What data is there to support IV push fosphenytoin? What is the maximum recommended IV push dose?

Comment by InpharmD Researcher

A 2025 review suggests intravenous push (IVP) fosphenytoin for status epilepticus at a maximum dose of 1,500 mg phenytoin equivalents (mgPE). This recommendation is based on fosphenytoin's superior safety profile over phenytoin, with a lower risk of cardiac events and hypotension. The dose is suggested to be administered at a maximum rate of 150 mgPE/min, allowing for faster treatment in urgent situations. When researching individual studies, the majority utilize IV loading dose in its wording, while one study used IV bolus. In these studies, fosphenytoin appears to be safe and effective, but loading dose may not be synonymous to an IV push.

Background

According to a 2025 review, an option for the urgent treatment of status epilepticus (SE) is intravenous push (IVP) fosphenytoin (FPT) administered at a dose of up to 1,500 mg phenytoin equivalents (mgPE) and at a maximum rate of 150 mgPE/min. This recommendation is supported by FPT's more favorable safety profile compared to phenytoin (PHT), specifically a lower risk of cardiac arrhythmias and hypotension, and its ability to be administered more rapidly. While clinical trials like ESETT found FPT, levetiracetam, and valproate to have similar efficacy, the faster administration of IVP FPT is a critical advantage in time-sensitive situations. For maintenance dosing or in non-urgent scenarios, IVP phenytoin may be a cost-effective alternative, but it requires strict adherence to a slower infusion rate (not exceeding 50 mg/min) and proper dilution to mitigate risks of cardiac events and tissue injury from extravasation. Overall, successful implementation of an IVP strategy for these agents necessitates comprehensive staff education to prevent administration errors. [1]

References:

[1] Aljadeed R, Gilbert BW, Karaze T, Rech MA. Intravenous push administration of anti-seizure medications. Front Neurol. 2025;15:1503025. Published 2025 Jan 27. doi:10.3389/fneur.2024.1503025
Literature Review

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

What data is there to support IV push fosphenytoin? What is the maximum recommended IV push dose?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

Randomized Trial of Lacosamide versus Fosphenytoin for Nonconvulsive Seizures
Design

Noninferiority, prospective, multicenter, randomized treatment trial

N= 74
Objective To evaluate the comparative effectiveness of the antiseizure drugs lacosamide (LCM) and fosphenytoin (fPHT) in controlling nonconvulsive seizures (NCSs) in critically ill patients
Study Groups

LCM (n= 37)

fPHT (n= 37)
Inclusion Criteria Age 18 years or older; undergoing cEEG for detection of NCSs; at least 1 electrographic seizure lasting at least 10 seconds and <30 minutes; seizures frequent enough to warrant intravenous ASD; seizure within 6 hours of randomization
Exclusion Criteria Already treated with fPHT, PHT, or LCM; known hypersensitivity or contraindication to either drug; anoxic encephalopathy; undergoing therapeutic hypothermia; generalized convulsive seizures during cEEG; electrographic SE with seizures lasting >30 minutes per hour of cEEG
Methods Subjects were randomized to initial treatment with IV fPHT (20mg phenytoin equivalents/kg) bolus or IV LCM (400mg) over 30 minutes. A 2-hour grace period was allowed before efficacy assessments. If seizures occurred, a rebolus of IV fPHT 5mg PE/kg or IV LCM 200mg was administered. Subjects were observed for 24 hours for further seizures. Crossover to the other drug was allowed if the first was ineffective
Duration August 21, 2012 to December 20, 2013
Outcome Measures

Primary: Absence of electrographic seizures for 24 hours

Secondary: Percentage of subjects requiring rebolus, crossover treatment, change in seizure burden
Baseline Characteristics   LCM (n= 37) fPHT (n= 37)
Mean age, years 63.6 63.6
Female 19 19
History of epilepsy Yes Yes
Use of ASDs Yes Yes
Results   LCM (n= 30) fPHT (n= 32) p-value
Seizure control (24 hours) 19 (63.3%) 16 (50%) 0.02
Rebolus required 16 (45.7%) 13 (35.1%) 0.41
Crossover treatment 15 (42.9%) 10 (27.0%) 0.18
Adverse Events TEAEs were similar in both arms, occurring in 9 of 35 (25.7%) LCM and 9 of 37 (24.3%) fPHT subjects. Serious adverse events (SAEs) occurred in 5 of 35 (14.3%) LCM and 4 of 37 (10.8%) fPHT subjects. TEAEs of special interest (cardiac arrhythmias, hypotension, respiratory failure, and multiorgan hypersensitivity reactions) occurred in 4 of 35 (11.4%) LCM and 5 of 37 (13.5%) fPHT subjects
Study Author Conclusions LCM was noninferior to fPHT in controlling NCS, and TEAEs were comparable. LCM can be considered an alternative to fPHT in the treatment of NCSs detected on cEEG.
Critique The study was a well-designed prospective, randomized trial that successfully demonstrated noninferiority of LCM to fPHT. However, the study was limited by a smaller sample size than initially planned due to withdrawal of funding. The lack of blinding for treating physicians could introduce bias, and the study did not include a placebo arm, which limits the ability to determine the absolute efficacy of the treatments. Additionally, the study did not address the impact of treatment on long-term outcomes or the effectiveness in more severe forms of seizures like NCSE.

 

References:

Husain AM, Lee JW, Kolls BJ, et al. Randomized trial of lacosamide versus fosphenytoin for nonconvulsive seizures. Ann Neurol. 2018;83(6):1174-1185. doi:10.1002/ana.25249

Evaluation of Intravenous Phenytoin and Fosphenytoin Loading Doses: Influence of Obesity and Sex
Design

Retrospective, single-center cohort study

N= 195
Objective To examine the influence of obesity and sex on phenytoin loading doses
Study Groups

Nonobese (n= 141)

Obese (n= 54)
Inclusion Criteria Patients 18 years or older, received IV phenytoin ≥10 mg/kg or fosphenytoin ≥10 mg phenytoin equivalents (PE)/kg, and had a free phenytoin concentration drawn between 1 and 6 hours after the end of the infusion
Exclusion Criteria Pediatric and pregnant patients, patients with detectable baseline phenytoin concentrations
Methods

Retrospective cohort study comparing free phenytoin or fosphenytoin serum concentrations following loading doses in male versus female and nonobese versus obese patients. An equation for determining loading doses in obese patients was evaluated.

While not explicitly stated, a loading dose would imply that fophenytoin was administered as an IV bolus.
Duration June 1, 2014, to October 31, 2017
Outcome Measures

Primary: Effects of obesity and sex on serum phenytoin concentrations
Baseline Characteristics   Nonobese (n = 141) Obese (n = 54) P Value
Age (years) 60.9 (41.1-72) 57.4 (45.4-68.7) 0.52
Sex - Male 83 (58.9%) 27 (50%) 0.26
Sex - Female 58 (41.1%) 27 (50%)  
Weight, kg - TBW 68.0 (58.1-79.1) 104.2 (85.4-130.0) <0.001
Weight, kg - IBW 63.8 (55.9-73.0) 63.8 (54.1-73.1) 0.98
BMI, kg/m2 23.2 (21.2-25.8) 35.9 (32.5-39.9) <0.001
Albumin, g/dL 3.9 (3.5-4.3) 3.8 (3.1-4.1) 0.041
Serum creatinine, mg/dL 1.07 ± 0.9 1.04 ± 0.6 0.89
AST, IU/L 43.6 ± 70.7 36.3 ± 25.6 0.53
ALT, IU/L 56.9 ± 237.4 31.4 ± 19.2 0.51
Alkaline phosphatase, IU/L 77.0 (64.0-121.0) 89.5 (66.0-128.8) 0.18
Total bilirubin, mg/dL 0.7 ± 0.6 0.7 ± 1.1 0.98
Drug - Phenytoin 41 (29.1%) 17 (31.5%) 0.74
Drug - Fosphenytoin 100 (70.9%) 37 (68.5%)  
Results Dose (mg) Nonobese (n = 141) Obese (n = 54) P Value
Dose (mg) 1270 (1000-1490) 1700 (1517-2000) <0.001
Dose (mg/kg TBW) 20.0 (18.6-20.0) 17.0 (14.9-20.0) <0.001
Free level (µg/mL) 1.8 (1.5-2.1) 1.7 (1.4-2.0) 0.16
Free level distribution - <1 µg/mL 8 (5.7%) 3 (5.6%) 0.78
Free level distribution - 1-2 µg/mL 92 (65.2%) 38 (70.1%) --
Free level distribution - >2 µg/mL 41 (29.1%) 13 (24.1%) --
Time level obtained postdose (hours) 3.4 ± 1.4 3.1 ± 1.3 0.28
Adverse Events 22 patients experienced hypotension (systolic blood pressure <90 mm Hg or mean arterial pressure <70 mm Hg), with no difference between obese (27%) and nonobese (18%) cohorts (P = 0.356). Nystagmus was noted in 2 patients, one with a free phenytoin concentration >2.0 mg/L
Study Author Conclusions

Phenytoin and fosphenytoin loading doses of at least 15 mg/kg of actual body weight are more likely to lead to desired free phenytoin concentrations. Obese female patients need a larger weight-based dose than male patients to achieve similar postload phenytoin concentrations.
Critique

The study's retrospective design limits the ability to capture precise peak concentrations and may introduce data availability issues. The small sample size of the obese cohort and lack of data on concomitant medications that could interact with phenytoin are additional limitations. However, the study provides valuable insights into dosing considerations for obese patients, highlighting the need for individualized dosing strategies based on actual body weight rather than relying solely on standard equations.

 

References:

DasGupta R, Alaniz C, Burghardt D. Evaluation of Intravenous Phenytoin and Fosphenytoin Loading Doses: Influence of Obesity and Sex. Ann Pharmacother. 2019;53(5):458-463. doi:10.1177/1060028018818785

Evaluation of Two Fosphenytoin Loading Dose Regimens and Monitoring in Infants and Neonates Less Than Six Months of Age
Design

Retrospective cohort study

N= 41
Objective To compare the free serum concentrations after different fosphenytoin loading dose strategies in patients younger than 6 months old and to investigate the frequency of seizure cessation following a loading dose of fosphenytoin
Study Groups

15 mg/kg group (n= 12)

20 mg/kg group (n= 29)
Inclusion Criteria Patients younger than 6 months old with a postload free phenytoin serum concentration collected during the specified time frame
Exclusion Criteria Patients who received more than 1 dose of fosphenytoin prior to a free concentration being collected
Methods

Patients were divided into two groups based on the fosphenytoin loading dose received (15 mg/kg vs 20 mg/kg). Data collection included demographic information, fosphenytoin dose, time of administration, time of sampling, free phenytoin serum concentration results, concomitant antiepileptic agents, albumin serum concentration, and total bilirubin serum concentration. Descriptive statistics and statistical tests were used to compare outcomes between groups.

While not explicitly stated, a loading dose suggests that fosphenytoin would be administered as a bolus or IV push.
Duration August 1, 2014, to February 1, 2018
Outcome Measures Free phenytoin serum concentrations, frequency of seizure cessation
Baseline Characteristics   15 mg/kg Group (n = 12) 20 mg/kg Group (n = 29) p value
Term birth, n (%) 7 (58.3) 25 (86.2) 0.0929
Male, n (%) 8 (66.7) 19 (65.5) 1.0000
NICU admission, n (%) 12 (100) 13 (44.8) 0.0010
Age, median (range), days 2.5 (1–40) 28 (0–169) 0.0101
Weight, median (range), kg 2.91 (0.99–4.31) 4.12 (2.39–8.60) 0.0021
Results   15 mg/kg Group 20 mg/kg Group p-value
Average free phenytoin concentration, mg/L 2.45 ± 0.54 2.52 ± 0.66 0.747
Seizure cessation, n (%) 3 (25%) 13 (45%) 0.305
Adverse Events Not specifically reported due to the retrospective nature and difficulty in identifying adverse effects in the neonatal population
Study Author Conclusions

The study demonstrates that a traditional range of fosphenytoin loading dose (15–20 mg/kg) led to elevated postloading dose free phenytoin serum concentrations in the majority of patients with a seizure cessation rate of approximately 39%. The optimal dose and target concentration for this patient population remain unclear.
Critique The study is limited by its retrospective design, small sample size, and single-center setting, which may affect the generalizability of the findings. The lack of a priori definitions for seizures and seizure cessation, as well as the difficulty in identifying adverse effects in neonates, are additional limitations. However, the study provides valuable insights into the variability of free phenytoin concentrations in this population and highlights the need for further research to determine optimal dosing strategies.

 

References:

Bohannon KK, Leung N, Cook AM, et al. Evaluation of Two Fosphenytoin Loading Dose Regimens and Monitoring in Infants and Neonates Less Than Six Months of Age. J Pediatr Pharmacol Ther. 2020;25(7):617-622. doi:10.5863/1551-6776-25.7.617