Cutaneous allergic drug reactions: update on pathophysiology,diagnostic procedures and differential diagnosic

Important changes in the understanding and management of drug hypersensitivity reactions during the last years result from the increasing importance of biologics in medical practice, which differ in their spectrum of adverse drug reactions (ADRs) from the classical covalent drugs. With regard to covalent drugs, ampicillin and amoxicillin as well as clavulanic acid play an increasing role among ADRs to betalactam antibiotics. Fluoroquinolones are mainly the cause of anaphylactic and photosensitivity reactions. Especially in allergic reactions to NSAIDs, pseudoallergic reactions should be considered in the differential diagnosis. In opposite to the main cutaneous allergic drug reactions such as urticaria or maculopapular skin rash, in which antibiotics are the main culprits, in severe drug allergic reactions such as SJS (Stevens-Johnson Syndrome), TEN (Toxic Epidermal Necrolysis), or DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) Syndrome, compounds like allopurinol and anticonvulsants are the main causes. Similar mutations in the IL36R gene, which were found in both patients with an AGEP (Acute Generalized Exanthematous Pustulosis) and pustular psoriasis, make the differential diagnosis more difficult and raise the question whether there is a difference between these diseases or whether AGEP is not just a drug induced pustular psoriasis. Finally, some special aspects of side effects of biologics and targeted therapies respectively are discussed.     

Toxic Epidermal Necrolysis induced by rarely implicated drugs

Toxic Epidermal Necrolysis (TEN) and Steven-Johnson Syndrome (SJS) are serious disorders commonly caused as idiosyncratic reactions to drugs, the most common ones being oxicams, anticonvulsants, allopurinol, and sulfonamides. We present a case of TEN in a patient who developed the lesions after ingesting multiple drugs including paracetamol, metoclopramide, antihistamines, and multivitamins. These drugs have rarely been implicated in this disorder. The suspected drugs in this case were paracetamol and metoclopramide. However, the role of other drugs could not be ruled out definitely. The patient was managed with antibiotics, corticosteroids, and parenteral fluids and recovered well.     

Utilization of hospital and outpatient care for adverse cutaneous reactions to medications

PURPOSE: To quantify hospitalizations, visits to office based physicians, hospital clinics and emergency departments with primary diagnoses of skin conditions that are often due to drug reaction. METHODS: I analyzed data from the National Hospital Discharge Summary (1997-2001), National Ambulatory Care Survey (1995-2000) and National Hospital Ambulatory Care Survey (1995-2000) to determine the number of hospitalizations and visits with primary diagnoses of skin conditions that are often attributed to drugs. Using statistical methods for surveys, I determined the demographic characteristics of patients with these diagnoses and compared them with patients seeking care for other reasons. RESULTS: In the United States, there are about 5000 hospitalizations each year with a primary diagnosis of erythema multiform, Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis, of which 35% are specifically ascribed to drugs. Annually, there are more than 100,000 outpatient visits for these diagnoses and about two million visits for immediate hypersensitivity reactions that may be due to drugs. Outpatient visits for drug eruptions and drug allergies that include a skin component exceed 500,000 annually. CONCLUSIONS: Skin conditions often attributed to drugs are frequent reasons for hospitalization and physician visits. Optimal care of the individual patients with these conditions requires careful attention to drugs as a possible cause.     

Hypersensitivity to lamotrigine and nonaromatic anticonvulsant drugs: a review

Lamotrigine and nonaromatic antiepileptic drugs (valproate, gabapentin, and topiramate) are associated with hypersensitivity reactions, mainly cutaneous eruptions. The underlying mechanisms of these manifestations are not yet completely understood. A cell-mediated pathogenic mechanism has been demonstrated in some cases on the basis of positive patch tests and/or lymphocyte transformation tests. Moreover, an in vitro lymphocyte toxicity assay, which exposes the patient's lymphocytes to arene oxides, has detected lymphocyte susceptibility to toxic metabolites in patients with hypersensitivity reactions to lamotrigine. Subjects with a history of mild hypersensitivity reactions and negative allergologic tests can be challenged with the suspected drugs. Challenge tests can also be useful to identify safe alternatives. Our study reports hypersensitivity reactions to lamotrigine and to nonaromatic antiepileptic drugs, especially those assessed by allergologic tests.     

Imatinib mesylate and dermatology part 2: a review of the cutaneous side effects of imatinib mesylate

Cutaneous reactions to imatinib are common and occur in 9.5% to 69% of patients depending on the series reported. Maculopapular eruptions, erythematous eruptions, edema, and periorbital edema are the most common adverse events observed. Imatinib can also induce severe skin eruptions and generalized skin eruptions. Toxic epidermal necrolysis and Stevens Johnson syndrome has been linked to the use of imatinib. Imatinib has caused acute generalized exanthematous pustulosis. Purpuric vasculitis and mycosis fungoides-like reactions has occurred after imatinib use. Rarer side effects include: hypopigmentation, lichenoid reactions, pityriasiform eruptions, pityriasis rosea, psoriasis, reactivation or induction of porphyria cutanea tarda, neutrophilic eccrine hidradenitis, Sweet's syndrome, erythema nodosum, EBV-positive cutaneous B-cell lymphoproliferative disease, possible induction of squamous cell, hyaline cell syringomas, follicular mucinosis, pseudolymphoma-type drug eruptions, and malpighian epitheliomas. Most cutaneous eruptions caused by imatinib do not necessitate discontinuance of imatinib and are usually self limited, despite continued treatment. Administration of oral or topical corticosteroids can ameliorate some of imatinib's cutaneous side effects.     

Adverse reactions of Topiramate and Lamotrigine in children

PURPOSE: To review the adverse drug reactions (ADRs) of Topiramate and Lamotrigine among children in Israel, and to compare the two drugs, based on their side effect profile and tolerability among this population. METHODS: We performed a cross-sectional study. Four paediatric neurologists from three different tertiary medical centres in Israel documented all cases of children from birth to the age 18 years, treated with Topiramate and/or Lamotrigine in their respective outpatient clinics and hospital wards. All present ADRs and their characteristics were recorded. RESULTS: Reports on 45 and 65 children treated with Topiramate and Lamotrigine respectively, were received. Half of the children treated with Topiramate suffered from one or more ADRs, as opposed to one-third of the children treated with Lamotrigine (p = 0.03). Most reactions were considered mild to moderate. There were no deaths or hospitalisations, but the drug had to be discontinued in about 10% of the patients due to ADRs. Most Topiramate and Lamotrigine ADRs appeared early in the treatment and were more frequent when Topiramate was an add-on versus a monotherapy drug. Most ADRs of both Topiramate and Lamotrigine were related to the central nervous system; while poor appetite, drowsiness, speech difficulties and weight loss were observed only with Topiramate, and rash and headaches only with Lamotrigine. Nervousness and seizure aggravation were more frequent ADRs of Topiramate whereas sleep disturbances were observed more in children treated with Lamotrigine. CONCLUSION: Results of this study indicate that Lamotrigine causes ADRs less frequently than Topiramate; however both medications are generally well tolerated. Topiramate and Lamotrigine differ in their central nervous system side effect profile.     

A comparative study of vigabatrin vs. carbamazepine in monotherapy of newly diagnosed partial seizures in children

Carbamazepine (CBZ) is a drug of choice for the treatment of simple or complex partial seizures and secondary generalized seizures in adults and children. Vigabatrin (VGB) is a relatively new second line antiepileptic drug and was first registered for use in Poland more than ten years ago. Few reports have been published on the comparison of efficacy of VGB in children with epilepsy. The objective of this study is to evaluate the safety, efficacy and EEG effects of initial VGB monotherapy compared with initial CBZ monotherapy in children with newly diagnosed epilepsy. We present results of a prospective, outpatient and open study carried out in the University Hospital Center in Bia?ystok. Twenty-six children with partial epilepsy treated with VGB and 28 patients treated with CBZ were studied. The evaluation of the efficacy of the two drugs did not reveal any significant differences. Very good (reduction > 75%) seizure control was achieved in 22 out of 26 patients (84.6%) in the VGB group. One patient had a 50-75% decrease of seizures (good effect), similarly one child had a 25-50% reduction of seizures (mild effect). In two patients, we observed increased seizures (myoclonic jerks). Very good seizure control was achieved in 17 out of 28 patients (60.7%) in the CBZ group. Good seizure control was achieved in 5 out of 28 patients (17.8%) and mild control was seen in two children. No improvement was observed in 4 (14%) of the patients. The EEG background activity was improved in VGB-treated patients. No effect on the EEG background activity was observed in CBZ-treated children. VGB seems to be a safe and effective antiepileptic drug as primary monotherapy for epilepsy in children with similar proportion of side effects as CBZ.     

Carbamazepine-induced hepato-splenomegaly with erythematous rashes in a child

Carbamazepine is an antiepileptic drug. In clinical trials the total incidence of reported adverse reaction to this drug is 4.5 per million at defined daily doses, corresponding to 2.7 per million at prescribed daily doses. Among the adverse reactions of carbamazepine, most often reported are skin reactions (48%), hematological (14%), hepatic disorder (10%). Herein, we present a case with erythematous skin rashes and hepato-splenomegaly.     

Lamotrigine drug interactions in combination therapy and the influence of therapeutic drug monitoring on clinical outcomes in paediatric patients

The aim was to study the impact of therapeutic drug monitoring (TDM) on paediatric patients on lamotrigine therapy and the evaluation of possible drug interactions, especially in triple antiepileptic drug combinations. During the period of 2001‐2015, 1308 pre‐dose samples were taken from 430 patients <15 years of age as part of routine TDM. Drug interactions were evaluated using calculation of lamotrigine clearance. Valproic acid decreased lamotrigine clearance by 54% in bitherapy, and by 21% in triple therapy with carbamazepine. Carbamazepine increased lamotrigine clearance by 191% in bitherapy. Levetiracetam and topiramate had no effect. The upper limit of lamotrigine therapeutic range (TR) was exceeded in 2% of cases in monotherapy, and in 6%‐7% of cases in bi‐ or triple therapy. About 61% of plasma levels were found within the TR during 2001‐2005, compared to 75% and 74% during 2006‐2010 and 2011‐2015, respectively. Adverse drug reactions (ADRs) were reported in 22 cases. Higher number of supratherapeutic levels in combination therapy led to a 3‐fold increase in incidence of ADRs. Seizures occurred more often daily and monthly during 2001‐2005 and in patients with three or four antiepileptic drugs in combination. Carbamazepine only partially compensated for the inhibitory effect of valproic acid. Lamotrigine clearance in monotherapy in children is similar to adults, but in polytherapy was found higher susceptibility to induction. A significantly higher number of supratherapeutic lamotrigine levels were found in combinations with valproate. Despite poor correlation with TR, both seizure frequency and ADRs declined after the implementation of TDM.     

119例重症药疹的回顾性分析

目的：探讨重症药疹的临床特点、常见致敏药物及治疗,为临床安全用药,减少重症药疹发生提供参考。方法：对华山医院2006年1月-2012年12月收治的119例重症药疹患者的临床资料进行回顾性分析。结果：致敏药物类别以抗菌药物最多见（43例,30．1％）,最易引起重症药疹的两种药物为卡马西平（32例,26．9％）和别嘌呤醇（23例,19．3％）;药疹类型中,重症多形性红斑型为最常见的重症药疹;中毒性表皮坏死松解型为最凶险的类型,死亡2例,死因均为呼吸衰竭。结论：对易致重症药疹的药物临床使用中应加强药学监护,发现异常及时停药,并早期、足量使用糖皮质激素,控制并发症的发生。     

Risk-benefit assessment of carbamazepine in children

Carbamazepine is an effective antiepileptic drug for the treatment of partial and convulsive generalised epilepsy in adults and children. The pharmacokinetic profile in children is similar to that in adults, but the half-life in long term paediatric therapy is between 6 and 12 hours, compared with 15 hours in adults. Autoinduction is present. The most common adverse effects are neurological and dose-related, and occur in up to 50% of patients treated, usually on dosage initiation or dose elevation. Most dissipate over time and require no alteration in dosage. Idiosyncratic effects include hypersensitivity, hepatic and haematological reactions. A benign leucopenia occurs in 10 to 12% of adults and children and appears to be unrelated to aplastic anaemia which occurs in approximately 1 in 575,000 treated patients per year. Carbamazepine is reported to have cognitive and behavioural advantages over other antiepileptic drugs. Overall, carbamazepine has become a major antiepileptic drug in children as well as adults.     

New antiepileptic drugs: review on drug interactions.

During the Past decade, nine new antiepileptic drugs (AEDs) namely, Felbamate, Gabapentin, Levetiracetam, Lamotrigine, Oxcarbazepine, Tiagabine, Topiramate, Vigabatrin and Zonisamide have been marketed worldwide. The introduction of these drugs increased appreciably the number of therapeutic combinations used in the treatment of epilepsy and with it, the risk of drug interactions. In general, these newer antiepileptic drugs exhibit a lower potential for drug interactions than the classic AEDs, like phenytoin, carbamazepine and valproic acid, mostly because of their pharmacokinetic characteristics. For example, vigabatrin, levetiracetam and gabapentin, exhibit few or no interactions with other AEDs. Felbamate, tiagabine, topiramate and zonisamide are sensitive to induction by known anticonvulsants with inducing effects but are less vulnerable to inhibition by common drug inhibitors. Felbamate, topiramate and oxcarbazepine are mild inducers and may affect the disposition of oral contraceptives with a risk of failure of contraception. These drugs also inhibit CYP2C19 and may affect the disposition of phenytoin. Lamotrigine is eliminated mostly by glucuronidation and is susceptible to inhibition by valproic acid and induction by classic AEDs such as phenytoin, carbamazepine, phenobarbital and primidone.     

Toxic epidermal necrolysis and fluoxetine: a case report

Toxic epidermal necrolysis (TEN) is a distinct clinical entity within a spectrum of adverse cutaneous drug reactions. It is characterized by >30% of the body surface area of skin detachment with an average reported mortality of 25-35%. Drug induced TEN is associated with various antibiotics, anticonvulsants and other drugs. While adverse cutaneous drug reactions are common with antidepressants, the majority eruptions are benign and easily treated. TEN is rarely reported in association with selective serotonin reuptake inhibitors (SSRI's). We describe TEN in a 34-year-old patient from Mozambique associated with the addition of fluoxetine for a major depressive episode with psychotic features.     

Lamotrigine and Stevens-Johnson Syndrome Prevention

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.     

Treatment of partial seizures in childhood : an overview

The treatment of partial seizures in children is based on the use of first generation and recently introduced antiepileptic drugs as well as nonpharmacological treatments such as the ketogenic diet, vagus nerve stimulation and surgical therapy. The present review discusses the efficacy and tolerability of different treatment options for partial seizures in childhood. Few adjunctive or monotherapy, placebo-controlled or comparative trials of the first-generation antiepileptic drugs and some of the more recently introduced antiepileptic drugs have been performed in children. This can be explained by the fact that it is only relatively recently (1989) that the International League against Epilepsy proposed that randomised, controlled trials be included among the required criteria for assessing the efficacy and tolerability of an antiepileptic agent. This led to controlled, comparative trials among older antiepileptic drugs (phenobarbital, phenytoin, carbamazepine and valproic acid), both in adults and in paediatric patients, being performed relatively 'late', based on when these drugs were first introduced. Carbamazepine and valproic acid may still be considered as first-line antiepileptic therapies for children with partial seizures. Phenobarbital and phenytoin are mostly considered as last choice drugs because of their adverse event profiles. The new generation of antiepileptic agents has added to the first- and second-line treatment options for paediatric partial seizures. To date, there are sufficient data to support the clinical use of some of the recently introduced antiepileptic drugs (e.g. oxcarbazepine, topiramate, gabapentin and lamotrigine) as adjunctive or first-line monotherapy. Because of the risk of visual field constriction with vigabatrin, the use of this drug is currently limited to patients refractory to other medications. Tiagabine, felbamate, levetiracetam and zonisamide have been shown to be effective in adults with partial seizures; however, at present there are not yet enough data on the efficacy of these drugs in children to support consideration of their use as either first-line or add-on therapy in this patient population, although controlled studies are expected shortly. Furthermore, the use of felbamate is considerably limited by rare, but severe, hepatic and haematological toxicity. Controlled trials for paediatric partial seizures are still lacking for the ketogenic diet and vagus nerve stimulation, though they may represent, in given patients, useful adjunctive alternative treatments for refractory partial seizures. In conclusion, further trials are needed to determine an optimal sequence of first- and second-line therapies and to establish whether other newer antiepileptic drugs merit consideration as initial therapy in children with partial seizures.     

Levetiracetam: a novel antiepileptic drug.

Levetiracetam is a new antiepileptic drug, structurally and mechanistically dissimilar to other marketed antiepileptic drugs. It is effective in reducing partial seizures in patients with epilepsy, both as adjunctive treatment and as monotherapy. Levetiracetam has many therapeutic advantages for patients with epilepsy. It has favorable pharmacokinetic characteristics (good bioavailability, linear pharmacokinetics, insignificant protein binding, lack of hepatic metabolism, and rapid achievement of steady-state concentrations) and a low potential for drug interactions. Recommended starting dosages are considered to be clinically effective; therefore, patients can have some protection from seizures soon after they begin levetiracetam. The most common adverse effects observed with levetiracetam are mild and include somnolence, asthenia, and dizziness. Clinical experience and data from meta-analyses indicate that levetiracetam is well tolerated, with efficacy comparable or slightly better than that observed with other new antiepileptic drugs. Levetiracetam may be particularly useful in patients who are unresponsive to other antiepileptic drugs, patients receiving drugs with increased potential for drug interactions, or those with hepatic impairment.     

Newer antiepileptic drugs in bipolar disorder: rationale for use and role in therapy

Antiepileptic drugs (AEDS) are used regularly in the treatment of patients with bipolar disorders. Carbamazepine and valproic acid (sodium valproate) are effective as antimanic treatments, and the success of these medications has prompted investigation of other AEDs as possible treatments in patients with mood disorders. Lamotrigine appears to be the most promising of the newer AEDs with respect to effects in mood disorders. Current evidence suggests efficacy of this drug both as monotherapy and as an adjunctive agent in bipolar depression, and studies are underway to clarify its efficacy in mood stabilisation and rapid cycling, as currently available data are equivocal. Use of gabapentin is not as well supported in the literature, although data from open trials using it as an adjunctive agent suggest that it may be helpful in patients with bipolar depression. There have been some open trials and case reports supporting the use of topiramate as an adjunctive agent for the treatment of mania; however, data from controlled trials are not yet available. Further controlled trials of lamotrigine, gabapentin or topiramate as monotherapy and adjunctive treatment are needed to clarify their potential roles in the treatment of patients with mood disorders.     

Population pharmacokinetics of lamotrigine adjunctive therapy in adults with epilepsy

Plasma concentrations of lamotrigine, an antiepileptic drug obtained in three adult controlled clinical trials conducted in the United States were pooled and analyzed using NONMEM, a population pharmacokinetic computer program, to facilitate development of dosing guidelines. A total of 2,407 lamotrigine plasma concentrations from 527 patients with epilepsy were analyzed. Regression equations for oral clearance were developed as a function of body size, age (18-64 years), gender, race, and use of concomitant antiepileptic drugs. The population mean apparent oral clearance of lamotrigine in adult patients receiving one concomitant enzyme-inducing antiepileptic drug and not valproic acid was estimated to be 1 mL/min/kg. Gender and age did not affect clearance significantly. On average, clearance was reduced by 25% in non-whites and increased by 13% in patients receiving more than one concomitant enzyme-inducing antiepileptic agent. Lamotrigine did not influence the disposition of phenytoin or carbamazepine. Dosing adjustments for lamotrigine in patients receiving concomitant enzyme-inducing antiepileptic drugs and not valproic acid should not be necessary for age, gender, or the number of concomitant enzyme-inducing antiepileptic drugs. Lamotrigine does not influence the dosing requirements for phenytoin or carbamazepine.     

Economic analysis of newer antiepileptic drugs

In the last 20 years, several second-generation antiepileptic drugs (AEDs) have been marketed. These newer drugs are expensive and have no established superiority over the first-generation compounds in terms of efficacy when used as monotherapy. A systematic review of economic studies dealing with the newer AEDs has been performed to put these drugs in a wider perspective. A number of economic analysis studies of second-generation AEDs have examined these compounds as monotherapy or adjunctive therapy. Almost all monotherapy studies showed newer AEDs as having similar effectiveness but significantly higher acquisition costs than first-generation drugs. The evidence from adjunctive therapy studies was more conflicting. Lamotrigine appeared to be a cost-effective drug when higher thresholds were used, or when savings were defined by the cost of surgery. Levetiracetam also appeared to be cost effective when the costs of surgical investigation were discounted.In a decision model that included quantification of the uncertainty associated with the decision regarding the cost effectiveness of AEDs, second-generation drugs used as monotherapy for newly diagnosed partial epilepsy produced similar benefits but were more expensive than older drugs. The newer AEDs were more effective but more expensive than existing monotherapies in patients with refractory partial epilepsy, but may be cost effective at higher thresholds, and continue to be cost effective in patients responding to the assigned drug. In patients with newly diagnosed generalized epilepsy, valproate was more cost effective than lamotrigine.The results of current economic studies are difficult to assess and compare because of a number of methodological drawbacks. Future studies should be implemented using a standardized approach to define the costs and outcomes of representative cohorts of patients with newly diagnosed epilepsy recruited from different countries and followed prospectively.     

The Use of Lamotrigine and Other Antiepileptic Drugs in Paediatric Patients at a Malaysian Hospital

Objective: (1) To determine the effect of lamotrigine add-on therapy on the seizure frequency and cost in paediatric patients. (2) To determine the prescribing pattern of other antiepileptic drugs (AEDs). Method: A retrospective study of medical records was carried out from October 2000 to June 2001 at the paediatric clinic, Hospital Pulau Pinang. Main outcome measure: Seizure frequency, cost of drug and types of AED prescribed. Results: A total of 209 medical records were retrieved during the study period. Lamotrigine (LTG) was prescribed in 29 patients as add-on therapy. In 18 patients, there was a significant reduction in seizure frequency after the addition of LTG. Approximately 70% experienced a reduction in seizure frequency of more than 50%. Side effects of LTG were considered mild and manageable. However, drug cost after the addition of LTG increased by 103%. In the remaining 180 patients, the most common AED prescribed was sodium valproate (VPA). Only 15% of the patients received combination therapy. Mean monthly cost of monotherapy was found to be RM 24.4 while monthly cost of combination therapy was RM 45.4 (1 Euro–RM 5.00). Conclusion: The majority of paediatric patients in the study are on AED monotherapy and only a small percentage was prescribed lamotrigine. The use of lamotrigine is associated with better seizure control but with an increase in drug cost.