Clinical medicine profile
Fingolimod
Therapeutic agent (verify pharmacological class)
- Route
- See product SmPC
- Schedule
- POM
- ATC
- Not assigned
- PPB status
- registered
Safety essentials
The information most likely to change a prescribing or dispensing decision.
Contraindications
- 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 [see Warnings and Precautions ( 5.1 )] 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 [see Warnings and Precautions ( 5.14 )].
- Recent myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure with hospitalization, or Class III/IV heart failure.
- ( 4 ) History of Mobitz Type II 2 nd degree or 3 rd degree AV block or sick sinus syndrome, unless patient has a pacemaker.
- ( 4 ) Baseline QTc interval ≥500 msec.
- ( 4 ) Cardiac arrhythmias requiring anti-arrhythmic treatment with Class Ia or Class III anti-arrhythmic drugs.
- ( 4 ) Hypersensitivity to fingolimod or its excipients.
Precautions
- Infections: Fingolimod may increase the risk.
- Obtain a complete blood count (CBC) before initiating treatment.
- Monitor for infection during treatment and for 2 months after discontinuation.
- Do not start in patients with active infections.
- ( 5.2 ) • Progressive Multifocal Leukoencephalopathy (PML): Withhold fingolimod at the first sign or symptom suggestive of PML.
- ( 5.3 ) • Macular Edema : Increases the risk of macular edema.
- Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with fingolimod.
- Conduct an evaluation of the fundus, including the macula, 3 to 4 months after treatment start, periodically while on therapy and any time there is a change in vision.
- Consider discontinuing fingolimod if macular edema develops.
- Diabetes mellitus and uveitis increase the risk.
- ( 5.4 ) • Liver Injury : Obtain liver enzyme results before initiation and periodically during treatment.
- Closely monitor patients with severe hepatic impairment.
Dosing matrix
Population and organ-function guidance, shown together for faster comparison.
· Assessments are required prior to initiating fingolimod capsules. ( 2.1 ) · 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. ( 2.2 , 2.3 ) · 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. ( 2.4 ) 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 10 to below 12 years, atrioventricular (AV) block, or if lowest postdose heart rate is at the end of the observation period. ( 2.4 ) o Monitor symptomatic bradycardia with ECG until resolved. Continue overnight if intervention is required; repeat first-dose monitoring for second dose. ( 2.4 ) 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. ( 2.4 , 7.1 ) 2.1 Assessment Prior to Initiating Fingolimod Cardiac Evaluation Obtain a cardiac evaluation in patients with certain preexisting conditions [ see Warnings and Precautions ( 5.1 )] . Prior to starting treatment, determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7.5 )] . Complete Blood Count (CBC) Review results of a recent CBC [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.6 )] . Serum 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 [see Warnings and Precautions ( 5.5 )] . Ophthalmic Assessment Obtain a baseline evaluation of the fundus, including the macula, near the start of the treatment with fingolimod [see Warnings and Precautions ( 5.4 )] . Skin Examination 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 [see Warnings and Precautions ( 5.12 )]. Prior Medications 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 [see Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.4 )] . Vaccinations 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 [see Warnings and Precautions ( 5.2 )] . 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 [see Dosage and Administration (2.4, 2.5)]. 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 [see Warnings and Precautions ( 5.1 ), Clinical Pharmacology ( 12.2 )]. 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. Additional Monitoring 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 [see Warnings and Precautions ( 5.1 )]; 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 [see Warnings and Precautions ( 5.1 ), Drug Interactions ( 7.1 )]; in patients receiving concurrent therapy with drugs that slow heart rate or AV conduction [ see Drug Interactions ( 7.5 )]. 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 [see Dosage and Administration ( 2.4 )] . 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 3 and 4 of treatment, first-dose procedures are recommended after treatment interruption of more than 7 days.
8.4 Pediatric Use Safety and effectiveness of fingolimod hydrochloride for the treatment of relapsing forms of multiple sclerosis in pediatric patients 10 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) [see Clinical Studies (14.2)]. 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. Juvenile Animal Toxicity Data 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 6 to 8 weeks after the end of treatment. Overall, a no-effect dose for adverse developmental effects in juvenile animals was not identified.
Review renal impairment dosing; many agents need CrCl/eGFR adjustment.
- CrCl 0–120: Confirm renal dosing in product SmPC / primary label.
Review hepatic impairment dosing; monitor LFTs if agent is hepatically cleared or hepatotoxic.
Use, effects & interactions
Indications
- (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in patients 10 years of age and older.
- Fingolimod capsules are 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.
Adverse effects
- labeling: Bradyarrhythmia and Atrioventricular Blocks [see Warnings and Precautions ( 5.1 )] Infections [see Warnings and Precautions ( 5.2 )] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions ( 5.3 )] Macular Edema [see Warnings and Precautions ( 5.4 )] Liver Injury [ see Warnings and Precautions ( 5.5 ) ] Posterior Reversible Encephalopathy Syndrome [ see Warnings and Precautions ( 5.6 ) ] Respiratory Effects [ see Warnings and Precautions ( 5.7 ) ] Fetal Risk [see Warnings and Precautions ( 5.8 )] Severe Increase in Disability After Stopping Fingolimod [see Warnings and Precautions ( 5.9 )] Tumefactive Multiple Sclerosis [see Warnings and Precautions ( 5.10 )] Increased Blood Pressure [see Warnings and Precautions ( 5.11 )] Malignancies [see Warnings and Precautions ( 5.12 ) ] Immune System Effects Following fingolimod Discontinuation [see Warnings and Precautions ( 5.13 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.14 )] Most common adverse reactions (incidence ≥10% and greater than placebo): Headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity.
- ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-272-7901 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adults In clinical trials (Studies 1, 2, and 3), a total of 1,212 patients with relapsing forms of multiple sclerosis received fingolimod capsule 0.5 mg.
- This included 783 patients who received fingolimod capsule 0.5 mg in the 2-year placebo-controlled trials (Studies 1 and 3) and 429 patients who received fingolimod capsule 0.5 mg in the 1-year active-controlled trial (Study 2).
- The overall exposure in the controlled trials was equivalent to 1,716 person-years .
- Approximately 1,000 patients received at least 2 years of treatment with fingolimod capsule 0.5 mg.
- In all clinical studies, including uncontrolled extension studies, the exposure to fingolimod capsule 0.5 mg was approximately 4,119 person-years.
- In placebo-controlled trials, the most frequent adverse reactions (incidence ≥10% and greater than placebo) for fingolimod capsule 0.5 mg were headache, liver transaminase elevation, diarrhea, cough, influenza, sinusitis, back pain, abdominal pain, and pain in extremity.
- Adverse events that led to treatment discontinuation and occurred in more than 1% of patients taking fingolimod capsule 0.5 mg, were serum transaminase elevations (4.7% compared to 1% on placebo) and basal cell carcinoma (1% compared to 0.5% on placebo).
- Table 1 lists adverse reactions in clinical studies in adults that occurred in ≥ 1% of fingolimod-treated patients and ≥ 1% higher rate than for placebo.
- Table 1: Adverse Reactions Reported in Adult Studies 1 and 3 (Occurring in ≥1% of Patients and Reported for fingolimod capsule 0.5 mg at ≥1% Higher Rate Than for Placebo) Adverse drug reactions Fingolimod capsule 0.5 mg N=783% Placebo N=773 % Infections Influenza 11 8 Sinusitis 11 8 Bronchitis 8 5 Herpes zoster 2 1 Tinea versicolor 2 ˂1 Cardiac disorders Bradycardia 3 1 Nervous system disorders Headache 25 24 Migraine 6 4 Gastrointestinal disorders Nausea 13 12 Diarrhea 13 10 Abdominal pain 11 10 General disorders and administration-site conditions Asthenia 2 1 Musculoskeletal and connective tissue disorders Back pain 10 9 Pain in extremity 10 7 Skin and subcutaneous tissue disorders Alopecia 3 2 Actinic keratosis 2 1 Investigations Liver transaminase elevations (ALT/GGT/AST) 15 4 Blood triglycerides increased 3 1 Respiratory, thoracic, and mediastinal disorders Cough 12 11 Dyspnea 9 7 Eye disorders Vision blurred 4 2 Vascular disorders Hypertension 8 4 Blood and lymphatic system disorders Lymphopenia 7 ˂1 Leukopenia 2 ˂1 Neoplasms benign, malignant, and unspecified (including cysts and polyps) Skin papilloma 3 2 Basal cell carcinoma 2 1 Abbreviations: ALT, alanine transaminase
- AST, aspartate transferase
- GGT, gamma-glutamyl transferase.
- Adverse reactions of seizure, dizziness, pneumonia, eczema, and pruritus were also reported in Studies 1 and 3, but did not meet the reporting rate criteria for inclusion in Table 1 (difference was less than 1%).
Drug interactions
Open multi-drug checker ↗- No administration of live attenuated vaccines during, and for 2 months after stopping treatment with the drug
- ketoconazole
- It was derived from myriocin (an immunosuppressive natural prod- uct).
Mechanism & disposition
metabolite, fingolimod-phosphate.
Read complete mechanism
metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which fingolimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.
Product-specific
Product-specific
See product SmPC
The T max of fingolimod is 12 to 16 hours. The apparent absolute oral bioavailability is 93%. Food intake does not alter C max or (AUC) of fingolimod or fingolimod-phosphate. Therefore, fingolimod may be taken without regard to meals. Steady-state blood concentrations are reached...
Fingolimod highly (86%) distributes in red blood cells. Fingolimod-phosphate has a smaller uptake in blood cells of <17%. Fingolimod and fingolimod-phosphate are >99.7% protein bound. Fingolimod and fingolimod-phosphate protein binding is not altered by renal or hepatic impairmen...
The biotransformation of fingolimod in humans occurs by 3 main pathways: by reversible stereoselective phosphorylation to the pharmacologically active ( S )-enantiomer of fingolimod-phosphate, by oxidative biotransformation catalyzed mainly by the cytochrome P450 4F2 (CYP4F2) and...
Fingolimod blood clearance is 6.3±2.3 L/h, and the average apparent terminal
(t 1/2 ) is 6 to 9 days. Blood levels of fingolimod-phosphate decline in parallel with those of fingolimod in the terminal phase, yielding similar half-lives for both. After oral administration, about 81% of the dose is slowly excreted in the urine as inactive metabolites. Fingol...
Pregnancy, lactation & diet
8.1 Pregnancy Risk Summary 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 (see Data). 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 (see Data). 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. 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 [see Warnings and Precautions ( 5.9 )]. Data Human Data In a prospective observational fingolimod pregnancy registry (GPR) (2011 -2024), 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. Animal Data 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.
8.3 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 [see Use in Specific Populations ( 8.1 )]. Contraception 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 [see Warnings and Precautions ( 5.8 ) and Use in Specific Populations ( 8.1 )] . 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 [see Warnings and Precautions ( 5.8 , 5.13 )] .
Brands & loaded prices
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Sources & review state
Decision support only. Confirm patient-specific decisions against the current product SmPC, Kenya STG/EML, and professional judgement.