Lamotrigine-associated rash: to rechallenge or not to rechallenge?

Abstract

The major burden of illness in bipolar disorder (BD) is in the depressive pole. Lamotrigine has been shown to be useful in the long-term prophylaxis of depressive episodes in BD. Current guidelines recommend discontinuing lamotrigine in patients who develop rash. Our objective in this paper is to review literature to identify possible predictors of serious vs. benign rash that might help guide clinical decision-making and recommend titration strategy for re-introduction of lamotrigine, if indicated. We performed a search of the literature between 1966 and July 2008 to investigate the phenomenon of lamotrigine-induced rash and rechallenge procedures. The search identified six reports, and we were able to identify another case series from reviewing the bibliography of all of the above papers. We reviewed all the papers of lamotrigine rash rechallenge that resulted from the literature search. These papers describe 44 cases of lamotrigine rechallenge. Currently, there are 39 reported cases in the literature of successful lamotrigine rechallenge after a rash and five cases with rash recurrence. There are some characteristics of the rash that can help identify serious cases from benign ones. In addition, very slow titration of lamotrigine is crucial to the reduction of rash recurrence rate. Several cases that develop benign rash on lamotrigine can be rechallenged without adverse consequences. We believe that lamotrigine rechallenge in bipolar depression is an under-utilized option in our clinical armamentarium, and further studies are needed to guide us in this area.

Risks and management of antiepileptic drug induced skin reactions in the adult out-patient setting

“…Several publications suggest, if LTG related cutaneous reaction is without red flag signs, it is safe to either treat through with or without antihistamine cover, or lower the dosage until resolution and rechallenge with slower titration regimen [29,42,43]. Serious adverse cutaneous reactions are rare, with only 0.3% of those with a rash requiring hospitalization.…”

Korean Medication Algorithm Project for Bipolar Disorder 2018 (KMAP-BP 2018): Fourth Revision

“…The KMAP-BP 2018 recommends reducing the dose of LMT when benign skin rashes develop, although treatment recommendations specify that LMT should be discontinued in patients who develop a rash, regardless of type and severity, unless the rash is clearly not drug related. 58) However, the incidence of serious rashes is rather low in patients with a mood disorder (0.08% in adult patients with monotherapy and 0.13% in adult patients with adjunctive therapy) when compared to patients with epilepsy (0.3% in adults patients with adjunctive therapy), 59) and there are several reports that LMT can be successfully reintroduced after emergence of a rash with a low dose and slow titration schedule. 58) Thus, the Korean experts recommended carefully continuing LMT at a reduced dose because of the risk of destabilizing symptoms and its unique role in the long-term prophylaxis of depressive episodes, although there have been no reliable data to support this recommendation until now.…”

Rechallenge of lamotrigine after development of rash

“…It typically occurs between day 5 and week 8 of LTG administration because of the delay required to activate the body's immune response; however there have been case reports of SJS developing after 6 months of LTG initiation 6-8. Patients who develop SJS or TEN may initially present as having flu-like symptoms followed by painful red or purple colored rashes characterized by widespread erythema, necrosis, and bullous detachment of the epidermis and mucous membranes 9. These classically develop in the face and upper torso and can take weeks to months of recovery time 9.…”

“…Patients who develop SJS or TEN may initially present as having flu-like symptoms followed by painful red or purple colored rashes characterized by widespread erythema, necrosis, and bullous detachment of the epidermis and mucous membranes 9. These classically develop in the face and upper torso and can take weeks to months of recovery time 9. Stevens-Johnson syndrome and TEN are associated with a mortality rate of up to 10% and 45%, respectively, because of sepsis 10.…”

“…Therefore, many patients end up being taken off LTG and not rechallenged despite its potential effectiveness. If a patient is rechallenged with LTG, it is recommended to wait at least 4 weeks, and the recommended starting dose ranges from 5 mg every 3 days to 12.5 mg daily 9,12,13. Although most case reports involving LTG rechallenge use a slower titration,14-17 this is not always followed in clinical practice.…”