LYXIA

Multiple sclerosis, or MS, is a devastating inflammatory disease that often progresses and causes severe neurological, physical, and cognitive effects.

Fingolimod is a sphingosine 1-phosphate receptor modulator for the treatment of relapsing-remitting multiple sclerosis.

It was developed by Novartis and initially approved by the FDA in 2010.

Fingolimod was also studied for the treatment of COVID-19, the disease caused by infection with the SARS-CoV-2 virus. 13, 14.

Fingolimod is indicated for the treatment of patients aged and above with relapsing forms of multiple sclerosis, which may include clinically isolated syndrome, relapsing-remitting disease, as well as active secondary progressive disease. 12,

In multiple sclerosis, fingolimod binds to sphingosine receptors, reducing its associated neuroinflammation.

In COVID-19, it may reduce lung inflammation and improve the clinical outcomes of patients with this disease.

Fingolimod causes a transient reduction in heart rate and AV conduction during treatment initiation.

It has the potential to prolong the QT interval.

Sphingosine 1-phosphate receptor 5 Modulator Sphingosine 1-phosphate receptor 1 Modulator Sphingosine 1-phosphate receptor 3 Modulator.

Fingolimod is slowly but efficiently absorbed in the gastrointestinal tract.

AUC varies greatly, depending on the patient, and pharmacokinetic studies demonstrate a range of AUC values for fingolimod.

Tmax of fingolimod ranges between 12-16 hours and its bioavailability is 90-93%.

Steady-state concentrations of fingolimod are achieved within 1-2 months after initiation when it is administered in a single daily dose. 5, 12.

The volume of distribution of fingolimod is about 1200±260 L. It is approximately 86% distributed in the red blood cells (RBC). 5, 12.

Sphingosine kinase metabolizes fingolimod to an active metabolite, fingolimod phosphate.

Fingolimod metabolism occurs via 3 major metabolic pathways: firstly, phosphorylation of the (S)-enantiomer of fingolimod-phosphate (pharmacologically active), secondly, oxidation by cytochrome P450 4F2 (CYP4F2), and thirdly, fatty acid-like metabolism to various inactive metabolites.

The formation of inactive non-polar ceramide analogs of fingolimod also occurs during its metabolism. 5, 12 Hover over products below to view reaction partners Fingolimod Fingolimod phosphate.

About 81% of an oral dose of fingolimod is excreted in the urine in the form of inactive metabolites.

Intact fingolimod and its active metabolite account for less than 2.5% of the dose, and can be found excreted in the feces.

The half-life of fingolimod and its active metabolite ranges from 6-9 days. 5, 12.

Fingolimod blood clearance is 6.3±2.3 L/h, 12 according to prescribing information.

Another resource mentions it ranges from 6-8 L/h.

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LD50 of fingolimod in rats ranges from 300-600 mg/kg.

Prescribing information for fingolimod does not mention symptoms or management of an overdose 12, however, a case report of an intentional overdose with 14 mg of fingolimod and 2 g phenoxymethylpenicillin resulted in hypotension in bradycardia, resolved by administering atropine.

Since fingolimod has been associated with cardiotoxicity, it would be reasonable to expect cardiac effects such as bradycardia and heart block in the case of an overdose. 9, 12.

Fingolimod capsules are 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 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 in fingolimod capsules.

Observed reactions include rash, urticaria and angioedema upon treatment initiation.

Recent myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure with hospitalization, or Class III/IV heart failure.

II 2 nd degree or 3 rd degree AV block or sick sinus syndrome, unless patient has a pacemaker.

QTc interval ≥500 msec.

Cardiac arrhythmias requiring anti-arrhythmic treatment with Class Ia or Class III anti-arrhythmic drugs.

Hypersensitivity to fingolimod or its excipients.

· Assessments are required prior to initiating fingolimod capsules. · Recommended dosage for adults and pediatric patients (10 years of age and older) weighing more than 40 kg: 0.5 mg orally once daily, with or without food. · First-Dose Monitoring (including reinitiation after discontinuation greater than 14 days and dose increases): o Observe all patients for bradycardia for at least 6 hours; monitor pulse and blood pressure hourly.

Electrocardiograms (ECGs) prior to dosing and at end of observation period required. o Monitor until resolution if heart rate < 45 beats per minute (bpm) in adults, < 55 bpm in patients aged 12 years and above, or < 60 bpm in pediatric patients aged to below 12 years, atrioventricular (AV) block, or if lowest postdose heart rate is at the end of the observation period. o Monitor symptomatic bradycardia with ECG until resolved.

Continue overnight if intervention is required; repeat first-dose monitoring for second dose. o Observe patients overnight if at higher risk of symptomatic bradycardia, heart block, prolonged QTc interval, or if taking drugs with known risk of torsades de pointes. 2.1 Assessment Prior to Initiating Fingolimod Cardiac Evaluation Obtain a cardiac evaluation in patients with certain preexisting conditions.

Prior to starting treatment, determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction.

Count (CBC) Review results of a recent CBC.

Transaminases (ALT and AST) and Total Bilirubin Levels Prior to starting treatment with fingolimod (i.e., within 6 months), obtain serum transaminases [alanine transaminase (ALT) and aspartate transferase (AST)] and total bilirubin levels.

Obtain a baseline evaluation of the fundus, including the macula, near the start of the treatment with fingolimod.

Obtain a baseline skin examination prior to or shortly after initiation of fingolimod.

If a suspicious skin lesion is observed, it should be promptly evaluated.

If patients are taking antineoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with fingolimod.

Test patients for antibodies to varicella zoster virus (VZV) before initiating fingolimod; VZV vaccination of antibody.

• negative patients is recommended prior to commencing treatment with fingolimod.

It is recommended that pediatric patients if possible, complete all immunizations in accordance with current immunization guidelines prior to initiating fingolimod therapy. 2.2 Important Administration Instructions Patients who initiate fingolimod and those who reinitiate treatment after discontinuation for longer than 14 days, require first-dose monitoring.

This monitoring is also recommended when the dose is increased in pediatric patients.

Fingolimod capsules can be taken with or without food. 2.3 Recommended Dosage In adults and pediatric patients 10 years of age and older weighing more than 40 kg, the recommended dosage of fingolimod capsules is 0.5 mg orally once-daily.

Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit. 2.4 First-Dose Monitoring Initiation of fingolimod capsules treatment results in a decrease in heart rate, for which monitoring is recommended.

Prior to dosing and at the end of the observation period, obtain an electrocardiogram (ECG) in all patients.

First 6-Hour Monitoring Administer the first dose of fingolimod in a setting in which resources to appropriately manage symptomatic bradycardia are available.

Monitor all patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement.

After 6-Hour Monitoring Continue monitoring until the abnormality resolves if any of the following is present (even in the absence of symptoms) after 6 hours: the heart rate 6 hours postdose is less than 45 beats per minute (bpm) in adults, less than 55 bpm in pediatric patients 12 years of age and older, or less than 60 bpm in pediatric patients 10 or 11 years of age; the heart rate 6 hours postdose is at the lowest value postdose suggesting that the maximum pharmacodynamic effect on the heart may not have occurred; the ECG 6 hours postdose shows new onset second degree or higher atrioventricular (AV) block.

If postdose symptomatic bradycardia occurs, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no pharmacological treatment is required.

If pharmacological treatment is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose.

Overnight Monitoring Continuous overnight

ECG monitoring in a medical facility should be instituted: in patients that require pharmacologic intervention for symptomatic bradycardia.

In these patients, the first-dose monitoring strategy should be repeated after the second dose of fingolimod; in patients with some preexisting heart and cerebrovascular conditions; in patients with a prolonged QTc interval before dosing or during 6-hour observation, or at additional risk for QT prolongation, or on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes; in patients receiving concurrent therapy with drugs that slow heart rate or AV conduction. 2.5 Monitoring After Reinitiation of Therapy Following Discontinuation When restarting fingolimod capsules after discontinuation for more than 14 days after the first month of treatment, perform first-dose monitoring, because effects on heart rate and AV conduction may recur on reintroduction of fingolimod capsules treatment.

The same precautions (first-dose monitoring) as for initial dosing are applicable.

Within the first 2 weeks of treatment, first-dose procedures are recommended after interruption of 1 day or more; during Weeks and 4 of treatment, first-dose procedures are recommended after treatment interruption of more than 7 days.

Fingolimod capsules 0.5 mg are supplied as follows: hard gelatin capsules with a white opaque body with two radial band imprinted with yellow ink and bright yellow cap imprinted with “FIG 0.5 mg” with black ink.

Container pack of 28 capsules NDC 67877-476-56 Container pack of 30 capsules NDC 67877-476-30 Carton of 10 capsules containing 1 blister pack of 10 capsules NDC 67877-476-33 Carton of 7 capsules containing 1 blister card of 7 capsules NDC 67877-476-32 Carton of 28 capsules two fold blister card of 14 capsules NDC 67877-476-58 16.2 Storage and Handling Fingolimod capsules should be stored at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15ºC to 30ºC (59ºF to 86ºF) .

Protect from moisture.

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.

Based on findings from animal studies, fingolimod may cause fetal harm when administered to a pregnant woman.

In oral studies conducted in rats and rabbits, fingolimod demonstrated developmental toxicity, including an increase in malformations (rats) and embryolethality, when given to pregnant animals.

In rats, the highest no-effect dose was less than the recommended human dose of 0.5 mg/day on a body surface area (mg/m2) basis.

The most common fetal visceral malformations in rats were persistent truncus arteriosus and ventricular septal defect.

The receptor affected by fingolimod (sphingosine 1-phosphate receptor) is known to be involved in vascular formation during embryogenesis.

Advise pregnant women of the potential risk to a fetus.

In the

US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

The background risk of major birth defects and miscarriage for the indicated population is unknown.

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.

In a prospective observational fingolimod pregnancy registry (GPR), the rate of major birth defects among 147 live births, stillbirths, or terminations of pregnancy due to fetal anomalies from women who were administered fingolimod during the first trimester was 8.2% (95% CI: 4.3-13.8) using the European Registration of Congenital Anomalies and Twin classification and 10.9% (95% CI: 6.4-17.1) using the Metropolitan Atlanta Congenital Defects Program classification.

The most frequent major birth defects were congenital heart defects, renal/urinary malformations, and limb/musculoskeletal malformations.

Study limitations include no adjustment for confounders, no re-adjudication in case of spontaneous resolution, lack of an internal comparator cohort, and small sample size.

In fingolimod prospective pharmacovigilance data, the most frequent major birth defect types were similar to those reported in the GPR.

The pattern of malformations reported for fingolimod is similar to that observed in the general population.

There is no evidence of clustering of specific birth defects with fingolimod.

When fingolimod was orally administered to pregnant rats during the period of organogenesis (0, 0.03, 0.1, and 0.3 mg/kg/day or 0, 1, 3, and 10 mg/kg/day), increased incidences of fetal malformations and embryofetal deaths were observed at all but the lowest dose tested (0.03 mg/kg/day), which is less than the recommended human dose (RHD) on a mg/m 2 basis.

Oral administration to pregnant rabbits during organogenesis (0, 0.5, 1.5, and 5 mg/kg/day) resulted in increased incidences of embryofetal mortality and fetal growth retardation at the mid and high doses.

The no-effect dose for these effects in rabbits (0.5 mg/kg/day) is approximately 20 times the RHD on a mg/m 2 basis.

When fingolimod was orally administered to female rats during pregnancy and lactation (0, 0.05, 0.15, and 0.5 mg/kg/day), pup survival was decreased at all doses and a neurobehavioral (learning) deficit was seen in offspring at the high dose.

The low-effect dose of 0.05 mg/kg/day is similar to the RHD on a mg/m 2 basis.

Females and Males of Reproductive Potential Pregnancy Testing The pregnancy status of females of reproductive potential should be verified prior to starting treatment with fingolimod.

Before initiation of fingolimod treatment, females of reproductive potential should be counseled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with fingolimod.

Since it takes approximately 2 months to eliminate the compound from the body after stopping treatment, the potential risk to the fetus may persist and women should use effective contraception during this period.

Safety and effectiveness of fingolimod hydrochloride for the treatment of relapsing forms of multiple sclerosis in pediatric patients to less than 18 years of age were established in one randomized, double-blind clinical study in 215 patients (fingolimod hydrochloride n = 107; intramuscular interferon (IFN) beta-1a n = 108) .

In the controlled pediatric study, the safety profile in pediatric patients (10 to less than 18 years of age) receiving fingolimod hydrochloride 0.5 mg daily was similar to that seen in adult patients.

In the pediatric study, cases of seizures were reported in 5.6% of fingolimod-treated patients and 0.9% of interferon beta-1a-treated patients.

It is recommended that pediatric patients, if possible, complete all immunizations in accordance with current immunization guidelines prior to initiating fingolimod therapy.

Safety and effectiveness of fingolimod in pediatric patients below the age of 10 years have not been established.

In a study in which fingolimod (0.3, 1.5, or 7.5 mg/kg/day) was orally administered to young rats from weaning through sexual maturity, changes in bone mineral density and persistent neurobehavioral impairment (altered auditory startle) were observed at all doses.

Delayed sexual maturation was noted in females at the highest dose tested and in males at all doses.

The bone changes observed in fingolimod-treated juvenile rats are consistent with a reported role of S1P in the regulation of bone mineral homeostasis.

When fingolimod (0.5 or 5 mg/kg/day) was orally administered to rats from the neonatal period through sexual maturity, a marked decrease in T-cell dependent antibody response was observed at both doses.

This effect had not fully recovered by to 8 weeks after the end of treatment.

Overall, a no-effect dose for adverse developmental effects in juvenile animals was not identified.

MS studies of fingolimod did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients.

Fingolimod should be used with caution in patients aged 65 years and over, reflecting the greater frequency of decreased hepatic, or renal, function and of concomitant disease or other drug therapy.