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FOSPHENYTOIN

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Fosphenytoin is a prodrug of phenytoin. The anticonvulsant activity of fosphenytoin is attributable to phenytoin.

Specific Substances

    1) 2,4-Imidazolidinedione, 5,5-diphenyl-3-((phosphonooxy)methyl)-, disodium salt
    2) 93390-81-9 (fosphenytoin)
    3) 92134-98-0 (fosphenytoin sodium)
    4) Molecular Formula: C16H13N2Na2O6P
    1.2.1) MOLECULAR FORMULA
    1) C16H13N2Na2O6P (RTECS, 2006)

Available Forms Sources

    A) FORMS
    1) Fosphenytoin is supplied in vials containing a ready-mixed solution of 75 mg/mL fosphenytoin sodium, which is equivalent to 50 mg/mL phenytoin sodium (Prod Info CEREBYX(R) intravenous injection, 2014).
    B) USES
    1) Fosphenytoin is a prodrug of phenytoin. Fosphenytoin sodium is indicated as a short-term substitute for oral phenytoin in patients with seizure disorders and should only be used when oral phenytoin administration is not possible (Prod Info CEREBYX(R) intravenous injection, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Fosphenytoin is an anticonvulsant prodrug of phenytoin, used for seizure prophylaxis and treatment.
    B) PHARMACOLOGY: Fosphenytoin is an anticonvulsant that is metabolized to phenytoin and regulates voltage-dependent sodium and calcium channels and enhances sodium-potassium ATPase activity. The modulation of voltage-dependent sodium channels is the primary means of anticonvulsant activity.
    C) TOXICOLOGY: Toxicity is an extension of therapeutic effects. Patients may develop CNS depression, ataxia, nausea, vomiting and eventually coma and respiratory depression. Cardiac effects are much less common with IV infusion than with phenytoin because propylene glycol is not used as a diluent for fosphenytoin.
    D) EPIDEMIOLOGY: Poisoning is uncommon and rarely severe.
    E) WITH THERAPEUTIC USE
    1) The most common side effects of fosphenytoin administration are pruritus, hypotension, dysrhythmias, nystagmus, dizziness, somnolence, lightheadedness, ataxia, paresthesias, headache, tremor, agitation, hypesthesia, dysarthria, vertigo, hyperreflexia, intracranial hypertension, and altered mental status. OTHER EFFECTS: Nausea, vomiting, injection site pain and inflammation, hyperglycemia, hypocalcemia, pelvic pain, asthenia, and back pain.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, lethargy, nystagmus, ataxia, dysarthria, hyperreflexia, and mild sedation.
    2) SEVERE TOXICITY: Hypotension, dysrhythmias, asystole, CNS depression, mental status changes, hallucinations, hypocalcemia, coma, metabolic acidosis, and cardiac arrest may occur.
    0.2.20) REPRODUCTIVE
    A) FDA Pregnancy Category D.
    B) Fosphenytoin is a prodrug of phenytoin. Teratogenic effects have been seen in infants exposed to phenytoin and other hydantoin anticonvulsants in utero.
    C) Prenatal exposure to phenytoin may increase the risk of congenital malformations, such as orofacial clefts, cardiac defects, dysmorphic facial features, as well as nail and digit hypoplasia. Prenatal exposure may also increase the risk for adverse developmental outcomes.
    D) Both male and female rats given fosphenytoin demonstrated NO effects on fertility.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of fosphenytoin in humans. Phenytoin is listed as possibly carcinogenic to humans (ie, Group 2B rating from the International Agency for Research on Cancer).

Laboratory Monitoring

    A) Monitor vital signs, pulse oximetry, and mental status. Monitor serial phenytoin concentrations (fosphenytoin is metabolized to phenytoin).
    B) Toxic effects are rare at plasma phenytoin concentrations less than 20 mcg/mL (80 mcmol/L), but are common in patients with plasma concentrations greater than 30 mcg/mL (120 mcmol/L). They should be checked 2 hours after IV infusion and 4 hours after IM administration.
    C) Monitor serum electrolytes, kidney function, and liver enzymes in symptomatic patients.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) The vast majority of fosphenytoin overdoses require only supportive care.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treat patients who develop respiratory depression, bradycardia, and asystole per ACLS guidelines. Hypotension and tachycardia should be treated with crystalloid infusions. Hypotension and tachycardia are usually the result of accelerated infusions; however, anaphylactoid reactions should remain on your differential. CNS effects are usually self-limiting and will usually resolve with careful observation. Note that some symptoms may persist for 7 to 10 days.
    C) DECONTAMINATION
    1) PREHOSPITAL: Fosphenytoin is administered parenterally; gastrointestinal decontamination is not useful.
    2) HOSPITAL: Fosphenytoin is administered parenterally; gastrointestinal decontamination is not useful.
    D) AIRWAY MANAGEMENT
    1) Perform early in patients with severe intoxication (CNS or respiratory depression).
    E) ANTIDOTE
    1) None
    F) HYPOTENSIVE EPISODE
    1) Administer IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids.
    G) ACIDOSIS
    1) Metabolic acidosis has been reported following fosphenytoin overdose. Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg.
    H) ENHANCED ELIMINATION PROCEDURE
    1) Multidose activated charcoal has been shown to have limited benefit and is not recommended by ACCT or EAPCCT. Hemodialysis may be considered following a significant exposure. Fosphenytoin is highly protein bound which substantially limits clearance with hemodialysis; however, at high concentrations, an increasing fraction of the drug is unbound and amenable to hemodialysis. Hemoperfusion may be more effective. The decision to perform hemodialysis or hemoperfusion should be weighed carefully against the risks of the procedure as there are no studies that demonstrate any clinical benefit and toxic effects are usually not severe.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: None. Fosphenytoin is administered parenterally in the hospital setting.
    2) OBSERVATION CRITERIA: Patients with inadvertent dosing errors should be observed for dysrhythmias and hypotension for 6 hours.
    3) ADMISSION CRITERIA: Patients with ataxia, cardiac dysrhythmias, or hypotension should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (dysrhythmias, hypotension, CNS depression), or in whom the diagnosis is not clear.
    J) PITFALLS
    1) Not identifying a possible septic patient, anaphylactoid reaction, not adequately protecting the patient's airway, and failure to identify other cases of seizures.
    K) PHARMACOKINETICS
    1) Fosphenytoin is rapidly metabolized by phosphatase to phenytoin. It is 95% to 99% protein bound as fosphenytoin and 70% to 80% bound as phenytoin. Phenytoin is extensively metabolized in the liver and metabolites are excreted renally. The half-life of fosphenytoin is 15 minutes and 12 to 29 hours for phenytoin.
    L) TOXICOKINETICS
    1) As fosphenytoin is only available as an IV solution, onset of symptoms generally occurs within 5 minutes to 30 minutes; toxicity may persist for several days. At high concentrations, phenytoin undergoes zero order kinetics, and half-life is exceedingly prolonged.
    M) DIFFERENTIAL DIAGNOSIS
    1) Phenytoin overdose, anaphylactoid or anaphylaxis reaction, sepsis, cerebellar stroke, vertebral artery dissection.

Range Of Toxicity

    A) TOXICITY: Acute exposures greater than 20 mg/kg PE or serum concentration greater than 20 mcg/mL may cause toxicity. Massive overdoses of fosphenytoin (on the order of 10 times the therapeutic dose), associated with serious adverse events, including death, have resulted from misinterpretation of vial labeling of fosphenytoin. An adult developed coma after receiving 10 times the prescribed fosphenytoin (prescribed dose: 375 mg) for postoperative prophylaxis of seizures. She recovered following supportive care. Lateral gaze nystagmus generally appears at phenytoin concentrations greater than 20 mcg/mL (80 mcmol/L), ataxia at concentrations 30 mcg/mL (120 mcmol/L), and dysarthria and lethargy at concentrations greater than 40 mcg/mL (160 mcmol/L).
    B) THERAPEUTIC DOSE: ADULTS: The recommended loading dose of fosphenytoin is 15 to 20 mg of phenytoin equivalents (PE) per kg given IV at a rate of 100 to 150 mg PE/minute. MAXIMUM IV rate: 150 mg PE/min. CHILDREN: The safety and effectiveness of fosphenytoin in children have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Fosphenytoin is an anticonvulsant prodrug of phenytoin, used for seizure prophylaxis and treatment.
    B) PHARMACOLOGY: Fosphenytoin is an anticonvulsant that is metabolized to phenytoin and regulates voltage-dependent sodium and calcium channels and enhances sodium-potassium ATPase activity. The modulation of voltage-dependent sodium channels is the primary means of anticonvulsant activity.
    C) TOXICOLOGY: Toxicity is an extension of therapeutic effects. Patients may develop CNS depression, ataxia, nausea, vomiting and eventually coma and respiratory depression. Cardiac effects are much less common with IV infusion than with phenytoin because propylene glycol is not used as a diluent for fosphenytoin.
    D) EPIDEMIOLOGY: Poisoning is uncommon and rarely severe.
    E) WITH THERAPEUTIC USE
    1) The most common side effects of fosphenytoin administration are pruritus, hypotension, dysrhythmias, nystagmus, dizziness, somnolence, lightheadedness, ataxia, paresthesias, headache, tremor, agitation, hypesthesia, dysarthria, vertigo, hyperreflexia, intracranial hypertension, and altered mental status. OTHER EFFECTS: Nausea, vomiting, injection site pain and inflammation, hyperglycemia, hypocalcemia, pelvic pain, asthenia, and back pain.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, lethargy, nystagmus, ataxia, dysarthria, hyperreflexia, and mild sedation.
    2) SEVERE TOXICITY: Hypotension, dysrhythmias, asystole, CNS depression, mental status changes, hallucinations, hypocalcemia, coma, metabolic acidosis, and cardiac arrest may occur.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever and chills have been reported with fosphenytoin therapy (Prod Info CEREBYX(R) injection, 2002).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) COLOR VISION DEFICIENCY: Blue-yellow color vision deficiencies have been reported in patients with signs of phenytoin-induced neurotoxicity, with no correlation to phenytoin serum concentrations (Bayer et al, 1997).
    2) NYSTAGMUS: Nystagmus, related to derived phenytoin, has been commonly reported after intramuscular and intravenous fosphenytoin (Prod Info CEREBYX(R) injection, 2002; Leppik et al, 1990a; Gerber et al, 1988). Also amblyopia has been reported (Prod Info CEREBYX(R) injection, 2002).
    B) WITH POISONING/EXPOSURE
    1) OPHTHALMOPLEGIA: Nearly complete external ophthalmoplegia was reported with a rapid onset following overdose and a duration of one day (Grant & Schuman, 1993).
    2) OSCILLOPSIA: A very fine vertical or horizontal periodic dancing of the eyes has been noted (Grant & Schuman, 1993).
    3) NYSTAGMUS: Nystagmus is commonly seen with toxic concentrations of phenytoin (Kozer et al, 2002; Turkdogan et al, 2002; Brandolese et al, 2001; Lau et al, 2000; Grant & Schuman, 1993). Absent nystagmus is a significant negative finding.
    4) DIPLOPIA: Diplopia may occur (Grillone & Myssiorek, 1992).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) TINNITUS: Tinnitus has been reported with fosphenytoin use (Prod Info CEREBYX(R) injection, 2002).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) An estimated rate of 1 adverse cardiac event per 200,000 administrations (Adams et al, 2006). In a multicenter trial, there was a 1% rate of cardiovascular adverse events including hypotension and tachycardia (Coplin et al, 2002).
    b) CASE SERIES: Bradycardia was reported in a review of 9 of 29 cases from the Food and Drug Administration's Adverse Event Reporting System databank. This databank was searched for possible fosphenytoin toxicity reports submitted during 1997-2002 (Adams et al, 2006).
    2) WITH POISONING/EXPOSURE
    a) Bradycardia has been reported in case reports of fosphenytoin overdose (Prod Info CEREBYX(R) intravenous injection, 2013).
    b) CASE REPORT: An 18-month-old boy weighing 11 kg was inadvertently administered 2000 mg of IV fosphenytoin and developed bradycardia then asystole. Despite 3 hours of aggressive resuscitation, including prolonged CPR, epinephrine, atropine, magnesium, albumin and exchange transfusion, spontaneous circulation was not restored (Watson et al, 2004).
    B) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia has been reported in case reports of fosphenytoin overdose (Prod Info CEREBYX(R) intravenous injection, 2013).
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been reported following high doses and rapid rates of infusion of intravenous fosphenytoin, which does NOT contain the diluent propylene glycol (Prod Info CEREBYX(R) injection, 2002).
    b) An estimated rate of 1 adverse cardiac event per 200,000 administrations (Adams et al, 2006). In a multicenter trial, there was a 1% rate of cardiovascular adverse events including hypotension and tachycardia (Coplin et al, 2002).
    c) CASE SERIES: Hypotension was reported in 10 of 29 cases from the Food and Drug Administration's Adverse Event Reporting System databank. This databank was searched for possible fosphenytoin toxicity reports submitted during 1997-2002 (Adams et al, 2006).
    1) CASE REPORT: Hypotension, respiratory failure and sinus arrest with a ventricular escape rate of 35 beats/min developed in an 83-year-old woman after receiving approximately 800 phenytoin equivalents (PE) of fosphenytoin at a rate of 150 PE/min. The patient required intubation and a transvenous pacemaker. After 18 hours, sinus rhythm returned and she fully recovered (Adams et al, 2006).
    2) CASE REPORT: An 87-year-old man who presented in hypertensive crisis experienced a precipitous fall in pulse and blood pressure while receiving fosphenytoin intravenously at a rate of 150 PE/min. The patient required intubation. The ECG showed an absence of P waves with a junctional escape rate of 50 beats/min. Notched T waves were also noted. The fosphenytoin was discontinued and the patient fully recovered (Adams et al, 2006).
    2) WITH POISONING/EXPOSURE
    a) Hypotension has been reported in case reports of fosphenytoin overdose (Prod Info CEREBYX(R) intravenous injection, 2013).
    b) CASE REPORT: Hypotension (systolic blood pressure, 30 torr) was reported in a 13-day-old infant after an inadvertent intravenous fosphenytoin overdose of 300 mg (110 mg/kg) (phenytoin equivalent) as a 15 minute infusion. Bradycardia was followed by asystole. The infant recovered following resuscitation and vasopressors (Lieber & Snodgrass, 1998).
    c) CASE REPORT: A 2-year-old boy with a history of seizure disorder was admitted to the intensive care unit in status epilepticus and metabolic acidosis. He received lorazepam and fosphenytoin IV. The patent inadvertently received three 10 mL vials of fosphenytoin (1500 mg PE) instead of 3 mL of fosphenytoin (150 mg PE). Shortly after administration, ventricular tachycardia developed followed by ventricular fibrillation and cardiac arrest. Resuscitation was successful. Vasopressors were necessary to maintain a systolic blood pressure of 70 to 80 mm Hg; however, despite multiple vasopressors profound hypotension persisted and the patient expired 18 hours after exposure. Phenytoin concentration was greater than 72 mcg/mL, declining to 40 mcg/mL prior to his death (Litovitz et al, 1999).
    D) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Slowed atrial and ventricular conduction and ventricular fibrillation have been reported following high-dose infusions of phenytoin. These effects are more typically reported in elderly or gravely ill patients (Prod Info CEREBYX(R) injection, 2002).
    2) WITH POISONING/EXPOSURE
    a) Bradyasystolic arrest has been reported in a 13-day-old infant following an intravenous overdose of fosphenytoin 300 mg (110 mg/kg) (Lieber & Snodgrass, 1998), and in an 8-month-old child following intravenous fosphenytoin infusion 750 mg (71 mg/kg) over 15 minutes (Rose et al, 1998).
    E) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Hypotension, respiratory failure, and sinus arrest with the ventricular escape rate of 35 beats/min developed in an 83-year-old woman after receiving approximately 800 phenytoin equivalents (PE) of fosphenytoin at a rate of 150 PE/min. The patient required intubation and a transvenous pacemaker. After 18 hours, sinus rhythm returned and she fully recovered (Adams et al, 2006).
    b) CASE REPORT: An 87-year-old man in hypertensive crisis experienced a precipitous fall in pulse and blood pressure while receiving fosphenytoin intravenously at a rate of 150 PE/min. The patient required intubation. The ECG showed an absence of p waves with a junctional escape rate of 50 beats/min. Notched t waves were also noted. The fosphenytoin was discontinued and the patient fully recovered (Adams et al, 2006).
    c) CASE REPORT: Prolongation of the ST segment and the QT interval (merging of T and P waves) were noted in a 23-year-old man who received fosphenytoin, 1500 mg phenytoin equivalents IV over 85 minutes. The patient was normocalcemic prior to receiving the fosphenytoin. After the dose, the patient experienced new onset reductions in both total and ionized serum calcium concentrations. The ECG changes noted in this case were consistent with hypocalcemia. During the time of the ECG changes, the patient's plasma phenytoin concentrations were within therapeutic range and the blood pressure was stable (Keegan et al, 2002).
    F) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Cardiac arrest resulting in death was reported in 10 of 29 cases in a review of the Food and Drug Administration's Adverse Event Reporting System databank. This databank was searched for possible fosphenytoin toxicity reports submitted during 1997-2002 (Adams et al, 2006).
    2) WITH POISONING/EXPOSURE
    a) Asystole and cardiac arrest have been reported in case reports of fosphenytoin overdose (Prod Info CEREBYX(R) intravenous injection, 2013).
    b) CASE REPORT: A 6-year-old boy was admitted after a fall resulted in a fractured right temporal bone and a small subdural hematoma. Seizures developed and a loading dose of fosphenytoin 15 mg PE/kg IV was ordered. At 20 kg, the child's dose was calculated as 300 mg PE. Once administered, the child experienced a cardiac arrest and resuscitation was unsuccessful. It was then discovered that 3000 mg PE of fosphenytoin had been given in error (Institute for Safe Medication Practices, 1999).
    c) CASE REPORT: Hypotension and bradycardia, followed by asystole, was reported in a 13-day-old infant following an overdose of intravenous fosphenytoin 300 mg (110 mg/kg) as a 15 minute infusion. Sinus rhythm returned after 25 minutes of cardiopulmonary resuscitation (Lieber & Snodgrass, 1998).
    d) CASE REPORT: A 2-year-old boy with a history of seizure disorder was admitted to the intensive care unit in status epilepticus and metabolic acidosis. He received lorazepam and fosphenytoin IV. The patent inadvertently received three 10 mL vials of fosphenytoin (1500 mg PE) instead of 3 mL of fosphenytoin (150 mg PE). Shortly after administration, ventricular tachycardia developed followed by ventricular fibrillation and cardiac arrest. Resuscitation was successful. Vasopressors were necessary to maintain a systolic blood pressure of 70 to 80 mm Hg; however, despite multiple vasopressors profound hypotension persisted and the patient expired 18 hours after exposure. Phenytoin concentration was greater than 72 mcg/mL, declining to 40 mcg/mL prior to his death (Litovitz et al, 1999).
    e) CASE REPORT: An 18-month-old boy weighing 11 kg was inadvertently administered 2000 mg of IV fosphenytoin, and developed bradycardia then asystole. Despite 3 hours of aggressive resuscitation, including prolonged CPR, epinephrine, atropine, magnesium, albumin and exchange transfusion, spontaneous circulation was not restored (Watson et al, 2004).
    G) CARDIOMYOPATHY
    1) WITH POISONING/EXPOSURE
    a) PEDIATRIC CASE REPORT: A 9-month-old developmentally delayed infant developed severe cardiomyopathy after an inadvertent infusion of fosphenytoin 125 mg/kg rather than 15 to 20 mg/kg to treat new onset seizures in the setting of an upper respiratory infection. The infant required intubation for acute respiratory failure shortly after the exposure and was transferred to a second facility with normal vital signs. However, within a few hours she developed severe cardiogenic shock. Examination showed tachycardia (139 beats/minute), hypotension (75/40 mm Hg), hypoxemia and increased O2 demand (1 FiO2), weak peripheral pulses, and increased capillary refill time. She was treated with multiple vasoactive agents and hydrocortisone. She received further treatment with activated charcoal, folate, phenobarbital, and albumin. Her initial serum phenytoin level was 72 mcg/mL (109 mcg/mL when corrected for low albumin) (normal: 10 to 20 mcg/mL). As the phenytoin level declined, she gradually improved and serum phenytoin was undetectable 7 days after the exposure. An evaluation for metabolic, infectious or genetic causes of dilated cardiomyopathy was unremarkable. At a 7-month follow up, her cardiac assessment was normal (Grageda et al, 2013).
    H) EDEMA
    1) WITH THERAPEUTIC USE
    a) Facial edema has been reported with fosphenytoin use (Prod Info CEREBYX(R) injection, 2002).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) The most common side effects of fosphenytoin administration are nystagmus, dizziness, and somnolence occurring in 44%, 31%, and 20% of patients, respectively. Other central nervous system adverse effects include light-headedness, ataxia, and unsteadiness . As with phenytoin, these effects have been more frequent with higher doses of fosphenytoin (Prod Info CEREBYX(R) injection, 2002).
    b) Paresthesias, characterized by a tingling sensation localized to the groin, lower back, abdomen, and head and neck regions, have been reported with fosphenytoin administration (Prod Info CEREBYX(R) injection, 2002).
    c) Other central nervous system effects reported by the manufacturer include headache, stupor, incoordination, extrapyramidal syndrome, tremor, agitation, hypesthesia, dysarthria, vertigo and cerebral edema . Also reported frequently, an increase in reflexes, speech disorder, dysarthria, intracranial hypertension and altered mental status (Prod Info CEREBYX(R) injection, 2002).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 39-year-old woman with meningioma who developed partial seizures after a neurosurgery, received 5 units of fosphenytoin 750 mg in 1 hour infusion instead of 5 units of fosphenytoin 250 mg in 1 hour infusion and presented with nystagmus, a vestibular syndrome with an altered consciousness, and dyspnea. A phenytoin plasma concentration of 49.75 mcg/mL (therapeutic range: 10 to 20 mcg/mL) was obtained 2 days after fosphenytoin administration. Following supportive care, her condition improved 3 days later without further sequelae (Gaies et al, 2011).
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness has been reported after fosphenytoin administration occurring in 31% of patients (Prod Info CEREBYX(R) injection, 2002; Leppik et al, 1990a; Leppik et al, 1989; Gerber et al, 1988). As with phenytoin, dizziness has been more frequent with higher doses of fosphenytoin. One large multicenter trial reported a 3.5% CNS adverse event rate including dizziness and recurrent seizures (Coplin et al, 2002).
    C) NYSTAGMUS
    1) WITH THERAPEUTIC USE
    a) Nystagmus has been reported after fosphenytoin administration occurring in 44% of patients. Nystagmus has been more frequent with higher doses of fosphenytoin (Prod Info CEREBYX(R) injection, 2002; Leppik et al, 1990a; Leppik et al, 1989; Gerber et al, 1988).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 39-year-old woman with meningioma who developed partial seizures after a neurosurgery, received 5 units of fosphenytoin 750 mg in 1 hour infusion instead of 5 units of fosphenytoin 250 mg in 1 hour infusion, and presented with nystagmus, a vestibular syndrome with an altered consciousness, and dyspnea. A phenytoin plasma concentration of 49.75 mcg/mL (therapeutic range: 10 to 20 mcg/mL) was obtained 2 days after fosphenytoin administration. Following supportive care, her condition improved 3 days later without further sequelae (Gaies et al, 2011).
    D) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Paresthesias, characterized by a tingling sensation localized to the groin, lower back, abdomen, and head and neck regions, have been reported with fosphenytoin administration (Leppik et al, 1989; Leppik et al, 1990a). This event was reported in 21% of epileptic patients after intravenous fosphenytoin (150 to 450 mg at a rate of 75 mg/minute) in one study; abatement of symptoms was generally seen within one hour after the infusion (Leppik et al, 1990a). Paresthesias may occur more frequently with more rapid infusion rates (eg, 150 mg/minute) (Leppik et al, 1989). It was reported in 4% of patients receiving intramuscular fosphenytoin (Prod Info CEREBYX(R) injection, 2002).
    E) LETHARGY
    1) WITH POISONING/EXPOSURE
    a) Lethargy has been reported in case reports of fosphenytoin overdose (Prod Info CEREBYX(R) intravenous injection, 2013).
    F) COMA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 74-year-old woman (weight, 58 kg) with chronic subdural hematoma developed coma (Glasgow score of 7) after receiving 10 times the prescribed fosphenytoin (prescribed dose: 375 mg) for postoperative prophylaxis of seizures. The phenytoin blood concentration was 79 mcg/mL (normal 10 to 20 mcg/mL). Following supportive care, including 5 days of mechanical ventilation, she gradually improved. No cardiovascular effects were observed. Her phenytoin serum concentration returned to therapeutic range on day 8. She was discharged after 20 days of hospitalization (Presutti et al, 2000).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been reported infrequently with intravenous administration of fosphenytoin administration (Prod Info CEREBYX(R) injection, 2002; Coplin et al, 2002; Leppik et al, 1989).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting have been reported in case reports of fosphenytoin overdose (Prod Info CEREBYX(R) intravenous injection, 2013).
    B) GASTROINTESTINAL TRACT FINDING
    1) WITH THERAPEUTIC USE
    a) Dry mouth, constipation, and taste perversion have been reported with fosphenytoin (Prod Info CEREBYX(R) injection, 2002).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Metabolic acidosis has been reported in case reports of fosphenytoin overdose (Prod Info CEREBYX(R) intravenous injection, 2013).
    b) The manufacturer has suggested that formate an active metabolite of fosphenytoin may contribute to the overall toxicity observed in overdose. Its theorized that severe anion-gap metabolic acidosis may be associated with formate toxicity secondary to fosphenytoin exposure (Prod Info CEREBYX(R) intravenous injection, 2013).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus is a common complication of intravenous fosphenytoin administration, occurring in 49% of patients in clinical trials (Prod Info CEREBYX(R) injection, 2002) and up to 80% in one study (Rudis et al, 2004). With intramuscular administration, pruritus has been reported in approximately 3% of patients (Prod Info CEREBYX(R) injection, 2002).
    b) Pruritus (6%) followed by vein burning (0.5%) were the most common cutaneous effects in a multicenter trial (Coplin et al, 2002).
    B) PHLEBITIS
    1) WITH THERAPEUTIC USE
    a) Intravenous fosphenytoin has NOT been associated with significant venous irritation or phlebitis (Leppik et al, 1990a; Jamerson et al, 1994; Jamerson et al, 1990b).
    b) In a double-blind, randomized, crossover study involving healthy subjects (n=12), the degree of venous irritation/phlebitis was compared following equimolar doses of intravenous phenytoin (250 mg/5 mL over 30 minutes) and intravenous fosphenytoin (375 mg/5 mL over 30 minutes). Infusion site pain was seen with phenytoin infusions in all subjects, whereas phlebitis occurred in 66% and cording in 41%. Tenderness and erythema at the infusion site were common at the end of phenytoin infusions and 24 hours after an infusion. With fosphenytoin, phlebitis developed in only one subject (8%) and no subject exhibited cording or erythema. Pain at the infusion site was observed in 2 of 12 subjects (16%) (Jamerson et al, 1994).
    C) INJECTION SITE PAIN
    1) WITH THERAPEUTIC USE
    a) Infrequent reports of injection site pain and inflammation have been documented (less than 16% of patients) (Jamerson et al, 1994).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Pelvic pain, asthenia, back pain, and myasthenia have been reported with fosphenytoin therapy (Prod Info CEREBYX(R) injection, 2002).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Hyperglycemia has been reported which results from phenytoin's inhibitory effect on insulin release (Prod Info CEREBYX(R) injection, 2002).
    2) WITH POISONING/EXPOSURE
    a) Hyperglycemia may rarely be noted and is due to altered carbohydrate tolerance. No significant change in electrolytes, glucose, WBC, or alkaline phosphatase was found after acute phenytoin overdose (Wagner & Leikin, 1986).

Reproductive

    3.20.1) SUMMARY
    A) FDA Pregnancy Category D.
    B) Fosphenytoin is a prodrug of phenytoin. Teratogenic effects have been seen in infants exposed to phenytoin and other hydantoin anticonvulsants in utero.
    C) Prenatal exposure to phenytoin may increase the risk of congenital malformations, such as orofacial clefts, cardiac defects, dysmorphic facial features, as well as nail and digit hypoplasia. Prenatal exposure may also increase the risk for adverse developmental outcomes.
    D) Both male and female rats given fosphenytoin demonstrated NO effects on fertility.
    3.20.2) TERATOGENICITY
    A) FETAL/NEONATAL ADVERSE REACTIONS
    1) If phenytoin or carbamazepine (or any prodrugs) are used in pregnant women, there is a substantially increased risk of teratogenicity with many combinations of other anticonvulsants. The teratogenicity of these drugs is largely or wholly related to the levels of the reactive epoxide metabolites (Buehler et al, 1990; Van Dyke et al, 1991; Finnell et al, 1992). The epoxide/parent drug ratio is generally increased when phenytoin or carbamazepine is combined with each other, any other CYP inducers, or drugs which inhibit epoxide hydrolase, such as valproic acid, progabide, and lamotrigine (Bianchetti et al, 1987; Ramsay et al, 1990; Spina et al, 1996).
    2) A 2- to 3-fold increase in the incidence of major malformations, minor anomalies, growth abnormalities, and mental deficiency have been reported in children exposed to phenytoin alone or in combination with other antiepileptic agents during pregnancy. Malignancies, including neuroblastoma, have also been reported (Prod Info CEREBYX(R) intravenous injection, 2015).
    3) A possible risk of birth defects with the folic acid antagonist, phenytoin, has been reported when used during the first trimester of pregnancy (Hernandez-Diaz et al, 2000). Increased risk of neural-tube defects, cardiovascular defects, oral clefts, and urinary tract defects were reported. A distinctive pattern of physical abnormalities in infants following the use of phenytoin during pregnancy was found, as opposed to effects of epilepsy itself (Holmes et al, 2001).
    4) A multisystem pattern of abnormalities has been reported in infants of mothers who received hydantoin anticonvulsants (Schardein, 1985a). Developmental data suggest a prevalence of 10% to 30% infants affected with fetal hydantoin syndrome from mothers ingesting phenytoin 100 to 800 mg/kg during the first trimester or beyond (Adams et al, 1990; Lewis et al, 1998).
    B) ANIMAL STUDIES
    1) During animal studies, treatment with phenytoin resulted in teratogenicity and developmental toxicity at clinically relevant doses (Prod Info CEREBYX(R) intravenous injection, 2015; Schardein, 1985; Singh & Shah, 1989).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified fosphenytoin as FDA pregnancy category D (Prod Info CEREBYX(R) intravenous injection, 2015).
    B) MATERNAL ADVERSE REACTIONS
    1) An increase in seizure frequency may occur due to altered phenytoin pharmacokinetics during pregnancy. Therefore, monitoring of phenytoin plasma concentrations is recommended (Prod Info CEREBYX(R) intravenous injection, 2015).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) No data are available to determine if fosphenytoin is excreted in human milk (Prod Info CEREBYX(R) intravenous injection, 2015), but unchanged fosphenytoin in breast milk is unlikely due to its rapid conversion to phenytoin (Jamerson et al, 1990a; Boucher et al, 1989a; Hussey et al, 1990; Boucher et al, 1989a). Phenytoin is excreted in low concentrations in breast milk, but the effects on the nursing infant from exposure to the drug remain unknown (Prod Info CEREBYX(R) intravenous injection, 2015).
    2) Do not breastfeed while taking this drug (Prod Info CEREBYX(R) intravenous injection, 2015).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) In animal studies, altered estrous cycles, delayed mating, prolonged gestation length, and developmental toxicity were reported in female animals following treatment with fosphenytoin at doses of 50 mg phenytoin sodium equivalents/kg or higher. There were no effects on male fertility (Prod Info CEREBYX(R) intravenous injection, 2015).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS93390-81-9 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any carcinogenic potential of fosphenytoin in humans. Phenytoin is listed as possibly carcinogenic to humans (ie, Group 2B rating from the International Agency for Research on Cancer).
    3.21.3) HUMAN STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential of fosphenytoin in humans (Prod Info CEREBYX(R) intravenous injection, 2015).
    B) International Agency for Research on Cancer (IARC) Rating
    1) Phenytoin is listed as possibly carcinogenic to humans (ie, Group 2B rating from the International Agency for Research on Cancer) (2:100).
    3.21.4) ANIMAL STUDIES
    A) HEPATOCELLULAR TUMORS
    1) The incidence of hepatocellular tumors was increased in mice administered phenytoin at doses of 45 and 90 mg/kg/day. There were no drug related increases in tumors in rats administered phenytoin at doses up to 120 mg/kg/day (Prod Info CEREBYX(R) intravenous injection, 2015).

Genotoxicity

    A) Cultured V79 Chinese hamster lung cells demonstrated increased structural chromosome aberration frequency with exposure to fosphenytoin in the presence of metabolic activation (Prod Info CEREBYX(R) intravenous injection, 2015).
    B) Bacteria (Ames test) and Chinese hamster lung cells (in vitro) demonstrated no evidence of mutagenicity (Prod Info CEREBYX(R) intravenous injection, 2015).
    C) An in vivo mouse bone marrow micronucleus test demonstrated no evidence of clastogenic activity (Prod Info CEREBYX(R) intravenous injection, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, pulse oximetry, and mental status. Monitor serial phenytoin concentrations (fosphenytoin is metabolized to phenytoin).
    B) Toxic effects are rare at plasma phenytoin concentrations less than 20 mcg/mL (80 mcmol/L), but are common in patients with plasma concentrations greater than 30 mcg/mL (120 mcmol/L). They should be checked 2 hours after IV infusion and 4 hours after IM administration.
    C) Monitor serum electrolytes, kidney function, and liver enzymes in symptomatic patients.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.
    4.1.2) SERUM/BLOOD
    A) TOXICITY
    1) Phenytoin concentrations should not be obtained until conversion from fosphenytoin is complete, at least 4 hours after IM administration and 2 hours after IV administration (Prod Info CEREBYX(R) injection, 2002).
    2) Total serum phenytoin (free phenytoin concentration when possible) will allow assessment of severity of toxicity.
    3) Serum phenytoin concentrations tend to correlate with the acute neurological symptoms observed.
    4) Nystagmus is commonly seen with toxic serum concentrations of phenytoin (Kozer et al, 2002).
    5) Intoxication is rare with total phenytoin blood concentrations under 20 mcg/mL (2 mg%) (79.3 mcmol/L), or unbound phenytoin concentrations below 1.5 mcg/L (0.15 mg%, 6.0 mcmol/L).
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, including calcium, renal function tests and liver enzymes in patients with significant toxicity.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Serial neurologic examinations may be necessary during follow-up in patients with severe phenytoin-induced ataxia (Luef et al, 1996).
    b) ECG, blood pressure and respiratory function should be monitored during an infusion, after rapid IV infusion, following IV overdose and throughout the period where maximal serum phenytoin concentrations occur (Prod Info CEREBYX(R) injection, 2002).

Methods

    A) ANALYTICAL METHODS
    1) IMMUNOANALYTICAL TECHNIQUES - TDx(R)/TdxFLx(TM) (fluorescence polarization) and Emit (R) 2000 (enzyme multiplied), may significantly over estimate plasma phenytoin concentrations because of the cross reactivity with fosphenytoin (Prod Info CEREBYX(R) injection, 2002).
    2) EDTA - Tubes containing EDTA as an anticoagulant should be used prior to complete in vivo conversion of fosphenytoin to phenytoin to minimize the ex vivo conversion of fosphenytoin to phenytoin (Prod Info CEREBYX(R) injection, 2002).
    3) CHROMATOGRAPHIC ASSAY METHODS - Gas chromatography and high performance liquid chromatography methods accurately quantitate phenytoin concentrations in the presence of fosphenytoin (Prod Info CEREBYX(R) injection, 2002). It should be noted that phenytoin levels measured before the complete conversion of fosphenytoin to phenytoin will not accurately reflect the maximum phenytoin serum concentration (Prod Info CEREBYX(R) injection, 2002).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with ataxia, cardiac dysrhythmias, or hypotension should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) None. Fosphenytoin is administered parenterally in the hospital setting.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (dysrhythmias, hypotension, CNS depression), or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with inadvertent dosing errors should be observed for dysrhythmias and hypotension for 6 hours.

Monitoring

    A) Monitor vital signs, pulse oximetry, and mental status. Monitor serial phenytoin concentrations (fosphenytoin is metabolized to phenytoin).
    B) Toxic effects are rare at plasma phenytoin concentrations less than 20 mcg/mL (80 mcmol/L), but are common in patients with plasma concentrations greater than 30 mcg/mL (120 mcmol/L). They should be checked 2 hours after IV infusion and 4 hours after IM administration.
    C) Monitor serum electrolytes, kidney function, and liver enzymes in symptomatic patients.
    D) Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Fosphenytoin is administered parenterally; gastrointestinal decontamination is not useful.
    6.5.3) TREATMENT
    A) GENERAL TREATMENT
    1) See the PARENTERAL EXPOSURE treatment section for further information.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis may be considered following a significant exposure. Fosphenytoin is highly protein bound which substantially limits clearance with hemodialysis; however, at high concentrations, an increasing fraction of the drug is unbound and amenable to hemodialysis. Hemoperfusion may be more effective. The decision to perform hemodialysis or hemoperfusion should be weighed carefully against the risks of the procedure as there are no studies that demonstrate any clinical benefit and toxic effects are usually not severe.
    B) HEMODIALYSIS
    1) Hemodialysis may be of some benefit following a fosphenytoin overdose because phenytoin is not completely bound to plasma proteins (Prod Info CEREBYX(R) injection, 2002). Fosphenytoin is highly protein bound which substantially limits clearance with hemodialysis; however at high concentrations an increasing fraction of the drug is unbound and amenable to hemodialysis. The decision to perform hemodialysis should be weighed carefully against the risks of the procedure as there are no studies that demonstrate any clinical benefit and toxic effects are usually not severe.
    C) HEMOPERFUSION
    1) In one case, the successful use of charcoal hemoperfusion has been reported in the treatment of a phenytoin overdose. Plasma concentrations of total and free phenytoin fell rapidly, from 40.0 mcg/mL and 3.6 mcg/mL to 16.2 mcg/mL and 1.5 mcg/mL, respectively, following 3 hours of hemoperfusion. The fraction of protein-bound phenytoin remained constant (approximately 90%). Bound phenytoin was reported to dissociate from plasma proteins in the presence of activated charcoal, becoming adsorbed to the charcoal. In this case, charcoal hemoperfusion was effective for the removal of a drug that binds to plasma proteins with a low binding constant (Kawasaki et al, 2000).
    D) PLASMAPHERESIS
    1) Plasmapheresis removes only a small amount of the burden of phenytoin, and in one case the plasma concentration had even increased after plasma exchange (White et al, 1987). Plasmapheresis is of limited value (Silberstein & Shaw, 1986; Larsen et al, 1986).
    E) HEMOFILTRATION
    1) Continuous venous-venous hemofiltration (CVVH) with charcoal filter has been used in an 8-month-old child who sustained bradyasystolic arrest after infusion of 750 milligrams fosphenytoin over 15 minutes. Serum phenytoin concentrations were 77.2 mcg/mL (total) 1 hour after infusion, 73.8 mcg/mL (total) and 13 mcg/mL (free) 8 hours later, and 82 mcg/mL (total) 16 hours later. Approximately 24 hours after the infusion CVVH was performed for 4 hours. About one hr after completion of CVVH, total and free serum phenytoin concentrations were 33.9 mcg/mL and 3.9 mcg/mL, respectively (Rose et al, 1998).

Range Of Toxicity

Summary

    A) TOXICITY: Acute exposures greater than 20 mg/kg PE or serum concentration greater than 20 mcg/mL may cause toxicity. Massive overdoses of fosphenytoin (on the order of 10 times the therapeutic dose), associated with serious adverse events, including death, have resulted from misinterpretation of vial labeling of fosphenytoin. An adult developed coma after receiving 10 times the prescribed fosphenytoin (prescribed dose: 375 mg) for postoperative prophylaxis of seizures. She recovered following supportive care. Lateral gaze nystagmus generally appears at phenytoin concentrations greater than 20 mcg/mL (80 mcmol/L), ataxia at concentrations 30 mcg/mL (120 mcmol/L), and dysarthria and lethargy at concentrations greater than 40 mcg/mL (160 mcmol/L).
    B) THERAPEUTIC DOSE: ADULTS: The recommended loading dose of fosphenytoin is 15 to 20 mg of phenytoin equivalents (PE) per kg given IV at a rate of 100 to 150 mg PE/minute. MAXIMUM IV rate: 150 mg PE/min. CHILDREN: The safety and effectiveness of fosphenytoin in children have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) EQUIVALENT DOSES
    1) DO NOT CONFUSE THE AMOUNT OF DRUG TO GIVEN IN PHENYTOIN EQUIVALENTS (PE) WITH THE CONCENTRATION OF THE DRUG IN THE VIAL: The dosage of fosphenytoin is expressed in terms of phenytoin equivalents (PE) to avoid the need for molecular weight-based adjustments when switching between the 2 agents. Fosphenytoin vials contain a concentration of 50 mg PE/mL. The 2-mL vial contains a total of 100 mg PE and the 10-mL vial contains a total of 500 mg PE. Medication errors have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to mean the total concentration of the vial was 50 mg PE. Overdoses from these errors has led to 2- to 10-fold overdoses with serious adverse effects, even fatalities (Prod Info CEREBYX(R) intravenous injection solution, 2016; Parker F, 2006).
    B) STATUS EPILEPTICUS
    1) The recommended loading dose of fosphenytoin is 15 to 20 mg of phenytoin equivalents (PE) per kg given at a rate of 100 to 150 mg PE/minute IV. MAXIMUM IV rate: 150 mg PE/min (Prod Info CEREBYX(R) intravenous injection solution, 2016).
    2) Concomitant administration of an intravenous benzodiazepine is recommended for the control of status epilepticus (Prod Info CEREBYX(R) intravenous injection solution, 2016).
    C) SEIZURE DISORDER: FOR SHORT-TERM ADMINISTRATION WHEN ORAL PHENYTOIN CANNOT BE GIVEN
    1) The recommended loading dose of fosphenytoin is 10 to 20 mg phenytoin sodium equivalents (PE)/kg given IV or IM at a maximum rate of no greater than 150 mg PE/min. The initial daily maintenance dose of fosphenytoin is 4 to 6 mg PE/kg/day given in divided doses. After the administration of a loading dose, start the maintenance dose at the next dosing interval (Prod Info CEREBYX(R) intravenous injection solution, 2016).
    7.2.2) PEDIATRIC
    A) The safety and effectiveness of fosphenytoin in pediatric patients have not been established (Prod Info CEREBYX(R) intravenous injection solution, 2016).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) Massive overdoses of fosphenytoin have resulted from misinterpretation of vial labeling. Practitioners have confused the Phenytoin Equivalent (PE) per mL and the total vial mL content. Fosphenytoin vials, both the 2 mL and the 10 mL vials, have a 50 mg PE/mL concentration. Therefore, the 2 mL vials contain a total of 100 mg PE and the 10 mL vials contain 500 mg PE (Parker F, 2006).
    2) Lateral gaze nystagmus generally appears at phenytoin concentrations greater than 20 mcg/mL (80 mcmol/L), ataxia at concentrations 30 mcg/mL (120 mcmol/L), and dysarthria and lethargy at concentrations greater than 40 mcg/mL (160 mcmol/L) (Prod Info CEREBYX(R) intravenous injection, 2013).
    B) PEDIATRIC
    1) CASE REPORT: A 15-month-old boy with Down's Syndrome suffered a seizure and was taken to the Emergency Department. An order was written for 200 mg of fosphenytoin and the dose was administered. Shortly after receiving the dose the patient expired. It was then determined that 2000 mg of fosphenytoin was inadvertently given. Post mortem serum phenytoin concentration was 110 mcg/mL (Litovitz et al, 2002).
    2) CASE REPORT: A 6-year-old boy was admitted after a fall resulting in a fractured right temporal bone and small subdural hematoma occurred. Seizures developed and a loading dose of fosphenytoin 15 mg PE/kg IV was ordered. At 20 kg, the child's dose was calculated as 300 mg PE. Once administered, the child experienced a cardiac arrest and resuscitation was unsuccessful. It was then discovered that 3000 mg PE of fosphenytoin had been given in error (Institute for Safe Medication Practices, 1999).
    3) CASE REPORT: A 2-year-old boy with a history of seizure disorder was admitted to the ICU in status epilepticus and metabolic acidosis. Lorazepam and fosphenytoin IV were given. A total of three 10 mL vials of fosphenytoin (1500 mg PE) was administered instead of 3 mL of fosphenytoin (150 mg PE). Shortly after fosphenytoin administration, the patient went into ventricular tachycardia followed by ventricular fibrillation and cardiac arrest. Resuscitation was successful and a vasopressor infusion was required to maintain a systolic blood pressure of 70 to 80 mm Hg. Despite multiple vasopressors, the child remained profoundly hypotensive and expired 18 hours later. The phenytoin concentration was greater than 72 mcg/mL, declining to 40 mcg/mL prior to death (Litovitz et al, 1999).
    4) CASE REPORT: An 18-month-old boy weighing 11 kg was inadvertently administered 2000 mg of IV fosphenytoin and developed bradycardia then asystole. Despite 3 hours of aggressive resuscitation, including prolonged CPR, epinephrine, atropine, magnesium, albumin and an exchange transfusion the patient died (Watson et al, 2004).

Maximum Tolerated Exposure

    A) ADULT
    1) CASE REPORT: A 74-year-old woman (weight, 58 kg) with chronic subdural hematoma developed coma after receiving 10 times the prescribed fosphenytoin (prescribed dose: 375 mg) for postoperative prophylaxis of seizures. The phenytoin blood concentration was 79 mcg/mL (normal 10 to 20 mcg/mL). Following supportive care, including 5 days of mechanical ventilation, she gradually improved. No cardiovascular effects were observed. Her phenytoin serum concentration returned to therapeutic range on day 8. She was discharged after 20 days of hospitalization (Presutti et al, 2000).
    B) PEDIATRIC
    1) CASE REPORT: A 9-month-old developmentally delayed infant developed severe cardiomyopathy after an inadvertent infusion of fosphenytoin 125 mg/kg rather than 15 to 20 mg/kg. She was treated with multiple vasoactive agents and hydrocortisone. She received further treatment with activated charcoal, folate, phenobarbital, and albumin. As her phenytoin level declined, she gradually improved. Serum phenytoin was undetectable 7 days after the exposure. At 7-month follow up, her cardiac assessment was normal (Grageda et al, 2013).
    2) CASE REPORT: Hypotension (systolic blood pressure, 30 torr) was reported in a 13-day-old infant after an inadvertent intravenous fosphenytoin overdose of 300 mg (110 mg/kg) (phenytoin equivalent) as a 15 minute infusion. Bradycardia followed by asystole occurred. The infant recovered following resuscitation and vasopressors (Lieber & Snodgrass, 1998).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) An upper limit for therapeutic phenytoin serum concentration is generally considered as 20 micrograms/milliliter (80 micromoles/liter). In some cases, though, supratherapeutic levels are required to control seizures. In a 9-year-old girl, levels as high as 41 micrograms/milliliter (163 micromoles/liter) were necessary to control her seizure disorder. No signs of toxicity, other than nystagmus, were evident at this serum concentration (Kozer et al, 2002).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORT: A 74-year-old woman (weight, 58 kg) with chronic subdural hematoma developed coma (Glasgow score of 7) after receiving 10 times the prescribed fosphenytoin (prescribed dose: 375 mg) for postoperative prophylaxis of seizures. The phenytoin blood concentration was 79 mcg/mL (normal 10 to 20 mcg/mL). Following supportive care, including 5 days of mechanical ventilation, she gradually improved. No cardiovascular effects were observed. Her phenytoin serum concentration returned to therapeutic range on day 8. She was discharged after 20 days of hospitalization (Presutti et al, 2000).
    2) CASE REPORT: A 15-month-old male with Down's Syndrome received 2000 mg of fosphenytoin. The patient's post mortem serum phenytoin concentration was 110 mcg/mL (Litovitz et al, 2002).
    3) CASE REPORT: A 2-year-old boy with a history of seizure disorder received three 10 mL vials of fosphenytoin (1500 mg PE). His phenytoin level was greater than 72 mcg/mL, declining to 40 mcg/mL prior to his death (Litovitz et al, 1999).

Workplace Standards

    A) ACGIH TLV Values for CAS93390-81-9 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS93390-81-9 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS93390-81-9 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS93390-81-9 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) PHENYTOIN

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Fosphenytoin is an anticonvulsant that is metabolized to phenytoin and regulates voltage-dependent sodium and calcium channels and enhances sodium-potassium ATPase activity. The modulation of voltage-dependent sodium channels is the primary means of anticonvulsant activity (Prod Info CEREBYX(R) intravenous injection, 2015; Jamerson et al, 1990; Boucher et al, 1989; Leppik et al, 1990).

Physicochemical

Physical Characteristics

    A) Clear, colorless to pale yellow, sterile solution (Prod Info CEREBYX(R) injection, 2002)

Ph

    A) 8.6 to 9.0 (Prod Info CEREBYX(R) injection, 2002)

Molecular Weight

    A) 406.24 (Prod Info CEREBYX(R) injection, 2002)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
    4) 62 FR 58840: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 1997.
    5) 65 FR 14186: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    6) 65 FR 39264: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    7) 65 FR 77866: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2000.
    8) 66 FR 21940: Notice of the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances - Proposed AEGL Values, Environmental Protection Agency, NAC/AEGL Committee. National Archives and Records Administration (NARA) and the Government Publishing Office (GPO), Washington, DC, 2001.
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