Etifoxine

Clinical data
Trade names	Stresam
Other names	Étifoxine; Etifoxin; Etafenoxine; Etafenoxin; EFX; Hoe 36801; Hoe-36,801
AHFS/Drugs.com	International Drug Names
Pregnancy category	Not recommended[1]
Routes of administration	Oral administration[2]
ATC code	N05BX03 (WHO)
Legal status
Legal status	In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	90%[3]
Protein binding	88–95%[4]
Metabolism	Liver[5]
Metabolites	Several (including diethyletifoxine)[5]
Eliminationhalf-life	Etifoxine: 6 hours[5] Diethyletifoxine: 20 hours[5]
Excretion	Mainlyurine, alsobile[5][2]
Identifiers
IUPAC name 6-Chloro-N-ethyl-4-methyl-4-phenyl-4H-benzo[d][1,3]oxazin-2-amine
CAS Number	21715-46-8 Y 56776-32-0 (hydrochloride)
PubChemCID	30768
IUPHAR/BPS	5468
DrugBank	DB08986 Y
ChemSpider	28547 Y
UNII	X24X82MX4X
KEGG	D07320 Y
ChEMBL	ChEMBL2106227 Y
CompTox Dashboard(EPA)	DTXSID00865010
ECHA InfoCard	100.158.584
Chemical and physical data
Formula	C17H17ClN2O
Molar mass	300.79 g·mol−1
3D model (JSmol)	Interactive image
SMILES ClC1=CC=C2N=C(NCC)OC(C3=CC=CC=C3)(C)C2=C1
InChI InChI=1S/C17H17ClN2O/c1-3-19-16-20-15-10-9-13(18)11-14(15)17(2,21-16)12-7-5-4-6-8-12/h4-11H,3H2,1-2H3,(H,19,20) Y Key:IBYCYJFUEJQSMK-UHFFFAOYSA-N Y
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Etifoxine, sold under the trade nameStresam among others, is anonbenzodiazepineanxiolytic agent, primarily indicated for short-term management ofadjustment disorder, specifically instances of situational depression accompanied byanxiety, such as stress-induced anxiety.^[2][6] Administration isby mouth.^[7]Side effects associated with etifoxine use include slightdrowsiness,headache,skin eruptions, andallergic reactions.^[2][8][9] In rare cases, etifoxine has been linked to severeskin andliver toxicity, as well asmenstrual bleeding between periods.^[8][1] Unlikebenzodiazepines, etifoxine does not causesedation orlack of coordination.^[10][3] Etifoxine acts as aligand fortranslocator proteins.^[10]

Etifoxine was developed in the 1960s and was introduced for medical use in France in 1979.^[11] Its marketed in 53 countries worldwide, although it remains unavailable in the United States.^[7][11][12] Throughout the 2010s and early 2020s, the safety profile of etifoxine was scrutinized within France and theEuropean Union, prompted by reports of toxicity.^[13][8][7] The investigation revealed that instances of toxicity were infrequent, and etifoxine was allowed to remain on the market.^[13][8][7]

As of 2022, across the European countries where etifoxine has been approved (including France, Luxembourg, Malta, Romania and Bulgaria), the main approved indication is for the treatment of the psychosomatic manifestations of anxiety.^[7]

When etifoxine was first approved in France in 1979, the original indication was for the treatment of "psychosomatic manifestations ofanxiety, for instanceautonomicdystonia, particularly withcardiovascular expression".^{[7][13][8][1]}

Over time, the indication for etifoxine has been more formalized as the treatment ofadjustment disorder (situational depression) with anxiety (ADWA) (for example,stress-related anxiety).^[7][14][3] Etifoxine has been found to reduce scores on theHamilton Anxiety Rating Scale (HAM‑A) in people with adjustment disorder with anxiety by approximately 50 to 75% after 4 weeks of treatment inclinical trials (as per the AMETIS, ETILOR, ETIZAL, STRETI studies).^[7] The medication is similarly effective or more effective thanbenzodiazepines likelorazepam,alprazolam, andclonazepam and more effective thanbuspirone for adjustment disorder with anxiety on the basis of directly comparativerandomized controlled trials.^{[14][3][15][16][17][4]} However, in the AMETIS study, both etifoxine and lorazepam failed to show greater effectiveness overplacebo.^[7]

In the trials comparing etifoxine to clonazepam, lorazepam, and alprazolam, total daily doses of the benzodiazepines were limited to their maintenance daily dose, set at 1 mg clonazepam, 2 mg lorazepam, and 1.5 mg alprazolam, divided across 3 doses per day. Such an inflexible dosing regime limits the utility benzodiazepines offer in practice; e.g. lorazepam and alprazolam can be used as needed for situational anxiety in which continuous use is unnecessary or excessive, while clonazepam can be titrated to response when continuous relief is indicated, up to a maximum of 4 mg a day, four times greater than the dose used in comparison with etifoxine over the 24 week duration of the trial. In general, they offer a degree of personalization that is not possible with etifoxine. Indeed, better evidence is required before etifoxine can be said to replace benzodiazepines in practice, especially considering the trials above were relatively small in size, along with the high attrition rates and lack of personalization of the benzodiazepines used.

The usual dosage of etifoxine (as thehydrochloridesalt) is 150 to 200 mg per day in divided doses of 50 to 100 mg two to three times per day (e.g., 50 mg–50 mg–100 mg).^{[2][7][6][18][1][19][20]} It is taken for a few days to a few weeks, but no longer than 12 weeks.^{[2][13][7][5]}

Etifoxine is provided in the form oforalcapsules containing 50 mg etifoxine hydrochloride.^{[2][1][21][22]}

Etifoxine iscontraindicated in people withcirculatory shock, severeliver impairment, severekidney impairment,myasthenia gravis,galactosemia (due tolactose in thedrug formulation), severerespiratory failure, andhypersensitivity (allergy) to etifoxine.^[2][5] The medication is not recommended in children or adolescents under the age of 18^[5] and is not recommended duringpregnancy andbreastfeeding due to insufficient data.^[2][1] Caution is warranted with regard to combining etifoxine and othercentral depressants such asbenzodiazepines,centralanalgesics,antipsychotics,sedativeantihistamines, andalcohol.^[2][1]

Side effects of etifoxine include slightdrowsiness andheadache.^[2][9] Rarely, etifoxine can cause benignskin eruptions orrashes andallergic reactions such ashives andangioedema.^[2][8][1] Etifoxine shows less adverse effects ofanterograde amnesia,sedation, impaired psychomotor performance, andwithdrawal syndromes than those ofbenzodiazepines.^[5] No cases ofmisuse ordependence with etifoxine were identified in a Frenchpharmacovigilance survey, which is also in contrast to benzodiazepines.^[8]

Etifoxine has been associated rarely with cases of severedermal toxicity andliver toxicity.^[8][23] Skin and subcutaneous disorders are the most frequently reported, but these generally resolve after drug cessation.^[3] A 2012 review of etifoxine by the French National Pharmacovigilance Committee determined that etifoxine was safe and continued to provide a favorable alternative to benzodiazepine anxiolytics. The committee found (for a ten-year pharmacovigilance period) that safety concerns were rare or very rare and that the incidence of idiosyncratic hepatic (liver) problems were very rare.^[13]

Unlike benzodiazepines, etifoxine may produce its anxiolytic effects through a dual mechanism, by directly binding toGABA_A receptors and (purportedly, exact binding site undetermined) to the mitochondrialtranslocator protein (TSPO). This results in stimulation of thebiosynthesis ofendogenousneurosteroids, for instanceallopregnanolone, a highlypotent GABA_A receptor positive allosteric modulator.^[24]

At GABA_A receptors etifoxine binds at the α+β− interface and preferentially potentiates α₂β₃γ₂ and α₃β₃γ₂ receptor types.^[25] This direct allosteric potentiation can only be observed at relatively high concentrations (starting at >1 mM) and is perhaps not physiologically relevant at normal human doses.^[26] This is different from benzodiazepines and etifoxine can be used alongside benzodiazepines to potentiate their effects without competing for binding sites;^[27] however, it also means that the direct effects of etifoxine are not reversed by the benzodiazepine antagonistflumazenil.^[28]

Etifoxine is taken viaoral administration.^[2][5] It is rapidlyabsorbed from thegastrointestinal tract.^[5] It is well-absorbed, with abioavailability of 90%.^[2][3] Thetime to peak levels of etifoxine is 2 to 3 hours.^[5] Theplasma protein binding of etifoxine is 88 to 95%.^[4] It does not bind toblood cells.^[2] The drug is known to cross theplacental barrier.^[2] Etifoxine ismetabolized in theliver into severalmetabolites.^[5] One of these metabolites, diethyletifoxine, ispharmacologically active.^[5] Theelimination half-life of etifoxine is 6 hours and of diethyletifoxine is almost 20 hours.^[5] Etifoxine iseliminated in three phases.^[2] The drug isexcreted mainly inurine in the form of metabolites.^[5] It is also excreted inbile.^[5] Only small amounts are excreted unchanged.^[5]

Etifoxine is anonbenzodiazepine—that is, it is similarly aGABA_A receptor positive allosteric modulator but itschemical structure is distinct from that ofbenzodiazepines.^[3][29] Instead, it is abenzoxazinederivative.^[3]

Etifoxine is used pharmaceutically as thehydrochloridesalt.^[30][31]

(S)-Etifoxine, the (S)enantiomer of etifoxine, was under development by Anvyl Pharmaceuticals for the treatment ofneuropathic pain, but development was discontinued.^[32] Adeuterated form of etifoxine with improvedpharmacokinetics known asdeuterated etifoxine (GRX-917) is under development by GABA Therapeutics for the treatmentanxiety andmood disorders.^{[33][34][24][35]}

Etifoxine was developed byHoechst in the 1960s.^[11][36] It was introduced for medical use inFrance in 1979.^[11] Since at least 2000, etifoxine has been marketed by the Frenchpharmaceutical company Biocodex.^{[31][29][37][19]} Following reports ofpost-marketingtoxicity, thesafety of etifoxine was reassessed by the French government^[13][8] and theEuropean Medicines Agency (EMA).^[38][39] In January 2022, the EMA "finalized its review of Stresam and concluded that the medicine can continue to be used for the treatment of anxiety disorders, but it must not be used in patients who previously had severe skin reactions or severe liver problems after taking etifoxine."^[38][39]

Etifoxine is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française.^[30][31] It is also known by the older and much-lesser-used synonymetafenoxine^[40] and by its developmental code nameHoe 36801.^[30][31] Etifoxine is marketed under the brand nameStresam.^[30][31][19] It has also been marketed under the brand nameStrezam.

Etifoxine has been marketed in 53 countries as of 2022.^[7][11] Some of the countries in which etifoxine has been marketed includeArgentina,Bulgaria,Chile,France,Luxembourg,Malta,Romania,South Africa,Thailand andUkraine.^{[19][13][7][31]} Etifoxine is not approved for use by theUnited StatesFood and Drug Administration (FDA) or theEuropean Medicines Agency (EMA) of theEuropean Union, and hence is not marketed in these regions.^[11][7] However, etifoxine is marketed in five European Union member states (France, Bulgaria, Luxembourg, Malta, Romania)^[13][7] and Ukraine^[41]

• Alpidem

• Stesam (etifoxine hydrochloride) Summary of Product Characteristics (SPC)
• Stresam (etifoxine hydrochloride) Patient Leaflet
• Stresam (etifoxine hydrochloride) Package Insert
• Etifoxine French Commission Nationale de Pharmacovigilance Review (Original French)
• Etifoxine French Commission Nationale de Pharmacovigilance Review (English Translation)
• Etifoxine European Medicines Agency Assessment Report

• Anxiolytics
• Benzoxazines
• Chloroarenes
• Dermatoxins
• GABAA receptor positive allosteric modulators
• Hepatotoxins
• TSPO ligands

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• CS1: long volume value
• Articles with short description
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