Fingolimod Hydrochloride

Class: Biologic Response Modifiers
Chemical Name: 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol hydrochloride
Molecular Formula: C₁₉H₃₃NO₂•HCl
CAS Number: 162359-56-0
Brands: Gilenya

REMS:

FDA approved a REMS for fingolimod to ensure that the benefits of a drug outweigh the risks. The REMS may apply to one or more preparations of fingolimod and consists of the following: medication guide and communication plan. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

A sphingosine 1-phosphate (S1P) receptor modulator with immunomodulatory and disease-modifying activity in multiple sclerosis.^{1 3 4 10 31}

Uses for Fingolimod Hydrochloride

Multiple Sclerosis (MS)

Used to reduce the frequency of clinical exacerbations and delay the accumulation of physical disability in adults with relapsing forms of MS (e.g., relapsing-remitting MS [RRMS]).^{1 2 3 4 10}

Used as first-line therapy for relapsing MS;^{1 30 31 33 38} additional studies needed to determine optimal role and safety profile, particularly during long-term use and in comparison with other disease-modifying therapies (e.g., glatiramer acetate, interferon beta, natalizumab).^{3 33 34 38}

May be useful in patients who prefer to avoid parenteral administration and/or in those who have had an inadequate response to other first-line therapies (e.g., glatiramer acetate, interferon beta).^{31 33}

Currently not FDA-labeled for use in patients with primary-progressive MS†.^{1 40}

Autoimmune Neuropathy

Designated an orphan drug by FDA for treatment of chronic inflammatory demyelinating polyneuropathy†; not labeled for this orphan indication by FDA.³²

Fingolimod Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to food.^{1 2 11}

Observe patient in physician’s office or clinic for 6 hours after the first dose or after subsequent doses when dosing has been interrupted for >2 weeks for bradycardia and possible AV block.^{1 31} (See Bradycardia and AV Block under Cautions.)

Risk Evaluation and Mitigation Strategy (REMS)

A REMS has been required and approved by FDA for fingolimod.⁵ The goal of this REMS program is to inform patients and healthcare providers about the serious risks associated with fingolimod therapy (e.g., bradycardia and AV block at treatment initiation, infections, macular edema, respiratory effects, hepatic effects, fetal risk).⁵ (See Cautions.)

REMS program consists of a medication guide to be dispensed with every fingolimod prescription and a communication plan requiring initial and periodic communications from the manufacturer to certain targeted groups of healthcare providers.⁵

Dosage

Available as fingolimod hydrochloride; dosage expressed in terms of fingolimod.¹

Adults

Multiple Sclerosis

Oral

0.5 mg once daily.¹ Higher dosages associated with a greater incidence of adverse reactions without additional benefit.^{1 3 4}

Special Populations

Hepatic Impairment

Severe hepatic impairment: monitor closely.¹ Routine dosage adjustment does not appear necessary.¹

Mild or moderate hepatic impairment: routine dosage adjustment not necessary.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

Routine dosage adjustment does not appear necessary.¹ (See Renal Impairment under Cautions.)

Geriatric Patients

Dosage adjustment not necessary.^{1 13} (See Geriatric Use under Cautions.)

Cautions for Fingolimod Hydrochloride

Contraindications

• 
  

  None.¹

  
  

Warnings/Precautions

Bradycardia and AV Block

Initiation of fingolimod therapy causes a decrease in heart rate, usually beginning within an hour and becoming maximal about 6 hours after the first dose.¹ Observe all patients for signs and symptoms of bradycardia for 6 hours after first dose.^{1 3 4 31} If post-dose bradycardia-related symptoms occur, initiate appropriate management and continue observation until symptoms resolve.¹

Transient AV conduction delays (e.g., first-degree AV block, second-degree AV block) may occur when initiating therapy.^{1 4 20} Conduction abnormalities usually are transient, asymptomatic, and resolve within the first 24 hours on treatment, but occasionally require treatment with atropine or isoproterenol.¹ (See Specific Drugs and Laboratory Tests under Interactions.)

To identify underlying risk factors for bradycardia and AV block, obtain baseline ECG before starting fingolimod if a recent one (i.e., within 6 months) is not available in patients receiving antiarrhythmic agents (e.g., β-adrenergic blocking agents, calcium-channel blocking agents), patients with cardiac risk factors (e.g., history of syncope, sitting heart rate <55 bpm, second-degree or higher AV block, sick sinus syndrome, prolonged QT interval, ischemic heart disease, CHF), and patients with a slow or irregular heart beat.¹

If fingolimod is discontinued for >2 weeks, effects on heart rate and AV conduction may recur upon reinitiation of therapy; follow the same precautions recommended for initial dosing in such cases.¹

Infectious Complications

Fingolimod causes a dose-dependent reduction in peripheral lymphocyte count to 20–30% of baseline values (see Actions).¹ May increase risk of infections; some are serious.¹ Before initiating treatment, a recent CBC (i.e., within 6 months) should be available.¹ Do not begin treatment in patients with active acute or chronic infections until infection(s) is resolved.¹

Monitor patients for signs and symptoms of infection during and for 2 months after discontinuing therapy.¹ (See Advice to Patients.) If a serious infection develops, consider drug discontinuance, at least temporarily, and reassess benefits and risks prior to re-initiation of therapy.¹

Has not been administered concomitantly with antineoplastic, immunosuppressive, or immunomodulating therapies used for MS.¹ Concomitant use expected to increase risk of immunosuppression.¹

Test patients who do not have a history of chickenpox or have not received vaccination against varicella zoster virus (VZV) for antibodies to VZV before initiating fingolimod.¹ Consider VZV vaccination of antibody-negative patients prior to initiating fingolimod treatment; postpone initiation of fingolimod therapy for 1 month following vaccination.¹

Macular Edema

Macular edema occurred in 0.4% of fingolimod-treated patients in controlled studies, usually within the first 3–4 months.^{1 3 4 31} Some patients presented with blurred vision or decreased visual acuity; others were asymptomatic and diagnosed upon routine ophthalmologic examination.¹ Macular edema generally improved or resolved after drug discontinuance with or without treatment, although some patients had residual visual acuity loss even after resolution of the macular edema.^{1 3 4 31}

Perform an adequate ophthalmologic evaluation at baseline and 3–4 months after treatment initiation.¹ If patient reports visual disturbances at any time during therapy, perform an additional ophthalmologic evaluation.¹

Patients with diabetes mellitus or a history of uveitis are at increased risk for macular edema and should have regular ophthalmologic evaluations during therapy.¹

Respiratory Effects

May decrease pulmonary function tests.¹ Dose-dependent reductions in FEV₁ and diffusion lung capacity for carbon monoxide (DLCO) observed as early as 1 month after beginning therapy.¹

Obtain spirometry and DLCO when clinically indicated (see Advice to Patients).¹ FEV₁ changes appear reversible after discontinuing fingolimod; insufficient information to determine reversibility of the decrease in DLCO.¹

Hepatic Effects

May increase liver transaminase concentrations.^{1 4} Most of these elevations occur within 3–4 months.¹ Recent (i.e., within past 6 months) liver enzyme results should be available before initiating treatment.¹

Monitor liver enzymes in patients who develop symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, dark urine).¹ Discontinue fingolimod if clinically important liver injury is confirmed.¹ Patients with preexisting liver disease may be at increased risk of developing elevated liver enzymes with fingolimod.¹

Fetal/Neonatal Morbidity and Mortality

Animal studies indicate fingolimod may cause fetal harm.¹ Use effective contraception in women of childbearing potential during and for 2 months after discontinuance of therapy.¹ (See Pregnancy under Cautions and see also Advice to Patients.)

BP Effects

May increase BP.¹ Monitor BP during therapy.¹

In clinical studies, fingolimod-treated patients had average increases of approximately 2 mm Hg in SBP and approximately 1 mm Hg in DBP; increases first detected approximately 2 months following treatment initiation and persisted with continued treatment.¹ Hypertension reported in 5% of patients receiving fingolimod in controlled trials.¹

Immunosuppression Following Discontinuance

Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts, for ≤2 months following the last dose; initiating other drugs during this period warrants the same considerations needed for concomitant administration (e.g., risk of additive immunosuppressive effects).¹ (See Specific Drugs and Laboratory Tests under Interactions.)

Specific Populations

Pregnancy

Category C.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Gilenya pregnancy registry (for clinicians and patients) at 877-598-7237.^{1 2 37}

Effects on labor and delivery are unknown.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.^{1 2} Discontinue nursing or the drug.^{1 2}

Pediatric Use

Safety and effectiveness not established in patients <18 years of age.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.¹ Use with caution because of possible age-related decreases in hepatic and/or renal function and concomitant disease and drug therapy.¹

Hepatic Impairment

Closely monitor patients with severe hepatic impairment since fingolimod exposure is doubled, and risk of adverse reactions may be greater.^{1 13 14} (See Hepatic Impairment under Dosage and Administration and see also Absorption: Special Populations under Pharmacokinetics.)

Renal Impairment

Increased systemic exposure (up to 13-fold) of some fingolimod metabolites observed in patients with severe renal impairment; toxicity of these metabolites not fully explored.¹ (See Renal Impairment under Dosage and Administration and see also Absorption: Special Populations under Pharmacokinetics.)

Common Adverse Effects

Headache,^{1 3 4} influenza,^{1 3 4} diarrhea,^{1 3 4} back pain,^{1 3 4} elevations in serum transaminase concentrations,^{1 3 4} cough.^{1 4}

Interactions for Fingolimod Hydrochloride

Primarily metabolized by CYP4F2 with a minor contribution by CYP isoenzymes 2D6, 2E1, 3A4, and 4F12.^{1 27} Fingolimod has little or no inhibitory activity on CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11.¹ Similarly, fingolimod-phosphate has little or no inhibitory activity on CYP isoenzymes 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4.¹ Fingolimod does not substantially induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 3A4, 4F2, and P-glycoprotein.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP isoenzymes 4F2, 2D6, 2E1, 3A4, and 4F12: Potential pharmacokinetic interaction (possible altered exposure of fingolimod and/or fingolimod-phosphate).¹ Multiple CYP isoenzymes are involved in fingolimod’s metabolism; substantial inhibition unlikely in the presence of an inhibitor of a single specific CYP isoenzyme.¹

Specific Drugs and Laboratory Tests

Drug or Test	Interaction	Comments
Amantadine	Clinically important pharmacokinetic interaction unlikely1
Amitriptyline	Clinically important pharmacokinetic interaction unlikely1
Antiarrhythmic agents, class Ia (e.g., quinidine, procainamide) and class III (e.g., amiodarone, sotalol)	Possible increased risk of torsades de pointes in patients with bradycardia1	Monitor closely1
Antidepressants, SSRIs (e.g., fluoxetine, paroxetine)	Pharmacokinetic interaction with fluoxetine and paroxetine unlikely1
Atropine	Pharmacokinetic interaction unlikely1 16
Baclofen	Clinically important pharmacokinetic interaction unlikely1
β-Adrenergic blocking agents (e.g., atenolol)	Possible additive bradycardic effect1 17 31 Atenolol: Additional 15% reduction of heart rate upon fingolimod initiation; clinically important pharmacokinetic interaction unlikely1 17	Carefully monitor during initiation of fingolimod therapy1
Calcium-channel blocking agents (e.g., diltiazem)	Potential for increased risk of bradycardia1 17 Diltiazem: Clinically important pharmacokinetic interaction unlikely; additive effect on bradycardia not observed with diltiazem in a study in healthy individuals1 17	Carefully monitor during initiation of fingolimod therapy1
Carbamazepine	Pharmacokinetic interaction unlikely1
Corticosteroids	Increased risk of immunosuppression; clinically important pharmacokinetic interaction unlikely1
Cyclosporine	Pharmacokinetics of single-dose fingolimod and steady-state cyclosporine not altered during concurrent administration1 19
Gabapentin	Clinically important pharmacokinetic interaction unlikely1
Immunomodulating therapies (e.g., antineoplastic or immunosuppressive therapies)	Increased risk of immunosuppression1	Use caution when switching patients from long-acting MS therapies with immunosuppressive effects (e.g., natalizumab, mitoxantrone) to fingolimod1 38
Isoproterenol	Single-dose fingolimod and fingolimod-phosphate exposure not substantially altered during concurrent administration1 15
Ketoconazole	Blood levels of fingolimod and fingolimod-phosphate increased 1.7-fold during concurrent administration; possible increased risk of adverse effects with fingolimod1 18 31	Closely monitor patients receiving systemic ketoconazole concomitantly; consider fingolimod dosage reduction if necessary1 18 31
Lymphocyte counts	Fingolimod reduces blood lymphocyte counts via redistribution in secondary lymphoid organs1	Do not utilize peripheral blood lymphocyte count to evaluate lymphocyte subset status1 Ensure availability of a recent CBC before initiating fingolimod therapy1
Modafinil	Clinically important pharmacokinetic interaction unlikely1
Oxybutynin chloride	Clinically important pharmacokinetic interaction unlikely1
Pregabalin	Clinically important pharmacokinetic interaction unlikely1
Vaccines	Vaccination may be less effective during and for up to 2 months following fingolimod therapy1 Risk of infection with live attenuated vaccines1	Avoid use of live attenuated vaccines during and for 2 months after fingolimod treatment1 (see Infectious Complications under Cautions)

Fingolimod Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Apparent absolute oral bioavailability is 93%.¹ Peak blood concentrations attained approximately 12–16 hours following oral administration.^{1 6 12}

Food

Food does not alter peak concentrations or AUC of fingolimod or fingolimod-phosphate.^{1 11}

Plasma Concentrations

Steady-state concentrations achieved within 1–2 months following once-daily oral administration.¹

Special Populations

Severe renal impairment: Peak blood concentrations and AUCs of fingolimod increased by 32 and 43%, respectively; peak blood concentrations and AUCs of fingolimod-phosphate increased by 25 and 14%, respectively.¹ Systemic exposure of 2 fingolimod metabolites (M2 and M3) increased (by threefold and 13-fold, respectively).¹

Mild or moderate renal impairment: Pharmacokinetics not evaluated.¹

Mild, moderate, or severe hepatic impairment: Fingolimod AUCs increased by 12, 44, and 103%, respectively.¹

Severe hepatic impairment: Peak concentrations of fingolimod-phosphate decreased by 22%; AUC not substantially changed.¹

Distribution

Extent

Fingolimod extensively distributes into body tissues.¹

Fingolimod: Highly distributes (86%) in RBCs.¹

Fingolimod-phosphate: Smaller uptake in blood cells (<17%).¹

Plasma Protein Binding

Fingolimod and fingolimod-phosphate: >99.7%.¹

Elimination

Metabolism

Biotransformation occurs by 3 main pathways: reversible stereoselective phosphorylation to the pharmacologically active S-enantiomer of fingolimod-phosphate, oxidative biotransformation mainly via the CYP4F2 isoenzyme and subsequent fatty acid-like degradation to inactive metabolites, and formation of pharmacologically inactive nonpolar ceramide analogs of fingolimod.^{1 28}

Primarily metabolized via CYP4F2 with a minor contribution by CYP isoenzymes 2D6, 2E1, 3A4, and 4F12.^{1 27}

Elimination Route

About 81% of the dose is slowly excreted in urine as inactive metabolites.^{1 28} Fingolimod and fingolimod-phosphate are not excreted intact in urine, but are the major components in feces with amounts of each representing <2.5% of the dose.^{1 28}

Half-life

Fingolimod: 6–9 days; fingolimod-phosphate appears to have a similar half-life.^{1 6 11 12}

Special Populations

Severe renal impairment: Half-life of fingolimod is unchanged.¹

Mild hepatic impairment: Half-life of fingolimod is unchanged.¹

Moderate or severe hepatic impairment: Half-life of fingolimod is prolonged by about 50%.¹

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15-30°C); protect from moisture.¹

Actions

• 
  

  Derived from the fungal metabolite myriocin; used orally as a disease-modifying treatment for multiple sclerosis (MS).^{1 6 7 21 29 31}

  
  


• 
  

  Sphingosine kinase, predominantly type 2, metabolizes fingolimod to the active metabolite, fingolimod-phosphate.^{1 7 23 24} Fingolimod-phosphate is a sphingosine 1-phosphate (S1P) receptor modulator and binds with high affinity to S1P receptor subtypes 1, 3, 4, and 5.^{1 7 8}

  
  


• 
  

  The S1P₁ receptor regulates lymphocyte egress from both the thymus and peripheral lymphoid organs and is essential for lymphocyte recirculation.^{25 26} Binding of fingolimod-phosphate to S1P₁ blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in the peripheral blood and CNS.^{1 7 8 9 21 25 26}

  
  


• 
  

  Exact mechanism of fingolimod’s therapeutic effects in MS unknown; may involve reduction of lymphocyte migration into the CNS.^{1 21 22 25 26}

  
  


• 
  

  Preclinical findings suggest fingolimod may directly affect neuropathologic processes such as neurodegeneration, gliosis, and endogenous repair mechanisms within the CNS through modulation of S1P receptors expressed on neural cells.^{3 29 30}

  
  

Advice to Patients

• 
  

  Must provide fingolimod medication guide to patient each time the drug is dispensed (see Risk Evaluation and Mitigation Strategy under Dosage and Administration); importance of patient reading the medication guide prior to initiating fingolimod therapy and each time the prescription is refilled.^{1 2 5}

  
  


• 
  

  Importance of patients being counseled on and understanding the benefits and potential risks of treatment with fingolimod.¹

  
  


• 
  

  Risk of decreased or irregular heartbeat.^{1 2} Importance of advising patients that initiation of fingolimod results in a transient decrease in heart rate, particularly after the first dose, and that they will be observed in their clinician’s office or other facility for 6 hours after the first dose.^{1 2} Advise patients that if fingolimod is discontinued for >2 weeks, heart rate effects similar to those observed on treatment initiation may be seen and observation for 6 hours will again be needed upon treatment re-initiation.^{1 2} Advise patients to contact their clinician if dizziness, tiredness, or a slow or irregular heartbeat occurs.²

  
  


• 
  

  Possible increased risk of infections.^{1 2} Inform patients that fingolimod may lower the number of lymphocytes in their blood.² Importance of advising patients to immediately contact their clinician if they develop any symptoms of infection (e.g., fever, chills, tiredness, body aches, nausea, vomiting) during and for 2 months following drug discontinuance.^{1 2}

  
  


• 
  

  Importance of patients informing clinicians of recent vaccination (within the past 1 month) before starting fingolimod.² Advise patients that some vaccines should be avoided during treatment with fingolimod and for 2 months after drug discontinuance.¹ Advise patients who have not had chickenpox or varicella zoster virus (VZV) vaccination to consider VZV vaccination prior to starting fingolimod therapy.^{1 2}

  
  


• 
  

  Risk of macular edema, which may cause some of the same visual symptoms as an MS attack (optic neuritis); some patients may not notice any symptoms.^{1 2} Macular edema usually starts in the first 3 to 4 months of fingolimod therapy; clinician should test their vision before starting fingolimod therapy and 3 to 4 months after initiating treatment as well as any time the patient notices vision changes during therapy.^{1 2} Advise patients to immediately contact their clinician if they experience any vision changes (e.g., blurriness or shadows in the center of vision, a blind spot in the center of vision, sensitivity to light, unusually colored or tinted vision).^{1 2} Inform patients that their risk of developing macular edema may be higher if they have diabetes or have had uveitis.^{1 2}

  
  


• 
  

  Risk of breathing problems.^{1 2} Importance of advising patients to immediately contact their clinician if they experience any trouble breathing (e.g., new onset or worsening of shortness of breath).^{1 2}

  
  


• 
  

  Risk of increased liver enzymes.^{1 2} Importance of advising patients to contact their clinician if they experience unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice, and/or dark urine.^{1 2}

  
  


• 
  

  Importance of informing patients that fingolimod may cause fetal harm.^{1 2} Importance of discussing this possible fetal risk with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant.^{1 2} Advise women of childbearing age of the need for effective contraception during and for 2 months after stopping fingolimod treatment.^{1 2} Importance of advising patients to immediately inform their clinician if they become pregnant while taking fingolimod or within 2 months after stopping treatment.^{1 2} Importance of informing women who become pregnant while taking fingolimod about existence of the pregnancy registry (see Pregnancy under Cautions).²

  
  


• 
  

  Importance of women informing clinicians if they are or plan to breast-feed.²

  
  


• 
  

  Importance of advising patients that fingolimod remains in the blood and continues to have effects, including decreased blood lymphocyte counts, for up to 2 months following the last dose.¹

  
  


• 
  

  Importance of patient informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, vitamins, and herbal supplements, as well as any concomitant illnesses (e.g., heart disease, liver disease, diabetes, history of uveitis).^{1 2}

  
  


• 
  

  Importance of advising patients not to discontinue fingolimod without talking with their clinician.²

  
  


• 
  

  Importance of informing patients of other important precautionary information.^{1 2} (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Fingolimod Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	0.5 mg (of fingolimod)	Gilenya	Novartis

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Gilenya 0.5MG Capsules (NOVARTIS): 28/$3,880.04 or 84/$11,438.29

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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16. Kovarik JM, Slade A, Riviere GJ et al. The ability of atropine to prevent and reverse the negative chronotropic effect of fingolimod in healthy subjects. Br J Clin Pharmacol. 2008; 66:199-206. [PubMed 18507656]

17. Kovarik JM, Lu M, Riviere GJ. The effect on heart rate of combining single-dose fingolimod with steady-state atenolol or diltiazem in healthy subjects. Eur J Clin Pharmacol. 2008; 64:457-63. [PubMed 18196225]

18. Kovarik JM, Dole K, Riviere GJ et al. Ketoconazole increases fingolimod blood levels in a drug interaction via CYP4F2 inhibition. J Clin Pharmacol. 2009; 49:212-8. [PubMed 19118083]

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20. Schmouder R, Serra D, Wang Y et al. FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects. J Clin Pharmacol. 2006; 46:895-904. [PubMed 16855074]

21. Massberg S, von Andrian UH. Fingolimod and sphingosine-1-phosphate--modifiers of lymphocyte migration. N Engl J Med. 2006; 355:1088-91. [PubMed 16971715]

22. Fujino M, Funeshima N, Kitazawa Y et al. Amelioration of experimental autoimmune encephalomyelitis in Lewis rats by FTY720 treatment. J Pharmacol Exp Ther. 2003; 305:70-7. [PubMed 12649354]

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24. Paugh SW, Payne SG, Barbour SE et al. The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett. 2003; 554:189-93. [PubMed 14596938]

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30. Foster CA, Howard LM, Elke Persohn et al. Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J Pharmacol Exp Ther. 2007; 323:469-76. [PubMed 17682127]

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