Gilenya Adverse Reactions

Summary of the safety profile: The most frequent adverse reactions (incidence ≥10%) at the 0.5 mg dose were headache (24.5%), hepatic enzyme increased (15.2%), diarrhoea (12.6%), cough (12.3%), influenza (11.4%), sinusitis (10.9%) and back pain (10.0%).
Tabulated list of adverse reactions: Adverse reactions reported in clinical trials and derived from post-marketing experience via spontaneous case reports or literature cases are shown as follows. 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. (See Table 5.)

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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 fingolimod-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 Precautions).
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 Precautions). 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 treatment. The risk of recurrence after re-challenge has not been evaluated.
Macular oedema incidence is increased in multiple sclerosis patients with a history of uveitis (17% with a history of uveitis vs. 0.6% without a history of uveitis). Gilenya has not been studied in multiple sclerosis patients with diabetes mellitus, a disease which is associated with an increased risk for macular oedema (see Precautions). 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 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 fingolimod 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 fingolimod 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 Precautions and Pharmacology: Pharmacodynamics under Actions).
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 fingolimod 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 fingolimod 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, fingolimod 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 Gilenya (see also Blood pressure effects under Precautions).
Liver function: Increased hepatic enzymes have been reported in adult and paediatric multiple sclerosis patients treated with Gilenya. In clinical studies, 8.0% and 1.8% of adult patients treated with fingolimod 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 treatment. 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 fingolimod therapy, the ALT levels returned to normal within approximately 5 months (see also Liver injury under Precautions).
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 fingolimod 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 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 (see Respiratory effects under Precautions).
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 non-Hodgkin's 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) (see also Malignancies under Precautions).
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 Pharmacology: Pharmacodynamics under Actions), 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.
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.