苯巴那酯(cenobamate)详细说明书:适应症、用法用量、副作用、注意事项

Based on the actual clinical response and the individual tolerance of the patient, the daily dosage can be gradually increased from the initial 50 mg to the appropriate dose (50 mg/day can be increased every 2 weeks).

But please be sure to use the drug within the recommended dose. Excessive titration is not only unhelpful but may also cause serious adverse reactions.

5. Precautions for discontinuing medication

It is necessary to gradually reduce the dosage and discontinue the medication within at least 2 weeks.

A drug should be discontinued suddenly only if there are safety concerns.

6. Dose adjustment for special populations

(1) Patients with liver function impairment

The recommended maximum dose for partial epileptic seizures (oral administration), mild or moderate liver impairment (Child-Pugh Class A or B) is 200 mg once a day, and use is not recommended for severe liver impairment.

(2) Patients with renal impairment

For patients with mild to moderate renal impairment (creatinine clearance 30~<90mL/min) or severe renal impairment (creatinine clearance <30mL/min), dose reduction should be considered.

(3) Elderly patients

It is recommended to choose the dose carefully (usually starting from the lower limit of the dose range).

Recommended article:

Contraindications of cenobamate

1. People who are known to be allergic to cenobamate or any excipients in the preparation.

2. Patients with familial short QT syndrome.

Cenobamate (cenobamate) Precautions

1. Anaphylaxis

Multiple organ hypersensitivity reactions

There have been reports of multiorgan hypersensitivity reactions (also known as drug reactions with eosinophilia and systemic symptoms, DRESS), which may be fatal or life-threatening. Clinical manifestations are variable but typically include fever, rash, lymphadenopathy, and/or facial swelling, with involvement of other organ systems (eg, eosinophilia, hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis).

Treatment should be started at a low dose and gradually increased every 2 weeks as recommended.

If symptoms of multi-organ hypersensitivity occur, the patient should be evaluated immediately. If no other cause can be identified, phenibutate should be permanently discontinued.

2. QT interval shortening

Reports show QT interval shortening.

‌Familial short QT syndrome‌is associated with an increased risk of sudden death and ventricular arrhythmias (especially ventricular fibrillation), which is more likely to occur when the corrected QT interval (QTc) is <300 milliseconds.

Contraindicated in patients with familial short QT syndrome.

Use with caution when combined with other drugs that shorten the QT interval.

3. Risk of suicide

Anti-epileptic drugs may increase the risk of suicide (behavior or ideation). It has been observed in patients with epilepsy, mental disorders (bipolar disorder, depression, anxiety) and other diseases (migraine, neuralgia): the risk in the medication group (0.43%) is approximately twice that of the placebo group (0.24%). The risk appears as early as 1 week after medication and lasts until 24 weeks. The risk in patients with epilepsy is higher than that in patients with other indications.

It is necessary to closely observe changes in the patient's behavior and be wary of suicidal tendencies or worsening depression.

This needs to be weighed against the risks of untreated disease itself (which also comes with morbidity and risk of suicide).

4. Nervous system effects

May cause a variety of adverse reactions:

Dizziness, gait/coordination disorders (such as dizziness, nystagmus, balance disorder, ataxia), cognitive dysfunction, drowsiness, fatigue.

Do not drive or operate machinery while taking medication.

Especially when used in combination with sedatives, central suppression monitoring should be strengthened to prevent the additive adverse reactions of the two.

5. Ophthalmic effects

Reported adverse reactions include: diplopia, blurred vision, and visual impairment.

Precautions for discontinuation of medication

Sudden discontinuation of medication may greatly increase the frequency of epileptic seizures and even cause status epilepticus.

Routine treatment should be gradually reduced over at least 2 weeks.

Immediate discontinuation of the drug may only be considered if serious adverse reactions occur.

6. Abuse potential and dependence

It belongs to Class C-V controlled drugs. Reported cases show that it may produce euphoria, confusion and sedation, and may lead to physical dependence and withdrawal syndrome (shown as insomnia, loss of appetite, depression, tremor and amnesia). It is recommended to gradually reduce and discontinue the drug.

Special population use of cenobamate

1. Pregnancy period

There are currently insufficient human research data; in animal studies, when clinically relevant doses were given, developmental toxicity was observed, specifically manifested as increased embryo-fetal mortality, reduced fetal and offspring weight, and neurobehavioral and reproductive impairment in offspring.

2. Women and men of childbearing potential

Women of childbearing potential who receive oral contraceptives should additionally take or switch to non-hormonal contraceptive measures.

3. Lactation period

It is currently unclear whether cenobamate will be secreted into breast milk; its impact on milk secretion or breastfed infants is also unclear.

It is necessary to comprehensively consider the benefits of breastfeeding, the importance of phebanate to the mother, and also consider the potential adverse effects that the drug or underlying maternal diseases may have on the breastfed infant.

4. Pediatric use

The safety and effectiveness of phenobarnate in pediatric patients have not been established.

5. Medication in the Elderly

Currently, there is insufficient research experience on elderly patients, and it is impossible to determine whether their drug response is different from that of younger patients. The elderly population has a higher incidence of decreased liver, renal, and/or cardiac function, often with other underlying medical conditions and multiple medications, and this needs to be considered.

6. Hepatic Impairment

When patients with hepatic impairment use phenobarate, their systemic drug exposure will increase.

This drug should be used with caution in patients with mild to moderate hepatic impairment (Child-Pugh class A or B). The recommended maximum dose for such patients is 200 mg once daily; further dose reduction may be considered if necessary.

Relevant studies have not been conducted in patients with severe hepatic impairment and use is not recommended for such patients.

7. Renal Impairment

When patients with renal impairment use phenobanamate, their systemic drug exposure will increase.

Patients with mild to moderate renal impairment (creatinine clearance 30~<90mL/min) or severe renal impairment (creatinine clearance <30mL/min) should use it with caution and consider reducing the dose.

The effect of hemodialysis on the pharmacokinetics of phenobanate has not yet been studied, and the use of this drug is not recommended for patients with end-stage renal disease receiving dialysis treatment.

Common adverse reactions of cenobamate

Adverse reactions with an incidence rate of ≥10% include: drowsiness, dizziness, fatigue, diplopia, and headache.

Recommended articles:

Pharmacokinetics of cenobamate

‌1. Absorption‌

‌(1) Bioavailability‌

After a single oral dose of 5-750 mg, the area under the plasma concentration-time curve (AUC) increases in a dose-proportional manner; while the peak plasma concentration (Cmax) increases in a dose-proportional manner.

Steady-state plasma concentration is reached after approximately 2 weeks of daily administration.

Oral absorption rate ≥88%.

The median peak time is 1-4 hours.

‌(2) Food influence‌

High-fat diet does not affect its pharmacokinetic properties.

‌2. Distribution‌

‌Plasma protein binding rate‌: 60% (mainly binds albumin).

3. Metabolism‌

Mainly through glucuronidation metabolism mediated by UGT2B7, and secondarily through UGT2B4.

Part of it is metabolized by CYP isoenzymes 2E1, 2A6 and 2B6, and a small amount is metabolized by CYP2C19 and CYP3A4/5.

‌4. Excretion route‌

About 93% of the radioactive dose is excreted through urine (87.8%) and feces (5.2%), and >50% is excreted within 72 hours.

‌Half-life‌50-60 hours.

Drug interactions with cenobamate

Metabolized by glucuronidation by UGT2B7 and, to a lesser extent, UGT2B4. Also metabolized by CYP isoenzymes 2E1, 2A6 and 2B6 and, to a lesser extent, CYP2C19 and CYP3A4/5.

In vitro, inhibits CYP isoenzymes 2B6, 2C19, and 3A, but not CYP1A2, CYP2C8, CYP2C9, or CYP2D6. Induces CYP2B6, CYP2C8, and CYP3A4, but not CYP1A2, CYP2C9, or CYP2C19.

Not a substrate for the efflux transporter P-glycoprotein (P-gp). It is also not a substrate of breast cancer resistance protein (BCRP), multidrug and toxin extrusion transporter (MATE) 1 or MATE2/K, organic ion transporter (OAT) 1 and OAT3, or organic cation transporter (OCT) 2. Does not inhibit P-gp, OAT1, OAT3, OCT1, OCT2, organic anion transport proteins (OATP) 1B1 and OATP1B3, or bile salt extrusion protein (BSEP).

1. Interactions between drugs metabolized by hepatic microsomal enzymes

(1) CYP2B6 and CYP3A substrates

may reduce the plasma concentration and efficacy of substrate drugs. Consider increasing the dosage of substrate drugs if necessary.

(2)CYP2C19 substrates

It may increase the plasma concentration of the substrate drug, thereby increasing the risk of adverse reactions. If adverse reactions are observed, consider reducing the dose of the substrate drug if clinically appropriate.

2. Drugs that shorten the QT interval

Have potential additional effects on the QT interval; please be cautious when using them simultaneously.

3. Specific drugs

(1) Alcohol

may increase the risk of drowsiness and sedation, but no clinically important pharmacokinetic effects have been observed.

(2) Bupropion

The peak concentration and AUC of bupropion are reduced by 23% and 39% respectively. Increase the dose of bupropion as needed.

(3) Carbamazepine

The peak concentration and AUC of carbamazepine are each reduced by 23%, and the dose of carbamazepine is increased when clinically appropriate.

(4) Clobazam

The plasma concentration of desmethylclobazam (the active metabolite of clobazam) increases. Consider reducing the dose of clobazam.

(5) Central nervous system depressants

May increase the risk of adverse neurological reactions, including drowsiness and sedation.

(6) Lacosamide

No clinically important effects on lacosamide pharmacokinetics were observed.

(7) Lamotrigine

The concentration of lamotrigine is expected to decrease by 21-52%, which may have a superimposed effect of shortening the QT interval. The dose of lamotrigine should be increased when clinically appropriate, and caution should be used in combination.

(8)Levetiracetam

No clinically important effects on the pharmacokinetics of levetiracetam have been observed.

(9) Midazolam

The peak concentration and AUC of midazolam were reduced by 61% and 72% respectively. Increase the dose of midazolam as needed.

(10) Omeprazole

The peak concentration and AUC of omeprazole increased by 83% and 107% respectively. If adverse reactions occur, the dose of omeprazole should be reduced if clinically appropriate.

(11) Oral contraceptives

May reduce oral contraceptive concentration and efficacy, use additional or alternative non-hormonal contraceptive measures.

(12)Oxcarbazepine

The possibility of interaction is low.

(13) Phenobarbital

The peak concentration and AUC of phenobarbital increased by 34% and 37% respectively. Consider reducing the phenobarbital dose under clinically appropriate circumstances.

(14) Phenytoin

The peak concentration and AUC of phenytoin increased by 70% and 84% respectively; the exposure of cinopamine decreased by 27-28%, and the phenytoin dose was gradually reduced (up to 50%) when titrating cinopamine.

(15) Primidone

It may have the additive effect of shortening the QT interval, so caution should be used in combination.

(16) Rufinamide

It may have the additive effect of shortening the QT interval, so caution should be used in combination.

(17) Valproic acid

Has no effect on valproic acid pharmacokinetics.

‌The mechanism of action of cenobamate‌

The anti-epileptic mechanism is not yet clear, but it may be through: inhibiting voltage-gated sodium currents and reducing repetitive neuronal discharges; acting as a positive allosteric regulator of γ-aminobutyric acid (GABAA) ion channels.

‌How to store cenobamate

‌Storage conditions for tablets‌ are 25°C (15-30°C fluctuation is allowed).