction of heart rate at
fingolimod treatment initiation, an effect not seen with diltiazem. Treatment with Fegona should not be initiated
in patients receiving beta blockers, or other substances which may decrease heart rate, such as class Ia and III
antiarrhythmics, calcium channel blockers (such as verapamil or diltiazem), ivabradine, digoxin,
anticholinesteratic agents or pilocarpine because of the potential additive effects on heart rate (see sections 4.4
and 4.8). If treatment with Fegona is considered in such patients, advice from a cardiologist should be sought
regarding the switch to non heart-rate lowering medicinal products or appropriate monitoring for treatment
initiation, at least overnight monitoring is recommended, 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 to its
metabolism, notably in the case of strong induction of CYP3A4. Potent inhibitors of transporter proteins are not
expected to influence fingolimod disposition. Co-administration of fingolimod with ketoconazole 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 of fingolimod 2 mg
reduced the AUC of fingolimod and its metabolite by approximately 40%. Other strong 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 this could potentially impair the efficacy, their coadministration 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 by substrates of
the main transporter proteins.
Co-administration of fingolimod with ciclosporin did not elicit any change in the ciclosporin or fingolimod
exposure. Therefore, fingolimod is not expected to alter the pharmacokinetics of medicinal products that are
CYP3A4 substrates.
Co-administration of fingolimod with oral contraceptives (ethinylestradiol and levonorgestrel) did not elicit any
change in oral contraceptive exposure. No interaction studies have been performed with oral contraceptives
containing other progestagens, however an effect of fingolimod on their exposure is not expected
 

Women of childbearing potential / Contraception in females
Before initiation of treatment in women of childbearing potential, a negative pregnancy test result needs to be
available and counselling should be provided regarding the potential for serious risk to the foetus and the need
for effective contraception during treatment with Fegona. Since it takes approximately two months to eliminate
fingolimod from the body on stopping treatment (see section 4.4), the potential risk to the foetus may persist
and contraception should be continued during that period.
Pregnancy
While on treatment, women should not become pregnant and active contraception is recommended. If a woman
becomes pregnant while taking Fegona, discontinuation of Fegona is recommended.
Animal studies have shown reproductive toxicity including foetal loss and organ defects, notably persistent
truncus arteriosus and ventricular septal defect (see section 5.3). Furthermore, the receptor affected by
fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during
embryogenesis. There are very limited data from the use of fingolimod in pregnant women.
There are no data on the effects of fingolimod on labour and delivery.
Breast-feeding
Fingolimod is excreted in milk of treated animals during lactation (see section 5.3). Due to the potential for
serious adverse reactions to fingolimod in nursing infants, women receiving Fegona should not breastfeed.
Fertility
Data from preclinical studies do not suggest that fingolimod would be associated with an increased risk of
reduced fertility (see section 5.3).
Pregnancy Category: C
 

Fegona has no or negligible influence on the ability to drive and use machines.
However, dizziness or drowsiness may occasionally occur when initiating therapy with Fegona. On initiation of
Fegona treatment it is recommended that patients be observed for a period of 6 hours (see section 4.4,
Bradyarrhythmia)
 

Summary of the safety profile
Adverse reactions reported with Fegona 0.5 mg in Studies D2301 (FREEDOMS) and D2309 (FREEDOMS II)
are shown below. Adverse reactions derived from post-marketing experience with Fegona via spontaneous case
reports or literature cases are also reported. 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

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 Fegona-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 (see section 4.4).
Human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancer, has
been reported under treatment with fingolimod in the post-marketing setting. Due to the immunosuppressive
properties of fingolimod, vaccination against HPV should be considered prior to treatment initiation with
fingolimod taking into account vaccination recommendations. Cancer screening, 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 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 Fegona. 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). Fegona has not been studied in multiple sclerosis
patients with diabetes mellitus, a disease which is associated with an increased risk for macular oedema (see
section 4.4). 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 Fegona treatment results in a transient decrease in heart rate and may also be associated with
atrioventricular conduction delays. In multiple sclerosis clinical studies the maximal decline in heart rate was
seen within 6 hours after treatment initiation, with declines in mean heart rate of 12-13 beats per minute for
Fegona 0.5 mg. Heart rate below 40 beats per minute in adults, and below 50 beats per minute in paediatric
patients, was rarely observed in patients on Fegona 0.5 mg. The average heart rate returned towards baseline
within 1 month of chronic treatment. Bradycardia was generally asymptomatic but some patients experienced
mild to moderate symptoms, including hypotension, dizziness, fatigue and/or palpitations, which resolved
within the first 24 hours after 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 it occurred 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% adult patients on Fegona 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 Fegona. 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 Fegona 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 Fegona is uncertain.
Blood pressure
In multiple sclerosis clinical studies Fegona 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. This increase persisted with continued treatment. Hypertension was reported in
6.5% of patients on fingolimod 0.5 mg and in 3.3% of patients on placebo. In the post-marketing setting, cases
of hypertension have been reported within the first month of treatment initiation and on the first day of
treatment that may require treatment with antihypertensive agents or discontinuation of Fegona (see also section
4.4, Blood pressure effects).
Liver function
Increased hepatic enzymes have been reported in adult and paediatric multiple sclerosis patients treated with
Fegona. In clinical studies 8.0% and 1.8% of adult patients treated with Fegona 0.5 mg experienced an
asymptomatic elevation in serum levels of ALT of ≥3x ULN (upper limit of normal) 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 within the first 12 months. ALT levels returned to normal
within approximately 2 months after discontinuation of Fegona. In a small number of patients (N=10 on 1.25
mg, N=2 on 0.5 mg) who experienced ALT elevations ≥5x ULN and who continued on Fegona therapy, the
ALT levels returned to normal within approximately 5 months (see also section 4.4, Liver function).
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.
Cases of seizures, including status epilepticus, have been reported with the use of Fegona in clinical studies and
in the post-marketing setting.
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 Fegona 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, including cases of cutaneous T-cell
lymphoma (mycosis fungoides).
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.
Paediatric population
In the controlled paediatric trial D2311 (see section 5.1), the safety profile in paediatric patients (10 to below 18
years of age) receiving fingolimod 0.25 mg or 0.5 mg daily was overall similar to that seen in adult patients.
There were, nevertheless, more neurological and psychiatric disorders observed in the study. Caution is needed
in this subgroup due to very limited knowledge available from the clinical study.
In the paediatric study, cases of seizures were reported in 5.6% of fingolimod-treated patients and 0.9% of
interferon beta-1a-treated patients.
Depression and anxiety are known to occur with increased frequency in the multiple sclerosis population.
Depression and anxiety have also been reported in paediatric patients treated with fingolimod.
Mild isolated bilirubin increases have been noted in paediatric patients on fingolimod.
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.
Fegona should not be used in patients with severe hepatic impairment (Child-Pugh class C) (see section 4.3).
Fegona should be introduced cautiously in mild and moderate hepatic impaired patients (see section 4.2).
Clinical experience and pharmacokinetic information in patients aged above 65 years are limited.
fingolimod should be used with caution in patients aged 65 years and over (see section 4.2).

Single doses up to 80 times the recommended dose (0.5 mg) were well tolerated in healthy adult volunteers. At
40 mg, 5 of 6 subjects reported mild chest tightness or discomfort which was clinically consistent with small
airway reactivity.
Fingolimod can induce bradycardia 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 Fegona persists beyond
6 hours and progressively attenuates over subsequent days of treatment (see section 4.4 for details). There have
been reports of slow atrioventricular conduction, with isolated reports of transient, spontaneously resolving
complete AV block (see sections 4.4 and 4.8).
• The National Pharmacovigilance and Drug Safety Centre (NPC)
• Fax: +966-11-205-7662
• Call NPC at +966-11-2038222, Ext: 2317-2356-2340
• Reporting hotline: 19999
• E-mail: npc.drug@sfda.gov.sa
• Website: www.sfda.gov.sa/npc
-Other GCC states /other countries
-Please contact the relevant competent
 PLEASE CONTACT THE RELEVANT COMPETENT AUTHORITY.
If the overdose constitutes first exposure to Fegona, 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 (see
section 4.4).
Additionally, if after 6 hours the heart rate is <45 bpm in adults, <55 bpm in paediatric patients aged 12 years
and above, or <60 bpm in paediatric patients aged 10 years to below 12 years, 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
 

Pharmacotherapeutic group: Immunosuppressants, 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 (see sections 4.4 and 4.8). 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.
S1P4 could partially contribute to the effect but was not the main receptor responsible for the lymphoid
depletion. The mechanism of action of bradycardia and vasoconstriction were also studied in vitro in guinea
pigs and isolated rabbit aorta and coronary artery. It was concluded that bradycardia could be mediated
primarily by activation of inward-rectifying potassium channel or G-protein activated inwardly rectifying
K+ channel (IKACh/GIRK) and that vasoconstriction seems to be mediated 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 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 betaagonists.
Clinical efficacy and safety
The efficacy of Fegona has been demonstrated in two studies which evaluated once-daily doses of fingolimod
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 relapse during the prior year.
Expanded Disability Status Score (EDSS) was between 0 and 5.5. A third study targeting the same adult patient
population was completed after registration of Fegona.
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

Pharmacokinetic data were obtained in healthy adult volunteers, in renal transplant adult patients and in
multiple sclerosis adult 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, Fegona may be taken without regard to meals (see
section 4.2).
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 Fegona 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 halflives 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) (see section
4.3). Fingolimod should be introduced cautiously in mild and moderate hepatic impaired patients (see section
4.2).
Clinical experience and pharmacokinetic information in patients aged above 65 years are limited. Fegona
should be used with caution in patients aged 65 years and over (see section 4.2).
Paediatric population
In paediatric patients (10 years of age and above), fingolimod-phosphate concentrations increase in an apparent
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 compared to 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 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.
Juvenile animal studies
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 keyhole limpet haemocyanin
(KLH), which were not considered adverse. Overall, the treatment-related effects of 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 (reduced auditory startle response) observed at doses of 1.5
mg/kg and higher in juvenile animals and the absence of smooth muscle hypertrophy in the lungs of the juvenile
rats
 

Capsule core:
Cellulose, microcrystalline Talc
Capsule shell: Gelatin
Titanium dioxide Iron oxide
yellow
Printing ink: Shellac
Propylene glycol
Ammonia solution, concentrated Potassium
hydroxide
Iron oxide black
 

Not applicable
 

2 years

Do not store above 25°C.
Store in the original package in order to protect from moisture
 

OPA/AL/PVC - aluminum blisters. Cartons of 28 hard capsules
 

No special requirements