Phenytoin Drug Profile According to Clinical consideration

Phynetoin therapeutic uses Mechanism of action

1. Phenytoin Drug Profile
Drug Class: Anticonvulsant (Antiepileptic Drug - AED), Hydantoin derivative.
Mechanism of Action: Phenytoin primarily exerts its anticonvulsant effects by stabilizing
neuronal membranes and inhibiting the spread of seizure activity. It does this by modulating
voltage-gated sodium channels in neurons, prolonging their inactive state. This prevents rapid,
repetitive firing of action potentials. Phenytoin also has effects on calcium channels and
modulates neurotransmitters like GABA and glutamate, though its primary mechanism is
thought to be sodium channel blockade. Phenytoin exhibits saturable (Michaelis-Menten)
kinetics, meaning a small increase in dose can lead to a disproportionately large increase in
plasma concentration, making dose adjustments challenging.
Boxed Warnings (FDA Black Box Warnings)
The FDA has issued boxed warnings for phenytoin due to significant risks:
Rate of Administration (Intravenous Phenytoin): The rate of intravenous (IV) phenytoin
administration should not exceed 50 mg per minute in adults and 1 to 3 mg/kg/minute
(or 50 mg per minute, whichever is slower) in pediatric patients due to the risk of severe
cardiovascular adverse reactions, including hypotension and cardiac arrhythmias
(bradycardia, asystole, ventricular fibrillation, and heart block). These events have led to
fatalities. Careful cardiac monitoring (ECG, blood pressure) is essential during and after
IV administration.
"Purple Glove Syndrome": Severe local skin reactions, including tissue damage,
necrosis, and gangrene, have occurred at or near the injection site of IV phenytoin,
sometimes requiring fasciotomies, amputation, or skin grafting. This syndrome may
occur with or without extravasation. Careful monitoring of the IV site and proper
administration techniques are crucial.
Therapeutic Indications
Phenytoin is FDA-approved for the control of:
Generalized Tonic-Clonic Seizures (Grand Mal Seizures): Both prevention and
treatment.
Complex Partial Seizures (Psychomotor or Temporal Lobe Seizures):
Prevention and Treatment of Seizures During or After Neurosurgery.
Status Epilepticus: For the emergency management of convulsive status epilepticus
(often after a benzodiazepine).

2. Note: Phenytoin is generally not effective for absence seizures and may even exacerbate them.
Dosage Forms Available
Phenytoin is available in various oral and parenteral formulations:
Oral:
oCapsules (extended-release): 30 mg, 50 mg, 100 mg, 200 mg, 300 mg (e.g.,
Dilantin Kapseals). These are designed for once or twice daily dosing.
oChewable Tablets: 50 mg.
oOral Suspension: 125 mg/5 mL.
Parenteral (Injectable):
oInjection: 50 mg/mL (for intravenous or intramuscular administration).
oFosphenytoin: A prodrug of phenytoin, available as an injection (150 mg/2 mL
equivalent to 100 mg phenytoin sodium or 75 mg phenytoin base) for IV or IM
use. Fosphenytoin can be infused more rapidly and causes fewer injection site
reactions than phenytoin.
Dosage and Administration
Phenytoin dosage is highly individualized and requires careful monitoring of plasma
concentrations (therapeutic range typically 10−20μg/mL for total phenytoin, or 1−2μg/mL for
free phenytoin).
Adults:
Oral Loading Dose (rarely used, mostly in hospitalized settings): 15-20 mg/kg, given in
3 divided doses separated by 2-4 hours to minimize GI upset.
Oral Maintenance Dose (Capsules/Tablets/Suspension):
oInitial: 100 mg orally three times daily.
oTypical Maintenance: 300 mg to 400 mg per day, given as a single daily dose or
in divided doses (e.g., 100 mg three times daily, or 300 mg once daily for
extended-release).
oDosage adjustments should be made in small increments (30−50 mg at a time)
and only after steady-state levels have been achieved (usually 7-10 days after a
dose change) due to saturable kinetics.

3. Status Epilepticus (IV Loading Dose):
oAdults: 15-20 mg/kg IV, administered at a rate not exceeding 50 mg/minute.
oMaintenance: Following loading, 100 mg orally or IV every 6-8 hours.
Neurosurgery Prophylaxis (IV):
oLoading: 10-20 mg/kg IV, followed by 100 mg IV or orally every 6-8 hours.
Children:
Oral Loading Dose: 15-20 mg/kg, given in 3 divided doses (e.g., 5-7 mg/kg/dose).
Oral Maintenance Dose:
oInitial: 5 mg/kg/day orally in 2 or 3 divided doses.
oTypical Maintenance: 4-8 mg/kg/day, divided in 2 or 3 doses.
oMaximum Daily Dose: 300 mg/day for children > 6 years.
Status Epilepticus (IV Loading Dose): 15-20 mg/kg IV, administered at a rate not
exceeding 1-3 mg/kg/minute or 50 mg/minute, whichever is slower.
Patients with Renal or Hepatic Impairment:
Renal Impairment: Phenytoin is primarily metabolized by the liver. Renal excretion of
unchanged drug is minor. However, in renal failure, protein binding may be reduced,
increasing the fraction of unbound (active) drug. Monitoring of free phenytoin levels is
more useful than total levels. Dose adjustment may be needed based on clinical
response and free levels.
Hepatic Impairment: Phenytoin is extensively metabolized by the liver. Hepatic
impairment can significantly impair metabolism, leading to increased plasma
concentrations and prolonged half-life. Reduce dosage and monitor total and free
phenytoin levels closely. Lower initial doses and slower titration are recommended.
Administration:
Oral: Take capsules with plenty of water. Extended-release capsules should not be
opened or crushed. Oral suspension should be shaken well before use. Administer
maintenance doses at consistent times each day.
Intravenous (IV) Phenytoin:

4. oMust be diluted only with 0.9% Sodium Chloride Injection. Do NOT dilute with
dextrose solutions as precipitation occurs.
oAdminister via a large peripheral or central vein using an in-line filter (0.22
micron or 0.45 micron).
oRate: No faster than 50 mg/minute in adults (1-3 mg/kg/min or 50 mg/min,
whichever is slower, in children). Rapid administration can cause severe
hypotension, bradycardia, and cardiac arrest.
oMonitor ECG, blood pressure, and respiratory function continuously during and
after IV infusion.
oFlush the IV line with saline before and after administration to prevent local
irritation ("purple glove syndrome").
Intramuscular (IM) Phenytoin: IM administration is generally not recommended due to
erratic absorption, pain at the injection site, tissue damage, and crystal formation. If
used, the dose should be 50% higher than the oral dose. Fosphenytoin is preferred for
IM administration.
Precautions
Narrow Therapeutic Index: Phenytoin has a narrow therapeutic index, meaning the
difference between effective and toxic doses is small. Close monitoring of plasma drug
levels is crucial.
Saturable Kinetics: Small dose increases can lead to disproportionately large increases
in plasma levels, increasing the risk of toxicity.
Cardiovascular Effects (IV Administration): As highlighted in the boxed warning,
profound hypotension and cardiac arrhythmias can occur with rapid IV infusion.
"Purple Glove Syndrome": Severe local reactions, including tissue necrosis, at the
injection site. Proper IV technique and avoidance of IM use are critical.
Hepatic Toxicity: Rare but potentially severe hepatic dysfunction (hepatitis, jaundice)
can occur, sometimes leading to liver failure. Discontinue if symptoms of acute
hepatotoxicity appear.
Hematologic Effects: Rare but serious blood dyscrasias, including aplastic anemia,
agranulocytosis, leukopenia, thrombocytopenia, and pure red cell aplasia. Routine
complete blood counts (CBC) are recommended.
Severe Cutaneous Adverse Reactions (SCARs):

5. oStevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN):
Potentially life-threatening skin reactions. Discontinue at the first sign of rash,
unless the rash is clearly not drug-related.
oDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS) /
Hypersensitivity Syndrome: A severe, multi-organ delayed hypersensitivity
reaction. Discontinue immediately if suspected.
oAcute Generalized Exanthematous Pustulosis (AGEP).
oGenetic Risk (HLA-B*1502 allele): Patients of Asian ancestry should be screened
for HLA-B*1502 prior to initiating phenytoin due to increased risk of SJS/TEN.
Lymphadenopathy/Pseudolymphoma: Benign lymphoid hyperplasia can occur.
Discontinue if persistent lymphadenopathy develops.
Osteomalacia/Bone Effects: Long-term phenytoin use can interfere with vitamin D
metabolism, leading to osteomalacia, osteoporosis, and increased fracture risk.
Supplementation with vitamin D and calcium may be necessary.
Folic Acid Deficiency: Phenytoin can interfere with folate absorption, potentially leading
to megaloblastic anemia. Folic acid supplementation may be needed.
Hyperglycemia: Phenytoin can inhibit insulin release, leading to hyperglycemia. Monitor
blood glucose, especially in diabetics.
Gingival Hyperplasia: Overgrowth of gum tissue, a common side effect with chronic use.
Good oral hygiene is essential.
Hirsutism: Excessive hair growth, particularly in women.
Teratogenicity: Phenytoin is associated with fetal hydantoin syndrome (craniofacial
anomalies, digital hypoplasia, growth deficiency, developmental delay). Use in
pregnancy only if the benefits outweigh the risks. Folate supplementation is highly
recommended for women of childbearing potential.
Withdrawal Seizures: Abrupt discontinuation of phenytoin can precipitate status
epilepticus. Taper gradually under medical supervision.
Suicidal Ideation: Antiepileptic drugs, including phenytoin, may increase the risk of
suicidal thoughts or behavior. Monitor patients for mood changes.
Side Effects
Side effects are often dose-related and more common at higher plasma concentrations.

6. Very Common (≥ 10%):
CNS: Nystagmus (involuntary eye movements), ataxia (impaired coordination), slurred
speech (dysarthria), dizziness, drowsiness, headache, confusion.
Gingival: Gingival hyperplasia (gum overgrowth).
Common (1-9%):
CNS: Tremor, insomnia, nervousness, unsteadiness, peripheral neuropathy (with long-
term use).
Gastrointestinal: Nausea, vomiting, constipation, epigastric pain.
Dermatologic: Rash (maculopapular or morbilliform, usually benign, but can precede
SCARs).
Hematologic: Leukopenia (mild), thrombocytopenia (mild).
Endocrine/Metabolic: Osteomalacia, hyperglycemia.
Other: Hirsutism (excessive hair growth), coarse facial features.
Less Common / Serious Side Effects (< 1% or Post-marketing reports):
CNS: Dystonia, choreoathetosis, seizures (paradoxical, at toxic levels), encephalopathy.
Cardiovascular: Hypotension, bradycardia, cardiac arrest (with rapid IV).
Hepatic: Hepatitis, jaundice, liver failure.
Hematologic: Aplastic anemia, agranulocytosis, severe leukopenia, thrombocytopenia,
pure red cell aplasia, megaloblastic anemia.
Dermatologic: Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Drug
Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Hypersensitivity
Syndrome, acute generalized exanthematous pustulosis (AGEP), lupus erythematosus-
like syndrome.
Lymphatic: Lymphadenopathy, pseudolymphoma.
Other: Fever, injection site reactions (purple glove syndrome), visual disturbances
(blurred vision, diplopia), dyskinesias.
Contraindications

7. Known Hypersensitivity: To phenytoin, other hydantoin derivatives (e.g., fosphenytoin),
or any component of the formulation.
Sinus Bradycardia, Sinoatrial Block, Second- or Third-Degree AV Block, Adams-Stokes
Syndrome: Due to its potential to depress cardiac conduction and automaticity.
Coadministration with Delavirdine: Due to potential for loss of virologic response and
possible resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs).
Coadministration with Rilpivirine: Due to potential for loss of virologic response and
possible resistance to NNRTIs.
Drug Interactions and Their Management
Phenytoin is notoriously complex regarding drug interactions. It is a potent inducer of multiple
cytochrome P450 (CYP) enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP3A4, UGT) and can also
be affected by inhibitors of these enzymes. It also competes for protein binding sites.
1.Drugs that Increase Phenytoin Levels (CYP Inhibitors, Protein Binding Displacers):
oExamples: Amiodarone, chloramphenicol, cimetidine, disulfiram, fluconazole,
fluoxetine, fluvoxamine, isoniazid, metronidazole, miconazole, omeprazole,
phenylbutazone, sulfamethoxazole-trimethoprim, ticlopidine, topiramate,
valproic acid.
oManagement: These drugs inhibit phenytoin metabolism or displace it from
protein binding sites, increasing free and/or total phenytoin levels and the risk of
toxicity. Monitor phenytoin levels (especially free levels if possible) and clinical
signs of toxicity. Phenytoin dose reduction is often necessary.
2.Drugs that Decrease Phenytoin Levels (CYP Inducers):
oExamples: Carbamazepine, phenobarbital, rifampin, chronic alcohol use (acute
alcohol use can inhibit), St. John's Wort.
oManagement: These drugs induce phenytoin metabolism, decreasing its levels
and potentially leading to loss of seizure control. Monitor phenytoin levels and
clinical response. Phenytoin dose increase may be necessary.
3.Drugs whose Metabolism is Induced by Phenytoin (Reduced Efficacy of Co-
administered Drug):
oExamples:
Oral Contraceptives: Significant interaction, can lead to contraceptive
failure.

8. Oral Anticoagulants (e.g., Warfarin): Can reduce anticoagulant effect
(initial inhibition may occur, but chronic induction dominates).
Corticosteroids: Reduced efficacy.
Doxycycline: Reduced efficacy.
Cyclosporine, Tacrolimus: Reduced immunosuppressant levels,
increasing risk of rejection.
Quetiapine: Reduced antipsychotic levels.
Protease Inhibitors (e.g., Darunavir, Lopinavir), Non-Nucleoside Reverse
Transcriptase Inhibitors (NNRTIs - e.g., Efavirenz, Nevirapine): Reduced
antiretroviral levels, leading to virologic failure.
Tiagabine, Lamotrigine, Carbamazepine, Topiramate: Reduced levels of
other AEDs.
oManagement: For oral contraceptives, advise alternative or additional non-
hormonal contraception. For other drugs, monitor levels (if available) and
clinical response. Dose adjustments of the co-administered drug are frequently
required.
4.Drugs that Increase Phenytoin Toxicity without Altering Levels:
oExamples: Alcohol (acute ingestion), benzodiazepines (some), other CNS
depressants.
oInteraction: Additive CNS depressant effects.
oManagement: Avoid excessive alcohol intake. Use other CNS depressants
cautiously.
5.Folates:
oInteraction: Folic acid can theoretically decrease phenytoin levels, and phenytoin
can decrease folate levels.
oManagement: Patients on phenytoin often require folate supplementation, but
high doses of folate may decrease phenytoin efficacy. Monitor phenytoin levels.
6.Antacids:
oInteraction: Antacids containing magnesium or aluminum can reduce phenytoin
absorption if given concurrently.

9. oManagement: Separate antacid and phenytoin administration by at least 2-3
hours.
7.Enteral Nutrition/Tube Feeds:
oInteraction: Phenytoin binds to components in enteral feeding formulas,
reducing its absorption and serum levels.
oManagement: Stop tube feeds 1-2 hours before and after phenytoin
administration. Dilute phenytoin in 30-60 mL of saline and flush the tube before
and after. Monitor phenytoin levels closely. Alternatively, consider IV
fosphenytoin.