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Medicines Q&As
Q&A 444.3
How can we minimise the risks to patients when using intravenous
phenytoin in status epilepticus (SE)?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at https://www.sps.nhs.uk/articles/about-ukmi-medicinesqas/
January 2017
Background
Intravenous phenytoin is one of a number of treatments that can be used to manage status
epilepticus (SE); this is a condition where a convulsive seizure continues for a prolonged period
(longer than 5 minutes), or when convulsive seizures occur one after the other with no recovery
between. Convulsive status epilepticus is an emergency and requires immediate medical attention1.
The use of intravenous phenytoin in this situation requires care as there are a number of factors that
can lead to patient risk and harm. These factors and how to manage them are discussed below. This
Q and A focusses on adults.
Answer
1. When should phenytoin be used in SE?
It is important that the most appropriate choice of medicine is used in SE. This choice varies
with the stage of SE and the response to prior treatment; phenytoin is not a first line
treatment. NICE has produced a clinical guideline for the diagnosis and management of
epilepsy2. This guideline suggests the following approach for using anti-epileptic drugs
(AEDs) in SE.
Table 1. NICE Guidance: Emergency AED therapy for convulsive status epilepticus in adults2
(see NICE guidance for separate chart for children).
Premonitory
Diazepam 10−20 mg given rectally, repeated once 15 minutes later if status
stage (precontinues to threaten, or midazolam 10 mg given buccally.
hospital)
If seizures continue, treat as below.
Early status
Lorazepam (intravenous) 0.1 mg/kg (usually a 4 mg bolus, repeated once after
10−20 minutes; rate not critical).
Give usual AED medication if already on treatment.
For sustained control or if seizures continue, treat as below.
Established
Phenytoin infusion at a dose of 15–18 mg/kg* at a rate of 50 mg/minute* or
status
fosphenytoin infusion at a dose of 15−20 mg phenytoin equivalents (PE)/kg at a
rate of 50–100 mg PE/minute and/or phenobarbital bolus of 10–15 mg/kg at a
rate of 100 mg/minute**.
Refractory
General anaesthesia, with one of:
status a

propofol (1–2 mg/kg bolus, then 2–10 mg/kg/hour) titrated to effect

midazolam (0.1–0.2 mg/kg bolus, then 0.05–0.5 mg/kg/hour) titrated to
effect

thiopental sodium (3–5 mg/kg bolus, then 3–5 mg/kg/hour) titrated to
effect; after 2–3 days infusion rate needs reduction as fat stores are saturated

anaesthetic continued for 12−24 hours after the last clinical or
electrographic seizure, then dose tapered.
a In the above scheme, the refractory stage (general anaesthesia) is reached 60/90 minutes after
the initial therapy.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
*The administration rate of phenytoin recommended here is 50 mg/min. This is generally
recognised as the maximum rate that phenytoin should be given at3. The BNF now
recommends for adults a dose of 20 mg/kg in SE; this is in line with other expert advice and it
is thought that this dose is more practical to calculate and may lead to fewer errors 4.
**Local practice may dictate that the high phenobarbital dose (10-15mg/kg) is only given if the
patient is intubated due to the risk of respiratory failure especially if benzodiazepines have
been previously administered5.
The BNF summarises the approach as follows3:
If, after initial treatment with benzodiazepines, seizures recur or fail to respond 25 minutes
after onset, phenytoin sodium, fosphenytoin, or phenobarbital sodium should be used; contact
intensive care unit if seizures continue.
If these measures fail to control seizures 45 minutes after onset, anaesthesia with thiopental
or in adults, a non-barbiturate anaesthetic such as propofol (unlicensed indication) should be
instituted with full intensive care support.
2. Why are the pharmacokinetics of phenytoin such a key issue?
There are a number of pharmacokinetic/pharmacodynamic factors that are important 6 but
there are two specific issues that are highlighted here.
a. Therapeutic and Toxic Plasma Concentrations. Phenytoin’s anti-epileptic effects in
controlling seizures and its serious acute toxic effects (cardiac and CNS toxicity
leading to arrhythmias, hypotension, and cardiovascular collapse) are directly related
to its concentration in the plasma.




Its beneficial anti-epileptic effects are generally accepted as being related to
plasma concentrations of 10-20 mg/L.
Toxic effects are seen with plasma concentrations greater than 20 mg/L.
Nystagmus, ataxia and diminished mental capacity can be seen with
concentrations in the range 30-40 mg/L.
Precise estimates of the concentrations related to cardiac toxicity are not well
understood but it is associated with rapid intravenous injection, presumably due
to transient, high concentrations.
This defines phenytoin as one of the medicines that has a narrow therapeutic range
or a narrow therapeutic index meaning that the difference between a safe and
effective plasma concentration and a toxic one is small.
b. Capacity limited metabolism. Unlike many drugs, whose rate of metabolism is
directly proportional to the plasma concentration, phenytoin exhibits non-linear
pharmacokinetics at concentrations in the therapeutic range (10-20 mg/L). That
means that for a small increase in a therapeutic dose, there can be a disproportionate
increase in the steady state plasma concentration. So unlike, for example,
gentamicin where a 25% increase in the dose would result in an increase of 25% in
the steady state concentration, a similar increase in a phenytoin dose could lead to a
much larger, disproportionate increase in the steady state concentration. This is one
of the factors that make adjustment of phenytoin maintenance doses more difficult
than other drugs.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
3. What dose of phenytoin should be used?
The BNF3 recommends for adults a dose of 20 mg/kg (maximum 2 grams) by slow
intravenous injection or infusion (with blood pressure and ECG monitoring), 20 mg/kg (max.
2 g) at a rate not exceeding 1 mg/kg/minute (max. 50 mg per minute), as a loading dose. As
the dose of phenytoin in this situation is based on the patient’s weight an accurate estimate of
weight is important.
Initiating treatment should not be delayed for phenytoin plasma concentration results.
If phenytoin plasma concentrations are available to confirm that phenytoin is not present or
the patient is not normally prescribed, or does not take it, they may receive the recommended
loading dose by slow IV injection or infusion.
If however the patient is being prescribed phenytoin and they are likely to have taken it and so
have an existing plasma concentration of phenytoin, albeit sub-therapeutic, this must be taken
into account when choosing a dose to use.
One such approach7 to managing this issue is illustrated below:
If phenytoin is already present but the patient is still not controlled, a 'top-up' loading dose
may be useful.
Phenytoin sodium 'top-up' dose (mg) = (20 - measured concentration (mg/L)) x 0.7 x wt (kg)
Table 2 gives the approximate increase in concentration following single “top-up” doses of
250–750 mg. For example, if the patient weighs 70 kg and has a measured concentration of 5
mg/L, a single dose of 750 mg will increase the concentration to around 2 0mg/L (5 mg/L + 15
mg/L).
Table 2 – Increase in phenytoin concentration with 'top-up' doses (adapted from6)
Body Weight
50 kg
60 kg
70 kg
80 kg
Top up Dose
Concentration increase with 'top-up' dose
250 mg
7 mg/L
6 mg/L
5 mg/L
4.5 mg/L
500 mg
14 mg/L
12 mg/L
10 mg/L
9 mg/L
750 mg
21 mg/L
18 mg/L
15 mg/L
13.5 mg/L
Where it is not possible to measure phenytoin plasma concentration in a patient known to
have been taking phenytoin, one suggested approach is to give half the recommended
loading dose until levels are available8. Another approach3 is to limit the loading dose to
500mg in this situation.
4.
How should phenytoin be administered intravenously?
Intravenous phenytoin may be given either by slow injection or by infusion. Phenytoin
injection has a high pH and may irritate small veins or cause tissue damage in the case of
extravasation. The high osmolality of the injection increases this risk when given undiluted.
Phenytoin injection is also susceptible to dangerous precipitation if diluted or mixed with other
medicines (reducing the effective dose administered). Further details can be found in the
individual Summaries of Product Characteristics9 or the Injectable Medicines Guide10.
Key points include:
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As




Phenytoin for IV use is available in solution of 50 mg/mL.
The maximum administration rate in adults is 50 mg per minute.
A syringe driver should be used to control the rate of administration.
If diluted, use only sodium chloride 0.9% to a maximum phenytoin concentration of
10mg per mL and use a 0.22-0.5 micron in-line filter.
5. What is the “Maximum” Administration Rate of Phenytoin
The BNF3 recommends a maximum administration rate of phenytoin in adults of 1 mg/kg/minute
(max. 50 mg per minute). One of the key reasons for specifying a maximum rate is to reduce the
risk of cardiac adverse effects. Weight based rates are recommended for neonates and children.
As the table below illustrates, manufacturers vary in their recommendations:
Manufacturer and
SPC link9
Epanutin Ready Mixed
Parenteral
Pfizer
eMC Link
General advice on
maximum
administration rate in
adults
Should be injected
slowly intravenously, at
a rate not exceeding 50
mg per minute in adults
Phenytoin Hikma 50
mg / ml solution for
injection
Hikma
eMC Link
The initial dose is 1
ampoule of Phenytoin
(equivalent to 230 mg
phenytoin),
administered at a
maximum rate of 0.5
ml/min (equivalent to
23 mg phenytoin per
minute).
Phenytoin Injection BP
Hospira
eMC Link
Administer slowly, at a
rate not exceeding 50
mg/minute
intravenously in adults.
General advice on
maximum
administration rate in
children
In neonates… The
drug should be injected
slowly intravenously at
a rate of 1-3
mg/kg/min.
Rate of injection is
reduced according to
the weight/age of the
child or neonate.
Children up to 12
years. The maximum
injection rate is 1
mg/kg bodyweight per
minute
Neonates. Phenytoin
should be injected
slowly intravenously at
a rate of 1-3 mg/kg/min
In neonates, the drug
should be administered
at a rate not exceeding
1-3 mg/kg/min.
Other advice on
administration rate
Severe complications
are most commonly
encountered in elderly
or gravely ill patients.
In elderly or gravely ill
patients the drug
should be administered
at a rate not exceeding
25 mg/minute, and if
necessary, at a slow
rate of 5 to 10
mg/minute.
A review11 of the cardiovascular safety of IV phenytoin administration in epilepsy found that
hypotension and arrhythmias were associated with rapid rates of infusion with authors of some
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
studies reviewed advocating lower rates of 25-40mg per minute. In conclusion, the authors of this
review considered that rates of 50mg per minute were safe in young patients and a rate of 25mg
per minute should be used in patients over 50 years. This because older patients have a higher
risk of hypotension.
A retrospective review12 of haemodynamic data in 37 Cardiac Intensive Care Unit patients who
received loading doses of phenytoin (mean dose 17.5mg/kg, range 16.5-18.5 mg/kg) at a rate of
less than 50mg per minute showed that there was a drop in mean arterial pressure of 12.6mm Hg
(mean) within one hour of the infusion starting. One of the patients had a cardiac arrest. Mean
infusion rates of adrenaline, noradrenaline and dobutamine all increased and 11 patient required
new inotropes. The authors suggest that phenytoin should be administered cautiously in CICU
patients with a slower infusion rate.
The American Hospital Pharmacy Service13 recommends:
“For the treatment of status epilepticus, in geriatric patients with heart disease, it has been
recommended that the drug be given at a rate of 50 mg over 2–3 minutes. Most clinicians
recommend that adults be given 15–18 mg/kg of phenytoin sodium IV at a rate not greater than
25–50 mg/minute (maximum total dose of 1.5 g in 24 hours)”
The routine use of the maximum rate of 50mg per minute is questionable. It seems reasonable to
suggest that in some patient groups, particularly older patients or those who are
haemodynamically unstable, phenytoin should be given at a slower rate of 25mg per minute,
rather than the maximum recommended rate of 50mg per minute, together with blood pressure
and ECG monitoring.
6.
Avoid confusion between phenytoin and fosphenytoin.
The potential, arising from their obvious similarity in name and therapeutic use, for error
arising from confusing phenytoin and fosphenytoin should be recognised.
Summary
Phenytoin is prone to errors in its prescribing, dose calculation, preparation and administration and,
as it is relatively rarely used, a lack of familiarity when managing a medical emergency such as SE
may lead to patient harm.
The risks of patient harm can be reduced by ensuring that the teams who may be called upon to use
IV phenytoin in SE are familiar with the risks and are supported by training, protocols and equipment.
Limitations
This Q and A is based generally on tertiary information sources rather than a full literature review.
The guidance is primarily based on treating adults.
Quality Assurance
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Prepared by
Trevor Beswick
South West Medicines Information and Training
Date Prepared
4 January 2017
Expert Comment
Fraser Brown. Medication Safety Officer, Ashford and St Peter’s Hospitals NHS FT
Evelyn Frank. Clinical Lead Pharmacist, National Hospital for Neurology and Neurosurgery
Alison Thomson. Senior Lecturer Strathclyde Institute of Pharmacy and Biomedical Sciences
University of Strathclyde
Tony Dunne. Directorate Pharmacist, Adult Critical Care, Anaesthetics and Theatres,Manchester
Royal Infirmary
Checked by
Julia Kuczynska
South West Medicines Information and Training
Date of check
10 January 2017
Search Strategy
NICE Guidance
NHS Evidence
British National Formulary
Standard Textbooks
eMC
References
1. NICE Epilepsies: diagnosis and management CG137 Updated February 2016. Viewed on line
3/11/16. https://www.nice.org.uk/guidance/cg137/chapter/appendix-g-abbreviations-andglossary#convulsive-status-epilepticus-2
2. NICE Epilepsies: diagnosis and management CG137 Appendix F. Protocols for treating convulsive
status epilepticus in adults and children (adults published in 2004 and children published in 2011).
Viewed on line 3/11/16. https://www.nice.org.uk/guidance/cg137/chapter/Appendix-F-Protocols-fortreating-convulsive-status-epilepticus-in-adults-and-children-adults-published-in-2004-and-childrenpublished-in-2011
3. NHS Evidence BNF section 4.8.2 Viewed on line 3/11/16.
https://www.evidence.nhs.uk/formulary/bnf/current/4-central-nervous-system/48-antiepilepticdrugs/482-drugs-used-in-status-epilepticus
4. NHS Evidence BNF Viewed on line 18/11/16.
http://www.evidence.nhs.uk/formulary/bnf/current/frequently-asked-questionsclinical/central-nervoussystem/why-has-the-intravenous-loading-dose-of-phenytoin-in-status-epilepticus-changed-from-18mgkg-to-20-mgkg
5. Personal Communication. Evelyn Frank. Clinical Lead Pharmacist, National Hospital for
Neurology and Neurosurgery
6. Winter ME. Basic Clinical Pharmacokinetics 5th Ed 2010. Chapter 10 Phenytoin.
Available through NICE Evidence Search at www.evidence.nhs.uk
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7. NHS Greater Glasgow and Clyde. GGC Medicines Adult Therapeutics Handbook. Viewed on line
3/11/16. http://app.ggcprescribing.org.uk/guidelines/central-nervous-system/guideline-for-phenytoindose-calculations/
8. Manno EM. Status Epilepticus. Current Treatment Strategies. Neurohospitalist 2011;1:23-31.
Viewed on-line 3/11/16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726103/
9. Datapharm. EMC. Viewed on-line 3/11/16. https://www.medicines.org.uk/emc/
10. NHS Injectable Medicines Guide viewed on-line 3/11/16. http://medusa.wales.nhs.uk/
(subscription required)
11. Guldiken B, Remi J, Noachtar S. Cardiovascular adverse effects of phenytoin. J Neurol.
2016;263: 861-870. http://link.springer.com/article/10.1007/s00415-015-7967-1
12. McCall p, Owen K, Smith R et al Cardiovascular instability following phenytoin administration in
cardiac intensive care (conference abstract). EACTA
http://www.actacc.org/abstracts/abstract.asp?a=SIJEGOKI243478SAOCOM25062014_66
13. McEvoy G (Ed in Chief), American Society of Health-System Pharmacists. AHFS Drug
Information. [online] London: Pharmaceutical Press http://www.medicinescomplete.com/ (23/12/2016)
Available through NICE Evidence Search at www.evidence.nhs.uk
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