Dilantin-125

Name: Dilantin-125

Pharmacology

Mechanism of Action

Promotes Na+ efflux or decreases Na+ influx from membranes in motor cortex neurons; stabilizes neuronal membrane

Slows conduction velocity

Absorption

Bioavailability: May vary between different manufacturers; dependent on formulation

Onset: 1 week (PO); 2-24 hr (PO with loading dose); 0.5-1 hr (IV)

Peak plasma time: 1.5-3 hr (immediate-release); 4-12 hr (extended-release)

Distribution

Protein bound: 95% (adults); 85% (infants); 80% (neonates)

Vd: 0.6-0.7 L/kg (adults); 0.7 L/kg (children); 0.7-0.8 L/kg (infants); 0.8-0.9 L/kg (full-term neonate); 1-1.2 L/kg (premature neonate)

Metabolism

Metabolized by hepatic P450 enzyme CYP2C9

Metabolites: Inactive

Enzymes induced: CYP3A4

Elimination

Half-life: 22 hr (PO); 10-15 hr (IV)

Excretion: Urine

Pharmacogenomics

HLA variants

  • Patients with HLA-B*1502 with are more likely to have a severe dermatologic reaction (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome) when taking phenytoin
  • This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including Han Chinese, Filipinos, Malaysians, South Asian Indians, and Thais

Epoxide genotypes

  • Maternal epoxide (EPHX1) genotypes 113*H and 139*R are associated with risk of fetal hydantoin syndrome among pregnant women taking phenytoin
  • Increased levels of the reactive epoxide metabolites by either inhibiting the detoxification of these metabolites by epoxide hydrolase or by increasing conversion to epoxide metabolites by inducing CYP3A4, 2C9, or 2C19

Genetic testing laboratories (for HLA variants)

  • Kashi Clinical Laboratories (www.kashilab.com)
  • LabCorp (http://www.labcorp.com/)
  • Specialty Laboratories (http://www.specialtylabs.com)
  • Quest (http://www.questdiagnostics.com)

What is Dilantin?

Phenytoin is an oral and injectable anti-seizure medication first synthesized in 1908.

Why is Dilantin prescribed to patients?

Phenytoin is an anti-seizure medication (anticonvulsant) used for preventing or treating generalized tonic-clonic (grand mal) seizures, complex partial seizures (psychomotor seizures), and seizures occurring during or after neurosurgery. It may be used alone or with phenobarbital or other anticonvulsants.

What is the dosage for Dilantin?

The dosing of phenytoin is patient specific. It may be given once, twice, 3, or 4 times daily. Doses are often adjusted to find the optimal dose based on measurement of blood levels. Taking phenytoin with food may reduce some of the side effects. Elderly patients, debilitated persons, and patients with certain kidney or liver diseases may need lower doses. The suspension should not be given at the same time as tube feedings since tube feedings bind to phenytoin and reduce its absorption. The recommended adult dose is 100 mg two to four times daily. Some patients may require 200 mg three times daily. Patients stabilized on 100 mg three times daily may receive 300 mg once daily of the extended release capsules.

Which drugs or supplements interact with Dilantin?

There are many potential drug interactions with phenytoin. Phenytoin can increase the metabolism (elimination) of many drugs, reducing their concentrations in the body. Drugs that may be affected include:

  • digoxin (Lanoxin),
  • carbamazepine (Tegretol, Tegretol XR, Equetro, Carbatrol),
  • clonazepam (Klonopin),
  • corticosteroids (for example, prednisone),
  • cyclosporine,
  • disopyramide,
  • doxycycline,
  • estrogens,
  • oral contraceptives,
  • paroxetine (Paxil, Paxil CR, Pexeva),
  • quinidine,
  • tacrolimus (Prograf),
  • theophylline,
  • phenobarbital,
  • valproic acid (Depakote, Depakote ER, Depakene, Depacon, Stavzor), and
  • warfarin (Coumadin).

Phenytoin can interact with these drugs not only when it is added to therapy but also when it is discontinued. In the latter case, the concentration of the other drugs may increase. Sometimes the effect may be unpredictable. Phenytoin's metabolism may be affected by other drugs. Drugs that increase phenytoin blood levels and toxicity include:

  • acute alcohol intake,
  • amiodarone (Coradone),
  • chlordiazepoxide,
  • cimetidine (Tagamet),
  • diazepam (Valium, Diastat),
  • dicumarol,
  • disulfiram,
  • estrogens,
  • ethosuximide,
  • fluoxetine (Prozac),
  • fluorouracil,
  • fluvoxamine (Luvox),
  • isoniazid,
  •  methylphenidate (Concerta),
  • omeprazole (Prilosec),
  • sertraline (Zoloft),
  • tolbutamide, and
  • trazodone (Desyrel).

Drugs that may decrease phenytoin levels and reduce effectiveness include carbamazepine, chronic alcohol abuse, reserpine, and sucralfate (Carafate).

The oral absorption of phenytoin can be reduced by any of the following:

  • antacids containing magnesium,
  • calcium carbonate, or aluminum;
  • calcium salts; or enteral feeding products (tube feedings).

Separating the administration of phenytoin and enteral feeding products, antacids, or calcium salts by at least 2 hours will help avoid this interaction.

Clinical pharmacology

Mechanism Of Action

Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures.

Pharmacokinetics And Drug Metabolism

The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5–7 half-lives) after initiation of therapy with recommended doses of 300 mg/day.

When serum level determinations are necessary, they should be obtained at least 5–7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient’s next scheduled dose. Peak levels indicate an individual’s threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin-125 Suspension, peak levels occur 1½–3 hours after administration.

Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin.

In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal.

Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more.

Special Populations

Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see DOSAGE AND ADMINISTRATION). Unbound phenytoin concentrations may be more useful in these patient populations.

Age: Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20-30 years of age). Phenytoin dosing requirements are highly variable and must be individualized (see DOSAGE AND ADMINISTRATION).

Gender and Race: Gender and race have no significant impact on phenytoin pharmacokinetics.

Pediatrics: Initially, 5 mg/kg/day in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily. A recommended daily maintenance dosage is usually 4 to 8 mg/kg. Children over 6 years and adolescents may require the minimum adult dose (300 mg/day).

  • Antacids
  • Information on Birth Control Pills
  • Seizure (Epilepsy)
  • Seizures Symptoms and Types

Dilantin-125 Description

DILANTIN (phenytoin) is related to the barbiturates in chemical structure, but has a five-membered ring. The chemical name is 5,5-diphenyl-2,4 imidazolidinedione, having the following structural formula:

Each 5 mL of the oral suspension contains 125 mg of phenytoin, USP; alcohol, USP (maximum content not greater than 0.6 percent); banana flavor; carboxymethylcellulose sodium, USP; citric acid, anhydrous, USP; glycerin, USP; magnesium aluminum silicate, NF; orange oil concentrate; polysorbate 40, NF; purified water, USP; sodium benzoate, NF; sucrose, NF; vanillin, NF; and FD&C yellow No. 6.

Dilantin-125 - Clinical Pharmacology

Mechanism of Action

The precise mechanism by which phenytoin exerts its therapeutic effect has not been established but is thought to involve the voltage-dependent blockade of membrane sodium channels resulting in a reduction in sustained high-frequency neuronal discharges.

Pharmacokinetics

Absorption

For Dilantin-125 Suspension, peak levels occur 1½ to 3 hours after administration. Steady-state therapeutic levels are achieved at least 7 to 10 days (5 to 7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5 to 7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved.

Distribution

Phenytoin is extensively bound to serum plasma proteins.

Elimination

The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours.

Metabolism

Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high serum levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more.

In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, variant CYP2C9 and CYP2C19 alleles, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin serum levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal.

Excretion

Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion.

Specific Populations

Age: Geriatric Population:

Phenytoin clearance tends to decrease with increasing age (20% less in patients over 70 years of age relative to that in patients 20 to 30 years of age). Since phenytoin clearance is decreased slightly in elderly patients, lower or less frequent dosing may be required [see Dosage and Administration (2.7)].

Sex/Race:

Gender and race have no significant impact on phenytoin pharmacokinetics.

Renal or Hepatic Impairment:

Increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia has been reported.

Pregnancy:

It has been reported in the literature that the plasma clearance of phenytoin generally increased during pregnancy, reached a peak in the third trimester and returned to the level of pre-pregnancy after few weeks or months of delivery.

Drug Interaction Studies

Phenytoin is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19.

Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes [see Drug Interactions (7.1, 7.2)].

How Supplied/Storage and Handling

How Supplied

Dilantin-125 Oral Suspension is supplied as follows:

Package Configuration Strength NDC
8-oz bottles 125 mg phenytoin/5mL 0071-2214-20

Dilantin-125 Suspension (phenytoin oral suspension, USP), 125 mg phenytoin/5 mL contains a maximum alcohol content not greater than 0.6 percent in an orange suspension with an orange-vanilla flavor.

Storage and Handling

Store at 20° to 25°C (68° to 77°F); see USP controlled room temperature.

Protect from light. Do not freeze.

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