A Comprehensive Monograph on Phenytoin (DB00252)

1.0 Introduction and Executive Summary

1.1 Overview of Phenytoin's Stature

Phenytoin stands as a foundational, first-generation antiepileptic drug (AED) that has been a cornerstone in the management of epilepsy for over eight decades.[1] First synthesized in 1908 and recognized for its anticonvulsant properties in 1938, it represented a paradigm shift in neurologic therapy by offering effective seizure control without the profound sedative effects of its predecessors, like phenobarbital.[2] Its enduring importance is underscored by its inclusion on the World Health Organization's List of Essential Medicines, a testament to its established efficacy, widespread availability, and critical role in global health.[2] Despite the development of numerous newer AEDs with more favorable pharmacokinetic profiles, phenytoin remains a vital therapeutic option, particularly for tonic-clonic and focal seizures, as well as in the acute management of status epilepticus.[1]

1.2 The Central Therapeutic Dichotomy

The clinical narrative of phenytoin is defined by a profound dichotomy: the tension between its proven, potent efficacy and its exceptionally challenging pharmacokinetic and safety profile. The utility of this drug is governed by two fundamental characteristics that demand constant clinical vigilance. The first is its narrow therapeutic index, with a very small window between effective serum concentrations (typically 10-20 mg/L) and those associated with toxicity.[1] The second, and more critical, feature is its non-linear, saturable metabolism.[1] Unlike most drugs, where dose and serum level share a predictable, linear relationship, phenytoin’s metabolic pathways become overwhelmed at concentrations within the therapeutic range. This creates a "pharmacokinetic cliff," where a small, seemingly minor adjustment in dosage or a change in the patient's metabolic capacity can cause a sudden, disproportionate, and precipitous surge in serum levels, pushing the patient from a state of therapeutic control into severe toxicity. This single property is the unifying explanation for the drug's notorious unpredictability, the absolute necessity of therapeutic drug monitoring, the severity of overdoses from small errors, and the profound clinical impact of its numerous drug-drug and drug-nutrient interactions.

1.3 Executive Summary of Key Findings

This report provides an exhaustive analysis of phenytoin, synthesizing data from chemical, pharmacological, clinical, and regulatory sources into a definitive reference for clinicians and researchers.

• Mechanism of Action: Phenytoin exerts its primary effect as a use-dependent and voltage-dependent blocker of voltage-gated sodium channels (VGSCs) in the brain's motor cortex. By selectively binding to and stabilizing the inactive state of these channels, it reduces the ability of neurons to sustain the high-frequency repetitive firing characteristic of seizure activity, thereby preventing the spread of seizures from an epileptic focus.[1]
• Clinical Indications: It is FDA-approved for the control of tonic-clonic (grand mal) seizures, complex partial (psychomotor) seizures, and the prevention and treatment of seizures occurring during or after neurosurgery. Its intravenous formulation is a second-line agent for the management of status epilepticus.[2]
• Pharmacokinetics: The clinical management of phenytoin is dominated by its complex pharmacokinetics. It exhibits zero-order, saturable metabolism via the CYP2C9 and CYP2C19 enzyme systems, is highly bound (~90%) to plasma albumin, and is a potent inducer of the CYP3A4 enzyme system. These factors create a high potential for inter-patient variability and a vast profile of clinically significant drug interactions.[1]
• Safety and Toxicity: Its adverse effect profile is extensive, ranging from common, dose-related effects like nystagmus and ataxia, and chronic effects like gingival hyperplasia, to rare but life-threatening idiosyncratic reactions such as Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Intravenous administration carries the unique risk of severe local tissue injury known as Purple Glove Syndrome, a complication related to the drug's formulation.[2]
• Clinical Management: Safe and effective use of phenytoin is critically dependent on individualized dosing guided by therapeutic drug monitoring (TDM). Clinicians must maintain extreme vigilance regarding potential drug-drug interactions and the significant drug-nutrient interaction with enteral tube feedings, which can drastically reduce absorption and lead to therapeutic failure.[5]

2.0 Drug Identity, History, and Regulatory Landscape

2.1 Nomenclature and Chemical Identification

Phenytoin is a hydantoin derivative, structurally related to the barbiturates but possessing a five-membered ring instead of a six-membered one.[15] Its unambiguous chemical identity is established by a standardized set of nomenclature and identifiers. The formal chemical name is 5,5-diphenylimidazolidine-2,4-dione, and it is also commonly referred to by the synonyms 5,5-Diphenylhydantoin and Diphenylhydantoin.[17] Its chemical structure consists of a hydantoin core with two phenyl group substituents at the fifth carbon position, which are crucial for its anticonvulsant activity.[17]

The fundamental chemical and physical properties of phenytoin are consolidated in Table 2.1. This information is essential for researchers, formulation scientists, and pharmacists, providing a definitive reference for its identification and behavior. The compound's extremely poor water solubility is a particularly critical physical property, as it dictates the formulation strategies required for both oral and parenteral administration and underlies some of its administration challenges, such as its incompatibility with dextrose solutions and its erratic absorption when given intramuscularly.[1]

Table 2.1: Chemical and Physical Properties of Phenytoin

Property	Value	Source(s)
IUPAC Name	5,5-diphenylimidazolidine-2,4-dione	2
CAS Number	57-41-0	17
DrugBank ID	DB00252	3
Molecular Formula	C15​H12​N2​O2​	18
Molecular Weight	252.27 g/mol	18
Physical Appearance	Fine white to almost white crystalline powder	17
Melting Point	Approximately 298 °C	18
pKa	8.0-9.2	6
Solubility	Insoluble in water, chloroform, benzene, ether; slightly soluble in acetone, alcohol	18
InChIKey	CXOFVDLJLONNDW-UHFFFAOYSA-N	3
SMILES	C1=CC=C(C=C1)C2(C(=O)NC(=O)N2)C3=CC=CC=C3	17
ChEBI ID	CHEBI:8107	2
PubChem CID	1775	2
UNII	6158TKW0C5	2

2.2 Historical Development and Key Milestones

The history of phenytoin is a landmark story in modern pharmacology. It was first synthesized in 1908 by the German chemist Heinrich Biltz, but its therapeutic potential remained undiscovered for three decades.[2] In 1938, a systematic investigation by American scientists H. Houston Merritt and Tracy Putnam, who were searching for non-sedating anticonvulsants, identified phenytoin's remarkable ability to control seizures in animal models without causing the drowsiness associated with the then-standard treatment, phenobarbital.[2] This discovery was a watershed moment, fundamentally separating anticonvulsant activity from sedation and paving the way for a new era in epilepsy management that prioritized not only seizure control but also patient functionality and quality of life. Following this discovery, phenytoin was rapidly adopted into clinical practice, receiving its first approval from the U.S. Food and Drug Administration (FDA) in 1939 for the treatment of epilepsy, with a broader approval for seizure use following in 1953.[1]

2.3 Global Regulatory Status and Major Manufacturers

Phenytoin is marketed globally under a multitude of brand names, with the most recognized being Dilantin, historically marketed by Parke-Davis and now by Viatris (a company formed from a merger including Pfizer's Upjohn division), and Epanutin in many international markets.[2] As a long-established drug, it is widely available as a generic medication, which has led to a complex and fragmented global market.[2]

The major players in the generic phenytoin market include large multinational corporations such as Teva Pharmaceuticals, Mylan (now part of Viatris), and Sandoz, alongside prominent Indian firms like Sun Pharma and Lupin Ltd.[25] The active pharmaceutical ingredient (API) is produced by a diverse group of manufacturers, including Unichem Labs and Harman Finochem in India, and Sumitomo Chemical in Japan.[28] This distributed global supply chain contributes to the drug's low cost and broad accessibility but also introduces vulnerabilities. A notable example was the 2020 voluntary recall of phenytoin oral suspension by Taro Pharmaceuticals due to a manufacturing issue that could lead to inconsistent dosing—a particularly dangerous flaw for a narrow therapeutic index drug where precision is paramount.[29]

The regulatory history of phenytoin also serves as a modern case study in pharmaceutical economics and market regulation. In the United Kingdom, a significant controversy arose after Pfizer sold the marketing license for Epanutin to the distributor Flynn Pharma. By de-branding the drug, the companies were able to circumvent existing price regulations for branded medicines, leading to a price increase of over 2,000%. This action cost the UK's National Health Service (NHS) tens of millions of pounds annually and resulted in a landmark investigation by the Competition and Markets Authority (CMA), which imposed record fines on both Pfizer and Flynn Pharma for exploiting a dominant market position to charge "excessive and unfair" prices.[2] This incident highlights how regulatory frameworks, not just manufacturing costs, can be primary drivers of price for legacy essential medicines and reveals a systemic vulnerability that can be exploited.

In the United States, phenytoin has also faced regulatory scrutiny. In 2008, it was placed on the FDA's Potential Signals of Serious Risks List for further evaluation of safety concerns, which subsequently led to updated warnings on the product label regarding Purple Glove Syndrome.[2] In Europe, phenytoin is not centrally authorized by the European Medicines Agency (EMA) but is approved at the national level in various member states. The EMA's databases reflect its widespread use, documenting its numerous drug interactions with centrally authorized medicines (e.g., Rukobia, Zebinix) and its inclusion in a large number of clinical trials conducted within the EU for both approved and investigational uses.[31]

3.0 Pharmacodynamics: The Molecular Basis of Action

3.1 Primary Mechanism: Modulation of Voltage-Gated Sodium Channels (VGSCs)

The primary anticonvulsant effect of phenytoin is mediated through its action on voltage-gated sodium channels (VGSCs), with the principal site of action being the motor cortex of the brain.[15] Phenytoin's mechanism is sophisticated, characterized by both use-dependent and voltage-dependent blockade of these channels.[1] It does not act as a simple physical plug. Instead, it selectively binds with high affinity to the VGSC when the channel is in its

inactive state—the conformation it assumes immediately after opening and closing during an action potential.[6]

By binding to this inactive state, phenytoin stabilizes it, significantly prolonging the channel's refractory period and slowing its rate of recovery to the resting, closed state from which it can be activated again.[7] This action has a profound pharmacological consequence: it stabilizes the neuronal membrane against the hyperexcitability that drives seizure activity. The drug effectively acts as a filter, reducing the neuron's ability to fire action potentials at the high frequencies characteristic of an epileptic discharge.[7] This selective targeting of rapidly firing neurons is the key to phenytoin's therapeutic efficacy. It allows the drug to potently suppress pathological, high-frequency activity while having a minimal effect on neurons firing at a normal, physiological rate. This explains how phenytoin can exert powerful anticonvulsant effects without causing global central nervous system depression or sedation.

3.2 Effects on Neuronal Excitability and Seizure Propagation

The molecular action of phenytoin translates directly into its effects on neuronal circuits. By stabilizing the inactive state of VGSCs, it potently suppresses sustained, high-frequency repetitive firing of action potentials, the cellular hallmark of a focal seizure.[8] This action is critical in preventing the amplification and spread of seizure activity.

A key aspect of this is the reduction of post-tetanic potentiation (PTP) at synapses.[15] PTP is a form of short-term synaptic plasticity where a high-frequency burst of stimulation leads to enhanced neurotransmitter release in subsequent signals. In the context of epilepsy, PTP can facilitate the recruitment of adjacent neurons into the seizure discharge. By inhibiting PTP, phenytoin effectively dampens this pathological amplification, preventing a focal seizure from "detonating" adjacent cortical areas and spreading throughout the brain.[1] This mechanism directly explains its efficacy in controlling focal (partial) seizures and preventing their evolution into generalized tonic-clonic seizures. Furthermore, phenytoin has been shown to reduce the maximal activity of brain stem centers that are responsible for generating the tonic phase of tonic-clonic (grand mal) seizures, contributing to its effectiveness against this seizure type.[15]

This specific mechanism of action also directly predicts the drug's clinical limitations. Absence seizures, for instance, are not driven by high-frequency sodium channel-dependent firing but rather by oscillations in thalamocortical circuits involving low-voltage-activated (T-type) calcium channels. As phenytoin's mechanism does not target this underlying pathophysiology, it is ineffective for treating pure absence seizures and may even exacerbate them by suppressing competing tonic-clonic activity.[2]

3.3 Secondary and Ancillary Pharmacological Effects

While its primary action is on neuronal VGSCs, phenytoin exhibits effects on other ion channels and tissues. It has minor inhibitory effects on calcium channels, which may play a small, ancillary role in modulating neurotransmitter release and neuronal excitability.[7]

More significantly, phenytoin also acts on VGSCs in other excitable tissues, most notably the heart. This action underlies its classification as a Vaughn Williams Class IB antiarrhythmic agent, similar to lidocaine.[12] By blocking cardiac sodium channels, it can suppress abnormal ventricular automaticity, which explains its historical and off-label use for treating certain ventricular arrhythmias, especially those precipitated by digitalis toxicity.[2] This same cardiac mechanism, however, is also responsible for its potential to cause significant cardiovascular toxicity, including bradycardia, atrioventricular (AV) block, and hypotension, particularly when administered rapidly via the intravenous route.[12]

At the genetic level, phenytoin's targets are the protein products of the SCN family of genes, which encode the various alpha subunits of VGSCs expressed throughout the nervous system and in cardiac and skeletal muscle. These include the primary brain-expressed subunits SCN1A, SCN2A, and SCN3A, as well as numerous others.[8]

4.0 Pharmacokinetics: A Profile of Non-Linearity

The clinical use and management of phenytoin are overwhelmingly dictated by its unique and complex pharmacokinetic profile. Unlike most medications, it exhibits non-linear, saturable kinetics at therapeutic concentrations, making its behavior unpredictable without careful monitoring.

4.1 Absorption

Phenytoin is classified as a Biopharmaceutics Classification System (BCS) Class II drug, meaning it has high membrane permeability but poor aqueous solubility.[11] While it is generally completely absorbed after oral administration, the rate of absorption can be slow and variable, influenced heavily by the specific formulation.[1] For immediate-release formulations (oral suspension, chewable tablets), peak plasma concentrations are typically reached within 1.5 to 3 hours. For extended-release capsules, this peak is delayed to between 4 and 12 hours.[1]

Significant differences exist between formulations that must be considered in clinical practice. The chewable tablets and oral suspension contain phenytoin as a free acid, whereas the extended-release capsules and parenteral solution contain the sodium salt. The free acid form contains approximately 8% more active drug by weight than the sodium salt, a difference that is clinically meaningful for a narrow therapeutic index drug. Therefore, switching a patient between these formulations requires careful dose adjustment and therapeutic drug monitoring to avoid under-dosing or toxicity.[40]

Intramuscular (IM) administration is strongly discouraged. Due to its poor water solubility, phenytoin crystallizes in the muscle tissue, leading to slow, erratic, and incomplete absorption, as well as a high risk of sterile abscess formation, pain, and local tissue necrosis.[1]

A critical interaction occurs with enteral nutrition. Co-administration of phenytoin with continuous enteral tube feedings can dramatically reduce its absorption, with studies showing decreases in serum levels by as much as 50-75%.[14] This interaction is believed to result from the physical binding of phenytoin to components of the nutrient formula (such as proteins or cations) within the gastrointestinal lumen, rather than adsorption to the feeding tube itself.[43] This can lead to a profound loss of seizure control in critically ill patients.

4.2 Distribution

Phenytoin has a large volume of distribution (Vd), distributing widely into all body tissues and binding firmly to tissue components.[1] Notably, its concentrations in the central nervous system are often higher than those in the serum, reflecting its lipophilic nature and effective penetration of the blood-brain barrier.[1]

A defining pharmacokinetic feature of phenytoin is its high degree of binding (~90%) to plasma proteins, almost exclusively to albumin.[1] This is of immense clinical importance because only the unbound, or "free," fraction of the drug (~10%) is pharmacologically active and able to cross the blood-brain barrier to exert its effect.[1] Any condition that alters protein binding can significantly change the concentration of active drug without changing the

total drug concentration that is typically measured by clinical laboratories.

In states of hypoalbuminemia (e.g., liver disease, kidney disease, malnutrition, pregnancy) or in the presence of uremia, the fraction of unbound phenytoin increases.[2] Similarly, other highly protein-bound drugs, such as salicylates and valproate, can displace phenytoin from its binding sites on albumin, also increasing the free fraction.[1] In these situations, a patient may exhibit clear signs of toxicity (e.g., nystagmus, ataxia) even when their measured total phenytoin level is within the "therapeutic" range. This discrepancy makes monitoring total phenytoin levels alone potentially misleading and dangerous in these populations. Clinical management in such cases requires either the direct measurement of unbound phenytoin levels or the use of a correction formula, such as the Winter-Tozer formula, to estimate the physiologically relevant free concentration.[12]

4.3 Metabolism

Phenytoin's metabolism is the source of its greatest clinical challenges. It is metabolized almost entirely in the liver by the cytochrome P450 enzyme system.[1] The primary metabolic pathway, accounting for 80-90% of its clearance, is hydroxylation to the inactive metabolite 5-(4'-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). This reaction is predominantly catalyzed by

CYP2C9, with a smaller contribution (10-20%) from CYP2C19.[1]

The most critical pharmacokinetic property of phenytoin is that this metabolic pathway is saturable at clinically relevant concentrations. At plasma levels below approximately 10 mg/L, elimination follows predictable first-order kinetics, where the rate of elimination is proportional to the drug concentration. However, as serum levels enter the therapeutic range, the CYP2C9 enzyme system becomes saturated. At this point, the metabolism switches to zero-order kinetics, where the body can only eliminate a fixed, constant amount of the drug per unit of time, regardless of how high the concentration gets.[1]

The clinical consequences of this metabolic saturation are profound:

1. Disproportionate Dose-Level Relationship: Once the system is saturated, even a small increase in the daily dose can lead to a very large and unpredictable increase in the steady-state serum concentration and drug half-life.[1] This is the "pharmacokinetic cliff" that makes dosing so difficult.
2. Prolonged Half-Life in Overdose: While the average half-life at therapeutic doses is around 22 hours, this can become significantly prolonged during overdose, delaying clearance and extending the period of toxicity.[1]
3. High Inter-individual Variability: The maximum capacity of the metabolic system varies between individuals, making it impossible to predict the dose-concentration relationship for any given patient without TDM.[5]

Simultaneously, phenytoin plays a dual role in drug interactions. While it is a victim of drugs that inhibit or induce its metabolism, it is also a potent perpetrator of interactions through its action as a strong inducer of other enzymes, most notably CYP3A4.[1] This induction accelerates the metabolism and reduces the effectiveness of a wide array of co-administered drugs, including oral contraceptives, many statins, immunosuppressants, and some anticoagulants.

4.4 Excretion

Following hepatic metabolism, the inactive metabolites of phenytoin, primarily p-HPPH glucuronide, are excreted in the bile, reabsorbed from the intestinal tract, and ultimately eliminated in the urine.[1] A very small fraction of the drug, only 1-5%, is excreted unchanged in the urine.[1]

4.5 Pharmacogenomics

Genetic variations play a significant role in phenytoin metabolism and safety.

• CYP2C9 Variants: Individuals with genetic polymorphisms in the CYP2C9 gene that result in reduced enzyme activity ("poor metabolizers") are at a substantially higher risk of developing phenytoin toxicity. These patients clear the drug much more slowly and require significantly lower doses to achieve therapeutic concentrations.[8]
• HLA-B*15:02 Allele: The presence of the human leukocyte antigen (HLA) allele HLA-B*15:02, which is more common in individuals of Asian ancestry, is strongly associated with an increased risk of developing the life-threatening skin reactions SJS and TEN when treated with phenytoin and other aromatic anticonvulsants.[46] Genetic screening for this allele is recommended in these populations before initiating therapy.

5.0 Clinical Efficacy and Therapeutic Applications

5.1 FDA-Approved Indications

Phenytoin is a well-established antiepileptic drug with specific, FDA-approved indications that directly reflect its mechanism of action against high-frequency neuronal firing.

• Tonic-Clonic (Grand Mal) Seizures: It is indicated for the prophylactic management and long-term control of generalized tonic-clonic seizures.[2]
• Complex Partial (Psychomotor/Temporal Lobe) Seizures: It is effective for the control of focal seizures with complex symptomatology, also known as psychomotor or temporal lobe seizures.[1]
• Neurosurgery-Associated Seizures: It is approved for both the prevention and treatment of seizures that may occur during or following neurosurgical procedures.[2]
• Status Epilepticus: The intravenous formulation of phenytoin (or its prodrug, fosphenytoin) is a cornerstone in the management of convulsive (tonic-clonic) status epilepticus. It is typically administered as a second-line agent after initial attempts to terminate the seizure with a benzodiazepine have been made.[1] Its role is not to provide immediate seizure cessation, which is the function of the faster-acting benzodiazepine, but rather to provide a longer-lasting anticonvulsant effect to prevent seizure recurrence. This clinical protocol acknowledges a key practical limitation of IV phenytoin: its onset of action is relatively slow, taking up to 30 minutes to become effective, making it unsuitable as a first-line monotherapy in this emergency setting.[2]

5.2 Off-Label and Investigational Uses

Phenytoin's sodium-channel-blocking properties have led to its use in several off-label applications, with varying levels of evidence.

• Cardiac Arrhythmias: As a Class IB antiarrhythmic, phenytoin has been used to treat ventricular arrhythmias, particularly those that are refractory to conventional agents or are induced by digitalis toxicity.[2] This use is a direct extension of its primary mechanism to cardiac myocytes.
• Neuropathic Pain: It has been used for various neuropathic pain conditions, including trigeminal neuralgia.[1] While it can be effective, other agents like carbamazepine are often considered first-line for this indication.[49]
• Mental Health Disorders: There is very limited and weak evidence supporting the use of phenytoin in psychiatry, specifically for managing symptoms of mania, impulsivity, and agitation associated with bipolar disorder.[50] The mechanistic link is tenuous, and this remains a fringe application not supported by robust clinical trial data.[49]
• Topical Wound Healing: An emerging investigational use is the topical application of phenytoin to promote the healing of chronic skin wounds. Clinical trials have explored its use in venous leg ulcers and diabetic foot ulcers, with some tentative evidence suggesting a benefit.[2]

5.3 Evidence from Clinical Trials

Phenytoin's efficacy has been established over decades of clinical use and further examined in modern clinical trials. A Phase 3 trial (NCT00210782) directly compared its effectiveness and safety against topiramate for patients with new-onset epilepsy requiring rapid treatment initiation.[51] Numerous Phase 1 studies have been conducted to investigate its complex pharmacokinetics, including bioequivalence studies comparing different formulations (e.g., NCT01355068) and drug-drug interaction studies assessing its metabolic interplay with other compounds like itraconazole and poziotinib (e.g., NCT04981704, NCT06719557).[52] The European Union Clinical Trials Register also lists a variety of studies investigating phenytoin, including its use for painful polyneuropathy and post-traumatic brain injury seizures, reflecting ongoing research into its therapeutic potential.[32]

6.0 Dosage, Administration, and Therapeutic Monitoring

The safe and effective use of phenytoin requires meticulous attention to dosing, formulation selection, and administration protocols, all guided by therapeutic drug monitoring.

6.1 Available Formulations and Bioequivalence

Phenytoin is available in several oral and parenteral formulations that are not interchangeable.

• Oral Formulations:
• Extended-Release Capsules (e.g., Dilantin Kapseals®): These contain phenytoin sodium and are available in strengths of 30 mg, 100 mg, 200 mg, and 300 mg. They are the only oral formulation suitable for once-daily dosing, but only after seizure control has been established on a divided-dose regimen.[53]
• Chewable Tablets (e.g., Dilantin Infatabs®): These are 50 mg scored tablets containing phenytoin free acid. They are an immediate-release formulation and are explicitly marked as NOT FOR ONCE-A-DAY DOSING.[40]
• Oral Suspension: Typically available as 125 mg/5 mL, this formulation also contains phenytoin free acid. It requires vigorous shaking before each dose to ensure uniform drug distribution and prevent dosing errors.[9]
• Parenteral Formulation:
• Intravenous (IV) Injection: This is a 50 mg/mL solution of phenytoin sodium in a highly alkaline vehicle (pH 12) containing 40% propylene glycol and 10% alcohol to maintain solubility.[41] It is chemically incompatible with dextrose solutions and will precipitate.[1]

The existence of multiple, non-equivalent formulations creates a significant risk for medication errors. An inadvertent switch from a sodium salt product to a free acid product results in an ~8% increase in the active drug dose.[40] More dangerously, substituting an immediate-release product for an extended-release one for once-daily dosing can lead to a sharp, toxic peak in serum concentration. Such switches must be managed with extreme care and accompanied by TDM.[40]

6.2 Dosing Regimens: Adult, Pediatric, and Special Populations

Dosing must be individualized based on clinical response and serum concentrations. Table 6.1 summarizes general dosing guidelines.

Table 6.1: Dosing Guidelines for Phenytoin by Formulation and Patient Population

Population	Indication	Formulation	Loading Dose	Maintenance Dose	Source(s)
Adult	Seizure Control	Extended-Release Capsules	N/A	Start: 100 mg TID. Maintenance: 300-400 mg/day, given once daily or divided. Max: 600 mg/day.	53
Adult	Seizure Control	Chewable Tablets / Suspension	N/A	Start: 100 mg (or 5 mL) TID. Maintenance: 300-400 mg/day in 2-3 divided doses.	9
Adult	Rapid Oral Loading	Extended-Release Capsules	1 g total, given as 400 mg, then 300 mg, then 300 mg at 2-hour intervals.	Begin standard maintenance 24 hours after loading dose.	53
Adult	Status Epilepticus	IV Injection	15-20 mg/kg IV.	100 mg IV/PO every 6-8 hours.	38
Pediatric (>6 yrs)	Seizure Control	All Oral	N/A	Start: 5 mg/kg/day in 2-3 divided doses. Maintenance: 4-8 mg/kg/day. Max: 300 mg/day.	40
Pediatric (Neonate)	Seizure Control	Oral Suspension	N/A	Start: 5 mg/kg/day in 2 divided doses.	38
Pediatric	Status Epilepticus	IV Injection	15-20 mg/kg IV.	Maintenance depends on age (e.g., 8-10 mg/kg/day for 6mo-4yr).	41

Special populations require dose adjustments. Elderly patients often have reduced clearance and may need lower or less frequent dosing.[40] Patients with hepatic or renal disease should not receive an oral loading dose, may require decreased maintenance doses, and need monitoring of unbound levels due to altered protein binding.[2] During pregnancy, plasma volume expansion and altered metabolism often necessitate dose increases to maintain therapeutic levels, with frequent monitoring.[2]

6.3 Intravenous Administration Protocols

The IV administration of phenytoin is governed by strict safety protocols designed to mitigate the direct toxicity of its formulation vehicle. The high pH and propylene glycol content of the injection solution are caustic to tissues and can act as a cardiac depressant.[12]

• Rate of Infusion: This is a critical safety parameter. The infusion rate must not exceed 50 mg/min in adults and 1-3 mg/kg/min (or 50 mg/min, whichever is slower) in pediatric patients. Faster rates are associated with a high risk of severe hypotension, cardiac arrhythmias (bradycardia, heart block), and cardiovascular collapse.[12]
• Dilution and Filtration: Phenytoin injection must be diluted in normal saline only. It is incompatible with and will precipitate in dextrose-containing solutions. The final concentration in the infusion solution should not be less than 5 mg/mL. The infusion must be administered through an in-line filter of 0.22 to 0.55 microns to remove any microscopic precipitates.[1]
• Administration Site and Flushing: To minimize local venous irritation and the risk of extravasation, IV phenytoin should be administered through a large-gauge catheter into a large peripheral or central vein. The line must be flushed with sterile saline both before and after the phenytoin infusion.[56]

6.4 Therapeutic Drug Monitoring (TDM)

TDM is not optional but is an absolute requirement for the safe and effective use of phenytoin. It is necessitated by the drug's narrow therapeutic index, high inter-patient variability, and non-linear, saturable kinetics.[5]

• Therapeutic Range:
• Total Phenytoin Concentration: The generally accepted therapeutic range is 10 to 20 mcg/mL (or mg/L).[12]
• Unbound (Free) Phenytoin Concentration: The therapeutic range for the pharmacologically active free fraction is 1 to 2 mcg/mL.[37] Monitoring unbound levels is essential for patients with conditions known to alter protein binding (e.g., renal failure, hypoalbuminemia).[40]
• Timing of Monitoring: It takes approximately 7 to 10 days to reach steady-state serum concentrations after initiating or changing a dose. Therefore, dose adjustments should not be made at intervals shorter than this.[15] Trough levels, drawn just before a scheduled dose, are used to assess therapeutic efficacy and compliance, while peak levels can help identify the threshold for dose-related side effects.[40]

7.0 Adverse Effects, Toxicity, and Safety Profile

Phenytoin is associated with a wide spectrum of adverse effects, ranging from common and dose-dependent side effects to rare, idiosyncratic, and life-threatening reactions.

7.1 Common and Dose-Dependent Adverse Reactions

Many of the most common adverse effects of phenytoin are neurological and directly related to the serum concentration, often emerging as levels approach or exceed the upper end of the therapeutic range. These include nystagmus (involuntary eye movements), ataxia (impaired coordination and balance), slurred speech, dizziness, somnolence, mental confusion, tremor, and headache.[12] Nystagmus, particularly on lateral gaze, is one of the earliest signs of rising levels and can be present even within the therapeutic range.[12] Gastrointestinal effects such as nausea, vomiting, and constipation are also common but can often be mitigated by taking the medication with food.[2]

7.2 Serious and Idiosyncratic Reactions

Beyond the predictable dose-related effects, phenytoin can cause severe and potentially fatal idiosyncratic reactions.

• Serious Dermatologic Reactions:
• Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): These are rare but devastating mucocutaneous reactions characterized by an initial flu-like prodrome followed by the rapid development of a painful, blistering rash and subsequent sloughing of the epidermis. The risk is significantly elevated in patients of Asian descent carrying the HLA-B*1502 allele. Phenytoin should be discontinued immediately at the first sign of a potentially serious rash.[2]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Also known as Anticonvulsant Hypersensitivity Syndrome, DRESS is a multi-organ reaction that typically presents 2 to 8 weeks after starting the drug. It is characterized by a triad of fever, rash, and internal organ involvement, which can include hepatitis, nephritis, myocarditis, and pneumonitis.[1]
• Hepatotoxicity: Liver injury can range from asymptomatic elevation of transaminases to acute toxic hepatitis, which can be fatal.[2]
• Hematologic Effects: Phenytoin can cause severe blood dyscrasias, including agranulocytosis, aplastic anemia, leukopenia, and thrombocytopenia. It can also cause a predictable megaloblastic anemia due to its interference with folate metabolism.[1]
• Cardiovascular Events: While primarily associated with rapid IV administration, severe cardiac events including profound hypotension, bradycardia, all degrees of heart block, ventricular fibrillation, and asystole have been reported.[12]

7.3 Chronic Use-Associated Effects

Long-term therapy with phenytoin is associated with a distinct set of adverse effects affecting multiple organ systems.

• Gingival Hyperplasia: Overgrowth of the gum tissue is a very common effect, particularly in younger patients. It can be cosmetically disfiguring and can interfere with oral hygiene. The severity can often be minimized with meticulous dental care.[2]
• Endocrine and Dermatologic Effects: Chronic use can lead to a coarsening of facial features, enlargement of the lips, and hirsutism (excessive hair growth on the face and body).[2]
• Bone Health: Phenytoin induces hepatic enzymes that accelerate the metabolism of Vitamin D. This can lead to Vitamin D deficiency, resulting in bone demineralization (osteopenia, osteomalacia) and an increased risk of osteoporosis and fractures over time.[1]
• Neurologic Effects: Long-term use is associated with the development of a sensory peripheral neuropathy. More seriously, it can cause irreversible cerebellar atrophy, the degree of which appears to be related to the duration of treatment.[2]
• Lymphadenopathy: Phenytoin has been linked to a range of lymph node abnormalities, from benign hyperplasia and pseudolymphoma to an increased risk of malignancies such as lymphoma and Hodgkin's disease.[16]

Table 7.2: Adverse Effects of Phenytoin by System Organ Class and Frequency

System Organ Class	Frequency	Adverse Effects
Nervous System	Very Common (≥10%)	Nystagmus, dizziness, somnolence, ataxia 46
	Common (1-10%)	Headache, stupor, incoordination, tremor, slurred speech, taste perversion 46
	Frequency not reported	Cerebellar atrophy (chronic use), peripheral neuropathy, dyskinesias, encephalopathy 2
Gastrointestinal	Very Common (≥10%)	Nausea 46
	Common (1-10%)	Vomiting, constipation, dry mouth 46
	Frequency not reported	Gingival hyperplasia (chronic use) 2
Dermatologic	Very Common (≥10%)	Rash (typically maculopapular) 46
	Frequency not reported	Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), DRESS, hirsutism, coarsening of facial features, enlargement of lips 2
Hematologic	Uncommon (0.1-1%)	Thrombocytopenia, leukopenia, anemia 46
	Frequency not reported	Agranulocytosis, aplastic anemia, pancytopenia, megaloblastic anemia 2
Cardiovascular	Common (1-10%)	Hypotension (with IV use) 46
	Frequency not reported	Bradycardia, heart block, ventricular fibrillation, asystole, cardiovascular collapse (with IV use) 12
Musculoskeletal	Frequency not reported	Osteopenia, osteomalacia, osteoporosis, increased fracture risk (chronic use), Purple Glove Syndrome (IV use) 9
Hepatic	Frequency not reported	Elevated liver enzymes, toxic hepatitis 2
Immunologic	Frequency not reported	Hypersensitivity syndrome (DRESS), lymphadenopathy, pseudolymphoma, immunoglobulin abnormalities 16

7.4 Management of Acute Toxicity and Overdose

Acute phenytoin toxicity is a medical emergency. The clinical presentation correlates loosely but predictably with the total serum concentration, providing a useful guide for assessment.

Table 7.3: Phenytoin Serum Concentrations and Associated Signs of Toxicity

Total Serum Concentration (mg/L)	Associated Clinical Signs and Symptoms	Source(s)
10 - 20	Therapeutic range; occasional mild horizontal nystagmus on lateral gaze may be seen.	12
20 - 30	Nystagmus becomes more pronounced.	12
30 - 40	Ataxia, slurred speech, tremors, nausea, and vomiting.	12
40 - 50	Lethargy, confusion, hyperactivity.	12
> 50	Coma and, paradoxically, seizures.	12

Management of phenytoin overdose is primarily supportive, as no specific antidote or reversal agent exists.[12]

• Decontamination: In cases of acute oral ingestion, a single dose of activated charcoal can be administered to bind the drug and prevent further absorption. This is particularly useful for large or extended-release ingestions where absorption may be prolonged. Gastric lavage and induced emesis are not recommended.[12]
• Supportive Care: The mainstay of treatment is meticulous supportive care. This includes monitoring and maintaining the patient's airway, breathing, and circulation (ABCs). Hypotension should be treated with intravenous fluids and, if necessary, vasopressors. Cardiac arrhythmias, such as bradycardia, should be managed according to standard advanced cardiac life support (ACLS) protocols.[12]
• Enhanced Elimination: Due to high protein binding, phenytoin is not efficiently removed by standard hemodialysis. While some guidelines suggest considering hemodialysis in cases of extreme toxicity (e.g., coma), its clinical benefit is controversial and it is rarely used. Consultation with a medical toxicologist is highly recommended in all cases of significant overdose.[12]

8.0 Contraindications, Warnings, and Precautions

8.1 Absolute Contraindications

The use of phenytoin is absolutely contraindicated in certain patient populations where the risk of severe harm is unacceptably high.

• Hypersensitivity: Patients with a known history of hypersensitivity to phenytoin or other hydantoin-class anticonvulsants (e.g., ethotoin, fosphenytoin) should not receive the drug.[2]
• Significant Cardiac Conduction Abnormalities (IV Use): Due to its Class IB antiarrhythmic effects on ventricular automaticity and AV conduction, the intravenous formulation of phenytoin is contraindicated in patients with sinus bradycardia, sinoatrial block, second- or third-degree atrioventricular (AV) block, and Adams-Stokes syndrome.[2] Administering a drug that slows cardiac conduction to a patient with a pre-existing conduction system disease can precipitate complete heart block or asystole.
• Coadministration with Delavirdine: Phenytoin is a potent inducer of CYP3A4, the enzyme that metabolizes the non-nucleoside reverse transcriptase inhibitor (NNRTI) delavirdine. Coadministration will cause a rapid decrease in delavirdine levels, leading to a loss of virologic response and the potential for developing HIV resistance. Therefore, this combination is contraindicated.[41]

8.2 Black Box Warnings and Major Precautions

The FDA and other regulatory bodies mandate several critical warnings for phenytoin.

• Cardiovascular Risk with Intravenous Administration: This is a major boxed warning. Rapid IV infusion can cause severe hypotension, cardiac arrhythmias, and cardiovascular collapse. The infusion rate must be strictly controlled.[39]
• Suicidal Behavior and Ideation: In common with all antiepileptic drugs, phenytoin carries an increased risk of suicidal thoughts and behavior. Patients, families, and caregivers should be counseled to monitor for the emergence or worsening of depression, unusual changes in mood or behavior, or suicidal ideation.[16]
• Abrupt Withdrawal: Suddenly stopping phenytoin therapy can precipitate an increase in seizure frequency or trigger status epilepticus. If the drug must be discontinued, the dosage should be tapered gradually over a period of weeks, unless a rapid withdrawal is necessitated by a serious hypersensitivity reaction.[47]
• Serious Dermatologic Reactions: The risk of life-threatening skin reactions like SJS, TEN, and DRESS requires immediate discontinuation of the drug at the first sign of a suspicious rash.[24]

8.3 Use in Special Populations

• Pregnancy (Pregnancy Category D): Phenytoin is a known human teratogen and its use during pregnancy is a complex risk-benefit decision. In utero exposure is associated with a constellation of birth defects known as Fetal Hydantoin Syndrome, which includes craniofacial abnormalities (cleft lip/palate, broad nasal bridge), hypoplasia of the nails and distal phalanges, and growth deficiency.[2] However, uncontrolled maternal seizures also pose a significant risk to the fetus. Therefore, if phenytoin is deemed essential for seizure control, it may be continued at the lowest effective dose, with frequent TDM. Doses often need to be increased during pregnancy due to altered pharmacokinetics.[2] Newborns exposed to phenytoin in utero are also at risk for a hemorrhagic disease due to Vitamin K deficiency, requiring prophylactic Vitamin K administration at birth.[24]
• Lactation: Phenytoin is excreted in low concentrations into human breast milk. Due to the potential for adverse effects in the nursing infant, the manufacturer does not recommend breastfeeding while taking the medication.[2]
• Hepatic and Renal Impairment: Patients with significant liver or kidney disease are at high risk for toxicity. Metabolism may be impaired, and decreased serum albumin leads to a higher fraction of active, unbound drug. Oral loading doses should be avoided, and maintenance doses should be reduced and guided by monitoring of unbound phenytoin levels.[2]
• Elderly: Geriatric patients may exhibit increased sensitivity to phenytoin's effects. They often have decreased metabolic clearance and may have lower serum albumin, both of which necessitate starting with lower doses and titrating more cautiously.[2]

9.0 Clinically Significant Interactions

Phenytoin's interaction profile is vast and complex, stemming from its narrow therapeutic index, saturable metabolism, high protein binding, and potent enzyme-inducing properties. Clinicians must maintain a high index of suspicion for interactions whenever any new medication is added to or removed from a patient's regimen.

9.1 Drug-Drug Interactions

The interactions can be broadly categorized by their underlying mechanism. Table 9.1 provides a framework for understanding and predicting these interactions.

Table 9.1: Major Drug-Drug Interactions with Phenytoin, Categorized by Mechanism

Interacting Drug/Class	Mechanism of Interaction	Effect on Phenytoin Level	Effect on Other Drug's Level	Clinical Management/Recommendation	Source(s)
CYP2C9/2C19 Inhibitors (e.g., Fluconazole, Amiodarone, Cimetidine, Isoniazid, Sulfonamides)	Inhibition of phenytoin's primary metabolic pathway.	Increased (Risk of Toxicity)	Minimal	Monitor phenytoin levels closely. Prophylactic dose reduction of phenytoin may be necessary when starting the inhibitor.	1
Enzyme Inducers (e.g., Carbamazepine, Rifampin, Phenobarbital, St. John's Wort, Chronic Alcohol)	Induction of CYP enzymes, accelerating phenytoin metabolism.	Decreased (Risk of Seizures)	Variable (may also be decreased)	Monitor phenytoin levels closely. Dose increase of phenytoin may be required to maintain therapeutic levels.	1
CYP3A4 Substrates (e.g., Oral Contraceptives, Warfarin, Cyclosporine, many Statins, Doxycycline, Quetiapine)	Phenytoin is a potent inducer of CYP3A4, accelerating the substrate's metabolism.	Minimal	Decreased (Loss of Efficacy)	Anticipate reduced effect of the other drug. Dose increases may be needed. Counsel patients on backup contraception. Monitor INR closely with warfarin.	4
Highly Protein-Bound Drugs (e.g., Valproate, Salicylates, Warfarin)	Displacement of phenytoin from its binding sites on albumin.	Total level may decrease or stay the same, but unbound (active) level increases.	Variable	Risk of toxicity despite "normal" total levels. Monitor for clinical signs of toxicity. Consider monitoring unbound phenytoin levels.	1
CNS Depressants (e.g., Alcohol, Opioids, Benzodiazepines, Barbiturates)	Additive pharmacodynamic effects.	No change	No change	Increased risk of sedation, respiratory depression, and cognitive impairment. Use with caution and counsel patient.	4

9.2 Drug-Food/Nutrient Interactions

• Enteral Nutrition ("Tube Feedings"): This is one of the most clinically important and frequently encountered interactions with phenytoin. The concurrent administration of phenytoin suspension with continuous enteral nutrition formulas leads to a significant reduction in phenytoin absorption and bioavailability.[42] Research has shown this is not due to the drug adsorbing to the plastic feeding tube, but rather a physicochemical interaction occurring within the GI tract, where phenytoin binds to components of the formula (e.g., proteins, electrolytes).[14] This interaction can reduce serum levels by over 70%, placing the patient at high risk for breakthrough seizures.[42] The standard management strategy is to hold the enteral feeding for at least 1 to 2 hours before and 1 to 2 hours after the administration of each phenytoin dose. The feeding tube should be flushed with water before and after the dose. Even with this intervention, empiric dose increases and frequent TDM are often necessary.[14]
• Alcohol: The interaction with alcohol is complex. Acute alcohol ingestion can inhibit phenytoin metabolism, leading to increased serum levels and risk of toxicity. In contrast, chronic alcohol abuse induces hepatic enzymes, which can accelerate phenytoin metabolism and decrease serum levels, potentially leading to loss of seizure control.[2]
• Antacids and Cation-Containing Products: Antacids and supplements containing calcium, magnesium, or aluminum can interfere with phenytoin absorption. Administration should be separated by at least 2 to 3 hours.[4]

10.0 Special Topic In-Depth: Purple Glove Syndrome (PGS)

10.1 Presentation and Clinical Course

Purple Glove Syndrome (PGS) is a rare, but potentially devastating, iatrogenic complication specifically associated with the intravenous administration of phenytoin.[12] It is defined by the progressive development of pain, edema, and a characteristic purple or bluish discoloration of the limb, typically beginning at the IV insertion site and spreading distally towards the hand or foot.[63]

The onset is usually within hours of the infusion.[63] The clinical course is variable. In mild cases, the symptoms may resolve within days to weeks with conservative management. However, in severe cases, PGS can progress to the formation of blisters, extensive skin necrosis, and sloughing of the skin.[12] The underlying edema can become so severe that it causes a compartment syndrome, compromising vascular flow and leading to limb ischemia that may necessitate urgent surgical intervention, such as fasciotomy, skin grafting, or, in the most extreme cases, amputation.[63]

10.2 Pathophysiology and Risk Factors

The exact pathophysiology of PGS remains poorly understood, but it is recognized as being distinct from simple IV infiltration or extravasation.[63] It is fundamentally a formulation-related toxicity rather than a direct pharmacological effect of the phenytoin molecule. The leading theory attributes the tissue injury to the chemical properties of the phenytoin injection vehicle. To solubilize the poorly soluble phenytoin, the solution is formulated at a highly alkaline pH of 12 with sodium hydroxide and contains high concentrations of the excipients propylene glycol and ethanol, all of which are known tissue irritants.[63] It is believed that leakage of this caustic solution into the interstitial space, even in microscopic amounts without obvious extravasation, can trigger a cascade of vasoconstriction, endothelial damage, increased vascular permeability, and microthrombus formation, leading to the characteristic edema, discoloration, and ischemic injury.[64]

Several risk factors have been identified that increase the likelihood of developing PGS. These include advanced age, the administration of large or multiple doses of IV phenytoin, rapid infusion rates, and the use of small peripheral veins for administration.[63]

10.3 Management and Prevention Strategies

Once PGS is suspected, the phenytoin infusion must be discontinued immediately. Management is primarily supportive and aimed at limiting tissue damage and providing symptomatic relief. Standard measures include elevation of the affected limb to reduce edema, application of heat to promote vasodilation and comfort, and appropriate pain management.[65] The limb should be monitored closely for signs of vascular compromise or developing compartment syndrome, which would require urgent surgical consultation.[64]

Prevention is the most effective strategy. This includes strict adherence to all IV administration protocols: using a large-bore catheter in a large vein, ensuring the line is patent with a saline flush before and after infusion, and never exceeding the maximum recommended infusion rate.[64] However, the most definitive method of prevention is to avoid the problematic formulation altogether. The development of

fosphenytoin, a water-soluble phosphate ester prodrug of phenytoin, has been a major advance in safety. Fosphenytoin is rapidly converted to phenytoin in the body but can be administered in a standard aqueous solution without the caustic excipients. It is associated with a dramatically lower risk of local tissue reactions and is now considered the preferred parenteral agent when IV phenytoin therapy is required, effectively making PGS a preventable complication.[63]

11.0 Conclusion and Clinical Recommendations

11.1 Synthesizing the Profile of a High-Risk, High-Reward Drug

Phenytoin embodies the classic profile of a high-risk, high-reward medication. Its legacy is built on decades of proven, potent efficacy in controlling some of the most severe types of seizures. It remains an indispensable tool in the global neurology armamentarium due to its effectiveness, low cost, and long history of clinical experience. However, this efficacy is inextricably bound to a formidable set of clinical challenges. Its utility is entirely dependent on the clinician's deep understanding and respect for its non-linear, saturable pharmacokinetics, its vast and complex drug interaction profile, and its significant potential for both dose-dependent and idiosyncratic toxicity. Phenytoin is not a drug that tolerates imprecision; it demands a high level of clinical vigilance, expertise, and meticulous patient management to be used safely.

11.2 Key Recommendations for Safe Clinical Practice

To harness the therapeutic benefits of phenytoin while mitigating its inherent risks, the following clinical practices are essential:

• Mandate Therapeutic Drug Monitoring (TDM): TDM is not an optional adjunct but a mandatory component of safe phenytoin therapy. Regular monitoring of serum concentrations is the only reliable way to navigate its non-linear kinetics, ensure therapeutic levels, and avoid toxicity. In patients with altered protein binding (e.g., renal/hepatic disease, hypoalbuminemia), monitoring of unbound (free) levels should be strongly considered.
• Prioritize Patient and Caregiver Education: Patients must be thoroughly educated on the critical importance of strict adherence to their prescribed dose and schedule. They must be taught to recognize the early signs of toxicity (e.g., nystagmus, ataxia, confusion) and severe adverse reactions (e.g., rash, fever) and to seek immediate medical attention if they occur. They must also be counseled to consult with their physician or pharmacist before starting, stopping, or changing the dose of any other medication, including over-the-counter products and herbal supplements like St. John's Wort.
• Ensure Formulation-Specific Prescribing and Dispensing: Clinicians and pharmacists must be acutely aware of the different phenytoin formulations (extended-release capsules, chewable tablets, suspension) and their lack of interchangeability. Prescriptions should be precise, and safeguards should be in place to prevent dispensing errors that could lead to dangerous changes in bioavailability and peak serum levels.
• Maintain Vigilance in High-Risk Scenarios: Extra caution and more frequent monitoring are imperative in high-risk populations, including the elderly, pregnant women, and patients with renal or hepatic impairment. For patients receiving enteral nutrition, the drug-nutrient interaction must be anticipated and managed proactively by holding feeds and monitoring levels closely.
• Adhere to Strict Intravenous Administration Protocols: The risk of severe cardiovascular events and local tissue injury with IV phenytoin is significant. The maximum infusion rate must never be exceeded. Whenever possible, fosphenytoin should be considered the preferred parenteral agent to eliminate the risk of Purple Glove Syndrome and reduce the risk of infusion-related adverse events.

11.3 Future Outlook

In an era increasingly dominated by newer antiepileptic drugs that offer simpler linear kinetics and more favorable tolerability profiles, phenytoin's role has become more specialized. However, it is unlikely to disappear from clinical practice. Its low cost ensures its continued importance in resource-limited settings worldwide. Its long-established efficacy, particularly in the acute management of status epilepticus and for specific seizure types, guarantees its place as a critical, albeit challenging, therapeutic option for the foreseeable future. The continued safe use of phenytoin will depend on preserving and passing down the clinical wisdom required to manage its unique and demanding properties.

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