fosphenytoin (Rx)

Brand and Other Names:Cerebyx
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

injectable solution

  • 100mg PE/2mL (2mL)
  • 500mg PE/10mL (10mL)
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Generalized Convulsive Status Epilepticus

15-20 mg PE/kg IV, infuse at 100-150 mg PE/min 

Nonemergent Seizure

Load: 10-20 mg PE/kg IV/IM; infuse slowly over 30 min; not to exceed 150 mg PE/min) 

Initial maintenance: 4-6 mg PE/kg/day IV/IM in divided doses

After administration of a loading dose, maintenance doses should typically be started at the next identified dosing interval

Short-Term Substitution for PO Phenytoin

Can be substituted for PO phenytoin therapy at the same total daily dose; however, Dilantin capsules are 90% bioavailable PO while fosphenytoin is 100% bioavailable IM and IV

Plasma phenytoin concentrations my increase when fosphenytoin administered IM or IV

Safety and efficacy not established

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Interactions

Interaction Checker

and fosphenytoin

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            IV

            • Pruritis (40-50%)
            • Dizziness (31%)
            • Somnolence (20%)
            • Ataxia (11%)

            IM

            • Nystagmus (15%)

            1-10%

            IV

            • Tinnitus (6-10%)
            • Deafness (2-5%)

            IM

            • Somnolence (6-10%)
            • Bruising (7%)
            • Pruritis (2-5%)
            • Nausea (5%)
            • Vomiting (3%)
            • Weakness (4%)

            <1%

            Taste change (>1%)

            Frequency Not Defined

            Hypotension (esp with high rates of IV infusion)

            Hypertension

            Dysarthria

            Fever

            Increased reflex

            Intracranial HTN

            Hypesthesia

            Sensory disturbances (burning, itching, paresthesia), withdrawal-precipitated seizures

            Rash

            Constipation

            Hypokalemia

            Cytopenias (can be fatal)

            Hepatic injury

            Myasthenia

            Pneumonia

            IV

            • Hypotension, vasodilation, tachycardia
            • Agitation, asthenia, headache, EPS, paresthesia, stupor, tremor
            • Dry mouth, nausea, vomiting
            • Pelvic and back pain
            • Diplopia, nystagmus
            • Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms (DRESS) or anaphylaxis; coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities
            • Special Senses: Altered taste sensation including metallic taste
            • Urogenital: Peyronie’s disease

            IM

            • Asthenia, ataxia, decreased reflex, dizziness, headache, paresthesia, tremor
            • Nausea, vomiting
            • Eccymosis
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            Warnings

            Black Box Warnings

            Cardiovascular risk associated with rapid infusion rates

            • Risk of hypotension and arrhythmias with infusion rates that exceed 150 mg/minute of phenytoin sodium equivalents (PE)
            • Careful cardiac monitoring is needed during and after administering IV administration; these events have also been reported at or below 150 mg PE/minute
            • Recommended doses should not be changed when substituting fosphenytoin for phenytoin or vice versa; they are not equivalent on mg to mg basis
            • Reduce infusion rate or discontinuation may be needed

            Contraindications

            Known hypersensitivity to hydantoins

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

            Not indicated for absence seizures or seizures secondary to hypoglycemia or other metabolic disorder

            Coadministration with delavirdine; potential for loss of virologic response and possible resistance to delavirdine or to the pharmacologic class of NNRTIs

            Cautions

            Do NOT give IM for status epilepticus initial dose

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

            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

            Adverse cardiovascular reactions include severe hypotension and cardiac arrhythmias; because of risks of cardiac and local toxicity associated with IV fosphenytoin, oral phenytoin should be used whenever possible

            Patients administered 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

            Plasma concentrations of phenytoin sustained above optimal 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, determination of plasma phenytoin concentrations recommended fosphenytoin dose reduction indicated if phenytoin concentrations excessive; if symptoms persist, discontinue therapy

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

            Hematopoietic complications, some fatal, have occasionally been reported in association with administration of phenytoin; these have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression; 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

            Phenytoin has potential to lower serum folate levels

            Discontinue at first sign of rash, unless rash is clearly not drug-related; if signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy considered; serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), reported with phenytoin treatment

            If rash occurs, evaluate for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity

            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

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            Pregnancy & Lactation

            Pregnancy Category: D

            Lactation: Excretion in milk unknown; not recommended

            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.

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            Pharmacology

            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

            Pharmacokinetics

            Half-Life: 15 min (phenytoin)

            Peak Plasma Time: 15 min (IM); 3 hr (phenytoin)

            Therapeutic phenytoin level: 10-20 mcg/mL

            Bioavailability: ~100% IV/IM

            Protein Bound: 95-99%; 70-88% (phenytoin)

            Vd: 4.3-10.8 L

            Metabolism: Liver

            Metabolite: PhenytoinExcretion: urine (metabolites)

            Excretion: 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)
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            Administration

            IV Incompatibilities

            Y-site: fenoldopam, midazolam

            IV Preparation

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

            IV Administration

            Maximum IV infusion rate: 150 mg PE/min

            Monitor: Phenytoin level 2 hr after IV, 4 hr after IM

            All dosing in mg "phenytoin equivalents" (PE); 75 mg fosphenytoin equivalent to 50 mg phenytoin

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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