​The correlation between new antiepileptic drugs and drug-induced liver injury: a real-world study from the FDA's adverse event reporting system

Antiepileptic drugs (ASMs) treatment increases the risk of drug-induced liver injury (DILI) in patients with epilepsy, especially traditional antiepileptic drugs.

In an article published in the journal Epilepsy & Behavior, Brad K.
Kamitaki, a scholar from the United States, tried to quantify the report of drug-induced liver injury caused by traditional and new anti-epileptic drugs, and explored the relationship between new anti-epileptic drugs and drug-induced liver injury.
Correlation.

Research Introduction Among the more than 45 million patients with active epilepsy worldwide, most of them require long-term use of anti-epileptic drugs to control their seizures.

A variety of antiepileptic drugs are hepatotoxic and can cause specific drug-induced liver damage.

A large cohort study estimates that up to 10% of patients diagnosed with drug-induced liver injury will develop acute liver failure, require liver transplantation in severe cases, and even die.

Researchers checked the recent FDA adverse event reporting system data to confirm the correlation between new anti-epileptic drugs and drug-induced liver injury.

The researchers calculated the reported odds ratio (ROR) and 95% confidence interval (CI) of each drug-related liver injury associated with a single anti-epileptic drug relative to all non-anti-epileptic drugs.

Research results ➤ From July 2018 to March 2020, the FDA adverse event reporting system reported a total of 2,673,081 independent adverse events.
The number of reported drug-induced liver injury was 45,097 (1.
7%), of which 2,175 were drug-induced liver injury The cases were attributed to anti-epileptic drugs (4.
8% of all drug-induced liver injury reports).Of the 2,175 cases of antiepileptic drug-related drug-induced liver injury, 97.
2% were "serious" reactions: death (262) disability (26) hospitalization (1,232) life-threatening reactions (248) congenital abnormalities or birth defects (4) And other serious reactions (1,475) ➤ Anti-epileptic drugs such as carbamazepine, phenobarbital, oxcarbazepine, phenytoin, valproic acid, lamotrigine, clobazan, levetiracetam, and diazepam, The incidence of drug-induced liver injury is higher than that of non-antiepileptic drugs (see Table 1).

Among them, oxcarbazepine, lamotrigine and levetiracetam three new anti-epileptic drugs are significantly related to drug-induced liver injury.

Most new anti-epileptic drugs such as topiramate have not increased the chance of drug-induced liver injury (see Figure 1).

 Table 1 Antiepileptic drug-induced liver injury event counts and related report odds ratio (ROR) in the FDA adverse event reporting system database from July 2018 to March 2020 Figure 1 Reported odds ratio (ROR) value of drug-induced liver injury Note : The ROR of liver injury induced by Biaohong drugs is greater than 1.

ROR: represents the ratio of the odds of an adverse event of a particular drug or drug category to the same adverse event reported for all other drugs.

For example, a ROR of 1 for certain antiepileptic drugs (ASMs) means that ASMs and all non-ASMs have an equal probability of drug-induced liver injury.

 Research conclusions The study found that carbamazepine (ROR 2.
92), phenobarbital (ROR 2.
91), phenytoin (ROR 2.
40) and valproic acid (ROR 2.
22), traditional antiepileptic drugs, have the highest risk of drug-induced liver injury.

The new anti-epileptic drugs oxcarbazepine, levetiracetam, and lamotrigine are also significantly associated with a higher incidence of drug-induced liver injury.

Oxcarbazepine (ROR 2.
58) ranks third in ROR in this study, and its structural analogue carbamazepine causes a similar proportion of drug-induced liver damage.Lamotrigine (ROR 2.
06) can induce Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) and drug eruption with eosinophilia and systemic symptoms (DRESS), all of which can further develop into liver failure /Multiple organ failure.

Levetiracetam (ROR 1.
56), commonly used in patients with liver disease or a previous diagnosis of DRESS, is also associated with rare drug-induced liver injury.

The study confirmed that carbamazepine, phenobarbital, oxcarbazepine, phenytoin, valproic acid, lamotrigine, and levetiracetam are associated with a relatively high incidence of liver toxicity.

Most new anti-epileptic drugs such as topiramate have no significant correlation with liver toxicity.

 References: KamitakiBK, et al.
Drug-induced liver injury associated with antiseizure medications from the FDA Adverse Event Reporting System(FAERS).
Epilepsy Behav.
2021 Apr;117:107832.