What comparative data is available supporting the safety and efficacy of IV push vs. IV infusion Vimpat (lacosamide)?

Comment by InpharmD Researcher

Vimpat prescribing information recommends rapid infusion occurs over at least 15 minutes in adults and 30 minutes in children. A search of clinical literature identified three studies where push infusion was observed to be similar in safety with improved administration timing compared to a conventional piggyback (see tables 1-3). However, each of these studies was severely limited by factors such as retrospective design, lack of a comparator group, lack of efficacy outcomes, or small sample size.

Background

A 2017 systematic review evaluated the use of intravenous (IV) lacosamide in status epilepticus (SE) included 522 SE episodes (51.7% female) in 486 adults and 36 children and adolescents. In adult studies, the most commonly reported initial IV loading dose was 400 mg, ranging from 50 to 600 mg, with the highest infusion rate up to 40 mg/min. The overall efficacy of IV lacosamide was estimated to be 57%, with a better success rate in focal motor SE (92%; 34/39) compared to generalized-convulsive SE (57%, 82/145; p= 0.013) and nonconvulsive SE (61%, 30/49; p<0.001). The most frequent adverse events observed during treatment were dizziness, abnormal vision, diplopia, and ataxia. The authors concluded that the strength of lacosamide is the lack of interaction potential and the option for intravenous use in emergency situations requiring rapid titration. Unfortunately, IV push was not evaluated in this review article. [1]

Relevant Prescribing Information

ADMINISTRATION:
The recommended infusion duration is 30 to 60 minutes; however, infusions as rapid as 15 minutes can be administered in adults if required. Infusion durations less than 30 minutes are generally not recommended in pediatric patients.

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What comparative data is available supporting the safety and efficacy of IV push vs. IV infusion Vimpat?

Please see Tables 1-3 for your response.

Safety and Efficiency of Intravenous Push Lacosamide Administration
Design	Single-center, retrospective cohort study N= 166
Objective	To compare safety outcomes and efficiency of administration in patients receiving lacosamide intravenous (IV) push compared to IV piggyback
Study Groups	IV push (n= 78) IV piggyback (n= 88)
Inclusion Criteria	Received lacosamide via IV piggyback administration from June 1 to December 31, 2016, and via IV push administration from January 1, 2017, to July 17, 2017
Exclusion Criteria	Received lacosamide via IV piggyback during the IV push time frame
Methods	Eligible patients received lacosamide IV push at a rate of 80 mg/min, or IV piggybacks, compounded in 50 mL of normal saline. Safety was evaluated by examining the incidence of infusion site reactions documented by the bedside nurse, bradycardia (heart rate [HR]<50 beats per minute), and hypotension (systolic blood pressure [SBP]<90 mm Hg), up to 2 hours after lacosamide administration.
Duration	June 2016 to July 2017
Outcome Measures	Primary: time from order verification to nurse administration of lacosamide, as documented in the electronic medical record by bar code medication administration Secondary: incidence of PR interval prolongation (defined as PR interval greater than 200 ms, in patients who had at least one EKG and time from order entry to administration
Baseline Characteristics		IV push (n= 78)	IV piggyback (n= 88)	p-value
	Age, years	62 (51 to 69)	62 (49 to 68)	0.67
	Male	44.9%	42%	0.71
	Weight, kg	77.3 (67 to 92)	78.9 (61.9 to 98)	0.67
	Location ICU ED Floor	60% 6% 33%	43% 15% 42%	0.03 0.08 0.25
	Initial dose ≤100 150 to 200 250 to 300 400	15% 69% 5% 10%	31% 56% 3% 10%	0.02 0.07 0.58 0.99
	Vitals Systolic blood pressure Diastolic blood pressure Heart rate	136 ± 25 74 ± 18 86 ±16	129 ± 25 74 ± 19 86 ± 18	0.09 0.91 0.82
	Cocurrent medicaations Antihypertensive Vasoactive sedative/analgesic	41% 15% 60%	35% 14% 76%	0.44 0.75 0.03

Results	Endpoint	IV push (n= 78)	IV piggyback (n= 88)	p-value
	STAT order priority
	Time from order verification to administration All orders, hours:minutes STAT orders, hours:minutes	54% 00:35 (00:10 to 01:25) 00:21 (00:07 to 01:25)	55% 01:49 (01:10 to 02:58) 01:36 (01:02 to 01:45)	0.99 <0.001 <0.001
	PR interval	66.7%	19.3%	<0.001

Adverse Events	Common Adverse Events: Hypotension (10% vs. 8%); bradycardia (3% vs. 2%)
Study Author Conclusions	Vast improvement was shown in administration efficiency without an increase in adverse effects. The ability to administer antiepileptic medications (AED) faster may impact the AED drug of choice, making lacosamide a viable option for urgent seizure control.
InpharmD Researcher Critique	Due to its retrospective nature, the study may be subject to selection bias. Of note, more patients in the IV push group were treated in areas with more aggressive monitoring (ICU) that may have impacted the rates of hypotension and bradycardia.

References:

Davidson KE, Newell J, Alsherbini K, Krushinski J, Jones GM. Safety and Efficiency of Intravenous Push Lacosamide Administration. Neurocrit Care. 2018 Dec;29(3):491-495. doi: 10.1007/s12028-018-0560-6. PMID: 29949010.

Cardiac effects of rapid intravenous loading of lacosamide in patients with epilepsy
Design	Retrospective, single-center study N= 85
Objective	To investigate the direct and immediate adverse cardiac and hemodynamic events after rapid intravenous (IV) loading of lacosamide in the setting of status epilepticus or acute repetitive seizures
Study Groups	All patients (n= 85)
Inclusion Criteria	Age ≥18; received a single rapid loading dose of 400 mg IV lacosamide; treated for status epilepticus or acute repetitive seizures; had well-documented ECG findings, blood pressure (BP), and heart rate (HR) before and after an IV infusion of lacosamide
Exclusion Criteria	Received a different loading dose of lacosamide; lack of post-infusion ECG data
Methods	Eligible patients received a single rapid loading dose of 400 mg IV lacosamide at a hospital in Seoul, Korea. The pre-lacosamide (at the time of admission or just before an IV infusion) and post-lacosamide ECG findings (within 30 min after an IV infusion) were collected for all patients. The medical records of consecutive patients were reviewed retrospectively.
Duration	January 2019 through December 2020
Outcome Measures	ECG and hemodynamic parameters at baseline and 30 minutes after IV lacosamide
Baseline Characteristics		All patients (n= 85)
	Previous seizure medication Lorazepam Other*	40 (47.1%) 8 (9%)
	Age, median years (interquatile range [IQR]) > 60	58 (40.5 to 77) 40 (47.1%)
	Male	48 (56.5%)
	Lacosamide dose per body weight, mg/kg (range)	6.8 (3.8 to 12.1)
	Etiology Acute symptomatic cryptogenic	30 (35.3%) 55 (64.7%)
	Seizure type Status epilepticus Acute repetitive	77 (90.6%) 8 (9.4%)
	* Other: sodium channel blockers (carbamazepine, oxcarbazepine, lamotrigine)
Results	Endpoint	All patients (n= 85)
		Pre-lacosamide	Post-lacosamide	p-value
	Blood pressure, mmHg Systolic Diastolic	129.7 74.5	129.6 75.2	0.810 0.239
	Heart rate (beats/min)	91.7	86.9	0.01
	ECG parameters, msec PR interval QTc interval	169.3 452.7	184.5 450	<0.01 0.696
	There were significant increases in the mean PR interval and decreases in the mean heart rate.
Adverse Events	Common Adverse Events: at least one cardiac adverse event (32.9%); new-onset first-degree atrioventricular block (22.4%); hypotension (8.2%)
	Serious Adverse Events: atrial fibrillation and bradycardia (2.4%); atrial flutter (1.2%)
Study Author Conclusions	In cases of epilepsy emergencies, adverse cardiac events commonly developed after IV loading of LCM, although most adverse events were mild in severity or not clinically significant. Elderly patients or patients with underlying cardiac diseases were prone to exhibiting a more prolonged PR interval after IV loading of LCM. Thus, the loading dose of IV LCM should be infused under careful ECG monitoring in these patients.
InpharmD Researcher Critique	This study was limited by retrospective nature, small sample size, and lack of comparison with other anti-seizure medications. Additionally, despite the wide range of body weight, all patients received lacosamide 400 mg, and a higher dose may be necessary to achieve a therapeutic blood concentration in overweight patients.

References:

Kim HK, Lee H, Bae EK, Kim DW. Cardiac effects of rapid intravenous loading of lacosamide in patients with epilepsy. Epilepsy Res. 2021;176:106710. doi:10.1016/j.eplepsyres.2021.106710

Safety of Intravenous Push Lacosamide Compared With Intravenous Piggyback at a Tertiary Academic Medical Center
Design	Single-center retrospective pre/post cohort analysis N= 175 (1,189 injections)
Objective	To compare the safety profile, including cardiovascular effects, sedative effects, and intravenous (IV) site reactions of intravenous push (IVP) and intravenous piggyback (IVPB) lacosamide administration
Study Groups	IVP (n= 102) IVPB (n= 73)
Inclusion Criteria	Adult patients with documented administrations of IV lacosamide during the study index
Exclusion Criteria	Patients aged <18 years, a baseline heart rate of <50 beats per minute (BPM), a baseline systolic blood pressure <90 mm Hg, or a confirmed diagnosis of atrioventricular conduction disease
Methods	Electronic health records were reviewed to identify eligible patients, pertinent vital signs, and relevant clinical assessments. Pre- and post-lacosamide HR and BP were defined as the closest measured value within 2 hours of administration. Medication-related sedation was assessed using the Richmond Agitation and Sedation Scale (RASS) or the Glasgow Coma Scale (GCS), which were recorded within 6 hours of administration. Sedation was defined as a decrease in score of ≥ 1 on either scale. After lacosamide administration, the severity of peripheral IV site reactions, such as phlebitis or infiltration, was also assessed based on the institutional grading system (0 = no symptoms; 4= most severe reactions).
Duration	May 2017 to July 2018
Outcome Measures	Safety outcome: hypotension (a systolic blood pressure [SBP] <90 mm Hg or a ≥30% reduction from baseline SBP), bradycardia (heart rate [HR] <50 BPM or a ≥30% reduction in baseline HR), medication-related sedation, and IV site reactions such as phlebitis and infiltration, clinical significant events requiring fluid resuscitation or vasopressor
Baseline Characteristics		IVP (n= 102)	IVPB (n= 73)	p-value
	Mean age, years	60.4 ± 14.6	59.1 ± 12	0.53
	Male	52 (50.98%)	40 (54.8%)	0.62
	Caucasian	76 (74.51%)	57 (78.08%)	0.59
	Mean weight, kg	72.6 ± 17.6	82.5 ± 20.4	< 0.05
	Cardiovascular disease Hypertension Congestive/acute decompensated heart failure Arrythmia	44 (43.14%) 6 (5.88%) 7 (6.86%)	32 (43.84%) 3 (4.11%) 4 (5.48%)	0.93 0.6 0.71
	Neurological disease Cerebral vascular accident Seizure disorder Traumatic brain injury	21 (20.59%) 87 (85.29%) 4 (3.92%)	12 (16.44%) 44 (60.27%) 5 (6.85%)	0.49 < 0.05 0.39
		IVP (n = 587)	IVPB (n = 602)
	Lacosamide dosage, mg Mean 100 150 200	157.58 162 (27.60%) 78 (13.29%) 303 (51.62%)	150 205 (34.05) 192 (31.89) 202 (33.55)
	Up to 400 mg lacosamide was administered via IVP (n= 3; 0.51%).
Results	Endpoint	IVP (n= 102)	IVPB (n= 73)	p-value
	Cardiovascular events Bradycardia 100 mg 200 mg Total requiring intervention Hypotension 100 mg 150 mg 200 mg Total requiring intervention	- - 0/127 (0) 1/276 (0.36%) 0/514 (0) - 1/112 (0.89%) 0/72 (0) 14/256 (5.47%) 1/476 (0.21%)	- - 3/187 (1.60%) 2/181 (1.10%) 0/459 (0) - 2/185 (1.08%) 1/87 (1.15%) 4/168 (2.38%) 0/441 (0)	- - - 0.34 - - 0.88 - 0.12 -
	Sedation events 50 mg 100 mg 150 mg 200 mg 400 mg	- 7/24 (29.166) 14/137 (10.22) 11/78 (14.10) 20/225 (8.89) 1/2 (50)	- 0/1 (0) 19/136 (13.97) 13/132 (9.85) 14/123 (11.38) 0/0 (0)	- 0.34 0.35 0.46 - 0.87
	Infusion site reactions Phlebitis code 1 Infiltration code 1 2	- - 2/388 (0.52) - 4/388 (1.03) 1/388 (0.26)	- - 0/239 (0) - 2/239 (0.84) 0 (0)	- - - - 0.81 -
	Only dosing cohorts presented are those in which an adverse drug reaction occurred.
Adverse Events	See results above
Study Author Conclusions	Intravenous push lacosamide was associated with a similar incidence of cardiovascular, neurological, and infusion site-related adverse events compared with IVPB, in which nearly every adverse event was deemed clinically insignificant. Lacosamide administered via IVP may be considered a safe alternative method of administration in the acute care setting.
InpharmD Researcher Critique	Given the retrospective nature of the study, human errors might occur while documenting vital signs or other clinical assessments. Since the analysis was conducted in acute care, inpatient setting, the use of IVP might be more appropriate in similar settings, such as intensive care units, stepdown units, and emergency departments, to yield comparable safety outcomes.

References:

McLaughlin K, Carabetta S, Hunt N, Schuler BR, Ting C, Tran LK, Szumita PM, Anger KE. Safety of Intravenous Push Lacosamide Compared With Intravenous Piggyback at a Tertiary Academic Medical Center. Ann Pharmacother. 2021 Feb;55(2):181-186. doi: 10.1177/1060028020943569. Epub 2020 Jul 19. PMID: 32686466.