fosphenytoin

Contraindicated in:

Hypersensitivity;
Sinus bradycardia, sinoatrial block, 2nd- or 3rd-degree AV heart block or Adams-Stokes syndrome;
Prior acute hepatotoxicity due to fosphenytoin or phenytoin.

Use Cautiously in:

Renal impairment;
Hepatic impairment (↓ dose);
CYP2C9 intermediate or poor metabolizers (↑ risk of phenytoin toxicity);
OB: ↑risk of congenital anomalies; ↑ risk of hemorrhage in newborn if used at term;
Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant.

Exercise Extreme Caution in:

Patients positive for HLA-B*1502 allele or carriers of CYP2C9*3 variant (unless benefits clearly outweigh the risks) (↑ risk of serious skin reactions).

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypotension (with rapid IV administration), tachycardia

Derm: pruritus, ACUTE GENERALIZED EXANTHEMATOUS PUSTULOSIS, DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), purple glove syndrome, rash, STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS

EENT: amblyopia, deafness, diplopia, tinnitus

GI: dry mouth, nausea, taste perversion, tongue disorder, vomiting

Hemat: lymphadenopathy, megaloblastic anemia, pure red cell aplasia

MS: back pain

Neuro: ataxia, dizziness, drowsiness, nystagmus, agitation, brain edema, dysarthria, extrapyramidal syndrome, headache, hypoesthesia, incoordination, paresthesia, stupor, tremor, vertigo

Misc: ANGIOEDEMA, pelvic pain

Interactions ⬆ ⬇

Drug-drug:

Disulfiram, acute ingestion of alcohol, amiodarone, capecitabine, chloramphenicol, chlordiazepoxide, cimetidine, diazepam, estrogens, ethosuximide, felbamate, fluconazole, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, halothane, isoniazid, itraconazole, ketoconazole, methylphenidate, miconazole, omeprazole, oxcarbazepine, phenothiazines, salicylates, sertraline, sulfonamides, topiramate, trazodone, voriconazole, and warfarin may ↑ phenytoin levels.
Barbiturates, bleomycin, carbamazepine, carboplatin, cisplatin, diazoxide, doxorubicin, folic acid, fosamprenavir, methotrexate, nelfinavir, rifampin, ritonavir, theophylline, vigabatrin, and chronic ingestion of alcohol may ↓ phenytoin levels.
Phenytoin may ↓ levels and effectiveness of albendazole, amiodarone, atorvastatin, benzodiazepines, carbamazepine, chloramphenicol, clozapine, corticosteroids, cyclosporine, digoxin, disopyramide, doxycycline, efavirenz, estrogens, felbamate, fluconazole, fluvastatin, folic acid, furosemide, irinotecan, itraconazole, ketoconazole, lamotrigine, lopinavir/ritonavir, methadone, mexiletine, nelfinavir, nifedipine, nimodipine, nisoldipine, oral contraceptives, oxcarbazepine, paclitaxel, paroxetine, posaconazole, propafenone, quetiapine, quinidine, rifampin, ritonavir, sertraline, simvastatin, tacrolimus, theophylline, topiramate, tricyclic antidepressants, verapamil, vitamin D, voriconazole, warfarin, and zonisamide.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness.

Availability ⬆ ⬇

(Generic available)

Solution for injection: 50 mg PE/mL; 75 mg PE/mL

Route/Dosage ⬆ ⬇

Note: Doses of fosphenytoin should be expressed as phenytoin sodium equivalents [PE].

Status Epilepticus

IV (Adults and Children ): 15–20 mg PE/kg.

Nonemergent and Maintenance Dosing

IV IM (Adults and Children >16 yr): Loading dose: 10–20 mg PE/kg. Maintenance dose: 4–6 mg PE/kg/day (start 12 hr after loading dose; administer in 2–3 divided doses).
IV (Children Birth to 16 yr): Loading dose: 10–15 mg PE/kg. Maintenance dose: 2–4 mg PE/kg given 12 hr after loading dose; then 4–8 mg PE/kg/day (in 2 divided doses).

US Brand Names ⬆ ⬇

Action ⬆ ⬇

Limits seizure propagation by altering ion transport.
May also decrease synaptic transmission.
Fosphenytoin is rapidly converted to phenytoin, which is responsible for its pharmacologic effects.

Therapeutic effects:

Diminished seizure activity.

Classifications ⬆ ⬇

Therapeutic Classification: anticonvulsants

Pharmacokinetics ⬆ ⬇

Absorption: Rapidly converted to phenytoin after IV administration and completely absorbed after IM administration.

Distribution: Distributes into CSF and other body tissues and fluids. Preferentially distributes into fatty tissue.

Protein Binding: Fosphenytoin: 95–99%; phenytoin: 90–95%.

Metabolism/Excretion: Mostly metabolized by the liver via the CYP2C9 isoenzyme and to a lesser extent by the CYP2C19 isoenzyme; the CYP2C9 isoenzyme exhibits genetic polymorphism (intermediate or poor metabolizers may have significantly ↑ fosphenytoin concentrations and an ↑ risk of adverse reactions).; minimal amounts excreted in the urine.

Half-Life: Fosphenytoin: 15 min; phenytoin: 22 hr (range 7–42 hr).

Time/Action Profile ⬆ ⬇

(anticonvulsant effect)

ROUTE	ONSET	PEAK	DURATION
IM	unknown	30 min	up to 24 hr
IV	15–45 min	15–60 min	up to 24 hr

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of fosphenytoin to patient. Advise patient against sudden discontinuation of drug, as this may ↑ seizure frequency. Advise patient to read Medication Guide before starting and periodically during therapy in case of changes.
Emphasize the importance of routine exams to monitor progress. Patient should have routine physical exams, especially monitoring skin and lymph nodes, and EEG testing.
Instruct patient to notify health care provider if any rash (particularly with fever, flu-like symptoms, or swollen lymph nodes) develops during the 1–2 wk of therapy.
Advise patient and family to notify health care provider if thoughts about suicide or dying, attempts to commit suicide, new or worse depression, behavioral changes, new or worse anxiety, feeling very agitated or restless, panic attacks, trouble sleeping, new or worse irritability, acting aggressive, being angry or violent, acting on dangerous impulses, an extreme ↑ in activity and talking, or other unusual changes in behavior or mood occur.
Medical ID describing disease process and medication regimen should be worn at all times in case of emergencies.
May cause drowsiness or dizziness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known. Do not resume driving until physician gives clearance based on control of seizure disorder.
Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care provider before taking other medications, especially St. John's wort. Avoid drinking alcohol during treatment.
Rep: May cause fetal harm. Advise women of reproductive potential to use an additional nonhormonal method of contraception during therapy and until next menstrual period. Instruct patient to notify health care provider if pregnancy is planned or suspected or if breastfeeding. To prevent a potentially life-threatening bleeding disorder related to ↓ levels of vitamin K–dependent clotting factors in newborns exposed to phenytoin in utero, administer vitamin K to the mother before delivery and to the neonate after birth. Encourage patients who become pregnant to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling 1-888-233-2334 or on the web at www.aedpregnancyregistry.org. Enrollment must be done by patients themselves.

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Indications ⬇

Contraind./Precautions ⬆ ⬇