Rhabdomyolysis associated with newer-generation anti-seizure medications (ASMs): a real-world retrospective and pharmacovigilance study

Abstract

Objective: Rhabdomyolysis is a potentially fatal adverse reaction mostly triggered by certain medications. Few real-world studies have shown a clear association between newer-generation anti-seizure medications (ASMs) and rhabdomyolysis. We sought to quantify the risk and evaluate the clinical features and management of rhabdomyolysis associated with newer-generation ASMs.Methods: Data were retrieved from the US FDA Adverse Event Reporting System database (FAERS) from 2018 to 2022 on newer-generation ASMs to identify rhabdomyolysis events, and disproportionality analyses were conducted by estimating the reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs). Furthermore, case reports from 2012 to 31 December 2022 on newer-generation ASMs-induced rhabdomyolysis were retrieved for retrospective analysis.Results: A total of 1,130 rhabdomyolysis reports from the FAERS database were considered. Levetiracetam had the greatest proportion and the highest positive signal values of rhabdomyolysis. The RORs (95% CIs) for newer-generation ASMs were, in descending order, levetiracetam 8.01 (7.26–8.84), lamotrigine 3.78 (3.25–4.40), oxcarbazepine 3.47 (2.53–4.75), pregabalin 2.75 (2.43–3.12), lacosamide 1.85 (1.29–2.65), topiramate 1.64 (1.25–2.15), and gabapentin 1.32 (1.13–1.55). Twenty-six case reports showed evidence of rhabdomyolysis, and levetiracetam (65.4%) was the most frequently reported agent. The median age was 32 years; typical initial symptoms included muscle weakness (34.8%), myalgia (34.8%), backache (17.4%), fatigue (13.0%) and leg pain (8.7%). The median time to onset of rhabdomyolysis was 2 days. All cases had elevated creatine phosphokinase (CPK), and some cases were accompanied by elevated creatinine (57.1%) and myoglobinuria (53.8%). Cessation of ASMs could lead to complete clinical remission. The median time for creatine phosphokinase (CPK) normalization was 8 days.Conclusion: This study identified 7 newer-generation ASMs with significant rhabdomyolysis reporting associations. Prescribers should be more aware of this risk and teach patients to recognize rhabdomyolysis signs/symptoms early.

Pregabalin-induced rhabdomyolysis: a case series and literature analysis

“…[12][13][14][15][16] By studying a new generation of antiepileptic drugrelated rhabdomyolysis cases, Deng et al found that rhabdomyolysis caused by the antiepileptic drug levetiracetam may be due to the presence of receptor SV2A protein in muscle fibres. 17 Intracellular calcium has a high affinity for pregabalin because of widespread distribution of the voltagedependent calcium channel a 2/d1 subunit in the brain and skeletal muscle. 18 The role of a 2/d1 subunits in the observed adverse effects of pregabalin treatment on skeletal muscle needs to be investigated in future research.…”

Brivaracetam-Associated Rhabdomyolysis Requiring Renal Replacement Therapy: A Case Report and Review of the Literature

“…Rhabdomyolysis is another serious adverse reaction that is linked to several newer-generation ASMs, including levetiracetam, pregabalin, lamotrigine, gabapentin, topiramate, oxcarbazepine and lacosamide [ 4 , 5 ]. Of the ASMs, levetiracetam has the largest number of published case reports describing its association with rhabdomyolysis [ 4 ].…”

“…Rhabdomyolysis is another serious adverse reaction that is linked to several newer-generation ASMs, including levetiracetam, pregabalin, lamotrigine, gabapentin, topiramate, oxcarbazepine and lacosamide [ 4 , 5 ]. Of the ASMs, levetiracetam has the largest number of published case reports describing its association with rhabdomyolysis [ 4 ]. A query in the FDA adverse events reporting system (FAERS) retrieved 923 reports of levetiracetam-associated rhabdomyolysis, 39 of which resulted in patient mortality [ 6 ].…”