Strezam®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT STRESAM® (STRESam®)

Composition:

Active substance: ethofenoxine hydrochloride;

1 capsule contains ethofenoxine hydrochloride 50 mg;

Excipients: lactose monohydrate; talc; microcrystalline cellulose; colloidal anhydrous silicon dioxide; magnesium stearate;

capsule shell: titanium dioxide (E 171); indigotine (E 132); gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties: size № 2 capsules with a blue cap and an opaque white body, containing a white powder.

Pharmacotherapeutic group. Agents acting on the nervous system. Psycholeptics. Anxiolytics. Other anxiolytics. Ethofenoxine. ATC code N05B X03.

Pharmacological properties.

Pharmacodynamics.

In therapeutic doses, ethifenone hydrochloride exhibits anxiolytic properties and exerts a neurovegetative regulatory effect.

In vitro and in vivo studies in animals have shown that the anxiolytic effect of ethifenone is due to a dual mechanism of action (direct and indirect) on GABAA receptors to enhance GABAergic transmission:

• Direct action on the GABAA receptor through positive allosteric modulation by binding predominantly to β2 or β3 subunits; studies indicate that the binding site of ethifenone on the GABAA receptor differs from that of benzodiazepines;
• Indirect action by increasing the production of neurosteroids in the brain (through activation of mitochondrial protein translocation), including allopregnanolone, which are positive allosteric modulators of the GABAA receptor.

Clinical studies have not revealed any withdrawal effects or dependence potential (physical or psychological).

Animal studies did not show the possibility of developing pharmacological dependence on ethifenone.

Pharmacokinetics.

Ethifenone hydrochloride is well absorbed in the gastrointestinal tract. It is rapidly metabolized, does not bind to blood cells, and its plasma levels decrease slowly in three phases. The drug and its main metabolite are excreted primarily in the urine. Ethifenone hydrochloride crosses the placental barrier.

Clinical characteristics.

Indications.

Psychosomatic manifestations of anxiety.

Contraindications.

Hypersensitivity to the components of the medicinal product, shock state, myasthenia gravis, severe impairment of liver and/or kidney function.

The drug is contraindicated in patients who have previously experienced severe hepatitis or cytolytic syndrome during prior treatment with etifoxine; in patients who previously had severe skin reactions, including DRESS syndrome, Stevens–Johnson syndrome (SJS), and generalized exfoliative dermatitis, during prior treatment with etifoxine.

Pregnancy or breastfeeding.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Stresam® with medicinal products that depress the central nervous system (morphine derivatives (analgesics, antitussives, and opioid substitution therapy for drug dependence), benzodiazepines, hypnotics, neuroleptics, H1-histamine receptor blockers, antidepressants, centrally-acting antihypertensive agents, baclofen, thalidomide) may result in mutual potentiation of effects.

Alcohol enhances the sedative effect of Stresam®.

Concomitant use of Stresam® with alcohol or with medicinal products that depress the central nervous system (morphine derivatives (analgesics, antitussives, and opioid substitution therapy for drug dependence), benzodiazepines, hypnotics, neuroleptics, H1-histamine receptor blockers, antidepressants, centrally-acting antihypertensive agents, baclofen, thalidomide) may impair reaction speed, which in turn may pose a danger when driving or operating machinery. Consumption of alcohol, medicinal products containing alcohol, and medicinal products that depress the central nervous system is not recommended during treatment with this drug.

Special precautions for use.

The consumption of alcohol and the use of other centrally-acting agents (haloperidol, diazepam, imipramine, etc.) is not recommended during treatment with Stresam®.

If skin or allergic reactions or severe liver disorders occur, treatment with etifoxine should be discontinued immediately.

The drug contains lactose; therefore, it is not recommended for patients with congenital galactosemia, glucose/galactose malabsorption syndrome, or lactase deficiency.

Severe skin reactions

Very rare cases of severe skin reactions have been reported, including drug-induced eosinophilia with systemic symptoms (DRESS syndrome), Stevens–Johnson syndrome (SJS), and generalized exfoliative dermatitis associated with the use of etifoxine. The onset of toxic skin reactions during Stresam® treatment usually ranged from several days to 1 month, depending on the type of reaction. Post-marketing surveillance data indicate that the outcome of skin reactions after discontinuation of etifoxine was mostly favorable. There have been no reports of fatal outcomes associated with severe cutaneous adverse reactions during etifoxine treatment. Patients should be informed about the risk of skin toxicity and carefully monitored for cutaneous signs and symptoms. If a skin toxicity reaction occurs during etifoxine treatment, the drug should be discontinued immediately and must never be re-administered.

Severe hepatic reactions

During post-marketing surveillance, very rare severe cases of cytolysis syndrome associated with etifoxine intake have been reported. According to post-marketing data, hepatic reactions following etifoxine administration mostly occurred between 2 weeks and 1 month after treatment initiation. The drug should be used with caution in patients with risk factors for liver dysfunction, particularly elderly patients, patients with a history of viral hepatitis, or any other conditions identified by the physician on an individual basis. Liver function abnormalities may be asymptomatic and detectable only through specific laboratory tests. In patients with risk factors for liver dysfunction, liver function tests should be performed before starting etifoxine treatment and approximately one month after treatment initiation. If hepatic toxicity occurs during etifoxine treatment, the drug should be discontinued immediately and must never be re-administered.

Lymphocytic colitis

Several cases of lymphocytic colitis associated with etifoxine intake have been reported during post-marketing surveillance. In patients receiving etifoxine who develop watery diarrhea, appropriate diagnostic evaluation should be considered, and the drug should be discontinued immediately.

Metrorrhagia

Cases of metrorrhagia have been reported during post-marketing surveillance in women taking oral contraceptives concurrently with etifoxine treatment.

Use during pregnancy or breastfeeding

The use of this drug is contraindicated in pregnant women.

If it is necessary to use the drug, breastfeeding should be discontinued.

Ability to affect reaction speed when driving vehicles or operating machinery

Due to significant individual adverse reactions (dizziness, drowsiness), there is a possibility of temporary impairment of the ability to drive vehicles or operate potentially hazardous machinery during treatment with this drug.

Dosage and Administration.

The dose and duration of treatment are determined individually by a physician, depending on the severity of the disease.

For adults, the recommended dosage is 3–4 capsules taken in 2–3 divided doses. The capsules should be taken before meals with a small amount of water.

The treatment course lasts from several days to several weeks.

Children. The drug is not prescribed to children due to insufficient clinical data.

Overdose.

Manifests as arterial hypotension. There is a risk of developing drowsiness. Gastric lavage is recommended. If necessary, symptomatic treatment should be administered. There is no specific antidote.

Adverse Reactions

Dizziness may occasionally occur, typically at the beginning of treatment and usually resolves spontaneously with continued therapy.

Classification of adverse reactions by organ systems and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Within each frequency group, adverse events are listed in order of decreasing severity.

Nervous system disorders:
Rare – mild drowsiness at the beginning of treatment, which resolves spontaneously during continued therapy.

Skin and subcutaneous tissue disorders:
Rare – skin rashes: maculopapular rash, erythema multiforme, pruritus, facial swelling;
Very rare – allergic reactions: urticaria, angioedema; severe skin reactions: DRESS syndrome, Stevens-Johnson syndrome, generalized exfoliative dermatitis;
Frequency not known – anaphylactic shock, leukocytoclastic vasculitis.

Immune system disorders:
Very rare – urticaria, angioedema, angioedermatitis;
Frequency not known – anaphylactic shock, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), Stevens-Johnson syndrome, leukocytoclastic vasculitis.

Hepatobiliary disorders:
Very rare – liver injury: hepatitis, cytolytic hepatitis.

Reproductive system and breast disorders:
Very rare – intermenstrual bleeding in women taking oral contraceptives.

Gastrointestinal disorders:
Very rare – lymphocytic colitis.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after marketing authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse events via the national reporting system.

Shelf life.
3 years.

Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.
12 capsules in a blister, 5 blisters in a carton.
20 capsules in a blister, 3 blisters in a carton.

Prescription category.
Prescription only.

Manufacturer.
BIOCODEX.

Manufacturer's address and place of business.
1 Avenue Blaise Pascal, 60000 Beauvais, France.