GILENYA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for GILENYA (GILENYA).
Fingolimod is a sphingosine 1-phosphate receptor modulator. It is phosphorylated to fingolimod-phosphate, which binds to S1P receptors 1, 3, 4, and 5. It blocks lymphocyte egress from lymph nodes by acting as a functional antagonist at S1P1 receptors, reducing peripheral blood lymphocyte count and central nervous system inflammation.
| Metabolism | Primarily metabolized by CYP4F2, and to a lesser extent by CYP2D6, CYP2E1, CYP3A4, and CYP4F12. Extensive first-pass metabolism via reversible stereoselective phosphorylation to active metabolite fingolimod-phosphate; also undergoes oxidative metabolism. Elimination half-life is approximately 6-9 days. |
| Excretion | Fingolimod is primarily eliminated via fecal excretion (81%) and to a lesser extent via renal excretion (<1% as unchanged drug). Biliary excretion accounts for a minor portion. The major metabolic pathway is via CYP4F2-mediated hydroxylation, followed by glucuronidation and elimination in feces. |
| Half-life | The terminal elimination half-life of fingolimod is approximately 6–9 days (mean 8.4 days). Due to the prolonged half-life, steady-state is achieved after 1–2 months of daily dosing, and lymphopenia may persist for up to 2 months after treatment cessation. |
| Protein binding | Fingolimod is approximately 99.7% bound to plasma proteins, primarily to albumin and lipoproteins (including α1-acid glycoprotein). The main active metabolite, fingolimod-phosphate, is also highly bound (>99%). |
| Volume of Distribution | The volume of distribution (Vd) is approximately 17 L/kg (range 7–30 L/kg), indicating extensive tissue distribution, especially into erythrocytes (about 20% of total drug in blood) and sequestration in central nervous system and lymphoid tissues. |
| Bioavailability | Oral bioavailability is approximately 93% (range 84–98%). Absorption is not significantly affected by food, but to reduce the risk of bradycardia and atrioventricular block, the first dose should be taken in the morning after a low-fat or fat-free meal. |
| Onset of Action | Oral: A reduction in peripheral lymphocyte count is observed within 4–6 hours, with maximal lymphocyte sequestration by 24–48 hours. However, clinical efficacy in relapsing-remitting multiple sclerosis is typically seen after several weeks of continuous therapy. |
| Duration of Action | Oral: The immunosuppressive effect on lymphocyte recirculation persists for 6–8 weeks after the last dose, corresponding to the drug's long half-life. Close monitoring for infection is recommended during this period. |
0.5 mg orally once daily, with or without food
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to severe renal impairment including dialysis; monitor patients with severe renal impairment for bradycardia at treatment initiation |
| Liver impairment | Contraindicated in patients with severe hepatic impairment (Child-Pugh class C). No dose adjustment required for mild or moderate hepatic impairment (Child-Pugh class A and B) but initiate with caution and monitor liver enzymes |
| Pediatric use | Approved for pediatric patients aged 10 years and older: for body weight ≤40 kg, 0.25 mg orally once daily; for body weight >40 kg, standard adult dose of 0.5 mg orally once daily |
| Geriatric use | No specific dose adjustment recommended; use with caution due to potential for decreased renal function and increased sensitivity to bradycardia, monitor heart rate and blood pressure |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for GILENYA (GILENYA).
| Breastfeeding | Not recommended during breastfeeding. Fingolimod is excreted in animal milk; unknown if excreted in human milk. M/P ratio not established. Potential for serious adverse reactions in nursing infants, including bradycardia, infections, and immunosuppression. |
| Teratogenic Risk | FDA Pregnancy Category C. First trimester: potential for fetal harm based on animal studies (increased incidence of fetal malformations, including ventricular septal defects, at doses similar to human exposure). Second and third trimesters: limited human data; animal studies show reduced fetal weight and increased fetal mortality. Risk cannot be excluded; use only if benefit outweighs risk. |
■ FDA Black Box Warning
Risk of bradyarrhythmia and atrioventricular block, requiring first-dose monitoring for at least 6 hours, including hourly pulse and blood pressure measurement, and ECG before and after first dose. Risk of infections, including fatal cryptococcal infections and other opportunistic infections. Risk of macular edema, especially in patients with uveitis or diabetes mellitus. Risk of posterior reversible encephalopathy syndrome (PRES). Risk of cutaneous malignancies (basal cell carcinoma, melanoma, Merkel cell carcinoma). Risk of fetal harm; advise females of reproductive potential of potential risk and need for effective contraception.
| Serious Effects |
["Hypersensitivity to fingolimod or any excipient","Recent myocardial infarction (within last 6 months)","Unstable angina","Stroke or transient ischemic attack (within last 6 months)","History of second-degree Mobitz type II or third-degree AV block, sick sinus syndrome, or sinoatrial block unless patient has an implanted pacemaker","Baseline QTc interval ≥500 msec","Treatment with Class Ia or Class III antiarrhythmics","Severe untreated sleep apnea","Concomitant use of pimozide"]
| Precautions | ["Bradyarrhythmia: First-dose monitoring required; avoid in patients with sinoatrial block, sick sinus syndrome, second-degree or third-degree AV block unless pacemaker present.","Infections: Monitor for infections; consider suspending treatment if serious infection occurs. Vaccination against varicella zoster virus recommended before initiation.","Macular edema: Ophthalmologic evaluation before and 3-4 months after starting treatment; more frequent assessments in patients with diabetes or uveitis.","Respiratory effects: Dose-dependent decrease in forced expiratory volume and diffusion capacity; monitor pulmonary function if clinically indicated.","Elevated liver enzymes: Monitor liver enzymes before and during treatment; discontinue if significant liver injury occurs.","Fetal harm: Effective contraception required during and for 2 months after discontinuation.","Cutaneous malignancies: Baseline and routine dermatologic evaluations recommended.","Immune system effects: Avoid live attenuated vaccines during and for 2 months after treatment.","Posterior reversible encephalopathy syndrome (PRES): Evaluate rapidly if symptoms such as severe headache, altered mental status, visual disturbances, or seizures occur.","Increased blood pressure: Monitor blood pressure.","Reactivation of hepatitis B virus in carriers: Screen before initiation.","Tumor risk: Overall increased risk of malignancies, especially skin cancers and lymphomas."] |
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| Fetal Monitoring | Monitor for bradycardia and heart block at treatment initiation. During pregnancy: monitor fetal growth via ultrasound every 4 weeks due to risk of low birth weight. After delivery: monitor neonate for bradycardia, hypoglycemia, and infections. Perform complete blood count and liver function tests periodically. |
| Fertility Effects | In animal studies, no adverse effects on male or female fertility at clinically relevant doses. Human data insufficient. May theoretically impair fertility due to immunosuppression, but no specific evidence. |