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Valproate (Depakote; Depakene) Inhibition of Lamotrigine (Lamictal) and the Risk of Rash and Steven-Johnson Syndrome

Summary:

  • It is important to note that the coadministration of valproic acid and lamotrigine is possible given their FDA approved indications in epilepsy and bipolar disorder.
  • Unfortunately, lamotrigine has a black box warning (BBW) because of its association with causing serious skin rashes, including Stevens-Johnson Syndrome.  While the overall occurrence is low, it appears that pediatric patients are at greater risk with a reported incidence of 0.8% (8 per 1,000) and 0.3% (3 per 1,000) in adults on adjunct therapy for epilepsy.
  • The 2-3 fold increase in lamotrigine levels results from valproate's inhibition of UGT2B7 (a phase II glucuronidation pathway for lamotrigine inactivation and elimination), and is not a result of either of drug being substrates or inhibitors of CYP450 enzymes or drug transporters (such as P-gp, multidrug resistance-associated protein 2 (MRP2) or breast cancer resistance protein (BCRP)).
  • Since the risk increases in pediatric patients and those being exposed to higher concentrations of lamotrigine, it is recommended that lamotrigine be started at low doses and titrated slowly over several weeks.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewer:
Jon D. Herrington, PharmD, BCPS, BCOP
Last Reviewed: October 2015

Explanation

  • This is one of many drug-drug interactions where clinicians cannot rely solely on knowing the cytochrome P450 enzyme system for predicting drug interactions.  As it relates to this question, it is important to note that the coadministration of valproic acid and lamotrigine is possible given their FDA approved indications.  Regardless of the formulation used (divalproex sodium (as 1:1 sodium valproate:valproic acid; Depakote) or valproic acid only (Depakene)), the active form in the body is valproate and is approved as monotherapy and adjunctive therapy in complex partial seizures and pediatric patients (>10 years of age).  Similarly, lamotrigine is indicated as adjunctive therapy for partial seizures, generalized seizures of Lennox-Gastaut syndrome, and primary generalized tonic-clonic seizures in adult and pediatric patients (>2 years of age).  It is also important to note that both are FDA approved for treatment of Bipolar I Disorder, thus highlighting the possibility of their coadministration.  

    Unfortunately, lamotrigine has a black box warning (BBW) because of its association with causing serious skin rashes, including Stevens-Johnson Syndrome.  While the overall occurrence is low, it does appear that pediatric patients are at greater risk with a reported incidence of 0.8% (8 per 1,000) for pediatric patients  (< 16 years of age) and 0.3% (3 per 1,000) in adults on adjunct therapy for epilepsy.  In addition to age, other associated risk factors include coadministration of lamotrigine with valproate (regardless of formulation), exceeding the recommended initial doses of lamotrigine, and titrating the dose of lamotrigine too quickly.  Interestingly, neither valproate nor lamotrigine are known substrates or inhibitors of the cytochrome P450 enzyme system commonly associated with drug-drug interactions.  Also, it does not appear that the drug interaction is occurring at the level of transporters since valproic acid is not a substrate or inhibitor of P-glycoprotein (P-gp; an efflux pump) like lamotrigine, nor are either of them known substrates or inhibitors of other efflux pumps. (i.e. multidrug resistance-associated protein 2 (MRP2) or breast cancer resistance protein (BCRP)).  How then does valproic acid cause an increase in the levels of lamotrigine and subsequently increase the risk for serious skin rashes in some patients. 

    The interaction occurs through a phase II glucuronidation metabolic pathway catalyzed by a series of enzymes known as uridine diphosphate glucuronosyltransferase (UGT).  This process makes the lamotrigine more water soluble to facilitate elimination from the body.  Lamotrigine is primarily metabolized by UGT1A4 and 2B7 to its major inactive metabolite, 2-N-glucuronide conjugate, with most being found in the urine.  Because of this level of dependency on glucuronidation for lamotrigine's inactivation and elimination, anything that inhibits either one of these UGT enzymes will affect lamotrigine levels.  Valproate is a known inhibitor of UGT2B7 but does not effect UGT1A4.  One study showed that the AUC for lamotrigine increased 2.6 fold in patients taking valproate 500 mg twice daily.7  Additionally, the half-life of lamotrigine increases from 25 hrs to 70 hrs with coadministration of valproate.  It appears that valproate doses between 250-500 mg/day results in the maximal inhibition of lamotrigine metabolism.2

                                       Valproic Acid and Lamotrigine Drug Interaction

    While the incidence appears to be low, the higher incidence in pediatric patients and those being exposed to higher doses of lamotrigine warrants consideration of this interaction since the skin rashes can be life threatening.  As such, it is recommended that patients being newly started on lamotrigine undergo a minimum of a 5 week dose titration phase where patients are started out at lower than normal maintenance doses and increased slowly in 2 week intervals.

    References:

    1. Abbott Pharmaceuticals PR Ltd. Divalproex sodium (Depakote) product insert.  Barceloneta, PR.  October 2006.  Last accessed on 12/13/2008.   
    2. GlaxoSmithKline.  Lamotrigine (Lamictal) product insert.  Greenville, NC.  May 2007.  Last accessed on 12/13/2008. 
    3. Potschka H, Fedrowitz M, Loscher W.  P-glycoprotein-mediated efflux of phenobarbital, lamotrigine, and felbamate at the blood brain barrier: evidence from microdialysis experiments in rats.  Neurosci Lett.  2002;327:173-176.   
    4. Baltes S, Fedrowitz M, Tortos CL et al.  Valproic acid is not a substrate for P-glycoprotein or multidrug resistance proteins 1 and 2 in a number of in vitro and in vivo transport assays.  J Pharmacol Exp Ther.  2007;320(1):331-43.     
    5. Cerveny L, Pavek P, Malakova J et al.  Lack of interactions between breast cancer resistance protein (BCRP/ABCG2) and selected antiepileptic agents. Epilepsia.   2006;47(3):461-468.
    6. Rowland A, Elliot DJ, Williams JA et al.  In vitro characterization of lamotrigine N2-glucuronidation and the lamotrigine-valproic acid interaction. Drug Metab Dispos.  2006;34(6):1055-62.
    7. Morris RG, Black AB, Lam E et al.  Clinical study of lamotrigine and valproic acid in patients with epilepsy: using a drug interaction to advantage?  Ther Drug Monit.   2000;22:656-660.
    8. Patterson RM, Hoyle PC, Editorial Staff of the Publishers of Lawyers' Medical Cyclopedia eds.  Drugs in Litigation: Damage Awards Involving Prescription and Nonprescription Drugs.  2007 Edition.  LexisNexis.  San Francisco, CA.
    9. Saukas v. Walker St. Pharm., 2005 Mich. App. LEXIS 1847 (Mich. Ct. App. 2005).

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MESH Terms & Keywords

  • Valproate, Valproic Acid, Depakote, Depakene, Lamitcal, Lamotrigine, Rash, Steven Johns Syndrome