Sizatoin

Approved Medical Indications:

• Epilepsy (Seizure Disorders):
• Management of generalized tonic-clonic (grand mal) seizures
• Management of complex partial seizures
• Prevention and treatment of seizures occurring during or after neurosurgery
• Status Epilepticus:
• As second-line therapy after benzodiazepines for generalized convulsive status epilepticus
• Seizure Prophylaxis:
• Following traumatic brain injury or neurosurgical procedures (short-term)

Clinically Accepted Off-Label Uses:

• Digoxin-Induced Ventricular Arrhythmias:
• Treatment of life-threatening ventricular arrhythmias, especially when caused by digitalis toxicity
• Trigeminal Neuralgia (Refractory Cases):
• Used in patients not responsive to first-line therapies such as carbamazepine
• Peripheral Neuropathic Pain:
• Occasionally used in selected cases, although evidence is limited

Adults:

• Oral (Seizure Control):
• Initial: 100 mg orally three times daily
• Maintenance: 300–400 mg/day in divided doses
• Maximum dose: 600 mg/day (based on therapeutic response and serum levels)
• IV (Status Epilepticus):
• Loading dose: 15–20 mg/kg IV, infused at a maximum rate of 50 mg/min
• Maintenance: 100 mg IV every 6–8 hours or as a continuous infusion

Pediatric Patients:

• Oral:
• Initial dose: 5 mg/kg/day in 2–3 divided doses
• Maintenance: 4–8 mg/kg/day
• Maximum: Usually ≤300 mg/day
• IV:
• Loading dose: 15–20 mg/kg IV at 1–3 mg/kg/min (not to exceed 50 mg/min)

Elderly:

• Initiate at the lower end of dosing range
• Monitor closely due to reduced hepatic metabolism and altered protein binding

Hepatic/Renal Impairment:

• Use with caution in hepatic impairment (hepatically metabolized)
• Monitor free phenytoin levels rather than total in hypoalbuminemia, renal failure, or liver disease

Administration Notes:

• IV: Dilute in normal saline only; filter required; administer slowly to avoid cardiovascular toxicity
• Oral Suspension: Shake well; do not interchange with tablets or capsules without adjusting dose
• Avoid IM use: Due to risk of tissue necrosis and unpredictable absorption

Phenytoin Sodium works by selectively inhibiting voltage-gated sodium channels in the neuronal membrane. This stabilizes hyperexcited neural membranes and inhibits repetitive firing of action potentials, thereby reducing seizure activity and preventing the spread of abnormal electrical discharges in the brain. It prolongs the inactivated state of sodium channels, reducing neuronal excitability. This action also contributes to its antiarrhythmic properties by suppressing abnormal cardiac automaticity.

• Absorption:
• Oral bioavailability: ~70–100%
• Time to peak plasma concentration: 3–12 hours (oral); 1–3 hours (IV)
• Distribution:
• Volume of distribution: ~0.6–0.8 L/kg
• Highly protein bound (90–95%), mainly to albumin
• Metabolism:
• Hepatic metabolism via CYP2C9 and CYP2C19
• Exhibits non-linear (zero-order) kinetics at therapeutic levels
• Elimination:
• Primarily excreted as inactive metabolites in urine
• Half-life: ~7 to 42 hours (variable due to non-linear kinetics)
• Clearance is saturable and may vary significantly between individuals

• Pregnancy:
• FDA Category D
• Associated with fetal hydantoin syndrome: craniofacial abnormalities, growth retardation, cardiac defects, and neurodevelopmental delays
• Use only if potential benefit justifies potential risk
• Lactation:
• Excreted into breast milk in small amounts
• Considered generally safe during breastfeeding
• Infants should be monitored for sedation, poor feeding, and developmental milestones

• Primary Class: Antiepileptic (Anticonvulsant)
• Subclasses:
• Hydantoin derivative
• Class IB antiarrhythmic (off-label)

• Known hypersensitivity to phenytoin, hydantoin derivatives, or excipients
• Sinus bradycardia
• Sinoatrial block or second- or third-degree AV block
• Adams-Stokes syndrome
• Concurrent use with delavirdine (due to reduced antiviral effectiveness)
• Intramuscular use for status epilepticus

• Cardiac Risks (Black Box Warning):
• Rapid IV administration may cause severe hypotension and cardiac arrhythmias
• Do not exceed 50 mg/min (adults)
• Dermatologic Reactions:
• Risk of serious skin reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), especially in Asian patients with HLA-B*1502 allele
• Hepatic Dysfunction:
• Risk of hepatotoxicity; monitor liver enzymes regularly
• Hematologic Effects:
• Aplastic anemia, leukopenia, agranulocytosis, and thrombocytopenia reported
• Bone Health:
• Long-term use associated with osteomalacia and vitamin D deficiency
• Neurotoxicity:
• Symptoms include ataxia, confusion, nystagmus, and slurred speech at high serum levels
• Suicidality:
• Risk of suicidal behavior or ideation; monitor closely

Common:

• Central Nervous System:
• Dizziness, drowsiness, confusion, tremor, ataxia, headache
• Gastrointestinal:
• Nausea, constipation, vomiting
• Gingival/Oral:
• Gingival hyperplasia (especially in children)
• Dermatologic:
• Acne, rash, hirsutism, facial coarsening

Serious:

• Stevens-Johnson Syndrome (SJS) and TEN
• Hepatic failure
• Blood dyscrasias (agranulocytosis, thrombocytopenia, aplastic anemia)
• Lupus-like syndrome
• Purple glove syndrome (IV use)

CYP450 Involvement:

• Inducer of CYP3A4, CYP2C9, CYP2C19
• Subject to multiple metabolic interactions

Major Interactions:

• Oral Contraceptives: Decreased efficacy due to enzyme induction
• Warfarin: May reduce or enhance anticoagulant effect
• Valproic Acid: Displaces phenytoin from protein binding → increased free drug levels
• Carbamazepine/Phenobarbital: Increased risk of CNS toxicity or reduced phenytoin levels
• Delavirdine: Contraindicated; reduced antiviral levels

Food & Alcohol:

• Alcohol: Acute intake inhibits phenytoin metabolism; chronic use induces metabolism
• Food may delay but not reduce total absorption

• HLA-B*1502 Screening: Strongly recommended for patients of Asian descent before initiation
• Therapeutic Drug Monitoring: Emphasis on monitoring free phenytoin levels in patients with low albumin or renal/hepatic impairment
• FDA Labeling Updates: Enhanced warnings regarding suicidal ideation and skin reactions

• Oral Forms (Capsules, Tablets, Suspension):
• Store at 20°C to 25°C (68°F to 77°F)
• Protect from moisture and light
• Suspension: Shake well before each use
• IV Formulations:
• Store at 15°C to 30°C (59°F to 86°F)
• Do not refrigerate (may precipitate)
• Use diluted solution immediately; discard unused portion