Identification

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Name
Siponimod
Accession Number
DB12371
Type
Small Molecule
Groups
Approved, Investigational
Description

Siponimod, also known as Mayzent, by Novartis, is a new drug formulated for the management of Multiple Sclerosis (MS). It was approved by the FDA on March 26, 2019 6. This drug is a considered a sphingosine-1-phosphate (S1P) receptor modulator and is thought to play a role in suppressing the central nervous system inflammation that is associated with MS Label.

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system that is chronic and inflammatory, disrupting communication between the brain and other parts of the body. Most patients diagnosed with this illness experience their initial disease symptoms between the age of 20 to 40, often the most productive years of life. Symptoms may include but are not limited to fatigue, gait changes, bowel or bladder dysfunction, abnormal muscle twitching, vision disturbance, and depressing or mood swings 7. MS is one of the most common causes of neurological disability in young adults and is found to occur more frequently in women than in men 1,6.

Structure
Thumb
Synonyms
  • Siponimod
External IDs
BAF-312 / BAF312 / NVP-BAF312-NX
Product Ingredients
IngredientUNIICASInChI Key
Siponimod fumarateZ7G02XZ0M61234627-85-0JNLIKIBISICTMS-PEJBKAKVSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MayzentTablet, film coated0.25 mg/1OralNovartis Pharmaceuticals Corporation2019-03-26Not applicableUs
MayzentTablet, film coated2 mg/1OralNovartis Pharmaceuticals Corporation2019-03-26Not applicableUs
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
RR6P8L282I
CAS number
1230487-00-9
Weight
Average: 516.605
Monoisotopic: 516.259977484
Chemical Formula
C29H35F3N2O3
InChI Key
KIHYPELVXPAIDH-HNSNBQBZSA-N
InChI
InChI=1S/C29H35F3N2O3/c1-3-21-14-23(10-11-24(21)15-34-16-25(17-34)28(35)36)19(2)33-37-18-20-9-12-26(22-7-5-4-6-8-22)27(13-20)29(30,31)32/h9-14,22,25H,3-8,15-18H2,1-2H3,(H,35,36)/b33-19+
IUPAC Name
1-({4-[(1E)-1-({[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy}imino)ethyl]-2-ethylphenyl}methyl)azetidine-3-carboxylic acid
SMILES
CCC1=CC(=CC=C1CN1CC(C1)C(O)=O)C(\C)=N\OCC1=CC=C(C2CCCCC2)C(=C1)C(F)(F)F

Pharmacology

Indication

This drug is 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 adults Label.

Associated Conditions
Pharmacodynamics

Immune system effects

Siponimod causes a dose-dependent decrease of the peripheral blood lymphocyte count within 6 hours of the first dose, caused by the reversible accumulation of lymphocytes in lymphoid tissues, due to lack of lymphocyte release Label. This results in a decrease in the inflammation that is involved in multiple sclerosis. Lymphocyte counts return to normal in 90% of patients within 10 days after the cessation of therapy Label.

Effects on heart rate and rhythm

Siponimod causes a temporary decrease in heart rate and atrioventricular conduction upon beginning treatment. The maximum fall in heart rate is observed in the first 6 hours post ingestion. Autonomic heart responses, including diurnal variation of heart rate and response to exercise activities, are not altered by siponimod treatment Label.

Effects on pulmonary function

Dose-dependent decreases in absolute forced expiratory volume over a time frame of 1 second were noted in siponimod-treated patients and were higher than in patients taking placebo Label.

Mechanism of action

Inflammation of the white and gray matter tissues in the central nervous system caused by localized immune cell infiltration and their cytokines are the initial cause of damage in MS. B lymphocytes and their cytokines are other factors in the pathogenesis of MS. Lymphotoxin [or transforming growth factor beta (TGF-β)] and TNF-α produced by these cells encourage inflammation 1. The S1P receptor is an important receptor related to the function of lymphocytes and can be found in the central nervous system 4. S1P receptor (S1PR) signaling is associated with a wide variety of physiological processes for lymphocytes, including their egress and recirculation 2,3.

Siponimod is classified as a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds with high affinity to both S1P receptors 1 and 5. This drug blocks the ability of lymphocytes to release from the lymph nodes, decreasing the number of lymphocytes found in the peripheral blood. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is not known at this time, but may involve the abovementioned decrease of lymphocytes into the central nervous system, decreasing the inflammatory effects of MS Label.

TargetActionsOrganism
USphingosine 1-phosphate receptor 5
modulator
Humans
USphingosine 1-phosphate receptor 1Not AvailableHumans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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Absorption

The time (Tmax) to attain maximum plasma concentrations (Cmax) after oral administration of immediate-release oral doses of siponimod was found to be approximately 4 hours ( with a range 3 - 8 hours). Siponimod is heavily absorbed (at a rate greater than or equal to 70%). The absolute oral bioavailability of siponimod is about 84%. Steady-state concentrations were attained after approximately 6 days of daily administration of a single dose of siponimod Label.

Effects of food on absorption

Food ingestion leads to delayed siponimod absorption (the median Tmax increased by approximately 2-3 hours). Food intake has no effect on the systemic exposure of siponimod (Cmax and AUC). Therefore, siponimod may be taken without regard to food Label.

Volume of distribution

Siponimod distributes to body tissues with an average volume of distribution of 124 L. Siponimod fraction mesaured in plasma is 68% in humans. Animal studies demonstrate that siponimod readily crosses the blood-brain-barrier Label.

Protein binding

Protein binding of siponimod is higher than 99.9% in healthy patients as well as hepatic and renal impaired patients Label.

Because of the high plasma protein binding of siponimod, hemodialysis is not likely to change the total and unbound siponimod concentration and no dose adjustments are expected based on this Label.

Metabolism

Siponimod is extensively metabolized, mainly by CYP2C9 enzyme (79.3%), and subsequently by CYP3A4 enzyme (18.5%). The pharmacological activity of the main metabolites M3 and M17 is not expected to be responsible for the clinical effect and the safety of siponimod in humans Label.

Route of elimination

Siponimod is eliminated from the systemic circulation mainly due to metabolism, and subsequent biliary/fecal excretion. Unchanged siponimod was not detected in urine Label.

Half life

The apparent elimination half-life is approximately 30 hours Label.

Clearance

Apparent systemic clearance of 3.11 L/h has been estimated in MS patients Label.

Toxicity

Carcinogenesis

Oral carcinogenicity studies of siponimod were performed in mice and rats. There was an increase in malignant lymphoma in females at all doses and in hemangiosarcoma and combined hemangioma and hemangiosarcoma at all doses in males and females. The lowest dose tested is approximately 5 times the recommended human dose (RHD) of 2 mg/day Label.

Mutagenesis

Siponimod was negative in several in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo (micronucleus in mouse and rat) assays Label.

Impairment of fertility

When siponimod was administered orally (0, 2, 20, or 200 mg/kg) to male rats (mated with untreated females) before and throughout the mating period, there was a dose-related increase in the precoital interval at any dose. A decrease in implantation sites, an increase in preimplantation loss, and a decrease in the number of viable fetuses were noted at the highest dose tested. The higher no-effect dose for adverse effects on fertility (20 mg/kg) is approximately 100 times the recommended human dose Label.

When siponimod was administered orally (0, 0.1, 0.3, or 1 mg/kg) to female rats (mated with untreated males) prior to and during mating, and continuing to Day 6 of gestation, no effects on fertility were noted up to the highest dose studied (1 mg/kg). Plasma siponimod exposure (AUC) at the highest dose studied is about 16 times that in humans at the recommended human dose Label.

Use in pregnancy and lactation

Siponimod may cause fetal harm, based on the results of animal studies. Because it takes about 10 days to eliminate this drug from the body, women of childbearing potential should use adequate contraception to avoid pregnancy during and for 10 days after the cessation of treatment Label. No data currently exist regarding the presence of siponimod in human milk Label. A study in lactating rats demonstrated excretion of the drug and/or its metabolites in milk. The benefits nursing should be considered as well as the mother’s clinical requirement for this drug and any possible adverse effects on the breastfed infant from siponimod Label.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
(R)-warfarinThe metabolism of Siponimod can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Siponimod can be decreased when combined with (S)-Warfarin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidThe risk or severity of hypertension can be increased when 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid is combined with Siponimod.
1-benzylimidazoleThe risk or severity of hypertension can be increased when 1-benzylimidazole is combined with Siponimod.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Siponimod.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of hypertension can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Siponimod.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of hypertension can be increased when Siponimod is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of hypertension can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Siponimod.
4-hydroxycoumarinThe metabolism of Siponimod can be decreased when combined with 4-hydroxycoumarin.
4-MethoxyamphetamineThe risk or severity of hypertension can be increased when 4-Methoxyamphetamine is combined with Siponimod.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
Not Available

References

General References
  1. Ghasemi N, Razavi S, Nikzad E: Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. 2017 Apr-Jun;19(1):1-10. Epub 2016 Dec 21. [PubMed:28367411]
  2. Chiba K, Matsuyuki H, Maeda Y, Sugahara K: Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. Cell Mol Immunol. 2006 Feb;3(1):11-9. [PubMed:16549044]
  3. Garris CS, Blaho VA, Hla T, Han MH: Sphingosine-1-phosphate receptor 1 signalling in T cells: trafficking and beyond. Immunology. 2014 Jul;142(3):347-53. doi: 10.1111/imm.12272. [PubMed:24597601]
  4. Healy LM, Antel JP: Sphingosine-1-Phosphate Receptors in the Central Nervous and Immune Systems. Curr Drug Targets. 2016;17(16):1841-1850. [PubMed:26424391]
  5. Dumitrescu L, Constantinescu CS, Tanasescu R: Siponimod for the treatment of secondary progressive multiple sclerosis. Expert Opin Pharmacother. 2019 Feb;20(2):143-150. doi: 10.1080/14656566.2018.1551363. Epub 2018 Dec 5. [PubMed:30517042]
  6. FDA approves new oral drug to treat multiple sclerosis [Link]
  7. MS Society Document, Canada [Link]
External Links
PubChem Compound
44599207
PubChem Substance
347828622
ChemSpider
29315058
BindingDB
50428142
ChEMBL
CHEMBL2336071
Wikipedia
Siponimod
FDA label
Download (982 KB)
MSDS
Download (22.4 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailableHepatic Impairment1
1CompletedOtherImpaired kidney function1
1CompletedTreatmentHealthy Volunteers1
2CompletedTreatmentAutoimmune Diseases / Autoimmune Diseases of the Nervous System / Immune System Diseases / Nervous System Diseases / Relapsing Remitting Multiple Sclerosis (RRMS)1
2CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
2RecruitingTreatmentHemorrhagic Stroke / Intracerebral Hemorrhage (ICH)1
2TerminatedTreatmentActive Dermatomyositis1
2TerminatedTreatmentDermatomyositis / Polymyositis1
2TerminatedTreatmentPolymyositis1
3Active Not RecruitingTreatmentSecondary Progressive Multiple Sclerosis (SPMS)1
3RecruitingTreatmentDisseminated Sclerosis / Multiple Sclerosis, Relapsing MS, Advancing Multiple Sclerosis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Tablet, film coatedOral0.25 mg/1
Tablet, film coatedOral2 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8492441No2013-07-232030-11-30Us
US7939519No2011-05-102024-05-19Us
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)111-112https://www.trc-canada.com/product-detail/?CatNum=S487800&CAS=342026-92-0&Chemical_Name=Sipoglitazar&Mol_Formula=C₂₅H₂₅N₃O₄S
boiling point (°C)419https://comptox.epa.gov/dashboard/dsstoxdb/calculation_details?model_id=27&search=153847
water solubility100 mg/mL , warm water https://www.selleckchem.com/products/baf312-siponimod.html
logP6.77https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL2336071/
pKa2.69 (Acidic), 9.15 (Basic)https://www.ebi.ac.uk/chembl/compound_report_card/CHEMBL2336071/
Predicted Properties
PropertyValueSource
Water Solubility0.00032 mg/mLALOGPS
logP5.85ALOGPS
logP4.31ChemAxon
logS-6.2ALOGPS
pKa (Strongest Acidic)3.33ChemAxon
pKa (Strongest Basic)8.5ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area62.13 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity138.6 m3·mol-1ChemAxon
Polarizability55.99 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as trifluoromethylbenzenes. These are organofluorine compounds that contain a benzene ring substituted with one or more trifluoromethyl groups.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Trifluoromethylbenzenes
Direct Parent
Trifluoromethylbenzenes
Alternative Parents
Phenylmethylamines / Benzylamines / Azetidinecarboxylic acids / Aralkylamines / Trialkylamines / Amino acids / Monocarboxylic acids and derivatives / Carboxylic acids / Azacyclic compounds / Organopnictogen compounds
show 5 more
Substituents
Trifluoromethylbenzene / Benzylamine / Phenylmethylamine / Azetidinecarboxylic acid / Aralkylamine / Amino acid or derivatives / Azetidine / Amino acid / Tertiary amine / Tertiary aliphatic amine
show 19 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Modulator
General Function
Sphingosine-1-phosphate receptor activity
Specific Function
Receptor for the lysosphingolipid sphingosine 1-phosphate (S1P). S1P is a bioactive lysophospholipid that elicits diverse physiological effect on most types of cells and tissues. Is coupled to both...
Gene Name
S1PR5
Uniprot ID
Q9H228
Uniprot Name
Sphingosine 1-phosphate receptor 5
Molecular Weight
41774.515 Da
References
  1. Gajofatto A: Spotlight on siponimod and its potential in the treatment of secondary progressive multiple sclerosis: the evidence to date. Drug Des Devel Ther. 2017 Nov 2;11:3153-3157. doi: 10.2147/DDDT.S122249. eCollection 2017. [PubMed:29138536]
  2. Glaenzel U, Jin Y, Nufer R, Li W, Schroer K, Adam-Stitah S, Peter van Marle S, Legangneux E, Borell H, James AD, Meissner A, Camenisch G, Gardin A: Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism. Drug Metab Dispos. 2018 Jul;46(7):1001-1013. doi: 10.1124/dmd.117.079574. Epub 2018 May 7. [PubMed:29735753]
  3. O'Sullivan C, Schubart A, Mir AK, Dev KK: The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures. J Neuroinflammation. 2016 Feb 8;13:31. doi: 10.1186/s12974-016-0494-x. [PubMed:26856814]
  4. Siponimod FDA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Sphingosine-1-phosphate receptor activity
Specific Function
G-protein coupled receptor for the bioactive lysosphingolipid sphingosine 1-phosphate (S1P) that seems to be coupled to the G(i) subclass of heteromeric G proteins. Signaling leads to the activatio...
Gene Name
S1PR1
Uniprot ID
P21453
Uniprot Name
Sphingosine 1-phosphate receptor 1
Molecular Weight
42810.195 Da
References
  1. Pan S, Gray NS, Gao W, Mi Y, Fan Y, Wang X, Tuntland T, Che J, Lefebvre S, Chen Y, Chu A, Hinterding K, Gardin A, End P, Heining P, Bruns C, Cooke NG, Nuesslein-Hildesheim B: Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator. ACS Med Chem Lett. 2013 Jan 4;4(3):333-7. doi: 10.1021/ml300396r. eCollection 2013 Mar 14. [PubMed:24900670]
  2. Gianguzza M, Dolcemascolo G: On the ultrastructure of the test cells of Ascidia malaca during oogenesis. Acta Embryol Exp (Palermo). 1979;(2):173-89. [PubMed:517042]
  3. Gajofatto A: Spotlight on siponimod and its potential in the treatment of secondary progressive multiple sclerosis: the evidence to date. Drug Des Devel Ther. 2017 Nov 2;11:3153-3157. doi: 10.2147/DDDT.S122249. eCollection 2017. [PubMed:29138536]
  4. Siponimod FDA label [File]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Glaenzel U, Jin Y, Nufer R, Li W, Schroer K, Adam-Stitah S, Peter van Marle S, Legangneux E, Borell H, James AD, Meissner A, Camenisch G, Gardin A: Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism. Drug Metab Dispos. 2018 Jul;46(7):1001-1013. doi: 10.1124/dmd.117.079574. Epub 2018 May 7. [PubMed:29735753]
  2. Siponimod FDA label [File]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Glaenzel U, Jin Y, Nufer R, Li W, Schroer K, Adam-Stitah S, Peter van Marle S, Legangneux E, Borell H, James AD, Meissner A, Camenisch G, Gardin A: Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism. Drug Metab Dispos. 2018 Jul;46(7):1001-1013. doi: 10.1124/dmd.117.079574. Epub 2018 May 7. [PubMed:29735753]
  2. Siponimod FDA label [File]

Drug created on October 20, 2016 16:06 / Updated on December 02, 2019 09:24