Fosphenytoin Sodium

Indications

Fosphenytoin Sodium is used for: Fosphenytoin is indicated for short-term parenteral administration when other means of Phenytoin administration are unavailable, inappropriate or deemed less advantageous. Fosphenytoin can be used for the control of, generalized convulsive status epilepticus, prevention and treatment of seizures, occurring during neurosurgery or head injury. It can also be substituted, short-term, for oral Phenytoin.

Adult Dose

Parenteral Adult: As phenytoin Na equivalents (PSE): (The dose, concentration in dosing solutions, and infusion rate of IV Fosphenytoin is expressed as Phenytoin Sodium equivalents (PE); (Fosphenytoin Sodium 1.5 mg equivalent to Phenytoin Sodium 1 mg) to avoid the need to perform molecular weight-based adjustments when converting between Fosphenytoin and Phenytoin Sodium doses.) Status Epilepticus: By intravenous infusion (at a rate of 100-150 mg (PE)/minute), initially 15 mg (P/E)/kg then By intramuscular injection or By intravenous infusion (at a rate of 50-100 mg (PE)/minute), 4-5 mg (P/E)/kg daily in 1-2 divided doses, Prophylaxis or treatment of seizures associated with neurosurgery or head injury: By intramuscular injection or By intravenous infusion (at a rate of 50-100 mg (PE)/minute, initially 10-15 mg (PE)/kg then 4-5 mg (PE)/kg daily (in 1-2 divided doses), Temporary substitution for oral Phenytoin: By intramuscular injection or by intravenous infusion (at a rate of 50-100 mg (PE)/minute), same dose and dosing frequency as oral Phenytoin therapy. Dose adjusted according to response and through plasma-phenytoin concentration. Elderly: Lower loading dose and/or infusion rate, and lower or less frequent maintenance dose. Hepatic impairment: Dose reduction or slower infusion may be needed.

Child Dose

Parenteral As phenytoin Na equivalents (PSE): (The dose, concentration in dosing solutions, and infusion rate of IV Fosphenytoin is expressed as Phenytoin Sodium equivalents (PE); (Fosphenytoin Sodium 1.5 mg equivalent to Phenytoin Sodium 1 mg) to avoid the need to perform molecular weight-based adjustments when converting between Fosphenytoin and Phenytoin Sodium doses.) Status Epilepticus: Child >5 years: By intravenous infusion (at a rate of 2-3 mg (PE)/kg/minute), initially 15 mg (PE)/kg then By intravenous infusion (at a rate of 1-2 mg (PE)/kg/minute), 4-5 mg (PE)/kg daily in 1-4 divided doses, Prophylaxis or treatment of seizures associated with neurosurgery or head injury: Child >5 years: By intravenous infusion (at a rate of 1-2 mg (PE)/kg/minute), initially 10-15 mg (PE)/kg then 4-5 mg (PE)/kg daily in 1-4 divided doses, Temporary substitution for oral Phenytoin: Child >5 years: By intravenous infusion (at a rate of 1-2 mg (PE)/kg/minute), same dose and dosing frequency as oral Phenytoin therapy. Dose adjusted according to response and through plasma-phenytoin concentration. Renal impairment: Dose reduction or slower infusion may be needed. Hepatic impairment: Dose reduction or slower infusion may be needed.

Renal Dose

Renal impairment: Dose reduction or slower infusion may be needed.

Administration

Reconstitution: Prior to IV infusion, dilute Fosphenytoin in 5% Dextrose or 0.9% Saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/ml.

Contra Indications

Fosphenytoin is contraindicated in patients who have demonstrated hypersensitivity to Fosphenytoin or its ingredients, or to Phenytoin or other Hydantoins. Fosphenytoin is also contraindicated in patients with sinus bradycardia, sino-atrial block, second and third degree A-V block, and Adams-Stokes syndrome.

Precautions

Patient w/ phosphate restriction, hypoalbuminaemia, hypotension, severe myocardial insufficiency, DM. May exacerbate porphyria. Not effective for the treatment of absence seizures and seizures associated w/ hypoglycaemia or other metabolic causes. Avoid abrupt withdrawal. Renal and hepatic impairment. Elderly. Pregnancy and lactation. Patient Counselling May impair ability to drive or operate machinery. Monitoring Parameters Monitor BP, cardiac and resp function; vital signs, haematologic and hepatic function, plasma phenytoin concentrations.

Pregnancy-Lactation

Pregnancy In humans, prenatal exposure to phenytoin (the active metabolite of fosphenytoin) may increase risks for congenital malformations and other adverse development outcomes; an increased incidence of major malformations (such as orofacial clefts and cardiac defects) and abnormalities characteristic of fetal hydantoin syndrome (dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities [including microcephaly], and cognitive deficits) 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 Lactation It is not known whether fosphenytoin is secreted in human milk; following administration of phenytoin (the active metabolite of fosphenytoin), phenytoin is secreted in human milk; the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition

Interactions

No drugs are known to interfere with the conversion of Fosphenytoin to Phenytoin. Drugs that may increase plasma Phenytoin concentrations include: Acute alcohol intake, Amiodarone, Chloramphenicol, Chlordiazepoxide, Cimetidine, Diazepam, Dicumarol, Disulfiram, Estrogens, Ethosuximide, Fluoxetine, H2-Antagonists, Halothane, Isoniazid, Methylphenidate, Phenothiazines, Phenylbutazone, Salicylates, Succinimides, Sulfonamides, Tolbutamide, Trazodone. Drugs that may decrease plasma phenytoin concentrations include: Carbamazepine, chronic alcohol abuse, Reserpine. Drugs that may either increase or decrease plasma Phenytoin concentrations include: Phenobarbital, Valproic Acid, and Sodium Valproate. Similarly, the effects of Phenytoin on Phenobarbital, Valproic Acid and Sodium plasma Valproate concentrations are unpredictable. Potentially Fatal: May cause loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

Adverse Effects

Side effects of Fosphenytoin Sodium : >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

Mechanism of Action

Fosphenytoin is a diphosphate ester salt of phenytoin which acts as a water soluble prodrug of phenytoin. After admin, plasma esterases convert fosphenytoin to phosphate, formaldehyde, and phenytoin as the active moiety; phenytoin stabilises neuronal membranes and decreases seizure activity by increasing efflux or decreasing influx of Na ions across cell membranes in the motor cortex during generation of nerve impulses.