/clinical/,/clinical/cckm-tools/,/clinical/cckm-tools/content/,/clinical/cckm-tools/content/cpg/,/clinical/cckm-tools/content/cpg/medications/,

/clinical/cckm-tools/content/cpg/medications/name-97567-en.cckm

201607203

page

100

UWHC,UWMF,

Tools,

Clinical Hub,UW Health Clinical Tool Search,UW Health Clinical Tool Search,Clinical Practice Guidelines,Medications

Fosphenytoin and Phenytoin – Adult/Pediatric - Inpatient

Fosphenytoin and Phenytoin – Adult/Pediatric - Inpatient - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Medications


1
Fosphenytoin and Phenytoin
– Adult/Pediatric – Inpatient
Clinical Practice Guideline
Table of Contents
SCOPE ...................................................................................................................................... 4
METHODOLOGY ...................................................................................................................... 4
DEFINITIONS: ........................................................................................................................... 5
INTRODUCTION ....................................................................................................................... 5
RECOMMENDATIONS .............................................................................................................. 6
UW HEALTH IMPLEMENTATION ............................................................................................14
INTERNAL REFERENCES .......................................................................................................14
EXTERNAL REFERENCES .....................................................................................................14
CPG Contact for Changes: CPG Contact for Content:
Philip Trapskin, PharmD, BCPS Name: Cindy Gaston, PharmD, BCPS
Phone Number: 608-263-1328 Phone Number: 608-265-8161
Email Address: PTrapskin@uwhealth.org Email Address:cgaston@uwhealth.org
Note: Active Table of Contents
Click to follow link
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

2
Guideline Update Author(s):
Sheila Aton, PharmD; Aaron Steffenhagen, PharmD; Brian LaRowe, RPh; Paul Rutecki,
MD; Ryan Dilley, DPH 4; Joel Ambord, PharmD.
Coordinating Team Members:
Cindy Gaston, PharmD, BCPS
Review Individuals/Bodies:
MUE Subcommittee – May 2015
P&T Committee
Committee Approvals/Dates:
P&T Committee/March 2002
P&T Committee/December 2007
P&T Committee/May 2012
Release Date: July 2015
Next Review Date: June 2018
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

3
Executive Summary
Guideline Overview
These clinical practice guidelines are intended to guide clinicians in the use of
fosphenytoin or phenytoin in adult and pediatric inpatients.
Key Practice Recommendations
1. Dosing and administration of injectable fosphenytoin
2. Dosing and administration of injectable phenytoin
3. Dosing of phenytoin orally or via nasogastric/feeding tube
4. Monitoring of therapeutic blood concentrations for fosphenytoin and phenytoin
Pertinent UWHC Policies & Procedures
UW Health Guidelines for the Dosing of Medications in Patients Receiving Continuous Enteral
Feedings
UW Health Guidelines for the Intravenous Administration of Formulary Drugs in Adults
UW Health Guidelines for the Intravenous Administration of Formulary Drugs in Pediatrics
UW Health Drug Concentration Monitoring Protocol
UW Health Guideline for Non-chemotherapeutic Agents: Prevention and Treatment of Chemical
Phlebitis and Extravasation of Peripherally Administered Non-chemotherapeutic Agents
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

4
Scope
Disease/Conditions:
All adult and pediatric inpatients requiring treatment of new onset or previously
controlled seizures, including status epilepticus.
Avoid phenytoin/fosphenytoin in the neonatal population. In the rare case that phenytoin
would be used in a neonate, it should be considered only on an individual basis.
Intended Users:
This guideline is intended to be used by physicians, pharmacists, and nurses.
CPG objective:
The objective of this guideline is to improve the use of phenytoin and fosphenytoin
through improved dosing, administration, and monitoring to improve patient safety,
tolerance and efficacy.
Target Population:
All adult and pediatric inpatients requiring treatment of new onset or previously
controlled seizures, including status epilepticus
Interventions and Practices Considered:
Partial loading (for subtherapeutic drug levels), loading dose, status epilepticus,
monitoring, administration
Major Outcomes Considered:
Safe and effective use of fosphenytoin and phenytoin
Guideline Metrics:
Adequate control or prevention of seizures. Maintenance of therapeutic drug levels.
Methodology
Methods Used to Collect/Select the Evidence:
A review of PubMed database, International Pharmaceutical Abstracts database, and
Google Scholar was conducted with the keywords: fosphenytoin, phenytoin,
administration, monitoring, seizure, and antiepileptic. Also, expert opinions were
consulted throughout UWHC during the construction of the CPG.
Methods Used to Assess the Quality and Strength of the Evidence:
Review of the literature and weighing according to the rating scheme (see below).
Rating Scheme for the Strength of the Evidence:
A modified Grading of Recommendations Assessment, Development and Evaluation
(GRADE) developed by the American Heart Association and American College of
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

5
Cardiology (Figure 1) has been used to assess the Quality and Strength of the Evidence
in this Clinical Practice Guideline.1
Figure 1. Quality of Evidence and Strength of Recommendation Grading Matrix
Definitions:
1. Fosphenytoin is dosed in phenytoin equivalents (PE) 1 PE fosphenytoin = 1 mg
phenytoin sodium = 1.5 mg fosphenytoin sodium
2. Total body weight (TBW) is defined as the actual total mass of the patient in
kilograms
Introduction
Fosphenytoin is a water soluble prodrug of phenytoin which is rapidly converted to
phenytoin after intravenous (IV) or intramuscular (IM) administration. Fosphenytoin
does not require propylene glycol or alcohol as organic solvents to keep it in solution;
therefore, it is less irritating to tissues and presents a lesser risk of causing hypotension.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

6
Recommendations
1. Fosphenytoin is the injectable hydantoin of choice at UWHC, secondary to safety
concerns with the administration of injectable phenytoin. 2
Table 1. Administration Characteristics of Injectable Fosphenytoin2
Characteristic Fosphenytoin Sodium
Dose
(Based on TBW)
Fosphenytoin is dosed in phenytoin equivalents (PE)
1 PE fosphenytoin = 1 mg phenytoin sodium = 1.5 mg fosphenytoin sodium
Adults:
Status Epilepticus: 18 to 20 mg PE/kg IV
Repetitive seizure: 18 to 20 mg PE/kg IV
Loading dose: 18 to 20 mg PE/kg given IV or IM
NOTE: Loading dose in obese patients may be calculated based on the
following formula: Dosing weight (DBW) = (IBW) + [1.33 x (measured weight
– IBW)]
Daily maintenance dose: 4 to 6 mg PE/kg IV
Pediatrics:
Loading dose: 18 to 20 mg PE/kg IV
Maintenance dose: 2 to 3 mg PE/kg IV dosed two times daily (4 to 6 mg
PE/kg/day), though significantly higher dosing may be needed based upon
levels.
Route IV or IM administered in 1 to 4 injection sites (maximum volume for IM
injection is 3 mL)
Rate To decrease the risk of adverse reactions such as paresthesias, pruritus,
and hypotension.
Adults:
For indications other than status epilepticus, fosphenytoin should be
administered at a rate less than 150 mg PE/min; (25 to 100 mg PE/min is
suggested).
Pediatrics:
Administer at a rate of 1 to 3 mg PE/kg/min with a maximum of 50 mg
PE/min.
Monitoring
(for doses >300 mg
PE)
Continuous cardiac monitoring (rate, rhythm, and blood pressure) and
observation throughout the period when maximum blood phenytoin
concentrations occur (approximately 10 to 20 minutes after the end of
fosphenytoin infusions)
Blood concentration may be obtained 2 hours after IV dose or 4 hours after
IM dose
Therapeutic
Phenytoin
Concentration
10 to 20 mcg/mL total phenytoin
1 to 2 mcg/mL unbound phenytoin
Infusion Final filter NOT required between IV catheter and IV tubing
Diluent for IV
administration
5% dextrose or 0.9% sodium chloride to final concentration of 1.5 to 25 mg
PE/mL
Stability Stable at 1, 8, and 20 mg PE per milliliter in 0.9% sodium chloride and 5%
dextrose at 25oC for 30 days in a glass container and at 4oC and -20oC for
30 days in a PVC bag
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

7
1.1. Dosing and administration of injectable fosphenytoin4
1.2. Fosphenytoin may be administered up to 150 mg phenytoin equivalents
(PE)/minute. 4 (Class I, Level B)
1.2.1. Fosphenytoin is compatible with dextrose and saline IV fluids.4
1.2.2. While fosphenytoin is the injectable hydantoin of choice at UWHC, when
unavailable due to a drug recall or shortage, injectable phenytoin may be
used as an alternative.
1.3. Appropriate in patients who require short-term parenteral administration (either
IM or IV).(Class I, Level C)
1.3.1. Fosphenytoin should not be used for maintenance therapy in patients able
to take enteral medications. (Class III, Level C)
1.4. Monitoring of fosphenytoin2
1.4.1. Continuous telemetry monitoring with blood pressure measurement at a
minimum of every 15 minutes is required for administration of
fosphenytoin IV doses greater than 300 mg PE and should be continued
for 10 to 20 minutes after the infusion is completed. 4 (Class I, Level B)
1.4.2. Draw phenytoin concentrations at least 2 hours after completion of IV
administration and 4 hours after IM administration. 4 (Class I, Level B)
1.5. Dosing of injectable fosphenytoin2
1.5.1. Dose on total body weight (TBW) in kilograms.(Class 1 Level A) 4
1.5.2. Dosing recommendations: 4
1.5.2.1. Adults
1.5.2.1.1. Status epilepticus loading dose: 18 to 20 mg PE/kg IV at
a rate not to exceed 150 mg PE/min in adults or IM in 1
to 4 injection sites. If seizures continue after the loading
dose, then an additional 10 mg PE/kg IV or IM may be
given in divided doses of 5 mg PE/kg IV or IM. 2,4(Class
I, Level B)3
1.5.2.2. NOTE: The loading dose for obese patients may be calculated
using an adjusted body weight based on the following
formula(Class IIa, Level C)9 :
Dosing weight (kg) = ideal body weight (IBW) + [1.33 x (measured weight – IBW)]
1.5.2.2.1. Recurrent, repetitive seizures: 18 to 20 mg PE/kg IV at a
rate not to exceed 150 mg PE/min in adults or IM in 1 to
4 injection sites. 2,4(Class I, Level B)2
1.5.2.2.2. Non-emergent loading dose: 18 to 20 mg PE/kg IV at a
rate not to exceed 150 mg PE/min in adults or IM in 1 to
4 injection sites. 2,4(Class I, Level B)2
1.5.2.2.3. Maintenance dose: Same as previous regimen, if
applicable, or 2 to 3 mg PE/kg/dose two times daily (4 to
6 mg PE/kg/day). Begin maintenance dose 18 to 24
hours after the loading dose, or at the next convenient
administration time. 2,4 (Class I, Level B)
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

8
1.5.2.3. Pediatrics
1.5.2.3.1. Loading dose: 18 to 20 mg PE/kg x one dose IV;
administer at a rate of 1 to 3 mg PE/kg/min with a
maximum of 50 mg PE/min in pediatrics. If seizures
continue after the loading dose, then an additional 10
mg PE/kg IV may be given in divided doses of 5 mg
PE/kg IV.2,4 (Class I, Level B)
1.5.2.4. Maintenance dose: Same as previous regimen, if applicable, or 2
to 3 mg PE/kg/IV dose two times daily (4 to 6 mg PE/kg/day),
though significantly higher dosing may be needed based upon
levels. 4 (Class I, Level B)
1.5.2.5. Patients with subtherapeutic phenytoin concentrations: Partial
loading dose mg PE = (desired concentration – actual
concentration) x 0.7 (Vd) x TBW in kg. (Vd = volume of distribution;
TBW = total body weight) 6 (Class IIa Level A)6
2. Dosing and administration of injectable phenytoin 5
2.1. Dose conversion from fosphenytoin to phenytoin is a 1:1 ratio, with 1mg PE
fosphenytoin = 1 mg phenytoin.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

9
Table 2. Administration Characteristics of Injectable Phenytoin5
Characteristic Phenytoin Sodium
Dose
(Based on TBW)
Adults:
Status Epilepticus: 18 to 20 mg/kg IV
Repetitive seizure: 18 to 20 mg/kg IV
Loading dose: 18 to 20 mg/kg given IV or IM
Loading dose in obese patients may be calculated based on the
following formula: Dosing weight (DBW) = (IBW) + [1.33 x (measured
weight – IBW)]
Daily maintenance dose: 4 to 6 mg/kg IV
Pediatrics:
Loading dose: 18 to 20 mg/kg IV
Maintenance dose: 2 to 3 mg/kg/ IV dose two times daily (4 to 6
mg/kg/day), though significantly higher dosing may be needed based
upon levels.
Route
IV administration only, central access preferred
Rate Adults:
For indications other than status epilepticus, phenytoin should be
administered at a rate less than 50 mg/min in adults and a rate of 1 to 3
mg/kg/min with a maximum of 50 mg/min in pediatrics to decrease the
risk of adverse reactions such as arrhythmias and hypotension. (Class
IIa, Level of Evidence C)
Pediatrics:
Administer at a rate of 1 to 3 mg/kg/min with a maximum of 50 mg /min
in pediatric patients
Monitoring
(for doses >300
mg PE)
Continuous cardiac monitoring (rate, rhythm, and blood pressure) and
observation throughout the period when maximum blood phenytoin
concentrations occur (approximately 10 to 20 minutes after the end of
phenytoin infusions)
Blood concentration may be obtained 1 hour after IV dose
Therapeutic
Phenytoin
Concentration
10 to 20 mcg/mL total phenytoin
1 to 2 mcg/mL unbound phenytoin
Diluent for IV
administration 0.9% sodium chloride to final concentration of 6.7 mg/mL to 50 mg/mL.
2
2.2. Adults
2.2.1. Loading dose: 18 to 20 mg/kg x one dose IV; administer at a rate not to
exceed 50 mg/min in adults. If seizures continue after the loading dose,
then an additional 10 mg/kg IV may be given in divided doses of 5 mg/kg
IV. 2 (Class I Level A)
2.2.2. The loading dose for obese patients may be calculated using an adjusted
body weight based on the following formula:
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

10
Dosing weight (kg) = ideal body weight (IBW) + [1.33 x (measured
weight – IBW)] (Class IIa, Level C)9
2.2.3. Maintenance dose5: 2 to 3 mg/kg/dose two times daily (4 to 6 mg/kg/day)
(Class I, Level B)
2.3. Pediatrics
2.3.1. Loading dose: 18 to 20 mg/kg x one dose IV; administer at a rate of 1 to 3
mg/kg/min with a maximum of 50 mg/min in pediatrics. If seizures continue
after the loading dose, then an additional 10 mg/kg IV may be given in
divided doses of 5 mg/kg IV.5 (Class I Level C)
2.3.2. Maintenance dose: 2 to 3 mg/kg/dose two times daily (4 to 6 mg/kg/day),
though significantly higher dosing may be needed based upon levels. 5
(Class IIa Level B)
2.4. Administration
2.4.1. Injectable phenytoin contains 40% propylene glycol as an organic solvent
to keep it in solution; therefore it poses a risk for hypotension, vascular
and soft tissue irritation, and can cause pain on injection.2 Monitoring
should be appropriate to these risks.
2.4.2. Do not administer via intramuscular injection. (Class III, Level A)5
2.4.3. Phenytoin rate of administration may not exceed 50 mg/min. (Class I,
Level A)5
2.4.4. Injectable phenytoin is not compatible with dextrose fluids and must be
prepared with 0.9% sodium chloride IV at a concentration of 6.7 mg/mL to
50 mg/mL.2 Precipitation can occur at more dilute concentrations. (Class I,
Level B)5
2.4.5. Central venous catheter access is preferred for phenytoin administration.
While peripheral administration may be necessary, it is reasonable to
administer phenytoin through the cubital fossa vein or larger. (Class IIa,
Level C)
2.4.6. Because phenytoin is a vesicant, care should be taken to prevent
extravasation when it is necessary to administer via a peripheral line.
2.4.7. Patients who are hemodynamically unstable or have a history of
underlying cardiovascular problems may be more susceptible to the
adverse cardiovascular effects of injectable phenytoin and therefore it may
be optimal to receive fosphenytoin.2(Class IIa, Level A)
2.5. Monitoring of injectable phenytoin 5
2.5.1. Monitoring with EKG should be done when administering a dose greater
than 300 mg. If hypotension occurs, stop the infusion and resume at a
lower rate when hypotension resolves2. (Class I, Level B)
2.5.2. Monitor Continuous telemetry and blood pressure at a minimum of every
15 minutes for IV dose administration of phenytoin greater than 300 mg,
and should be continued for 10 to 20 minutes after the infusion is
completed. Single doses of 300 mg or more may not be given less than 1
hour apart without telemetry monitoring. 5 (Class I, Level B)
2.5.3. Concentration monitoring
2.5.3.1. A phenytoin level may be drawn 18 to 24 hours post load and/or one
hour post load6 (Class IIa Level B)
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

11
2.5.3.2. Non-steady state concentrations may be considered between days 3
to 5 to assess trend and again, between days 10 to 14 when blood
concentration is at steady state. (Class IIb, Level C)
3. Dosing of phenytoin orally or via nasogastric/feeding tube 5
3.1. Patients with new onset seizures who are loaded orally:
3.1.1. The recommended loading dose for enteral administration is 20 mg x TBW
(kg). Divide the total dose and give no more than 6 mg/kg (or 400 mg) per
dose every 2 to 4 hours. Use chewable tablets or suspension. When
possible, change to extended release capsules at 4 to 6 mg/kg/day. (Class
IIa, Level C)
3.1.2. The loading dose for obese patients may be calculated using an adjusted
body weight based on the following formula: 9 (Class IIa, Level C)
Dosing weight (kg) = ideal body weight (IBW) + [1.33 x (measured weight – IBW)]
3.1.3. Phenytoin concentrations may be considered 18 to 24 hours post-load.
Follow up concentrations are the same as for parenteral fosphenytoin.
(Class IIb, Level C)
3.2. Evaluation of patients with breakthrough seizures:
3.2.1. Draw blood concentration as soon as possible.(Class IIa Level C)
3.2.2. Patients with subtherapeutic phenytoin concentrations: 6 (Class IIa Level
B)
Partial loading dose mg = (desired concentration – actual concentration) x 0.7 L/kg (Vd) x
TBW in kg.
(Vd = volume of distribution; TBW = total body weight)
3.2.3. The bioavailability of enteral phenytoin (liquid, chewable tablets, and
extended-release capsules) is approximately 90%. When given orally,
divide the total dose as calculated and give no more than 6 mg/kg (or 400
mg) per dose every 2 to 4 hours. Use of chewable tablets or suspension
may maximize the amount of drug absorbed, provide more rapid increase
in blood concentrations, and minimize gastrointestinal side effects. (Class
IIa, Level C)
3.2.4. Give the loading dose in addition to the patient’s maintenance dose(s) for
that day. (Class IIA Level C)
3.3. Administration of phenytoin suspension and tube feedings (Class I, Level C)
3.3.1. Turn off tube feedings one hour prior to administration of phenytoin
suspension.
3.3.2. Before administration, shake the suspension well.
3.3.3. Draw the drug up in an appropriate syringe (catheter-tipped) for the tube
and administer via tube.
3.3.4. Draw up approximately 30 to 60 mL of water in the syringe and flush the
tube.
3.3.5. Turn tube feedings on one hour after the administration of the phenytoin
suspension after checking tube placement.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

12
3.3.6. Patients receiving continuous enteral feedings will be without nutrition for
2 hours with each dose administered. Therefore, phenytoin should be
dosed no more than two times daily in order to limit interruptions to
achieve adequate nutrition. The rate of the enteral feedings should be
adjusted so that the same amount of enteral feeding is given in 24 hours.
4. Monitoring of therapeutic blood concentrations for fosphenytoin and phenytoin
Table 3. Fosphenytoin and Phenytoin Blood Concentration Monitoring2,5
Desired total concentration:10-20 mcg/mL
Fosphenytoin: 18 to 24 hr post-load; however,
if given IV may draw 2 hr post-load, if IM may
draw 4 hr post-load. Draw trough (non-steady
state) in 3 to 5 days and steady state at day
10 to 14. If phenytoin given orally, may draw
trough in 18 to 24 hours.
The therapeutic concentration is 10 to 20
mcg/mL for bound/total phenytoin and 1 to 2
mcg/mL for unbound phenytoin. In patients
with renal impairment (CrCl < 10 mL/min), use
the HPLC unbound method for phenytoin
concentrations. (Class I, Level A)
Unbound phenytoin concentration: Draw
unbound concentration if: CrCl <10 mL/min*,
albumin <3.2 gm/dL, using valproic acid or
high dose aspirin, neonate, pregnant, end
stage liver disease, burn patient or
unexplained toxicity.
If albumin <3.2 gm/dL and only total
concentration is available, may ESTIMATE:
Ccorrected = Cobserved________
(0.25 X albumin
concentration)+0.1
In patients treated with phenytoin and valproic
acid (VPA) then ESTIMATE:
Cunbound phenytoin = Cphenytoin [0.095 +
0.001(Cvalproic acid)]
Follow up concentration should be measured
unbound.
*
If CrCl <10 mL/min use HPLC method.
Oral Loading Dose= 18-20 mg X TBW (kg)
Divide the total dose and give no more than 6
mg/kg (or 400 mg) per dose every 2 to 4 hours
as chewable tablets or suspension.
If patient has had recent phenytoin therapy,
obtain baseline phenytoin concentration. Dose
on total body weight (TBW) in kilograms.
Partial IV Load: give in addition to daily
dose(s)
(Cdesired* - Cobserved)X Vd= mg/kg/dose**
*Recommend using 20 for desired level as
formula tends to under predict.
Vd=volume of distribution=0.7 L/kg (TBW)
TBW= total body weight
**If given orally, increase dose by 10%.
Usual maintenance dose = 2 to 3 mg PE/kg/dose
two times daily (4 to 6 mg PE/kg/day)
In geriatric patients consider 1.5 to 2
mg/PE/kg/dose tow times daily(3 to 4 mg
PE/kg/day)
Start maintenance dose 18 to 24 hours post
load, or at next dosing interval
To increase phenytoin maintenance dose
(steady state concentration):
If <7 mcg/mL ↑ by 100 mg/day
If 7-12 mcg/mL ↑ by 50 mg/day
If 13-15 mcg/mL May ↑ by 30 mg/day
If >15 mcg/ mL May ↑ by 30 mg every
other day
TBW – total body weight; CrCl – creatinine clearance; C – concentration; Vd – volume of distribution
5. Desired range is a total concentration of 10 to 20 mcg/m.5 (Class I, Level A)
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

13
5.1. Some patients may have a therapeutic response at concentrations < 10
mcg/mL. Others may require concentrations > 20 mcg/mL and not exhibit signs
of toxicity. Some patients may exhibit signs of toxicity with concentration at 10 to
20 mcg/mL. Use clinical judgment.
5.2. It is important to consider whether the phenytoin concentration is at steady state
when assessing blood concentrations before making dosage adjustments.
Phenytoin exhibits non-linear kinetics and takes 7 to 10 days to reach steady
state in patients with normal elimination. 5 (Class I, Level A)
5.3. Assessing effectiveness for loading doses of parenteral fosphenytoin in patients
with new onset, acute, repetitive seizures:
5.3.1. It may be reasonable to draw concentration 18 to 24 hours and/or 4 hours
post-load, if needed. Non-steady state concentrations can be drawn
between days 3 to 5 to assess trend and again between days 10 to 14
when concentration is at steady state. Draw trough concentrations. (Class
IIb, Level C)
5.4. Use HPLC unbound methodology for patients with significant renal impairment
or failure (CrCl<10 mL/min). (Class I, Level C)
5.5. Patients with new onset seizures who are loaded orally
5.5.1. Phenytoin concentrations may be drawn 24 hours post-load (Class IIa
Level C)
5.6. Patients on established maintenance therapy without breakthrough seizures or
signs of toxicity
5.6.1. It is reasonable to draw an annual trough concentration. (Class IIa, Level
C)
5.7. A therapeutic trough unbound phenytoin concentration is 1 to 2 mcg/mL (Class
I, Level A) 5
5.7.1. It is reasonable to monitor of unbound phenytoin concentrations in the
following scenarios ( Class IIa, Level C)
5.7.1.1. Decreased renal function (CrCl < 10 mL/min), use HPLC method
5.7.1.2. Hypoalbuminemia (<3.2 g/dL)
5.7.1.3. Patients on valproic acid or other significant protein binding
displacers
5.7.1.4. Unexplained toxicity, such as mental status changes
5.7.1.5. Pregnancy
5.7.1.6. Burn patients
5.7.1.7. Neonates
5.7.1.8. End stage liver disease
5.7.2. If an unbound concentration is indicated, but none have been drawn, it
can be estimated. The estimated concentration is useful for evaluating the
current concentration; however the next concentration drawn should be a
measured unbound concentration. The “corrected” total concentration can
be estimated using the following formula: 6
Ccorrected = Cobserved / [(0.25 x Calbumin) + 0.1].
This is not a substitute for an actual lab value. A level must be drawn for
accurate information. (Class I, Level C)
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

14
5.7.3. In patients treated with both phenytoin and valproic acid, estimated
unbound phenytoin concentration can be calculated when total phenytoin,
total valproic acid, and albumin concentrations are known. 7,8 (Class I,
Level C)
Cunbound phenytoin = Cphenytoin (0.095 + 0.001 (Cvalproic acid)]
UW Health Implementation
Potential Benefits/Harms:
The dosing, administration, and monitoring instructions for fosphenytoin and phenytoin
are complex. Implementation of this clinical practice guideline will provide a consistent
approach to ensuring the safe and efficacious use of these agents.
Implementation Tools/Plan
This clinical practice guideline will be posted on UConnect and associated with
medication order records for fosphenytoin and phenytoin.
Disclaimer
CPGs are described to assist clinicians by providing a framework for the evaluation and
treatment of patients. This Clinical Practice Guideline outlines the preferred approach
for most patients. It is not intended to replace a clinician’s judgment or to establish a
protocol for all patients. It is understood that some patients will not fit the clinical
condition contemplated by a guideline and that a guideline will rarely establish the only
appropriate approach to a problem.
Internal References
UW Health Guidelines for the Dosing of Medications in Patients Receiving Continuous Enteral
Feedings
UW Health Guidelines for the Intravenous Administration of Formulary Drugs in Adults
UW Health Guidelines for the Intravenous Administration of Formulary Drugs in Pediatrics
UW Health Drug Concentration Monitoring Protocol
UW Health Guideline for Non-chemotherapeutic Agents: Prevention and Treatment of Chemical
Phlebitis and Extravasation of Peripherally Administered Non-chemotherapeutic Agents
External References
1. Tricoci P, Allen J, Kramer J, Califf R, Smith S. Scientific evidence underlying
the ACC/AHA Clinical Practice Guidelines. JAMA. 2009;301(8):831-841.
2. Meek PD, Davis SN, Collins DM, et al. Guidelines for nonemergency use of
parenteral phenytoin products: proceedings of. Arch Intern Med. Dec 13-27
1999;159(22):2639-2644.
3. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments
for generalized convulsive status epilepticus. N Engl J Med. Sep 17
1998;339(12):792-798.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org

15
4. Cerebyx (fosphenytoin). [Prescribing Information]. New York, NY. Parke-
Davis; 2011.
5. Dilantin (package insert). [Prescribing Information]. New York, NY. Pfizer
Parke-Davis; 2005.
6. Anderson GD, Pak C, Doane KW, et al. Revised Winter-Tozer equation for
normalized phenytoin concentrations in trauma. Ann Pharmacother. Mar
1997;31(3):279-284.
7. Haidukewych D, Zielinski JJ, Rodin EA. Derivation and evaluation of an
equation for prediction of free carbamazepine. Ther Drug Monit. Sep
1989;11(5):528-532.
8. Kerrick JM, Wolff DL, Graves NM. Predicting unbound phenytoin
concentrations in patients receiving valproic acid. Ann Pharmacother. May
1995;29(5):470-474.
9. Abernethy DR, Greenblatt DJ, Phenytoin disposition in obesity. Determination
of loading dose. Arch Neurol. 1985 May;42(5):468-71
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 07/2015CCKM@uwhealth.org