Phenobarbital/Lamotrigine CoadministrationInduced Blood Dyscrasia in a Patient with Epilepsy

Antonio Siniscalchi, Luca Gallelli, Giuseppina Calabr, Grazia Angela Tolotta, and Giovambattista De Sarro

he development of blood abnormalities during antiepileptic drug treatment has been recorded.1,2 In fact, hematologic adverse effects were reported in patients with epilepsy during phenobarbital (leukopenia) and lamotrigine (thrombocytopenia and leukopenia) monotherapy.3-7 Although the underlying mechanism in antiepileptic druginduced blood abnormalities is unknown, a drug interaction during antiepileptic drug treatment could induce adverse effects8; however, the new antiepileptic drugs have safer hematologic profiles than do conventional antiepileptic drugs.9 We report on a patient with epilepsy who developed leukopenia and thrombocytopenia during phenobarbital/lamotrigine treatment. Case Report A 45-year-old woman (weight 55 kg, height 167 cm) with a 10-year history of complex partial seizures being treated with phenobarbital 100 mg/day presented on May 18, 2009, due to the development of complex partial seizure episodes (8 episodes/month in the last 6 months). Clinical history excluded alcohol and othAuthor information provided at end of text.

OBJECTIVE: To report on a patient with epilepsy who developed leukopenia and thrombocytopenia during phenobarbital/lamotrigine treatment.

A 45-year-old woman with a 10-year history of complex partial seizures being treated with phenobarbital 100 mg/day presented due to the development of complex partial seizure episodes (8 episodes/month in the last 6 months). Results of laboratory tests on admission showed normal platelets (250 103/L) and white blood cells (8.2 103/L). After clinical evaluation, lamotrigine titrated to a final dose of 100 mg twice daily was added to the phenobarbital. About 2 months later no epileptic manifestations were reported, but hematologic tests revealed a decrease in both platelets (36 103/L) and white blood cells (2.0 103/L). One day later, phenobarbital was discontinued and the patient developed 2 episodes of complex partial seizure. Levetiracetam titrated to 1500 mg/day was added to lamotrigine, with a normalization of platelets (260 103/L) and white blood cell (7.9 103/L) counts about 20 days later. After a few days, levetiracetam was discontinued and phenobarbital rechallenge during lamotrigine treatment induced a new blood dyscrasia in about 2 weeks (platelets 80 103/L; white blood cells 3.2 103/L). Phenobarbital was discontinued and levetiracetam was restarted, with a recovery of normal hematopoiesis in 25 days. The patient is presently receiving treatment with both lamotrigine 200 mg/day and levetiracetam 1500 mg/day and shows no seizure symptoms, blood abnormalities, or other adverse effects.
DISCUSSION: Using the Horn Drug Interaction Probability Scale, we estimated a probable relationship between the drug-drug interaction and blood dyscrasia. The underlying mechanism of this interaction has not been well characterized. Cytochrome P450 enzyme induction by phenobarbital could be responsible for the production of reactive metabolites of lamotrigine that might be causative for the observed hematologic effects. A pharmacodynamic interaction between the 2 drugs is also a possible mechanism of this interaction. CONCLUSIONS:

CASE REPORT:

Our patient with epilepsy developed blood dyscrasia during lamotrigine/phenobarbital treatment. Clinicians should carefully monitor hematologic parameters during lamotrigine/phenobarbital treatment.

KEY WORDS: drug-drug interaction, leukopenia, lamotrigine, phenobarbital, thrombocytopenia.

Ann Pharmacother 2010;44:2031-4.

Published Online, 23 Nov 2010, theannals.com, DOI 10.1345/aph.1P335

theannals.com

The Annals of Pharmacotherapy

2010 December, Volume 44

2031

A Siniscalchi et al.

er drug abuse; moreover, she reported no significant past medical or surgical events. Family history was unremarkable. After neurologic evaluation, a baseline electroencephalogram disclosed mild, generalized background alpha activity throughout the recording. Blood chemical tests did not reveal any abnormality (platelets 250 103/L [reference range 142- 424]; white blood cell count 8.2 103/L [4.6-10.6]), and phenobarbital plasma concentrations were also within normal range (35 g/mL [15- 40]). One week later lamotrigine 50 mg/daily was added for seizure control. Two weeks later, June 8, 2009, no laboratory abnormalities and no adverse drug reactions were observed, so the lamotrigine dosage was increased to 100 mg twice daily. During follow-up on July 6, 2009, no clinical seizure activity was reported, while hematologic testing revealed a significant decrease in both platelets (36 103/L) and white blood cells (2.0 103/L) (Figure 1). Clinical and laboratory findings (enclosed bone marrow aspiration and biopsy) excluded the presence of leukemia, lymphoma, or other hematologic

diseases. Pharmacologic evaluation documented normal plasma concentrations of both drugs (phenobarbital 34.9 g/mL, lamotrigine 2.9 g/mL [2- 4]); however, even though no interaction was evident, phenobarbital was discontinued the next day. Two days later the patient developed 2 episodes of complex partial seizure, so levetiracetam titrated to a final dose of 1500 mg/day was added to lamotrigine, with a normalization of clinical seizure activity. Platelets and white blood cells returned to normal levels (260 and 7.9 103/L, respectively) about 20 days later (Figure 1). After obtaining informed consent from the patient, we decided to further investigate the possible adverse effect, and 1 day after the discontinuation of levetiracetam, phenobarbital rechallenge (100 mg/day) induced a new progressive decrease of both platelets (80 103/L) and white blood cells (3.2 103/L) in about 2 weeks (Figure 1). Phenobarbital was titrated to discontinuation over 10 days and levetiracetam was restarted, with a spontaneous recovery of normal hematopoiesis in 25 days (Figure 1).

Figure 1. White blood cell count and platelet count during treatment with phenobarbital (PB), lamotrigine (LMT), and levetiracetam (LEV).

2032

The Annals of Pharmacotherapy

2010 December, Volume 44

theannals.com

Phenobarbital/Lamotrigine CoadministrationInduced Blood Dyscrasia in a Patient with Epilepsy

In order to evaluate the relationship between the blood abnormality and drug-drug interaction, the Horn Drug Interaction Probability Scale was applied, estimating a probable relationship between the drug-drug interaction and blood abnormality.10 As of June 2010, the patient is receiving lamotrigine 200 mg/day (plasma concentration 3.6 g/mL) and levetiracetam 1500 mg/day (plasma concentration 12 g/mL) and shows no seizure symptoms, blood abnormalities (platelets 265 103/L; white blood cells 8.7 103/L), or other adverse effects. Discussion We report a case of leukopenia and thrombocytopenia that developed during phenobarbital/lamotrigine treatment in a patient with epilepsy. Phenobarbital did not control our patients seizures, so lamotrigine titrated to a final dose of 200 mg/day was added. Previous studies have reported that rapid dosage escalation with lamotrigine is able to induce idiosyncratic reactions such as skin rash; in contrast, in our patient, the escalation was performed over 2 weeks and no idiosyncratic reactions occurred, but 1 month later a decrease in both platelets and white blood cells was recorded. Lamotrigine treatment has been reported to be related to the development of hematologic toxicity4-7; however, because of phenobarbitals poor control of the patients seizures, we chose to discontinue it rather than the lamotrigine. During phenobarbital treatment, the patient developed 8 episodes/month of complex partial seizure in the last 6 months. Phenobarbital discontinuation induced a normalization in platelets and white blood cell count, while its rechallenge during lamotrigine therapy induced the development of blood abnormalities. Both pharmacologic evaluation and the Horn Drug Interaction Probability Scale documented a probable relationship between this drug-drug interaction and blood abnormality. It has been reported that lamotrigine and nonaromatic antiepileptic drugs (valproate, gabapentin, and topiramate) are hydroxylated to toxic metabolites (ie, arene oxides). If the detoxification of this toxic metabolite is insufficient, the covalent binding of such metabolites to cell macromolecules could lead to cell death and, by acting as haptens, to secondary hypersensitivity reactions.11 In particular, lamotrigine is primarily metabolized to its N-glucuronide and only minor amounts are converted by cytochrome P450 enzymes to an arene oxide intermediate able to induce systemic diseases.12 A pharmacokinetic interaction between phenobarbital and lamotrigine has been well reported in patients with epilepsy.13,14 Phenobarbital is a cytochrome P450 enzyme inductor,14 and even if our patients lamotrigine concentration was within normal range (2.9 g/mL; on follow-up 11 months later, 3.6
theannals.com

g/mL), we observed, in agreement with literature data,13 a reduction of lamotrigine plasma values during phenobarbital treatment. Therefore, it is possible that cytochrome P450 enzyme induction by phenobarbital could be responsible for the production of reactive metabolites of lamotrigine that might be causative for the observed hematologic effects. However, it is important to note that this could be a possible mechanism, but we cannot exclude a pharmacodynamic interaction. In fact, adverse events induced by pharmacodynamic interactions were documented in patients during polytherapy for epilepsy.15 Several studies reported that the addition of lamotrigine to carbamazepine may induce a pharmacodynamic interaction, resulting in carbamazepine toxicity.16 However, several reports documented that levetiracetam is also able to induce blood abnormality,17,18 but we did not note any alteration in blood cell count during levetiracetam/lamotrigine coadministration. In conclusion, our patient with epilepsy developed blood dyscrasia during lamotrigine/phenobarbital treatment, suggesting that greater care should be taken in monitoring hematologic parameters during such treatment. Further studies should be performed both to validate this observation and to evaluate the percentage of patients with hematologic toxicities during lamotrigine/phenobarbital treatment.
Antonio Siniscalchi MD, Department of Neuroscience, Neurology Division, Annunziata Hospital, Cosenza, Italy

Luca Gallelli MD PhD, Chair of Pharmacology, Department of Experimental and Clinical Medicine, School of Medicine, University Magna Graecia of Catanzaro; Clinical Pharmacology Unit, Mater Domini University Hospital, Catanzaro, Italy Giuseppina Calabr MD, Department of Experimental and Clinical Medicine, School of Medicine, University Magna Graecia of Catanzaro Grazia Angela Tolotta MD, Chair of Pharmacology, Department of Experimental and Clinical Medicine, School of Medicine, University Magna Graecia of Catanzaro; Clinical Pharmacology Unit, Mater Domini University Hospital Giovambattista De Sarro MD, Chair of Pharmacology, Department of Experimental and Clinical Medicine, School of Medicine, University Magna Graecia of Catanzaro; Clinical Pharmacology Unit, Mater Domini University Hospital Correspondence: Dr. Gallelli, gallelli@unicz.it

Reprints/Online Access: www.theannals.com/cgi/reprint/aph.1P335 Conflict of interest: Authors reported none

References
1. Wyllie E, Wyllie R. Routine laboratory monitoring for serious adverse effects of antiepileptic medications: the controversy. Epilepsia 1991;32: S74-9. 2. OConnor CR, Schraeder PL, Kurland AH, OConnor WH. Evaluation of the mechanisms of antiepileptic drugrelated chronic leukopenia. Epilepsia 1994;35:149-54. 3. Kwan P, Brodie MJ. Phenobarbital for the treatment of epilepsy in the 21st century: a critical review. Epilepsia 2004;45:1141-9. 4. Mackay FJ, Wilton LV, Pearce GL, Freemanatle SN, Mann RD. Safety of long-term lamotrigine in epilepsy. Epilepsia 1997;38:881-6.
I

The Annals of Pharmacotherapy

2010 December, Volume 44

2033

A Siniscalchi et al. 5. Nicholson RJ, Kelly KP, Grant IS. Leucopenia associated with lamotrigine. BJM 1995;310:504. 6. de Camargo OA, Bode H. Agranulocytosis associated with lamotrigine. BJM 1999;318:1179. 7. Ural AU, Avcu F, Gokcil Z, Nevruz O, Cetin T. Leucopenia and thrombocytopenia possibly associated with lamotrigine use in a patient. Epileptic Disord 2005;7:33-5. 8. Patsalos PN, Frscher W, Pisani F, van Rijn CM. The importance of drug interactions in epilepsy therapy. Epilepsia 2002;43:365-85. 9. Johannessen Landmerk C, Patsalos PN. Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev Neurother 2010;10:119-40. 10. Horn JR, Hansten PD, Chan L-N. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007;41:674-80. DOI 10.1345/aph.1H423 11. Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf 1999;21:489-501. 12. Maggs JL, Naisbitt DJ, Tettey JN, Pirmohamed M, Park BK. Metabolism of lamotrigine to reactive arene oxide intermediate. Chem Res Toxicol 2000;13:1075-81. 13. Bottinger Y, Svenssson Jo, Stahle L. Lamotrigine drug interactions in a TDM material. Ther Drug Monit 1999;21:171- 4. 14. May TW, Rambeck B, Jurgens U. Serum concentrations of lamotrigine in epileptic patients: the influence of dose and comedication. Ther Drug Monit 1996;18:523-31. 15. Deckers CL, Hekster YA, Keyser A, Meinardi H, Renier WO. Reappraisal of polytherapy in epilepsy: a critical review of drug load and adverse effects. Epilepsia 1997;38:570-5. 16. Besag FM, Berry DJ, Pool F, Newbery JE, Subel B. Carbamazepine toxicity with lamotrigine: pharmacokinetic or pharmacodynamic interaction? Epilepsia 1998;39:183-7. 17. Hacquard M, Richard S, Lacour JC, Lecompte T, Vespignani H. Levetiracetam-induced platelet dysfunction. Epilepsy Res 2009;86:94-6. 18. Gallerani M, Mari E, Boari B, Carletti R, Marra A, Cavallo M. Pancytopenia associated with levetiracetam treatment. Clin Drug Investig 2009;29:747-51. DOI 10.2165/11319450-000000000-00000

MEDICAL ABBREVIATIONS
30,000 Conveniences at the Expense of Communications and Safety 14th Edition By Neil M. Davis
392 pp / Paperbound / ISBN 0-931431-14-2 / 2009 / $28.95

The 14th edition includes a do not use list of dangerous abbreviations in addition to the 30,000 meanings for the abbreviations, acronyms, and symbols. The book also contains a cross-referenced list of 3,400 generic and trade drug names. Each copy includes a single-user access license for the web version of the book which is updated with over 80 new entries per month. This license is valid for 12 months from the date of initial log-in. Essential to medical professionals for order interpretation, data entry, unit dose cart filling, and prescription interpretation. A must to ensure patient safety and reduce medication errors.

ORDER ONLINE AND SAVE 10% ON YOUR PURCHASE

Harvey Whitney Books Company PO Box 42696 Cincinnati OH 45242-0696 Order Toll-Free: 877-742-7631 hwbooks.com
2034
I

The Annals of Pharmacotherapy

2010 December, Volume 44

theannals.com