fosphenytoin (Rx)

>10%

Adults and children

• Body as a whole: Fever, injection-site reaction, infection, chills, face edema, injection-site pain
• Cardiovascular: Hypertension
• Digestive: Constipation
• Metabolic and nutritional: Hypokalemia
• Musculoskeletal: Myasthenia; Infrequent: myopathy, leg cramps, arthralgia, myalgia
• Nervous: Reflexes increased, speech disorder, dysarthria, intracranial hypertension, thinking abnormal, nervousness
• Respiratory: Pneumonia
• Skin and appendages: Rash

IV, adults

• Pruritus (49%)
• Nystagmus (44%)
• Dizziness (31%)
• Somnolence (20%)
• Ataxia (11%)

IV, children and adolescents

• Vomiting (21%)
• Nystagmus (18%)

IM

• Nystagmus (15%)

1-10%

Adults and children

• Body as a whole: Sepsis, injection-site inflammation, injection-site edema, injection-site hemorrhage, flu syndrome, malaise, generalized edema, shock, photosensitivity reaction, cachexia, cryptococcosis
• Endocrine: Diabetes insipidus
• Hematologic and lymphatic: Thrombocytopenia, anemia, leukocytosis, cyanosis, hypochromic anemia, leukopenia, lymphadenopathy, petechia
• Metabolic and nutritional: Hyperglycemia, hypophosphatemia, alkalosis, acidosis, dehydration, hyperkalemia, ketosis
• Musculoskeletal: Myopathy, leg cramps, arthralgia, myalgia
• Nervous: Confusion, twitching, Babinski sign positive, circumoral paresthesia, hemiplegia, hypotonia, convulsion, extrapyramidal syndrome, insomnia, meningitis, depersonalization, CNS depression, depression, hypokinesia, hyperkinesia, paralysis, psychosis, aphasia, emotional lability, coma, hyperesthesia, myoclonus, personality disorder, acute brain syndrome, encephalitis, subdural hematoma, encephalopathy, hostility, akathisia, amnesia, neurosis
• Skin and appendages: Maculopapular rash, urticaria, sweating, skin discoloration, contact dermatitis, pustular rash, skin nodule
• Special senses: Visual field defect, eye pain, conjunctivitis, photophobia, hyperacusis, mydriasis, parosmia, ear pain, taste loss
• Urogenital: Urinary retention, oliguria, dysuria, vaginitis, albuminuria, genital edema, kidney failure, polyuria, urethral pain, urinary incontinence, vaginal moniliasis

IV, adults

• Nausea (9%)
• Tinnitus (9%)
• Hypotension (8%)
• Stupor (8%)
• Vasodilatation (6%)
• Pelvic pain (4%)
• Tongue disorder (4%)
• Dry mouth (4%)
• Incoordination (4%)
• Paresthesia (4%)
• Extrapyramidal syndrome (4%)
• Tremor (3%)
• Agitation (3%)
• Diplopia (3%)
• Taste perversion (3%)
• Amblyopia (2%)
• Deafness (2%)
• Hypesthesia (2%)
• Dysarthria (2%)
• Vertigo (2%)
• Brain edema (2%)
• Vomiting (2%)
• Asthenia (2%)
• Back pain (2%)
• Headache (2%)

IV, children and adolescents

• Ataxia (10%)
• Fever (8%)
• Nervousness (7%)
• Pruritus (6%)
• Somnolence (6%)
• Hypotension (5%)
• Rash (5%)

IM

• Tremor (10%)
• Headache (9%)
• Asthenia (9%)
• Ataxia (8%)
• Incoordination (8%)
• Somnolence (7%)
• Dizziness (5%)
• Nausea (5%)
• Paresthesia (4%)
• Reflexes decreased (3%)
• Pruritus (3%)
• Vomiting (3%)

Postmarketing Reports

Body as a whole: Anaphylaxis, angioedema

Laboratory test abnormality: Decrease serum concentrations of T4; may also produce lower than normal values for dexamethasone or metyrapone tests; increase serum levels of gamma glutamyl transpeptidase

Nervous system disorders: Dyskinesia

Contraindications

Hypersensitivity to or its inactive ingredients, or to phenytoin or other hydantoins

Sinus bradycardia, sinoatrial block, 2nd or 3rd degree AV block, Adams-Stokes syndrome

Prior history of acute hepatotoxicity attributable to fosphenytoin or phenytoin

Coadministration with delavirdine

Cautions

Do NOT give IM for status epilepticus initial dose

Renal, hepatic or other hypoalbuminemic disease: monitor unbound phenytoin concentration

Do not abruptly discontinue antiepileptic drugs because of the possibility of increased seizure frequency, including status epilepticus; in the event of an allergic or hypersensitivity reaction, rapid substitution of alternative therapy may be necessary

Associated with exacerbation of porphyria; exercise caution when fosphenytoin is used in patients with this disease

Hyperglycemia, resulting from phenytoin’s inhibitory effect on insulin release, reported; phenytoin may also raise serum glucose concentrations in diabetic patients

Do not discontinue antiepileptic drugs abruptly because of possibility of increased seizure frequency, including status epilepticus; reduce dose gradually when necessary; in the event of allergic or hypersensitivity reaction, rapid substitution of alternative therapy, not belonging to hydantoin chemical class is necessary

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, reported with phenytoin; discontinue and do not readminister if acute hepatotoxicity occurs

Hematopoietic complications (eg, thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia with or without bone marrow suppression), some fatal, have occasionally been reported; in cases of lymphadenopathy, follow-up observation for an extended period is indicated

Consider phosphate load (0.0037 mmol phosphate/mg PE fosphenytoin) when treating patients who require phosphate restriction, such as those with severe renal impairment

Safety/efficacy not evaluated for administration > 5 days

Consider alternatives to structurally similar drugs such as carboxamides (eg, carbamazepine), barbiturates, succinimides, and oxazolidinediones (eg, trimethadione) in patients who experienced phenytoin hypersensitivity

Angioedema reported with phenytoin and fosphenytoin; discontinue immediately if symptoms of angioedema (eg, facial, perioral, or upper airway swelling) occur

Severe burning, itching, and/or paresthesia were reported; IV fosphenytoin at doses of 20 mg PE/kg at 150 mg PE/min are expected to experience discomfort of some degree; occurrence and intensity of discomfort can be lessened by slowing or temporarily stopping the infusion

Local toxicity (Purple Glove Syndrome) that includes edema, discoloration, and pain distal to the site of injection has been reported following peripheral IV injection; may or may not be associated with extravasation; this syndrome may not develop for several days after injection

May cause fetal harm when administered to pregnant females

Hyperglycemia, resulting from inhibitory effect of phenytoin on insulin release, has been reported; phenytoin may also raise serum glucose concentrations in diabetic patients

Serum levels of phenytoin (the active metabolite of fosphenytoin) sustained above therapeutic range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely, irreversible cerebellar dysfunction and/or cerebellar atrophy; at first sign of acute toxicity, check serum levels immediately; reduce dose if serum levels are excessive; discontinue therapy if symptoms persist

Patients with decreased CYP2C9 function

• Small percentage of treated individuals have been shown to metabolize phenytoin slowly; slow metabolism may be caused by limited enzyme availability and lack of induction
• Patients who are intermediate or poor metabolizers of CYP2C9 substrates (eg, *1/*3, *2/*2, *3/*3) may exhibit increased phenytoin serum concentrations compared to patients who are normal metabolizers (eg, *1/*1); patients who are known to be intermediate or poor metabolizers may ultimately require lower doses to maintain similar steady-state concentrations compared to normal metabolizers
• In patients who are known to be carriers of the decreased function CYP2C9*2 or *3 alleles (intermediate and poor metabolizers), consider starting at the low end of the dosage range and monitor serum concentrations to maintain total phenytoin concentrations of 10 to 20 mcg/mL; if early signs of dose-related central nervous system (CNS) toxicity develop, serum concentrations should be checked immediately

Cardiovascular risk associated with rapid infusion

• Rapid IV administration increases the risk of adverse cardiovascular reactions, including severe hypotension and cardiac arrhythmias (eg, bradycardia, heart block, QT prolongation, ventricular tachycardia, ventricular fibrillation); use oral phenytoin whenever possible
• Carefully monitor cardiac and respiratory function and after IV administration; consider reducing rate or discontinuing dose

Severe cutaneous reactions

• Can cause severe cutaneous adverse reactions (SCARs), which may be fatal
• Reported reactions include toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
• Onset is usually within 28 days, but can occur later
• Discontinue at the first sign of a rash, unless the rash is clearly not drug-related
• If signs or symptoms suggest a severe cutaneous adverse reaction, do not resume drug; consider alternant therapy
• Studies in patients of Chinese ancestry have found a strong association between risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene in patients taking carbamazepine
• Limited evidence suggests that HLA-B*1502 or CYP2C9*3 may also be a risk factor for the development of SJS/TEN in patients taking other antiepileptic drugs

DRESS

• DRESS, also known as multiorgan hypersensitivity, reported in patients taking antiepileptic drugs, including phenytoin and fosphenytoin
• Some of these events have been fatal or life-threatening
• DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection); eosinophilia is often present
• Early manifestations of hypersensitivity (eg, fever or lymphadenopathy) may be present even though rash is not evident
• If such signs or symptoms are present, evaluate patient immediately; discontinue drug if unable to confirm other etiology for the rash

Dosing errors

• Do not confuse amount of drug to be given in PE with concentration of drug in vial
• Medication errors associated with fosphenytoin have resulted in wrong dose being administer

Drug interaction overview

• CYP2C9 and CYP2C19 substrate; potent inducer of hepatic drug-metabolizing enzymes
• Extensively bound to human plasma proteins
• Addition or withdrawal of these agents in patients on phenytoin therapy may require an dosage adjustment of the phenytoin to achieve optimal clinical outcome

• Drugs that may increase phenytoin concentration

  • Antiepileptic drugs (ie, ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate)
  • Azoles (ie, fluconazole, ketoconazole, itraconazole, miconazole, voriconazole)
  • Antineoplastic agents (eg, capecitabine, fluorouracil)
  • Antidepressants (ie, fluoxetine, fluvoxamine, sertraline)
  • Gastric acid reducing agents (eg, H2 antagonists, omeprazole)
  • Sulfonamides (eg, sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole/trimethoprim)
  • Acute alcohol intake, amiodarone, chloramphenicol, chlordiazepoxide, disulfiram, estrogen, fluvastatin, isoniazid, methylphenidate, phenothiazines, salicylates, ticlopidine, tolbutamide, trazodone, warfarin
  • Drugs highly bound to albumin could increase the unbound fraction of fosphenytoin

• Drug that may decrease phenytoin serum levels

  • Antineoplastic agents, usually in combination (eg, bleomycin, carboplatin, cisplatin, methotrexate
  • Antiviral agents (eg, fosamprenavir, nelfinavir, ritonavir)
  • Antiepileptic drugs (eg, carbamazepine, vigabatrin)
  • Chronic alcohol abuse, diazepam, diazoxide, folic acid, reserpine, rifampin, St. John wort, theophylline
  • Drugs that may either increase or decrease phenytoin serum levels H5
  • Antiepileptic drugs (eg, phenobarbital, valproate sodium, valproic acid)

• Drugs that decrease efficacy by phenytoin

  • Azoles (eg, fluconazole, ketoconazole, itraconazole, posaconazole, voriconazole)
  • Antineoplastic agents (eg, irinotecan, paclitaxel, teniposide)
  • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin
  • Coadministration with NNRTIs may cause loss of virologic response and possible resistance to NNRTIs (eg, delavirdine)
  • Cisatracurium, pancuronium, rocuronium and vecuronium: resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents has occurred in patients chronically administered phenytoin; closely monitor for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher
  • Others: Corticosteroids, doxycycline, estrogens, furosemide, oral contraceptives, paroxetine, quinidine, rifampin, sertraline, theophylline, and vitamin D

• Drugs whose level is decreased by phenytoin

  • Antiepileptic drugs (eg, carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine)
  • Antilipidemic agents (eg, atorvastatin, fluvastatin, simvastatin)
  • Antiviral agents (eg, efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir)
  • Fosamprenavir: Phenytoin is coadministered with fosamprenavir alone may decrease the concentration of amprenavir (active metabolite); when phenytoin is coadministered with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir
  • Calcium channel blockers (eg, nifedipine, nimodipine, nisoldipine, verapamil)
  • Others: Albendazole (decreases active metabolite), chlorpropamide, clozapine, cyclosporine, digoxin, disopyramide, folic acid, methadone, mexiletine, praziquantel, quetiapine

• Drug/laboratory test interactions

  • Exercise caution when using immunoanalytical methods to measure serum phenytoin concentrations following administration

Pregnancy

Exposure of phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes

Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects

In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy

There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy

Pregnancy exposure registry

• Monitors pregnancy outcomes in women exposed to antiepileptic drugs during pregnancy
• Advised to pregnant females to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling the toll free number 1-888-233-2334, and must be done by patients themselves
• Information on the registry can also be found at http://www.aedpregnancyregistry.org/

Animal data

• Administration to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses

Clinical considerations

• An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics
• Consider periodic measurement of serum phenytoin concentrations to provide the appropriate dosage adjustment; postpartum restoration of original dosage may be necessary
• A potentially life-threatening bleeding disorder related to decreased levels of vitamin K-dependent clotting factors may occur in newborns exposed to phenytoin in utero; may be prevented with vitamin K administration to mother before delivery and to neonate after birth

Lactation

It is not known whether fosphenytoin is secreted in human milk

Following administration of phenytoin, phenytoin is secreted in human milk

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Converted to phenytoin after injection; stabilizes neuronal membranes and decrease seizure activity by increasing efflux or decreasin influx of sodium ions across cell membranes in the motor cortex during generation of nerve impulses

Absorption

Bioavailability (IM): Completely bioavailable

Peak plasma concentration

• IV: When administered by IV infusion, maximum plasma fosphenytoin concentrations are achieved at the end of the infusion
• IM: Following IM administration, plasma concentration are lower but more sustained than IV due to time required for absorption of fosphenytoin from the injection site

Peak plasma time

• IM: ~30 minutes postdose

Distribution

Protein bound: ~95-99% to human plasma proteins, primarily albumin

Vd: 4.3-10.8 L

Metabolism

Fosphenytoin is rapidly converted via hydrolysis to phenytoin; phenytoin is metabolized in the liver and forms metabolites.

Elimination

Half-life: ~ 15 min (conversion of fosphenytoin to phenytoin)

Excretion: Not in urine

Pharmacogenomics

Patients with HLA-B*1502 with are more likely to have a severe dermatologic reaction (eg, TEN, Stevens-Johnson syndrome) when taking phenytoin

This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais

Maternal epoxide (EPHX1) genotypes 113*H and 139*R are associated with risk of fetal hydantoin syndrome among pregnant women taking phenytoin

Increased levels of the reactive epoxide metabolites by either inhibiting the detoxification of these metabolites by epoxide hydrolase or by increasing conversion to epoxide metabolites by inducing CYP3A4, 2C9, or 2C19

Genetic testing laboratories

• The following companies provide genetic testing for HLA variants
• Kashi Clinical Laboratories (www.kashilab.com)
• LabCorp (http://www.labcorp.com/)
• Specialty Laboratories (http://www.specialtylabs.com)
• Quest (http://www.questdialgnotics.com)

IV Incompatibilities

Y-site: fenoldopam, midazolam

IV Preparation

Dilute in D5W or NS to concentration of 1.5-25 mg PE/mL

IV Administration

Express all dosing in mg "phenytoin equivalents" (PE); 1 mg PE is equivalent to 1 mg phenytoin sodium

Do not confuse the concentration with the total amount of drug in the vial

IV infusion preferred route for emergent use and for pediatrics because of delayed absorption

Maximum IV infusion rate

• Adults (≥17 years): Not to exceed 150 mg PE/min
• Birth to <17 years: 2 mg PE/kg/min (or 100 mg PE/min, whichever is slower)

Monitor

• Continuous monitoring of ECG, BP, and respiratory function essential; observe patient throughout the period where maximal serum phenytoin concentrations occur, ~10-20 min after the end of infusions
• Phenytoin levels: Obtain 2 hr after IV or 4 hr after IM

Storage

Unused vials

• Cerebyx, generic: Refrigerate at 2-8ºC (36-46ºF); do not store at room temperature for more than 48 hr
• Sesquient: Store at room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86∫F)
• Vials that develop particulate matter should not be used
• After opening, discard any unused solution in vials

Diluted infusions

• Stable at 1, 8, and 20 mg PE/mL in normal saline or D5W at 25ºC (77ºF) for 30 days in glass container and at 4-20ºC (39-68ºF) for 30 days in PVC bag