Usage
Fosphenytoin is an anticonvulsant, specifically a hydantoin derivative, prescribed for the short-term management of seizures. It is a prodrug of phenytoin and is utilized when oral phenytoin administration is not feasible. Its primary indications include:
- Status epilepticus: Treatment of generalized tonic-clonic status epilepticus.
- Seizures during neurosurgery: Prevention and treatment of seizures occurring during or after neurosurgical procedures.
- Short-term parenteral replacement: Temporary substitution for oral phenytoin when oral administration is impossible.
It exerts its anticonvulsant effect by modulating neuronal excitability, primarily by inhibiting voltage-gated sodium channels in the brain, thereby reducing the repetitive firing of neurons and spread of seizure activity.
Alternate Names
While “fosphenytoin sodium” is the generic name, it is sometimes referred to simply as fosphenytoin. It is marketed under brand names such as Cerebyx and Sesquient. Dosing is expressed in phenytoin equivalents (PE), where 1.5 mg of fosphenytoin sodium is equivalent to 1 mg of phenytoin sodium.
How It Works
Pharmacodynamics: Fosphenytoin is rapidly converted to phenytoin after administration. Phenytoin stabilizes neuronal membranes by inhibiting voltage-gated sodium channels, decreasing neuronal excitability and reducing seizure propagation. This action occurs preferentially in neurons firing at high frequency, limiting the spread of abnormal electrical discharges associated with seizures without significantly affecting normal neuronal function.
Pharmacokinetics: Fosphenytoin is administered intravenously (IV) or intramuscularly (IM). After administration, it undergoes rapid and complete conversion to phenytoin, primarily by phosphatases in the liver and red blood cells. Phenytoin itself exhibits saturable metabolism, primarily by hepatic CYP2C9 and to a lesser extent by CYP2C19. Elimination is mainly through hepatic metabolism with subsequent renal excretion of inactive metabolites.
The rate of fosphenytoin conversion to phenytoin is relatively rapid, allowing for prompt achievement of therapeutic phenytoin levels. Phenytoin has a narrow therapeutic index, and its pharmacokinetics can be influenced by various factors including hepatic and renal function, concomitant medications, and genetic polymorphisms.
Dosage
All doses are expressed as phenytoin sodium equivalents (PE).
Standard Dosage
Adults:
- Loading Dose: 10-20 mg PE/kg IV (not to exceed 150 mg PE/minute). In status epilepticus, 15-20 mg PE/kg IV is typical (not to exceed 150 mg PE/minute).
- Maintenance Dose: 4-6 mg PE/kg/day IV divided into two or three doses, with an infusion rate not exceeding 150 mg PE/min.
Children (≥5 years):
- Loading Dose: 10-15 mg PE/kg IV (infusion rate not exceeding 2 mg PE/kg/minute or 150 mg PE/minute, whichever is slower). In status epilepticus, 15-20 mg PE/kg IV (infusion rate not exceeding 3 mg PE/kg/min or 150 mg PE/min, whichever is slower).
- Maintenance Dose: 4-5 mg PE/kg/day IV divided into 1-4 doses. Infusion rate is 1-2 mg/kg/min (or 100 mg PE/min, whichever is slower).
Special Cases:
- Elderly Patients: Dose reduction and slower infusion rate are recommended due to age-related physiological changes. Close monitoring is advised.
- Patients with Renal Impairment: Dose adjustment and serum phenytoin level monitoring based on the unbound (free) fraction is needed.
- Patients with Hepatic Dysfunction: Similar to renal impairment, dose adjustment and monitoring of free phenytoin levels is crucial.
- Patients with Comorbid Conditions: Careful consideration and dose modification may be required based on specific comorbid conditions.
Clinical Use Cases
- Intubation/Surgical Procedures/Mechanical Ventilation/ICU Use/Emergency Situations: Dosages are generally consistent with standard adult or pediatric loading and maintenance doses. Close monitoring of cardiovascular and respiratory function is essential, especially during rapid IV administration. Status epilepticus requires prompt administration of a loading dose (15-20 mg PE/kg IV, not to exceed 150 mg PE/minute) often following a benzodiazepine. If IV access is unavailable, loading doses may be given IM in adults.
Dosage Adjustments
Dosage adjustments may be necessary for patients with renal or hepatic impairment, hypoalbuminemia, or genetic polymorphisms affecting drug metabolism (e.g., CYP2C9). Therapeutic drug monitoring of serum phenytoin levels is recommended to guide dosage adjustments and ensure therapeutic levels while minimizing the risk of toxicity.
Side Effects
Common Side Effects:
Dizziness, drowsiness, nystagmus, ataxia, headache, nausea, constipation, vomiting, itching, tremor, muscle weakness.
Rare but Serious Side Effects:
Hypotension, cardiac arrhythmias, severe skin reactions (e.g., DRESS syndrome), blood dyscrasias, hepatotoxicity, suicidal ideation.
Long-Term Effects:
Osteomalacia, gingival hyperplasia, peripheral neuropathy, cognitive impairment.
Adverse Drug Reactions (ADR):
DRESS syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, aplastic anemia, severe hypotension, arrhythmias.
Contraindications
- Hypersensitivity to fosphenytoin, phenytoin, or other hydantoins.
- Sinoatrial block, second- or third-degree atrioventricular block, Adams-Stokes syndrome.
- History of acute hepatotoxicity attributed to fosphenytoin or phenytoin.
- Concomitant use with delavirdine.
Drug Interactions
Fosphenytoin interacts with numerous medications, including:
- CYP450 inducers/inhibitors (e.g., phenobarbital, carbamazepine, fluconazole, ketoconazole)
- Anticoagulants (e.g., warfarin)
- Immunosuppressants (e.g., cyclosporine)
- Antibiotics (e.g., doxycycline)
- Antineoplastics (e.g., methotrexate)
Alcohol, grapefruit juice, and other substances can also interact with fosphenytoin. Consult a comprehensive drug interaction resource for a complete list.
Pregnancy and Breastfeeding
Fosphenytoin is classified as Pregnancy Category D. It can cause fetal harm and is associated with an increased risk of congenital malformations. The benefits of therapy must be weighed against potential risks. Phenytoin is excreted in breast milk, though generally in low concentrations. Monitor infants for adverse effects. Breastfeeding is generally not recommended while taking fosphenytoin.
Drug Profile Summary
- Mechanism of Action: Inhibits voltage-gated sodium channels, reducing neuronal excitability.
- Side Effects: Dizziness, drowsiness, nystagmus, ataxia, hypotension, cardiac arrhythmias, serious skin reactions.
- Contraindications: Hypersensitivity, heart blocks, prior hepatotoxicity, concomitant delavirdine.
- Drug Interactions: Numerous drug interactions, including CYP450 inducers/inhibitors, anticoagulants.
- Pregnancy & Breastfeeding: Pregnancy Category D; not recommended while breastfeeding.
- Dosage: See detailed dosage section above.
- Monitoring Parameters: Serum phenytoin levels, ECG, blood pressure, respiratory function, liver function tests, complete blood counts.
Popular Combinations
While fosphenytoin is usually used alone for acute seizure management, it can sometimes be combined with other anticonvulsants in specific situations. However, careful monitoring for drug interactions is necessary.
Precautions
- Administer IV infusions slowly (not to exceed 150 mg PE/min in adults or 2 mg PE/kg/min in children) to minimize the risk of cardiovascular adverse effects.
- Monitor ECG, blood pressure, and respiratory function during and after IV administration.
- Screen for HLA-B*15:02 allele in patients with Asian ancestry to assess risk of severe cutaneous adverse reactions.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Fosphenytoin?
A: See detailed dosage section above.
Q2: How is Fosphenytoin administered?
A: Fosphenytoin is administered intravenously (IV) or intramuscularly (IM), with IV being the preferred route.
Q3: What are the major drug interactions with Fosphenytoin?
A: Fosphenytoin interacts with numerous drugs, notably CYP450 inducers/inhibitors, anticoagulants, and some antibiotics. Consult a comprehensive drug interaction resource for a complete list.
Q4: Can Fosphenytoin be used during pregnancy?
A: Fosphenytoin is Pregnancy Category D and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Q5: Is Fosphenytoin safe for breastfeeding mothers?
A: Fosphenytoin is excreted in breast milk and breastfeeding is generally not recommended.
Q6: What are the common side effects of Fosphenytoin?
A: Common side effects include dizziness, drowsiness, nystagmus, ataxia, nausea, and itching.
A: Fosphenytoin is rapidly converted to phenytoin, which is then metabolized primarily by hepatic CYP2C9.
Q8: What are the signs of Fosphenytoin overdose?
A: Overdose symptoms include nystagmus, ataxia, dysarthria, nausea, vomiting, lethargy, cardiac arrhythmias, hypotension, and coma.
Q9: What monitoring is necessary for patients receiving Fosphenytoin?
A: Monitor serum phenytoin levels, ECG, blood pressure, respiratory function, liver function tests, and complete blood counts.
Q10: What is the difference between fosphenytoin and phenytoin?
A: Fosphenytoin is a prodrug of phenytoin. It is water-soluble, allowing for less painful and more rapid administration compared to phenytoin, which is formulated in propylene glycol.
