Should IVP administration of valproate be administered undiluted or diluted?

Comment by InpharmD Researcher

There is no clear consensus or standardized guidance on whether valproate should be administered by intravenous push (IVP) in an undiluted form or after dilution with a compatible diluent. The Depacon (Valproate sodium) IV injection package insert suggests that valproate should always be diluted with 50mL of diluent prior to administration. However, the available literature is mixed, with some studies administering valproate in a diluted form and others using undiluted preparations. Additional research is warranted to assess benefit, risk, and impact on clinical efficacy if valproate is administered in an undiluted or diluted form.

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Background

A 2025 review article examines the use of intravenous push (IVP) administration of anti-seizure medications, including valproic acid (VPA) as a strategy to enhance the rapid management of status epilepticus (SE) in emergency departments. It was highlighted that VPA is a multifaceted antiepileptic medication with several mechanisms of action that contribute to its therapeutic effects. Despite its long-standing availability of over 40 years, there is limited evidence supporting its use as an IVP medication. Effective bolus and infusion doses range from 15 to 45 mg/kg with an infusion rate of 6 mg/kg/min, yielding infusion times between 2.5 to 7.5 minutes. Safety profiles from multiple studies indicate a low incidence of adverse events (<10%), including dizziness, thrombocytopenia, and mild hypotension, which appear independent of infusion rates. Some studies, though not involving patients with SE, have shown that rapid administration of undiluted valproate is well-tolerated without significant adverse effects, thus supporting its use in emergencies. In a systematic review and meta-analysis, VPA emerged as the most effective agent in terminating benzodiazepine-resistant SE compared to levetiracetam, phenytoin, and phenobarbital. Given its broad applications and high termination rate of SE, further research is warranted to explore its efficacy and safety with rapid IVP administration in treating SE. [1]

A 2007 study investigated the protein binding parameters of undiluted VPA sodium administered as a rapid intravenous infusion in epilepsy patients from the Limdi et al. study (See Table 1). A total of 40 epileptic patients were administered 20 or 30 mg/kg loading dose at a rate of 6 or 10 mg/kg/min. Aside from the indication of VPA, patients were relatively healthy. Using the one-binding site model, the data suggests that VPA 30 mg/kg loading dose produced higher total and unbound concentrations versus 20 mg/kg. However, the estimated dissociation constant of 9.3 mg/L was found to be within the therapeutic range of unbound VPA concentrations among healthy historical controls (5-15 mg/mL). Please refer to Table 3 for a comprehensive overview of this study. [2]

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
[2] Dutta S, Faught E, Limdi NA. Valproate protein binding following rapid intravenous administration of high doses of valproic acid in patients with epilepsy. J Clin Pharm Ther. 2007;32(4):365-371. doi:10.1111/j.1365-2710.2007.00831.x
Relevant Prescribing Information

According to the package insert, Depacon (Valproate sodium) IV Injection should be administered intravenously as a 60 minute infusion and be diluted with at least 50 mL of a compatible diluent. [3]

References: [3] Depacon (Valproate sodium injection). Prescribing information. AbbVie Inc; 2013.
Literature Review

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

Should IVP administration of valproate be administered undiluted or diluted?

Level of evidence

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


Please see Tables 1-3 for your response.

 

Safety of Rapid Intravenous Loading of Valproate

Design

Open-label, prospective trial

N= 40

Objective

 To evaluate the safety of administration of undiluted valproic acid (VPA) sodium (20 or 30 mg/kg/min) administered intravenously at rates of 6 or 10 mg/kg/min

Study Groups

20 mg/kg (n= 20)

30 mg/kg (n= 20)

Inclusion Criteria

 Age 19 years or older, taking VPA to control seizures or epilepsy indication for use

Exclusion Criteria

 Allergy to VPA, liver disease, status epileptics, concurrent high-dose lamotrigine therapy

Methods

VPA sodium was prepared from 5 mL vials (equivalent to 100 mg valproic acid) as an undiluted solution to be infused via peripheral access by manual injection, using a stopwatch to monitor administration rate. IV access was confirmed with a saline flush before and after dosing. Patients were divided to receive 20 mg/kg or 30 mg/kg as loading dose, with each cohort group further divided to be infused at a rate of 6 mg/kg/min or 10 mg/kg/min.

6 mg/kg/min = 3.3 min administration time for a 20 mg/kg dose and 5 min for a 30 mg/kg dose

10 mg/kg/min = 2 min administration time for a 20 mg/kg dose and 3 min for a 30 mg/kg dose

Duration

 Up to 24 hours monitoring

Outcome Measures

 Local tolerance graded on a 1-10 scale (0= none, 10= worst), heart rate (HR), mean arterial pressure (MAP), changes in vital signs and level of consciousness

Baseline Characteristics

  

All patients (N= 40)

  

Age, years

 39  

Female

13   

Race

White

Black

Hispanic

Asian

 

28

9

2

1

  
 

20 mg/kg (n= 20)

 30 mg/kg (n= 20)  

Weight, kg (standard deviation [SD])

 91.8 (27.8) 73.2 (14.2)  

Valproate dose, mg (SD)

 1834.0 (556.1) 2190.6 (439.3)  

Results

Endpoint

20 mg/kg (n= 20)

30 mg/kg (n= 20)

p-Value

Local tolerance (SD)

Pain/burning

Paresthesia

Duration

 

5.5 (2.5)

2.9 (3.2)

2.1 (0.5)

 

5.9 (2.3)

2.3 (3.3)

2.3 (0.4)

 

0.71

0.67

0.31
 

6 mg/kg/min infusion rate (n= 20)

10 mg/kg/min infusion rate (n= 20)

  

Local tolerance (SD)

Pain/burning

Paresthesia

Duration

 

5.4 (2.2)

1.0 (2.5)

2.2 (0.6)

 

5.9 (2.7)

4.5 (2.9)

2.1 (0.2)

 

0.63

0.005

0.47

The results of the repeated measures analysis showed that there were no significant changes in MAP (p= 0.7) and HR (p= 0.9) over time

Adverse Events

 There were 3 complaints of sedation and 1 complaint of nausea among treated patients. No patients reported a decline in level of consciousness

Study Author Conclusions

 Rapid administration of undiluted valproate is safe and well tolerated at infusion rate up to 10 mg/kg/min and doses of up to 30 mg/kg. The lack of serious cardiovascular, neurological, hepatic, or local adverse effects supports the use of VPA in emergent situations.

InpharmD Researcher Critique

Based on the weight of patients, the max infusion rate could have exceeded a 200 mg/min infusion rate. However, there is a lack of investigation for patients that would have received high infusion rates due to their weight.



References:
[1] Limdi NA, Knowlton RK, Cofield SS, et al. Safety of rapid intravenous loading of valproate. Epilepsia. 2007;48(3):478-483. doi:10.1111/j.1528-1167.2007.00989.x
Randomized Clinical Trial of Intravenous Valproate (Orifil) and Dexamethasone in Patients with Migraine Disorder
Design

Prospective, randomized clinical trial

N=31
Objective

To compare the therapeutic effects of intravenous valproate (Orifil) and intravenous dexamethasone (IVDEX) as abortive therapy in patients with migraine status
Study Groups

IVVP (Orifil) (n=19)

IVDEX (n=12)
Inclusion Criteria

Patients with migraine status recruited from the Emergency Division and Headache Clinic in 2011
Exclusion Criteria

Patients aged <18 years, pregnant women, patients with liver failure, dementia, aphasia, and psychiatric disorders
Methods

An intravenous line was established for two groups of patients to evaluate headache relief from different treatments. The first group received an infusion of 16 mg of IVDEX, diluted in 150 cc of normal saline, administered over 10 minutes. Patients weighing at least 90 kg were given 20 mg of IVDEX. The second group received 900 mg of IVVP (Orifil), similarly diluted in 150 cc of normal saline and infused over 10 minutes, with a dosage increase to 1200 mg for those weighing 90 kg or more. Following the infusion, patients in both groups rated the severity of their headaches at the point of maximum relief within a 3-hour period post-infusion.
Duration 2011
Outcome Measures

Primary: Therapeutic effects on pain score

Secondary: Relapse of headache within 72 hours
Baseline Characteristics

Clinical characteristic /Therapeutic group

 IVVP Orifil N=19 IV DEX N=12

Mean age, years

 33.895±13.337 32.500±11.188

Mean migraine history, per month

 6.263±8.993 6.000±8.068

Presence of aura

 38.84% 8.34%

Recovery from nausea

 68.42% 91.67%

Recovery from photophobia

 78.95% 91.67%

Pain-free response after treatment

 26.32% 33.33%
Results  

IVVP (Orifil)

 IVDEX

No recurrence

 6 4

Mild recurrence

 8 4

Severe recurrence

 5 4
Adverse Events

None of the patients in the IVVP (Orifil) group or IVDEX group exhibited drug-related side effects within 72 hours post infusion.
Study Author Conclusions

A meticulous review of the literature shows that our study is the only clinical trial to date to compare 16 mg IVDEX with 900 mg IVVP (Orifil) in patients with migraine status. In our study, IVVP (Orifil) was similar to IVDEX as abortive therapy and IVVP (Orifil) appears to offer a safe and well-tolerated abortive treatment.
Critique

The study's strengths include its randomized design and focus on a specific patient population with migraine status. However, the small sample size and lack of a placebo control group limit the generalizability of the findings. Additionally, the study did not explore long-term outcomes or compare the treatments to other standard migraine therapies.
References:
[1] Foroughipour M, Ghandehari K, Khazaei M, Ahmadi F, Shariatinezhad K, Ghandehari K. Randomized clinical trial of intravenous valproate (orifil) and dexamethasone in patients with migraine disorder. Iran J Med Sci. 2013;38(2 Suppl):150-155.

Valproate protein binding following rapid intravenous administration of high doses of valproic acid in patients with epilepsy
Design

Open-label, prospective, safety and pharmacokinetic study

N= 40
Objective

To characterize protein binding in patients with epilepsy who achieve transient high (>150 mg/L) total plasma concentrations following rapid valproate infusion at very high doses
Study Groups

20 mg/kg VPA (n= 20)

30 mg/kg VPA (n= 20)
Inclusion Criteria

Patients with epilepsy administered 20 or 30 mg/kg loading doses of undiluted valproate sodium injection
Exclusion Criteria

Not specified
Methods

Patients were administered 20 or 30 mg/kg loading doses (6 or 10 mg/kg/min) of undiluted valproate sodium injection. Total and unbound valproic acid concentrations were used to assess VPA binding to plasma albumin. One- and two-binding site models were explored in a nonlinear mixed effects population analysis framework. Blood samples were collected at baseline and at various intervals post-infusion for determination of plasma concentrations of VPA.
Duration

Not specified
Outcome Measures

Primary: Characterization of VPA protein binding using one-binding site model

Secondary: Influence of covariates on binding site association constant (K)
Baseline Characteristics  

20 mg/kg (n= 20)

 30 mg/kg (n= 20)

Total dose, mg

 1796 ± 552 2192 ± 428

Age, years

 37.2 ± 14.3 40.8 ± 15.0

Weight, kg

 89.9 ± 27.6 73.3 ± 13.9

Male

 65% 70%

White race

 80% 60%

Co-therapy with enzyme-inducing AEDs

 15% 50%
Results  

Estimate ± SE
Number of binding sites, mM-1

1.98 ± 0.0865
Binding site association constant, mM-1

15.5 ± 2.28 
Intersubject variance for K, mM-1

0.100 ± 0.0348 
Intersubject coefficients of variation (CV)

32%
Intrasubject CV

14%
Adverse Events

Not specified
Study Author Conclusions

A one-binding site model without any significant covariates for binding constants optimally described VPA protein binding. As the estimated dissociation constant (1/K, 64.5μm or 9.3mg/L) was within the therapeutic range (5–15mg/L) for unbound VPA concentrations, protein binding was nonlinear. Although the range of unbound fraction and VPA concentrations were much higher than previous studies, the dissociation constant was consistent with historical data in normal healthy adults and epilepsy patients receiving lower doses.
Critique The study provided valuable insights into VPA protein binding at high concentrations, but the small sample size and lack of significant covariates may limit the generalizability of the findings. Additionally, the exclusion of data from participants with high unbound fractions could impact the robustness of the model.
References:
[1] Dutta S, Faught E, Limdi NA. Valproate protein binding following rapid intravenous administration of high doses of valproic acid in patients with epilepsy. J Clin Pharm Ther. 2007;32(4):365-371. doi:10.1111/j.1365-2710.2007.00831.x