Tofisopam

Usage

• Tofisopam is prescribed for the short-term management of anxiety disorders, including generalized anxiety disorder (GAD). It is also used to alleviate anxiety symptoms associated with psychosomatic disorders and as an adjunct treatment for alcohol withdrawal syndrome.
• Pharmacological classification: Anxiolytic, atypical benzodiazepine derivative.
• Mechanism of Action: Tofisopam enhances the binding of gamma-aminobutyric acid (GABA) to its receptors. This interaction leads to increased inhibitory neurotransmission, reducing neuronal excitability and producing a calming effect. Unlike typical benzodiazepines, Tofisopam lacks prominent sedative, anticonvulsant, and muscle relaxant properties.

Alternate Names

• International Nonproprietary Name (INN): Tofisopam
• Other names: 6-(3,4-Dimethoxyphenyl)-2-ethyl-9,10-dimethoxy-3-methyl-4,5-diazabicyclo[5.4.0]undeca-3,5,7,9,11-pentaene.
• Brand names: Emandaxin, Grandaxin, Sériel, Tofizopam, Teromide, Tofisoprime, Nextril.

How It Works

• Pharmacodynamics: Tofisopam primarily exerts its anxiolytic effects through modulating GABAergic neurotransmission. It enhances GABA’s action at the GABA_A receptor, leading to increased chloride influx and neuronal hyperpolarization. This reduces neuronal excitability and promotes a calming effect. Tofisopam’s atypical structure results in minimal sedative, muscle relaxant, or anticonvulsant effects compared to classical benzodiazepines. It is also a phosphodiesterase 10A (PDE10A) inhibitor, although the clinical significance of this is not fully understood. Some research indicates it inhibits CYP3A4.
• Pharmacokinetics: Tofisopam is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. Peak plasma concentrations are typically reached within 1-2 hours. It is metabolized in the liver, and its metabolites are pharmacologically inactive. Tofisopam is primarily excreted in urine. The elimination half-life is approximately 6-8 hours.

Dosage

Standard Dosage

Adults:

• The standard dosage ranges from 50-100mg, taken one to three times daily, with a maximum daily dose of 300mg.
• The dosage should be individualized based on the severity of symptoms and patient response.

Children:

• The safety and efficacy of Tofisopam in children and adolescents under 18 years of age have not been established, and its use is generally not recommended.

Special Cases:

• Elderly Patients: A reduced dosage, typically half the standard adult dose, is recommended due to age-related decline in hepatic and renal function.
• Patients with Renal Impairment: Dosage adjustment is necessary, usually a reduction to about half the standard adult dose.
• Patients with Hepatic Dysfunction: Careful monitoring and dosage adjustments are required due to the potential for impaired metabolism.
• Patients with Comorbid Conditions: Dose adjustments may be needed based on the specific comorbidity and potential drug interactions.

Clinical Use Cases

• Data regarding clinical use cases for intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations is not available.

Dosage Adjustments

• Dose adjustments are made based on the patient’s response to therapy, age, renal function, and hepatic function.
• In patients with renal or hepatic impairment, the dose should be reduced to approximately half the standard adult dose.

Side Effects

Common Side Effects

• Nausea, dry mouth, dizziness, drowsiness, headache, loss of appetite, constipation, abdominal pain, skin rash, and itching.

Rare but Serious Side Effects

• Allergic reactions (e.g., skin rash, itching, swelling), paradoxical reactions (e.g., increased anxiety, insomnia, agitation), and hepatic dysfunction.

Long-Term Effects

• While Tofisopam is less likely to cause dependence than classical benzodiazepines, long-term use can still lead to tolerance and withdrawal symptoms upon discontinuation.

Adverse Drug Reactions (ADR)

• Severe allergic reactions (anaphylaxis), paradoxical reactions (increased anxiety, agitation, aggression), and hepatotoxicity.

Contraindications

• Hypersensitivity to Tofisopam or any of its components.
• Severe respiratory insufficiency.
• Aggressive-impulsive psychopathy.
• Myasthenia gravis.
• Sleep apnea.
• First trimester of pregnancy and breastfeeding.
• Concomitant use of tacrolimus, sirolimus, or cyclosporine.

Drug Interactions

• Tofisopam may interact with other CNS depressants (e.g., alcohol, opioids, barbiturates, antihistamines, other benzodiazepines), enhancing their sedative effects.
• CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin) may increase Tofisopam plasma levels, and inducers (e.g., rifampicin, carbamazepine, phenytoin) may decrease its effectiveness.
• Concomitant use with other anxiolytics, antidepressants, or antipsychotics should be carefully monitored for additive effects.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Not well established but considered a Pregnancy Category D drug by some sources, indicating potential fetal risk. Use during pregnancy is generally not recommended unless the potential benefits outweigh the risks.
• Tofisopam can cross the placenta. Animal studies have not shown direct reproductive toxicity.
• Breastfeeding: Tofisopam is excreted in breast milk and may have adverse effects on the nursing infant. Breastfeeding is generally not recommended during Tofisopam therapy.

Drug Profile Summary

• Mechanism of Action: Enhances GABA binding to GABA_A receptors, increasing inhibitory neurotransmission and reducing neuronal excitability.
• Side Effects: Nausea, dry mouth, dizziness, drowsiness, headache. Rare: allergic reactions, paradoxical reactions.
• Contraindications: Hypersensitivity, severe respiratory insufficiency, aggressive-impulsive psychopathy, pregnancy (first trimester), breastfeeding, concomitant use of tacrolimus, sirolimus, or cyclosporine.
• Drug Interactions: CNS depressants, CYP3A4 inhibitors and inducers, other anxiolytics, antidepressants, and antipsychotics.
• Pregnancy & Breastfeeding: Generally not recommended during pregnancy and breastfeeding.
• Dosage: Adults: 50-100mg 1-3 times daily (max 300mg/day). Elderly and renally impaired: Dose reduction is recommended.
• Monitoring Parameters: Monitor for therapeutic response, adverse reactions, and potential drug interactions. Liver function tests may be considered with prolonged use.

Popular Combinations

Information about popular combinations isn’t available.

Precautions

• General Precautions: Assess for allergies, renal and hepatic function, and potential drug interactions.
• Specific Populations: Use with caution in elderly patients, patients with renal or hepatic impairment, and pregnant or breastfeeding women (generally not recommended).
• Lifestyle Considerations: Avoid alcohol and other CNS depressants. Caution should be exercised when operating machinery or driving.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Tofisopam?

A: The recommended adult dosage is 50-100 mg, one to three times daily, with a maximum daily dose of 300mg. Elderly patients and those with renal or hepatic impairment may require dose reductions.

Q2: What are the common side effects of Tofisopam?

A: Common side effects include nausea, dry mouth, dizziness, drowsiness, headache, and gastrointestinal disturbances.

Q3: Is Tofisopam safe during pregnancy?

A: Tofisopam is generally not recommended during pregnancy, especially during the first trimester, due to potential fetal risks. Consult a healthcare professional for individualized advice.

Q4: Can I take Tofisopam while breastfeeding?

A: Tofisopam is excreted in breast milk and may cause adverse effects in nursing infants. Breastfeeding while taking Tofisopam is generally not recommended.

Q5: How does Tofisopam differ from other benzodiazepines?

A: Tofisopam is an atypical benzodiazepine that lacks the significant sedative, anticonvulsant, and muscle relaxant properties of classical benzodiazepines.

Q6: What should I do if I miss a dose of Tofisopam?

A: If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose and return to your regular dosing schedule. Do not double the dose.

Q7: What are the contraindications for Tofisopam use?

A: Contraindications include hypersensitivity to Tofisopam, severe respiratory insufficiency, aggressive-impulsive psychopathy, myasthenia gravis, sleep apnea, first trimester of pregnancy, breastfeeding, and concomitant use with tacrolimus, sirolimus, or cyclosporine.

Q8: Can I drink alcohol while taking Tofisopam?

A: No. Alcohol should be avoided while taking Tofisopam as it can enhance the sedative effects and increase the risk of adverse events.

Q9: How long can I take Tofisopam?

A: Tofisopam is generally recommended for short-term use to avoid the risk of tolerance and dependence. The duration of treatment will be determined by your healthcare provider based on individual needs and response to therapy.