Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome Probably Induced by a Lamotrigine–Ginseng Drug Interaction Amy P. Myers,1,* Troy A. Watson,2 and Steven B. Strock3 1
Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, Tennessee; 2University of Tennessee College of Pharmacy, Memphis, Tennessee; 3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
The likelihood of a drug reaction with lamotrigine is increased by dose escalation that is too rapid or drug interactions that increase the concentration of lamotrigine. There is a well-documented interaction between valproic acid and lamotrigine in which lamotrigine levels are increased, subsequently increasing the risk of a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by fever, lymphadenopathy, diffuse maculopapular rash, multivisceral involvement, eosinophilia, and atypical lymphocytes and has a mortality rate of 10–40%. We describe the first case, to our knowledge, of DRESS syndrome that was probably induced by a drug interaction between lamotrigine and ginseng. A 44-year-old white man presented to the emergency department after experiencing a possible seizure. His medical history included two other lifetime events concerning for seizures at ages 14 and 29 years old. After referral to the neurology clinic, he was diagnosed with generalized tonic-clonic seizure disorder, and lamotrigine was started with up-titration according to the drug’s package insert to a goal dosage of 150 mg twice/day. The patient had also been taking deer antler velvet and ginseng that he continued during his lamotrigine therapy. On day 43 of therapy, the patient presented to the emergency department with a pruritic rash that had started on his extremities and spread to his torso. He was thought to have experienced a drug reaction to lamotrigine, and the drug was discontinued. Thirteen days later, the patient was admitted from the acute care clinic for inpatient observation due to laboratory abnormalities in the setting of continued rash, headache, and myalgias. His admission laboratory results on that day were remarkable for leukocytosis, with a white blood cell count up to 17.6 9 103/ mm3, with a prominent eosinophilia of 3.04 9 103/mm3; his liver enzyme levels were also elevated, with an aspartate aminotransferase level of 191 U/L, alanine aminotransferase level 473 U/L, alkaline phosphatase level 465 U/L, and total bilirubin level 1.4 mg/dl. Use of the Drug Interaction Probability Scale indicated that a drug interaction between lamotrigine and ginseng was the probable cause (score of 5). The proposed mechanism of the interaction is ginseng inhibition of the uridine diphosphate glucuronosyltransferase 2B7 enzyme, similar to the mechanism of the interaction with valproic acid. Clinicians should be aware of this probable drug interaction and avoid coadministration of ginseng and lamotrigine or use a more conservative dose titration of lamotrigine for patients who are also taking ginseng. KEY WORDS DRESS, lamotrigine, ginseng, drug interaction. (Pharmacotherapy 2015;35(3):e9–e12) doi: 10.1002/phar.1550 Amy Myers: Centers for Medicare and Medicaid Services, Health Care Innovation Challenge (grant no. 1C1CMS331006-02-00). *Address for correspondence: Amy Myers, 1211 Medical Center Drive B-131 Nashville, TN 37232; Phone: 205-2531607; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
A drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, also known as drug-induced hypersensitivity syndrome (DIHS), is characterized by fever, lymphadenopathy, diffuse maculopapular rash, multivisceral involvement, eosinophilia, and atypical lympho-
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PHARMACOTHERAPY Volume 35, Number 3, 2015
cytes. The syndrome has a mortality rate of 10– 40%. Internal organ involvement is present in ~90% of patients and most commonly involves the liver, kidneys, and lungs, with the liver the most frequent. Most patients begin to develop signs and symptoms 2 weeks after initiating an insulting drug therapy.1–4 The precise incidence of DRESS syndrome is unknown but is thought to range from 1 in 1000–1 in 10,000 individuals.5–7 The exact mechanism is not fully understood, but three components are considered: deficiency or abnormality of the epoxide hydroxylase enzyme that detoxifies the metabolites of aromatic amine anticonvulsants (metabolic pathway), associated reactivation of herpes-type viruses, and ethnic predisposition with certain human leukocyte antigen subtypes.7, 8 There is a well-documented interaction between valproic acid and lamotrigine in which lamotrigine levels are increased, subsequently increasing the risk of DRESS syndrome.9–11 We describe a case of DRESS syndrome in a patient who was taking ginseng and lamotrigine. No documented evidence of this drug–drug interaction could be found in our review of the literature. Case Report A 44-year-old white man presented to a local hospital emergency department after experiencing a possible seizure. His medical history included depression, gastroesophageal reflux disease, and congenital gastrointestinal abnormalities, as well as two other lifetime events concerning for seizures at ages 14 and 29 years. He had no history of smoking and reported eight alcoholic drinks per week. The patient reported having a rash on exposure to penicillin. His home medications included deer antler vel-
vet and ginseng, which were started 4 months earlier, as well as sildenafil as needed. The patient was not taking any antiepileptic medications. At the time of presentation for this seizure, the patient was referred to the neurology clinic. A subsequent electroencephalogram showed R-anterior midtemporal slow-wave activity, and magnetic resonance imaging of the brain showed T2 hyperintensities in the left and right cerebellum. He was diagnosed with generalized tonicclonic seizure disorder, and lamotrigine was started with up-titration according to the drug’s package insert to a goal dosage of 150 mg twice/ day. The patient continued both deer antler velvet and ginseng during his lamotrigine therapy (Table 1). On day 19 of lamotrigine therapy, the patient contacted the clinic and reported a mild dull headache. On day 29 of therapy, however, the patient continued to increase his lamotrigine dose from 50 to 100 mg/day as instructed in the package insert. On day 35 of lamotrigine therapy, the patient reported an erythematous, pruritic, swollen rash on the inside of his left arm that had been present for 1 week. A second rash on his face that had also been present for 1 week was noted at that time and was thought to represent acne. The patient was advised to continue lamotrigine 150 mg/day and was given hydrocortisone cream for his rash, with instructions to call the clinic if his rash progressed. On day 43 of lamotrigine treatment, the patient presented to the emergency department with a chief complaint of pruritic rash for the past 24 hours. The rash had started on his extremities and then spread to his torso. On review of systems, the patient reported mild chest tightness without associated shortness of breath; his vital signs were normal. No laboratory studies were obtained. The patient was
Table 1. Timeline of Lamotrigine Dosing and the Patient’s Symptoms Day
Lamotrigine dose received by patienta
Day of lamotrigine therapy 0 Initiated at 25 mg once/day 15 50 mg once/day 19 50 mg once/day 29 100 mg once/day 35 150 mg once/day 43 Lamotrigine discontinued Day after discontinuation of lamotrigine therapy 6 – 11 – 13 Lamotrigine level < 1.0 lg/ml NA = not applicable.
Symptoms
Setting of patient contact
Seizure (before initiating lamotrigine) NA Headache Unknown Itchy rash on inside of arm Diffuse rash
Neurology clinic NA Neurology clinic NA Neurology clinic Emergency department
Persistent rash and headache Same as above, plus myalgia and emesis Same as above
Neurology clinic Acute care clinic Inpatient medicine ward
DRESS WITH LAMOTRIGINE AND GINSENG INTERACTION Myers et al thought to have experienced a drug reaction to lamotrigine, so the drug was discontinued, and he was discharged home. On day 6 after discontinuation of lamotrigine therapy, the patient called the neurology clinic for his persistent rash and a new headache. He was given a methylprednisolone dose pack for the rash and was told to take naproxen, up to 500 mg twice/day for 3 days, for his headache. On day 11 after discontinuation of therapy, the patient presented to an acute care clinic with a persistent headache for the past 10 days, diffuse myalgias for 5 days, dark urine for 2 days, and one episode of emesis 4 days earlier. A urine dipstick was positive for urobilinogen, and ciprofloxacin was started for possible prostatitis. A complete metabolic panel drawn at the time of the clinic visit later returned with liver enzyme levels elevated in an obstructive pattern; thus the patient was contacted and admitted to the inpatient medicine ward. The patient reported taking 2–3 acetaminophen 500-mg tablets/day for headache and denied drinking any alcohol since starting lamotrigine. Admission laboratory results (day 13 after discontinuation of lamotrigine therapy) were notable for leukocytosis, with a white blood cell count up to 17.6 9 103/mm3, with prominent eosinophilia of 3.04 9 103/mm3. His liver enzyme levels remained elevated, with an aspartate aminotransferase level of 191 U/L, alanine aminotransferase level 473 U/L, alkaline phosphatase level 465 U/L, and total bilirubin level 1.4 mg/dl (Table 2). The patient’s lamotrigine level was less than1 lg/ml indicating lamotrigine clearance, his acetaminophen level was normal at 3.4 lg/ml, and his alcohol level was negative. Hepatitis A, B, and C panels were negative for acute hepatitis. His creatine kinase level was normal at 12 U/L, antinuclear antibody was negative, and a monospot test was positive, but Epstein-Barr virus quantification showed less
e11
than 200 copies/ml. Human herpesvirus (HHV) immunoglobulin G was positive, indicating a past or present infection, but, unfortunately, no HHV-6 or HHV-7 polymerase chain reaction testing was performed. Inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, and ferritin levels, were elevated. Abdominal ultrasound was performed and was read as normal without evidence of biliary obstruction. The patient was diagnosed with DRESS syndrome based on the following criteria: rash on more than 50% of his body, eosinophilia, myalgias, and liver involvement. He was discharged on hospital day 2 with instructions to follow up with the neurology clinic. His liver function tests and eosinophil level normalized by day 19 after discontinuation of lamotrigine. Discussion Lamotrigine is hepatically eliminated through glucuronidation by the uridine diphosphate glucuronosyltransferase (UGT) enzyme, with an elimination half-life that can range from 12.6– 58.8 hours. Lamotrigine metabolism can be susceptible to both hepatic microsomal enzymeinducing and enzyme-inhibiting agents.12–14 For example, valproic acid is a broad-spectrum inhibitor of UGT enzymes, epoxide hydrolase, and cytochrome P450 2C enzymes.15 The inhibition of UGT enzymes by valproic acid causes a longer elimination half-life that can lead to elevated levels of lamotrigine related to anticonvulsant hypersensitivity syndrome (e.g., DRESS syndrome). This interaction is well documented in the literature, and a more conservative titration of lamotrigine when used in combination with valproic acid is recommended in the package insert.12, 16, 17 This case report, to our knowledge, is the first description of a possible interaction between
Table 2. Laboratory Resultsa Day after discontinuation of lamotrigine therapy Baseline 11 12 13 19
Eosinophil count, 9103/mm3
White blood cell count, 9103/mm3
Albumin level, g/dl
Total bilirubin level, mg/dl
Alkaline phosphatase level, U/L
Aspartate aminotransferase level, U/L
Alanine aminotransferase level, U/L
0.1 2.02 3.04 3.65 1.51
10 15.3 17.6 16.3 8.8
4.3 3.5 – 2.8 3.5
0.6 – 1.4 0.9 0.7
78 515 465 451 303
20 250 191 177 40
23 591 473 375 86
a Normal ranges are as follows: eosinophil count 0–0.5 9 103/mm3; white blood cell count 3.9–10.7 9 103/mm3; albumin level 3.5–5.2 g/dl; total bilirubin level 0.2–1.2 mg/dl; alkaline phosphatase level 40–150 U/L; aspartate aminotransferase level 5–40 U/L; alanine aminotransferase level 0–55 U/L.
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ginseng and lamotrigine. An in vitro study found that the specific UGT enzymes responsible for the glucuronidation of lamotrigine were UGT2B7 and UGT1A4.18 The authors described inhibition of UGT2B7 by valproic acid as the cause of increased concentrations of lamotrigine when the two drugs are coadministered. Another study compared purified dry extract of ginseng to well-documented UGT inhibitors and demonstrated a significant inhibition of UGT1A1 and a weak inhibition of both UGT1A9 and UGT2B7 by ginseng.19 Thus it is likely that ginseng can exhibit this same mechanism of interaction. We postulate that the inhibition of UGT2B7 by ginseng predisposed our patient to a drug hypersensitivity reaction. The Drug Interaction Probability Scale (DIPS) was developed to provide a guide to evaluating drug interaction causation in patients.20 Specifically, it was developed to provide the probability of a drug–drug interaction and is widely regarded.21 The DIPS uses a series of questions relating to the potential drug interaction to estimate a probability score. Using the DIPS for our patient’s case, a score of 5 was calculated, indicating that the drug interaction was a probable cause of DRESS syndrome. The causality is supported by the timing of the exposure (temporal relationship), the knowledge that DRESS syndrome caused by lamotrigine is a dose-related effect, the elimination of other routine causes of the patient’s symptoms and laboratory results, and the fact that the DRESS syndrome can be precipitated by other drug interactions such as valproic acid and lamotrigine. Additional reports of this interaction or evidence of recurrence of the syndrome with rechallenge (which was not undertaken in our patient) would strengthen the causality of our proposed drug interaction between lamotrigine and ginseng. Conclusion Based on this case report, clinicians should exercise caution when initiating lamotrigine in patients who take herbal supplements, specifically ginseng. Extensive drug histories, including both over-the-counter and herbal products, should be conducted. We recommend a more conservative titration schedule, such as the one used for patients taking valproic acid, for patients taking ginseng or any herbal supplements that have an unknown effect on lamotrigine metabolism.
References 1. Kardaun SH, Sekula P, Valeyrie-Allanore L, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol 2013;169:1071–80. 2. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007;156:609–11. 3. Lee T, Lee YS, Yoon SY, et al. Characteristics of liver injury in drug-induced systemic hypersensitivity reactions [abstract 1]. J Am Acad Dermatol 2013;69:407–15. Epub 2013 Apr 28. 4. Pi~ nana E, Lei SH, Merino R, et al. DRESS-syndrome on sulfasalazine and naproxen treatment for juvenile idiopathic arthritis and reactivation of human herpevirus 6 in an 11-year-old Caucasian boy [abstract 1]. J Clin Pharm Ther 2010;35:365–70. 5. Fiszenson-Albala F, Auzerie V, Mahe E, et al. A 6-month prospective survey of cutaneous drug reactions in a hospital setting. Br J Dermatol 2003;149:1018–22. 6. Criado PR, Avancini J, Santi CG, Medrado AT, Rodrigues CE, de Carvalho JF. Drug reaction with eosinophilia and systemic symptoms (DRESS): a complex interaction of drugs, viruses and the immune system. Isr Med Assoc J 2012;14:577–82. 7. Bohan KH, Mansuri TF, Wilson NM. Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical care. Pharmacotherapy 2007;27:1425–39. 8. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med 2011;124:588–97. Epub 2011 May 17. 9. Rahman M, Haider N. Anticonvulsant hypersensitivity syndrome from addition of lamotrigine to divalproex [letter to the editor]. Am J Psychiatry 2005;162:1021. 10. Greiner C, Wittmann M, Haen E. Lamotrigine serum concentrations under valproate comedication: “contraindication” or “safe combination”? A case report. Pharmacopsychiatry 2007;40:287–9. 11. Gidal BE, Sheth R, Parnell J, Maloney K, Sale M. Evaluation of VPA dose and concentration effects on lamotrigine pharmacokinetics: implications for conversion to lamotrigine monotherapy [abstract 1]. Epilepsy Res 2003;57:85–93. 12. Information P. LAMICTAL chewable dispersible oral tablets, oral tablets, orally disintegrating tablets, lamotrigine chewable dispersible oral tablets, oral tablets, orally disintegrating tablets. Research Triangle Park, NC: GlaxoSmithKline; 2009. 13. Morris R, Black A, 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;22:656–60. 14. Burstein AH. Lamotrigine. Pharmacotherapy 1995;15:129–43. 15. Anderson GD. A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 1998;32:554–63. 16. Kocak S, Girisgin SA, Gul M, et al. Stevens-Johnson syndrome due to concomitant use of lamotrigine and valproic acid. Am J Clin Dermatol 2007;8:107–11. 17. Page RL II, O’Neil MG, Yarbrough DR III, et al. Fatal toxic epidermal necrolysis related to lamotrigine administration. Pharmacotherapy 1998;18:392–8. 18. Rowland A, Elliot DJ, Williams JA, Mackenzie PI, Dickinson RG, Miners JO. In vitro characterization of lamotrigine N2glucuronidation and the lamotrigine-valproic acid interaction. Drug Metab Dispos 2006;34:1055–62. Epub 2006 Mar 24. 19. Zheng YF, Bae SH, Choi EJ, et al. Evaluation of the in vitro/in vivo drug interaction potential of BST204, a purified dry extract of ginseng, and its four bioactive ginsenosides through cytochrome P450 inhibition/induction and UDP-glucuronosyltransferase inhibition. Food Chem Toxicol 2014;68:117–27. Epub 2014 Mar 12. 20. Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007;41:674–80. Epub 2007 Mar 27. 21. DeVane CL. Evidence for drug exposure causally associated with adverse events. Pharmacotherapy 2013;33:115–7.
Department of Pharmaceutical Services, Vanderbilt University Medical Center, Nashville, Tennessee; 2University of Tennessee College of Pharmacy, Memphis, Tennessee; 3Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
The likelihood of a drug reaction with lamotrigine is increased by dose escalation that is too rapid or drug interactions that increase the concentration of lamotrigine. There is a well-documented interaction between valproic acid and lamotrigine in which lamotrigine levels are increased, subsequently increasing the risk of a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. This syndrome is characterized by fever, lymphadenopathy, diffuse maculopapular rash, multivisceral involvement, eosinophilia, and atypical lymphocytes and has a mortality rate of 10–40%. We describe the first case, to our knowledge, of DRESS syndrome that was probably induced by a drug interaction between lamotrigine and ginseng. A 44-year-old white man presented to the emergency department after experiencing a possible seizure. His medical history included two other lifetime events concerning for seizures at ages 14 and 29 years old. After referral to the neurology clinic, he was diagnosed with generalized tonic-clonic seizure disorder, and lamotrigine was started with up-titration according to the drug’s package insert to a goal dosage of 150 mg twice/day. The patient had also been taking deer antler velvet and ginseng that he continued during his lamotrigine therapy. On day 43 of therapy, the patient presented to the emergency department with a pruritic rash that had started on his extremities and spread to his torso. He was thought to have experienced a drug reaction to lamotrigine, and the drug was discontinued. Thirteen days later, the patient was admitted from the acute care clinic for inpatient observation due to laboratory abnormalities in the setting of continued rash, headache, and myalgias. His admission laboratory results on that day were remarkable for leukocytosis, with a white blood cell count up to 17.6 9 103/ mm3, with a prominent eosinophilia of 3.04 9 103/mm3; his liver enzyme levels were also elevated, with an aspartate aminotransferase level of 191 U/L, alanine aminotransferase level 473 U/L, alkaline phosphatase level 465 U/L, and total bilirubin level 1.4 mg/dl. Use of the Drug Interaction Probability Scale indicated that a drug interaction between lamotrigine and ginseng was the probable cause (score of 5). The proposed mechanism of the interaction is ginseng inhibition of the uridine diphosphate glucuronosyltransferase 2B7 enzyme, similar to the mechanism of the interaction with valproic acid. Clinicians should be aware of this probable drug interaction and avoid coadministration of ginseng and lamotrigine or use a more conservative dose titration of lamotrigine for patients who are also taking ginseng. KEY WORDS DRESS, lamotrigine, ginseng, drug interaction. (Pharmacotherapy 2015;35(3):e9–e12) doi: 10.1002/phar.1550 Amy Myers: Centers for Medicare and Medicaid Services, Health Care Innovation Challenge (grant no. 1C1CMS331006-02-00). *Address for correspondence: Amy Myers, 1211 Medical Center Drive B-131 Nashville, TN 37232; Phone: 205-2531607; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
A drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, also known as drug-induced hypersensitivity syndrome (DIHS), is characterized by fever, lymphadenopathy, diffuse maculopapular rash, multivisceral involvement, eosinophilia, and atypical lympho-
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PHARMACOTHERAPY Volume 35, Number 3, 2015
cytes. The syndrome has a mortality rate of 10– 40%. Internal organ involvement is present in ~90% of patients and most commonly involves the liver, kidneys, and lungs, with the liver the most frequent. Most patients begin to develop signs and symptoms 2 weeks after initiating an insulting drug therapy.1–4 The precise incidence of DRESS syndrome is unknown but is thought to range from 1 in 1000–1 in 10,000 individuals.5–7 The exact mechanism is not fully understood, but three components are considered: deficiency or abnormality of the epoxide hydroxylase enzyme that detoxifies the metabolites of aromatic amine anticonvulsants (metabolic pathway), associated reactivation of herpes-type viruses, and ethnic predisposition with certain human leukocyte antigen subtypes.7, 8 There is a well-documented interaction between valproic acid and lamotrigine in which lamotrigine levels are increased, subsequently increasing the risk of DRESS syndrome.9–11 We describe a case of DRESS syndrome in a patient who was taking ginseng and lamotrigine. No documented evidence of this drug–drug interaction could be found in our review of the literature. Case Report A 44-year-old white man presented to a local hospital emergency department after experiencing a possible seizure. His medical history included depression, gastroesophageal reflux disease, and congenital gastrointestinal abnormalities, as well as two other lifetime events concerning for seizures at ages 14 and 29 years. He had no history of smoking and reported eight alcoholic drinks per week. The patient reported having a rash on exposure to penicillin. His home medications included deer antler vel-
vet and ginseng, which were started 4 months earlier, as well as sildenafil as needed. The patient was not taking any antiepileptic medications. At the time of presentation for this seizure, the patient was referred to the neurology clinic. A subsequent electroencephalogram showed R-anterior midtemporal slow-wave activity, and magnetic resonance imaging of the brain showed T2 hyperintensities in the left and right cerebellum. He was diagnosed with generalized tonicclonic seizure disorder, and lamotrigine was started with up-titration according to the drug’s package insert to a goal dosage of 150 mg twice/ day. The patient continued both deer antler velvet and ginseng during his lamotrigine therapy (Table 1). On day 19 of lamotrigine therapy, the patient contacted the clinic and reported a mild dull headache. On day 29 of therapy, however, the patient continued to increase his lamotrigine dose from 50 to 100 mg/day as instructed in the package insert. On day 35 of lamotrigine therapy, the patient reported an erythematous, pruritic, swollen rash on the inside of his left arm that had been present for 1 week. A second rash on his face that had also been present for 1 week was noted at that time and was thought to represent acne. The patient was advised to continue lamotrigine 150 mg/day and was given hydrocortisone cream for his rash, with instructions to call the clinic if his rash progressed. On day 43 of lamotrigine treatment, the patient presented to the emergency department with a chief complaint of pruritic rash for the past 24 hours. The rash had started on his extremities and then spread to his torso. On review of systems, the patient reported mild chest tightness without associated shortness of breath; his vital signs were normal. No laboratory studies were obtained. The patient was
Table 1. Timeline of Lamotrigine Dosing and the Patient’s Symptoms Day
Lamotrigine dose received by patienta
Day of lamotrigine therapy 0 Initiated at 25 mg once/day 15 50 mg once/day 19 50 mg once/day 29 100 mg once/day 35 150 mg once/day 43 Lamotrigine discontinued Day after discontinuation of lamotrigine therapy 6 – 11 – 13 Lamotrigine level < 1.0 lg/ml NA = not applicable.
Symptoms
Setting of patient contact
Seizure (before initiating lamotrigine) NA Headache Unknown Itchy rash on inside of arm Diffuse rash
Neurology clinic NA Neurology clinic NA Neurology clinic Emergency department
Persistent rash and headache Same as above, plus myalgia and emesis Same as above
Neurology clinic Acute care clinic Inpatient medicine ward
DRESS WITH LAMOTRIGINE AND GINSENG INTERACTION Myers et al thought to have experienced a drug reaction to lamotrigine, so the drug was discontinued, and he was discharged home. On day 6 after discontinuation of lamotrigine therapy, the patient called the neurology clinic for his persistent rash and a new headache. He was given a methylprednisolone dose pack for the rash and was told to take naproxen, up to 500 mg twice/day for 3 days, for his headache. On day 11 after discontinuation of therapy, the patient presented to an acute care clinic with a persistent headache for the past 10 days, diffuse myalgias for 5 days, dark urine for 2 days, and one episode of emesis 4 days earlier. A urine dipstick was positive for urobilinogen, and ciprofloxacin was started for possible prostatitis. A complete metabolic panel drawn at the time of the clinic visit later returned with liver enzyme levels elevated in an obstructive pattern; thus the patient was contacted and admitted to the inpatient medicine ward. The patient reported taking 2–3 acetaminophen 500-mg tablets/day for headache and denied drinking any alcohol since starting lamotrigine. Admission laboratory results (day 13 after discontinuation of lamotrigine therapy) were notable for leukocytosis, with a white blood cell count up to 17.6 9 103/mm3, with prominent eosinophilia of 3.04 9 103/mm3. His liver enzyme levels remained elevated, with an aspartate aminotransferase level of 191 U/L, alanine aminotransferase level 473 U/L, alkaline phosphatase level 465 U/L, and total bilirubin level 1.4 mg/dl (Table 2). The patient’s lamotrigine level was less than1 lg/ml indicating lamotrigine clearance, his acetaminophen level was normal at 3.4 lg/ml, and his alcohol level was negative. Hepatitis A, B, and C panels were negative for acute hepatitis. His creatine kinase level was normal at 12 U/L, antinuclear antibody was negative, and a monospot test was positive, but Epstein-Barr virus quantification showed less
e11
than 200 copies/ml. Human herpesvirus (HHV) immunoglobulin G was positive, indicating a past or present infection, but, unfortunately, no HHV-6 or HHV-7 polymerase chain reaction testing was performed. Inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, and ferritin levels, were elevated. Abdominal ultrasound was performed and was read as normal without evidence of biliary obstruction. The patient was diagnosed with DRESS syndrome based on the following criteria: rash on more than 50% of his body, eosinophilia, myalgias, and liver involvement. He was discharged on hospital day 2 with instructions to follow up with the neurology clinic. His liver function tests and eosinophil level normalized by day 19 after discontinuation of lamotrigine. Discussion Lamotrigine is hepatically eliminated through glucuronidation by the uridine diphosphate glucuronosyltransferase (UGT) enzyme, with an elimination half-life that can range from 12.6– 58.8 hours. Lamotrigine metabolism can be susceptible to both hepatic microsomal enzymeinducing and enzyme-inhibiting agents.12–14 For example, valproic acid is a broad-spectrum inhibitor of UGT enzymes, epoxide hydrolase, and cytochrome P450 2C enzymes.15 The inhibition of UGT enzymes by valproic acid causes a longer elimination half-life that can lead to elevated levels of lamotrigine related to anticonvulsant hypersensitivity syndrome (e.g., DRESS syndrome). This interaction is well documented in the literature, and a more conservative titration of lamotrigine when used in combination with valproic acid is recommended in the package insert.12, 16, 17 This case report, to our knowledge, is the first description of a possible interaction between
Table 2. Laboratory Resultsa Day after discontinuation of lamotrigine therapy Baseline 11 12 13 19
Eosinophil count, 9103/mm3
White blood cell count, 9103/mm3
Albumin level, g/dl
Total bilirubin level, mg/dl
Alkaline phosphatase level, U/L
Aspartate aminotransferase level, U/L
Alanine aminotransferase level, U/L
0.1 2.02 3.04 3.65 1.51
10 15.3 17.6 16.3 8.8
4.3 3.5 – 2.8 3.5
0.6 – 1.4 0.9 0.7
78 515 465 451 303
20 250 191 177 40
23 591 473 375 86
a Normal ranges are as follows: eosinophil count 0–0.5 9 103/mm3; white blood cell count 3.9–10.7 9 103/mm3; albumin level 3.5–5.2 g/dl; total bilirubin level 0.2–1.2 mg/dl; alkaline phosphatase level 40–150 U/L; aspartate aminotransferase level 5–40 U/L; alanine aminotransferase level 0–55 U/L.
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PHARMACOTHERAPY Volume 35, Number 3, 2015
ginseng and lamotrigine. An in vitro study found that the specific UGT enzymes responsible for the glucuronidation of lamotrigine were UGT2B7 and UGT1A4.18 The authors described inhibition of UGT2B7 by valproic acid as the cause of increased concentrations of lamotrigine when the two drugs are coadministered. Another study compared purified dry extract of ginseng to well-documented UGT inhibitors and demonstrated a significant inhibition of UGT1A1 and a weak inhibition of both UGT1A9 and UGT2B7 by ginseng.19 Thus it is likely that ginseng can exhibit this same mechanism of interaction. We postulate that the inhibition of UGT2B7 by ginseng predisposed our patient to a drug hypersensitivity reaction. The Drug Interaction Probability Scale (DIPS) was developed to provide a guide to evaluating drug interaction causation in patients.20 Specifically, it was developed to provide the probability of a drug–drug interaction and is widely regarded.21 The DIPS uses a series of questions relating to the potential drug interaction to estimate a probability score. Using the DIPS for our patient’s case, a score of 5 was calculated, indicating that the drug interaction was a probable cause of DRESS syndrome. The causality is supported by the timing of the exposure (temporal relationship), the knowledge that DRESS syndrome caused by lamotrigine is a dose-related effect, the elimination of other routine causes of the patient’s symptoms and laboratory results, and the fact that the DRESS syndrome can be precipitated by other drug interactions such as valproic acid and lamotrigine. Additional reports of this interaction or evidence of recurrence of the syndrome with rechallenge (which was not undertaken in our patient) would strengthen the causality of our proposed drug interaction between lamotrigine and ginseng. Conclusion Based on this case report, clinicians should exercise caution when initiating lamotrigine in patients who take herbal supplements, specifically ginseng. Extensive drug histories, including both over-the-counter and herbal products, should be conducted. We recommend a more conservative titration schedule, such as the one used for patients taking valproic acid, for patients taking ginseng or any herbal supplements that have an unknown effect on lamotrigine metabolism.
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