Lamotrigine-Valproic Acid Interaction Leading to Stevens–Johnson Syndrome

Abstract

Lamotrigine (LTG) is currently indicated as adjunctive therapy for focal and generalized tonic-clonic seizures and for treatment of bipolar disorder and neuropathic pain. A common concern with LTG in children is the frequency of appearance of skin rash. The intensity of this adverse effect can vary from transient mild rash to Stevens–Johnson syndrome (SJS), which can be fatal mainly when LTG is coadministered with valproic acid (VPA). Hereby, we present the case of an 8-year-old boy who suffered from SJS and other complications two weeks after LTG was added to his VPA treatment in order to control his seizures. VPA is known to decrease LTG clearance via reduced glucuronidation. In this case, the minor elimination pathway of LTG would play a more important role, and the formation of an arene oxide metabolite would be enhanced. As this reactive metabolite is detoxified mainly by enzymatic reactions, involving microsomal epoxide hydrolase and/or GSH-S-transferases and these enzymes are polymorphically expressed in humans, arene oxide toxicity is increased when epoxide hydrolase or GSH-S-transferases is either defective or inhibited or a depletion of intracellular glutathione levels is taking place. VPA can cause inhibition of epoxide hydrolase enzymes and/or depletion of glutathione levels leading to adverse cutaneous reactions.

Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and Future Strategies

“…The most common AEs of lamotrigine seen in the study were pharyngitis and fever, common childhood ailments, and only three patients prematurely discontinued treatment due to AEs. However, lamotrigine is associated with the development of rash, common particularly in younger patients [ 31 ], which can progress, albeit rarely, into the serious and occasionally fatal Stevens-Johnson syndrome (Table 1 ) [ 43 ]. This risk can be reduced by the mandatory slow titration of lamotrigine (combination therapy starting dosage 0.3 mg/kg/day), which is even slower with valproate (starting dosage 0.15 mg/kg/day) due to the enzyme inhibition of valproate and consequent increase in lamotrigine levels (Table 1 ).…”

Whole-Exome Sequencing in Patients Affected by Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Reveals New Variants Potentially Contributing to the Phenotype

“…51 LTG is extensively metabolised via UGT1A4, leading to the formation of LTG-N-2 and LTG-N-5 glucuronide which may affect LTG levels. 52,53 Patient SJS-17, who was affected by TEN, took LTG combined with valproic acid (VPA); the concomitant administration of these drugs has been associated with increased LTG serum concentration. Furthermore, it leads to its decreased clearance due to glucuronidation inhibition.…”

“…Interestingly, several reports have supported the clinical evidence stating that a combination of LTG and VPA can increase susceptibility to SJS/TEN. 53,55,56 Regarding metoclopramide, we identified one patient (SJS-16) who had developed TEN after taking this drug. To date, few cases of metoclopramide-induced SJS/TEN have been reported.…”

Potential Pharmacokinetic Drug-Drug Interactions between Cannabinoids and Drugs Used for Chronic Pain

“…BioMed Research International metabolite, if not effectively detoxified, can result in cellular damage [109]. Skin injuries, Stevens-Johnson syndrome, and toxic epidermal necrolysis are all reported adverse events related to lamotrigine use [110], mainly when the drug is coadministered with valproic acid [111][112][113], a well-known inhibitor of the glucuronidation pathway. Cannabinoids can act inhibiting UGTs [114] in the same way valproic acid does.…”