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Risk of a lamotrigine-related skin rash: Current meta-analysis and postmarketing cohort analysis

Open ArchivePublished:December 22, 2014DOI:https://doi.org/10.1016/j.seizure.2014.12.001

      Highlights

      • We reviewed studies to obtain the in incidence of rash in patients with LTG.
      • The incidence of rash with LTG was 9.98% from prospective studies.
      • LTG significantly increased the risk of rash than non-aromatic AEDs.

      Abstract

      Purpose

      We systematically reviewed studies to provide current evidence on the incidence and risk of skin rash in patients with LTG therapy.

      Methods

      PubMed and Scopus databases, up to 15 March 2014 were searched to identify relevant studies. Eligible studies included prospective studies, retrospective studies and postmarketing reports, which included data of skin rash in patients with LTG therapy.

      Results

      Forty-one articles met the entry criteria. A total of 4447 patients with LTG therapy from 26 prospective studies, 2977 patients from 8 retrospective studies, and 26,126 patients from 5/7 postmarketing reports were included. The overall incidence of skin rash with LTG therapy was 9.98% (444/4447) from prospective studies, 7.19% (214/2977) from retrospective studies, and 2.09% (547/26,126) from postmarketing reports. A meta-analysis of the risk of skin rash in 21 prospective studies, did not show a significant difference between patients with LTG and other drugs, including placebo, other ADEs or lithium (OR 0.99–2.41). In 6 respective studies, there was a significantly higher OR in patients with LTG compared with those with non-aromatic AEDs. However, there was no significant difference in rash risk between patients with LTG and aromatic AEDs.

      Conclusions

      Our study showed that LTG significantly increased the risk of developing a skin rash compared to non-aromatic AEDs. Our results support the need for large prospective population-based studies and clinical trials to determine whether LTG increases the risk of developing a skin rash than compared to other drugs.

      Keywords

      1. Introduction

      Lamotrigine (LTG) is the most commonly administered second-line antiepileptic-drugs (ADEs) and is also effective in the treatment of a variety of other abnormalities of neuronal excitability, including bipolar disorder [
      • Reid J.G.
      • Gitlin M.J.
      • Altshuler L.L.
      Lamotrigine in psychiatric disorders.
      ,
      • Clark C.T.
      • Klein A.M.
      • Perel J.M.
      • Helsel J.
      • Wisner K.L.
      Lamotrigine dosing for pregnant patients with bipolar disorder.
      ], and neuropathic pain [
      • Brix Finnerup N.
      • Hein Sindrup S.
      • Staehelin Jensen T.
      Management of painful neuropathies.
      ]. However, 10% of subjects in controlled trials are allergic to LTG and are susceptible to a wide spectrum of adverse cutaneous clinical manifestations including extremely painful and life-threatening conditions [
      • Yarbrough 3rd., D.R.
      Experience with toxic epidermal necrolysis treated in a burn center.
      ].
      Skin reactions are a common side effect of antiepileptic drugs (AEDs) and a major cause of treatment discontinuation. The clinical spectrum of these reactions is wide. Most skin reactions are common and mild maculopapular rashes that disappear within a few days after discontinuing drug use. Benign rashes are relatively common with aromatic AEDs, such as carbamazepine (CBZ), phenytoin (PHT), and phenobarbital (PB), with a frequency ranging from 5 to 15% of treated individuals. Some of the newer drugs also frequently cause skin rashes, particularly lamotrigine (LTG), and oxcarbazepine (OXC).
      The incidence of rash is now well recognized to be dose- and titration-dependent, and is related with concomitant therapy with valproic acid (VPA). Since the introduction of a gradual titration schedule in 1994, the rate of severe rashes with LTG has declined from 1 to 0.1–0.01 percent [
      • Mockenhaupt M.
      • Messenheimer J.
      • Tennis P.
      • Schlingmann J.
      Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptics.
      ]. However, there was not a substantial reduction observed in the rate of benign rashes, which has still remained between 8 and 11 percent [
      • Calabrese J.R.
      • Sullivan J.R.
      • Bowden C.L.
      • Suppes T.
      • Goldberg J.F.
      • Sachs G.S.
      • et al.
      Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management.
      ].
      Although LTG has been used in everyday clinical practice for nearly 25 years and the possibility of rash is now routinely managed, it is still not clearly known whether LTG increases the risk of developing a skin rash compared to other drugs. Here, we systematically reviewed published studies to provide current evidence on the incidence of LTG related skin rashes and compared this risk with other drugs.

      2. Methods

      2.1 Search strategy

      We searched the PubMed (data from 1990 to March 2014), and Scopus (up to March 2014) databases for relevant studies. The search terms used were: “lamotrigine”, “lamictal”, “rash”, and “skin reaction”. Studies were limited to human studies and were published in English.
      A cutaneous adverse reaction was defined as any types of rash (erythematous, maculo-papular, papular, pustular or unspecified) that could only be caused by an antiepileptic drug effect and that resulted in contacting a physician.

      2.2 Selection criteria

      To determine the practical significance of the study, we evaluated the incidence and the risk of developing a skin rash in patients who received LTG therapy. Thus, we included multiple dose levels of LTG treatment. We included all prospective, retrospective and postmarketing studies reporting a skin rash with LTG therapy. Clinical trials that met the following criteria were included in the meta-analysis: (1) prospective randomized controlled trials or open-label trials of patients receiving LTG treatment and its presence with a control group; (2) retrospective study, which included the data of LTG related rashes and could be compared with other drugs.
      We excluded reviews, editorials, single cases and case series, studies published only as abstracts, letters, or commentaries and studies they were a part of duplicate populations. For the meta-analysis, on the basis of the inclusion and exclusion criteria, we identified a total of 21 prospective case-controlled studies (1 study involving Asian subjects and 20 involving European–Caucasian subjects) (Table 1), and 6 retrospective studies (2 studies involving Asian subjects and 4 studies involving European–Caucasian subjects) (Table 2).
      Table 1Characteristics of published prospective studies reporting skin rash with LTG therapy.
      StudyCountryStudy fieldStudy typeAge groupNo. enrolledTreatment armMedian age (y)M/F (N/N)Median treatmentLTG dosageNo. analysisNo. rashNo. withdrawal
      Steiner et al. (1997)
      • Steiner T.J.
      • Findley L.J.
      • Yuen A.W.
      Lamotrigine versus placebo in the prophylaxis of migraine with and without aura.
      U.K.Pain migraineRCTsAdults110LTG35.86/313M200 mg/d37118
      LTG fixed dose200 mg/d1877
      LTG escalated dose200 mg/d1941
      Placebo38.48/323M4011
      Kapoor et al. (2010)
      • Kapoor R.
      • Furby J.
      • Hayton T.
      • Smith K.J.
      • Altmann D.R.
      • Brenner R.
      • et al.
      Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomized, double-blind, placebo-controlled, parallel-group trial.
      IrelandPain MSRCTsAdults120LTG51.916/4548M400 mg/d61123
      AdultsPlacebo50.127/4248M5932
      Simpson et al. (2003)
      • Simpson D.M.
      • McArthur J.C.
      • Olney R.
      • Clifford D.
      • So Y.
      • Ross D.
      • et al.
      Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial.
      USAPain HIVRCTsAdults220LTG46137/1311w402 mg/d150212
      Placebo4460/1711w7791
      Vinik et al. (2007)
      • Vinik A.I.
      • Tuchman M.
      • Safirstein B.
      • Corder C.
      • Kirby L.
      • Wilks K.
      • et al.
      Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies.
      USAPain DMRCTsAdults360LTG 20060.350/3819w200 mg/d889
      LTG 30060.050/4019w300 mg/d9010
      LTG 40059.651/3819w400 mg/d8914
      1Placebo59.866/2219w888
      Messenheimer et al. (1994)
      • Messenheimer J.
      • Ramsay R.E.
      • Willmore L.J.
      • Leroy R.F.
      • Zielinski J.J.
      • Mattson R.
      • et al.
      Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, cross-over trial.
      USAEpiRCTs cross over98LTG3541/4714w400 mg/d94143
      Placebo3541/4714w9661
      Motte et al. (1997)
      • Motte J.
      • Trevathan E.
      • Arvidsson J.F.
      • Barrera M.N.
      • Mullens E.L.
      • Manasco P.
      Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome.
      USAEpiRCTs3-25y169LTG9.654/2516w50–400 mg/d797
      Placebo10.945/4516w906
      van der loos et al. (2010)
      • van der Loos M.L.
      • Mulder P.
      • Hartong E.G.
      • Blom M.B.
      • Vergouwen A.C.
      • van Noorden M.S.
      • et al.
      Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.
      NertherlandBipolarRCTsAdults124LTG45.227/3716w649
      Placebo47.630/3016w604
      Calabrese et al. (1999)
      • Calabrese J.R.
      • Bowden C.L.
      • Sachs G.S.
      • Ascher J.A.
      • Monaghan E.
      • Rudd G.D.
      A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression.
      Lamictal study 602 GroupBipolarRCTsAdults194LTG 50 mg/d4122/447w50 mg/d669
      LTG 200 mg/d4228/357w200 mg/d637
      Placebo4227/387w657
      Calabrese et al. (2003)
      • Calabrese J.R.
      • Bowden C.L.
      • Sachs G.
      • Yatham L.N.
      • Behnke K.
      • Mehtonen O.P.
      • et al.
      A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder.
      Lamictal 605 study groupBipolarOpen-labelAdults966LTG42.4370/58616w200 mg/d958104
      RCTsLTG44.170/8918M50–200 mg/d16912
      Lithium43.648/7318M1215
      Placebo42.161/6018M1213
      Normannet al. (2002)
      • Normann C.
      • Hummel B.
      • Schärer L.O.
      • Hörn M.
      • Grunze H.
      • Walden J.
      Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study.
      GermanyBipolarRCTsAdults40LTG39.66/149w200 mg/d203
      Placebo37.97/139w201
      Bowden et al. (2003)
      • Bowden C.L.
      • Calabrese J.R.
      • Sachs G.
      • Yatham L.N.
      • Asghar S.A.
      • Hompland M.
      • et al.
      A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder.
      Lamictal 606 study groupBipolarOpen-labelAdults349LTG40.7172/1758–16w3473817
      RCTsAdults174LTG40.626/3318M5920
      Lithium41.922/2418M4642
      Placebo40.934/3518M6962
      Sajatovic et al. (2005)
      • Sajatovic M.
      • Gyulai L.
      • Calabrese J.R.
      • Thompson T.R.
      • Wilson B.G.
      • White R.
      • et al.
      Maintenance treatment outcomes in older patients with bipolar I disorder.
      USABipolarRCTsElderly98LTG60.516/1718M223 mg/d331
      Lithium60.113/2118M740.7 mg/d342
      Placebo62.217/1418M311
      Reunanen et al. (1996)
      • Reunanen M.
      • Dam M.
      • Yuen A.W.
      A randomised open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy.
      U.K.EpiRCTs12–72343LTG 1003354/6124w100 mg/d11562
      LTG 2003058/5324w200 mg/d11193
      CBZ6003250/6724w600 mg/d117106
      Brodie et al. (1995)
      • Brodie M.J.
      • Richens A.
      • Yuen A.W.
      Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group.
      U.K.EpiRCTs13–81260LTG2854/7712w150 mg/d1312512
      CBZ2758/7112w600 mg/d1292517
      Brodie et al. (1999)
      • Brodie M.J.
      • Overstall P.W.
      • Giorgi L.
      Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group.
      U.K.EpiRCTsElderly150LTG7755/4724w57–500 mg/d10293
      CBZ7628/2024w200–2000 mg/d48259
      ZengK et al. (2010)
      • Zeng K.
      • Wang X.
      • Xi Z.
      • Yan Y.
      Adverse effects of carbamazepine, phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients.
      ChinaEpiopen trialAdults512LTG3134/5224M8644
      CBZ2787/8124M16822
      PHT3036/2324M5911
      VPA28104/8824M19200
      Gilliam et al. (1998)
      • Gilliam F.
      • Vazquez B.
      • Sackellares J.C.
      • Chang G.Y.
      • Messenheimer J.
      • Nyberg J.
      • et al.
      An active-control trial of lamotrigine monotherapy for partial seizures.
      U.K.EpiRCTsAdults156LTG add on3733/438w500mgd768
      VPA add on3632/488w1000 mg/d806
      LTG alone3733/4312w500 mgd761
      VPA alone3632/4812w1000 mg/d801
      Steiner et al. (1999)
      • Steiner T.J.
      • Dellaportas C.I.
      • Findley L.J.
      • Gross M.
      • Gibberd F.B.
      • Perkin G.D.
      • et al.
      Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin.
      U.K.EpiRCTs13–70181LTG2847/396–48w150 mg/d8612
      PHT2754/416–48w300 mg.d959
      Labiner et al. (2009)
      • Labiner D.M.
      • Ettinger A.B.
      • Fakhoury T.A.
      • Chung S.S.
      • Shneker B.
      • Tatum Iv W.O.
      • et al.
      Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy.
      USAEpiRCTsAdults268LTG38.363/6912w400 mg/d1328
      LEV39.156/8012w2000 mg/d1369
      Kluger et al. (2001)
      • Kluger G.
      • Berz K.
      • Holthausen H.
      The long-term use of vigabatrin and lamotrigine in patients with severe childhood onset epilepsy.
      GermanyEpiOpen-labelChildren95LTG13.621/185y3952
      VGB11.130/26F561
      Licht et al. (2010)
      • Licht R.W.
      • Nielsen J.N.
      • Gram L.F.
      • Vestergaard P.
      • Bendz H.
      Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6).
      SwedenBipolarRCTsAdults155LTG38.237/405y400 mg/d776
      Lithium37.342/36785
      Brawn et al. (2006)
      • Brown E.B.
      • McElroy S.L.
      • Keck Jr., P.E.
      • Deldar A.
      • Adams D.H.
      • Tohen M.
      • et al.
      A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression.
      USABipolarRCTs410LTG37.277/1287w20514
      OFX36.887/1182056
      Brodie et al. (1997)
      • Brodie M.J.
      • Yuen A.W.
      Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 Study Group.
      U.K.EpiRCTs14–77347With VPA2848/6916w96 mg/d11720
      With CBZ3161/6816w347 mg/d1299
      With PHT3345/5016w359 mg/d950
      Farrell et al. (1996)
      • Farrell K.
      • Connolly M.B.
      • Munn R.
      • Peng S.
      • MacWilliam L.M.
      Prospective, open-label, add-on study of lamotrigine in 56 children with intractable generalized epilepsy.
      CanadaEpiOpen-labelChildren56With VPA24 M214
      Without VPA24 M351
      Calabrease et al. (1999)
      • Calabrese J.R.
      • Bowden C.L.
      • McElroy S.L.
      • Cookson J.
      • Andersen J.
      • Keck Jr., P.E.
      • et al.
      Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder.
      USABipolarOpen-labelAdults75With VPA48 W151
      LTG alone48 W606
      Beghi et al. (2003)
      • Beghi E.
      • Gatti G.
      • Tonini C.
      • Ben-Menachem E.
      • Chadwick D.W.
      • Nikanorova M.
      • et al.
      Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomised, pragmatic controlled trial.
      U.K.EpiOpen-labelAll age360LTG alone12M1587
      LTG add on1115
      Epi: epilepsy; MS: multiple sclerosis; HIV: HIV related neuropathic pain; DM: diabetic neuropathic pain; RCTs: randomized controlled trials; LTG: lamotrigine; VPA: valproic acid; PHT:phenytoin; CBZ: carbamazepine; PB: phenobarbital; LEV: leveritacetam; VGB: vigabatrin; OFX: olanzapine/fluoxetine combination.
      Table 2Characteristics of published retrospective studies reporting skin rash with LTG therapy.
      StudyCountryStudy fieldAge groupMedian treatment (weeks)Patients enrolledTreatment armNo of analysisNo of skin rash
      Wang et al. (2012)
      • Wang X.Q.
      • Lang S.Y.
      • Shi X.B.
      • Tian H.J.
      • Wang R.F.
      • Yang F.
      Antiepileptic drug-induced skin reactions: a retrospective study and analysis in 3793 Chinese patients with epilepsy.
      ChinaEpiAdults (≥18 y)February 1999–April 20103793LTG26123
      CBZ 58/1919; VPA 8/1754; OXC 15/214; TPM 7/667; GBP 1/52; LEV 2/121
      Chung et al. (2007)
      • Chung S.
      • Wang N.
      • Hank N.
      Comparative retention rates and long-term tolerability of new antiepileptic drugs.
      USAEpiAdults (17–89 y)104 weeks828LTG25118
      OXC 6/97; TPM 6/156; LEV 1/196; ZNS 4/128
      Arif et al. (2007)
      • Arif H.
      • Buchsbaum R.
      • Weintraub D.
      • Koyfman S.
      • Salas-Humara C.
      • Bazil C.W.
      • et al.
      Comparison and predictors of rash associated with 15 antiepileptic drugs.
      USAEpi>16 yJanuary 2000–January 20055025LTG103750
      CBZ 24/655; PHT 32/558; OXC 6/248; ZNS 10/219; GBP 1/378; VPA 3/411; LEV 4/627
      Hirsch et al. (2008)
      • Hirsch L.J.
      • Arif H.
      • Nahm E.A.
      • Buchsbaum R.
      • Resor Jr., S.R.
      • Bazil C.W.
      Cross-sensitivity of skin rashes with antiepileptic drug use.
      USAEpi≥12 yJanuary 2000–January 20051875LTG86477
      CBZ 62/745; OXC 10/201; PHT 85/716; PB 17/276; ZNS 12/174
      Alvestad et al. (2007)
      • Alvestad S.
      • Lydersen S.
      • Brodtkorb E.
      Influence by gender, age, and learning disability.
      NorwayEpiAdultsNo data2567 exposuresLTG35929
      CBZ 54/489; PHT 19/229; OXC 9/114; PB 4/211; VPA 1/391; LEV 1/155; TPM 0/141; VGB 0/144; GBP 0/73
      Mogami et al. (2012)
      • Mogami Y.
      • Takahashi Y.
      • Takayama R.
      • Ohtani H.
      • Ikeda H.
      • Imai K.
      • et al.
      Cutaneous adverse drug reaction in patients with epilepsy after acute encephalitis.
      JapanEpiAll ageFebruary 1996–May 200976LTG82
      CBZ 6/55; VPA 2/57; PB 5/35; PHT 4/32; GBP 0/13
      Shechter et al.
      • Shechter T.
      • Shorer Z.
      • Kramer U.
      • Lerman-Sagie T.
      • Ronen E.
      • Rotem R.
      • et al.
      Adverse reactions of topiramate and lamotrigine in children.
      IsraelEpiChildren6–14 w110LTG654
      TPM 0/45
      McDonald et al. (2004)
      • McDonald D.G.
      • Najam Y.
      • Keegan M.B.
      • Whooley M.
      • Madden D.
      • McMenamin J.B.
      The use of lamotrigine, vigabatrin and gabapentin as add-on therapy in intractable epilepsy of childhood.
      IrelandEpiChildrenFebruary 1996–September 2000251LTG13211
      VGB 0/129; GBP 0/39
      Epi: epilepsy; LTG: lamotrigine; VPA: valproic acid; PHT: phenytoin; CBZ: carbamazepine; PB: phenobarbital; OXC: oxcarbazepine; GBP: gabapentin; TPM: topiramate; LEV: leveritacetam; VGB: vigabatrin; ZNS: zonisamide.

      2.3 Data extraction and quality assessment

      We designed and piloted a standardized data abstraction form to capture all of the relevant study-level information required for analysis. Two independent investigators performed the data extraction (W.X.Q. and X.J.), and any discrepancy between the reviewers was resolved by consensus. For each study, the following information was obtained: the author's name, year of publication, trial phase, number of enrolled subjects, treatment arms, number of patients in the treatment and control groups when available, median age, median treatment duration, and adverse outcomes of interest (skin rash).

      2.4 Statistical analysis

      All of the analyses were performed using STATA 12.0 (StataCorp, College Station, Texas, USA). A p-value of less than 0.05 was considered statistically significant, and all of the tests were two-sided. The crude odds ratios (ORs) and 95% confidence intervals (CIs) were used to express the risk of skin rash with LTG therapy compared with other drugs. Forest plots were used to depict the visual representation of the meta-analysis results. Meta-analysis was performed using fixed-effects [
      • Mantel N.
      • Haenszel W.
      Statistical aspects of the analysis of data from retrospective studies of disease.
      ] or random-effects [
      • DerSimonian R.
      • Kacker R.
      Random-effects model for meta-analysis of clinical trials: an update.
      ] models. Heterogeneity was tested using w2-based Cochran's Q statistic [
      • Zintzaras E.
      • Ioannidis J.P.
      Heterogeneity testing in meta-analysis of genome searches.
      ] and I2 metric statistics [
      • Lau J.
      • Ioannidis J.P.
      • Schmid C.H.
      Quantitative synthesis in systematic reviews.
      ]. Random-effects models were used only when there was considerable heterogeneity (P < 0.05 or I2 > 50% among the studies).
      Studies were classified according to the study type (prospective study, retrospective study and postmarketing reports). In the first two group, all of the crude OR calculated by the original data were pooled. We performed the analyses on only the observed crude rate estimates, primarily because there was no study that reported adjusted estimates. We also performed the following specified subgroup analyses: different control groups (placebo, other antiepileptic drugs, or other antidepressive drugs), different groups of patients (epilepsy, bipolar or patients with neuropathic pain), prospective study, and retrospective study.

      3. Results

      3.1 Study selection and characteristics

      Our search yielded 748 records describing the use of LTG and a skin rash from the Pubmed and Scopus databases. The selection process is summarized in Fig. 1. After the exclusion of duplicate studies and a review of the abstracts, a total of 94 human clinical studies were identified with information on LTG therapy and benign rashes. Full-text articles were retrieved for these records and carefully studied. Finally, in the prospective studies, a total of 26 studies involving LTG-induced rash were used to evaluate rash incidence [
      • Steiner T.J.
      • Findley L.J.
      • Yuen A.W.
      Lamotrigine versus placebo in the prophylaxis of migraine with and without aura.
      ,
      • Kapoor R.
      • Furby J.
      • Hayton T.
      • Smith K.J.
      • Altmann D.R.
      • Brenner R.
      • et al.
      Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomized, double-blind, placebo-controlled, parallel-group trial.
      ,
      • Simpson D.M.
      • McArthur J.C.
      • Olney R.
      • Clifford D.
      • So Y.
      • Ross D.
      • et al.
      Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial.
      ,
      • Vinik A.I.
      • Tuchman M.
      • Safirstein B.
      • Corder C.
      • Kirby L.
      • Wilks K.
      • et al.
      Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies.
      ,
      • Messenheimer J.
      • Ramsay R.E.
      • Willmore L.J.
      • Leroy R.F.
      • Zielinski J.J.
      • Mattson R.
      • et al.
      Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, cross-over trial.
      ,
      • Motte J.
      • Trevathan E.
      • Arvidsson J.F.
      • Barrera M.N.
      • Mullens E.L.
      • Manasco P.
      Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome.
      ,
      • van der Loos M.L.
      • Mulder P.
      • Hartong E.G.
      • Blom M.B.
      • Vergouwen A.C.
      • van Noorden M.S.
      • et al.
      Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.
      ,
      • Calabrese J.R.
      • Bowden C.L.
      • Sachs G.S.
      • Ascher J.A.
      • Monaghan E.
      • Rudd G.D.
      A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression.
      ,
      • Calabrese J.R.
      • Bowden C.L.
      • Sachs G.
      • Yatham L.N.
      • Behnke K.
      • Mehtonen O.P.
      • et al.
      A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder.
      ,
      • Normann C.
      • Hummel B.
      • Schärer L.O.
      • Hörn M.
      • Grunze H.
      • Walden J.
      Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study.
      ,
      • Bowden C.L.
      • Calabrese J.R.
      • Sachs G.
      • Yatham L.N.
      • Asghar S.A.
      • Hompland M.
      • et al.
      A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder.
      ,
      • Sajatovic M.
      • Gyulai L.
      • Calabrese J.R.
      • Thompson T.R.
      • Wilson B.G.
      • White R.
      • et al.
      Maintenance treatment outcomes in older patients with bipolar I disorder.
      ,
      • Reunanen M.
      • Dam M.
      • Yuen A.W.
      A randomised open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy.
      ,
      • Brodie M.J.
      • Richens A.
      • Yuen A.W.
      Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group.
      ,
      • Brodie M.J.
      • Overstall P.W.
      • Giorgi L.
      Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group.
      ,
      • Zeng K.
      • Wang X.
      • Xi Z.
      • Yan Y.
      Adverse effects of carbamazepine, phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients.
      ,
      • Gilliam F.
      • Vazquez B.
      • Sackellares J.C.
      • Chang G.Y.
      • Messenheimer J.
      • Nyberg J.
      • et al.
      An active-control trial of lamotrigine monotherapy for partial seizures.
      ,
      • Steiner T.J.
      • Dellaportas C.I.
      • Findley L.J.
      • Gross M.
      • Gibberd F.B.
      • Perkin G.D.
      • et al.
      Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin.
      ,
      • Labiner D.M.
      • Ettinger A.B.
      • Fakhoury T.A.
      • Chung S.S.
      • Shneker B.
      • Tatum Iv W.O.
      • et al.
      Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy.
      ,
      • Kluger G.
      • Berz K.
      • Holthausen H.
      The long-term use of vigabatrin and lamotrigine in patients with severe childhood onset epilepsy.
      ,
      • Licht R.W.
      • Nielsen J.N.
      • Gram L.F.
      • Vestergaard P.
      • Bendz H.
      Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6).
      ,
      • Brown E.B.
      • McElroy S.L.
      • Keck Jr., P.E.
      • Deldar A.
      • Adams D.H.
      • Tohen M.
      • et al.
      A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression.
      ,
      • Brodie M.J.
      • Yuen A.W.
      Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 Study Group.
      ,
      • Farrell K.
      • Connolly M.B.
      • Munn R.
      • Peng S.
      • MacWilliam L.M.
      Prospective, open-label, add-on study of lamotrigine in 56 children with intractable generalized epilepsy.
      ,
      • Calabrese J.R.
      • Bowden C.L.
      • McElroy S.L.
      • Cookson J.
      • Andersen J.
      • Keck Jr., P.E.
      • et al.
      Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder.
      ,
      • Beghi E.
      • Gatti G.
      • Tonini C.
      • Ben-Menachem E.
      • Chadwick D.W.
      • Nikanorova M.
      • et al.
      Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomised, pragmatic controlled trial.
      ] and 21 articles with controls fulfilling the inclusion and exclusion criteria were identified for meta-analysis [
      • Steiner T.J.
      • Findley L.J.
      • Yuen A.W.
      Lamotrigine versus placebo in the prophylaxis of migraine with and without aura.
      ,
      • Kapoor R.
      • Furby J.
      • Hayton T.
      • Smith K.J.
      • Altmann D.R.
      • Brenner R.
      • et al.
      Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomized, double-blind, placebo-controlled, parallel-group trial.
      ,
      • Simpson D.M.
      • McArthur J.C.
      • Olney R.
      • Clifford D.
      • So Y.
      • Ross D.
      • et al.
      Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial.
      ,
      • Vinik A.I.
      • Tuchman M.
      • Safirstein B.
      • Corder C.
      • Kirby L.
      • Wilks K.
      • et al.
      Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies.
      ,
      • Messenheimer J.
      • Ramsay R.E.
      • Willmore L.J.
      • Leroy R.F.
      • Zielinski J.J.
      • Mattson R.
      • et al.
      Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, cross-over trial.
      ,
      • Motte J.
      • Trevathan E.
      • Arvidsson J.F.
      • Barrera M.N.
      • Mullens E.L.
      • Manasco P.
      Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome.
      ,
      • van der Loos M.L.
      • Mulder P.
      • Hartong E.G.
      • Blom M.B.
      • Vergouwen A.C.
      • van Noorden M.S.
      • et al.
      Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.
      ,
      • Calabrese J.R.
      • Bowden C.L.
      • Sachs G.S.
      • Ascher J.A.
      • Monaghan E.
      • Rudd G.D.
      A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression.
      ,
      • Calabrese J.R.
      • Bowden C.L.
      • Sachs G.
      • Yatham L.N.
      • Behnke K.
      • Mehtonen O.P.
      • et al.
      A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder.
      ,
      • Normann C.
      • Hummel B.
      • Schärer L.O.
      • Hörn M.
      • Grunze H.
      • Walden J.
      Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study.
      ,
      • Bowden C.L.
      • Calabrese J.R.
      • Sachs G.
      • Yatham L.N.
      • Asghar S.A.
      • Hompland M.
      • et al.
      A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder.
      ,
      • Sajatovic M.
      • Gyulai L.
      • Calabrese J.R.
      • Thompson T.R.
      • Wilson B.G.
      • White R.
      • et al.
      Maintenance treatment outcomes in older patients with bipolar I disorder.
      ,
      • Reunanen M.
      • Dam M.
      • Yuen A.W.
      A randomised open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy.
      ,
      • Brodie M.J.
      • Richens A.
      • Yuen A.W.
      Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group.
      ,
      • Brodie M.J.
      • Overstall P.W.
      • Giorgi L.
      Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group.
      ,
      • Zeng K.
      • Wang X.
      • Xi Z.
      • Yan Y.
      Adverse effects of carbamazepine, phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients.
      ,
      • Gilliam F.
      • Vazquez B.
      • Sackellares J.C.
      • Chang G.Y.
      • Messenheimer J.
      • Nyberg J.
      • et al.
      An active-control trial of lamotrigine monotherapy for partial seizures.
      ,
      • Steiner T.J.
      • Dellaportas C.I.
      • Findley L.J.
      • Gross M.
      • Gibberd F.B.
      • Perkin G.D.
      • et al.
      Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin.
      ,
      • Labiner D.M.
      • Ettinger A.B.
      • Fakhoury T.A.
      • Chung S.S.
      • Shneker B.
      • Tatum Iv W.O.
      • et al.
      Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy.
      ,
      • Kluger G.
      • Berz K.
      • Holthausen H.
      The long-term use of vigabatrin and lamotrigine in patients with severe childhood onset epilepsy.
      ,
      • Licht R.W.
      • Nielsen J.N.
      • Gram L.F.
      • Vestergaard P.
      • Bendz H.
      Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6).
      ] (Fig. 1 and Table 1). In this group, 4447 patients receiving LTG treatment were investigated, including a variety of diseases: epilepsy (13 trials) [
      • Messenheimer J.
      • Ramsay R.E.
      • Willmore L.J.
      • Leroy R.F.
      • Zielinski J.J.
      • Mattson R.
      • et al.
      Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, cross-over trial.
      ,
      • Motte J.
      • Trevathan E.
      • Arvidsson J.F.
      • Barrera M.N.
      • Mullens E.L.
      • Manasco P.
      Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome.
      ,
      • Reunanen M.
      • Dam M.
      • Yuen A.W.
      A randomised open multicentre comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy.
      ,
      • Brodie M.J.
      • Richens A.
      • Yuen A.W.
      Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. UK Lamotrigine/Carbamazepine Monotherapy Trial Group.
      ,
      • Brodie M.J.
      • Overstall P.W.
      • Giorgi L.
      Multicentre, double-blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group.
      ,
      • Zeng K.
      • Wang X.
      • Xi Z.
      • Yan Y.
      Adverse effects of carbamazepine, phenytoin, valproate and lamotrigine monotherapy in epileptic adult Chinese patients.
      ,
      • Gilliam F.
      • Vazquez B.
      • Sackellares J.C.
      • Chang G.Y.
      • Messenheimer J.
      • Nyberg J.
      • et al.
      An active-control trial of lamotrigine monotherapy for partial seizures.
      ,
      • Steiner T.J.
      • Dellaportas C.I.
      • Findley L.J.
      • Gross M.
      • Gibberd F.B.
      • Perkin G.D.
      • et al.
      Lamotrigine monotherapy in newly diagnosed untreated epilepsy: a double-blind comparison with phenytoin.
      ,
      • Labiner D.M.
      • Ettinger A.B.
      • Fakhoury T.A.
      • Chung S.S.
      • Shneker B.
      • Tatum Iv W.O.
      • et al.
      Effects of lamotrigine compared with levetiracetam on anger, hostility, and total mood in patients with partial epilepsy.
      ,
      • Kluger G.
      • Berz K.
      • Holthausen H.
      The long-term use of vigabatrin and lamotrigine in patients with severe childhood onset epilepsy.
      ,
      • Brodie M.J.
      • Yuen A.W.
      Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 Study Group.
      ,
      • Farrell K.
      • Connolly M.B.
      • Munn R.
      • Peng S.
      • MacWilliam L.M.
      Prospective, open-label, add-on study of lamotrigine in 56 children with intractable generalized epilepsy.
      ,
      • Beghi E.
      • Gatti G.
      • Tonini C.
      • Ben-Menachem E.
      • Chadwick D.W.
      • Nikanorova M.
      • et al.
      Adjunctive therapy versus alternative monotherapy in patients with partial epilepsy failing on a single drug: a multicentre, randomised, pragmatic controlled trial.
      ], dipolar disorder (9 trials) [
      • van der Loos M.L.
      • Mulder P.
      • Hartong E.G.
      • Blom M.B.
      • Vergouwen A.C.
      • van Noorden M.S.
      • et al.
      Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or placebo and paroxetine.
      ,
      • Calabrese J.R.
      • Bowden C.L.
      • Sachs G.S.
      • Ascher J.A.
      • Monaghan E.
      • Rudd G.D.
      A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression.
      ,
      • Calabrese J.R.
      • Bowden C.L.
      • Sachs G.
      • Yatham L.N.
      • Behnke K.
      • Mehtonen O.P.
      • et al.
      A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder.
      ,
      • Normann C.
      • Hummel B.
      • Schärer L.O.
      • Hörn M.
      • Grunze H.
      • Walden J.
      Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study.
      ,
      • Bowden C.L.
      • Calabrese J.R.
      • Sachs G.
      • Yatham L.N.
      • Asghar S.A.
      • Hompland M.
      • et al.
      A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder.
      ,
      • Sajatovic M.
      • Gyulai L.
      • Calabrese J.R.
      • Thompson T.R.
      • Wilson B.G.
      • White R.
      • et al.
      Maintenance treatment outcomes in older patients with bipolar I disorder.
      ,
      • Licht R.W.
      • Nielsen J.N.
      • Gram L.F.
      • Vestergaard P.
      • Bendz H.
      Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6).
      ,
      • Brown E.B.
      • McElroy S.L.
      • Keck Jr., P.E.
      • Deldar A.
      • Adams D.H.
      • Tohen M.
      • et al.
      A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression.
      ,
      • Calabrese J.R.
      • Bowden C.L.
      • McElroy S.L.
      • Cookson J.
      • Andersen J.
      • Keck Jr., P.E.
      • et al.
      Spectrum of activity of lamotrigine in treatment-refractory bipolar disorder.
      ], and neuropathic pain (1 magraine [
      • Steiner T.J.
      • Findley L.J.
      • Yuen A.W.
      Lamotrigine versus placebo in the prophylaxis of migraine with and without aura.
      ], 1 multiple sclerosis [
      • Kapoor R.
      • Furby J.
      • Hayton T.
      • Smith K.J.
      • Altmann D.R.
      • Brenner R.
      • et al.
      Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomized, double-blind, placebo-controlled, parallel-group trial.
      ], 1 HIV-related [
      • Simpson D.M.
      • McArthur J.C.
      • Olney R.
      • Clifford D.
      • So Y.
      • Ross D.
      • et al.
      Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial.
      ], and 1 diabetic [
      • Vinik A.I.
      • Tuchman M.
      • Safirstein B.
      • Corder C.
      • Kirby L.
      • Wilks K.
      • et al.
      Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies.
      ]). The sample sizes were within the range of 20–958 patients with LTG. The median age of study participants was 9.6–77 years.
      Figure thumbnail gr1
      Fig. 1Flow chart of selection of articles about skin rash in patients with LTG therapy.
      In the retrospective studies, 8 articles were used to evaluate rash incidence [
      • Wang X.Q.
      • Lang S.Y.
      • Shi X.B.
      • Tian H.J.
      • Wang R.F.
      • Yang F.
      Antiepileptic drug-induced skin reactions: a retrospective study and analysis in 3793 Chinese patients with epilepsy.
      ,
      • Chung S.
      • Wang N.
      • Hank N.
      Comparative retention rates and long-term tolerability of new antiepileptic drugs.
      ,
      • Arif H.
      • Buchsbaum R.
      • Weintraub D.
      • Koyfman S.
      • Salas-Humara C.
      • Bazil C.W.
      • et al.
      Comparison and predictors of rash associated with 15 antiepileptic drugs.
      ,
      • Hirsch L.J.
      • Arif H.
      • Nahm E.A.
      • Buchsbaum R.
      • Resor Jr., S.R.
      • Bazil C.W.
      Cross-sensitivity of skin rashes with antiepileptic drug use.
      ,
      • Alvestad S.
      • Lydersen S.
      • Brodtkorb E.
      Influence by gender, age, and learning disability.
      ,
      • Mogami Y.
      • Takahashi Y.
      • Takayama R.
      • Ohtani H.
      • Ikeda H.
      • Imai K.
      • et al.
      Cutaneous adverse drug reaction in patients with epilepsy after acute encephalitis.
      ,
      • Shechter T.
      • Shorer Z.
      • Kramer U.
      • Lerman-Sagie T.
      • Ronen E.
      • Rotem R.
      • et al.
      Adverse reactions of topiramate and lamotrigine in children.
      ,
      • McDonald D.G.
      • Najam Y.
      • Keegan M.B.
      • Whooley M.
      • Madden D.
      • McMenamin J.B.
      The use of lamotrigine, vigabatrin and gabapentin as add-on therapy in intractable epilepsy of childhood.
      ] and 6 studies fulfilling the inclusion criteria were identified for meta-analysis [
      • Wang X.Q.
      • Lang S.Y.
      • Shi X.B.
      • Tian H.J.
      • Wang R.F.
      • Yang F.
      Antiepileptic drug-induced skin reactions: a retrospective study and analysis in 3793 Chinese patients with epilepsy.
      ,
      • Chung S.
      • Wang N.
      • Hank N.
      Comparative retention rates and long-term tolerability of new antiepileptic drugs.
      ,
      • Arif H.
      • Buchsbaum R.
      • Weintraub D.
      • Koyfman S.
      • Salas-Humara C.
      • Bazil C.W.
      • et al.
      Comparison and predictors of rash associated with 15 antiepileptic drugs.
      ,
      • Hirsch L.J.
      • Arif H.
      • Nahm E.A.
      • Buchsbaum R.
      • Resor Jr., S.R.
      • Bazil C.W.
      Cross-sensitivity of skin rashes with antiepileptic drug use.
      ,
      • Alvestad S.
      • Lydersen S.
      • Brodtkorb E.
      Influence by gender, age, and learning disability.
      ,
      • Mogami Y.
      • Takahashi Y.
      • Takayama R.
      • Ohtani H.
      • Ikeda H.
      • Imai K.
      • et al.
      Cutaneous adverse drug reaction in patients with epilepsy after acute encephalitis.
      ], which were all derived from epileptic studies (Fig. 1 and Table 2). The sample sizes were within the range of 8–1037 patients treated with LTG. Two articles were pediatric studies, of which one study included all age groups and 5 studies included patients older than 12 years.
      There were 5/7 postmarketing studies that provided data on the skin rash incidence of LTG [
      • Mackay F.J.
      • Wilton L.V.
      • Pearce G.L.
      • Freemantle S.N.
      • Mann R.D.
      Safety of long-term lamotrigine in epilepsy.
      ,
      • Wong I.C.
      • Mawer G.E.
      • Sander J.W.
      Adverse event monitoring in lamotrigine patients: a pharmacoepidemiologic study in the United Kingdom.
      ,
      • Acharya N.V.
      • Pickering R.M.
      • Wilton L.W.
      • Shakir S.A.
      The safety and effectiveness of newer antiepileptics: a comparative postmarketing cohort study.
      ,
      • Lange-Asschenfeldt C.
      • Grohmann R.
      • Lange-Asschenfeldt B.
      • Engel R.R.
      • Rüther E.
      • Cordes J.
      Cutaneous adverse reactions to psychotropic drugs: data from a multicenter surveillance program.
      ,
      • Aurich-Barrera B.
      • Wilton L.
      • Brown D.
      • Shakir S.
      Paediatric postmarketing pharmacovigilance using prescription-event monitoring: comparison of the adverse event profiles of lamotrigine prescribed to children and adults in England.
      ] (Table 3). Four studies were performed in the U.K., which were performed by Prescription-Event Monitoring (PEM) to establish the safety of LTG and other drugs, in which the entire population of prescriptions issued was accessible [
      • Mackay F.J.
      • Wilton L.V.
      • Pearce G.L.
      • Freemantle S.N.
      • Mann R.D.
      Safety of long-term lamotrigine in epilepsy.
      ,
      • Wong I.C.
      • Mawer G.E.
      • Sander J.W.
      Adverse event monitoring in lamotrigine patients: a pharmacoepidemiologic study in the United Kingdom.
      ,
      • Acharya N.V.
      • Pickering R.M.
      • Wilton L.W.
      • Shakir S.A.
      The safety and effectiveness of newer antiepileptics: a comparative postmarketing cohort study.
      ,
      • Aurich-Barrera B.
      • Wilton L.
      • Brown D.
      • Shakir S.
      Paediatric postmarketing pharmacovigilance using prescription-event monitoring: comparison of the adverse event profiles of lamotrigine prescribed to children and adults in England.
      ]. One study was performed in Germany [
      • Lange-Asschenfeldt C.
      • Grohmann R.
      • Lange-Asschenfeldt B.
      • Engel R.R.
      • Rüther E.
      • Cordes J.
      Cutaneous adverse reactions to psychotropic drugs: data from a multicenter surveillance program.
      ], where the data were obtained from a database of 208,401 psychiatric inpatients who were monitored by the Safety surveillance project Drug Safety in Psychiatry from 1993 to 2005, which surveys clinically relevant adverse reactions to all marketed psychotropic drugs. One report was performed in Sweden [
      • Wallerstedt S.M.
      • Brunlöf G.
      • Sundström A.
      Rates of spontaneous reports of adverse drug reactions for drugs reported in children: a cross-sectional study with data from the Swedish adverse drug reaction database and the Swedish Prescribed Drug Register.
      ], which aimed to determine the extent of the spontaneous reporting of ADRs in children. One study was on the safety profile of antiepileptic drugs in Italy [
      • Iorio M.L.
      • Moretti U.
      • Colcera S.
      • Magro L.
      • Meneghelli I.
      • Motola D.
      • et al.
      Use and safety profile of antiepileptic drugs in Italy.
      ], from January 1988 to June 2005. Only 2/7 of these studies followed cohorts of more than 10,000 subjects [
      • Mackay F.J.
      • Wilton L.V.
      • Pearce G.L.
      • Freemantle S.N.
      • Mann R.D.
      Safety of long-term lamotrigine in epilepsy.
      ,
      • Lange-Asschenfeldt C.
      • Grohmann R.
      • Lange-Asschenfeldt B.
      • Engel R.R.
      • Rüther E.
      • Cordes J.
      Cutaneous adverse reactions to psychotropic drugs: data from a multicenter surveillance program.
      ].
      Table 3Characteristics of published postmarketing studies reporting skin rash with LTG therapy.
      StudyCountryAge groupA group rash (n)A group no rash (n)B group rash (n)B group no rash (n)A/BRemark
      Mackay et al. (1997)
      • Mackay F.J.
      • Wilton L.V.
      • Pearce G.L.
      • Freemantle S.N.
      • Mann R.D.
      Safety of long-term lamotrigine in epilepsy.
      U.K.C47155121210,529LTG 2–12 y/LTG total cohortID per 1000 patient-months in the first month of treatment
      Wong et al. (2001)
      • Wong I.C.
      • Mawer G.E.
      • Sander J.W.
      Adverse event monitoring in lamotrigine patients: a pharmacoepidemiologic study in the United Kingdom.
      U.K.All age (7–77 y)1009508353LTG/GBPEvent frequency during first six months after starting the drug
      10095012701LTG/VGB
      Acharya et al. (2005)
      • Acharya N.V.
      • Pickering R.M.
      • Wilton L.W.
      • Shakir S.A.
      The safety and effectiveness of newer antiepileptics: a comparative postmarketing cohort study.
      U.K.D20410,690122971LTG/GBPAdverse events causing treatment failure
      Iorio et al. (2007)
      • Iorio M.L.
      • Moretti U.
      • Colcera S.
      • Magro L.
      • Meneghelli I.
      • Motola D.
      • et al.
      Use and safety profile of antiepileptic drugs in Italy.
      ItalyAll ageLTG 34/51 (67%); CBZ 124/208 (60%); PB 68/98 (69%); GBP 20/80 (25%); PHT 30/56 (54%); VPA 14/55 (25%); OXC 11/43 (26%); VGB 0/35 (0%)RashSkin reactions/number of reports total
      SJS: PB 10; CBZ 13; PHT 7; LTG 4SJSSerious skin reactions
      TEN: PB 7; CBZ 1; PHT 1; LTG 1TEN
      Lange-Asschenfeldt et al. (2009)
      • Lange-Asschenfeldt C.
      • Grohmann R.
      • Lange-Asschenfeldt B.
      • Engel R.R.
      • Rüther E.
      • Cordes J.
      Cutaneous adverse reactions to psychotropic drugs: data from a multicenter surveillance program.
      GermanyAll age1727316018,706LTG/CBZCutaneous adverse reactions to psychotropic drugs
      17273131409LTG/OXC
      172731914,617LTG/VPA
      Aurich-Barrera et al. (2010)
      • Aurich-Barrera B.
      • Wilton L.
      • Brown D.
      • Shakir S.
      Paediatric postmarketing pharmacovigilance using prescription-event monitoring: comparison of the adverse event profiles of lamotrigine prescribed to children and adults in England.
      U.K.Children4824091317248LTG rash: children/adultsReasons for stopping
      5245247373LTG SJS: children/adults
      Wallerstedt et al. (2011)
      • Wallerstedt S.M.
      • Brunlöf G.
      • Sundström A.
      Rates of spontaneous reports of adverse drug reactions for drugs reported in children: a cross-sectional study with data from the Swedish adverse drug reaction database and the Swedish Prescribed Drug Register.
      SwedenChildren31654Serious individual case safety reports (ICSRs)
      C: mean age: male 29 y, female 30 y; D: mean age: 30.5 y; LTG: lamotrigine; VPA: valproic acid; CBZ: carbamazepine; OXC: oxcarbazepine; GBP: gabapentin; VGB: vigabatrin; ID: incidence density; SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis.

      3.2 Incidence of skin rash

      The overall incidence of skin rash with LTG treatment was 9.98% (444/4447) from 26 prospective clinical trials, 7.19% (214/2977) from 8 retrospective studies, and 2.09% (547/26,126) from 5 postmarketing reports.

      3.3 Odds ratio of skin rash

      3.3.1 Meta-analysis from prospective studies

      To investigate the specific contribution of LTG in the development of a skin rash, we independently evaluated the OR of LTG-associated skin rashes compared with placebo control, lithium, and other AEDs. Our results showed that the use of LTG did not significantly increase the risk of developing a skin rash over placebo [in neuropathic pain group (4 studies): OR 2.41, 95% CI: 0.99–5.91; in epilepsy group (2 studies): OR 1.99, 95% CI: 0.95–4.81; and in bipolar group (6 studies): OR 1.49, 95% CI: 0.87–2.56], lithium (5 articles: OR 1.12, 95% CI: 0.62–2.03), other aromatic AEDs (5 articles: OR 0.99, 95% CI: 0.53–1.84), or non-aromatic AEDs (3 articles: OR 1.44, 95% CI: 0.75–2.76) (Fig. 2). We did not perform a sensitivity analysis, and we studied the published bias to examine the stability and reliability of pooled OR of LTG-related skin rashes by the sequential omission of individual studies due to the small number of studies in each group.
      Figure thumbnail gr2
      Fig. 2The prospective studies about OR of LTG-skin rash compared with other drugs.

      3.3.2 Meta-analysis from retrospective studies

      All 6 retrospective studies were epileptic studies. There was a significantly higher OR in patients with LTG treatment compared with non-aromatic AEDs [VPA (4 studies): OR 13.21, 95% CI 6.71–26.01; TPM (3 studies): OR 4.16, 95% CI 1.82–9.47; GBP (2 studies): OR 11.71, 95% CI 2.88–47.58; LEV (4 studies): OR: 8.87, 95% CI 4.32–18.23], except ZNS [(3 studies): OR 1.35, 95% CI 0.88–2.08](Fig. 3). There was no significant difference in the rash risk between patients with LTG and aromatic AEDs [CBZ (6 studies): OR 1.41, 95% CI 0.93–2.15; OXC (5 studies): OR 1.38, 95% CI 0.99–1.92; and PHT (4 studies): OR 0.80, 95% CI 0.63–1.02], except PB [(3 studies): OR 1.99, 95% CI 1.25–3.17] (Fig. 4). Due to the small number of studies in each group, we did not perform a sensitivity analysis, and we studies the published bias to examine the stability and reliability of pooled OR of LTG-related skin rash.
      Figure thumbnail gr3
      Fig. 3The retrospective studies about OR of LTG-skin rash compared with non-aromatic AEDs.
      Figure thumbnail gr4
      Fig. 4The retrospective studies about OR of LTG-skin compared with aromatic AEDs.
      Furthermore, in prospective studies, we observed a low heterogeneity when studying LTG with placebo in epileptic patients, with placebo or lithium in bipolar patients, and with non-aromatic AEDs (I2 = 0%, 7.4%, 0%, 8.3%, respectively). However, a considerable heterogeneity of more than 50% was observed in cases of placebo in patients with neuropathic pain and aromatic AEDs (I2 = 59.9%, 54.7%, respectively).
      In retrospective studies, we observed a low heterogeneity when studying the LTG with OXC, PHT, VPA, GBP, LEV, and ZNS (I2 = 0%, 0%, 0%, 5%, 0%, 0%, respectively). However, a considerable heterogeneity of more than 50% was observed in cases of CBZ, TPM (I2 = 69.8%, 65.2%, respectively).

      4. Discussion

      Our estimates showed that the overall incidence of skin rash with LTG therapy was 9.98% from prospective studies, 7.19% from retrospective studies, and 2.09% from postmarketing reports. The prospective study results were consistent with the previous pooled prospective data for 3348 patients from placebo-controlled and open trials of LTG in adults, which showed that 10% of patients exposed to LTG developed a rash [
      • Manasco P.
      • Mullens L.
      • Matsuo F.
      Skin rash associated with Lamictal: incidence, time to onset and risk factors.
      ,
      • Guberman A.H.
      Lamotrigine-associated rash risk/benefit considerations in adults and children.
      ].
      This incidence is lower in retrospective studies compared to prospective studies, which indicates a limitation in this type of study. A retrospective study usually underestimates the true incidence due to recall bias or a physician bias when determining whether a specific rash is related to a given medication.
      The postmarketing studies use relatively different methods from prospective trials or retrospective studies, which were performed by a spontaneous report or Prescription-Event Monitoring (PEM) to establish the safety of LTG and other drugs. There were four studies performed in the U.K., one study performed in Germany, one study performed in Italy, and one study performed in Sweden. The Drug Safety Research Unit (DSRU) performed PEM [
      • Mann R.D.
      Prescription-event monitoring recent progress and future horizons.
      ,
      • Layton D.
      • Pearce G.L.
      • Shakir S.A.W.
      Safety profile of tolterodine as used in general practice in England: results of prescription-event monitoring.
      ] of newly marketed drugs with widespread use in general practice in England, particularly with drugs that are intended for long-term use. However, systematic postmarketing surveillance of AEDs is still generally lacking, and large-scale postmarketing surveillance was performed to assess the safety of LTG in U.K. [
      • Mackay F.J.
      • Wilton L.V.
      • Pearce G.L.
      • Freemantle S.N.
      • Mann R.D.
      Safety of long-term lamotrigine in epilepsy.
      ,
      • Wong I.C.
      • Mawer G.E.
      • Sander J.W.
      Adverse event monitoring in lamotrigine patients: a pharmacoepidemiologic study in the United Kingdom.
      ,
      • Acharya N.V.
      • Pickering R.M.
      • Wilton L.W.
      • Shakir S.A.
      The safety and effectiveness of newer antiepileptics: a comparative postmarketing cohort study.
      ,
      • Aurich-Barrera B.
      • Wilton L.
      • Brown D.
      • Shakir S.
      Paediatric postmarketing pharmacovigilance using prescription-event monitoring: comparison of the adverse event profiles of lamotrigine prescribed to children and adults in England.
      ].
      The main weakness of comparative PEM analysis is the potential for bias to confound differences between drugs [
      • Mann R.D.
      Prescription-event monitoring recent progress and future horizons.
      ,
      • Layton D.
      • Pearce G.L.
      • Shakir S.A.W.
      Safety profile of tolterodine as used in general practice in England: results of prescription-event monitoring.
      ]. Underreporting is a main disadvantage because the absolute number of ADR reports is not truly known. Data obtained from spontaneous reports or PEM when taken alone do not accurately quantify the risk associated with a drug. The reporting rate may vary over time and be influenced by factors, such as media attention. Although such studies cannot eliminate bias as effectively as RCTs, their strength lies where the RCT is often weakest, in providing a large number of patients from whom relative discontinuation rates can be precisely estimated.
      In this meta-analysis of 21 prospective studies, we did not find a significant difference between patients with LTG and other drugs, including placebo, other ADEs and lithium (OR 0.99–2.41). In 6 respective studies, there was a significantly higher OR in patients with LTG compared with non-aromatic AEDs, which indicated that LTG treatment might significantly increase the risk of developing skin rash compared to non-aromatic AEDs. There was no significant different in rash risk between patients with LTG and aromatic AEDs, except PB. Due to few prospective control studies, we did not determine whether this merely reflected a publication bias or whether the risk of skin rash with LTG therapy is truly not higher compared to other aromatic AEDs or placebo.
      Epilepsy is a serious chronic brain disorder that is characterized by recurrent unprovoked seizures that can be successfully treated and controlled using mono- or polytherapy in most patients. Skin reactions are a common side effect of AEDs and a major cause of treatment discontinuation [
      • Aouam K.
      • BelHadj Ali H.
      • Youssef M.
      • Chaabane A.
      • Amri M.
      • Boughattas N.A.
      • et al.
      Carbamazepine-induced DRESS and HHV6 primary infection: the importance of skin tests.
      ]. Benign rash is relatively common with aromatic AEDs, such as CBZ, PHT and PB, with a frequency ranging from 5% to 15% of treated individuals. In addition, several newer drugs also frequently cause skin rashes, particularly LTG and OXC. Wang et al. [
      • Wang X.Q.
      • Shi X.B.
      • Au R.
      • Chen F.S.
      • Wang F.
      • Lang S.Y.
      Influence of chemical structure on skin reactions induced by antiepileptic drugs – the role of the aromatic ring.
      ] reported that skin reactions were three times more frequent with aromatic AEDs compared to non-aromatic AEDs.

      5. Reliability of the study

      There are several limitations to this study. First, the number of studies that addressed skin rashes with LTG therapy is small, in which only 4447 patients with LTG treatment from 26 prospective studies and 2977 patients from 8 retrospective studies were included in this study. A few studies have reported serious life-threatening rashes; however, we could not obtain the incidence of a serious rash. Second, different study designs, treatment strategies, durations and concomitant administration of drugs contribute to an increase in the clinical heterogeneity of the meta-analysis, which make the interpretation of the meta-analysis more problematic. Third, the data did not allow us to perform multivariable regression to determine which variables were independently related with LTG-induced skin rash, including the LTG titration speed and cotreatment with VPA. Forth, it was not possible to use narrower age categories because the studies provided either overall estimates or age-specific estimates with different age categories. Finally, we could not perform a publication bias test in our review because the meta-analyses in each group were less than 10 studies, which are considered the baseline number for testing publication bias.
      Nevertheless, despite these limitations, our study provides a platform for vast heterogeneous data in studies exploring the risk of LTG-induced skin rash under a common roof and provides some important insights.

      6. Conclusion

      On the basis of the findings of the present study and the existing literature, the overall incidence of skin rash with LTG therapy was 9.98% from prospective studies, 7.19% from retrospective studies, and 2.09% from postmarketing reports. These data could potentially be used to assess the burden and analyze the risk of developing a skin rash in patients with LTG therapy. Our results showed that LTG significantly increased the risk of developing a skin rash compared to non-aromatic AEDs. Taken together, these results support the need for large prospective population-based studies and clinical trials to confirm whether LTG increases the risk of developing a skin rash compared to other drugs.

      Conflicts of interest statement

      None declared.

      Acknowledgments

      This work was supported by a National Natural Science Foundation grant funded by the Chinese government. (No. 81271438) We also thank Prof. Gilter (Department of Genetics, Stanford University School of Medicine) for inviting Dr. Wang as a visiting scholar of Stanford University and for providing access to published papers.

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