TASCENSO ODT is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in patients 10 years of age and older.

• Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure.
• Patients with a history or presence of Mobitz Type II second-degree or third-degree AV block or sick sinus syndrome, unless patient has a functioning pacemaker.
• Patients with a baseline QTc interval ≥ 500 msec.
• Patients with cardiac arrhythmias requiring anti-arrhythmic treatment with Class Ia or Class III anti-arrhythmic drugs.
• Patients who had a hypersensitivity reaction to fingolimod or any of the excipients in TASCENSO ODT. Observed reactions include rash, urticaria, and angioedema.
• Concomitant use with other products containing fingolimod.

Because of a risk for bradyarrhythmia and AV blocks, patients should be monitored during TASCENSO ODT treatment initiation.

Prior to dosing and at the end of the observation period, obtain an electrocardiogram (ECG) in all patients. Monitor all patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement.

Continue monitoring until the abnormality resolves if any of the following is present after 6 hours:

(1) The heart rate (HR) 6 hours postdose is <45 bpm in adults, <55 bpm in pediatric patients 12 years of age and older, or <60 bpm in pediatric patients 10 or 11 years of age.

(2) The HR 6 hours postdose is at the lowest value postdose suggesting that the maximum pharmacodynamic effect on the heart may not have occurred.

(3) The ECG 6 hours postdose shows new onset second degree or higher AV block.

Begin continuous ECG monitoring in patients with symptomatic bradycardia until resolution. If pharmacological intervention is required, continue ECG monitoring overnight in a medical facility, and repeat 6-hour monitoring after the second dose.

Some patients may experience a second decrease in HR within 24 hours after the first dose.

Patients with pre-existing ischemic heart disease, history of myocardial infarction (MI) or cardiac arrest, congestive heart failure (CHF), cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia or recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block, or on concomitant drugs that slow HR or AV conduction should be evaluated by a healthcare professional and, if treated with TASCENSO ODT, monitored overnight with continuous ECG in a medical facility after first dose due to higher risk of symptomatic bradycardia or heart block. Patients with or at risk for QT prolongation or on concomitant QT-prolonging drugs with a known risk of torsades de pointes should also be monitored overnight with continuous ECG.

Repeat first-dose monitoring if TASCENSO ODT is interrupted ≥1 day within first 2 weeks or >7 days during weeks 3 and 4, or >14 days after the first month of treatment because effects on HR and AV conduction may occur upon reinitiation. First-dose monitoring is also recommended when the dose is increased in pediatric patients.

TASCENSO ODT may increase risk of infections. Life threatening and fatal infections have occurred in association with fingolimod. A recent Complete Blood Count (CBC) should be available before initiating TASCENSO ODT. Consider suspending TASCENSO ODT if a patient develops a serious infection. Monitor for signs and symptoms of infection during treatment and up to 2 months after discontinuation. Do not start TASCENSO ODT in patients with active acute or chronic infections until infection is resolved. Two patients receiving a higher than recommended dose of fingolimod (1.25 mg) in conjunction with high-dose corticosteroid therapy died of herpetic infections. In the postmarketing setting with fingolimod, serious infections, some fatal, have been reported with opportunistic pathogens, including viruses (e.g. John Cunningham virus [JCV], herpes simplex viruses 1 and 2, varicella zoster virus [VZV]), fungi (e.g. cryptococci), bacteria (e.g. atypical mycobacteria), and Kaposi’s sarcoma. Patients with signs and symptoms consistent with any of these infections should undergo prompt diagnostic evaluation and treatment. Concomitant use with antineoplastic, immunosuppressive, or immune-modulating therapies are expected to increase the risk of additive immunosuppression. When switching to TASCENSO ODT from these types of therapies, consider their duration of effect and mode of action to avoid this risk.

Before initiating TASCENSO ODT, patients should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients is recommended prior to starting treatment. TASCENSO ODT initiation should be postponed for 1 month after vaccination. It is recommended that pediatric patients, if possible, complete all immunizations in accordance with current immunization guidelines prior to initiating TASCENSO ODT.

Human papilloma virus (HPV) infections, including papilloma, dysplasia, warts, and HPV-related cancer, have been reported in patients treated with fingolimod in the postmarketing setting. Vaccination against HPV should be considered prior to treatment initiation, taking into account vaccination recommendations. Cancer screening, including Papanicolaou (Pap) test, is recommended as per standard of care for patients using an immunosuppressive therapy.

Cases of PML occurred in patients with MS who received fingolimod in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by JCV that typically only occurs in patients who are immunocompromised, and usually leads to severe disability or death. PML has occurred in patients who had not been treated previously with natalizumab, which has a known association with PML, and who were not taking concomitant immunosuppressive or immunomodulatory medications.

Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body, clumsiness of limbs, visual disturbances, and changes in thinking, memory, and orientation, leading to confusion and personality changes.

MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with MS medications associated with PML, including fingolimod. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful. Any suspicious findings should lead to further investigation to allow for an early diagnosis of PML. Lower PML-related morbidity and mortality have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or differences in disease in these patients.

At the first sign or symptom suggestive of PML, withhold TASCENSO ODT and perform an appropriate diagnostic evaluation.

Immune Reconstitution Inflammatory Syndrome (IRIS) has been reported in patients treated with S1P receptor modulators, including fingolimod, who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

Fingolimod increases the risk of macular edema, with or without visual symptoms. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with TASCENSO ODT, 3 to 4 months after starting treatment, periodically while on therapy and any time there is a change in vision. Patients with diabetes mellitus or history of uveitis are at increased risk and should have regular ophthalmologic evaluations.

Clinically significant liver injury has occurred in patients treated with fingolimod in the postmarketing setting. Signs and symptoms of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as 10 days after the first dose and have also been reported after prolonged use. Cases of acute liver failure requiring liver transplant have been reported.

Elevation of liver enzymes (ALT, AST, and GGT) 3- and 5-fold the upper limit of normal and greater has occurred with fingolimod. The majority occurred within 6 to 9 months and returned to normal within 2 months after discontinuing fingolimod. Recurrence of liver transaminase elevations occurred with rechallenge in some patients.

Prior to starting treatment with TASCENSO ODT (within 6 months), obtain serum transaminases (ALT and AST) and total bilirubin levels, and periodically until 2 months after TASCENSO ODT discontinuation. Patients should be monitored for signs and symptoms of any hepatic injury. Treatment with TASCENSO ODT should be interrupted if the patient is found to have an ALT greater than 3 times the reference range with serum total bilirubin greater than 2 times the reference range. Patients with severe hepatic impairment should be closely monitored, as their risk of adverse reactions is greater.

Rare cases of PRES have been reported with fingolimod. Symptoms reported include sudden onset of severe headache, altered mental status, visual disturbances, and seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, TASCENSO ODT should be discontinued.

Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in patients treated with fingolimod as early as 1 month after initiation. Changes in FEV1 appear to be reversible after discontinuing fingolimod; however, there is insufficient information to determine reversibility of DLCO. Obtain spirometry and evaluate DLCO when clinically indicated.

TASCENSO ODT may cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Because it takes approximately 2 months to eliminate fingolimod from the body, advise females of reproductive potential to use effective contraception to avoid pregnancy during and for 2 months after stopping TASCENSO ODT treatment.

Severe increase in disability accompanied by multiple new lesions on MRI has been reported following discontinuation of fingolimod in the postmarketing setting. Most of these reported cases did not return to the functional status they had before stopping fingolimod. The increase in disability generally occurred within 12 weeks after stopping fingolimod, but was reported up to 24 weeks after fingolimod discontinuation.

The possibility of severe increase in disability should be considered in patients who discontinue TASCENSO ODT, including those who are pregnant or planning for pregnancy. Monitor patients for development of severe increase in disability following discontinuation of TASCENSO ODT and begin appropriate treatment as needed. After stopping TASCENSO ODT in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS).

MS relapses with tumefactive demyelinating lesions on imaging have been observed during fingolimod therapy and after discontinuation in the postmarketing setting. Most reported cases occurred within the first 9 months after initiation, but may occur at any point during treatment. Cases have also been reported within the first 4 months after discontinuation of fingolimod. Tumefactive MS should be considered when a severe MS relapse occurs during treatment, especially during initiation, or after discontinuation, prompting imaging evaluation and initiation of appropriate treatment.

Monitor BP during treatment with TASCENSO ODT. An average increase of 3 mm Hg in systolic and 2 mm Hg in diastolic BP was observed in clinical trials versus placebo.

The risk of cutaneous malignancies (including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma) is increased in patients treated with S1P receptor modulators. Melanoma, BCC, SCC, Kaposi’s sarcoma, and Merkel cell carcinoma have been reported with fingolimod in the postmarketing setting. Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients.

Cases of lymphoma, including both T-cell and B-cell types and CNS lymphoma, have occurred in patients receiving fingolimod. The reporting rate of non-Hodgkin lymphoma with fingolimod is greater than that expected in the general population. Cutaneous T-cell lymphoma (including mycosis fungoides) has also been reported in the postmarketing setting.

Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts for up to 2 months following the last dose. Lymphocyte counts generally return to normal range within 1 to 2 months of stopping therapy. Initiating other drugs during this period warrants the same considerations needed for concomitant administration.