Fosphenytoin is a prodrug that is metabolized to phenytoin, which works to decrease seizures by blocking sodium channels. It is given parenterally when rapid onset is required to treat seizures or status epilepticus. Fosphenytoin avoids complications of parenteral phenytoin such as poor solubility and tissue irritation. Metabolism occurs primarily in the liver, so patient factors like liver function and other medications affecting protein binding or hepatic metabolism must be considered. Close monitoring is needed due to potential adverse effects like hypotension, rash, and interactions. Interprofessional collaboration optimizes safety when using fosphenytoin in complex patients.

1. FOSPHENYTOIN SODIUM
INJECTION
REBECCA LONG
LAMAR UNIVERSITY

2. SEIZURE PATHOPHYSIOLOGY
The brain contains nerve cells called neurons. Each neuron is
comprised of:
• Cell body
• Axons - transmit information from the cell
• Dendrites - receive impulses from other axons
Axons release chemicals called neurotransmitters into the
synapse which bind to receptors on other cells’ dendrites
creating channels which allow ions to flow across the cell
membranes. This is referred to as action potential.
(Minczak, 2007).

3. SEIZURE PATHOPHYSIOLOGY
A seizure is an abnormal hypersynchronous firing of cortical
neurons. (Bromfield, Cavazos, & Sirven, 2006).
• Due to hyperexcitability of the neurons – can be caused by
hypoxia, poor blood flow, low blood sugar, or abnormal
electrolyte levels. (Minczak, 2007).
• Leads to aberrant motor and/or sensory symptoms which may
include tonic-clonic muscular contractions, paresthesias, or
hallucinations. (Bromfield, Cavazos, & Sirven, 2006).

4. INTENDED DRUG RESPONSE
• Fosphenytoin is a prodrug converted into phenytoin by the
body. Phenytoin works to decrease seizures by decreasing the
influx or increasing the efflux of sodium ions across neuronal
cell membranes. (Czosnowski, Whitman, & Aykroyd, 2017).
• This inhibits hyperexcitability caused by reduced membrane
sodium gradients. It further results in reduced post-tetanic
potentiation at synapses, preventing seizure foci from
stimulating activity in adjacent areas of the cortex. (DrugBank,
2017).

5. INTENDED DRUG RESPONSE
Parenteral phenytoin is associated with poor solubility, high
alkalinity, hypotension, cardiac arrhythmias, and soft tissue
injury with extravasation. (Curry & Kulling, 1998).
Fosphenytoin was developed to avoid many of these
complications. (Kirschbaum & Gurk-Turner, 1999).
• Causes little tissue irritation
• Results in no electrocardiogram changes and only mild
hypotension
• Dosing is expressed in milligrams phenytoin sodium units (PE).
• (Curry & Kulling, 1998).

6. PHARMACOKINETICS
• Bioavailability 100% with intravenous administration (Curry & Kulling, 1998) and 98-99%
with intramuscular (Kirschbaum & Gurk-Turner, 1999)
• Volume of distribution is 4.3 to 10.8 liters. (DrugBank, 2017).
• Therapeutic serum levels are attained within ten minutes of intravenous infusion or 90
minutes with intramuscular administration. (Curry & Kulling, 1998).
• Conversion to phenytoin by phosphatases primarily in the liver with conversion half-life of
8-21 minutes and is almost complete, therefore no significant exretion. (Kirschbaum &
Gurk-Turner, 1999)
• The enzymes CYP2C8, CYP2C19, CYP2B6, CYP2C9, CYP3A4 are involved in metabolism.
(DrugBank, 2017).
• Phenytoin is 90%-95% bound to plasma proteins, primarily albumin. (DrugBank, 2017).
• Protein-binding and liver metabolism make it necessary to monitor plasma phenytoin
levels closely in patients with known hepatic or renal disease or with other conditions
which may affect serum albumin. (Will Reed, personal interview, November 27, 2017).

7. INTERACTIONS
• Fosphenytoin conversion to phenytoin is not known to be
affected by other drugs. (FDA, 2015).
• Pharmacist Will Reed (personal interview, November 27, 2017)
advises caution when administering fosphenytoin with other
highly protein-bound drugs as such drugs bind to albumin and
can increase the unbound fraction of phenytoin.
• Inhibitory drug interactions and subsequent drug toxicity due
to saturable metabolism can occur when other drugs
metabolized through CYP2C9 and CYP2C19 are given. (FDA,
2015).
• There are over 1000 drugs known or suspected to interact with
fosphenytoin. (DrugBank, 2017).

8. ADVERSE DRUG REACTIONS (ADRS)
• Most severe with rapid infusion.
• Cardiac toxicity and hypotension
• Seizures and status epilepticus with abrupt withdrawal
• Hypersensitivity and allergic reactions
• Toxic epidermal necrolysis and Stevens-Johnson syndrome
• Drug-reaction with eosinophilia and systemic symptoms
(DRESS)
• Hepatoxicity and blood dyscrasias with or without DRESS
(FDA, 2015).

9. SIDE EFFECTS
• Most side effects of fosphenytoin are dose and rate dependent
• Recommended that dosage not exceed greater than or equal to
15mg PE/kilogram and rates not exceed greater than or equal
to 150mg PE/minute.
• Pruritus, tinnitus, nystagmus, somnolence, and ataxia occur
two to three times more frequently with higher doses or rates.
Paresthesias and pruritis were associated with higher doses and
were associated with intravenous administration but not with
intramuscular administration.
(FDA, 2015).

10. DRUGS AFFECTING BINDING
Fosphenytoin’s active metabolite, phenytoin is 95%-99% bound
to plasma proteins, especially albumin. It is susceptible to
competitive displacement by other highly albumin-bound drugs.
(FDA, 2015).
Specific drugs include:
• Salicylic acid (Czosnowski, Whitman, and Aykroyd, 2017).
• Valproic acid (Czosnowski, Whitman, and Aykroyd, 2017).
• Phenobarbital – high doses (Curry & Kulling, 1998).

11. PHARMACOGENOMICS
• HLA-B*1502 is an inherited allele variation of the HLA B gene
noted in patients of Asian, particularly Chinese, ancestry.
• HLAB*1502 may be a risk factor for the development of
Stevens-Johnson syndrome or toxic epidermal necrolysis with
administration of antiepileptic drugs including phenytoin.

12. INTERPROFESSIONAL COLLABORATION
Defined as “the collective involvement of various professional
healthcare providers working with patients, families, caregivers,
and communities to consider and communicate each other’s
unique perspective in delivering the highest quality of care.”
(Moss, Seifert, & O’Sullivan, 2016).

13. INTERPROFESSIONAL COLLABORATION
Pharmacist Will Reed (personal interview, November 27, 2017)
believes interprofessional rounding is the best way to promote
collaboration in the acute care setting.
• Physician, pharmacist, primary nurse, and, when applicable, the
physical therapist visit patients together to discuss the
individual patient’s condition, any confounding factors to care,
treatment plans, and the goals and desired outcomes.
• Discussions occur at the bedside, and the patient and family
are included.

14. SYNTHESIS: FOSPHENYTOIN USE IN THE
EMERGENCY DEPARTMENT
• Given parenterally to treat seizures and status epilepticus (FDA, 2015).
• Works by blocking sodium channels and diminishing action potentials. (DrugBank, 2017).
• Metabolized by the liver and protein-bound (Czosnowski, Whitman, and Aykroyd, 2017).
• Hepatic metabolism and protein-binding mean that liver function, renal function, and awareness of
other conditions affecting serum albumin are important to consider before administration. (W. Reed,
personal interview, November 27, 2017).
• Consideration must be given when patients are taking other protein-bound drugs or other CYP2C9 or
CYP2C19 metabolized drugs are given. (FDA, 2015).
• Dosage is always expressed as milligrams PE (FDA, 2015).
• Cardiac and hemodynamic monitoring are required due to cardiac and hypotensive ADRS (FDA, 2015).
• Rash during or after administration may be a sign of potentially life-threatening toxic epidermal
necrolysis, Stevens-Johnson syndrome or DRESS. Patients of Asian descent are most susceptible.
(FDA, 2015).
• Monitor for anaphylaxis or hypersensitivity (FDA, 2015).
Some large emergency departments have on-site pharmacists. Pharmacists,
physicians, and nurses are part of a team. Patient safety relies on consulting
team members when necessary. (Will Reed, personal interview, November 27,

15. REFERENCES
Bromfield, E.B., Cavazos, J.E., Sirven, J.L. (Eds.). (2006). Chapter 1, basic mechanisms underlying seizures
and epilepsy. An introduction to epilepsy. West Hartford, CT: American Epilepsy Society. Retrieved from
https://www.ncbi.nlm.nih.gov/books/NBK2510/
Curry, W.J., & Kulling, D.L. (1998). Newer antiepileptic drugs: gabapentin, lamotrigine, felbamate,
topiramate and fosphenytoin. American family physician, 57(3), 513-520. Retrieved from
http://www.aafp.org/afp/1998/0201/p513.html
Czosnowski, Q.A., Whitman, C.B., & Aykroyd, L. (2017). Seizure disorders. In V.P. Arcangelo, A.M.
Peterson. V. Wilber & J.A. Reinhold (Eds.), Pharmacotherapeutics for Advanced Practice: A practical
approach (4th ed.). (p. 659). Philadelphia: Wolters Kluwer.
DrugBank. (2017). Fosphenytoin. Retrieved from https://www.drugbank.ca/drugs/DB01320
Food and Drug Administration. (2015). Cerebyx (fosphenytoin sodium injection). Retrieved from
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020450s028lbl.pdf
Kirschbaum, K., & Gurk-Turner, C. (1999). Phenytoin vs fosphenytoin. BUMC proceedings, 12, pp. 168-
172. Retrieved from
http://www.baylorhealth.edu/Documents/BUMC%20Proceedings/1999%20Vol%2012/No.%203/12_%203
_%20Kirschbaum.pdf
Minczak, B. (2007). Focus on: Seizures – what is the mechanism underlying clinical manifestations of
seizure activity as seen in the ED?. ACEP news. Retrieved from https://www.acep.org/Clinical---
Practice-Management/Focus-On--Seizures---What-Is-the-Mechanism-Underlying-Clinical-
Manifestations-of-Seizure-Activity-as-Seen-in-the-ED-/#sm.00000pgk7hqakfkwsqv1qtkfb680e