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. 2023 Mar 22;24(4):495–509. doi: 10.1080/14656566.2023.2178898

Table 3.

Main adverse events and mitigation strategies for the approved S1PR modulators in people with MS.

Adverse event Suggested practical approach
Transient bradycardia A baseline ECG should be obtained in all patients starting a S1PR modulator. First dose observation is required in patients starting fingolimod and in at-risk patients starting siponimod, ozanimod or ponesimod (i.e. patients with sinus bradycardia, or history of first- or second-degree atrioventricular block, myocardial infarction, or heart failure). All patients starting fingolimod should have the ECG and blood pressure checked prior to and 6 hours after the first dose. The heart rate and blood pressure should be checked at least hourly during the first 6 hours and whenever the patient develops new symptoms; if available, continuous ECG monitoring is recommended, otherwise, check ECG if bradycardia occurs. In patients that need medical intervention for cardiac side effects throughout the first 6 hours, overnight monitoring in a medical facility and second dose monitoring are required. If the heart rate is lowest at the end of the first 6 hours, monitoring should be extended for at least 2 hours. Same precautions are required when increasing the fingolimod dose (see Table 2, pediatric population) and when reintroducing fingolimod after a treatment interruption (depending on the duration of the interruption and the time since the start of the treatment). The monitoring required for at-risk patients starting other S1PR modulators is similar (4 hours for ponesimod, 6 hours for siponimod and ozanimod). In patients treated with beta-blockers or calcium channel-blockers that have resting heart rates below 55 bpm, discontinuation of the bradycardia-inducing drug during the initiation of the S1PR modulator, should be considered.
Atrioventricular block and other cardiac side effects Patients with concomitant cardiac diseases that do not contraindicate S1PR modulators, should be monitored by a cardiologist during the S1PR modulator treatment and washout. Substances that may prolong the QTc interval should be avoided in patients at risk for QT prolongation (e.g. concomitant hypokalaemia).
Arterial hypertension Blood pressure should be regularly monitored during S1PR modulator treatment and washout. If required as per current standard of care, antihypertensive medication should be introduced, or the preexisting antihypertensive regimen should be adjusted.
Macular edema In patients at risk for macular edema (i.e. history of uveitis, diabetes mellitus), an ophthalmologic evaluation is required prior to starting the S1PR modulator and throughout the treatment. In all patients, even if asymptomatic, an ophthalmologic evaluation should be performed at 3–4 months after starting the S1PR modulator.
Liver dysfunction Check liver enzymes and bilirubin prior to the S1PR modulator initiation. For fingolimod and ponesimod: monitor liver enzymes and bilirubin in asymptomatic patients at 1, 3, 6, 9, and 12 months after treatment initiation, and periodically thereafter. For siponimod and ozanimod: monitor liver enzymes and bilirubin periodically. Treatment should be stopped in patients with liver enzymes more than 5 times the upper limit of normal, even if asymptomatic and without signs of liver failure, and in selected patients with liver enzymes 3–5 times the upper limit of normal, depending on the results of additional investigation and presence or absence of symptoms. The S1PR modulator can be resumed after the liver enzymes return to normal if the benefits outweigh the risks, especially if an alternative case of liver injury was found.
Lymphopenia A complete blood count should be performed before initiating a S1PR modulator and periodically thereafter (e.g. for fingolimod at 3 months and at least yearly thereafter). Peripheral lymphocyte counts may decrease to 20–30% of the baseline value. Confirmed absolute lymphocyte counts below 0.2x109/l should lead to the interruption of the S1PR modulator or a reduction of dose with subsequent reassessment. The severity of lymphopenia is related to an increased risk of infections.
Infections – upper respiratory tract, urinary tract, HPV, HSV or VZV meningitis, encephalitis, or meningoencephalitis, cryptococcal meningitis, PML A high index of suspicion for infections, including opportunistic, should be maintained during the S1PR modulator treatment and throughout the washout period. Patients should be advised to report symptoms of infections. When suspecting a serious infection, the S1PR modulator should be stopped until the infection is ruled out or cured. Specific investigations and treatments should not be delayed. After recovering from a serious infection, the possibility of restarting a S1PR modulator should be discussed with an infectious disease specialist.
In the absence of a health care professional confirmed history of chickenpox or documentation of a full course of VZV vaccination, VZV antibody testing should be performed. VZV antibody negative patients are recommended to undergo a full course of vaccination before starting the S1PR modulator.
A brain MRI should be performed prior to starting the S1PR modulator and periodically thereafter. Any MRI findings suggestive of PML, even in asymptomatic patients without prior natalizumab or immunosuppressant exposure, should prompt cerebrospinal fluid JCV DNA testing. Anti-JCV antibody testing in the peripheral blood prior to the S1PR modulator initiation and periodically thereafter should be considered, but negative results do not completely exclude the possibility of developing PML.
Cancers Basal cell carcinoma and other cutaneous neoplasms, including malignant melanoma, have been reported in patients treated with S1PR modulators. Patients should be advised to be vigilant for skin lesions and to avoid sunlight exposure without photoprotection. Medical evaluation for skin lesions is recommended at S1PR treatment initiation, and every 6 to 12 months thereafter or whenever a suspicious lesion is detected; any suspicious lesion should be evaluated by a dermatologist. Cases of lymphoma and HPV-related cancers have also been reported in people treated with S1PR modulators. HPV-related cancer screening is recommended as per standard of care. If cancer is suspected or diagnosed the S1PR modulator should be discontinued.
Vaccines and decreased vaccine efficacy Live attenuated vaccines should be avoided throughout the duration of the S1PR modulator treatment and during washout (because they may carry a risk of infection). Decreased vaccine efficacy has been observed in patients treated with S1PR modulators, especially fingolimod. Vaccination against VZV in antibody negative patients, and other vaccinations as per standard of care, including HPV, are recommended before starting the S1PR modulator treatment (see above). The benefits and risks of discontinuing fingolimod or other S1PR modulators to allow for effective vaccination should be considered on a case-by-case basis (see below).
Spontaneous abortion and birth defects Female patients of childbearing potential should be informed of the teratogenic risks of S1PR modulators, should have a negative pregnancy test when starting the S1PR modulator, and should use effective contraception methods that should be maintained during the washout period after treatment discontinuation. The outcome of any pregnancy in patients using S1PR modulators should be reported.
Paradoxical MS exacerbation (tumefactive lesions) Rare cases of paradoxical MS exacerbation with tumefactive lesions associated with MS relapse were reported at S1PR initiation (e.g. when switching from beta-interferons to fingolimod). In case of severe relapses occurring after S1PR initiation, a brain ± spinal cord MRI should be obtained. If a tumefactive lesion is found, discontinuation of the S1PR modulator should be considered on a case-by-case basis.
Other unexpected neurological manifestations In the presence of neurological (or psychiatric) symptoms and signs that are not compatible with a typical MS exacerbation, a brain ± spinal cord MRI should be obtained as soon as possible; CSF examination and other investigation may also be warranted. Besides the above mentioned neuroinfections and tumefactive MS lesions, cases of PRES have been reported in patients using S1PR modulaters. In case of PRES, the S1PR modulator should be discontinued.
Return of disease activity or MS rebound MS rebound after the discontinuation of S1PR modulator treatments has been reported. Patients on S1PR modulators should be advised against ‘drug holidays.’ Caution should be taken when recommending transient treatment discontinuation – e.g. for vaccination purposes.

Abbreviations: bpm = beats per minute; CSF = cerebrospinal fluid; DMTs = disease modifying treatments; DNA = deoxyribonucleic acid; ECG = electrocardiogram; HPV = human papilloma virus; HSV = herpes simplex virus; JCV = John Cunningham virus; MRI = magnetic resonance imaging; MS = multiple sclerosis; PML = progressive multifocal leukoencephalopathy; PRES = posterior reversible encephalopathy syndrome; S1PR = sphingosine 1-phosphate receptor; VZV = varicella zoster virus.