Fosphenytoin and Phenytoin – Adult/Pediatric – Inpatient Clinical Practice Guideline

Home , Fosphenytoin, Loading dose, Maintenance dose

Table of Contents SCOPE ...... 4 METHODOLOGY ...... 4 DEFINITIONS: ...... 5 INTRODUCTION ...... 5 RECOMMENDATIONS ...... 6 UW HEALTH IMPLEMENTATION ...... 14 INTERNAL REFERENCES ...... 14 EXTERNAL REFERENCES ...... 14

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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: [email protected] Email Address:[email protected]

Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 Fosphenytoin is dosed in phenytoin equivalents (PE) (Based on TBW) 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 Continuous cardiac monitoring (rate, rhythm, and blood pressure) and (for doses >300 mg observation throughout the period when maximum blood phenytoin PE) 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 10 to 20 mcg/mL total phenytoin Phenytoin Concentration 1 to 2 mcg/mL unbound phenytoin Infusion Final filter NOT required between IV catheter and IV tubing Diluent for IV 5% dextrose or 0.9% sodium chloride to final concentration of 1.5 to 25 mg administration 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 Table 2. Administration Characteristics of Injectable Phenytoin5 Characteristic Phenytoin Sodium Dose Adults: (Based on TBW) 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 Continuous cardiac monitoring (rate, rhythm, and blood pressure) and (for doses >300 observation throughout the period when maximum blood phenytoin mg PE) concentrations occur (approximately 10 to 20 minutes after the end of phenytoin infusions) Blood concentration may be obtained 1 hour after IV dose Therapeutic 10 to 20 mcg/mL total phenytoin Phenytoin Concentration 1 to 2 mcg/mL unbound phenytoin Diluent for IV 0.9% sodium chloride to final concentration of 6.7 mg/mL to 50 mg/mL.2 administration

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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 Oral Loading Dose= 18-20 mg X TBW (kg)

Fosphenytoin: 18 to 24 hr post-load; however, Divide the total dose and give no more than 6 if given IV may draw 2 hr post-load, if IM may mg/kg (or 400 mg) per dose every 2 to 4 hours draw 4 hr post-load. Draw trough (non-steady as chewable tablets or suspension. state) in 3 to 5 days and steady state at day If patient has had recent phenytoin therapy, 10 to 14. If phenytoin given orally, may draw obtain baseline phenytoin concentration. Dose trough in 18 to 24 hours. on total body weight (TBW) in kilograms. The therapeutic concentration is 10 to 20 mcg/mL for bound/total phenytoin and 1 to 2 Partial IV Load: give in addition to daily mcg/mL for unbound phenytoin. In patients dose(s) with renal impairment (CrCl < 10 mL/min), use (Cdesired* - Cobserved)X Vd= mg/kg/dose** the HPLC unbound method for phenytoin concentrations. (Class I, Level A) *Recommend using 20 for desired level as formula tends to under predict. Unbound phenytoin concentration: Draw * unbound concentration if: CrCl <10 mL/min , Vd=volume of distribution=0.7 L/kg (TBW) albumin <3.2 gm/dL, using valproic acid or TBW= total body weight high dose aspirin, neonate, pregnant, end stage liver disease, burn patient or **If given orally, increase dose by 10%. unexplained toxicity. Usual maintenance dose = 2 to 3 mg PE/kg/dose If albumin <3.2 gm/dL and only total two times daily (4 to 6 mg PE/kg/day) concentration is available, may ESTIMATE: In geriatric patients consider 1.5 to 2 Ccorrected = Cobserved______mg/PE/kg/dose tow times daily(3 to 4 mg (0.25 X albumin PE/kg/day) concentration)+0.1 Start maintenance dose 18 to 24 hours post In patients treated with phenytoin and valproic load, or at next dosing interval acid (VPA) then ESTIMATE: Cunbound phenytoin = Cphenytoin [0.095 + To increase phenytoin maintenance dose 0.001(Cvalproic acid)] (steady state concentration):

If <7 mcg/mL ↑ by 100 mg/day Follow up concentration should be measured If 7-12 mcg/mL ↑ by 50 mg/day unbound. If 13-15 mcg/mL May ↑ by 30 mg/day If >15 mcg/ mL May ↑ by 30 mg every *If CrCl <10 mL/min use HPLC method. 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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 University of Wisconsin Hospitals and Clinics Authority Contact: [email protected] Vermeulen, [email protected] Last Revised: 07/2015 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