Professional Documents
Culture Documents
Use of Keppra Is Neonatal Seizures at Tygerberg Hospital
Use of Keppra Is Neonatal Seizures at Tygerberg Hospital
doi: 10.1093/tropej/fmab041
Original Paper
ABSTRACT
Background: Intravenous phenobarbital remains the first-line therapy in the management of neo-
natal seizures. Shortages of intravenous phenobarbital in South Africa necessitated the addition
of oral levetiracetam as part of management of neonatal seizures.
Objective: We evaluated the pharmacokinetics of crushed immediate-release levetiracetam tablets
administered to neonates to terminate seizures.
Methods: A prospective, observational study of neonates admitted with seizures to Tygerberg
Hospital. Participants received crushed levetiracetam (diluted in saline) given orally or via naso-/
orogastric tube. At steady-state, pharmacokinetic sampling was performed at pre-dose, 1.5, 2.5 and 4
h post-dose. Maximum concentration (Cmax), time to Cmax (Tmax), trough concentrations (Ctrough)
and area under the concentration-time curve (AUC0–12) were calculated using non-compartmental
analysis. Seizure termination and safety profiles were documented.
Results: Nineteen participants were grouped into three dosing ranges: (i) 5–15 mg/kg/12-hourly, (ii)
15–25 mg/kg/12-hourly and (iii) 25–35 mg/kg/12-hourly. Range 1 demonstrated AUC0–12
167.0 6 45.6 h*lg/mL, Cmax 19.19 6 4.12 lg/mL and Ctrough 9.99 6 3.86 mg/mL. Range 2, AUC0–12
316.5 6 108.4 h*lg/mL, Cmax 35.12 6 10.54 mg/mL and Ctrough 19.25 6 8.48 mg/mL. Range 3, AUC0–12
C The Author(s) [2021]. Published by Oxford University Press. All rights reserved.
V
For permissions, please email: journals.permissions@oup.com 1
2 Crushed Levetiracetam Tablets
290.9 (range 176.14–405.59) h*lg/mL, Cmax 36.11 (range 27.58–44.64) mg/mL and Ctrough 13.03
(2.98–23.07) mg/mL. Seizures terminated in 17/19 (90%) neonates by day 3 and 19/19 (100%) by day
4 post-levetiracetam initiation.
Conclusion: Crushed levetiracetam has comparable pharmacokinetics to historical data. No phar-
macokinetic differences were observed between oral vs. naso-/orogastric administration. Crushed
levetiracetam tablets can be considered for neonates in low-resource settings where intravenous and
Intravenous preparations of antiepileptic medications are used in the management of neonatal seiz-
ures. Various established standard of care intravenous antiepileptic medicines are unavailable nation-
ally and internationally due to reasons outside our control. This stock shortage included intravenous
phenobarbitone which is the first-line treatment for paediatric seizures. Due to phenobarbital short-
age, levetiracetam has been identified by the neonatologists at Tygerberg Hospital, Cape Town,
South Africa, as a suitable treatment option due to its efficacy and safety profile. However, intraven-
ous levetiracetam and oral syrup is not registered in South Africa. Levetiracetam tablets are being
crushed, dissolved and administered to neonates. There are no data available on the absorption of
crushed levetiracetam tablets administered to neonates via a nasogastric tube. This study character-
ized the pharmacokinetic profile of crushed levetiracetam administered to neonates. We selected
neonates receiving levetiracetam from the neonatal wards at Tygerberg hospital and drew blood to
analyse the levetiracetam concentrations at 4 different time points. We found that the overall expos-
ure of crushed levetiracetam tablets were comparable to the exposures achieved in historical data of
the unaltered formulations. We concluded that crushed levetiracetam tablets can be considered for
neonates in low resource settings where intravenous and syrup access is limited.
[15]. To our knowledge, there are no available data on Health Research and Ethics Committee guidelines of
crushed levetiracetam in neonates. We sought to gather Stellenbosch University [16]. All participants meeting
more information and assess whether the current inclusion criteria received crushed levetiracetam be-
standard practice by the neonatology team of adminis- tween 10 and 30 mg/kg/12-hourly either orally or via
tering levetiracetam at a dosing range between 10 and a naso- or orogastric tube as per the attending neona-
age, sex and weight were recorded. Important clinical That is, it uses linear interpolation between data
findings of the gastrointestinal system were captured, points when levetiracetam concentration is increas-
together with the diagnosis, Apgar scores, daily ing (absorption phase) but logarithmic interpolation
Thompson scores and electrolyte abnormalities. when concentrations are decreasing (elimination
The Apgar score assigns a value of 0, 1 or 2 to heart phase). The choice of linear up/log down method
p valued
DISCUSSION
–
–
–
–
Our study demonstrated that the pharmacokinetics
of crushed levetiracetam tablets administered to neo-
Dose range 3 (25–35 mg/kg/12 h)
290.9 (176.14–405.59)e
nates are similar to the unaltered oral levetiracetam
36.11 (27.58–44.64)e
13.03 (2.98–23.07)e
formulation when dosed between 5 and 25 mg/kg/
1.5 (1.5)e,f
12-hourly. We found similar pharmacokinetics in
Cmax, maximum plasma concentration; Tmax, time to maximum concentration; AUC0–12, area under the curve from time 0 to 12 h; Ctrough, trough plasma concentration.
data
20.6 6 5.8
0.001
p value
0.88
0.22
–
19.25 6 8.48
15.6 6 5.3
322 6 71
0.07
0.26
0.34
9.99 6 3.86
8.4 6 3.8
(h*mg /mL)
PK parameters
Tmax (h)
e
c
f
a
Crushed Levetiracetam Tablets 7
All values expressed as medians and interquartile ranges. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax) and
area under the curve 0–12 h (AUC0–12).
a
The study was not powered to specifically compare naso- or orogastric administration vs. oral administration.
Fountain, et al. This could be explained by the dosage to suspected choanal stenosis, possibly contributing
variation within dosing range 2. This was in contrast to the seizures. Khan, et al. retrospectively investi-
with the first dosing range, where majority of the par- gated the administration of levetiracetam loading
ticipants received 10 mg/kg/12-hourly. The Tmax doses in 22 neonates. Following the loading dose,
values reported in our findings were in keeping with 32% achieved complete seizure cessation immediate-
the Tmax ranges reported by Fountain, et al. and others ly, 64% by 24 hours, 86% by 48 hours and 100% by
[18, 20, 21]. 72 hours [4]. The steady state of levetiracetam is
Trough concentrations do not correlate with reached within 36–48 hours; this could explain why
efficacy and have high variability [22–24]. Giroux, 79% of our participants achieved seizure cessation
et al. [23] found plasma concentrations between 5 day 2 on levetiracetam as the current practice is
and 40 mg/mL with 60% of the responders obtaining not to give an oral loading dose.
trough concentrations between 6.85 and 40 mg/mL.
Similarly, Sheinberg, et al. [24] reported a Ctrough Limitations
range between 2.5 and 38.5 mg/mL. All participants Our study had a few limitations. Firstly, due to
in our study fell within this range. Chhun, et al. [25] restricted blood sampling, we were unable to do a
investigated the appropriate dosing regimen in chil- full pharmacokinetic profile and we had extrapolated
dren required to attain the adult target concentration the AUC0–12. Secondly, we lacked a control group.
of 6–20 mg/ml. The probability of attaining the tar- Furthermore, we did not have other levetiracetam
get trough range of 6–20 mg/mL is 44% when dosed formulations within our facility to use as a compari-
at 10 mg/kg/12-hourly, 90% at 20 mg/kg/12-hourly son. Thirdly, dosing range 3 did not include an ad-
and 66% at 30 mg/kg/12-hourly . This explains why equate representation of participants, therefore we
most of the participants in the current study fell could not draw conclusions from the participants
within the 6–20 mg/mL target range. receiving levetiracetam doses >25 mg/kg/12-hourly.
The majority of participants had cessation of seiz- Fourthly, our limited sampling strategy that was
ures by day 3 after levetiracetam initiation which is largely around the absorption phase did not allow
in keeping with previous efficacy studies of levetira- for a population pharmacokinetic modelling to be
cetam in neonates [26–28]. In a prospective study of used to reconstruct a full pharmacokinetic profile.
intravenous levetiracetam in 16 neonates as first line Lastly, adverse events could have been under-
therapy, seizure cessation occurred on average at reported, because the most common side effects in
96 hours [6]. Another study reported 75% of neo- the paediatric population, such as irritability, somno-
nates with seizure cessation by 72 hours after initi- lence and hyperactivity as reported previously, are
ation of levetiracetam [29]. In our study, two difficult to assess in neonates [30]. Our study was
participants had abortion of seizures by day 4: one of not powered to evaluate efficacy of crushed levetira-
the two participants was diagnosed with intracranial cetam tablets in neonatal seizures. Hence, pros-
haemorrhage and the other with hypoxia secondary pective controlled studies should be conducted to
8 Crushed Levetiracetam Tablets
properly evaluate the efficacy of crushed levetirace- 3. Aceves J, Khan O, Mungall D, et al. Efficacy and tolerabil-
tam tablets in neonatal seizures. ity of intravenous levetiracetam in childrens. Front Neurol
Population pharmacokinetics modelling is the 2013;4:120.
4. Khan O, Chang E, Cipriani C, et al. Use of intravenous lev-
most suitable approach for analyses of sparse data,
etiracetam for management of acute seizures in neonates.
and considering that in the current study we sampled Pediatr Neurol 2011;44:265–9.
only during the absorption phase, future studies
20. Glauser TA, Mitchell WG, Weinstock A, et al. 25. Chhun S, Jullien V, Rey E, et al. Population pharmacokin-
Pharmacokinetics of levetiracetam in infants and young etics of levetiracetam and dosing recommendation in chil-
children with epilepsy. Epilepsia 2007;48:1117–22. dren with epilepsy. Epilepsia 2009;50:1150–7.
21. Pellock JM, Glauser TA, Bebin EM, et al. Pharmacokinetic 26. Kirmani BF, Crisp ED, Kayani S, et al. Role of intravenous
study of levetiracetam in children. Epilepsia 2001;42: levetiracetam in acute seizure management of children.
1574–9. Pediatr Neurol 2009;41:37–9.