New Product

Evaluation

Etifoxine
 Molecule Information
• Molecule name : Etifoxine

• Therapeutic class: Anti-anxiety agents

• Pharmacological class: Non-benzodiazepine anxiolytics.

• Innovator Company :Etifoxine was developed by Hoechst of Germany in the

1960s.

• Innovator brand name: Innovator brand name is unknown but other brand
name is STRESAM®(France).
 Regulatory Status

Country Approval Date of approval

India (DCGI) NOT KNOWN

United states (US FDA ) NOT APPROVED

• If under clinical development, tentative approval will be in …… Not Known

 Regulatory status in Europe
STRESAM® is authorized for the treatment of anxiety disorders in certain parts of
Europe.
• France

• Malta

• Bulgaria

• Romania
 Status in India
(Applicable only if not approved by DCGI)

File Name & Firm Name Recommendations

Drug Name,
Strength
ND/MA/ Sun Pharma The firm presented their proposal of manufacturing and marketing of Etifoxine
22/000079 hydrochloride capsules 50 mg along with BE study results and Phase III clinical trial
Etifoxine protocol.
hydrochloride After detailed deliberation, the committee recommended that the protocol should
capsules 50 mg be amended with respect to the following:
1. Inclusion and exclusion criteria should be amended. Only patients with
generalized anxiety disorder are included. All other anxiety disorders are excluded.
2. Detailed assessment for cognitive effects to be included. Accordingly, the firm
should submit a revised protocol to CDSCO for further

Recommendations of the SEC (Neurology & Psychiatry) made in its 82nd meeting held on 21.07.2022 at CDSCO (HQ), New Delhi

11/25/2024 05:17:43 AM 5
 Indication and Dosage
• Indication of STRESAM®: Psychosomatic manifestations of anxiety such as
autonomic dystonia.

• Dosage :Usually 3 to 4 capsules a day, taken as 2 or 3 divided doses.

Treatment duration : a few days to a few weeks.

• Strength of STRESAM® : Etifoxine hydrochloride 50 mg

https://www.ema.europa.eu/en/medicines/human/referrals/etifoxine-containing-medicinal-products assessed on 29-03-23

 Prevalence of Anxiety

• According to WHO: In 2019, 301 million people were living with an anxiety disorder
including 58 million children and adolescents.

• Indian data from World mental health survey 2005 estimated the 12
month prevalence of Anxiety disorder to be 3.41%.

Manjunatha et al. Prevalence and its correlates of anxiety disorders from India’s National Mental Health Survey 2016. Indian Journal of Psychiatry 64(2):p 138-142, Mar–Apr 2022.
 Mechanism of action

• Etifoxine appears to produce anxiolytic effects

directly by binding to β2 or β3 subunits of the GABA A
receptor complex

• GABAA action is produced by increasing the

frequency of chloride channel opening resulting in
hyperpolarization of the neurons and decreased
firing, thus producing calming effects on the brain by
reducing the excitability neurons.

• It also modulates GABAA receptors via stimulation of

neurosteroid production after the binding of etifoxine
to the 18 kDa translocator protein (TSPO) of the outer
mitochondrial membrane, previously known as the
peripheral benzodiazepine receptor (PBR).
 Clinical evidence

Etifoxine was non-inferior to clonazepam on

reduction of anxiety symptoms, adverse
effects, and clinical improvement.

Objective : To determine whether etifoxine, a non-benzodiazepine drug of the benzoxazine family, is non-
inferior compared with clonazepam in the treatment of anxiety disorders.
• The primary objective was a non-inferiority comparison between etifoxine and clonazepam in the decrease
of anxiety symptoms (HAM-A) at 12 weeks of treatment.
• Secondary outcomes included the evaluation of medication side effects (UKU), anxiety symptoms at 24
weeks of treatment, and clinical improvement (CGI).
Intervention :The experimental group received 150 mg/day of Etifoxine and the control 1 mg/day of
clonazepam, both in three daily doses for 12 weeks.

HMA :Hamilton Anxiety Rating Scale, UKU :Udvalg for Kliniske Undersøgelser, CGI :Clinical global impression
Results

The main findings of this study were as

follows:
(1) HAM-A scores favoured etifoxine
compared with clonazepam at the
12- and 24-week follow-ups, with
significant differences on both
evaluations
(2) there were less adverse side effects
in etifoxine group, measured by UKU
(3) etifoxine is noninferior
to clonazepam in clinical improvement
at the 12-week
evaluation, measured by CGI-I
Objective :The aim of this double-blind randomized parallel group study was to compare (non-inferiority test) the efficacies
of etifoxine, a non-benzodiazepine anxiolytic drug, and lorazepam, a benzodiazepine, for ADWA outpatients followed by
general practitioners

Intervention 191 outpatients (mean age: 43, female: 66%) were assigned to receive etifoxine (50 mg tid) or
lorazepam (0.5-0.5-1 mg /day) for 28 days. Efficacy was evaluated on days 7 and 28 of the treatment.

Results:
• The two drugs were found equivalent in efficacy on Day 28 (respective HAM-A score decrease: 54.6% vs 52.3%).
However, more etifoxine recipients were responders to the treatment (HAM-A score decreased by 50%).

• Clinical improvement (based on CGI,SAS-SR, and Sheehan scores) was observed in both treatment arms, but was
better in etifoxine group with regard to percentage of patients improved markedly and of patients with markedly
diminished anxiety without side effects.
 Results

Clinical Global Impression: global improvement on Day

Evolution of mean HAM-A total score by visit, in ITT population
28 in ITT population Compared to lorazepam
 Clinical Efficacy
• Study design :DSM-IV criteria for adjustment disorders
with anxiety 4-week double-blind RCT Multicenter
Outpatients (GPs) N=170 Etifoxine vs BUS Superiority
test. 11.5
11.18
11

10.5
Results :
10
• Patients were treated for 4 weeks with etifoxine (150- 9.5
9.48

200 mg/d), or buspirone (15-20 mg/d).

9
• Greater improvement in HAM-A with ETX vs BUS at W4 8.5
(p<0.05) Greater improvement in CGI with ETX at Buspirone Etifoxine

D7,D14 and D28. HAM-A at Day 28

• Also both etifoxine and buspirone show clinical efficacy

and safety.
Servant D et al Encephale. 1998 Nov-Dec;24(6):569-74.
• Etifoxine treatment is
neuroprotective for further
neuropathic insults.

• Etifoxine treatment normalizes and

amplifies serotoninergic and
noradrenergic brainstem controls of
pain.
This study demonstrates in the
elderly that a single dose of
etifoxine does neither impair
alertness nor any of the
cognitive parameters
evaluated. Etifoxine may be a
good option when anxiolytic
treatment is required,
especially in elderly people.
 Pharmacokinetics

• Absorption: After oral administration, etifoxine is rapidly absorbed by the gastrointestinal

tract. Time to reach maximal concentration (TMAX) in the blood is 2-3 hours.
• Distribution : It doesn’t binds to any blood cells. Its half-life is about 6 hours and half-life
of its active metabolite is almost 20 hours.
• Metabolism :It is metabolized rapidly in the liver to form several metabolites.
• Elimination :It is mainly excreted in the urine as metabolites, and also excreted in the bile.
Small amounts are excreted in unchanged form.

Choi, Y.M. and Kim, K.H. (2015) “Etifoxine for pain patients with anxiety,” The Korean Journal of Pain, 28(1), pp. 4–10.
 Advantages

• Distinct site of action(β2 , β3 subunits) from that of benzodiazepines.

• Indirect TSPO binding and stimulate the neurosteriod production, thus modulating
GABAA receptors.
• Etifoxine has very low dependence when compared with benzodiazepines.
• Etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired
psychomotor performance, and withdrawal syndromes than those of
benzodiazepines.
• Etifoxine attenuates stress-induced corticotrophin-releasinghormone (CRH)
activation.
• Therefore, it may be helpful in the treatment of selected anxious patients with
altered autonomic symptomatology

Choi, Y.M. and Kim, K.H. (2015) “Etifoxine for pain patients with anxiety,” The Korean Journal of Pain, 28(1), pp. 4–10 .
 Advantages
• The average dosage is 150 mg per day for no more than 12 weeks.

• The most common adverse effect is drowsiness at the initial stage.

• It does not usually cause any withdrawal syndromes.

• Etifoxine shows less adverse effects of anterograde amnesia, sedation, impaired

psychomotor performance, and withdrawal syndromes than those of
benzodiazepines.

The risk or severity of adverse effects can be

increased when Etifoxine is combined with
Benzodiazepine.
 Limitations

• Rare severe liver injuries and toxidermia have been suspected to be associated with
Etifoxine treatment.
• It can also cross the placental barrier , it is not recommended to use Etifoxine during
the pregnancy whatever is the term.
Contraindicated in patients :
• States of shock.
• Severely impaired liver and/or renal function.
• Myasthenia gravis.

https://www.ema.europa.eu/en/medicines/human/referrals/etifoxine-containing-medicinal-products assessed on 29-03-23

Market
 Opinion
• Etifoxine is a non-BZD anxiolytic drug with selectivity for the β subunit of the GABA A receptor.
• Both direct and indirect (via neurosteroid synthesis) facilitation of GABAergic
neurotransmission, leading to a potential indirect serotonergic activity.
• Etifoxine attenuates CNS and whole-body inflammation and immunity processes known to be
associated with anxiety.
• Efficacy of etifoxine in the symptomatic treatment of anxiety, particularly in patients with
ADWA, with daily doses of 150–200 mg.
• The tolerability profile of etifoxine is better than that of BZDs, notably because of a lack of
effect on memory and vigilance.
• Treatment cessation does not induce drug dependence, withdrawal, or rebound anxiety.
• The anxiolytic efficacy of etifoxine, its good tolerability and the absence of drug dependence is
strong arguments in favor of using etifoxine in the management of ADWA.
Adjustment disorders with anxiety (ADWA)
 • Clinical studies have demonstrated the efficacy of etifoxine in the symptomatic treatment of
anxiety, particularly in patients with ADWA, with daily doses of 150–200 mg

• The tolerability profile of etifoxine is better than that of BZDs, notably because of a lack of effect
on memory and vigilance. In addition, treatment cessation does not induce drug dependence,
withdrawal, or rebound anxiety

Adjustment disorders with anxiety (ADWA)

Nuss P, Ferreri F, Bourin M. An update on the anxiolytic and neuroprotective properties of etifoxine: from brain GABA modulation to a
whole-body mode of action. Neuropsychiatr Dis Treat. 2019 Jul 3;15:1781-1795.
 • The first multicenter, randomized, controlled, double-blind study evaluating the efficacy of etifoxine vs
buspirone in 170 patients with a primary diagnosis of ADWA was carried out in France in 1998
• Patients were treated for 4 weeks with either etifoxine (150–200 mg/day; n=83), or buspirone (15–20
mg/day; n=87)
• Results showed the superiority of etifoxine over buspirone for the mean HAM-A score at 4 weeks
• The etifoxine group had a significantly better CGI-Global Improvement score than the buspirone group
from Day 7 of treatment onwards (p<0.001 on Day 7, and p=0.02 on Days 14 and 28)
• The CGI-Efficacy Index on Days 14 and 28 was also better for etifoxine
• CNS-related adverse events (somnolence, vertigo, and headache) were reported in 40.7% of the
etifoxine-treated patients and 58.6% of the patients in the buspirone group.

Clinical Global Impression (CGI) Scale-Global Improvement score

Nuss P, Ferreri F, Bourin M. An update on the anxiolytic and neuroprotective properties of etifoxine: from brain GABA modulation to a
whole-body mode of action. Neuropsychiatr Dis Treat. 2019 Jul 3;15:1781-1795.
• In a second multicenter, controlled, randomized double-blind study, 191 outpatients (mean age: 43,
female: 66%) were assigned
• Etifoxine was compared with lorazepam in outpatients with ADWA followed by general practitioners
• Patients received either etifoxine (50 mg 3 times per day; n=93) or lorazepam (2 mg/day divided into
three administrations: 0.5 mg morning and noon, and 1.0 mg in the evenings; n=96) for 28 days
• All patients presented with clinical anxiety at inclusion, according to their HAM-A score (≥20)
• a higher number of patients responded to treatment, as expressed by a total decrease in the HAM-A
score from baseline to Day 28 of ≥50%, in the etifoxine group (72% vs 56%; p=0.0288)
• The CGI-Efficacy Index on Day 28 was better for etifoxine (p=0.038)
• Withdrawal symptoms were evaluated 1 week following treatment cessation
• The number of patients who experienced rebound anxiety after treatment cessation was significantly
greater (p=0.034) in the lorazepam group (eight patients) than in the etifoxine group (one patient)

Nuss P, Ferreri F, Bourin M. An update on the anxiolytic and neuroprotective properties of etifoxine: from brain GABA modulation to a
whole-body mode of action. Neuropsychiatr Dis Treat. 2019 Jul 3;15:1781-1795.
• In a study among patients with ADWA conducted in Russia, the efficacy of etifoxine was compared with
that of phenazepam, an anxiolytic BZD commonly used in Russia for the treatment of Ads
• This multicenter, open-label, randomized study recruited 90 patients, who received either etifoxine (150
mg/day) or phenazepam (1 mg/day) for 6 weeks. The primary endpoint was HAM-A on Day 42, adjusted
to Day 0
• Results indicated that tifoxine was superior to phenazepam (p=0.003 for HAM-A score on Day 42); More
etifoxine recipients than phenazepam recipients showed a tendency to marked improvement (CGI score
<3) on Day 42
• The CGI-Severity score fell in both groups, with a significant difference favoring etifoxine on Day 42
(p=0.004). The CGI-Efficacy Index on Day 42 was also better for etifoxine (p=0.004)
• Significant difference was observed between the two treatment arms with respect to the number of
adverse effects leading to discontinuation (8 in the phenazepam group vs 0 in the etifoxine
group; p=0.002)
• Concerning withdrawal symptoms after treatment cessation, three patients in the etifoxine group vs 26
in the phenazepam group experienced rebound anxiety between Days 42 and 49, according to the
irHAM-A scores
Nuss P, Ferreri F, Bourin M. An update on the anxiolytic and neuroprotective properties of etifoxine: from brain GABA modulation to a
whole-body mode of action. Neuropsychiatr Dis Treat. 2019 Jul 3;15:1781-1795.
• Thank You..!!!!