FOSPHENYTOIN SODIUM (Generic for CEREBYX)

General Administration Information
For storage information, see the specific product information within the How Supplied section.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 2
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.

Route-Specific Administration

Injectable Administration
-Always express the dosage, concentration, and infusion rate of fosphenytoin in phenytoin sodium equivalents (PE).
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Storage: Discard any unused product from single-use vials immediately. Of note, the Sesquient formulation is stored at room temperature prior to use, while other formulations (e.g., Cerebyx) require refrigeration and should not be stored at room temperature for more than 48 hours.
Intravenous Administration
Dilution
-Dilute in 5% Dextrose Injection or 0.9% Sodium Chloride Injection to a concentration ranging from 1.5 to 25 mg PE/mL.
-Storage: Diluted solution is stable for 4 hours at room temperature.

Intermittent IV Infusion

-Because of the risk of hypotension and other adverse reactions, administration rate is important; do not exceed recommended infusion rates for specific products.
-Cerebyx and generic equivalents: 1 to 2 mg PE/kg/minute. Max: 150 mg PE/minute for loading doses and 100 mg PE/minute for maintenance doses.
-Sesquient: 0.4 mg PE/kg/minute. This formulation contains betadex sulfobutyl ether sodium; the safety of faster administration in pediatric patients has not been established.
-Continuously monitor electrocardiogram (ECG), blood pressure, and respiratory function throughout infusion until 10 to 20 minutes post-infusion (when maximal phenytoin concentrations are achieved).
-Follow the loading dose with maintenance doses of fosphenytoin or phenytoin. Begin maintenance dosing at the next identified dosing interval.

Intramuscular Administration
-Do not administer fosphenytoin IM for the treatment of status epilepticus, as therapeutic concentrations may not be reached as quickly as with IV administration.
-Administer undiluted.
-Inject deeply into a large muscle mass (e.g., anterolateral thigh or deltoid [deltoid for children and adolescents only]).
-Doses may be divided into smaller volumes for simultaneous administration in more than 1 site. In controlled trials, IM doses were given as a single daily dose utilizing either 1 or 2 injection sites in volumes up to 20 mL for adult patients.
-Some patients may require the daily dosage of fosphenytoin to be administered in divided doses (e.g., 2 or 3 times daily) to provide adequate seizure control.

Agitation (3.3%), abnormal thinking (more than 1%), and nervousness (more than 1%) were reported in patients receiving fosphenytoin during clinical trials. Psychiatric effects reported in 0.1 to 1% of patients include confusion, depersonalization, depression, psychosis, emotional lability, personality disorder, hostility, amnesia, and neurosis. Antiepileptic drugs (AEDs) such as fosphenytoin increase the risk of suicidal ideation and behavior. Monitor all patients beginning treatment with AEDs or currently receiving such treatment closely for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. A pooled analysis of 199 placebo-controlled trials including 11 different AEDs showed that patients (5 years and older) receiving AEDs had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%), with an adjusted relative risk of 1.8 (95% CI 1.2 to 2.7). Four completed suicides occurred in patients treated with AEDs compared to none among controls. The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor and risk was generally consistent among all AEDs examined. Suicidal ideation or behavior have occurred as early as 1 week after AED initiation and may occur any time during treatment.

Do not exceed product-specific recommended infusion rates. The rate of intravenous administration of fosphenytoin is critically important to avoid or limit infusion-related reactions; untoward cardiovascular effects accompany the direct intravenous administration of fosphenytoin at rates greater than the maximum rate. Even when administered according to guidelines, cardiac adverse reactions may occur. Hypotension (5% to 7.7%), peripheral vasodilation (5.6%), sinus tachycardia (2.2%), and hypertension (more than 1%) have been reported in patients receiving fosphenytoin during clinical trials. Hypotension and arrhythmias are considered infusion-related reactions and are more likely to occur after high doses of fosphenytoin are given at high infusion rates. Cardiovascular effects reported in 0.1% to 1% of patients include cardiac arrest, syncope, cerebral hemorrhage, palpitations, sinus bradycardia, atrial flutter, bundle-branch block, cardiomegaly, cerebral infarct (stroke), orthostatic hypotension, pulmonary embolism, QT prolongation, thrombophlebitis, ventricular extrasystoles, and congestive heart failure. Atrial and ventricular conduction depression and ventricular fibrillation, leading to fatality, have occurred with fosphenytoin administration. Reactions to fosphenytoin occur more often in pediatric patients (particularly infants), those who are critically ill, or have pre-existing hypotension or severe myocardial insufficiency. Careful cardiac monitoring is needed during and after fosphenytoin administration. A reduction in the rate of administration or discontinuation of therapy may be necessary if cardiac reactions occur.

Fosphenytoin is known to cause transient, infusion-related paresthesias and pruritus not seen with intravenous (IV) use of phenytoin. During clinical trials comparing IV fosphenytoin to IV phenytoin, the following incidences were reported for fosphenytoin vs. phenytoin: paresthesias 4.4% vs. 0% and pruritus 48.9% vs. 4.5%. In controlled trials comparing intramuscular (IM) fosphenytoin to oral phenytoin, the following incidences were reported for fosphenytoin vs. phenytoin: paresthesias 3.9% vs. 3.3% and pruritus 2.8% vs. 0%. During all clinical trials, circumoral paresthesias occurred in 0.1% to 1% of patients. These reactions are dose- and rate-related, generally occurring within several minutes after start of infusion and subsiding approximately 10 minutes after end of infusion. Some patients may experience symptoms for hours. Sensations are typically described as itching, burning, or tingling, and are usually not at the site of infusion. Interestingly, the groin is the most common site of involvement. Patients receiving fosphenytoin doses of 20 mg PE/kg at 150 mg PE/minute are expected to experience some degree of discomfort. The frequency and intensity of the reaction can be reduced by slowing or temporarily stopping the infusion. Severity of the reaction does not increase with repeated administration and no permanent sequelae have been reported. The mechanism of the reaction is not known, but it does not appear to be allergic in nature; other phosphate ester drugs have been associated with similar sensations.

Osteomalacia has been associated with chronic phenytoin therapy and is considered to be due to phenytoin's interference with vitamin D metabolism. Though fosphenytoin is approved only for short-term use, because it is converted to phenytoin in vivo there may be an increased risk of rickets, bone fractures, osteopenia, and/or osteoporosis with prolonged use.

Lymphadenopathy has been associated with phenytoin and fosphenytoin therapy. Specific disorders observed have included benign lymph node hyperplasia, pseudolymphoma, lymphomas and Hodgkin's disease. Lymph node involvement may or may not be accompanied by pyrexia, rash, and liver involvement. Although these disorders appear infrequent, all cases of lymph node involvement necessitate follow-up, and fosphenytoin should be substituted with alternative antiepileptic agents.

Gingival hyperplasia is frequently associated with chronic phenytoin therapy. Data indicates approximately 50% of patients taking phenytoin will experience some degree of gingival overgrowth, often within 1 month after drug initiation. While some literature indicates correlation with dosage and duration of use, other studies emphasize the role of poor oral hygiene. Though fosphenytoin is approved only for short-term use, because it is converted to phenytoin in vivo emphasis should be placed on good personal oral hygiene and gum massage, as the presence of dental plaque may contribute to hyperplasia.

Elevated hepatic enzymes were reported in 0.1% to 1% of patients during clinical trial evaluation of fosphenytoin. Hepatotoxicity and acute hepatic failure have been reported with phenytoin therapy. These reactions usually occur in the first months of therapy and are associated with Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome that includes pyrexia, skin reactions, and lymphadenopathy. Other manifestations seen include jaundice, hepatomegaly, elevated hepatic enzymes, leukocytosis, and eosinophilia. Leukocytosis was reported in 0.1% to 1% of patients during clinical trial evaluation of fosphenytoin. Discontinue fosphenytoin immediately in the case of acute hepatotoxicity and do not readminister. Clinical outcomes for acute hepatotoxicity with phenytoin therapy are variable, ranging from acute recovery to fatality.

Ecchymosis was reported in 7.3% of patients receiving IM fosphenytoin vs. 4.9% of patients receiving oral phenytoin during clinical trials. Thrombocytopenia, anemia, leukocytosis, cyanosis, hypochromic anemia, leukopenia, and petechiae occurred in 0.1% to 1% of patients receiving fosphenytoin. Similar effects, including neutropenia, agranulocytosis, and pancytopenia, with or without bone marrow depression have been observed during phenytoin therapy. Some of these reactions, while infrequent, have been fatal. Monitor blood counts during fosphenytoin therapy. Pure red cell aplasia has also been reported with phenytoin use. Phenytoin has been reported to cause macrocytosis and megaloblastic anemia, which usually respond to folic acid therapy.

Pelvic pain (4.4%), back pain (2.2%), accidental injury (3.4%), and myasthenia (more than 1%) have been reported with fosphenytoin use during clinical trials. Musculoskeletal effects reported in 0.1% to 1% of patients included myopathy, muscle cramps (legs), arthralgia, and myalgia. The effects of fosphenytoin and phenytoin on acetylcholine receptor sensitivity have been associated with symptom exacerbation in patients with myasthenia gravis.

Pneumonia occurred in more than 1% of patients during clinical trials of fosphenytoin. Respiratory effects reported in 0.1% to 1% of patients include pharyngitis, sinusitis, hyperventilation, rhinitis, apnea, aspiration pneumonia, asthma (bronchospasm), dyspnea, atelectasis, increased cough, increased sputum, epistaxis, hypoxia, pneumothorax, hemoptysis, and bronchitis.

Nausea (4.5% to 8.9%), vomiting (2.2% to 21%), tongue disorder (4.4%), xerostomia (4.4%), and constipation (more than 1%) have been reported during clinical trials of fosphenytoin. Other gastrointestinal (GI) reactions reported in 0.1% to 1% of patients include dyspepsia, diarrhea, anorexia, GI bleeding, hypersalivation, tenesmus, tongue swelling, dysphagia, flatulence, gastritis, and ileus.

The following centrally-mediated reactions have been reported in clinical trials with fosphenytoin: headache (2.2% to 8.9%), nystagmus (15.1% to 44.4%), dizziness (5% to 31.1%), drowsiness (6.7% to 20%), ataxia (8.4% to 11.1%), stupor (7.7%), incoordination (4.4% to 7.8%), tremor (3.3% to 9.5%), hypesthesia (2.2%), vertigo (2.2%), hyporeflexia (2.8%), extrapyramidal syndrome (0.1% to 4.4%), and cerebral edema (0.1% to 2.2%). Drowsiness, dizziness, and nystagmus were reported at greater incidences with intravenous (IV) use. Interestingly, drowsiness, nystagmus, and ataxia were reported 2 to 3 times more often when fosphenytoin doses were 15 mg PE/kg or more and when recommended infusion rates were exceeded. More than 1% of patients receiving fosphenytoin experienced hyperreflexia, speech disorder, dysarthria, intracranial hypertension, and hypoesthesia. Reactions reported in 0.1% to 1% of patients included twitching, positive Babinski sign, hemiplegia, hypotonia, seizures, insomnia, meningitis, central nervous system (CNS) depression, paralysis, aphasia, coma, hyperesthesia, myoclonia, akathisia, hyperkinesis, hypokinesia, acute brain syndrome, encephalitis, subdural hematoma, migraine, and encephalopathy. Cerebellar atrophy has been reported with phenytoin use and appears to be more likely in the setting of elevated phenytoin concentrations and/or long-term use.

Tinnitus (8.9%), diplopia (3.3%), dysgeusia (more than 1%), amblyopia (2.2%), and hearing loss (0.1% to 2.2%) have been reported during clinical trials with fosphenytoin. Tinnitus was reported 2 to 3 times more often when fosphenytoin doses were 15 mg PE/kg or more and rates exceeded recommendations. Other adverse reactions related to the senses and reported in 0.1% to 1% of patients during clinical trials include visual field defect (visual impairment not specified), ocular pain, conjunctivitis, photophobia, hyperacusis, mydriasis, parosmia, and otalgia.

During clinical trials of fosphenytoin, the following genitourinary effects were reported in 0.1% to 1% of patients: urinary retention, oliguria, dysuria, vaginitis, albuminuria (proteinuria), genital swelling, renal failure (unspecified), polyuria, urethral pain, urinary incontinence, and vaginal moniliasis.

Hypokalemia was reported in more than 1% of patients during clinical trials of fosphenytoin. The following endocrine, metabolic, or nutritional effects were reported in 0.1% to 1% of patients: diabetes insipidus, hyperglycemia, hypophosphatemia, alkalosis, acidosis, dehydration, hyperkalemia, and ketosis. It is worth noting that fosphenytoin conversion to phenytoin liberates a phosphate by-product that could potentially cause hyperphosphatemia. Consider the phosphate load provided by fosphenytoin injection (0.0037 mmol phosphate/mg PE) in patients with renal impairment or failure.

Asthenia was reported in 2.2% to 3.9% of patients receiving fosphenytoin during clinical trials. Whole-body effects reported in more than 1% of patients include fever, infection, chills, and facial edema. Sepsis, flu-like syndrome, malaise, generalized edema, shock, cachexia, and cryptococcosis occurred in 0.1% to 1% of fosphenytoin patients.

Fosphenytoin can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Dermatological reactions can present as scarlatiniform or morbilliform (measles-like) rash, maculopapular rash, or a more serious response such as bullous rash, exfoliative dermatitis, purpura, lupus erythematosus (lupus-like symptoms), erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), or acute generalized exanthematous pustulosis (AGEP). Severe hypersensitivity reactions usually occur within 1 month of treatment; however, prolonged duration of therapy should not preclude the possibility of an association to the drug. If a rash develops, evaluate the patient for signs and symptoms of DRESS. Manifestations of DRESS typically include pyrexia, rash, and lymph node involvement in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Early manifestations of DRESS such as pyrexia and lymph node involvement may be present without evidence of a rash. Additional hypersensitivity reactions may include, but are not limited to, fever, sore throat, skin rash, periorbital or facial edema, angioedema, myalgia, arthralgia, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or yellowing of the eyes or skin. These signs and symptoms should be reported even if mild or occurring after extended use. Discontinue fosphenytoin immediately and begin alternative therapy if a severe hypersensitivity reaction occurs. Discontinue fosphenytoin in patients presenting with a rash or symptoms indicative of a hypersensitivity reaction in whom an unrelated etiology cannot be identified. Subsequent resumption of therapy should not occur in those with signs or symptoms suggestive of a severe reaction such as SJS, TEN, DRESS, or AGEP. Although treatment may be resumed after milder rashes (e.g., morbilliform or scarlatiniform) have resolved, further use of fosphenytoin is contraindicated if the rash recurs. During clinical trials, rash occurred in more than 1% of patients; maculopapular rash, urticaria, hyperhidrosis, skin discoloration, contact dermatitis, pustular rash, skin nodule, and photosensitivity were reported in 0.1% to 1% of patients. Anaphylactoid reactions/anaphylaxis and angioedema have been reported with postmarketing use. Phenytoin can produce hypertrichosis or hirsutism in some patients; while yet to be reported during fosphenytoin therapy, these effects may be more likely to occur with prolonged therapy.

Fosphenytoin intravenous (IV) infusion causes fewer injection site reactions than phenytoin. During clinical trials of fosphenytoin, injection site reaction (including injection site pain) occurred in more than 1% of patients; injection site inflammation, edema, and hemorrhage were reported in 0.1 to 1% of patients. Purple glove syndrome (PGS) is a potentially serious adverse effect of phenytoin and fosphenytoin intravenous administration, resulting in soft tissue injury, limb edema, skin discoloration, and pain distal to the injection site. In severe cases, PGS may progress to skin necrosis, limb ischemia, skin grafting, or amputation. PGS may or may not be associated with extravasation; it may not become evident for several days after the injection. Because of the risk of localized toxicity, recommended administration guidelines should be followed.

Anticonvulsants may enhance the hepatic breakdown of vitamin D into inactive polar metabolites. Patients receiving fosphenytoin for greater than 6 months should be monitored for vitamin D deficiency and receive supplementation when indicated by low serum concentrations. Anticonvulsants may also impair folate metabolism; patients should be monitored for folate deficiency and supplemented when necessary.

Fosphenytoin is contraindicated in patients with a hydantoin hypersensitivity (e.g., phenytoin, fosphenytoin, ethotoin). Hypersensitivity reactions to anticonvulsants may be severe and sometimes fatal. Consider an alternative to fosphenytoin if the patient or an immediate family member has a carbamazepine hypersensitivity, barbiturate hypersensitivity, succinimide hypersensitivity, or oxazolidinedione hypersensitivity. Hypersensitivity reactions to fosphenytoin have been reported in patients who previously experienced hypersensitivity to phenytoin, barbiturates, or carbamazepine. Estimates of cross-sensitivity vary but may range from 30% to 80%. Phenytoin, carbamazepine, and phenobarbital are all metabolized to hydroxylated aromatic compounds via the cytochrome P450 hepatic oxidative enzymes; arene oxide intermediates are formed during metabolism and are thought to be responsible for cross-sensitivity among these anticonvulsants in susceptible individuals. Some individuals may have a reduced ability to detoxify the intermediate toxic metabolites (e.g., arene oxides) of these anticonvulsants, which may be genetically mediated. However, studies of familial reactions have also shown that allergies to 1 anticonvulsant may not translate to allergies to others. There is no way to predict with certainty which patients will exhibit cross-sensitivity.

Fosphenytoin can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Avoid fosphenytoin in patients positive for HLA-B 1502 or in CYP2C9 3 carriers. If used in patients who are CYP2C9 2 or 3 carriers (intermediate or poor metabolizers), consider starting at the lower end of the dosage range and monitor serum concentrations to maintain total phenytoin concentrations of 10 to 20 mcg/mL. Studies have found a strong association between the risk of developing SCARs and the presence of HLA-B 1502, an inherited variant allele of the HLA-B gene, in patients taking carbamazepine. Limited evidence suggests HLA-B 1502 is a risk factor for the development of SCARs in patient taking other drugs associated with SCARs, including phenytoin and fosphenytoin. HLA-B 1502, the variant allele of human leukocyte antigen B, is most prevalent in Asian patients; prevalence ranges from 1% to over 10% in Oceania, East Asian, and South/Central Asian populations. It is less frequent in European populations (0 to 1%) and largely absent in African, Hispanic, and Native American populations. Retrospective, case-control, genome-wide association studies in patients of southeast Asian ancestry have also identified an increased risk of SCARs in carriers of the decreased function CYP2C9 3 variant, which has also been associated with decreased clearance of phenytoin. Additionally, patients who are intermediate or poor metabolizers of CYP2C9 (e.g., 1/3, 2/2, 3/3) may exhibit increased phenytoin concentrations compared to normal metabolizers (e.g., 1/1). The prevalence of CYP2C9 poor and intermediate metabolizer phenotype is about 2% to 3% and 35% in the White population, 0.5% to 4% and 15% to 36% in the Asian population, and less than 1% and 24% in the African American population, respectively.

Fosphenytoin is not effective for, and may worsen, petit mal (absence) seizures. If grand mal (tonic-clonic) and petit mal (absence) seizures are present, combined drug therapy is needed. Fosphenytoin and other hydantoins are not indicated for seizures due to hypoglycemia or other metabolic causes (e.g., hyponatremia). Appropriate diagnostic procedures should be performed as indicated.

Like other antiepileptic drugs, the abrupt discontinuation of fosphenytoin therapy can lead to increased seizure activity, including status epilepticus. Dosage reduction, substitution in therapy, or drug discontinuation should be done gradually. Allergic or hypersensitivity reactions may require rapid substitutions. In these cases, change therapy to an antiepileptic agent not belonging to the hydantoin class.

Use fosphenytoin with caution in patients with hematological disease or blood dyscrasias caused by drug therapies. Obtain baseline and periodic hematologic counts; closely monitor patients who develop neutropenia or thrombocytopenia. Consider drug discontinuation if significant bone marrow suppression develops. Although uncommon, phenytoin can cause hematological toxicity consisting of transient leukopenia, neutropenia, thrombocytopenia, or more severe reactions like agranulocytosis, aplastic anemia, and hemolytic anemia. The drug has also been rarely noted as a cause of methemoglobinemia. The risk of serious blood dyscrasias is rare. A cohort study of patients age 10 to 74 years reported 2.7 out of 100,000 prescriptions (95% CI 0.9 to 6.3) for phenytoin resulted in blood dyscrasia. Cumulative risk increased as length of antiepileptic treatment increased. Exercise caution when using fosphenytoin in patients suffering from porphyria as isolated reports have associated phenytoin with disease exacerbation.

Fosphenytoin is converted to phenytoin in vivo. There have been a number of reports suggesting a relationship between phenytoin and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's Disease. Lymph node involvement may occur with or without symptoms and signs resembling serum sickness (e.g., fever, rash, and liver involvement). Follow-up observation for an extended period is indicated for cases of lymphadenopathy and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Fosphenytoin is contraindicated in patients with conduction abnormalities such as sinus bradycardia, sinoatrial block, second or third degree AV block or bundle-branch block, and Adams-Stokes syndrome because of the effect of parenteral phenytoin on ventricular automaticity. Infusion-related reactions, specifically cardiovascular risks (e.g., hypotension, cardiac arrhythmias), have been associated with rapid intravenous infusion rates. The rate of intravenous administration of fosphenytoin is critically important to avoid or limit adverse cardiovascular reactions; do not exceed product-specific recommended infusion rates. Careful cardiac monitoring is needed during and after administering intravenous fosphenytoin. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these reactions have also been reported at or below the recommended infusion rate. Reduction in rate of administration or discontinuation of dosing may be needed if cardiovascular adverse reactions occur during or after intravenous infusion. Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias. Cardiac arrhythmias have included bradycardia, heart block, QT interval prolongation, ventricular tachycardia, and ventricular fibrillation which have resulted in asystole, cardiac arrest, and death. Cardiovascular adverse reactions to fosphenytoin occur more often in pediatric patients (especially infants), critically ill, or those with pre-existing hypotension or severe myocardial insufficiency or cardiac disease. However, cardiac reactions have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.

Acute alcoholic intake may increase phenytoin serum levels while chronic ethanol ingestion can induce hepatic oxidative enzymes, decreasing phenytoin serum concentrations. Such parameters may need to be considered when treating patients with a history of alcoholism or acute intermittent binge drinking.

Fosphenytoin is contraindicated in patients with a history of prior acute hepatotoxicity secondary to fosphenytoin or phenytoin therapy. Phenytoin-induced acute hepatotoxicity has been reported. Hepatotoxicity may be associated with jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis, rash, and eosinophilia; hepatotoxicity may be the result of hypersensitivity to the drug. It may be part of the spectrum of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) or may occur in isolation. Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment. Discontinue fosphenytoin if there is evidence of new or worsening hepatotoxicity. In patients with acute hepatotoxicity, do not re-administer fosphenytoin. Use fosphenytoin cautiously in patients with hyperbilirubinemia (which may manifest clinically as jaundice). Bilirubin displaces phenytoin from protein-binding sites, resulting in increased free phenytoin concentrations. Hypoalbuminemia also results in increased free phenytoin concentrations, which may increase the likelihood of drug toxicity. Hypoalbuminemia is common in the critically ill, as well as in patients with malnutrition, burns, and renal or hepatic disease. Fosphenytoin is a prodrug of phenytoin; phenytoin is eliminated via hepatic metabolism and should be used with caution in any patient with hepatic dysfunction. A small percentage of individuals metabolize phenytoin slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; slow metabolism appears to be genetically determined. Fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in patients with hepatic disease, potentiating the frequency and severity of adverse reactions. Dose adjustments may be necessary in patients with hepatic disease or genetic polymorphism.

Betadex sulfobutyl ether sodium, an inactive ingredient in the Sesquient formulation, is known to accumulate in patients with moderate to severe renal impairment. Closely monitor serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) in patients with severe renal impairment (eGFR 15 to 29 mL/minute/1.73m2) receiving this formulation. Consider changing to oral phenytoin if increases in SCr occur. Monitor free phenytoin concentrations in patients with renal disease since the fraction of unbound drug is increased in these patients. Fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance in those with renal impairment, potentiating the frequency and severity of adverse reactions. Consider the phosphate load provided by fosphenytoin (0.0037 mmol phosphate/mg PE) when treating patients who require phosphate restriction, such as those with severe renal impairment or renal failure. Fosphenytoin is converted to phenytoin in vivo, and also liberates formate (formaldehyde) and phosphate by-products during the conversion process.

Fosphenytoin may cause vision disturbances, dizziness, and abnormal thinking. Patients should be advised to use caution when participating in activities requiring coordination and concentration (e.g., getting in and out of bed). Serum concentrations of phenytoin sustained above the optimal range may produce confusional states referred to as 'delirium,' 'psychosis,' or 'encephalopathy,' or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, plasma concentrations are recommended. Dose reduction of fosphenytoin is indicated if plasma concentrations are excessive; if symptoms persist, termination of fosphenytoin therapy is recommended.

Monitor blood glucose closely when fosphenytoin is administered to patients with diabetes mellitus. Phenytoin has an inhibitory effect on insulin release and can cause hyperglycemia. There are case reports of hyperglycemia and even diabetic ketoacidosis (DKA) occurring as a result of phenytoin administration.

Patients with thyroid disease, especially hypothyroidism, should be monitored for signs of underactive thyroid. Fosphenytoin is converted to phenytoin in vivo. Phenytoin stimulates hepatic enzyme activity, which may cause an increased degradation of circulating concentrations of thyroid hormone (T3 and T4), with an accompanying increase in thyroid-stimulating hormone (TSH). Phenytoin reduces serum protein binding of levothyroxine, and total- and free-T4 may be reduced by 20% to 40%; however, most patients are clinically euthyroid.

Osteomalacia has been associated with chronic phenytoin therapy and is considered to be due to phenytoin's interference with vitamin D metabolism. There may be an increased risk of rickets, osteopenia, and/or osteoporosis in patients on prolonged fosphenytoin therapy.

Cranial irradiation administered to patients receiving phenytoin has been associated with erythema multiforme and/or Stevens-Johnson syndrome. Fosphenytoin should be used cautiously, if at all, in patients receiving radiation therapy.

Phenytoin, the active metabolite of fosphenytoin, has been reported to decrease acetylcholine receptor sensitivity; this action may exacerbate symptoms of myasthenia gravis.

The chronic use of phenytoin (or prolonged use of fosphenytoin) may cause gingival hyperplasia. Proper oral hygiene should be maintained in order to minimize the development of gingival hyperplasia and its complications (e.g., dental disease).

Neonatal coagulation defects have been reported in neonates with in utero exposure to phenytoin, and appear to result from drug-induced vitamin K deficiency in the fetus. Administration of vitamin K to the mother before obstetric delivery and to the neonate at birth has been shown to prevent this defect.

There is an increased risk of suicidal ideation and behavior in patients receiving antiepileptic drugs (AEDs). Suicidal ideation or behavior has occurred as early as 1 week after AED initiation and may occur any time during treatment. All patients beginning treatment with fosphenytoin should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Inform patients, caregivers, and families of the increased risk of suicidal thoughts and behaviors and advise them to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. A pooled analysis of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years and older) was conducted. There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor.

Description: Fosphenytoin is a water-soluble, parenteral prodrug of phenytoin, a hydantoin anticonvulsant. Though often used as a second therapy choice (after a benzodiazepine) to control status epilepticus in children and adolescents, fosphenytoin is traditionally considered a therapy of choice after phenobarbital in the neonate. In children and adolescents, fosphenytoin, levetiracetam, and valproate are equally effective in benzodiazepine-refractory status epilepticus. Intravenous (IV) or intramuscular (IM) fosphenytoin may be substituted short-term for oral phenytoin in situations where oral phenytoin is not appropriate or advantageous. Unlike phenytoin, fosphenytoin is soluble in standard intravenous solutions and is rapidly absorbed via the IM route. Fosphenytoin has fewer local adverse reactions and does not contain propylene glycol; thus, IV doses can be given at a faster rate. Since fosphenytoin is converted to phenytoin in vivo, systemic adverse reactions are generally similar between the 2 products. While fosphenytoin represents an improvement over phenytoin in terms of infusion-related reactions, fosphenytoin causes transient, infusion-related paresthesias and pruritus not seen with phenytoin. Fosphenytoin is more expensive than corresponding doses of generic phenytoin but is an attractive alternative in pediatric patients, where IV access is often limited and tenuous. Most fosphenytoin formulations require storage under refrigeration; however, Sesquient is a room temperature stable formulation of fosphenytoin available for intravenous use, allowing for point-of-care storage. Unlike other formulations, Sesquient contains the soluble carrier betadex sulfobutyl ether sodium, which limits its use in the pediatric population to non-urgent indications because of the slower infusion rate in patients 2 years and older. Additionally, this formulation is indicated for IV use only. Most fosphenytoin formulations are FDA-approved in pediatric patients as young as neonates; Sesquient is FDA-approved in patients 2 years and older.

NOTE: The dose, concentration, and infusion rate for fosphenytoin should always be prescribed and dispensed as phenytoin equivalents (PE). Fosphenytoin's dose is expressed as PE to avoid the need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin doses. Fosphenytoin is a prodrug of phenytoin and has an identical efficacy profile (1 mg phenytoin = 1 mg PE fosphenytoin). Based on pharmacokinetic studies, there is no significant difference in the conversion half-life of fosphenytoin to phenytoin in neonates, infants, children, and adolescents.

For the treatment of status epilepticus:
NOTE: The maximum infusion rate of Sesquient is slower (0.4 mg PE/kg/minute vs. 1 to 2 mg PE/kg/minute for Cerebyx and generic equivalents) due to its inactive ingredient betadex sulfobutyl ether sodium and does not allow for adequate treatment of status epilepticus.
Intravenous dosage (Cerebyx and generic equivalents):
Neonates: 15 to 20 mg PE/kg/dose IV as a single dose. Persons who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.
Infants, Children, and Adolescents: 15 to 20 mg PE/kg/dose (Max: 1,500 mg PE/dose) IV as a single dose; may administer additional 5 to 10 mg PE/kg/dose IV as a single dose after 10 minutes if needed. Persons who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.

For the non-emergent treatment of tonic-clonic seizures or partial seizures:
NOTE: There is no information on the safety of betadex sulfobutyl ether sodium, an inactive ingredient in Sesquient, in patients younger than 2 years.
-for non-emergent loading doses:
Intravenous or Intramuscular dosage (Cerebyx and generic equivalents):
Neonates: 10 to 15 mg PE/kg IV or IM load. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.
Infants, Children, and Adolescents: 10 to 15 mg PE/kg IV or IM load. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.
Intravenous dosage (Sesquient only):
Children and Adolescents 2 to 17 years: 10 to 15 mg PE/kg IV load. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose.
-for maintenance dosing when the use of oral phenytoin is not possible :
Intravenous or Intramuscular dosage (Cerebyx and generic equivalents):
Neonates: 2 to 4 mg PE/kg/dose IV or IM every 12 hours initially; individualize subsequent maintenance doses by monitoring serum phenytoin concentrations. Term neonates older than 7 days may require larger maintenance doses due to enhanced hepatic clearance; a dosing frequency of every 8 hours may also be preferred due to increased clearance. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9. A limited number of clinical studies have been conducted in neonates; there have been case reports of neonates having difficulty maintaining therapeutic concentrations and requiring higher than usual maintenance doses (up to 10 mg PE/kg/day).
Infants: 2 to 4 mg PE/kg/dose IV or IM every 12 hours initially; individualize subsequent maintenance doses by monitoring serum phenytoin concentrations. Infants may require larger maintenance doses due to enhanced hepatic clearance seen until 1 year of age; a dosing frequency of every 8 hours may also be preferred due to increased clearance. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9.
Children and Adolescents: 2 to 4 mg PE/kg/dose IV or IM every 12 hours initially; individualize subsequent maintenance doses by monitoring serum phenytoin concentrations. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9.
Intravenous dosage (Sesquient only):
Children and Adolescents 2 to 17 years: 2 to 4 mg PE/kg/dose IV every 12 hours initially; individualize subsequent maintenance doses by monitoring serum phenytoin concentrations. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9.
-for seizure prophylaxis as a short-term phenytoin substitute when oral phenytoin administration is not possible or inappropriate:
Intravenous or Intramuscular dosage (Cerebyx and generic equivalents):
Neonates: Fosphenytoin IV or IM can be substituted for oral phenytoin sodium at the same total daily dose and frequency (1 mg phenytoin = 1 mg PE fosphenytoin). The total daily dose may need to be divided into 2 or more doses to maintain seizure control; some patients may require more frequent dosing. Of note, fosphenytoin solution for injection and phenytoin capsules contain phenytoin sodium, which is 92% phenytoin. Chewable tablets and suspensions contain 100% phenytoin, and dosage adjustments may be needed when switching from these formulations to fosphenytoin, as small changes in dosage may lead to significant changes in serum phenytoin concentrations.
Infants, Children, and Adolescents: Fosphenytoin IV or IM can be substituted for oral phenytoin sodium at the same total daily dose and frequency (1 mg phenytoin = 1 mg PE fosphenytoin). The total daily dose may need to be divided into 2 or more doses to maintain seizure control; some patients may require more frequent dosing. Of note, fosphenytoin solution for injection and phenytoin capsules contain phenytoin sodium, which is 92% phenytoin. Chewable tablets and suspensions contain 100% phenytoin, and dosage adjustments may be needed when switching from these formulations to fosphenytoin, as small changes in dosage may lead to significant changes in serum phenytoin concentrations.
Intravenous dosage (Sesquient only):
Children and Adolescents 2 to 17 years: Fosphenytoin IV can be substituted for oral phenytoin sodium at the same total daily dose and frequency (1 mg phenytoin = 1 mg PE fosphenytoin). The total daily dose may need to be divided into 2 or more doses to maintain seizure control; some patients may require more frequent dosing. Of note, fosphenytoin solution for injection and phenytoin capsules contain phenytoin sodium, which is 92% phenytoin. Chewable tablets and suspensions contain 100% phenytoin, and dosage adjustments may be needed when switching from these formulations to fosphenytoin, as small changes in dosage may lead to significant changes in serum phenytoin concentrations.

For seizure prophylaxis or for seizure treatment during neurosurgery:
NOTE: The maximum infusion rate of Sesquient is slower (0.4 mg PE/kg/minute vs. 1 to 2 mg PE/kg/minute for Cerebyx and generic equivalents) due to its inactive ingredient betadex sulfobutyl ether sodium and does not allow for adequate treatment of seizures occurring during neurosurgery.
Intravenous or Intramuscular dosage (Cerebyx and generic equivalents):
Neonates: 10 to 15 mg PE/kg IV or IM load, then 2 to 4 mg PE/kg/dose IV or IM every 12 hours initially; individualize subsequent maintenance doses by monitoring serum phenytoin concentrations. Term neonates older than 7 days may require larger maintenance doses due to enhanced hepatic clearance; a dosing frequency of every 8 hours may also be preferred due to increased clearance. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9. A limited number of clinical studies have been conducted in neonates; there have been case reports of neonates having difficulty maintaining therapeutic concentrations and requiring higher than usual maintenance doses (up to 10 mg PE/kg/day).
Infants: 10 to 15 mg PE/kg IV or IM load, then 2 to 4 mg PE/kg/dose IV or IM every 12 hours initially; individualize subsequent maintenance doses by monitoring serum phenytoin concentrations. Infants may require larger maintenance doses due to enhanced hepatic clearance seen until 1 year of age; a dosing frequency of every 8 hours may also be preferred due to increased clearance. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9.
Children and Adolescents: 10 to 15 mg PE/kg IV or IM load, then 2 to 4 mg PE/kg/dose IV or IM every 12 hours initially; individualize subsequent maintenance doses by monitoring serum phenytoin concentrations. Patients who are intermediate or poor metabolizers of CYP2C9 should receive a standard loading dose. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9.

Therapeutic Drug Monitoring:
Usual therapeutic serum/plasma concentration (measured as phenytoin): 10 to 20 mcg/mL
-Serum phenytoin concentrations should be used to monitor therapy in patients receiving fosphenytoin. Free (i.e., unbound) phenytoin concentrations may be helpful in assessing patients with hypoalbuminemia or elevated BUN. Hypoalbuminemia is common in the critically ill, as well as in malnutrition and burn patients. Hyperbilirubinemia as well as coadministration of other protein-bound medications decrease phenytoin protein binding, enhancing concentrations of free drug and making free concentrations a useful tool.
-To assess a loading dose, measure phenytoin concentrations 2 hours after the end of intravenous (IV) infusion and 4 hours after intramuscular (IM) injection of fosphenytoin, when conversion of fosphenytoin to phenytoin is essentially complete. Trough concentrations are typically used to assess a maintenance doses.
-Seizure control signifies clinical efficacy. Therapeutic phenytoin serum concentrations are generally considered to be 10 to 20 mcg/mL (equivalent to 1 to 2 mcg/mL free phenytoin). Several days may be required to reach steady-state with a given maintenance dose.
-Toxicity is measured clinically. Lateral gaze nystagmus usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, and dysarthria and lethargy appear when the total phenytoin concentration is 40 mcg/mL or more. However, total phenytoin concentrations as high as 50 mcg/mL have been reported without evidence of toxicity. As much as 25 times the therapeutic phenytoin dose has been taken, resulting in plasma phenytoin concentrations over 100 mcg/mL, with complete recovery.

Maximum Dosage Limits:
-Neonates
Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenytoin concentrations and clinical parameters.
-Infants
Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenytoin concentrations and clinical parameters.
-Children
Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenytoin concentrations and clinical parameters.
-Adolescents
Specific maximum dosage information not available; individualize dosage based on monitoring of serum phenytoin concentrations and clinical parameters.

Patients with Hepatic Impairment Dosing
Monitor free phenytoin concentrations in patients with hepatic disease; adjust the dosage based on serum concentrations and clinical response.

Patients with Renal Impairment Dosing
Monitor free phenytoin concentrations in patients with renal impairment; adjust the dosage based on serum concentrations and clinical response. Consider the phosphate load provided by fosphenytoin (0.0037 mmol phosphate/mg PE) when treating patients with severe renal impairment.
In patients receiving Sesquient, closely monitor SCr and eGFR in those with severe renal impairment (eGFR 15 to 29 mL/minute/1.73m2). Consider changing to oral phenytoin if increases in SCr occur. Betadex sulfobutyl ether sodium, an inactive ingredient in this formulation, is known to accumulate in patients with moderate to severe renal impairment.

Intermittent hemodialysis
Phenytoin is not significantly removed during a standard hemodialysis session; therefore, supplemental dosing after hemodialysis is not necessary.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Fosphenytoin is a phosphate ester prodrug of the anticonvulsant phenytoin. Thus, phenytoin is responsible for all of the pharmacological effects of fosphenytoin. Phenytoin exerts its anticonvulsant effect mainly by limiting the spread of seizure activity and reducing seizure propagation unlike phenobarbital and carbamazepine, which elevate the seizure threshold. Because phenytoin does not elevate the seizure threshold, it is less effective against drug-induced or electroconvulsive-induced seizures.

The cellular mechanisms thought to be responsible for phenytoin's anticonvulsant activities include modulation of voltage-dependent sodium channels of neurons, inhibition of calcium flux across neuronal membranes, modulation of voltage-dependent calcium channels of neurons, and the enhancement of Na+/K+ ATPase activity of neurons and glial cells. The limitation of repetitive firing in neurons caused by slowing the rate of recovery in inactivated sodium channels is thought to be phenytoin's primary mechanism. Phenytoin exerts its anticonvulsant effects with less sedation than does phenobarbital. In toxic concentrations, phenytoin is excitatory and can induce seizures. Phenytoin is also a weak antiarrhythmic. Antiarrhythmic actions are also mediated through effects on sodium channels, in this case, in Purkinje fibers.

Pharmacokinetics: Fosphenytoin is administered via the intravenous or intramuscular routes only. While 150 mg of fosphenytoin yields 100 mg of phenytoin, fosphenytoin is dosed in phenytoin sodium equivalents (PE). Thus, 100 mg of phenytoin is equivalent to a 100 mg PE dose of fosphenytoin. After parenteral administration, fosphenytoin is quickly hydrolyzed to phenytoin (the active form), yielding 2 metabolites, phosphate and formaldehyde. While phosphate and formaldehyde have biologic effects, the amount produced appears to be too small to exert clinically significant biological effects. Formaldehyde is eventually converted to formate, which is, in turn, metabolized via a folate-dependent pathway. Each mmol of fosphenytoin is metabolized to 1 mmol of phenytoin, phosphate, and formate. The half-life of conversion of fosphenytoin to phenytoin is approximately 8 minutes.

Fosphenytoin is extensively bound (95% to 99%), primarily to albumin; binding is saturable (i.e., the percentage of bound drug decreases as total drug concentration increases). Phenytoin is also extensively bound to albumin, but less than fosphenytoin. Fosphenytoin effectively displaces phenytoin from protein binding sites, temporarily increasing the free fraction from 12% up to 30%, until fosphenytoin is converted to phenytoin (about 0.5 to 1 hour post-infusion). Phenytoin is extensively metabolized in the liver and excreted in the urine. Hepatic metabolism of phenytoin is saturable, leading to AUC values that increase disproportionately with increasing dose. The Vd increases with injection dose and rate and ranges from 4.3 to 10.8 liters in adults.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C19, P-gp. UGT
Fosphenytoin (converted to phenytoin) is an inducer of the hepatic cytochrome P450 microsomal isoenzymes CYP3A4, CYP2D6, CYP1A2, CYP2C9, and CYP2C19. Limited data suggest phenytoin is also a mild inducer of P-glycoprotein (P-gp) and UGT. Phenytoin is metabolized primarily by CYP2C9 (major) and CYP2C19 (minor); thus, several drugs may inhibit or induce phenytoin's metabolism. CYP2C9 activity is decreased in individuals with CYP2C9 2 and 3 alleles. Patients who are intermediate (e.g., 1/3, 2/2) or poor (e.g., 2/3, 3/3) metabolizers of CYP2C9 have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9 alleles (e.g., 5, 6, 8, 11) may also result in decreased clearance of phenytoin.


-Route-Specific Pharmacokinetics
Intravenous Route
The pharmacokinetics of intravenously-administered fosphenytoin are complex. Studies have determined a fosphenytoin dose and infusion rate that yields phenytoin plasma concentrations similar to those of conventional phenytoin at a rate of 50 mg/minute. For example, fosphenytoin 15 to 20 mg/kg PE infused at 100 to 150 mg PE/minute yields free phenytoin concentrations the same as 15 to 20 mg/kg phenytoin at 50 mg/minute in adults. Fosphenytoin is completely converted to phenytoin after IV administration. Peak plasma concentrations are achieved by the end of infusion. Conversion to phenytoin is complete within 2 hours after the end of the infusion.

Intramuscular Route
Fosphenytoin is completely bioavailable after IM administration. Peak fosphenytoin concentrations are achieved approximately 30 minutes after administration; peak phenytoin concentrations are observed after 3 hours. Due to time required for absorption from the IM site, plasma fosphenytoin concentrations are lower but more sustained when compared to IV administration. The pharmacokinetics of phenytoin after the IM administration of fosphenytoin are similar to those of orally administered phenytoin; these 2 products are considered interchangeable. Conversion to phenytoin is complete within 4 hours after administration.


-Special Populations
Pediatrics
Neonates
Fosphenytoin is highly protein-bound; in general, neonates have a more variable and lower level of protein binding compared to older populations. Hyperbilirubinemia, which is often present in critically ill neonates, may further decrease protein binding. The half-life of conversion of fosphenytoin to phenytoin is approximately 8 minutes, with no significant difference between neonates, infants, children, adolescents, and adults.

Infants, Children, and Adolescents
Infants and young children up to 24 months old may have enhanced hepatic clearance, leading to larger maintenance dose requirements of fosphenytoin. Limited data in children and adolescents 5 to 18 years of age demonstrate comparable pharmacokinetic profiles when compared to adult patients. The half-life of conversion of fosphenytoin to phenytoin is approximately 8 minutes in pediatric patients, with no significant difference between neonates, infants, children, and adolescents. Although more variable in pediatric patients, this value is comparable to that of adults.

Hepatic Impairment
Patients with hepatic disease may have an increased fraction of unbound phenytoin; interpret total phenytoin plasma concentrations with caution. Fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance, potentially increasing the frequency and severity of adverse reactions.

Renal Impairment
Patients with renal disease may have an increased fraction of unbound phenytoin; interpret total phenytoin plasma concentrations with caution. Fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance, potentially increasing the frequency and severity of adverse reactions.

Other
CYP2C9 Intermediate and Poor Metabolizers

CYP2C9 activity is decreased in individuals with CYP2C9 2 and 3 alleles. Patients who are intermediate (e.g., 1/3, 2/2) or poor (e.g., 2/3, 3/3) metabolizers of CYP2C9 have decreased clearance of phenytoin. Other decreased or nonfunctional CYP2C9 alleles (e.g., 5, 6, 8, 11) may also result in decreased clearance of phenytoin.