Lamotrigine and Stevens-Johnson Syndrome Prevention

Abstract

Stevens-Johnson Syndrome (SJS) is a rare life-threatening condition characterized by severe mucocutaneous epidermal necrolysis and detachment of the epidermis. The condition centers around a delayed-type hypersensitivity reaction with a complex etiology stemming from a variety of causes. The number one cause is medication-related—common ones including sulfonamides, antiepileptics, allopurinol, and nonsteroidal anti-inflammatory drugs. Genetics also play a role as several human leukocyte antigen (HLA) genotypes within certain ethnic groups have been implicated in adverse reactions to specific drugs. HLAB*15:02 has been identified in the Chinese and others of Southeast Asian origin to increase susceptibility to lamotrigine and carbamazepine-induced SJS. Furthermore, patients of Japanese origin with HLAB*31:01 and Koreans with HLA-B*44:03 are also at increased risk of SJS after receiving the same two drugs. Of the antiepileptics, one most commonly associated with SJS is lamotrigine, a pre-synaptic voltage-gated sodium channel inhibitor. Lamotrigine is an antiepileptic drug of the phenyltriazine class that is indicated for the prevention of focal and generalized seizures in epileptic patients as well as monotherapy or adjunctive maintenance treatment for Bipolar disorder. The occurrence of SJS is not a rigid contraindication to lamotrigine reintroduction in the same patient. To facilitate this, manufacturers have developed a strict re-challenge dosing regimen to facilitate successful reintroduction of lamotrigine. In order to prevent the recurrence of SJS during a re-challenge, timing of re-dose and initial rash severity must be considered. Therefore, to prevent SJS recurrence, prime lamotrigine re-challenge patients are those with mild initial rash that has not occurred within the previous 4 weeks. The Federal Food and Drug Administration recommends the testing HLA subtypes for those associated with SJS prior to starting lamotrigine.

Introduction

Stevens-Johnson Syndrome (SJS) is a rare life-threatening condition characterized by severe mucocutaneous epidermal necrolysis and detachment of the epidermis.¹ The condition centers around a delayed-type hypersensitivity reaction with a complex etiology stemming from a variety of causes. The number one cause is medication-related—common ones including sulfonamides, antiepileptics, allopurinol, and nonsteroidal anti-inflammatory drugs (NSAIDs).^2,3 Other causes of SJS include infectious processes such as human immunodeficiency virus, herpesvirus, and Mycoplasma pneumoniae, and noninfectious processes such as systemic lupus erythematosus, radiotherapy, and collagen diseases.² Additionally, SJS is classified based on a spectrum. SJS is given for body surface area affected less than 10%, SJS/ toxic epidermal necrolysis (TEN) overlap for 10%–30%, and TEN for greater than 30%.¹ Genetics also play a role as several human leukocyte antigen (HLA) genotypes within certain ethnic groups have been implicated in adverse reactions to specific drugs.³

The pathophysiology of SJS is not completely understood, but it is identified by widespread keratinocyte apoptosis. Several mediators are thought to be involved in this cell-mediated, cytotoxic reaction with T lymphocytes and natural killer cells (NK cells) as a probable primary cause with the induction of apoptosis.¹ Other mediators include cytotoxic proteins such as Fas-Fas ligand, tumor necrosis factor alpha, and perforin-granzyme B, but recent studies indicated that granulysin may be the key mediator of keratinocyte destruction in the reaction.⁴ Studies have shown granulysin is the most highly expressed cytotoxic molecule found in blisters of patients with SJS, and the levels of granulysin found within blisters correlate with disease severity.⁴ The mechanism that causes the activation of cytotoxic T lymphocytes and NK cells to release molecules such as granulysin is a subject of debate. Some theories hypothesize that a drug or its metabolite are directly presented as an antigen to T lymphocyte receptors, and other theories suggest that the drug or its metabolite bind noncovalently to the major histocompatibility complex and alter the binding cleft, resulting in a self-peptide capable of T cell activation.⁴ In either case, activated lymphocytes and NK cells result in extensive full-thickness keratinocyte necrosis and subepidermal bullae.³

Early signs of SJS can be extremely difficult to diagnose, often leading to misdiagnoses and a delay in treatment. Many patients will present with nonspecific prodromal symptoms occurring 1 to 3 weeks after drug introduction.³ Mucosal lesions often present first and can include oral, respiratory, conjunctival, and genitourinary regions.³ These lesions typically begin as diffuse ill-defined erythematous macules with purpuric centers that progress to vesicles and bullae before sloughing off after days.⁵ Diagnosis is made by skin biopsy with findings of full-thickness dermal necrosis.¹ This acute phase of SJS usually lasts between 8–12 days and may result in large, painful areas of denuded skin that will begin to undergo re-epithelialization about 1 week after onset of symptoms and can take up to 3 weeks.^2,6 Different treatment modalities have been used with varying degrees of success including intravenous immunoglobulin, corticosteroids, cyclosporine, and plasmapheresis; however, the mainstay of SJS treatment centers around early recognition, immediate cessation of causative drug, supportive care, and early transport to the burn unit if needed.³ The overall mortality for SJS is less than 10% for SJS and between 30 to 50% for TEN.^2,6 The most common causes of death in patients with SJS include co-infection and respiratory failure.³ Long-term complications can be disabling, particularly ocular complications, and the development of adhesions and strictures throughout the gastrointestinal and urogenital tracts can occur.³ If the skin involvement is extensive, the patient should be admitted to an intensive care unit or burn unit if possible.⁷

SJS Epidemiology/Pathophysiology/Risk Factors/Presentation

Presentation

SJS first presents with a prodromal phase occurring within the first few weeks where patients experience fever, malaise, rhinorrhea, photophobia, and erythema.⁷ After the prodromal period, patients enter a period largely dominated by cutaneous manifestations with development of mucosal and cutaneous lesions easily removed with pressure to the skin. This condition is deemed the Nikolsky sign and is a hallmark sign of SJS.^2,8 In SJS, epidermal detachment involves less than 10% of the body.⁹ Mucosal lesions primarily involve the oropharynx, conjunctiva, genitals, and the gastrointestinal tract.¹⁰ Lesions are flat and atypical, developing on the trunk and then spreading to the extremities.¹¹ Blood studies of SJS presents with anemia and leukopenia, acting as poor predictors of prognosis. Long term complications include changes in pigmentation, skin scarring, visual impairment, periodontal disease, gastrointestinal complications, and vaginal and urethral stenosis.^12,13

SJS Epidemiology

The incidence differs by country of origin, age, and associated conditions. In US adults, the incidence of SJS per million individuals ranged from 8.6 to 9.7.¹³ The incidence in South Korea ranged from 3.96 to 5 cases per million with an increase in patients older than 70 years old.¹⁴ The most common primary diagnoses among patients who received a secondary diagnosis of SJS include HIV/AIDS and various subtypes of septicemia. Other linked conditions include active cancers, acute kidney disease, HIV, multiple myeloma, leukemia, non-Hodgkin’s lymphoma, mycoplasma infection, pneumonia, epilepsy, and lupus.¹⁵ In the United States, the average length of stay for individuals hospitalized with SJS was 10 days. The strongest predictor of length of stay correlated with the number of comorbid conditions. Additionally, there were strong racial disparities associated with SJS. Non-whites were shown to have higher rates of SJS with longer hospital stays and increased mortality. Asians and African Americans had the highest rates of SJS in the United States.¹³ In contrast to adults in the US, the incidence of SJS in children was roughly 5.3 cases per million children. Although there were racial disparities seen in the incidence of SJS in US adults, these disparities were not observed in children. Similarly, to US adults, a higher number of chronic conditions were associated with an increased incidence of SJS in children. The mortality rate of SJS in US children was 0%.¹⁵

Pathophysiology

Although the pathogenesis of SJS is not completely understood, there exists multiple mechanisms to explain the pathological process of the syndrome. One mechanism was based on HLA phenotypes. The binding of certain molecules to HLA peptides can result in an immune response that triggers SJS. Various pharmacological agents are able to bypass processing from an antigen presenting cell and bind to specific HLA molecules or T-cell receptors resulting in an immune response.¹⁶ Furthermore, it has been shown that certain drugs such as abacavir and carbamazepine can modify certain HLA peptides, resulting in increased presentation of self-peptides and autoimmune reaction.¹⁷ In the early phases of SJS, cytotoxic CD8+ T-cells and natural killer like cytotoxic T-cells are the predominant cell type that mediate keratinocyte destruction. In the later stages of the disease, monocytes dominate.¹⁸ However, some studies have shown the presence of CD14+ monocytes in the early stages of the syndrome may lead to enhanced CD8+ T-cell toxicity and proliferation.¹⁹ In addition to T-cell mediated cytotoxicity, keratinocyte destruction can be mediated by various components of the apoptotic pathway. The upregulation of FasL by cytotoxic mediators such as TNF-alpha have been linked to keratinocyte apoptosis.²⁰ Other components of the apoptotic pathway such as TRAIL and TNF-like weak inducer of apoptosis (TWEAK) have been found to contribute to keratinocyte apoptosis in SJS.²¹

Risk Factors

The risk of developing SJS increases with infection, malignancy, autoimmune disorders, drug use, and certain HLA phenotypes. Hypersensitivity reactions to certain drugs is the leading cause. Multiple drugs include but not limited to lamotrigine, nevirapine, phenytoin, and NSAIDs (more commonly celecoxib and ibuprofen).⁹ Lamotrigine has been the number one drug and carbamazepine as the second associated with SJS. Allopurinol when prescribed at dosages of 200 mg or above have been shown to increase the risk of SJS.²² Furthermore, the presence of certain HLA phenotypes may act as a trigger in combination with certain medications. In the Asian population, the HLA-B 15:02 allele has been linked to carbamazepine induced SJS.²³ Associations between the HLA-B 57:01 allele and abacavir were noted as well as between the HLA-B 58:01 allele and allopurinol.^24,25 Another strong risk factor includes the presence of chronic comorbid conditions such as HIV, mycoplasma infections, and tuberculosis.²⁶ Individuals with HIV have an 1000-fold increase in developing adverse skin reactions and progression to SJS.²⁷ The presence of underlying conditions may also lead to ocular manifestations and a more severe illness presentation.²⁸ Additional risk factors include female sex and non-white ethnicity.¹³

Medications and SJS

SJS is a rare but severe side effect of many commonly administered drugs. Usually, most SJS reactions occur within two months of initial administration of an offending medication although some cases of delayed reactions have occurred. Severe reactions like SJS most likely arise after a starting dose is given or when a medication has been increased. Therefore, to minimize the risk of SJS after receiving a medication, practitioners begin with a low starting dose and titrate the dose slowly.²⁹ It is also advised that the patient avoid skipping doses of medication to prevent reintroduction of a high starting dose and increasing the risk for SJS. It should be noted that even with the most strict administration precautions, SJS can still occur, especially in the case of a patient changing brands of medication.³⁰

Roujeau et al. identified an extensive list of drugs with increased risk of SJS that includes sulfonamide antibiotics, chlormezanone, aminopenicillins, quinolones, cephalosporins, carbamazepine, phenobarbital, phenytoin, valproic acid, NSAIDs, allopurinol, and corticosteroids.³¹ From this extensive list, antiepileptic drugs (AEDs) have consistently been identified as major triggers of SJS with more than double the cases associated with NSAIDs.^29,32,33 Of the AEDs, the three drugs regularly associated with the highest risk of SJS are carbamazepine, lamotrigine, and phenytoin while other antiepileptics such as levetiracetam, topiramate, and clonazepam have a much lower risk.³² It should be noted that one study has shown that AEDs that do not list SJS within the side effect profile are not void of risk. Patients receiving agents without an SJS warning such as lorazepam, diazepam, and clorazepate have been diagnosed with SJS.²⁹ While a strong correlation has formed between SJS and AEDs, no evidence has emerged to explain such association. Some researchers theorize that the arene oxide metabolites of antiepileptics are the most likely potentiators of side effects like SJS.³² A less common but increasingly becoming more prominent in medication induced SJS is acetaminophen. Numerous case reports of SJS are established with medications containing various forms of acetaminophen.^34–37 This finding has been concerning enough to formulate a FDA safety announcement to discuss the risk of acetaminophen in SJS related syndromes.

Certain genetic factors increase the likelihood of SJS in response to certain AEDs, particularly lamotrigine and carbamazepine. HLAB*15:02 has been identified in the Chinese and others of Southeast Asian origin to increase susceptibility to lamotrigine and carbamazepine-induced SJS. Furthermore, patients of Japanese origin with HLAB*31:01 and Koreans with HLA-B*44:03 are also at increased risk of SJS after receiving the same two drugs. This strong correlation between HLA phenotypes and SJS has led to a FDA black box warning that requires screening for HLAB*15:02 before prescribing these AEDs.^33,38 While the genetic correlation between HLA phenotypes and SJS is strong, there has been no evidence to connect SJS with certain disease-associated epigenetic links. This is evident in Bloom and Amber’s study which showed that the incidence of SJS following lamotrigine administration did not vary between different indications for AED use, such as seizure disorders and bipolar disorde.³³

Related to the high prevalence of SJS among AEDs and other common medications along with many unknown underlying causes, patients should be counseled on signs of SJS and proactive steps to prevent progression. The patient should be aware of the risks of taking an AED and instructed to stop administration if any rash occurs. A hypersensitivity morbilliform rash is the most common original presentation, and patients should understand the risk of progression to SJS. In the absence of rash progression or systemic symptoms, the AED can be resumed. In contrast, presence of systemic symptoms should increase the clinical suspicion for SJS. If SJS occurs in a patient, the offending agent should never be resumed, and the patient should consider wearing a medical alert bracelet to prevent re-administration of the drug.^7,39

Lamotrigine Drug Information

Lamotrigine is an antiepileptic drug of the phenyltriazine class that is indicated for the prevention of focal and generalized seizures in epileptic patients as well as monotherapy or adjunctive maintenance treatment for Bipolar disorder.⁴⁰ Lamotrigine has multiple mechanisms of action which result in its broad spectrum anti-seizure properties as well as its novel thymoleptic and psychotropic effects.⁴¹

Lamotrigine has been approved for adjunctive or monotherapy for focal onset (simple) seizures after conversion from valproate or a different antiepileptic drug. It is also approved for adjunctive therapy for primary generalized tonic-clonic seizures, generalized absence seizures, and treatment of Lennox- Gastaut syndrome.^41,42

The efficacy of lamotrigine in maintenance treatment of Bipolar I Disorder was determined in two multicenter, double-blind, placebo-controlled studies in adults who met DSM-IV criteria for Bipolar I Disorder.⁴⁰ These studies showed that lamotrigine was effective as maintenance treatment for bipolar depression, rapid cycling bipolar disorder, and treatment-resistant mood disorders.⁴¹ Unlike many of the older mood stabilizers, lamotrigine exerts its effects mainly on the prevention of depressive symptoms associated with Bipolar I disease has been shown to delay the time to occurrence of mood symptoms and is most beneficial in delaying the onset of new depressive symptoms.⁴³ Lamotrigine is not currently approved for the treatment of acute bipolar depression, however a meta-analysis and one placebo-controlled study suggest possible efficacy.⁴⁴

Common side effects of lamotrigine include dizziness, visual disturbances, ataxia, nausea or vomiting and non-serious rash.⁴⁵ Serious rash including SJS is a rare but potentially fatal drug reaction associated with lamotrigine that must be monitored.⁴⁰ When combined with other medications such as valproate sodium, the risk of this reaction is increased.⁴⁰ Oral contraceptives can increase the clearance of lamotrigine and result in increased seizures.⁴⁵

Mechanism of Action

The exact mechanism in which lamotrigine exerts anti-epileptic and mood stabilizing effects is not entirely known. The anti-epileptic effects of lamotrigine are thought to be due to use-dependent blockade of neuronal voltage gated sodium channels.⁴¹ This blockade results in the stabilization of neuronal membranes and inhibition of presynaptic glutamate release, resulting in seizure prophylaxis.^40,43 This blockade occurs only during seizure activity, which is clinically beneficial in reducing the side effect profile outside of seizure activity.⁴¹ It is unknown why lamotrigine has more broad-spectrum anti-seizure activity than other sodium channel blockers such as phenytoin.

Lamotrigine also enhances the release of inhibitory gamma-aminobutyric acid (GABA), which further attenuates the overexcitability that leads to seizure activity.⁴³ The GABAergic effects of lamotrigine are not particularly robust; however, the enhancement of GABAergic transmission is not use-dependent, and therefore occurs outside of seizure activity and may contribute to some of the psychotropic effects.⁴¹ Lamotrigine shows weak calcium channel blockade compare to its effects on sodium channels, but this may be of interest in the use of calcium channel blockers in bipolar disorder.⁴¹ Other effects of lamotrigine include weak inhibitory effect of 5-HT₃ receptors as well as in vitro inhibition of dihydrofolate reductase.⁴² It is thought that lamotrigine may have anti-kindling effects, but studies in rats have shown variability, and it is unknown how these rat models relate to effects on epilepsy in humans.^40,41

Ion channel effects of lamotrigine contribute more importantly to anti-seizure effects and may be less important for thymoleptic effects.⁴¹ The exact mechanism in which lamotrigine acts as a mood stabilizer remains unclear, but its neuroprotective and antiglutamatergic effects are important candidates for the psychotropic effects.⁴¹ Although the varying mechanisms in which lamotrigine exerts effects overlap with many other anti-epileptic and mood stabilizing drugs, its novel clinical profile make it distinctive within these classes of medications.

Lamotrigine Pharmacokinetics/Pharmacodynamics

Many of the anti-epileptic effects of lamotrigine are due to its blockade of pre-synaptic voltage gated sodium channels. The blockade prevents the release of excitatory neurotransmitters such as glutamate which can contribute to seizure development.⁴⁶ Lamotrigine has a half-life of 24–40 hours and is 55% protein bound. The drug is metabolized in the liver and excreted by the kidneys. Hepatic enzyme inducers can decrease lamotrigine half-life to 14 hours.⁴⁷ Drugs such as phenobarbital, phenytoin, and carbamazepine have been shown to decrease the half-life of lamotrigine while drugs such as valproic acid have been shown to increase the half-life.⁴⁸ Lamotrigine is rapidly absorbed with a bioavailability of roughly 98%. The bioavailability of lamotrigine is equivalent between the tablet form taken with water and the chewable tablet which can be taken with or without water. Linear pharmacokinetics for lamotrigine have been demonstrated over the dose range of 50–400 mg.⁴⁹ The initial dose for adults is 12.5–25 mg/day. Maintenance dose is 200–600 mg/day typically divided into two dosages.⁴⁷ In healthy adults and patients with epilepsy, maximum plasma concentrations of the drug were achieved within 1 to 3 hours of oral administration when using these dosages. The mean volume of distribution of lamotrigine ranges from 0.9 to 1.3 L/kg following oral administration. The mean plasma clearance rate of lamotrigine is roughly .03 L/h/kg in healthy individuals.⁴⁹ There is no current reversal agent for lamotrigine, but in severe cases of overdose, gastric lavage and activated charcoal are indicated.⁵⁰

Lamotrigine Blackbox Warning

There are many adverse side effects associated with the use of lamotrigine. Side effects may include nausea or vomiting, irritability, visual disturbances, headaches, insomnia, dizziness, tremors, agitation, and conjunctivitis. More serious side effects of lamotrigine involve serious skin conditions such as Steven Johnson Syndrome, Toxic Epidermal Necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). These skin conditions are usually preceded with a rash, and many practitioners inform their patients to cease taking the drug if a rash develops. If a hypersensitivity rash develops without systemic symptoms after lamotrigine has been stopped, it may be safe to reestablish lamotrigine use. If the rash is accompanied by nonspecific flu-like symptoms such as a headache, a sore throat, GI symptoms, and a fever, a more serious side effect is likely the cause. In these situations, lamotrigine should not be retried.³⁰ In addition to these serious skin conditions, a new warning has been attached to the use of lamotrigine. In rare situations, this drug can cause an immune disorder known as hemophagocytic lymphohistiocytosis (HLH). In this disorder, the immune system becomes extremely overactive. This can lead to inflammation and internal damage involving the liver, kidneys, lungs, and blood cells. If patients develop persistent high fevers, signs of liver damage (jaundice, swelling in upper right abdomen), swollen lymph nodes, or nervous system problems (seizures, difficulty walking) after starting lamotrigine, HLH should be considered and diagnostic tests should be performed.⁵¹

HLA Phenotype Differences and Recommendations

Differences in HLA gene phenotypes and how they affect the development of various disease processes has been widely studied. Located on chromosome 6, they encode cell-surface antigen-presenting proteins and are responsible for regulating the immune system.⁵² Both HLA Class I and Class II genes display a high degree of allelic polymorphism, and the differential expression of alleles across global populations explains how different variants can be strongly associated with a disease state in one population but not in others.⁵³ Many genetic association studies have shown strong linkages between specific HLA alleles and cutaneous adverse drug reactions (cADRs). The spectrum of pathologies ranges from mild maculopapular exanthema (MPE) to life-threatening conditions such as drug reactions with eosinophilia and systemic symptoms (DRESS), SJS, and TEN.⁵³ Reactions such as SJS and TEN are a major cause of morbidity and mortality worldwide, pushing researchers to further study the role of genetics in these disease processes in order to come up with preventative and curative solutions.

The classic example is the association of HLA-B*1502 with carbamazepine (CBZ) induced SJS in the Han Chinese population. In 2004, Chung et al. studied 44 Han Chinese patients with CBZ induced SJS, including those with overlapping TEN, and found that the HLA-B*1502 was present in 100% of SJS/TEN cases.²³ Since this discovery, multiple other studies have corroborated this association not only in the Han Chinese population, but also in other populations including Thai, Vietnamese, and Malaysian populations.^23,52–54 Notably, the association is not seen in European and Japanese studies, which is predictable considering the relatively low frequency of the HLA-B*1502 allele within these populations.⁵³ It has been found that HLA-B*1502 does not appear to be linked to the milder pathology of MPE, and is therefore not a universal marker for the entire spectrum of AED-induced cADRS.⁵³ Due to the compelling evidence of the strong association of the HLA-B*1502 allele with CBZ induced SJS found in those of Asian descent, the United States Food and Drug Administration (FDA) mandated regulatory recommendations for genetic screening of the HLA-B*1502 biomarker prior to treatment with AEDs.⁵³ These recommendations have since been adopted worldwide, and have shown to be a cost-effective method for decreasing the incidence of AED associated cADRs as well as decreasing the morbidity and mortality associated with these conditions.⁵³

Small sample sizes have limited much of the research done on the associations between different HLA alleles with the newer AEDs, but current research and meta-analyses have worked to better define this gap. In 2018, a meta-analysis based off of data exclusively from Asian populations detected a significant association of HLA-B*1502 with lamotrigine induced SJS/TEN.⁵⁵ There was no significant association between HLA-B*1502 and the less severe spectrum disorder of MPE.⁵⁵ This study also showed a significant association between lamotrigine induced cADRs and HLA-A*2402, another highly studied allele in AED associated drug reactions.⁵⁵ This studied showed that HLA-A*2402 was a significant risk factor for lamotrigine induced SJS/TEN as well as the less severe MPE.⁵⁵ Another study showed that HLA-A*2402 is a common genetic risk factor in the Southern Han Chinese for cADRs induced by AEDs as a group, as well as the individual drugs carbamazepine and lamotrigine.⁵⁶ Because of this association, screening for HLA-A*2402 in Southern China may be considered in addition to screening for HLA-B*1502 prior to the initiation of AEDs.⁵⁶ Related to the small sample sizes, a much larger sample is needed to adequately characterize and confirm these associations with the newer AEDs such as lamotrigine. Because of lamotrigine’s similar aromatic structure to carbamazepine, caution is advised in prescribing lamotrigine to those of Asian background.⁵⁷

Another highly studied allele in AED-induced cADRs is HLA-A*31:01. Two independent genome wide association studies (GWAS) studies published in 2011 established the association of HLA-A*31:01 with a spectrum of CBZ-induced cADRs. In McCormack et al., the association between HLA-A*31:01 and CBZ-induced MPE, SJS, and TEN was established within the European population.⁵⁸ Similar findings were found in the Japanese GWAS publication, confirming the association of HLA-A*31:01 with a variety of cutaneous adverse drug pathologies among different ethnicities.⁵⁹ Corroborating studies from the Han Chinese and various other studies confirmed the strong association with HLA-A*31:01 and CBZ- induced DRESS and/or MPE but not for SJS/TEN.⁶⁰ There has been a lack of significant evidence to show the association of HLA-A*31:01 and AED-induced cADRs with AEDs other than CBZ.⁵³ Currently, there is no FDA mandated recommendation for HLA-A*31:01 genetic screening. However, the FDA has approved carbamazepine label and acknowledged the moderate risk association with the allele and cADRs.⁵³

Since these studies, many different populations have conducted research and have found many more HLA alleles associated with AED induced cADRs within their populations. Despite the many advances, researchers have made in the discovery of specific alleles, research with larger sample sizes across different ethnicities and the establishment of better screening tests is needed in order to improve recommendations and mandates for physicians in the treatment of patients requiring these drugs.

Lamotrigine, SJS: Possible Causes and Prevention

It is well known that many AEDs, especially phenytoin, lamotrigine, and carbamazepine, are associated with severe side effects such as SJS. Table 1 provides an summary of possible causes and prevention of SJS with Lamotrigine. The incidence of SJS associated with AEDs has been found to increase under certain circumstances. Many case reports have shown the administration of lamotrigine and valproic acid is often followed by new onset SJS. The classic patient case has usually received valproic acid for an extended period of time without adequate relief of neuropsychiatric symptoms. After adding lamotrigine to the valproic acid treatment regimen and gradually titrating the dose, many patients have developed the characteristic targetoid SJS skin lesions along with a morbilliform rash.^61–63 Valproic acid is thought to inhibit enzymatic activities that allow for the metabolism of lamotrigine.^62,63 More specifically, valproic acid is a well-known inhibitor of UDP-glucuronosyltransferases (UDPGTs), the main enzymes responsible for major pathway of lamotrigine metabolism. Without functioning UDPGTs, lamotrigine metabolism is shunted to a minor pathway involving CYP450 enzymes. Generation of arene oxide toxic metabolites via the CYP450 pathway are thought to initiate the SJS reaction via covalent binding to proteins, DNA, and RNA, therefore, mediating cell damage. Arene oxide metabolites are further processed into nontoxic forms via glutathione (GSH) and microsomal epoxide hydrolase (EPHX). Since these two enzymes are polymorphically expressed in humans, the arene oxide metabolites of lamotrigine can trigger SJS in patients with defective or non-functioning enzymes. Furthermore, in a similar mechanism, a depletion of glutathione can also initiate SJS. In addition to inhibiting UDPGTs as described above, valproic acid readily depletes glutathione as well, further increasing amount of harmful arene oxide metabolites.⁶²

In addition to affecting lamotrigine metabolism, the metabolism of valproic acid itself also plays a notable part in potentially triggering SJS. Valproic acid is processed by three pathways: glucuronidation (major), β-oxidation with L-carnitine, and ω-oxidation, with ω-oxidation contributing to the formation of another toxic metabolite, 4-en-VPA. Metabolism of valproic acid depletes L-carnitine via the β-oxidation pathway, and shunts a portion of metabolism to ω-oxidation, therefore adding another toxic metabolite to the arene oxides. In addition to producing another toxic metabolite, exhaustion of L-carnitine sources decreases the rate of valproic acid breakdown, leading to increased levels of valproic acid. This increased level of valproic acid allows for more inhibition of lamotrigine breakdown via UDPGTs as mentioned above and may increase the possibility of SJS.⁶²

Valproic acid is not the only agent shown to trigger SJS when given in combination with lamotrigine. In few studies when lamotrigine was added to an aripiprazole (antipsychotic) regimen, SJS ensued. Researchers have been unable to find an explanation since aripiprazole is not a CYP450 inhibitor, nor did patients have a previously identified food/drug allergy or recent viral illness. However, it is still of note to possibly proceed with caution if administering an antipsychotic and lamotrigine in combination.⁶⁴

Based on the above, multiple approaches can be implemented in order to decrease the likelihood of SJS during valproic acid and lamotrigine therapy. Searching for genetic polymorphisms in the GSH and EPHX genes that may indicate decreased or absent function of these enzymes is the most cumbersome method to prevent SJS. Even in the absence of undisputable polymorphisms, relatives should also be advised to avoid lamotrigine, due to an unidentified genetic link.⁷ Simpler approach involves supplementing patients taking valproic acid with depleted substances such as GSH or L-carnitine in order to facilitate lamotrigine or valproic acid metabolism, respectively. Finally, lamotrigine should be initiated at a lower starting dose and titrated more slowly when given with valproic acid.⁶⁴ All of these methods attempt to keep levels of lamotrigine and valproic acid low, since many toxic effects occur in excess concentrations.

The inhibitory interaction between valproic acid and lamotrigine should not be strictly viewed as a negative combination. There exist multiple clinical benefits of the interaction in a study of the pharmacokinetics of valproic acid and lamotrigine.⁶³ Valproic acid doses greater than 250 mg/day inhibit lamotrigine clearance by about 50% while a dose of 125 mg/day inhibits clearance by only 30%.⁶³ Understanding the specifics of this interaction allow for adequate dosing of lamotrigine when transitioning from valproic acid and lamotrigine polytherapy to lamotrigine-only monotherapy or vice versa. Furthermore, the inhibition that valproic acid provides can also assist in transitioning from polytherapy with an enzyme-inducing AED and lamotrigine therapy to lamotrigine-only monotherapy by opposing induction. Utilizing this information can allow practitioners to stabilize lamotrigine serum concentrations despite adjusting treatment regimens and thereby reduce the risk of associated SJS.⁶⁵

In addition to the above risk factors related to lamotrigine administration and the incidence of SJS, the age of the patient must also be taken into consideration. Guberman et. al found that children (classified as those under the age of 16) are at three times the risk of developing SJS after lamotrigine administration. The authors note that the increased incidence may be related to elevated starting doses and titration rates in children, along with the prevalence of coadministration of valproic acid. Since children are more likely to have elevated serum starting doses with the manufacturer’s recommended dose, dosing must be recalculated on a mg/kg basis in attempts to avoid the SJS reaction. Furthermore, the rates of SJS among children receiving lamotrigine and valproate polytherapy is greater than in adults. This suggests that coadministration with valproate should be avoided in younger patients.⁶⁶

Age is an important consideration in the administration of lamotrigine and subsequent risk of SJS. However, the search for risk factors that correlate to the progression of SJS to toxic epidermal necrolysis (TEN), a more severe form of SJS, has been difficult to establish. Two studies significantly disagreed on the relationship between age and sex of patients and the incidence of SJS vs TEN; each study found an exact opposite relationship from the other. In contrast, both studies agreed that there is no relationship between incidence of SJS or TEN and the lamotrigine dosage at onset or time to onset.^67,68 The Wang et al. study also noted no difference in SJS and TEN incidence and the number of total number of administered drugs at onset.⁶⁷ With conflicting information from these studies and the absence of any clear relationships in either, it is reasonable to conclude that factors such as sex, dosage at onset, time to onset, and total number of administered drugs at onset cannot predict if the rash is more likely to progress to SJS or TEN. As mentioned above, younger age is correlated with increased incidence of SJS, but other studies have failed to establish if SJS or TEN is the more likely final manifestation of the rash.^66–68 Therefore, there are no identified causative or preventative factors that can adequately predict the degree of rash progression after lamotrigine therapy.

After making the diagnosis of SJS, lamotrigine therapy is usually discontinued while the rash is treated with supportive therapies.⁶⁹ However, the occurrence of SJS is not a rigid contraindication to lamotrigine reintroduction in the same patient. Most often, the main indication for lamotrigine therapy re-challenge is related to its ability to effectively manage neurological symptoms. To facilitate this, manufacturers have developed a strict re-challenge dosing regimen to facilitate successful reintroduction of lamotrigine. In fact, most patients in one 2010 study successfully endured lamotrigine re-challenge with no recurrent signs of SJS. However, it should not be ignored that in suboptimal candidates, reintroduction of lamotrigine or a closely related drug can retrigger severe SJS.⁷ In order to prevent the recurrence of SJS during a re-challenge, timing of re-dose and initial rash severity must be taken into account. Houser and Graham showed that re-challenge of lamotrigine within four weeks of initial SJS reaction increased the rate of rash recurrence from 4% to 37%. Furthermore, patients with more severe initial SJS rashes were more likely to have a subsequent SJS rash upon re-challenge. Therefore, to prevent SJS recurrence, prime lamotrigine re-challenge patients are those with mild initial rash that has not occurred within the previous 4 weeks.⁷⁰

Conclusion

SJS is a life-threatening, delayed-type hypersensitivity disease that is characterized by mucocutaneous epidermal necrolysis and detachment of the epidermis. Symptoms usually begin with a prodromal phase that manifests as flu-like symptoms of malaise, fever, rhinorrhea, etc. Patients then develop mucocutaneous rash with a positive Nikolsky sign that is characteristic of SJS. Although SJS is rare, it bears a significant mortality rate of about 10% and should be treated promptly with supportive therapies. Certain risk factors are correlated to an increased incidence of SJS. These include infection, malignancy, autoimmune disorders, drug use, and certain HLA phenotypes. The most common triggers for SJS are medications such as NSAIDS, allopurinol, certain classes of antibiotics, and antiepileptics. Of the antiepileptics, one most commonly associated with SJS is lamotrigine, a pre-synaptic voltage-gated sodium channel inhibitor. The increased incidence of lamotrigine associated SJS has led to an FDA Blackbox warning to alert physicians and patients to its potentially harmful side effects. Patients should be made aware of the initial signs of rash and advised to discontinue lamotrigine therapy, as an initial effort to prevent SJS. Severe reactions like SJS are more likely when lamotrigine is administered at an elevated starting dose, rapidly titrated, or administered with valproic acid. To minimize SJS risk, strict starting doses and titration schedules have been developed. Furthermore, younger patients should receive lamotrigine based on a mg/kg calculation instead of the adult dosing regimen to decrease incidence of SJS. Finally, patients can reattempt lamotrigine therapy after an SJS reaction if desired given that the initial reaction was mild and occurred no less than one month prior.

Table 1. Possible Causes and Prevention of SJS with Administration of Lamotrigine.

Possible Causes		Possible Prevention
Lamotrigine + Valproic acid administration		Understand degree of inhibition of various doses of valproic acid/lamotrigine monotherapy
Decreased activity of GSH and EPHX		Genetic screening for GSH and EPHX polymorphism
Depletion of GSH (caused by valproic acid or other agents)		GSH supplementation
Depletion of L-carnitine		Concomitant L-carninitine therapy with valproic acid administration
Aripiprazole (and possibly other antipsychotics)		Lamotrigine monotherapy
High starting dose and/or rapid titration		Low lamotrigine starting dose and slow titration
Administration of lamotrigine under the age of 16 years old		Consider delaying lamotrigine therapy until an older age
Failure to inform patients to stop drug therapy at first signs of rash		Cessation of drug at first signs of rash
Lamotrigine rechallenge within 4 weeks of an SJS reaction or after severe initial SJS rash		Lamotrigine rechallenge after 4 weeks if initial SJS rash was mild to moderate in severity
Failure to educate patient about possible genetic links between lamotrigine and SJS		Advise relatives of SJS patient to also avoid offending agent