fosphenytoin

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

Contraind./Precautions ⬆ ⬇

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.

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).

Availability ⬆ ⬇

(Generic available)

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

Assessment ⬆ ⬇

Assess location, duration, frequency, and characteristics of seizure activity. EEG may be monitored periodically during therapy.
Monitor BP, ECG, and respiratory function continuously during administration of fosphenytoin and during period when peak serum phenytoin levels occur (10–20 min after administration).
Monitor patients for development of severe cutaneous adverse reactions such as exfoliative, purpuric, bullous rashes; lupus erythematosus; DRESS; SJS; and TEN. Advise patients of signs and symptoms of these reactions (prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, lymphadenopathy). If a severe cutaneous adverse reaction is suspected, interrupt therapy until etiology of reaction is determined. Drug may be resumed if rash determined not drug-related. If rash reappears, avoid further use of fosphenytoin. Stevens-Johnson syndrome and toxic epidermal necrolysis are significantly more common in patients with a particular HLA allele, HLA-B*1502 (occurs almost exclusively in patients with Asian ancestry, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais) and/or CYP2C9*3 carriers. Avoid using fosphenytoin as an alternative to carbamazepine for patients who test positive for these genetic variations.
Assess mental status (orientation, mood, behavior) before and periodically during therapy. Monitor closely for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.
Monitor injection site for edema, discoloration, and pain distal to the site of injection (described as "purple glove syndrome") frequently during therapy. May or may not be associated with extravasation. The syndrome may not develop for several days after injection of fosphenytoin.

Lab Test Considerations:

Fosphenytoin contains 0.0037 mmol phosphate per mg PE. Monitor serum phosphate concentrations in patients with renal insufficiency; may cause ↑ phosphate concentrations.
- May cause ↑ serum alkaline phosphatase, GGT, and glucose levels.
- Fosphenytoin therapy may be monitored using phenytoin levels. Optimal total plasma phenytoin concentrations are typically 10–20 mcg/mL (unbound plasma phenytoin concentrations of 1–2 mcg/mL).

Toxicity and Overdose:

Serum phenytoin levels should not be monitored until complete conversion from fosphenytoin to phenytoin has occurred (2 hr after IV or 4 hr after IM administration).
- Initial signs and symptoms of phenytoin toxicity include nystagmus, ataxia, confusion, nausea, slurred speech, and dizziness.

Implementation ⬆ ⬇

Do not confuse Cerebyx with Celebrex or Celexa.
Do not confuse concentration of fosphenytoin with total amount of drug in vial.
- When substituting fosphenytoin for oral phenytoin therapy, the same total daily dose may be given as a single dose. Unlike parenteral phenytoin, fosphenytoin may be given safely by the IM route.
- The anticonvulsant effect of fosphenytoin is not immediate. Additional measures (including parenteral benzodiazepines) are usually required in the immediate management of status epilepticus. Loading dose of fosphenytoin should be followed with the institution of maintenance anticonvulsant therapy.

IV Administration:

IV Push: Diluent: D5W or 0.9% NaCl. Concentration: 1.5–25 mg PE/mL. May be refrigerated for up to 48 hr.
Rate:
Administer at a rate of <150 mg PE/min in adults and <0.4 mg/kg/min in children 2–17 yr to minimize risk of hypotension and arrhythmias.
Y-Site Compatibility:
- acyclovir
- alemtuzumab
- allopurinol
- amifostine
- amikacin
- aminocaproic acid
- aminophylline
- amphotericin B lipid complex
- amphotericin B liposomal
- ampicillin
- ampicillin/sulbactam
- anidulafungin
- argatroban
- arsenic trioxide
- azithromycin
- aztreonam
- bivalirudin
- bleomycin
- bumetanide
- buprenorphine
- busulfan
- butorphanol
- carboplatin
- carmustine
- cefazolin
- cefepime
- cefotaxime
- cefotetan
- cefoxitin
- ceftazidime
- ceftolozane/tazobactam
- ceftriaxone
- cefuroxime
- ciprofloxacin
- cisatracurium
- cisplatin
- clindamycin
- cyclophosphamide
- cyclosporine
- cytarabine
- dacarbazine
- dactinomycin
- daptomycin
- dexamethasone
- dexmedetomidine
- dexrazoxane
- digoxin
- diltiazem
- diphenhydramine
- docetaxel
- doxorubicin liposomal
- doxycycline
- enalaprilat
- ephedrine
- epinephrine
- eptifibatide
- ertapenem
- erythromycin
- esmolol
- etoposide
- etoposide phosphate
- famotidine
- fentanyl
- fluconazole
- fludarabine
- fluorouracil
- foscarnet
- furosemide
- ganciclovir
- gemcitabine
- gemtuzumab ozogamicin
- gentamicin
- glycopyrrolate
- granisetron
- heparin
- hetastarch
- hydrocortisone
- hydromorphone
- ifosfamide
- imipenem/cilastatin
- insulin, regular
- isoproterenol
- ketotolac
- labetalol
- leucovorin
- levetiracetam
- levofloxacin
- lidocaine
- linezolid
- lorazepam
- magnesium sulfate
- mannitol
- melphalan
- meperidine
- meropenem
- meropenem/vaborbactam
- mesna
- methadone
- methotrexate
- methylprednisolone
- metoclopramide
- metoprolol
- metronidazole
- milrinone
- mitomycin
- morphine
- nafcillin
- nalbuphine
- naloxone
- nitroglycerin
- nitroprusside
- norepinephrine
- octreotide
- ondansetron
- oxaliplatin
- oxytocin
- paclitaxel
- palonosetron
- pamidronate
- pantoprazole
- pemetrexed
- pentobarbital
- phenobarbital
- phentolamine
- phenylephrine
- piperacillin/tazobactam
- plazomicin
- potassium acetate
- potassium chloride
- potassium phosphate
- procainamide
- propranolol
- remifentanil
- rocuronium
- sodium acetate
- sodium bicarbonate
- sodium phosphate
- succinylcholine
- sufentanil
- sulbactam/durlobactam
- tacrolimus
- tedizolid
- theophylline
- thiotepa
- tigecycline
- tirofiban
- tobramycin
- trimethoprim/sulfamethoxazole
- vancomycin
- vasopressin
- vecuronium
- vinblastine
- vincristine
- vinorelbine
- voriconazole
- zidovudine
- zoledronic acid
Y-Site Incompatibility:
- amiodarone
- amphotericin B deoxycholate
- calcium chloride
- calcium gluconate
- caspofungin
- chlorpromazine
- dantrolene
- daunorubicin hydrochloride
- diazepam
- dobutamine
- doxorubicin hydrochloride
- droperidol
- epirubicin
- haloperidol
- hydralazine
- hydroxyzine
- idarubicin
- irinotecan
- isavuconazonium
- midazolam
- mitoxantrone
- moxifloxacin
- mycophenolate
- nicardipine
- pentamidine
- phenytoin
- polymyxin B
- prochlorperazine
- topotecan
- verapamil

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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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇