Fingolimod

May result in transient and asymptomatic AV conduction delays, which typically resolve within 24 hours of treatment initiation; recurrence may be observed following discontinuation and subsequent reinitiation of therapy. Third-degree AV block and AV block with junctional escape occurred within the first 6 hours of the initial dose, and transient asystole and unexplained death have occurred within the first 24 hours; syncope has also occurred.

Initiation must occur in a setting with resources and personnel capable of appropriately managing symptomatic bradycardia. Following the first dose, heart rate may decrease as soon as 1 hour postdose, with the maximal decrease usually occurring ~6 hours postdose with recovery (but not to baseline levels) 8 to 10 hours postdose. A second heart rate decrease occurs within 24 hours after the first dose and may be more pronounced than the first 6-hour rate decrease. Most patients are asymptomatic; however, hypotension, dizziness, fatigue, palpitations, and/or chest pain may occur; symptoms usually resolve within 24 hours. With the second dose, heart rate may also decrease, but to a lesser magnitude than observed with the first dose. Heart rate typically returns to baseline after 1 month of chronic therapy.

Cases of cryptococcal meningitis and disseminated cryptococcal infections (including fatalities) have been reported. Cryptococcal infections have generally occurred after ~2 years of treatment, although may occur earlier (relationship between risk and duration of treatment is unknown). Patients with signs and symptoms of cryptococcal infections should undergo prompt diagnostic evaluation and treatment.

Elevated liver enzymes may occur; most elevations occurred within 6 to 9 months. Recurrence of liver transaminase elevations may occur with rechallenge. Liver injury with hepatocellular and/or cholestatic hepatitis has been reported. Obtain baseline liver enzymes and bilirubin in all patients prior to therapy initiation (within 6 months); monitor liver enzymes in patients who develop symptoms of hepatic dysfunction (eg, nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine). Discontinue treatment with confirmation of liver injury; transaminases tend to return to normal within 2 months of discontinuation.

Serious, life-threatening herpes infections, including fatalities (eg, disseminated primary herpes zoster and herpes simplex encephalitis) have occurred. Consider disseminated herpes infections as an etiology if an atypical MS relapse or multiorgan failure occurs. Consider varicella zoster virus vaccination prior to initiation of treatment in patients without a health care professional-confirmed history of chickenpox, without a documented full course of varicella zoster vaccination, and patients who are VZV antibody negative; postpone fingolimod treatment for 1 month after varicella zoster vaccination. Cases of Kaposi sarcoma (associated with human herpes virus-8) have been reported; if suspected, prompt diagnostic evaluation and management is required.

Hypersensitivity reactions, including rash, urticaria, and angioedema upon treatment initiation, have been reported.

Increased blood pressure may occur ~1 month after initiation of therapy; monitor blood pressure throughout treatment.

May increase risk of infection (including serious, life-threatening, and fatal infections) with opportunistic pathogens including viruses (eg, John Cunningham virus [JCV], herpes simplex virus 1 and 2, varicella-zoster virus), fungi (eg, cryptococci), and bacteria (eg, atypical mycobacteria), due to reversible dose-dependent reduction of lymphocytes. Lymphocyte counts may be decreased for up to 2 months following discontinuation of therapy. Obtain a complete blood cell count (CBC) (within 6 months or after discontinuation of prior therapy) before starting therapy. Monitor for signs and symptoms of infection; consider therapy interruption in patients who develop a serious infection; reassess benefits and risks prior to reinitiation of therapy. Do not initiate treatment in patients with acute or chronic infections until the infection has resolved. Use with caution in patients receiving concomitant immunosuppressant, immune modulating, or antineoplastic medications, or when switching from other immunosuppressants (consider the duration and mode of action for each substance to avoid additive effects). Patients with low lymphocyte counts at baseline and underweight females (BMI 2) are at higher risk for developing severe lymphopenia and should be monitored more closely (Warnke 2014).

Macular edema may occur, typically within the first 6 months of treatment. Patients may present with blurred vision, decreased visual acuity, or without symptoms. Signs and symptoms generally improve or resolve with discontinuation of treatment; however, residual decreased visual acuity has occurred in some patients. Patients with a history of diabetes mellitus or uveitis are at increased risk; use with caution. Ophthalmologic exams (including the fundus and macula) should be performed prior to therapy, 3 to 4 months after treatment initiation, and anytime visual disturbances are reported; more frequent examination is warranted in patients with diabetes or a history of uveitis.

Cases of lymphoma and skin cancers have been reported. Basal cell carcinoma and melanoma risk is increased with fingolimod use; monitor for suspicious skin lesions periodically (especially in patients with risk factors for skin cancer) and promptly evaluate. Patients should minimize exposure to sunlight and ultraviolet light by wearing protective clothing and sunscreen with high protection factor.

Posterior reversible encephalopathy syndrome (PRES) has been observed. Monitor for signs/symptoms of PRES (eg, sudden onset of severe headache, altered mental status, visual disturbances, seizure); symptoms are usually reversible, but may evolve into ischemic stroke or cerebral hemorrhage. Delayed diagnosis and treatment may result in permanent neurological sequelae. Discontinue use if PRES is suspected.

Cases of progressive multifocal leukoencephalopathy (PML) due to the JC virus (JCV) have been reported, including cases in patients who were not immunocompromised and had no prior exposure to immunosuppressant drugs, including natalizumab. The majority of PML cases occurred in patients treated with fingolimod for at least 2 years (relationship between risk and duration of treatment is unknown). At the first sign or symptom suggestive of PML, perform a diagnostic evaluation and withhold therapy; symptoms progress over days to weeks and may include progressive weakness on one side of the body or clumsiness of limbs, vision disturbances, and mental status changes. Cases of PML have been diagnosed based on MRI findings and the detection of JCV DNA in the CSF without specific PML signs/symptoms. Monitoring with MRI for signs that may be consistent with PML may be beneficial and allow for an early diagnosis of PML.

Reductions of forced expiratory volume in the first second of expiration (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) are dose dependent and may occur within the first month of therapy. FEV1 changes may be reversible with drug discontinuation. Use in multiple sclerosis (MS) patients with compromised respiratory function has not been evaluated. If clinically necessary, spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy.

May cause QT prolongation; patients with a prolonged QT interval at baseline (males: >450 msec; females: >470 msec) or during the first 6 hours of treatment initiation, or are at an increased risk of QT prolongation (eg, hypokalemia, hypomagnesemia, concomitant QT-prolonging drugs, congenital long-QT syndrome) require continuous overnight electrocardiogram (ECG) monitoring in a medical facility after the initial dose. Disease-related concerns:

Due to the risk of bradycardia and AV conduction delays, an ECG is required prior to initiation of therapy and after the initial observation period (6 hours) in all patients. Patients receiving concomitant therapy with drugs that slow heart rate or AV conduction (eg, beta-blockers, heart rate-lowering calcium channel blockers, digoxin) or with other cardiac risk factors (eg, AV block, sick sinus syndrome, prolonged QT interval, ischemic cardiac disease, history of myocardial infarction [MI], symptomatic bradycardia and/or cardiac arrest, heart failure, cerebrovascular disease, uncontrolled hypertension, recurrent syncope, severe sleep apnea [untreated]) require continuous overnight ECG monitoring in a medical facility after the first dose.

Use with caution and closely monitor patients with severe hepatic impairment. Use caution in patients with preexisting liver disease; may be at increased risk of increased liver enzymes. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings and precautions:

Cases of rebound syndrome (clinical and radiological signs of severe exacerbation beyond what was expected) have been reported; may occur within 4 to 16 weeks of stopping fingolimod treatment in patients with multiple sclerosis of varying severity and duration. In some cases, relapses have occurred despite the initiation of other disease-modifying therapies. Rebound symptoms have included back and extremity pain, confusion, constipation, diplopia, facial muscle spasms, fatigue, increased leg weakness, nausea paraparesis and paresthesias (Hatcher 2016; Willis 2016).