Managing Epilepsy With Phenytoin Sodium Extended-Release: A Comprehensive Guide

Overview:

Phenytoin sodium is a promising pharmacological agent for dealing with epilepsy where the person elicits repetitious seizure activities. In addition to epilepsy, it is also employed for various other seizure disorders. Phenytoin is also regarded as an antiepileptic medicine. In 1939, the drug regulatory authority of the United States, the Food and Drug Administration (FDA), endorsed the usage of Phenytoin sodium for tackling epilepsy. Earlier, it was also advised to counteract certain drug toxicities like tricyclic antidepressant toxicity (overdose intake of antidepressant medicines) and Digoxin toxicity.

Drug Group:

Phenytoin sodium is categorized under the class of anticonvulsant medicines, typically belonging to the first generation. It is a derivative of hydantoin, which checks the aberrant electrical processes in the brain. The chemical structure of Phenytoin sodium is similar to that of barbiturates, and 5,5-diphenyl-2,4-imidazolidinedione is the chemical name that denotes Phenytoin sodium.

Available Doses and Dosage Forms:

Phenytoin sodium is marketed in chewable tablet form, capsule form, particularly in extended-release formulations, and liquid form as oral suspension and injection material. 30 milligrams (mg) and 100 mg Phenytoin sodium capsules are the available and circulated dosages of extended-release Phenytoin capsules.

For Patients:

What Is Epilepsy?

Epilepsy is a specific neurological condition that is precipitated by aberrant signal generation in the brain cells. It is often manifested in the form of obvious seizures (turbulent and jerky movements of legs and arms). Nerve cells in the brain initiate certain electrical signals. It is through these signals the nerve cells communicate with each other and with muscle fibers and organs. Once the signals interact with the muscle fibers, they bring about movements. In epilepsy, there will be exaggerated and aberrant signal initiation in the nerves. Simultaneously, many nerves liberate signals to various target sites, eventually giving rise to abnormal and uncontrolled sensations, including body movement. The patient will lose their awareness and orientation during an epilepsy attack.

Epilepsy is considered to be a multifactorial condition, where numerous factors contribute to the development of this brain disorder. Aberrant brain functioning, developmental errors, alteration in the genes, abnormal growth within the brain, severe brain infections, and injury are identified to be the causative factors that can pave the way for epilepsy. In epileptic patients, the seizure activity is elicited even without any kind of provocation, unlike the seizures accompanying a high fever. Epilepsy is frequently reported in younger as well as older population groups.

Epilepsy is categorized into distinct groups considering the intensity and pattern of the seizure. Anti-epileptic medications are the mainstay medicines for tackling the manifestations of epilepsy. Various parameters like the patient's medical condition, health status, age, and seizure pattern aid in determining the most appropriate anti-epileptic medicine for that particular patient.

How Does Phenytoin Sodium Work?

Phenytoin sodium checks the aberrant brain function by hindering exaggerated impulse generation. It gears down the pace of signal production by acting on specific points in the brain cells. Once the impulse production is decelerated, repeated seizure activity will be suspended as it requires repetitious impulses to sustain the seizure. In this way, Phenytoin sodium works to check the manifestation of epilepsy.

What Is the Dosage of Phenytoin Sodium?

• Adult Dose: 300 milligrams (mg) of extended-release formulation of Phenytoin sodium is the widely preferred daily inceptive dose for the adult population, provided the patient has no prior encounter with Phenytoin sodium. During the treatment inception, 300 mg of Phenytoin sodium should be given in divided doses with a daily frequency of three. However, necessary adjustments in the dose will be advised by the concerned doctor if required. The maximum advisable daily dose for Phenytoin sodium is two 100 mg capsules at a frequency of three times. The extended-release formulation of Phenytoin sodium offers a once-a-day dosage regimen, where the patient can take 300 mg of Phenytoin sodium as a single dose. The once-a-day dosage regimen is often employed for non-compliant patients who are reluctant to stick to multiple dosage regimens. The Single dose regimen is initiated only in patients who elicited fruitful results with divided doses.

• Pediatric Dose: The dosage of Phenytoin sodium for the pediatric population is determined by taking into account the child’s body weight. Five milligrams per kilogram per day (mg/kg/day) is the recommended dosage, which should be administered as divided doses rather than a single dose.

How Effective Is Phenytoin Sodium?

Phenytoin sodium is a widely prescribed antiepileptic medicine with proven efficacy in tackling epileptic manifestations. Phenytoin sodium is reported to be highly potent in mitigating the manifestations of focal onset seizures (aberrant signal generation confined to a specific point in the brain), reported in most epileptic patients. However, it is not recommended as a single therapy for petit mal epilepsy (patients experience momentarily awareness loss). In such cases, Phenytoin sodium, in combination with other potent antiepileptic medication, is advised.

What Are the Things to Inform the Doctor Before Taking the Drug?

Before commencing the therapy using Phenytoin sodium, the concerned doctors should be informed of certain information concerning the patient.

• Any previous allergic or hypersensitivity encounter with Phenytoin sodium or other medicines that fall under the same class of anticonvulsant medications should be discussed with the doctor beforehand. Subsequent exposure to an allergic component can trigger alarming reactions in the body, which demand immediate medical attention. In addition, an allergic response to any of the components indicated in the drug label needs to be informed as it can also act as a potential trigger for severe allergic responses.

• It is imperative to keep the doctor aware of the patient’s medical history. A comprehensive medical history of the patient encompassing the underlying medical conditions and details of the patient’s past medical conditions helps the doctor evaluate the patient’s health status and assess the possibility of Phenytoin-induced worsening of any underlying ailments.

• Detailed drug history is another crucial piece of information that is essential to ensure the effectiveness of the medicine and its safety. The doctor should be informed about the patient’s drug history, encompassing dietary supplements, herbal medicines, and other over-the-counter medicines. Medicines belonging to the class of antacids, antifungals, anticoagulants, antivirals, immunosuppressants, and antimalarials can interfere with Phenytoin’s processing and actions. A patient's drug history aids in checking unwanted drug-to-drug associations and their potential impact on the patient’s body.

• The doctor should be made aware of the patient’s pregnancy and breastfeeding status. Phenytoin sodium can precipitate potential toxicities in the baby developing in the womb when consumed by the expectant mother. Effective birth control measures should be undertaken to check accidental conception during Phenytoin therapy. In addition, if the patient is planning for conception in the near future, the doctor should be informed about this so that appropriate changes in the medicine choice can be made beforehand.

How Is Phenytoin Sodium Administered?

The extended-release formulation of Phenytoin sodium capsules is made available in the market as capsules, and hence, the oral route is the indicated administration route. Chewable tablet forms and oral suspension forms are also available for oral intake, but the dose and drug concentration vary. Phenytoin capsule should be swallowed with a glass of water without fracturing or breaking it.

What Are the Side Effects of Phenytoin Sodium?

There is a wide range of side effects that are precipitated during Phenytoin therapy. Some of the frequently reported adverse effects concerning Phenytoin include the following:

• Sleeping disturbances, mental confusion, and dizziness are often found to be associated with Phenytoin therapy.

• Phenytoin intake can precipitate gastrointestinal issues in the form of vomiting, stomach pain, liver disorders, appetite loss, constipation, and nausea. Altered taste sensations and persisting headaches are other potential adverse effects of Phenytoin.

• Long-term therapy using Phenytoin often impacts speech. Speech becomes unclear and slurred. Exaggerated growth of the lips, gums, and hair is often elicited during Phenytoin therapy.

• Eyeball elicits fluttering movements, giving rise to nystagmus (aberrant eye movements). In addition, abnormal muscle twitching and body movements are also reported during the therapy.

• More severe forms of adverse reactions are presented in the form of skin reactions, widespread skin rashes, skin hives or bumps, blisters, abnormal skin pigmentation, and pinpoint blood-colored dots over the skin.

• Mouth ulcers, facial puffiness, exhaustion, short breaths, troubled breathing, chest discomfort, and heart racing are some of the alarming side effects that entail immediate medical care for the patient.

Dietary Considerations:

There are no specific dietary instructions that need to be followed while on Phenytoin therapy. At times, the concerned healthcare specialist may advise certain dietary considerations, taking into account the patient’s health status and concurrent medical conditions that the patient suffers from. In such cases, the patients should adhere to those instructions promptly.

Missed Dose:

The patients are instructed to strictly adhere to the dosage frequency and regimen advised by the doctors. It is better to follow a specific time for the intake of the medicines, which ensures a consistent concentration of medicine in the blood throughout the treatment course. However, at times, patients may fail to take the medicine in the stipulated time. In such cases, the patient can take the medicine once they become aware of the overlooked dose, provided there is enough time gap for the subsequent dose. If the patient recalls the overlooked dose at the time of the subsequent dose, it is advised to skip or disregard the missed one, and the patient can go ahead with the subsequent dose. It is strictly warned not to take double the prescribed dose to make up for the overlooked one, as it can bring in complex adverse reactions.

Overdose:

Consuming more than the estimated safe dose can bring about serious overdose issues. Neurological manifestations are mostly encountered upon oral overdose. In addition, it can severely impact the way in which the heart and its associated blood vessels function. However, cardiovascular effects are more pronounced with overdose induced by parenteral (through veins) introduction of Phenytoin. The Phenytoin dose exceeding two grams is estimated to be lethal and grave for the patient. The severity and intensity of neurological manifestations of Phenytoin are directly proportional to the drug’s concentration in the blood. It ranges from nystagmus (aberrant eye movement) to coma (unresponsive and unconscious state). Other manifestations like sleepiness, diminishing muscle control, fine tremors, unclear speech, and mental confusion are also identified during Phenytoin overdose. It entails immediate medical care; otherwise, it has the potential to precipitate death by multiorgan failures.

Storage:

Extended-release Phenytoin pills either come on blister packaging or in medicine bottles. It is advised to keep the pills in the packaging until the time of consumption. 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit) is the estimated safe temperature range for Phenytoin extended-release pill storage. Moisture, excessive heat, and sunlight can impact the pill constituents, hence mandating proper storage.

For Doctors:

Indication:

• Grand mal epilepsy.

• Psychomotor seizures.

• Seizures encountered during or after neurological surgery (prevention and management).

Dose:

1. Dosage for Adult Patients: An inceptive dose of 100 mg at a daily frequency of three times is recommended to be the standard dose of extended-release Phenytoin for patients with no prior exposure to Phenytoin sodium. After analyzing the patient's response to the inceptive dose, the doctor will modify the dosage accordingly and determine the accurate maintenance dose. The maintenance dose can be administered either as a single or divided dose:

• Single-Dose Regimen: Once the inceptive doses are well tolerated, a single-dose regimen can be initiated, where a single dose of 300 mg of extended-release Phenytoin pill formulation is administered on a daily basis. This regimen is mostly advised for non-compliant patients.

• Divided-Dose Regimen: 300 mg of daily dose is administered in the form of three divided doses of 100mg.

• Loading Dose: Oral loading dose is restricted to patients in the hospital with obvious access for constant monitoring of the drug’s concentration, who cannot tolerate parenteral administration.

2. Dosage for Pediatric Patients: For pediatric patients under six years of age, five milligrams per kilogram of body weight per day is the recommended daily dosage. No single-dose regimen is preferred for pediatric patients; the daily dose needs to be split into smaller doses and given at a daily frequency of two or three times.

Dosing Considerations:

Though there is a standard dosage regimen, the dosage requirement of Phenytoin sodium extended-release pills may vary on an individual basis. Post-dosage monitoring of the drug’s concentration in the blood aids the doctor in determining the most accurate dose for that particular patient so that necessary alterations in the dosage can be initiated. However, a minimum of seven days interval should be given between each dose change. While shifting from one Phenytoin formulation to another, appropriate dose correction needs to be made. Otherwise, it can end up in either enhanced or collapsed drug concentration in the blood.

What Are the Pharmacological Aspects of Phenytoin Sodium?

• Mechanism: Phenytoin sodium checks the exponential rise in membrane action potential by hindering the voltage-gated membrane sodium channels in the brain nerves. It hampers and restricts the continual release of neuronal signals. By restricting the action potential, the positive feedback mechanism will be interrupted, which eventually breaks the continuous firing of the action potential. In the absence of continuous, uninterrupted firing, sustained seizure activity cannot be precipitated, and in this way, Phenytoin sodium collapses the epileptic manifestations.

• Pharmacodynamics: Voltage-gated sodium channels are hindered by Phenytoin in such a way that it only curbs the firing at high frequency. This ensures that normal brain functioning and activities go unhindered and trouble-free, even in the presence of active Phenytoin in the blood.

• Pharmacokinetics: Being an extended-release formulation, the utmost blood concentration is attained in four to 12 hours post-oral intake. In a span of seven to 10 days, consistency in the blood concentration of Phenytoin sodium will be established. Plasma proteins are concerned with the distribution of the Phenytoin sodium drug molecules. However, once the drug molecules attach to these plasma proteins, they lose their pharmacological effectiveness. An appreciable concentration of free Phenytoin drug molecules is recorded in the central nervous system (CNS), which enhances the effectiveness of Phenytoin in tackling CNS issues. The liver enzymes, particularly the cytochrome P450 enzyme system, are concerned with the metabolism and breaking down of Phenytoin. Among the cytochrome P450 enzyme series, cytochrome P2C9 and P2C19 are responsible for the metabolism. Elimination and removal of Phenytoin from the body is primarily through the urinary route.

Toxicity:

Non-clinical toxicological studies have been conducted to demonstrate the carcinogenicity and mutagenicity associated with Phenytoin therapy. Long-term studies on mice with an appreciably higher dose of Phenytoin precipitated incidences of carcinogenesis in the form of hepatocellular tumors. However, studies on rats could not expose any carcinogenic association. Incidences of fertility impairment and clastogenic changes were neither reported in mice nor in rats.

Clinical Studies:

Comparative clinical studies have been conducted to elucidate the potency of Phenytoin sodium extended-release formulations in tackling epileptic manifestations. These randomized studies concluded that the efficacy of Phenytoin sodium is on par with other anticonvulsants like Sodium valproate.

What Are the Contraindications of Phenytoin Sodium?

Phenytoin is not advisable to all patients; there are certain conditions in which Phenytoin administration can pose health risks to the patients.

• Patients with known allergic encounters with Phenytoin are not advised to take oral extended-release formulations. Allergy or exaggerated reactivity to any of the medicines that belong to the group of hydantoins also carries the risk of eliciting an allergic response towards Phenytoin.

• Patients with a past incidence of functional impairment of the liver triggered by Phenytoin are also contraindicated to Phenytoin therapy.

• Pregnant women are not supposed to undergo therapy using Phenytoin, as it can bring about fetal harm and birth defects.

• Phenytoin therapy is contraindicated for patients who are simultaneously undergoing therapy using non-nucleoside reverse transcriptase inhibitors like Delavirdine.

Warnings and Precautions:

• Status Epilepticus: Phenytoin therapy should not be terminated all of a sudden; instead, gradual depreciation in the dose is advised to guide the withdrawal smoothly and safely. Sudden withdrawal from Phenytoin therapy precipitates status epilepticus.

• Grave Skin Reactions: Phenytoin therapy is capable of triggering grave skin reactions in the form of Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic syndrome (DRESS), toxic epidermal necrolysis, acute generalized exanthematous pustulosis (AGEP). These grave skin reactions are encountered within the first month after the commencement of Phenytoin therapy, and hence, patients should be cautioned about the appearance of skin rash.

• Suicidal Tendency: Being an antiepileptic drug, Phenytoin is capable of modifying one’s thought process. An enhanced suicidal tendency is elicited with all categories of anti-epileptic medications.

• Angioedema: Post-marketing surveillance reported incidences of angioedema during the course of Phenytoin therapy. In the event of facial puffiness, the patients should seek immediate medical guidance from the concerned doctor regarding the cessation of Phenytoin therapy.

• Familial Susceptibility to Drug Allergy: Patients with an obvious family history of exaggerated reactivity to certain other anticonvulsant drugs (that elicit structural resemblance with Phenytoin sodium) are susceptible to reflecting an allergic response upon Phenytoin therapy.

• Liver Toxicity: Long-term therapy using Phenytoin can potentially impair the functions of the liver, giving rise to various liver problems, like hepatomegaly, liver failure, and jaundice. It can even bring about fatal liver conditions. Also, impaired liver functioning gears down the metabolism of Phenytoin, which in turn enhances the drug’s concentration in the blood.

• Heart Issues: Phenytoin therapy enhances the susceptibility for heart failure when advised to patients with existing heart conditions.

• Blood Cell Count Discrepancies: Pancytopenia, agranulocytosis, leukopenia, granulocytopenia, and thrombocytopenia are also precipitated during Phenytoin therapy. Hence, periodic monitoring of the blood picture is crucial to keep track of discrepancies in the blood cell count.

• Impact on Bone: Phenytoin interferes with the processing of vitamin D in the body. Under the influence of Phenytoin, vitamin D metabolism gears up, which eventually gives rise to vitamin D deficiency. Depreciation in vitamin D is reflected in bone health in the form of collapsed bone density. Vitamin D deficiency is often associated with hypocalcemia.

• Worsen Porphyria: Phenytoin is capable of aggravating porphyria. Therefore, while advising Phenytoin therapy to patients diagnosed with porphyria, patients should be forewarned about the risk of porphyria exacerbation and necessary preventive measures should be taken to tackle the condition.

• Psychosis: An appreciable hike in the Phenytoin’s concentration beyond the pharmacological limit can bring in a state of psychosis.

• Enhanced Blood Sugar Level: Phenytoin can hamper the effects of insulin, which in turn gives rise to hyperglycemia.

What Are the Drug Interactions of Phenytoin Sodium?

Phenytoin sodium tends to elicit interactions with a wide spectrum of medicines.

• Simultaneous intake of Phenytoin with medicines like Ethosuximide, Topiramate, Fluconazole, Fluoxetine, Fluorouracil, Cimetidine, Sulfadiazine, Warfarin, or Amiodarone potentiates the Phenytoin’s concentration in the blood. It poses the risk of toxicity issues.

• Phenytoin’s interaction with drugs like Bleomycin, Ritonavir, Carbamazepine, and antacids brings about a remarkable collapse in Phenytoin’s concentration, making it less effective.

• Valproic acid, Valproate sodium, and Phenobarbital are certain other anticonvulsants that are capable of altering the concentration of Phenytoin when taken concurrently with Phenytoin.

• Simultaneous therapy using Phenytoin also collapses the potency of other drugs like Ketoconazole, Paclitaxel, Delavirdine, Pancuronium, Warfarin, and Rifampin. This interaction makes those medicines ineffective.

• Association with Phenytoin depletes the serum concentration of drugs like Atorvastatin, Carbamazepine, Ritonavir, Nifedipine, and Albendazole. As a result, the intended action of these drugs will be compromised considerably.

Specific Considerations:

• Phenytoin Sodium During Pregnancy: Phenytoin can induce teratogenic effects on the developing fetus. There are frequent reports of birth defects, malformations, and congenital syndrome in women who underwent Phenytoin therapy during conception. Fetal hydantoin syndrome is the widely reported birth defect precipitated by maternal intake of antiepileptic medicine during conception. Hence, expectant mothers are strictly advised to refrain from consuming antiepileptic medicines.

• Phenytoin Sodium During Lactation: Clinical evidence exposed the transmission of Phenytoin into the baby’s body through breastmilk when consumed by a lactating mother. Hence, it is not advisable for a lactating mother.

• Phenytoin Sodium for Geriatric Patients: Geriatric patients have compromised kidney and liver functions; hence, the dosing frequency needs to be curbed to mitigate toxicity issues.