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

Exclusion Criteria

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

Outcome Measures

Baseline Characteristics

IV push (n= 78)

IV piggyback (n= 88)

Age, years

Male

Weight, kg

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

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

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.

Design

Retrospective, single-center study

N= 85

Objective

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

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

Outcome Measures

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

Lacosamide dose per body weight, mg/kg (range)

Etiology

Acute symptomatic

cryptogenic

30 (35.3%)

55 (64.7%)

Seizure type

Status epilepticus

Acute repetitive 

77 (90.6%)

8 (9.4%)

Results

Endpoint

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

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

InpharmD Researcher Critique

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)

Mean age, years

Male

Caucasian 

Mean weight, kg

Cardiovascular disease

Hypertension 

Congestive/acute decompensated heart failure

Arrhythmia 

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

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

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.  

Design

Multicenter, retrospective study

N= 39

Objective

To assess the efficacy and safety of intravenous (IV) lacosamide (LCM) in status epilepticus (SE) after the failure of standard treatment

Study Groups

LCM first⁄second dose (n= 5)

LCM third dose (n= 19)

LCM fourth or later dose (n= 15)

Inclusion Criteria

Received at least one dose of LCM IV for treatment of SE

Exclusion Criteria

Not specified

Methods

LCM was administered after the failure of benzodiazepines or other standard drugs in all but one case. Patients received a median bolus dose of LCM 400 mg (range 200–400 mg), which was administered at 40–80 mg⁄min in patients with a documented infusion rate. 

Duration

Admission period: September 2008 through January 2010

Outcome Measures

Success rate (termination of SE defined as disappearance of electroencephalogram [EEG] status⁄seizure activity or disappearance of previous ictal symptoms without any suspicion of ongoing subclinical seizure activity) after receiving LCM 

Baseline Characteristics

All patients (N= 39)

Age, years

Female

Semiology of SE

Convulsive generalized

Complex partial

Simple focal

6 (15%)

16 (41%)

17 (44%)

Etiology

Acute symptomatic

Remote symptomatic (new onset of epilepsy)

Remote symptomatic (pre-existing epilepsy)

Others ⁄ unknown

10 (26%)

9 (23%)

19 (49%)

1 (3%)

AED medication before SE

LCM

LEV

VPA

PHT

LTG

Benzodiazepines

Others

None

SE, status epilepticus; LOC, loss of consciousness; AED, antiepileptic drug; LCM, lacosamide; LEV, levetiracetam; NCSE, non-convulsive status epilepticus; VPA, valproate; PHT, phenytoin; LTG, lamotrigine

Results

Endpoint

LCM first⁄second dose (n= 5)

LCM third (n= 19)

Latency onset SE after LCM 

Termination of SE by LCM*

< 6 h after LCM, No other AED after LCM

> 6 h after LCM, No other AED after LCM

3/5

2

1

11/19

4

7

3/15

1

2

*In five subjects, SE could not be terminated at all.

Adverse Events

One allergic skin reaction following LCM administration was observed although the simultaneous administration of domperidon in this patient may be a possible alternative etiology. 

No serious adverse event was observed.

Study Author Conclusions

Intravenous LCM may be an alternative treatment for established SE after the failure of standard therapy, or when standard agents are considered unsuitable.

InpharmD Researcher Critique

This study is subject to limitations inherent to any retrospective study such as confounding variables and selection bias. 

Safety Profile of High-Dose Intravenous Push Lacosamide

Design

Single-center, retrospective, single-arm analysis

N= 113

Objective

Study Groups

All subjects (N= 113)

Inclusion Criteria

Exclusion Criteria

Not stated

Methods

Collected baseline characteristics include patient location, heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Evaluation of the PR interval in LCM-treated patients lacks a standardized protocol and is left to the discretion of the treating clinician. Safety events are assessed using the Naranjo Adverse Drug Reaction Probability Scale.

Duration

May 2019 to May 2020

Outcome Measures

Primary: incidence of any of infusion site reactions (documentation of extravasation or infusion site irritation), hypotension (SBP less than 90 mmHg), and bradycardia (HR less than 50 bpm) within 2 hours of IVP lacosamide administration

Secondary: incidence of PR prolongation (greater than 200 milliseconds [msec]) if an EKG was measured

Baseline Characteristics

High-dose IVP lacosamide (N= 113)

Age, years

Male

Weight, kg

Telemetry

Location

ICU

ED

Floor

50.4%

25.7%

23.9%

Initial dose

300 mg

400 mg

14.2%

85.8%

Baseline vitals

SBP, mmHg

DBP, mmHg

HR, bpm

136 ± 25.3

79 ± 15.9

89

Concurrent medications

Antihypertensives

Vasoactive

Sedative / Analgesics

26.5%

8%

31%

Abbreviations: ICU = intensive care unit, ED = emergency department, SBP = systolic blood pressure, DBP = diastolic blood pressure, HR = heart rate 

Results

Endpoint

High-dose IVP lacosamide (n= 108) 

Primary

Bradycardia

Hypotension^a

Intravenous line infusion reactions

0

12 (11.1%)

7 (6.2%)

Secondary

PR interval prolongation^b

Average PR interval, msec

2/21 (9.5%)

156 ± 27.2

^a Hypotensive events occurred in 2 (12.5%) and 10 (10.3%) of patients who received lacosamide 300 mg and 400 mg, respectively. 

^b Patients who had an EKG within 2 hours and was associated with no bradycardic episodes or alterations in therapy. 

All events scored less than two on the Naranjo Adverse Drug Probability Scale, meaning the event was likely related to factors other than the medication.

Adverse Events

See Results

Study Author Conclusions

In conclusion, lacosamide 300 mg and 400 mg IVP administration have the potential to facilitate more rapid treatment of seizures without additional risk of infusion site reactions, hypotension, and bradycardia.

InpharmD Researcher Critique

This was a retrospective study solely focused on a single intervention without a comparative group. Not all necessary patient data for safety analysis were readily available in the electronic medical record. The limited documentation of EKG within the specified timeframe may have inaccurately represented the incidence of PR interval prolongation. Nursing documentation practices may have constrained the evaluation of infusion-related reactions. Concurrently administered agents were considered in assessing adverse effects, with the Naranjo assessment suggesting lacosamide was unlikely to have contributed to documented adverse events. Lastly, the study, conducted at a high-volume neurocritical care center where IVP lacosamide is standard practice, focused on a relatively larger sample of patients receiving doses exceeding 200 mg. 

Safety and Tolerability of Intravenous Push Lacosamide and Levetiracetam

Design

Retrospective, single-center, observational study

N= 86

Objective

To evaluate the safety and tolerability of undiluted intravenous (IV) push lacosamide and levetiracetam over 5 minutes

Study Groups

Lacosamide (n= 36)

Levetiracetam (n= 50)

Inclusion Criteria

Aged ≥ 18 years old; administered at least one dose of IV push lacosamide at any dose or levetiracetam at doses ≤ 1500 mg

Exclusion Criteria

Baseline heart rate (HR) < 50 beats per minute or systolic blood pressure (SBP) < 90 mmHg

Methods

Per institutional policies implemented on September 1st, 2019, lacosamide doses up to 400 mg could be administered via IV push over 5 minutes, while levetiracetam doses up to 1500 mg could be administered via IV push over 5 min. Commercially available solutions of lacosamide 200 mg/20 mL (10 mg/mL) and levetiracetam 500 mg/5 mL (100 mg/mL) were administered without requirements for further dilution prior to IV push. Doses could be administered via a peripheral or central line. Data were collected from a chart review of the electronic health record.

Duration

Between September 1, 2019 to May 31, 2020

Outcome Measures

Primary: incidence of hypotension or bradycardia

Secondary: safety outcomes, PR interval prolongation

Baseline Characteristics

Lacosamide (n= 36)

Levetiracetam (n= 50)

Age, years

Male

White

Weight, kg

Total number of doses administered

Dose, mg (IQR)*

68

200 (100-500)

79

500 (200-1,000)

Abbreviations: IQR, interquartile range

* Based on total number of doses administered

Results

Endpoint

Lacosamide (n= 36)

Levetiracetam (n= 50)

Safety outcomes

Hypotension ^a

Bradycardia ^b

Infusion-related events ^c

PR interval prolongation ^d

4 (11.1%)

2 (5.6%)

0

0

2 (4.0%)

4 (8.0%)

0

0

^a Hypotension defined as systolic blood pressure < 90 mmHg.

^b Bradycardia defined as heart rate < 50 beats per minute.

^c Infusion-related events defined as at least one of the following: phlebitis, infiltration, extravasation, tissue ischemia, thrombosis, and/or line infection.

^d PR interval prolongation defined as > 200 ms.

Adverse Events

See Results

Study Author Conclusions

In this safety-analysis cohort, undiluted lacosamide and levetiracetam were not associated with significant adverse events when administered via IV push over 5 min. This seems to be a safe alternative method of administration to intermittent infusion. A larger, prospective cohort is needed to confirm these findings.

InpharmD Researcher Critique

The small sample size and retrospective design of the study introduce risk for confounding in the results. Safety outcomes may be underreported in the electronic health record, and the minute amount of patients in the lacosamide arm further limit the ability to detect more rare treatment-related outcomes. The use of either a peripheral or central line, which the study did not stratify for, may similarly have had a potential effect on findings.

Intravenous lacosamide as successful treatment for nonconvulsive status epilepticus after failure of first-line therapy

Design

Case presentation

A 42-year-old female with history of severe cardioembolic stroke, multiple episodes of left hemispheric status epilepticus, previous oral antiepileptic drug therapy (levetiracetam 2,000 mg daily, lamotrigine, gabapentin, and gabapentin + lamotrigine [current regiment at the time of report]), and poor adherence was admitted with repeat episode of left hemispheric status epilepticus. She received diazepam 2.5 mg IV during transport and 6 mg of IV lorazepam; however, status epilepticus persisted ten minutes after lorazepam treatment. Based on the patient’s drug therapy and other considerations, lacosamide 200 mg was selected to be administered as IV bolus over three to five minutes.

After another three to five minutes, rhythmic epileptiform activity ceased. Patient stabilized over the next 48 hours. She was given 100 mg lacosamide orally once daily from day 2 in addition to lamotrigine and gabapentin (previous regimen). She also received domperidone 10 mg three times daily from day 2 for three days due to nausea. On day 6, skin itchiness and mild erythema of the upper back were observed, but these were resolved with dimetinden (histamine 1 receptor blocker) within two days. A 12-channel-ECG on day 3 after lacosamide initiation was completely normal, and the patient was discharged on day 7.

Study Author Conclusions

Lacosamide could be an alternative treatment for those who failed other treatments. However, larger studies are needed to assess safety and efficacy of this practice.