Gilenya Information
Gilenya ()
Gilenya () Dosage And Administration
The recommended dose of Gilenya () is 0.5 mg orally once daily. Patients should be observed for 6 hours after the first dose to monitor for signs and symptoms of bradycardia [see(5.1)]. Fingolimod doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefit.
Gilenya () can be taken with or without food.
Gilenya ()
Gilenya ()
Gilenya ()
Gilenya ()
Gilenya () Drug Interactions
Gilenya () has not been studied in patients with arrhythmias requiring treatment with Class Ia (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic drugs. Class Ia and Class III antiarrhythmic drugs have been associated with cases of torsades de pointes in patients with bradycardia. Since initiation of Gilenya () treatment results in decreased heart rate, patients on Class Ia or Class III antiarrhythmic drugs should be closely monitored [see (5.1)].
The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when coadministered with ketoconazole. Patients who use Gilenya () and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater.
Vaccination may be less effective during and for up to 2 months after discontinuation of treatment with Gilenya () [(12.2)]. The use of live attenuated vaccines should be avoided during and for 2 months after treatment with Gilenya () because of the risk of infection.
Antineoplastic, immunosuppressive or immune modulating therapies are expected to increase the risk of immunosuppression. Use caution when switching patients from long-acting therapies with immune effects such as natalizumab or mitoxantrone.
Experience with Gilenya () in patients receiving concurrent therapy with beta blockers is limited. These patients should be carefully monitored during initiation of therapy. When Gilenya () is used with atenolol, there is an additional 15% reduction of heart rate upon Gilenya () initiation, an effect not seen with diltiazem [see ].
Because Gilenya () reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a patient treated with Gilenya () . A recent CBC should be available before initiating treatment with Gilenya () .
Gilenya ()
Gilenya ()
Gilenya ()
Gilenya () Clinical Pharmacology
Heart rate and rhythm
Fingolimod causes a transient reduction in heart rate and AV conduction at treatment initiation [see (5.1)]. The maximal decline of heart rate is seen in the first 6 hours post-dose, with 70% of the negative chronotropic effect achieved on the first day. Heart rate progressively increases after the first day, returning to baseline values within 1 month of the start of chronic treatment.
Autonomic responses of the heart, including diurnal variation of heart rate and response to exercise, are not affected by fingolimod treatment.
Fingolimod treatment is not associated with a decrease in cardiac output.
Potential to prolong the QT interval
In a thorough QT interval study of doses of 1.25 or 2.5 mg fingolimod at steady-state, when a negative chronotropic effect of fingolimod was still present, fingolimod treatment resulted in a prolongation of QTc, with the upper bound of the 90% confidence interval (CI) of 14.0 ms. There is no consistent signal of increased incidence of QTc outliers, either absolute or change from baseline, associated with fingolimod treatment. In MS studies, there was no clinically relevant prolongation of QT interval, but patients at risk for QT prolongation were not included in clinical studies.
Immune system
Effects on immune cell numbers in the blood
In a study in which 12 subjects received Gilenya () 0.5 mg daily, the lymphocyte count decreased to approximately 60% of baseline within 4-6 hours after the first dose. With continued daily dosing, the lymphocyte count continued to decrease over a 2-week period, reaching a nadir count of approximately 500 cells/μL or approximately 30% of baseline. In a placebo-controlled study in 1272 MS patients (of whom 425 received fingolimod 0.5 mg daily and 418 received placebo), 18% (N=78) of patients on fingolimod 0.5 mg reached a nadir of
Chronic fingolimod dosing leads to a mild decrease in the neutrophil count to approximately 80% of baseline. Monocytes are unaffected by fingolimod.
Peripheral lymphocyte count increases are evident within days of stopping fingolimod treatment and typically normal counts are reached within 1 to 2 months.
Effect on antibody response
The immunogenicity of keyhole limpet Hemocyanin (KLH) and pneumococcal polysaccharide vaccine (PPV-23) immunization were assessed by IgM and IgG titers in a steady-state, randomized, placebo-controlled study in healthy volunteers. Compared to placebo, antigen-specific IgM titers were decreased by 91% and 25% in response to KLH and PPV, respectively, in subjects on Gilenya () 0.5 mg. Similarly, IgG titers were decreased by 45% and 50%, in response to KLH and PPV, respectively, in subjects on Gilenya () 0.5 mg daily compared to placebo. The responder rate for Gilenya () 0.5 mg as measured by the number of subjects with a >4-fold increase in KLH IgG was comparable to placebo and 25% lower for PPV-23 IgG, while the number of subjects with a >4 fold increase in KLH and PPV-23 IgM was 75% and 40% lower, respectively, compared to placebo. The capacity to mount a skin delayed-type hypersensitivity reaction to and tetanus toxoid was decreased by approximately 30% in subjects on Gilenya () 0.5 mg daily, compared to placebo. Immunologic responses were further decreased with fingolimod 1.25 mg (a dose higher than recommended in MS) [see (5.2)].
Pulmonary function
Single fingolimod doses ≥5 mg (10-fold the recommended dose) are associated with a dose-dependent increase in airway resistance. In a 14-day study of 0.5, 1.25, or 5 mg/day, fingolimod was not associated with impaired oxygenation or oxygen desaturation with exercise or an increase in airway responsiveness to methacholine. Subjects on fingolimod treatment had a normal bronchodilator response to inhaled beta-agonists.
In a 14-day placebo-controlled study of patients with moderate asthma, no effect was seen for Gilenya () 0.5mg (recommended dose in MS). A 10% reduction in mean FEV1 at 6 hour after dosing was observed in patients receiving fingolimod 1.25 mg (a dose higher than recommended for use in MS) on Day 10 of treatment. Fingolimod 1.25 mg was associated with a 5-fold increase in the use of rescue short acting beta-agonists.
Absorption
The T of fingolimod is 12-16 hours. The apparent absolute oral bioavailability is 93%.
Food intake does not alter Cor exposure (AUC) of fingolimod or fingolimod-phosphate. Therefore Gilenya () may be taken without regard to meals.
Steady-state blood concentrations are reached within 1 to 2 months following once-daily administration and steady-state levels are approximately 10-fold greater than with the initial dose.
Distribution
Fingolimod highly (86%) distributes in red blood cells. Fingolimod-phosphate has a smaller uptake in blood cells of 99.7% protein bound. Fingolimod and fingolimod-phosphate protein binding is not altered by renal or hepatic impairment.
Fingolimod is extensively distributed to body tissues with a volume of distribution of about 1200±260 L.
Metabolism
The biotransformation of fingolimod in humans occurs by three main pathways: by reversible stereoselective phosphorylation to the pharmacologically active ()-enantiomer of fingolimod-phosphate, by oxidative biotransformation mainly via the cytochrome P450 4F2 isoenzyme and subsequent fatty acid-like degradation to inactive metabolites, and by formation of pharmacologically inactive non-polar ceramide analogs of fingolimod.
Fingolimod is primarily metabolized via human CYP4F2 with a minor contribution of CYP2D6, 2E1, 3A4, and 4F12. Inhibitors or inducers of these isozymes might alter the exposure of fingolimod or fingolimod-phosphate. The involvement of multiple CYP isoenzymes in the oxidation of fingolimod suggests that the metabolism of fingolimod will not be subject to substantial inhibition in the presence of an inhibitor of a single specific CYP isozyme.
Following single oral administration of [C] fingolimod, the major fingolimod-related components in blood, as judged from their contribution to the AUC up to 816 hours post-dose of total radiolabeled components, are fingolimod itself (23.3%), fingolimod-phosphate (10.3%), and inactive metabolites [M3 carboxylic acid metabolite (8.3%), M29 ceramide metabolite (8.9%), and M30 ceramide metabolite (7.3%)].
Elimination
Fingolimod blood clearance is 6.3±2.3 L/h, and the average apparent terminal half-life (t) is 6-9 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. Fingolimod and fingolimod-phosphate are not excreted intact in urine but are the major components in the feces with amounts of each representing less than 2.5% of the dose.
Special Populations
Renal Impairment
In patients with severe renal impairment, fingolimod C and AUC are increased by 32% and 43%, respectively, and fingolimod-phosphate C and AUC are increased by 25% and 14%, respectively, with no change in apparent elimination half-life. Based on these findings, the Gilenya () 0.5 mg dose is appropriate for use in patients with renal impairment. The systemic exposure of two metabolites (M2 and M3) is increased by 3- and 13-fold, respectively. The toxicity of these metabolites has not been fully characterized.
A study in patients with mild or moderate renal impairment has not been conducted.
Hepatic Impairment
In subjects with mild, moderate, or severe hepatic impairment, no change in fingolimod C was observed, but fingolimod AUC was increased respectively by 12%, 44%, and 103%. In patients with severe hepatic impairment, fingolimod-phosphate C was decreased by 22% and AUC was not substantially changed. The pharmacokinetics of fingolimod-phosphate were not evaluated in patients with mild or moderate hepatic impairment. The apparent elimination half-life of fingolimod is unchanged in subjects with mild hepatic impairment, but is prolonged by about 50% in patients with moderate or severe hepatic impairment.
Patients with severe hepatic impairment should be closely monitored, as the risk of adverse reactions is greater [See (5.5)].
No dose adjustment is needed in patients with mild or moderate hepatic impairment.
Race
The effects of race on fingolimod and fingolimod-phosphate pharmacokinetics cannot be adequately assessed due to a low number of non-white patients in the clinical program.
Gender
Gender has no clinically significant influence on fingolimod and fingolimod-phosphate pharmacokinetics.
Geriatric patients
The mechanism for elimination and results from population pharmacokinetics suggest that dose adjustment would not be necessary in elderly patients. However, clinical experience in patients aged above 65 years is limited.
Pharmacokinetic interactions
Ketoconazole
The coadministration of ketoconazole (a potent inhibitor of CYP3A and CYP4F) 200 mg twice daily at steady-state and a single dose of fingolimod 5 mg led to a 70% increase in AUC of fingolimod and fingolimod-phosphate. Patients who use Gilenya () and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater. [See ]
Potential of fingolimod and fingolimod-phosphate to inhibit the metabolism of co-medications
In vitro inhibition studies in pooled human liver microsomes and specific metabolic probe substrates demonstrate that fingolimod has little or no capacity to inhibit the activity of the following CYP450 enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11, and similarly fingolimod-phosphate has little or no capacity to inhibit the activity of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 at concentrations up to three orders of magnitude of therapeutic concentrations. Therefore, fingolimod and fingolimod-phosphate are unlikely to reduce the clearance of drugs that are mainly cleared through metabolism by the major cytochrome P450 isoenzymes described above. The potential of fingolimod to inhibit CYP2C8 and fingolimod-phosphate to inhibit CYP2B6 is unknown.
Potential of fingolimod and fingolimod-phosphate to induce its own and/or the metabolism of co-medications
Fingolimod was examined for its potential to induce human CYP3A4, CYP1A2, CYP4F2, and MDR1 (P-glycoprotein) mRNA and CYP3A, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP4F2 activity in primary human hepatocytes. Fingolimod did not induce mRNA or activity of the different CYP450 enzymes and MDR1 with respect to the vehicle control; therefore, no clinically relevant induction of the tested CYP450 enzymes or MDR1 by fingolimod are expected at therapeutic concentrations. The potential of fingolimod-phosphate to induce CYP450 isoenzymes is unknown.
Transporters
Fingolimod as well as fingolimod-phosphate are not expected to inhibit the uptake of co-medications and/or biologics transported by OATP1B1, OATP1B3, or NTCP. Similarly, they are not expected to inhibit the efflux of co-medications and/or biologics transported by the breast cancer resistant protein (MXR), the bile salt export pump (BSEP), the multidrug resistance-associated protein 2 (MRP2), and MDR1-mediated transport at therapeutic concentrations.
Cyclosporine
The pharmacokinetics of single-dose fingolimod were not altered during coadministration with cyclosporine at steady-state, nor was cyclosporine steady-state pharmacokinetics altered by fingolimod. These data indicate that Gilenya () is unlikely to reduce the clearance of drugs mainly cleared by CYP3A4 and show that the potent inhibition of transporters MDR1, MRP2, and OATP-C does not influence fingolimod disposition.
Isoproterenol, atropine, atenolol, and diltiazem
Single-dose fingolimod and fingolimod-phosphate exposure was not altered by coadministered isoproterenol or atropine. Likewise, the single-dose pharmacokinetics of fingolimod and fingolimod-phosphate and the steady-state pharmacokinetics of both atenolol and diltiazem were unchanged during the coadministration of the latter two drugs individually with fingolimod.
Population pharmacokinetics analysis
A population pharmacokinetics evaluation performed in MS patients did not provide evidence for a significant effect of fluoxetine and paroxetine (strong CYP2D6 inhibitors) and carbamazepine (potent enzyme inducer) on fingolimod or fingolimod-phosphate pre-dose concentrations. In addition, the following commonly co-prescribed substances had no clinically relevant effect (
Gilenya ()
Gilenya ()
Gilenya ()
Gilenya () Patient Counseling Information
A Medication Guide is required for distribution with Gilenya () . Encourage patients to read the Gilenya () Medication Guide. The complete text of the Medication Guide is reprinted at the end of this document.
Gilenya ()
Gilenya ()
