Usage
Etifoxine hydrochloride is prescribed for the treatment of adjustment disorder with anxiety (ADWA), also known as situational anxiety or stress-related anxiety. It is also used for the management of psychosomatic manifestations of anxiety, such as autonomic nervous system imbalances, particularly those with cardiovascular symptoms. It is classified as a non-benzodiazepine anxiolytic. Although it is not a benzodiazepine, it acts on the GABAA receptor complex, enhancing GABAergic neurotransmission, similar to benzodiazepines. It also stimulates the production of neurosteroids, further enhancing GABAergic activity.
Alternate Names
Etifoxine hydrochloride is also known as etafenoxine. Brand names include Stresam.
How It Works
Pharmacodynamics: Etifoxine acts primarily on the central nervous system by enhancing the activity of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. It achieves this through a dual mechanism: directly, by acting as a positive allosteric modulator of the GABAA receptor complex, and indirectly, by stimulating the synthesis of 3α-reduced neurosteroids, endogenous positive allosteric modulators of GABAA receptors. This dual action results in increased inhibitory neurotransmission, reducing neuronal excitability and producing an anxiolytic effect.
Pharmacokinetics: Etifoxine is well-absorbed orally, reaching peak plasma concentration in 2–3 hours. It has high bioavailability (approximately 90%) and doesn’t bind to blood cells, but it strongly binds to plasma proteins (88–95%). Etifoxine is extensively metabolized in the liver, primarily via CYP3A4, producing several metabolites, including diethyl-etifoxine, which is also active. It is primarily eliminated through the kidneys, with a triphasic elimination profile. It crosses the placental barrier.
Mode of Action: Etifoxine binds to a specific site on the GABAA receptor complex, distinct from the benzodiazepine binding site, enhancing the receptor’s sensitivity to GABA. This binding increases the frequency of chloride channel opening, leading to hyperpolarization of the neuron and reduced neuronal excitability. Additionally, etifoxine stimulates the synthesis of neurosteroids, which further enhance GABAergic activity. This indirect action on GABAA receptors via TSPO is likely responsible for some of etifoxine’s neuroprotective, neuroplastic, and anti-inflammatory properties.
Elimination Pathways: Etifoxine and its metabolites are mainly excreted in urine.
Dosage
Standard Dosage
Adults: The usual dosage is 150-200 mg/day, divided into two or three doses (e.g., 50 mg three times a day or 50 mg twice a day plus 100 mg in the evening). The maximum recommended treatment duration is 12 weeks.
Children: Etifoxine is not recommended for use in children under 18 years of age due to a lack of safety and efficacy data.
Special Cases:
- Elderly Patients: Start with a lower dose (e.g., 50 mg twice a day) and titrate slowly as needed, considering age-related changes in renal and hepatic function.
- Patients with Renal Impairment: Dose adjustment may be required based on the degree of impairment. In patients with severe renal impairment (GFR < 30 mL/min), etifoxine is not recommended.
- Patients with Hepatic Dysfunction: Dose adjustment may be required, particularly in moderate to severe impairment. Close monitoring is recommended.
- Patients with Comorbid Conditions: Caution is advised in patients with pre-existing conditions like myasthenia gravis, respiratory failure, or galactosemia.
Clinical Use Cases
Etifoxine does not have established indications or dosage recommendations for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary use is in the management of adjustment disorder with anxiety and related psychosomatic manifestations.
Dosage Adjustments
Dose adjustments should be considered based on individual patient response, tolerability, and the presence of renal or hepatic impairment. Start with a lower dose and titrate gradually upwards as needed.
Side Effects
Common Side Effects:
The most common side effect is drowsiness, which usually occurs in the initial stages of treatment and tends to resolve with continued use. Other reported common side effects include headache, dizziness, and nausea.
Rare but Serious Side Effects:
Rare but serious side effects include skin rashes, urticaria, angioedema, hepatitis, and Stevens-Johnson syndrome. These require immediate medical attention.
Long-Term Effects:
There is limited data on long-term effects of etifoxine use beyond 12 weeks.
Adverse Drug Reactions (ADR):
Clinically significant ADRs include severe skin reactions, hepatic dysfunction, and hypersensitivity reactions.
Contraindications
Etifoxine is contraindicated in:
- Hypersensitivity to etifoxine or any of its components.
- Shock
- Myasthenia gravis
- Severe hepatic impairment
- Severe renal impairment
- Respiratory failure
- Galactosemia
Drug Interactions
Etifoxine may potentiate the effects of other central nervous system depressants, such as alcohol, benzodiazepines, opioids, and some antihistamines. It can also interact with drugs metabolized by CYP3A4, as etifoxine is both a substrate and an inducer of this enzyme. Co-administration with CYP3A4 inhibitors may increase etifoxine levels, while co-administration with CYP3A4 inducers may decrease etifoxine levels.
Pregnancy and Breastfeeding
Etifoxine is contraindicated during pregnancy and breastfeeding. There are no adequate and well-controlled studies in pregnant or breastfeeding women, and the drug’s potential benefits do not outweigh the potential risks to the fetus or neonate.
Drug Profile Summary
- Mechanism of Action: Enhances GABAergic neurotransmission via direct positive allosteric modulation of the GABAA receptor complex and indirect stimulation of neurosteroid synthesis.
- Side Effects: Drowsiness (common), skin rash, hepatitis (rare).
- Contraindications: Hypersensitivity, shock, myasthenia gravis, severe hepatic/renal impairment, respiratory failure, galactosemia, pregnancy, breastfeeding.
- Drug Interactions: CNS depressants, CYP3A4 substrates/inhibitors/inducers.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Adults: 150-200 mg/day divided into 2-3 doses; maximum 12 weeks. Children: Not recommended.
- Monitoring Parameters: Liver function tests, signs of hypersensitivity reactions.
Popular Combinations
There are no widely established popular combinations of etifoxine with other medications.
Precautions
- Assess patients for allergies, hepatic or renal dysfunction before initiating treatment.
- Monitor for signs of drowsiness and other adverse effects.
- Advise patients against concurrent alcohol consumption.
- Caution is necessary in elderly patients due to altered drug metabolism.
- Avoid abrupt discontinuation; taper the dose gradually.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Etifoxine?
A: The recommended dosage for adults is 150-200 mg/day, divided into two or three doses. Treatment should not exceed 12 weeks. It is not recommended for children under 18.
Q2: What is the mechanism of action of Etifoxine?
A: Etifoxine enhances GABAergic activity by directly modulating GABAA receptors and by stimulating neurosteroid synthesis.
Q3: Is Etifoxine a benzodiazepine?
A: No, etifoxine is not a benzodiazepine, though it shares a similar mechanism of action by enhancing GABAergic neurotransmission.
Q4: What are the common side effects of Etifoxine?
A: The most common side effect is drowsiness, particularly at the start of treatment.
Q5: Can Etifoxine be used during pregnancy or breastfeeding?
A: No, Etifoxine is contraindicated during pregnancy and breastfeeding.
Q6: What are the contraindications for Etifoxine?
A: Contraindications include hypersensitivity, shock, myasthenia gravis, severe hepatic or renal impairment, respiratory failure, and galactosemia.
Q7: Does Etifoxine interact with other medications?
A: Yes, it can interact with CNS depressants and drugs metabolized by CYP3A4.
Q8: How long can Etifoxine be used for?
A: Treatment duration should not exceed 12 weeks.
Q9: What should patients be advised about while taking Etifoxine?
A: Patients should be advised to avoid concurrent alcohol use, to be cautious operating machinery due to potential drowsiness, and to report any signs of hypersensitivity.
Q10: What is the difference between Etifoxine and Benzodiazepines?
A: Although both enhance GABAergic transmission, etifoxine has a distinct chemical structure and appears to have a lower risk of dependence and withdrawal symptoms compared to benzodiazepines. Also, it interacts differently with CYP enzymes. It potentiates the effect of benzodiazepines.
