Chapter 12
Drug Concentration Monitoring
CQ 12-1

When should serum concentrations of antiepileptic drugs bemonitored?
Summary
Measurement of serum concentrations of antiepileptic drugs is useful for the following purposes: (1) to establish
individual therapeutic ranges when the desired seizure control is obtained; (2) to diagnose adverse effects; (3) toevaluate adherence at the time of poor seizure control or breakthrough seizure; (4) to adjust doses in situations ofpharmacokinetic changes (such as in children, elderly patients, comorbid disorders, and change in dosage form); (5)to adjust doses when change in pharmacokinetics is predicted (such as during pregnancy and addition or removal ofdrugs having interactions); and (6) to adjust doses of drugs having dose-dependent pharmacokinetics (particularly
phenytoin).

Comment
Monitoring serum concentrations of antiepileptic drugs is useful in deciding patient’s medication regimen, if monitoringis done for a clear purpose and the results are interpreted properly along with other clinical factors. Serum concentrations ofantiepileptic drugs should not be monitored routinely without intended purposes. However, they should be measured when
there are clinical needs (Table 1)1).
The reference range of serum concentrations of a certain drug is not the same as its therapeutic range. The lower limit of
the reference range of serum concentrations is the concentration being more likely to produce an insufficient therapeutic
effect, and the upper limit is the concentration being more often associated with adverse effects. That is, the serum
concentrations of antiepileptic drugs within the reference range (so-called effective serum concentrations) indicate thatthey are expected to be effective with fewer adverse effects in most of the patients1).
The therapeutic range of serum concentrations for a certain patient is the range within which that patient has the best
seizure control. In most of the patients, the therapeutic range is within or overlaps with the reference range. However,treatment may be effective even when the serum concentration is lower than the reference range in some cases, or conversely
may be effective only when the concentration is higher than the reference range in other cases, because of large interindividual variability of the therapeutic range. Therefore, it is important to know the therapeutic range for each patient. The
dose should not be increased if the patient remains seizure-free at serum concentration lower than the reference range. On
the other hand, the dose might be increased to above the reference range if the patient has residual seizures without any
adverse effects. The reference range of serum concentration differs depending on age, epilepsy syndrome, and seizure type1, 2).
The reference range is determined based on the lowest serum concentration (the trough value, which is measured before
drug taking in the morning). However, it is difficult to measure the trough value in outpatient clinic, and serum concentration
measured at our clinics is usually higher than the trough. Therefore, it is not a concern if the measured value exceeds theupper limit of the therapeutic range. We should interpret the blood concentration considering the blood sampling time, thedrug taking time, and the time of maximum concentration (Tmax) of each drug (Table 1 in CQ 12-2 on page 104).
Antiepileptic drug exists in two forms in the blood: a protein-bound form and a free form. In patients with hypoproteinemia,
pregnancy, hepatic disorders or renal disorders, the amount of drug in the free form is larger than that in healthy subjects
even when the measured serum concentration is the same, and the efficacy and adverse effects are not the same as in normal
controls. Although the free form possesses antiepileptic effect, measurement of free form is not covered by medical insurance.
In general, the total serum concentrations of antiepileptic drugs, including both protein-bound form and free form, aremeasured and recorded.

Chapter 12  

101▪ References
1) Patsalos PN, Berry DJ, Bourgeois BFD, et al. Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: a position paper by the
Subcommission on Therapeutic Drug Monitoring, ILAE Commission on Therapeutic Strategies. Epilepsia. 2008; 49(7): 1239-1276.
2) Johannessen SI, Patsalos PN. Individual approach to laboratory monitoring of antiepileptic drugs. In: Wyllie E, Gidal BE, Goodkin HP, et al eds.
Willie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015. p.568-573.

Table 1. General indications for monitoring blood concentrations of antiepileptic drugs.
1. A fter initiation of treatment or after dose adjustment, when the clinician decides to aim at a target concentration
for that patient.
2. Once the desired seizure control state has been achieved, to establish the “individual therapeutic range.”
3. To determine the magnitude of a dose increase, particularly with antiepileptic drugs showing dose-dependent
pharmacokinetics (most notably, phenytoin).
4. W hen there are uncertainties in the differential diagnosis of signs or symptoms suggesting drug-related adverse
reaction, or when adverse effect is difficult to assess clinically (young children, patients with mental disability).
5. When seizures persist despite an adequate dosage.
6. W hen change in pharmacokinetics (consequently, required dose also change) is suspected, due to age,pregnancy, comorbidity, or drug interaction.
7. To assess changes in steady state drug concentration when a change in drug formulation or change to genericformulation is made.
8. When there is an unexpected change in clinical response.
9. To conform adherence when poor compliance is suspected.
(Modified from: Patsalos PN, Berry DJ, Bourgeois BFD, et al. Antiepileptic drugs—best practice guidelines fortherapeutic drug monitoring: a position paper by the Subcommission on Therapeutic Drug Monitoring, ILAE
Commission on Therapeutic Strategies. Epilepsia. 2008: 49(7); 1239: 1276.)

102Part IThe Clinical Practice Guidelines for Epilepsy 2018

CQ 12-2

Serum concentration monitoring is useful for which drugs?
Summary
The reference ranges of serum concentrations have been established for carbamazepine, phenytoin, phenobarbital,
primidone, valproate, and ethosuximide. Serum concentration monitoring is useful for these drugs. However, forsome other drugs, the serum concentration monitoring is not very useful because the reference ranges have notdetermined for them or they show remarkable fluctuations in serum concentration (Tables 1 and 2)1-5).

Comment
Because there are large interindividual variabilities in epileptogenesis and response to a given antiepileptic drug, it isdifficult to find a general therapeutic range of serum concentrations applicable to all patients. However, it is known that
there exists a range of serum concentrations at which seizures are controlled and dose-dependent adverse effects are rarely
seen in most of the patients. This range is called the “reference range” (so-called effective blood concentration).
Even for drugs with no established general reference ranges, serum concentration measurement is useful for comparisons
within an individual patient. Benzodiazepines play a role as an anti-convulsant by binding with benzodiazepine receptors
in the brain. Because the number of benzodiazepine receptors varies from person to person, it is difficult to determine thereference blood concentration range for all persons. The reference ranges for clobazam, nitrazepam and diazepam have notbeen reported. However, repetitive serum concentration measurements in one patient are useful for monitoring adverse
effects such as drowsiness in that patient.
Phenytoin is a drug showing big fluctuations in serum concentration, which requires attention. Because of the non-linear
relationship between dosage and serum concentration and the narrow therapeutic window, measurement of serum
concentration is critical for setting the optimal dosage. Especially, a rapid rise in serum concentration occurs at high doses1).
The serum concentration of lamotrigine decreases drastically when used concomitantly with enzyme-inducing drugs(phenytoin, carbamazepine, phenobarbital, and primidone), increases greatly when used in combination with valproate, anddeclines significantly during pregnancy. Serum level of carbamazepine decreases within 1–3 months after start of treatment,
due to enzyme self-induction. Therefore, serum concentration has to be monitored shortly after treatment initiation.

▪ References
1) Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015, p.376-700.
2) Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015,
p.593-768.
3) Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge: Cambridge University Press, 2010.
4) Drugs in Japan Forum, ed. Drugs in Japan: Ethical Drugs 2016 Edition. Tokyo: Jiho Inc., 2015 (in Japanese).
5) Johannessen SI, Johannessen-Landmark C, Perucca E. Pharmacokinetic optimization of therapy. In: Shorvon S, Perucca E, Engel J Jr eds. The
treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015, p.124-138.

Chapter 12  

103

Table 1. Therapeutic ranges of blood levels and pharmacokinetics of major antiepileptic drugs.
Maintenance dosea
Generic name(abbreviation)

Phenobarbital

PB

Primidone
Carbamazepine
Phenytoinf

PRM
CBZ
PHT

Valproate

Acetazolamide
Potassium bromide

VPA
VPA-R
ESM
CZP
NZP
CLB
CLBh
AZM
KBr

Gabapentin
Topiramate
Lamotriginei

GBP
TPM
LTG

sustained release

Ethosuximide
Clonazepam
Nitrazepam
ClobazamN-desmethyl

Adult
(mg)

Child
(mg/kg)

Dose increaserange

T1/2: elimination half-lifec (h)
Blood
conc.
Adult
reference
Adult Child
with
b
range
Child
(mg) (mg/kg) (µg/mL) monoenzyme
therapy
inducerd
almostunchanged

Tmax: peaktimec (h)
Adult

Child

10–26ealmostunchanged
7.5–16g

10–13
days

5–8
days

(1) with VPA(2) with enzyme inducerd(3) with (1) and (2)Levetiracetamj
Rufinamide
Stiripentol
Vigabatrin
Perampanel
Lacosamidem

LEV
RFNk
STP
VGB
PER l
LCM

by weight by weight

8–12l
200–400m

a: In children, the younger the age, the higher the dose per kg body weight is required to obtain a given blood concentration, themaintenance dose is higher, and half-life and peak time are shorter. In adolescents, pharmacokinetics are almost the same as adults.
b: If effective, blood concentration can stay low, or can be increased to higher than the therapeutic range as long as there is no adverse
effect.
c: This is the time for the concentration to decrease by half from the peak. The time until blood concentration decreases by one-half afteradministration is peak time + half-life. Half-life and peak time are in principle determined for monotherapy with drug taking after
meal. In combination therapy, half-life is shortened when the combination lowers blood level through interaction, and is prolonged
when the combination increases blood concentration (see “Interaction” in CQ 12-4 on page 109). Peak time is shortened significantlywith drug is taken when fasting.
d: Enzyme-inducing drugs: PB, PRM, CBZ and PHT. Increase drug metabolism in the liver, concomitant use shortens half-life oforiginal drug.
e: Value at the time when self-induction is completed (3–4 weeks after starting)f: For PHT, the higher the blood level, the longer is the half-life. L: low dose (blood level around 5 μg/mL), H: high dose (blood level
10 μg/mL or above)
g: Peak time of VPA sustained release preparation varies depending on the dosage form: 5 to 10 h for Selenica® R fine granule, 7.5 to 10 hfor Depakene® R tablet, and 13 to 16 h for Selenica® R tablet.
h: N-DMCLB is a metabolite of CLB. N-DMCLB has anticonvulsive action of approximately 1/4 strength of that of CLB. Whenclassified by CLB:N-DMCLB concentration ratio into three groups of approximately 1:2‒3 (10% of the subjects), around 1:10 (80%),
and around 1:50–100 (10%), drowsiness occurs at a higher rate as the CLB:NDMCLB concentration ratio increases.
i: In Japan, monotherapy use is approved only for partial seizure (including secondarily generalized seizures) and tonic clonic seizure in
16 year-old and above. To prevent rash (especially Stevens‒Johnson syndrome), follow the instructions in the package insert concerning
the initial dose, the dose increase range and the maximum dose of LTG.
j: Monotherapy use only for 4 year-old and above with partial seizure.

104

Part IThe Clinical Practice Guidelines for Epilepsy 2018

k: Covered by insurance for 4 year-old and above. Starting dose to maximum dose is as follows: 15 to < 30 kg in weight: 200‒1,000 mg,
30 to < 50 kg: 400‒1,800 mg, 50 to < 70 kg: 400‒2,400 mg, ≥ 70 kg: 400‒3,200 mg. Dose increase range is: 15 to < 30 kg: ≤ 200 mg,
and ≥ 30 kg: ≤ 400 mg. Official abbreviation is undecided and RUF is also commonly used.
l: Covered by insurance for 12 year-old and above. Official abbreviation is undecided and PRP is also commonly used.
m: Covered by insurance for 6 year-old and above.
(Compiled from: Shorvon S, Perucca E, Engel J Jr, eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015,
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds.: Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015, p.593‒768. / Patsalos PN, Bourgeois BFD: The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010. / Drugs in Japan Forum, ed. Drugs in Japan: Ethical Drugs 2016 edition. Tokyo: Jiho Inc., 2015.)

Table 2. Usefulness of measuring blood concentration.
Usefulness
Very useful
UsefulUseful to certain extent
Limited or undetermined

Antiepileptic drugs
Phenytoin, lamotrigine
Carbamazepine, phenobarbital, valproate, ruﬁnamide,
perampanel
Primidone, ethosuximide, zonisamide, topiramate
Clonazepam, clobazam, diazepam, nitrazepam,
acetazolamide, gabapentin, levetiracetam, potassium
bromide, stiripentol, vigabatrin, lacosamide(Compiled from: Johannessen SI, Johannessen-Landmark C, Perucca E. Pharmacokinetic
optimization of therapy. In: Shorvon S, Perucca E, Engel J Jr, eds. The treatment of
epilepsy, 4th ed. Chichester: Wiley Blackwell, 2015, p.124‒138.)

Chapter 12  

105

CQ 12-3

Is serum concentration monitoring a requisite in the treatmentof patients with hepatic or renal dysfunction?
Summary
Since the pharmacokinetics of antiepileptic drugs may alter in patients with hepatic or renal dysfunction, conduct
treatment based on serum concentrations of drugs. Dialysis reduces serum drug concentrations.

Comment
Antiepileptic drugs are mainly metabolized by the liver and excreted by the kidney. But the ratio of hepatic metabolism
and renal excretion varies depending on the drug. In patients with liver or kidney disorders, pay attention to the increase inserum concentrations of antiepileptic drugs, bearing in mind the metabolism and excretion routes and the ratio of hepatic
metabolism and renal excretion for each drug. Then, the doses should be reduced if necessary. For drugs that are metabolized
by the liver, serum concentrations do not change markedly in acute hepatitis since metabolic enzymes do not decrease, but
serum concentrations rise in cirrhosis because metabolic enzyme and hepatic blood flow are both reduced. In patients treatedwith hemodialysis, the blood levels of some drugs decrease, therefore consider dose increment1) (Table 1)2-4).

▪ References
1) Singh G. Management of medical comorbidity associated with epilepsy. In: Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4thedition. Chichester: Wiley Blackwell, 2015, p.245-258.
2) Spina E, Italiano D. Drug interactions. In: Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell,2016. p.344-359.
3) Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015. p.376-700.
4) Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015.
p.593-768.

106Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 1. Metabolic and excretion routes of major antiepileptic drugs, and dose adjustment ofantiepileptic drugs in the case of hepatic and renal impairment.

Phenytoin
Carbamazepine
Valproate
Phenobarbital
Primidone
Clobazam
Clonazepam
Zonisamide
Ethosuximide
Potassium bromide
Gabapentin
Topiramate
Lamotrigine
Levetiracetam
Rufinamide
Stiripentol
Vigabatrin
Perampanel
Lacosamide

Hepatic
metabolism (%)
90
90
85
55
45‒60
> 90
> 90
70
70
0
0
< 25
90
<3
85
75
10
70
30

Renal
excretion (%)
<2
<1
<5
25
20‒25
<1
<1
< 30
20
100
100
75
10
70
2
25
90
30
40

Adjustment during liver
impairment
Dose reduction
Dose reduction
Dose reduction
Slight dose reduction‒No need
Slight dose reduction‒No need
Dose reduction
Dose reduction
Dose reduction
Dose reduction
No needNo needNo need
Dose reduction
No need
Dose reduction
Dose reduction
No need e
Dose reduction
Dose reduction

Adjustment during
kidney impairment
No needNo needNo needSlight dose reduction
Slight dose reduction
No need e
No needSlight dose reduction
No need
Dose reduction
Dose reduction
Dose reduction
No need
Dose reduction
No needNo need
Dose reduction
No needSlight dose reduction(Compiled from: Spina E, Italiano D. Drug interactions. In: Shorvon S, Perucca E, Engel J Jr. eds. The treatment of epilepsy,
4th edition. Chichester: Wiley Blackwell, 2016. p.344‒359. / Shorvon S, Perucca E, Engel J Jr. eds. The treatment of epilepsy,
4th edition. Chichester: Wiley Blackwell, 2015. p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatmentof Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer, 2015. p.593‒768.)

Chapter 12  

107

CQ 12-4

What are the drugs that interact with antiepileptic drugs?
Summary 1-5)
When addition or removal of a given non-antiepileptic drug results in an increase in seizures or adverse effects,
suspect drug interaction with the antiepileptic drugs being used and consider measurement of serum concentrationsof the antiepileptic drugs. Conversely, when an antiepileptic drug is being added or removed, pay attention to thepossibility that the therapeutic effects of other drugs may alter, which may result in some changes in comorbid
symptoms.

Comment
Drug interactions include interactions between antiepileptic drugs (Table 1)1-3), interactions between antiepileptic drugs
and psychotropic drugs (Tables 2 and 3)1-5), and interactions between antiepileptic drugs and general drugs other thanpsychotropic drugs (Tables 4 and 5)1-5). Pay special attention when patients are complicated with psychiatric disease ordevelopmental disorder, or elderly people taking various drugs because of comorbidities.
Among antibiotics, clarithromycin and erythromycin inhibit the metabolism of carbamazepine, resulting in a large
increase in serum concentration of carbamazepine, causing dizziness, vertigo, and severe drowsiness. Carbapenem antibiotics(panipenem‒betamipron, meropen, imipenem‒cilastatin, doripenem, biapenem, tebipenem) are contraindicated when
taking valproate, as they significantly lower the serum concentration of valproate.
For antithrombotic drugs, warfarin used with phenytoin mutually increase the serum concentrations of each other, andthe blood level of rivaroxaban is lowered by carbamazepine, phenytoin or phenobarbital (see CQ 3-8 on page 30).

▪ References
1) Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015. p.376-700.
2) Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia: Wolters Kluwer,
2015. p.593-768.
3) Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge: Cambridge University Press, 2010.
4) Drugs in Japan Forum, ed. Drugs in Japan: Ethical Drugs 2016 edition. Tokyo: Jiho Inc., 2015 (in Japanese).
5) Sugai K: Interactions between antiepileptic drugs and other drugs and food. Shoni Naika (Japanese Journal of Pediatric Medicine) 2014; 46(9):1242-1247 (in Japanese).

108

Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 1. Interactions between epileptic drugs.
Added drug
VPA
PB
CBZ
PHT
ZNS
CZP
CLB
ESM
AZM
GBP
TPM
LTG
LEV
RFN
STP
VGB
PER
LCM

Blood concentration of the original antiepileptic drug
VPA PB CBZ PHT ZNS CZP CLB ESM AZM GBP TPM LTG LEV RFN STP VGB PER LCM
↑↑
↓a
↓b
↓
↓
↑
→
↓
↑↑
→
↑↑
↓
↓
→↓
↓
↓
↓
↓
→
↓↓
↓↓
↓
↓↓
↓↓
↓
↓↓ ↑↓→
↑
↓
↓
↓
↓↓
→
↓↓
↓↓
↓
↓
↓↓
→
↓↓
↓
↓↓
↑↓
↓↓
↓↓
↓
↓
↓↓
→
↓↓
↓↓
↓
↓↓
↓↓
→
↓↓
↓
c
→ →
→
→
↑
→
↓
→
→
→
↑↑
↑
↑d
↑↑
→
→
↑
↓
→
→
↑
→
→
↑
↑
→
→
→
→
→
→
→
→
→
→
→
↓
→
→
↑
→
→
→
↓
→
→
→
→
↓
→
→
→
→
→
→
→
→
→
→
→
→
→
→
↑
↓
↑
→
↓
↑
↑
↑↑
↑↑
↑↑
→
→
→
↓
→
↓
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→

Blood level: ↑ increase, ↑↑ marked increase, ↓ decrease, ↓↓ marked decrease, → unchanged.
In the case of marked increase or marked decrease, consider decrease or increase dose of the original antiepileptic drug.
a: Although total concentration decreases, CBZ‒epoxide increases and the effect is augmented, no need to increase dose.
b: Although total concentration decreases, free drug increases and the effect is augmented, no need to increase dose.
c: CBZ-epoxide increases.
d: Both CBZ and CBZ-epoxide increase
PRM is metabolized to PB and is the same as PB, therefore is omitted.
(Compiled from: Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015.
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015. p.593‒768. / Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010)

Chapter 12  

109

Table 2. Effects of psychotropic drugs on antiepileptic drugs (AED).
AED
PB
PRM
CBZ
PHT
VPA
CLB
NZP
ZNS
KBr
LTG
TPM

Blood concentrationof AED
↑
↑
↑
↑
↑
↑
↑
↑
↓
↑
↑
↓
↑

Psychotropic drugs that influence AED
Tricyclic antidepressant, zotepine, methylphenidate, tetracyclic antidepressant
Tricyclic antidepressant, zotepine, phenothiazines, methylphenidate
Quetiapine, chlorpromazine, paroxetine, haloperidol, fluvoxamine, risperidone
Tricyclic antidepressant, trazodone, fluvoxamine, methylphenidate, tetracyclic antidepressant
Chlorpromazine, tricyclic antidepressant, sertraline
Haloperidol , phenothiazines, fluvoxamine
Phenothiazines
Adverse effects increased by tricyclic antidepressantRisperidone
Phenothiazines (drowsiness, attention, concentration, reduced reflex movement worsened)
Sertraline
Olanzapine, risperidone (somnolence enhanced)
Amitriptyline, lithium*: Tricyclic antidepressants: imipramine, amitriptyline, nortriptyline, and amoxapine. Tetracyclic antidepressants: maprotiline andmianserin. Phenothiazines: chlorpromazine, levomepromazine, fluphenazine, and propericiazine.
**: CZP, AZM, ESM, GBP, LEV, RFN, STP, VGB, LCM: no description.
(Supplemented and modified from: Sugai K: Interactions between antiepileptic drugs and other drugs and food. Shoni Naika. 2014;
46(9): 1242-1247. / Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015.
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015. p.593‒768. / Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010.)

Table 3. Effects of antiepileptic drugs (AED) on psychotropic drugs.
AED
PB
PRM
CBZ
PHT
VPA
CZP
CLB
NZP
ZNS
KBr
TPM
RFN

Blood concentration
Psychotropic drugs that are influenced by AEDof psychotropic drugs
Tricyclic antidepressant, zotepine, phenothiazines, tetracyclic antidepressant↑Olanzapine, chlorpromazine, tricyclic antidepressant, paroxetine , haloperidol, tetracyclic↓
antidepressant, risperidone
Tricyclic antidepressant, zotepine, phenothiazines↑
Lithium↑
Aripiprazole, alprazolam, tricyclic antidepressant, sertraline, trazodone, paliperidone, paroxetine,↓
haloperidol , phenothiazines, tetracyclic antidepressant, risperidone
Tricyclic antidepressant, trazodone, fluvoxamine, tetracyclic antidepressant↑Quetiapine, tricyclic antidepressant, trazodone, paroxetine , tetracyclic antidepressant↓Aripiprazole, chlorpromazine, tricyclic antidepressant, paroxetine↑
Effect of phenothiazines enhanced↑
Haloperidol, phenothiazines↑
Phenothiazines↑
Adverse effects of tricyclic antidepressant increased↑↑
Phenothiazines (drowsiness, attention, concentration, reduced reflex movement worsened↑)
Amitriptyline, haloperidol, lithium↑
Risperidone↓
Triazolam↓*: Tricyclic antidepressants: imipramine, amitriptyline, nortriptyline, and amoxapine. Tetracyclic antidepressants: maprotiline andmianserin. Phenothiazines: chlorpromazine, levomepromazine, fluphenazine, and propericiazine**: AZM, ESM, GBP, LTG, LEV, STP, VGB, LCM: no description.
(Supplemented and modified from: Sugai K: Interactions between antiepileptic drugs and other drugs and food. Shoni Naika. 2014;
46(9): 1242-1247. / Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015.
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015. p.593‒768. / Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010.)

110

Part IThe Clinical Practice Guidelines for Epilepsy 2018

Table 4. Effects of general drugs other than psychotropic drugs on antiepileptic drugs (AED).

PB

Blood
concentration of
AED
↑
↓

PRM

contraindicated
↑

AED

CBZ

↑

↓

↑
PHT
↓
↑
VPA
↓

CZP

↑
↓
↑

CLB

↑

NZP

TPM

↑
↑
↓
↑
↓
↑

LTG

↓

PER

↑

ESM

AZM
GBP

General drugs other than psychotropic agents that influence AED
Chloramphenicol, antihistamines (hydroxyzine, diphenhydramine ), selegiline
Antacid
In the case of PB elixir: cyanamide, disulfiram (enhance alcohol reaction)
Selegiline, antihistamines
Azole antifungals (including miconazole, fluconazole, and itraconazole), isoniazid, omeprazole, Ca
channel blockers (including verapamil, amlodipine, nifedipine, and benidipine), quinupristin/
dalfopristin, chloramphenicol, salicylic acid, ciprofloxacin, cimetidine, diltiazem, sulfamethoxazoletrimethoprim, selegiline, danazol, darunavir , telaprevir, bicalutamide, verapamil, macrolide
antibiotics (including erythromycin, clarithromycin, and josamycin), ritonavir
Aminophylline, efavirenz, antacid, theophylline, rifampicin
Azole antifungals (including miconazole, fluconazole, itraconazole, and voriconazole), amiodarone,aminophylline, allopurinol, isoniazid, omeprazole, chloramphenicol, cyclosporine, disulfiram,
cimetidine, diltiazem, sulfamethoxazole-trimethoprim, tacrolimus, ticlopidine, theophylline,
nelfinavir, para-amino-salicylic acid, fluorouracil-based preparations (including tegafur preparations
and doxifluridine), fosfluconazole, warfarinAminophylline, salicylic acid, diazoxide, cisplatin, theophylline, nelfinavir, pyridoxine, vinca alkaloids(including vincristine), rifampicin
Isoniazid, salicylates (including aspirin), cimetidine, macrolide antibiotics (including erythromycin,
clarithromycin, and josamycin)
Carbapenem antibiotics (panipenem-betamipron, meropen, imipenem-cilastatin, doripenem,
biapenem, tebipenem), cholestyramine, cisplatin, naproxen, methotrexate, rifampicin
Isoniazid
Rifampicin
Selegiline
Cimetidine, drugs metabolized by CYP3A4 (including rifampicin), CYP3A4 inhibitors (including
ritonavir, corticosteroid preparations, and macrolide antibiotics), selegiline
Cimetidine, selegiline
High-dose aspirin
Ammonium chloride
Cimetidine, naproxen, morphine
Antacid (aluminum hydroxide, magnesium hydroxide)
Hydrochlorothiazide
Acetaminophen, atazanavir, oral contraceptives (including ethinylestradiol and norethisterone),ritonavir, rifampicin, lopinavir-ritonavir combination
Ketoconazole*: ZNS, KBr, LEV, RFN, STP, VGB, LCM: no description.
**: Underlined parts denote concomitant use contraindicated.
(Supplemented and modified from: Sugai K: Interactions between antiepileptic drugs and other drugs and food. Shoni Naika. 2014;
46(9): 1242-1247. / Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015.
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015. p.593‒768. / Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010.)

Chapter 12  

111

Table 5. Effects of antiepileptic drugs (AED) on general drugs other than psychotropic drugs.
AED

Blood concentrationof general drugs
↑

PB
↓

↑

PRM

↓
↑

CBZ

↓

↑

PHT

↓

↑
↑
↑
↑
↑
↑
↓
↑
↓
↓
↓

VPA
CZP
CLB
NZP
AZM
TPM
LTG
RFN
PER

General drugs other than psychotropic agents that are influenced by AED
Including thiazide hypotensive diuretics (orthostatic hypotension↑), selegiline, antihistamines(hydroxyzine, diphenhydramine)
Azelnidipine, aminophylline, imatinib, irinotecan, HIV protease inhibitors (including indinavir,
saquinavir, nelfinavir, and lopinavir), chloramphenicol, cyclosporine, tacrolimus, theophylline,
doxycycline, PDE5 inhibitors (sildenafil, tadalafil, vardenafil), felodipine, corticosteroids (including
dexamethasone), flecainide, verapamil, voriconazole, montelukast etc., estrogen-progestogenpreparations (including norgestrel and ethinylestradiol), rivaroxaban, warfarin
Antihistamines, thiazide hypotensive diuretics (including trichlormethiazide) (orthostatic
hypotension↑), selegiline
Doxycycline
Isoniazid (enhance hepatoxicity), cyclophosphamide, selegiline
Acetaminophen, aprepitant, aminophylline, albendazole, alprazolam, itraconazole, HIV proteaseinhibitors (including saquinavir, indinavir, nelfinavir, and lopinavir), etravirine, efavirenz, eplerenone,
eletriptan, ondansetron, caspofungin, anticancer drugs (axitinib, irinotecan, imatinib, gefitinib,
sunitinib, sorafenib, dasatinib, tamibarotene, temsirolimus, toremifene, nilotinib, lapatinib),
dienogest, digoxin, dihydropyridine calcium antagonists (including nifedipine, felodipine, andnilvadipine), sildenafil, solifenacin, tadalafil, dabigatran etexilate, theophylline, telaprevir, doxycycline,
donepezil, tramadol, nondepolarizing muscle relaxant (including vecuronium), corticosteroids(including prednisolone and dexamethasone), buprenorphine, praziquantel, flecainide, fosaprepitant,voriconazole, maraviroc, mirabegron, meglumine, immunosuppressants (cyclosporine, tacrolimus,
everolimus), estrogen-progestogen preparations, rivaroxaban, rilpivirine, warfarin
Warfarin
Azelnidipine, aminophylline, itraconazole, imatinib, irinotecan, indinavir, ondansetron, quinidine,
hypoglycemic agents (insulin, oral hypoglycemic agents), thyroid hormone preparations (including
levothyroxine), saquinavir, cyclosporine, disopyramide, tacrolimus, tadalafil, theophylline,deferasirox, doxycycline, nisoldipine, nifedipine, nelfinavir, nondepolarizing muscle relaxant(including vecuronium and pancuronium), PDE5 inhibitors (tadalafil, sildenafil, vardenafil),felodipine, corticosteroids (including dexamethasone), praziquantel, flecainide, verapamil,
voriconazole, mexiletine, estrogen / gestagen preparations (including norgestrel andethinylestradiol), rivaroxaban, warfarin
Warfarin
Selegiline
Drugs metabolized by CYP3A4 (including rifampicin), selegiline
Selegiline
ACTH, antihypertensive drugs, digitalis preparations (digoxin)
Metformin
Oral contraceptives (including ethinylestradiol and norethisterone), digoxin, pioglitazone
Oral contraceptives (including ethinylestradiol and norethisterone)
Oral contraceptives (including ethinylestradiol and norethisterone)
Oral contraceptives (including ethinylestradiol and norethisterone)
Oral contraceptives (including ethinylestradiol, and norethisterone)*: ZNS, ESM, KBr, LEV, STP, VGB, LCM: no description. However, STP has potent inhibitory effect on drug metabolic enzymes in theliver, and may increase the blood concentrations of various drugs.
**: Underlined parts denote concomitant use contraindicated.
(Supplemented and modified from: Sugai K: Interactions between antiepileptic drugs and other drugs and food. Shoni Naika. 2014;
46(9): 1242-1247. / Shorvon S, Perucca E, Engel J Jr eds. The treatment of epilepsy, 4th edition. Chichester: Wiley Blackwell, 2015.
p.376‒700. / Wyllie E, Gidal BE, Goodkin HP, et al eds. Wyllie’s Treatment of Epilepsy: Principles and Practice, 6th edition. Philadelphia:
Wolters Kluwer, 2015. p.593‒768. / Patsalos PN, Bourgeois BFD. The Epilepsy Prescriber’s Guide to Antiepileptic Drugs. Cambridge:
Cambridge University Press, 2010.)

112

Part IThe Clinical Practice Guidelines for Epilepsy 2018