Gilenya Special Precautions

Bradyarrhythmia: Initiation of 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 Adverse Reactions and Pharmacology: Pharmacodynamics under Actions).
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.
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 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 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 fingolimod 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 (see Dosage & Administration).
Very rare cases of T-wave inversion have been reported in adult 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 or significant bradycardia, Gilenya 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 Contraindications). In such patients, treatment with Gilenya 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 Interactions).
Fingolimod has not been studied in patients with arrhythmias requiring treatment with class Ia (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products. Class Ia and class III antiarrhythmic medicinal products have been associated with cases of torsades de pointes in patients with bradycardia (see Contraindications).
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). Since the initiation of fingolimod treatment is also associated with slowing of the heart rate (see also Description of selected adverse reactions: Bradyarrhythmia under Adverse Reactions), concomitant use of these substances during treatment initiation may be associated with severe bradycardia and heart block. Because of the potential additive effect on heart rate, treatment with Gilenya should not be initiated in patients who are concurrently treated with these substances (see also Interactions). In such patients, treatment with Gilenya should be considered only if the anticipated benefits outweigh the potential risks. If treatment with Gilenya 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 treatment cannot be stopped, cardiologist's advice should be sought to determine appropriate first-dose monitoring, at least overnight extended monitoring is recommended (see also Interactions).
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 Infections as follows, Malignancies: Cutaneous malignancies as follows, and Description of selected adverse reactions: Lymphomas under Adverse Reactions).
Infections: A core pharmacodynamic effect of fingolimod 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 Pharmacology: Pharmacodynamics under Actions).
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.
The immune system effects of Gilenya may increase the risk of infections, including opportunistic infections (see Adverse Reactions). 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 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.
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.
Herpes viral infection: Serious, life-threatening, and sometimes fatal cases of encephalitis, meningitis or meningoencephalitis caused by herpes simplex and varicella zoster viruses have occurred with Gilenya at any time during treatment. If herpes encephalitis, meningitis or meningoencephalitis occur, Gilenya should be discontinued and appropriate treatment for the respective infection should be administered.
Patients need to be assessed for their immunity to varicella (chickenpox) prior to Gilenya treatment. It is recommended that patients without a healthcare 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 fingolimod therapy. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with Gilenya (see Adverse Reactions). Initiation of treatment with fingolimod should be postponed for 1 month to allow full effect of vaccination to occur.
Cryptococcal meningitis: Cases of cryptococcal meningitis (a fungal infection), sometimes fatal, have been reported in the post-marketing setting after approximately 2-3 years of treatment, although an exact relationship with the duration of treatment is unknown (see Adverse Reactions). 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: Progressive multifocal leukoencephalopathy (PML) has been reported under fingolimod treatment since marketing authorisation (see Adverse Reactions). 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 the estimated risk appears to increase with cumulative exposure over time, 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. MRI findings may be apparent before clinical signs or symptoms. 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. Cases of asymptomatic PML based on MRI findings and positive JCV DNA in the cerebrospinal fluid have been reported in patients treated with fingolimod. If PML is suspected, MRI should be performed immediately for diagnostic purposes and treatment with fingolimod should be suspended until PML has been excluded. The incidence rate for PML appears to be higher for patients in Japan; the reasons are currently unknown.
Human papilloma virus infection: Human papilloma virus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancer, has been reported under treatment with fingolimod in the post-marketing setting (see Adverse Reactions). 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: 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 Adverse Reactions). 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 Adverse Reactions). Fingolimod has not been studied in multiple sclerosis patients with concomitant diabetes mellitus. It is recommended that multiple sclerosis patients with diabetes mellitus or a history of uveitis undergo an ophthalmological evaluation prior to initiating therapy and have follow-up evaluations while receiving therapy.
Continuation of treatment 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 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 injury: 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 fingolimod. Some cases of acute liver failure requiring liver transplant and clinically significant liver injury have also been reported. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as ten days after the first dose and have also been reported after prolonged use. 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.
Fingolimod has not been studied in patients with severe pre-existing hepatic injury (Child-Pugh class C) and should not be used in these patients (see Contraindications).
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. In the absence of clinical symptoms, liver transaminases and serum bilirubin should be monitored at months 1, 3, 6, 9 and 12 on therapy and periodically thereafter until 2 months after Gilenya discontinuation. In the absence of clinical symptoms, if liver transaminases are greater than 3 but less than 5 times the ULN without increase in serum bilirubin, more frequent monitoring including serum bilirubin and alkaline phosphatase (ALP) measurement should be instituted to determine if further increases occur and in order to discern if an alternative aetiology of hepatic dysfunction is present. If liver transaminases are at least 5 times the ULN or at least 3 times the ULN associated with any increase in serum bilirubin, Gilenya should be discontinued. Hepatic monitoring should be continued. If serum levels return to normal (including if an alternative cause of the hepatic dysfunction is discovered), Gilenya may be restarted based on a careful benefit-risk assessment of the patient.
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 and bilirubin checked promptly and treatment should be discontinued if significant liver injury is confirmed. Treatment should not be resumed unless a plausible alternative aetiology for the signs and symptoms of liver injury can be established.
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.
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.
Respiratory effects: Minor dose-dependent reductions in values for forced expiratory volume (FEV₁) and diffusion capacity for carbon monoxide (DLCO) were observed with fingolimod treatment starting at month 1 and remaining stable thereafter. Gilenya should be used with caution in patients with severe respiratory disease, pulmonary fibrosis and chronic obstructive pulmonary disease (see Adverse Reactions).
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 Adverse Reactions). 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 fingolimod when switching patients from teriflunomide, dimethyl fumarate or alemtuzumab treatment to Gilenya. When switching patients from another disease-modifying therapy to Gilenya, the elimination 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 elimination 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 (see Interactions).
Malignancies: Cutaneous malignancies: 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 (see Adverse Reactions). 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.
Lymphomas: There have been cases of lymphoma in clinical studies and the post-marketing setting (see Adverse Reactions). The cases reported were heterogeneous in nature, mainly non-Hodgkin's lymphoma, including B-cell and T-cell lymphomas. Cases of cutaneous T-cell lymphoma (mycosis fungoides) have been observed. A fatal case of Epstein-Barr virus (EBV) positive B-cell lymphoma has also been observed. If lymphoma is suspected, treatment should be discontinued.
Women of childbearing potential: Due to risk to the foetus, fingolimod is contraindicated during pregnancy and in women of childbearing potential not using effective contraception. Before initiation of treatment, women of childbearing potential must be informed of this risk to the foetus, must have a negative pregnancy test and must use effective contraception during treatment and for 2 months after treatment discontinuation (see Contraindications and Use in Pregnancy & Lactation and the information contained in the Physician Information Pack).
Tumefactive lesions: Rare cases of tumefactive lesions associated with MS relapse were reported in the post-marketing setting. In case of severe relapses, MRI should be performed to exclude tumefactive lesions. Discontinuation of treatment should be considered by the physician on a case-by-case basis taking into account individual benefits and risks.
Return of disease activity (rebound) after fingolimod discontinuation: In the post-marketing setting, severe exacerbation of disease has been observed rarely in some patients stopping fingolimod. This has generally been observed within 12 weeks after stopping fingolimod, but has also been reported up to 24 weeks after fingolimod discontinuation. Caution is therefore indicated when stopping fingolimod therapy. If discontinuation of fingolimod is deemed necessary, the possibility of recurrence of exceptionally high disease activity should be considered and patients should be monitored for relevant signs and symptoms and appropriate treatment initiated as required (see Stopping therapy as follows).
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 (see Pharmacology: Pharmacokinetics under Actions). Lymphocyte counts progressively return to normal range within 1-2 months of stopping therapy in most patients (see Pharmacology: Pharmacodynamics under Actions) 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) after fingolimod discontinuation as previously mentioned). If discontinuation of Gilenya is deemed necessary, patients should be monitored during this time for relevant signs of a possible rebound.
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.
Effects on ability to drive and use machines: Fingolimod has no or negligible influence on the ability to drive and use machines.
However, dizziness or drowsiness may occasionally occur when initiating treatment. On initiation of Gilenya, it is recommended that patients be observed for a period of 6 hours (see Bradyarrhythmia as previously mentioned).
Use in Children: 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 Gilenya to paediatric patients.
Precautions should be followed at the time of the first dose (see Bradyarrhythmia as previously mentioned). 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 under Adverse Reactions).
Mild isolated bilirubin increases have been noted in paediatric patients on Gilenya.
It is recommended that paediatric patients complete all immunisations in accordance with current immunisation guidelines before starting Gilenya therapy (see Infections as previously mentioned).
There are very limited data available in children between 10-12 years old, less than 40 kg or at Tanner stage <2 (see Adverse Reactions and Pharmacology: Pharmacodynamics under Actions). 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.