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 abnormali-
T ties during antiepileptic drug treat-
ment has been recorded.1,2 In fact, hema-
tologic adverse effects were reported in
patients with epilepsy during phenobarbi-
tal (leukopenia) and lamotrigine (throm-
bocytopenia and leukopenia) mono-
therapy.3-7
Although the underlying mechanism
in antiepileptic druginduced blood ab-
normalities is unknown, a drug interac-
tion during antiepileptic drug treatment
could induce adverse effects8; however,
the new antiepileptic drugs have safer
hematologic profiles than do convention-
al antiepileptic drugs.9 We report on a
patient with epilepsy who developed
leukopenia and thrombocytopenia dur-
ing 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 oth-
Author information provided at end of text.
theannals.com
OBJECTIVE: To report on a patient with epilepsy who developed leukopenia and
thrombocytopenia during phenobarbital/lamotrigine treatment.
CASE REPORT: 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: 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
The Annals of Pharmacotherapy n 2010 December, Volume 44 n 2031
A Siniscalchi et al.
er drug abuse; moreover, she reported no significant past
medical or surgical events. Family history was unremark-
able. After neurologic evaluation, a baseline electroen-
cephalogram disclosed mild, generalized background alpha
activity throughout the recording. Blood chemical tests did
not reveal any abnormality (platelets 250 103/L [refer-
ence 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 lamot-
rigine 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 find-
ings (enclosed bone marrow aspiration and biopsy) excluded
the presence of leukemia, lymphoma, or other hematologic
Figure 1. White blood cell count and platelet count during treatment with phenobarbital (PB), lamotrigine (LMT), and levetiracetam (LEV).
2032 n The Annals of Pharmacotherapy n 2010 December, Volume 44
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 dis-
continued the next day. Two days later the patient developed
2 episodes of complex partial seizure, so levetiracetam titrat-
ed 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, phe-
nobarbital rechallenge (100 mg/day) induced a new pro-
gressive 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 recov-
ery of normal hematopoiesis in 25 days (Figure 1).
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 In-
teraction Probability Scale was applied, estimating a prob-
able relationship between the drug-drug interaction and
blood abnormality.10 As of June 2010, the patient is receiv-
ing lamotrigine 200 mg/day (plasma concentration 3.6
g/mL) and levetiracetam 1500 mg/day (plasma concen-
tration 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 de-
crease 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, be-
cause of phenobarbitals poor control of the patients
seizures, we chose to discontinue it rather than the lamo-
trigine. During phenobarbital treatment, the patient devel-
oped 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 rechal-
lenge during lamotrigine therapy induced the development
of blood abnormalities. Both pharmacologic evaluation
and the Horn Drug Interaction Probability Scale docu-
mented a probable relationship between this drug-drug in-
teraction 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 macro-
molecules could lead to cell death and, by acting as hap-
tens, to secondary hypersensitivity reactions.11 In particu-
lar, lamotrigine is primarily metabolized to its N-glu-
curonide and only minor amounts are converted by
cytochrome P450 enzymes to an arene oxide intermediate
able to induce systemic diseases.12 A pharmacokinetic in-
teraction 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 The Annals of Pharmacotherapy
g/mL), we observed, in agreement with literature data,13
a reduction of lamotrigine plasma values during pheno-
barbital treatment. Therefore, it is possible that cy-
tochrome 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 ex-
clude 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 interac-
tion, resulting in carbamazepine toxicity.16 However, sev-
eral reports documented that levetiracetam is also able to
induce blood abnormality,17,18 but we did not note any al-
teration in blood cell count during levetiracetam/lamotrig-
ine coadministration.
In conclusion, our patient with epilepsy developed
blood dyscrasia during lamotrigine/phenobarbital treat-
ment, suggesting that greater care should be taken in moni-
toring hematologic parameters during such treatment. Fur-
ther studies should be performed both to validate this ob-
servation and to evaluate the percentage of patients with
hematologic toxicities during lamotrigine/phenobarbital
treatment.
Antonio Siniscalchi MD, Department of Neuroscience, Neurolo-
gy Division, Annunziata Hospital, Cosenza, Italy
Luca Gallelli MD PhD, Chair of Pharmacology, Department of Ex-
perimental and Clinical Medicine, School of Medicine, University
Magna Graecia of Catanzaro; Clinical Pharmacology Unit, Mater Do-
mini University Hospital, Catanzaro, Italy
Giuseppina Calabr MD, Department of Experimental and Clini-
cal Medicine, School of Medicine, University Magna Graecia of Catan-
zaro
Grazia Angela Tolotta MD, Chair of Pharmacology, Department
of Experimental and Clinical Medicine, School of Medicine, Univer-
sity Magna Graecia of Catanzaro; Clinical Pharmacology Unit, Mater
Domini University Hospital
Giovambattista De Sarro MD, Chair of Pharmacology, Depart-
ment 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
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