Gilenya

/ Novartis

General target population: The recommended dose of Fingolimod is one 0.5 mg capsule taken orally once daily, which can be taken with or without food. If a dose is missed, treatment should be continued with the next dose as planned.
First Dose: Initiation of Fingolimod treatment results in a decrease in heart . After the first dose of Fingolimod, the heart rate decrease starts within an hour and the Day 1 nadir generally occurs within approximately 6 hours, although the nadir can be observed up to 24 hours after the first dose in some patients. The first dose of Fingolimod should be administered in a setting in which resources to appropriately manage symptomatic bradycardia are available. In order to assess patient response to the first dose of Fingolimod, observe all patients for 6 hours for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain in all patients an electrocardiogram prior to dosing, and at the end of the observation period. Additional observation should be instituted until the finding has resolved in the following situations: If the heart rate 6 hours post-dose is <45 bpm Or if the heart rate 6 hours post-dose is at the lowest value post-dose (suggesting that the maximum pharmacodynamic effect on the heart may not have occurred). Patients with some pre-existing conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, history of symptomatic bradycardia, history of recurrent syncope, uncontrolled hypertension, severe untreated sleep apnea, AV block, sino-atrial heart block) may poorly tolerate the Fingolimod -induced bradycardia, or experience serious rhythm disturbances after the first dose of Fingolimod.
For recommendations related to switching patients from other disease modifying therapies to Fingolimod See prescribing information for full details.
Re-initiation of Therapy Following Discontinuation: If Fingolimod therapy is discontinued for more than 14 days, after the first month of treatment, the effects on heart rate and AV conduction may recur on reintroduction of Fingolimod treatment and the same precautions (first dose monitoring) as for initial dosing should apply. Within the first 2 weeks of treatment, first dose procedures are recommended after interruption of one day or more, during week 3 and 4 of treatment first dose procedures are recommended after treatment interruption of more than 7 days.
Dosing in special populations
Renal impairment: No Fingolimod dose adjustments are needed in patients with renal impairment.
Hepatic impairment: No Fingolimod dose adjustments are needed in patients with mild or moderate hepatic impairment. Fingolimod should be used with caution in patients with severe hepatic impairment (Child-Pugh class C).
Pediatrics patients: Fingolimod is not indicated for use in pediatric patients.
Geriatrics patients: Fingolimod should be used with caution in patients aged 65 years and over.
Ethnicity: No Fingolimod dose adjustments are needed based on ethnic origin.
Gender: No Fingolimod dose adjustments are needed based on gender.
Diabetic patients: Fingolimod should be used with caution in patients with diabetes mellitus due to a potential increased risk of macular edema.
For full details see prescribing information.

Indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability.

This medicinal product is contraindicated in patients who have:
• in the last 6 months experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization or Class III/IV heart failure
• a history or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker
• a baseline QTc interval ≥ 500 msec
• cardiac arrhythmias requiring anti-arrhythmic treatment with Class Ia or Class III anti-arrhythmic drugs
• had a hypersensitivity reaction to fingolimod or any of the excipients. Observed reactions include rash, urticaria and angioedema upon treatment initiation

Bradyarrhythmia and Atrioventricular Blocks: Because of a risk for bradyarrhythmia and AV blocks, patients should be monitored during treatment initiation.
Reduction in Heart Rate: After the first dose, the heart rate decrease starts within an hour. On Day 1, the maximum decline in heart rate generally occurs within 6 hours and recovers, although not to baseline levels, by 8 to 10 hours post-dose. Because of physiological diurnal variation, there is a second period of heart rate decrease within 24 hours after the first dose. In some patients, heart rate decrease during the second period is more pronounced than the decrease observed in the first 6 hours. Heart rates below 40 beats per minute (bpm) in adults occurred rarely.
Patients with some preexisting conditions (e.g., ischemic heart disease, history of myocardial infarction, congestive heart failure, history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia, history of recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block) may poorly tolerate the drug-induced bradycardia, or experience serious rhythm disturbances after the first dose of fingolimod.
Since initiation of fingolimod treatment, results in decreased heart rate and may prolong the QT interval, patients with a prolonged QTc interval (> 450 msec adult males, > 470 msec adult females) before dosing or during 6-hour observation, or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome), or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility.
Following the second dose, a further decrease in heart rate may occur when compared to the heart rate prior to the second dose, but this change is of a smaller magnitude than that observed following the first dose. With continued dosing, the heart rate returns to baseline within 1 month of chronic treatment.
Atrioventricular Blocks: Initiation of fingolimod treatment has resulted in transient AV conduction delays.
Postmarketing Experience: In the post-marketing setting, third-degree AV block and AV block with junctional escape have been observed during the first-dose 6-hour observation period with fingolimod. Isolated delayed onset events, including transient asystole and unexplained death, have occurred within 24 hours of the first dose. Cases of syncope were also reported after the first dose of fingolimod.
Infections: Fingolimod causes a dose-dependent reduction in peripheral lymphocyte count to 20%-30% of baseline values because of reversible sequestration of lymphocytes in lymphoid tissues. Fingolimod may therefore increase the risk of infections, some serious in nature. Life-threatening and fatal infections have occurred in association with fingolimod.
Before initiating treatment with fingolimod, a recent complete blood count (CBC) (i.e., within 6 months or after discontinuation of prior therapy) should be available. Consider suspending treatment with fingolimod if a patient develops a serious infection, and reassess the benefits and risks prior to re-initiation of therapy. Because the elimination of fingolimod after discontinuation may take up to 2 months, continue monitoring for infections throughout this period. Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved.
In the postmarketing setting, serious infections with opportunistic pathogens, including viruses (e.g., John Cunningham virus (JCV), herpes simplex viruses 1 and 2, varicella zoster virus), fungi (e.g., cryptococci), and bacteria (e.g., atypical mycobacteria) have been reported with fingolimod. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and appropriate treatment.
Progressive Multifocal Leukoencephalopathy:  Progressive Multifocal Leukoencephalopathy:  Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients with MS who received fingolimod in the post-marketing setting. Longer treatment duration increases the risk of PML in fingolimod-treated patients; the majority of cases have occurred in patients treated with fingolimod for at least 18 months.
At the first sign or symptom suggestive of PML, withhold fingolimod and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
Before initiating treatment with fingolimod, a baseline magnetic resonance imaging (MRI) should be available (usually within 3 months) as a reference.
If PML is confirmed, treatment with fingolimod should be discontinued.
Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients treated with S1P receptor modulators, including fingolimod, who developed PML and subsequently discontinued treatment. 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. Macular Edema: S1P receptor modulators, including GILENYA, have been associated with an increased risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with GILENYA. Perform an examination of the fundus, including the macula, 3 to 4 months after starting treatment, periodically while on therapy, and any time there is a change in vision.
A dose-dependent increase in the risk of macular edema occurred in the fingolimod clinical development program.
Macular edema over an extended period of time (i.e., 6 months) can lead to permanent visual loss. Consider discontinuing fingolimod if macular edema develops; this decision should include an assessment of the potential benefits and risks for the individual patient. The risk of recurrence after rechallenge has not been evaluated.
Macular Edema in Patients with History of Uveitis or Diabetes Mellitus
Patients with a history of uveitis and patients with diabetes mellitus are at increased risk of macular edema during fingolimod therapy.
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 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), fingolimod 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.
Because fingolimod exposure is doubled in patients with severe hepatic impairment, these patients should be closely monitored, as the risk of adverse reactions is greater.
Posterior Reversible Encephalopathy Syndrome: There have been rare cases of posterior reversible encephalopathy syndrome (PRES) reported in adult patients. Symptoms reported included 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, fingolimod should be discontinued.
Respiratory Effects: 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 treatment initiation. The changes in FEV1 appear to be reversible after treatment discontinuation. Spirometric evaluation of respiratory function and evaluation of DLCO should be performed during therapy with fingolimod if clinically indicated.
Fetal Risk: This medicinal product may cause fetal harm when administered to a pregnant woman. Available observational pregnancy registry data suggest that use of fingolimod is associated with an increased prevalence of major birth defects in comparison to the general population.  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 the treatment.
Severe Increase in Disability After Stopping the treatment: Severe increase in disability accompanied by multiple new lesions on MRI has been reported after discontinuation of fingolimod in the post-marketing setting. The increase in disability generally occurred within 12 weeks after stopping fingolimod, but was reported up to 24 weeks after treatment discontinuation.
Tumefactive Multiple Sclerosis: MS relapses with tumefactive demyelinating lesions on imaging have been observed during fingolimod therapy and after discontinuation in the post-marketing setting. Most reported cases of tumefactive MS in patients receiving Gilenya have occurred within the first 9 months after treatment initiation, but tumefactive MS may occur at any point during treatment. Cases of tumefactive MS have also been reported within the first 4 months after discontinuation.
Increased Blood Pressure: Increases in blood pressure have been observed in patients treated with fingolimod. Hypertension was reported as an adverse reaction in 8% of patients on fingolimod 0.5 mg and in 4% of patients on placebo. Monitor blood pressure (BP) in patients during treatment with fingolimod.
Malignancies:
Cutaneous Malignancies: 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. Use of fingolimod has been associated with an increased risk of BCC and melanoma.
Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUVA photochemotherapy is not recommended in patients taking fingolimod.
Lymphoma: 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 adjusted by age, gender, and region. Cutaneous T-cell lymphoma (including mycosis fungoides) has also been reported with fingolimod in the post-marketing setting.
Immune System Effects Following GILENYA Discontinuation: 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 the normal range within 1 to 2 months of stopping therapy. Because of the continuing pharmacodynamic effects of fingolimod, initiating other drugs during this period warrants the same considerations needed for concomitant administration (e.g., risk of additive immunosuppressant effects).
Hypersensitivity Reactions: Hypersensitivity reactions, including rash, urticaria, and angioedema have been reported in the post-marketing setting. Fingolimod is contraindicated in patients with history of hypersensitivity to fingolimod or any of its excipients.
See prescribing information for full details.

The following serious adverse reactions can occur in patients:
• Bradyarrhythmia and Atrioventricular Blocks
• Infections
• Progressive multifocal leukoencephalopathy
• Macular edema
• Liver injury
• Posterior reversible encephalopathy syndrome
• Respiratory effects
• Fetal risk
• Severe increase in disability after stopping gilenya
•Tumefactive multiple sclerosis
• Increased blood pressure
• Malignancies
• Immune system effects following fingolimod discontinuation
• Hypersensitivity reactions
See prescribing information for full details.

QT Prolonging Drugs: This medicinal product has not been studied in patients treated with drugs that prolong the QT interval. Drugs that prolong the QT interval have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of treatment results in decreased heart rate and may prolong the QT interval, patients on QT-prolonging drugs with a known risk of torsades de pointes (e.g., citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should be monitored overnight with continuous ECG in a medical facility.
Ketoconazole: The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole. Patients who use fingolimod and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is increased.
Vaccines: Fingolimod reduces the immune response to vaccination. Vaccination may be less effective during and for up to 2 months after discontinuation of treatment. Avoid the use of live attenuated vaccines during and for 2 months after treatment with fingolimod because of the risk of infection.
Antineoplastic, Immunosuppressive, or Immune-Modulating Therapies: Antineoplastic, immune-modulating, or immunosuppressive therapies, (including corticosteroids) are expected to increase the risk of immunosuppression, and the risk of additive immune system effects must be considered if these therapies are coadministered with fingolimod. When switching from drugs with prolonged immune effects, such as natalizumab, teriflunomide or mitoxantrone, the duration and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects when initiating fingolimod.
Drugs That Slow Heart Rate or Atrioventricular Conduction (e.g., beta blockers or diltiazem): Experience with fingolimod in patients receiving concurrent therapy with drugs that slow the heart rate or AV conduction (e.g., beta blockers, digoxin, or heart rate-slowing calcium channel blockers, such as diltiazem or verapamil) is limited. Because initiation of fingolimod treatment may result in an additional decrease in heart rate, concomitant use of these drugs during fingolimod initiation may be associated with severe bradycardia or heart block. Seek advice from the physician prescribing these drugs regarding the possibility to switch to drugs that do not slow the heart rate or atrioventricular conduction before initiating fingolimod. Patients who cannot switch should have overnight continuous ECG monitoring after the first dose.
Laboratory Test Interaction: Because fingolimod reduces blood lymphocyte counts via re-distribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of patients. A recent CBC should be available before initiating treatment with fingolimod.
See prescribing information for full details.

Pregnancy: Available observational pregnancy registry data suggest that use of fingolimod is associated with an increased prevalence of major birth defects in comparison to the general population. However, limitations in the number of exposed pregnant women and in the study design preclude definitive conclusions.
Data from prospective reports to the Pregnancy Registry are currently not sufficient to allow for an adequate assessment of the drug-associated risk for miscarriage.
Clinical Considerations: In females planning to become pregnant, fingolimod should be stopped 2 months before planned conception.
The possibility of severe increase in disability should be considered in women who discontinue or are considering discontinuation of fingolimod because of pregnancy or planned pregnancy. In many of the cases in which increase in disability was reported after stopping fingolimod, patients had stopped fingolimod because of pregnancy or planned pregnancy.
Breast-feeding: There are no data on the presence of fingolimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fingolimod and any potential adverse effects on the breastfed infant from fingolimod or from the underlying maternal condition.
See prescribing information for full details.

Fingolimod can induce bradycardia as well as AV conduction blocks (including complete AV block). The decline in heart rate usually starts within 1 hour of the first dose and is maximal within 6 hours in most patients. In case of overdosage, observe patients overnight with continuous ECG monitoring in a medical facility, and obtain regular measurements of blood pressure.
Neither dialysis nor plasma exchange results in removal of fingolimod from the body.

Storage: Do not store above 25°C; protect from moisture.