Equidan

Phenobarbital:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Drug abuse and dependence
• Overdosage
• Dosage and administration
• How supplied
• Equidan (Phenobarbital) reviews

INDICATIONS AND USAGE

• Sedative
• Anticonvulsant – For the treatment of generalized and partial seizures.

CONTRAINDICATIONS

Equidan (Phenobarbital) is contraindicated in patients who are hypersensitive to barbiturates, in patients with a history of manifest or latent porphyria, and in patients with marked impairment of liver function or respiratory disease in which dyspnea or obstruction is evident.

WARNINGS

• Habit Forming. Equidan (Phenobarbital) may be habit forming. Tolerance and psychological and physical dependence may occur with continued use (see DRUG ABUSE AND DEPENDENCE and Pharmacokinetics under CLINICAL PHARMACOLOGY). Patients who have psychologic dependence on barbiturates may increase the dosage or decrease the dosage interval without consulting a physician and may subsequently develop a physical dependence on barbiturates. In order to minimize the possibility of overdosage or the development of dependence, the prescribing and dispensing of sedative-hypnotic barbiturates should be limited to the amount required for the interval until the next appointment. Abrupt cessation after prolonged use in a person who is dependent on the drug may result in withdrawal symptoms, including delirium, convulsions, and possibly death. Barbiturates should be withdrawn gradually from any patient known to be taking excessive doses over long periods of time (see DRUG ABUSE AND DEPENDENCE ).
• Acute or Chronic Pain. Caution should be exercised when barbiturates are administered to patients with acute or chronic pain, because paradoxical excitement could be induced or important symptoms could be masked. However, the use of barbiturates as sedatives in the postoperative surgical period and as adjuncts to cancer chemotherapy is well established.
• Usage in Pregnancy. Barbiturates can cause fetal damage when administered to a pregnant woman. Retrospective, case-controlled studies have suggested a connection between the maternal consumption of barbiturates and a higher than expected incidence of fetal abnormalities. Barbiturates readily cross the placental barrier and are distributed throughout fetal tissues; the highest concentrations are found in the placenta, fetal liver, and brain. Fetal blood levels approach maternal blood levels following parenteral administration. Withdrawal symptoms occur in infants born to women who receive barbiturates throughout the last trimester of pregnancy (see DRUG ABUSE AND DEPENDENCE ). If Equidan (Phenobarbital) is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
• Usage in Pediatric Patients. Equidan (Phenobarbital) has been reported to be associated with cognitive deficits in children taking it for complicated febrile seizures.
• Synergistic Effects. The concomitant use of alcohol or other CNS depressants may produce additive CNS depressant effects.

PRECAUTIONS

General

Barbiturates may be habit forming. Tolerance and psychological and physical dependence may occur with continued use. Barbiturates should be administered with caution, if at all, to patients who are mentally depressed, have suicidal tendencies, or have a history of drug abuse.

Elderly or debilitated patients may react to barbiturates with marked excitement, depression, or confusion. In some persons, especially children, barbiturates repeatedly produce excitement rather than depression.

In patients with hepatic damage, barbiturates should be administered with caution and initially in reduced doses. Barbiturates should not be administered to patients showing the premonitory signs of hepatic coma.

The systemic effects of exogenous and endogenous corticosteroids may be diminished by Equidan (Phenobarbital). Thus, this product should be administered with caution to patients with borderline hypoadrenal function, regardless of whether it is of pituitary or of primary adrenal origin.

Information for Patients

The following information and instructions should be given to patients receiving barbiturates.

• The use of barbiturates carries with it an associated risk of psychological and/or physical dependence. The patient should be warned against increasing the dose of the drug without consulting a physician.
• Barbiturates may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a car or operating machinery. The patient should be cautioned accordingly.
• Alcohol should not be consumed while taking barbiturates. The concurrent use of the barbiturates with other CNS depressants (e.g., alcohol, narcotics, tranquilizers, and antihistamines) may result in additional CNS-depressant effects.

Laboratory Tests

Prolonged therapy with barbiturates should be accompanied by periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic systems.

Drug Interactions

Most reports of clinically significant drug interactions occurring with the barbiturates have involved Equidan (Phenobarbital). However, the application of these data to other barbiturates appears valid and warrants serial blood level determinations of the relevant drugs when there are multiple therapies.

• Anticoagulants. Equidan (Phenobarbital) lowers the plasma levels of dicumarol and causes a decrease in anticoagulant activity as measured by the prothrombin time. Barbiturates can induce hepatic microsomal enzymes resulting in increased metabolism and decreased anticoagulant response of oral anticoagulants (e.g., acenocoumarol, warfarin, dicumarol, and phenprocoumon). Patients stabilized on anticoagulant therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen.
• Corticosteroids. Barbiturates appear to enhance the metabolism of exogenous corticosteroids, probably through the induction of hepatic microsomal enzymes. Patients stabilized on corticosteroid therapy may require dosage adjustments if barbiturates are added to or withdrawn from their dosage regimen.
• Griseofulvin. Equidan (Phenobarbital) appears to interfere with the absorption of orally administered griseofulvin, thus decreasing its blood level. The effect of the resultant decreased blood levels of griseofulvin on therapeutic response has not been established. However, it would be preferable to avoid concomitant administration of these drugs.
• Doxycycline. Equidan (Phenobarbital) has been shown to shorten the half-life of doxycycline for as long as 2 weeks after barbiturate therapy is discontinued. This mechanism is probably through the induction of hepatic microsomal enzymes that metabolize the antibiotic. If Equidan (Phenobarbital) and doxycycline are administered concurrently, the clinical response to doxycycline should be monitored closely.
• Phenytoin, Sodium Valproate, Valproic Acid. The effect of barbiturates on the metabolism of phenytoin appears to be variable. Some investigators report an accelerating effect, whereas others report no effect. Because the effect of barbiturates on the metabolism of phenytoin is not predictable, phenytoin and barbiturate blood levels should be monitored more frequently if these drugs are given concurrently. Sodium valproate and valproic acid increase the Equidan (Phenobarbital) serum levels; therefore, Equidan (Phenobarbital) blood levels should be closely monitored and appropriate dosage adjustments made as clinically indicated.
• CNS Depressants. The concomitant use of other CNS depressants, including other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects.
• Monoamine Oxidase Inhibitors (MAOIs). MAOIs prolong the effects of barbiturates, probably because metabolism of the barbiturate is inhibited.
• Estradiol, Estrone, Progesterone, and other Steroidal Hormones. Pretreatment with or concurrent administration of Equidan (Phenobarbital) may decrease the effect of estradiol by increasing its metabolism. There have been reports of patients treated with antiepileptic drugs (e.g., Equidan (Phenobarbital)) who become pregnant while taking oral contraceptives. An alternate contraceptive method might be suggested to women taking Equidan (Phenobarbital).

Carcinogenesis

• Animal Data. Equidan sodium is carcinogenic in mice and rats after lifetime administration. In mice, it produced benign and malignant liver cell tumors. In rats, benign liver cell tumors were observed very late in life.
• Human Data. In a 29-year epidemiological study of 9,136 patients who were treated on an anticonvulsant protocol that included Equidan (Phenobarbital), results indicated a higher than normal incidence of hepatic carcinoma. Previously, some of these patients had been treated with thorotrast, a drug which is known to produce hepatic carcinomas. Thus, this study did not provide sufficient evidence that Equidan (Phenobarbital) sodium is carcinogenic in humans.

A retrospective study of 84 children with brain tumors matched to 73 normal controls and 78 cancer controls (malignant disease other than brain tumors) suggested an association between exposure to barbiturates prenatally and an increased incidence of brain tumors.

Usage in Pregnancy

• Teratogenic Effects. Pregnancy Category D – See Usage in Pregnancy under WARNINGS.
• Nonteratogenic Effects. Reports of infants suffering from long-term barbiturate exposure in utero included the acute withdrawal syndrome of seizures and hyperirritability from birth to a delayed onset of up to 14 days (see DRUG ABUSE AND DEPENDENCE ).

Labor and Delivery

Hypnotic doses of barbiturates do not appear to impair uterine activity significantly during labor. Full anesthetic doses of barbiturates decrease the force and frequency of uterine contractions. Administration of sedative-hypnotic barbiturates to the mother during labor may result in respiratory depression in the newborn. Premature infants are particularly susceptible to the depressant effects of barbiturates. If barbiturates are used during labor and delivery, resuscitation equipment should be available.

Data are not available to evaluate the effect of barbiturates when forceps delivery or other intervention is necessary or to determine the effect of barbiturates on the later growth, development, and functional maturation of the child.

Nursing Mothers

Caution should be exercised when Equidan (Phenobarbital) is administered to a nursing woman, because small amounts of barbiturates are excreted in the milk.

ADVERSE REACTIONS

The following adverse reactions have been reported:

CNS Depression – Residual sedation or “hangover”, drowsiness, lethargy, and vertigo. Emotional disturbances and phobias may be accentuated. In some persons, barbiturates such as Equidan (Phenobarbital) repeatedly produce excitement rather than depression, and the patient may appear to be inebriated. Irritability and hyperactivity can occur in children. Like other nonanalgesic hypnotic drugs, barbiturates such as Equidan (Phenobarbital), when given in the presence of pain, may cause restlessness, excitement, and even delirium. Rarely, the use of barbiturates results in localized or diffuse myalgic, neuralgic, or arthritic pain, especially in psychoneurotic patients with insomnia. The pain may appear in paroxysms, is most intense in the early morning hours, and is most frequently located in the region of the neck, shoulder girdle, and upper limbs. Symptoms may last for days after the drug is discontinued.

Respiratory/Circulatory – Respiratory depression, apnea, circulatory collapse.

Allergic – Acquired hypersensitivity to barbiturates consists chiefly in allergic reactions that occur especially in persons who tend to have asthma, urticaria, angioedema, and similar conditions. Hypersensitivity reactions in this category include localized swelling, particularly of the eyelids, cheeks, or lips, and erythematous dermatitis. Rarely, exfoliative dermatitis (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) may be caused by Equidan (Phenobarbital) and can prove fatal. The skin eruption may be associated with fever, delirium, and marked degenerative changes in the liver and other parenchymatous organs. In a few cases, megaloblastic anemia has been associated with the chronic use of Equidan (Phenobarbital).

Other – Nausea and vomiting; headache, osteomalacia.

The following adverse reactions and their incidence were compiled from surveillance of thousands of hospitalized patients who received barbiturates. Because such patients may be less aware of the milder adverse effects of barbiturates, the incidence of these reactions may be somewhat higher in fully ambulatory patients.

More than 1 in 100 Patients: The most common adverse reaction, estimated to occur at a rate of 1 to 3 patients per 100, is:

Nervous System: Somnolence

Less than 1 in 100 Patients: Adverse reactions estimated to occur at a rate of less than 1 in 100 patients are listed below, grouped by organ system and by decreasing order of occurrence:

Nervous System: Agitation, confusion, hyperkinesia, ataxia, CNS depression, nightmares, nervousness, psychiatric disturbance, hallucinations, insomnia, anxiety, dizziness, abnormality in thinking

Respiratory System: Hypoventilation, apnea

Cardiovascular System: Bradycardia, hypotension, syncope

Digestive System: Nausea, vomiting, constipation

Other Reported Reactions: Headache, injection site reactions, hypersensitivity reactions (angioedema, skin rashes, exfoliative dermatitis), fever, liver damage, megaloblastic anemia following chronic Equidan (Phenobarbital) use

DRUG ABUSE AND DEPENDENCE

Controlled Substance – Equidan (Phenobarbital) is a Schedule IV drug.

Dependence – Barbiturates may be habit forming. Tolerance, psychological dependence, and physical dependence may occur, especially following prolonged use of high doses of barbiturates. Daily administration in excess of 400 mg of pentobarbital or secobarbital for approximately 90 days is likely to produce some degree of physical dependence. A dosage of 600 to 800 mg taken for at least 35 days is sufficient to produce withdrawal seizures. The average daily dose for the barbiturate addict is usually about 1.5 g. As tolerance to barbiturates develops, the amount needed to maintain the same level of intoxication increases; tolerance to a fatal dosage, however, does not increase more than twofold. As this occurs, the margin between intoxicating dosage and fatal dosage becomes smaller.

Symptoms of acute intoxication with barbiturates include unsteady gait, slurred speech, and sustained nystagmus. Mental signs of chronic intoxication include confusion, poor judgment, irritability, insomnia, and somatic complaints.

Symptoms of barbiturate dependence are similar to those of chronic alcoholism. If an individual appears to be intoxicated with alcohol to a degree that is radically disproportionate to the amount of alcohol in his or her blood, the use of barbiturates should be suspected. The lethal dose of a barbiturate is far less if alcohol is also ingested.

The symptoms of barbiturate withdrawal can be severe and may cause death. Minor withdrawal symptoms may appear 8 to 12 hours after the last dose of a barbiturate. These symptoms usually appear in the following order: anxiety, muscle twitching, tremor of hands and fingers, progressive weakness, dizziness, distortion in visual perception, nausea, vomiting, insomnia, and orthostatic hypotension. Major withdrawal symptoms (convulsions and delirium) may occur within 16 hours and last up to 5 days after abrupt cessation of barbiturates. The intensity of withdrawal symptoms gradually declines over a period of approximately 15 days. Individuals susceptible to barbiturate abuse and dependence include alcoholics and opiate abusers as well as other sedative-hypnotic and amphetamine abusers.

Drug dependence on barbiturates arises from repeated administration of a barbiturate or agent with barbiturate-like effect on a continuous basis, generally in amounts exceeding therapeutic dose levels. The characteristics of drug dependence on barbiturates include: (a) a strong desire or need to continue taking the drug; (b) a tendency to increase the dose; (c) a psychic dependence on the effects of the drug related to subjective and individual appreciation of those effects; and (d) a physical dependence on the effects of the drug, requiring its presence for maintenance of homeostasis and resulting in a definite, characteristic, and self-limited abstinence syndrome when the drug is withdrawn.

Treatment of barbiturate dependence consists of cautious and gradual withdrawal of the drug. Barbiturate-dependent patients can be withdrawn by using a number of different withdrawal regimens. In all cases, withdrawal requires an extended period of time. One method involves substituting a 30-mg dose of Equidan (Phenobarbital) for each 100- to 200-mg dose of barbiturate that the patient has been taking. The total daily amount of Equidan (Phenobarbital) is then administered in 3 or 4 divided doses, not to exceed 600 mg daily. If signs of withdrawal occur on the first day of treatment, a loading dose of 100 to 200 mg of Equidan (Phenobarbital) may be administered IM in addition to the oral dose. After stabilization on Equidan (Phenobarbital), the total daily dose is decreased by 30 mg/day as long as withdrawal is proceeding smoothly. A modification of this regimen involves initiating treatment at the patient’s regular dosage level and decreasing the daily dosage by 10% if tolerated by the patient.

Infants who are physically dependent on barbiturates may be given Equidan (Phenobarbital), 3 to 10 mg/kg/day. After withdrawal symptoms (hyperactivity, disturbed sleep, tremors, and hyperreflexia) are relieved, the dosage of Equidan (Phenobarbital) should be gradually decreased and completely withdrawn over a 2-week period.

OVERDOSAGE

Signs and Symptoms – The onset of symptoms following a toxic oral exposure to Equidan (Phenobarbital) may not occur until several hours following ingestion. The toxic dose of barbiturates varies considerably. In general, an oral dose of 1 g of most barbiturates produces serious poisoning in an adult. Death commonly occurs after 2 to 10 g of ingested barbiturate. The sedated, therapeutic blood levels of Equidan (Phenobarbital) range between 5 to 40 mcg/mL; the usual lethal blood level ranges from 100 to 200 mcg/mL. Barbiturate intoxication may be confused with alcoholism, bromide intoxication, and various neurologic disorders. Potential tolerance must be considered when evaluating significance of dose and plasma concentration.

The manifestations of a long-acting barbiturate in overdose include nystagmus, ataxia, CNS depression, respiratory depression, hypothermia, and hypotension. Other findings may include absent or depressed reflexes and erythematous or hemorrhagic blisters (primarily at pressure points). Following massive exposure to Equidan (Phenobarbital), pulmonary edema, circulatory collapse with loss of peripheral vascular tone, cardiac arrest, and death may occur.

In extreme overdose, all electrical activity in the brain may cease, in which case a “flat” EEG normally equated with clinical death should not be accepted. This effect is fully reversible unless hypoxic damage occurs.

Consideration should be given to the possibility of barbiturate intoxication even in situations that appear to involve trauma.

Complications such as pneumonia, pulmonary edema, cardiac arrhythmias, congestive heart failure, and renal failure may occur. Uremia may increase CNS sensitivity to barbiturates if renal function is impaired. Differential diagnosis should include hypoglycemia, head trauma, cerebrovascular accidents, convulsive states, and diabetic coma.

Treatment – To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.

Alkalinization of urine hastens Equidan (Phenobarbital) excretion, but dialysis and hemoperfusion are more effective and cause less troublesome alterations in electrolyte equilibrium. If the patient has chronically abused sedatives, withdrawal reactions may be manifest following acute overdose.

DOSAGE AND ADMINISTRATION

The dose of Equidan (Phenobarbital) must be individualized with full knowledge of its particular characteristics. Factors of consideration are the patient’s age, weight, and condition.

Sedation:

For sedation, the drug may be administered in single dose of 30 to 120 mg repeated at intervals: frequency will be determined by the patient’s response. It is generally considered that no more than 400 mg of Equidan (Phenobarbital) should be administered during a 24-hour period.

Adults:

Daytime Sedation: 30 to 120 mg daily in 2 to 3 divided doses.

Oral Hypnotic: 100 to 200 mg.

Anticonvulsant Use – Clinical laboratory reference values should be used to determine the therapeutic anticonvulsant level of Equidan (Phenobarbital) in the serum. To achieve the blood levels considered therapeutic in pediatric patients, higher per-kilogram dosages are generally necessary for Equidan (Phenobarbital) and most other anticonvulsants. In children and infants, Equidan (Phenobarbital) at a loading dose of 15 to 20 mg/kg produces blood levels of about 20 mcg/mL shortly after administration.

Equidan (Phenobarbital) has been used in the treatment and prophylaxis of febrile seizures. However, it has not been established that prevention of febrile seizures influences the subsequent development of epilepsy.

Adults: 60 to 200 mg/day.

Pediatric Patients: 3 to 6 mg/kg/day.

Special Patient Population – Dosage should be reduced in the elderly or debilitated because these patients may be more sensitive to barbiturates. Dosage should be reduced for patients with impaired renal function or hepatic disease.

HOW SUPPLIED

Equidan (Phenobarbital) Tablets, USP 16.2 mg are white, round, biconvex, scored tablets, debossed “5011” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 100 NDC 0603-5165-21
• Bottles of 1000 NDC 0603-5165-32

Equidan (Phenobarbital) Tablets, USP 32.4 mg are white, round, biconvex, scored tablets, debossed “5012” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 30 NDC 0603-5166-16
• Bottles of 60 NDC 0603-5166-20
• Bottles of 90 NDC 0603-5166-02
• Bottles of 100 NDC 0603-5166-21
• Bottles of 120 NDC 0603-5166-22
• Bottles of 1000 NDC 0603-5166-32

Equidan (Phenobarbital) Tablets, USP 64.8 mg are white, round, biconvex, scored tablets, debossed “5013” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 100 NDC 0603-5167-21
• Bottles of 1000 NDC 0603-5167-32

Equidan (Phenobarbital) Tablets, USP 97.2 mg are white, round, biconvex, scored tablets, debossed “5014” and “V” on one side and plain on the reverse side, and supplied as follows:

• Bottles of 100 NDC 0603-5168-21
• Bottles of 1000 NDC 0603-5168-32

Manufactured for:

QUALITEST PHARMACEUTICALS

Huntsville, AL 35811

8180067

Rev 7/14

R4

Phenytoin:

• Description section
• Clinical pharmacology section
• Indications & usage section
• Contraindications section
• Warnings section
• Precautions section
• Adverse reactions section
• Overdosage section
• Dosage & administration section
• How supplied section
• Spl medguide section
• Equidan (Phenytoin) reviews

DESCRIPTION SECTION

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

Each extended Equidan (Phenytoin) sodium capsule, USP contains 100 mg Equidan (Phenytoin) sodium, USP. Each capsule also contains the following inactive ingredients: D&C Red #28, D&C Red #33, FD&C Blue #1, gelatin, hydroxypropyl cellulose, mannitol, magnesium stearate, talc and titanium dioxide. Product in vivo performance is characterized by a slow and extended rate of absorption with peak blood concentrations expected in 4 to 12 hours as contrasted to Prompt Equidan (Phenytoin) Sodium Capsules, USP with a rapid rate of absorption with peak blood concentration expected in 1½ to 3 hours.

CLINICAL PHARMACOLOGY SECTION

Mechanism of Action

Equidan (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, Equidan (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 post tetanic potentiation at synapses. Loss of post tetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Equidan (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 Equidan (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 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. 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 extended Equidan (Phenytoin) sodium capsules, peak serum levels occur 4 to 12 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 Equidan (Phenytoin).

In most patients maintained at a steady dosage, stable Equidan (Phenytoin) serum levels are achieved. There may be wide interpatient variability in Equidan (Phenytoin) serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of Equidan (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 Equidan (Phenytoin) plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As Equidan (Phenytoin) is highly protein bound, free Equidan (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 Equidan (Phenytoin) and its metabolites occurs partly with glomerular filtration but more importantly by tubular secretion. Because Equidan (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 Equidan (Phenytoin) in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total Equidan (Phenytoin) plasma concentrations should be made with caution. Unbound Equidan (Phenytoin) concentrations may be more useful in these patient populations.

Age: Equidan (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). Equidan (Phenytoin) dosing requirements are highly variable and must be individualized.

Gender and Race: Gender and race have no significant impact on Equidan (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).

INDICATIONS & USAGE SECTION

Extended Equidan (Phenytoin) sodium capsules, USP are indicated for the control of generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery.

Equidan (Phenytoin) serum level determinations may be necessary for optimal dosage adjustments.

CONTRAINDICATIONS SECTION

Equidan (Phenytoin), USP is contraindicated in those patients with a history of hypersensitivity to Equidan (Phenytoin), USP, its inactive ingredients, or other hydantoins.

Coadministration of extended Equidan (Phenytoin) sodium is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

WARNINGS SECTION

Effects of Abrupt Withdrawal

Abrupt withdrawal of Equidan (Phenytoin) in epileptic patients may precipitate status epilepticus. When, in the judgment of the clinician, the need for dosage reduction, discontinuation, or substitution of alternative antiepileptic medication arises, this should be done gradually. In the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. In this case, alternative therapy should be an antiepileptic drug not belonging to the hydantoin chemical class.

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including extended Equidan (Phenytoin) sodium, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing extended Equidan (Phenytoin) sodium or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Serious Dermatologic Reactions

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with Equidan (Phenytoin) treatment. The onset of symptoms is usually within 28 days, but can occur later. Extended Equidan (Phenytoin) sodium should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. If a rash occurs, the patient should be evaluated for signs and symptoms of Drug Reaction with Eosinophilia and Systemic Symptoms.

Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA B gene, in patients using carbamazepine. Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN in patients of Asian ancestry taking other antiepileptic drugs associated with SJS/TEN, including Equidan (Phenytoin). Consideration should be given to avoiding Equidan (Phenytoin) as an alternative for carbamazepine in patients positive for HLA-B*1502.

The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities and the level of dermatologic monitoring have not been studied.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including extended Equidan (Phenytoin) sodium. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Extended Equidan (Phenytoin) sodium should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Hypersensitivity

Extended Equidan (Phenytoin) sodium and other hydantoins are contraindicated in patients who have experienced Equidan (Phenytoin) hypersensitivity. Additionally, consider alternatives to structurally similar drugs such as carboxamides (e.g., carbamazepine), barbiturates, succinimides and oxazolidinediones (e.g., trimethadione) in these same patients. Similarly, if there is a history of hypersensitivity reactions to these structurally similar drugs in the patient or immediate family members, consider alternatives to extended Equidan (Phenytoin) sodium.

Hepatic Injury

Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with extended Equidan (Phenytoin) sodium. These events may be part of the spectrum of DRESS or may occur in isolation. Other common manifestations include jaundice, hepatomegaly, elevated serum transaminase levels, leukocytosis and eosinophilia. The clinical course of acute Equidan (Phenytoin) hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, extended Equidan (Phenytoin) sodium should be immediately discontinued and not readministered.

Hematopoietic System

Hematopoietic complications, some fatal, have occasionally been reported in association with administration of extended Equidan (Phenytoin) sodium. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis and pancytopenia with or without bone marrow suppression.

There have been a number of reports suggesting a relationship between Equidan (Phenytoin) and the development of lymphadenopathy (local or generalized) including benign lymph node hyperplasia, pseudolymphoma, lymphoma and Hodgkin’s disease. Although a cause and effect relationship has not been established, the occurrence of lymphadenopathy indicates the need to differentiate such a condition from other types of lymph node pathology. Lymph node involvement may occur with or without symptoms and signs of DRESS.

In all cases of lymphadenopathy, follow-up observation for an extended period is indicated and every effort should be made to achieve seizure control using alternative antiepileptic drugs.

Effects on Vitamin D and Bone

The chronic use of Equidan (Phenytoin) in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis and osteomalacia) and bone fractures. Equidan (Phenytoin) induces hepatic metabolizing enzymes. This may enhance the metabolism of vitamin D and decrease vitamin D levels, which may lead to vitamin D deficiency, hypocalcemia and hypophosphatemia. Consideration should be given to screening with bone-related laboratory and radiological tests as appropriate and initiating treatment plans according to established guidelines.

Effects of Alcohol Use on Equidan (Phenytoin) Serum Levels

Acute alcoholic intake may increase Equidan (Phenytoin) serum levels, while chronic alcohol use may decrease serum levels.

Exacerbation of Porphyria

In view of isolated reports associating Equidan (Phenytoin) with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

Usage In Pregnancy:

Clinical:

• 
  

  Risks to Mother. An increase in seizure frequency may occur during pregnancy because of altered Equidan (Phenytoin) pharmacokinetics. Periodic measurement of plasma Equidan (Phenytoin) concentrations may be valuable in the management of pregnant women as a guide to appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated.
  

• 
  

  Risks to the Fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential harm to the fetus.
  

Prenatal exposure to Equidan (Phenytoin) may increase the risks for congenital malformations and other adverse developmental outcomes. Increased frequencies of major malformations (such as orofacial clefts and cardiac defects), minor anomalies (dysmorphic facial features, nail and digit hypoplasia), growth abnormalities (including microcephaly) and mental deficiency have been reported among children born to epileptic women who took Equidan (Phenytoin) alone or in combination with other antiepileptic drugs during pregnancy. There have also been several reported cases of malignancies, including neuroblastoma, in children whose mothers received Equidan (Phenytoin) during pregnancy. The overall incidence of malformations for children of epileptic women treated with antiepileptic drugs (phenytoin and/or others) during pregnancy is about 10%, or two- to three-fold that in the general population. However, the relative contributions of antiepileptic drugs and other factors associated with epilepsy to this increased risk are uncertain and in most cases it has not been possible to attribute specific developmental abnormalities to particular antiepileptic drugs.

Patients should consult with their physicians to weigh the risks and benefits of Equidan (Phenytoin) during pregnancy.

Postpartum Period. A potentially life-threatening bleeding disorder related to decreased levels of vitamin K dependent clotting factors may occur in newborns exposed to Equidan (Phenytoin) in utero. This drug-induced condition can be prevented with vitamin K administration to the mother before delivery and to the neonate after birth.

Preclinical:

Increased resorption and malformation rates have been reported following administration of Equidan (Phenytoin) doses of 75 mg/kg or higher (approximately 120% of the maximum human loading dose or higher on a mg/m2 basis) to pregnant rabbits.

PRECAUTIONS SECTION

General:

The liver is the chief site of biotransformation of Equidan (Phenytoin); patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.

A small percentage of individuals who have been treated with Equidan (Phenytoin) have been shown to metabolize the drug slowly. Slow metabolism may be due to limited enzyme availability and lack of induction; it appears to be genetically determined. If early signs of dose-related CNS toxicity develop, plasma levels should be checked immediately.

Hyperglycemia, resulting from the drug’s inhibitory effects on insulin release, has been reported. Equidan (Phenytoin) may also raise the serum glucose level in diabetic patients.

Equidan (Phenytoin) is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated.

Equidan (Phenytoin) is not effective for absence (petit mal) seizures. If tonic-clonic (grand mal) and absence (petit mal) seizures are present, combined drug therapy is needed.

Serum levels of Equidan (Phenytoin) sustained above the optimal range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction. Accordingly, at the first sign of acute toxicity, plasma levels are recommended. Dose reduction of Equidan (Phenytoin) therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended.

Information for Patients

Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking extended Equidan (Phenytoin) sodium. Instruct patients to take extended Equidan (Phenytoin) sodium only as prescribed.

Patients taking Equidan (Phenytoin) should be advised of the importance of adhering strictly to the prescribed dosage regimen, and of informing the physician of any clinical condition in which it is not possible to take the drug orally as prescribed, e.g., surgery, etc.

Patients should be made aware of the early toxic signs and symptoms of potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. These symptoms may include, but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or jaundice. The patient should be advised that, because these signs and symptoms may signal a serious reaction, that they must report any occurrence immediately to a physician. In addition, the patient should be advised that these signs and symptoms should be reported even if mild or when occurring after extended use.

Patients should also be cautioned on the use of other drugs or alcoholic beverages without first seeking the physician’s advice.

The importance of good dental hygiene should be stressed in order to minimize the development of gingival hyperplasia and its complications.

Patients, their caregivers, and families should be counseled that AEDs, including extended Equidan (Phenytoin) sodium, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334.

Do not use capsules which are discolored.

Laboratory Tests:

Equidan (Phenytoin) serum level determinations may be necessary to achieve optimal dosage adjustments. Equidan (Phenytoin) doses are usually selected to attain therapeutic plasma total Equidan (Phenytoin) concentrations of 10 to 20 mcg/mL (unbound Equidan (Phenytoin) concentrations of 1 to 2 mcg/mL).

Drug Interactions:

Equidan (Phenytoin) is extensively bound to serum plasma proteins and is prone to competitive displacement. Equidan (Phenytoin) is metabolized by hepatic cytochrome P450 enzymes CYP2C9 and CYP2C19, and is particularly susceptible to inhibitory drug interactions because it is subject to saturable metabolism. Inhibition of metabolism may produce significant increases in circulating Equidan (Phenytoin) concentrations and enhance the risk of drug toxicity. Equidan (Phenytoin) is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for Equidan (Phenytoin) are especially helpful when possible drug interactions are suspected.

The most commonly occurring drug interactions are listed below:

Note: The list is not intended to be inclusive or comprehensive. Individual drug package inserts should be consulted.

Drugs that affect Equidan (Phenytoin) concentrations:

• Drugs that may increase Equidan (Phenytoin) serum levels include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, diazepam, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone and warfarin.
• Drugs that may decrease Equidan (Phenytoin) levels, include: anti-cancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate) carbamazepine, chronic alcohol abuse, folic acid, fosamprenavir, nelfinavir, reserpine, ritonavir, St. John’s Wort, sucralfate and vigabatrin.
• Administration of Equidan (Phenytoin) with preparations that increase gastric pH (e.g., supplements or antacids containing calcium carbonate, aluminum hydroxide and magnesium hydroxide) may affect the absorption of Equidan (Phenytoin). In most cases where interactions were seen, the effect is a decrease in Equidan (Phenytoin) levels when the drugs are taken at the same time. When possible, Equidan (Phenytoin) and these products should not be taken at the same time of day.
• Drugs that may either increase or decrease Equidan (Phenytoin) serum levels, include: phenobarbital, sodium valproate and valproic acid. Similarly, the effect of Equidan (Phenytoin) on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.
• The addition or withdrawal of these agents in patients on Equidan (Phenytoin) therapy may require an adjustment of the Equidan (Phenytoin) dose to achieve optimal clinical outcome.

Drugs affected by Equidan (Phenytoin):

• Drugs that should not be coadministered with Equidan (Phenytoin): Delavirdine.
• Drugs whose efficacy is impaired by Equidan (Phenytoin) include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, teniposide, theophylline and vitamin D.
• Increased and decreased PT/INR responses have been reported when Equidan (Phenytoin) is coadministered with warfarin.
• Equidan (Phenytoin) decreases plasma concentrations of active metabolites of albendazole, certain HIV antivirals (efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (felbamate, topiramate, oxcarbazepine, quetiapine) atorvastatin, cyclosporine, digoxin, fluvastatin, folic acid, mexiletine, nisoldipine, praziquantel and simvastatin.
• Equidan (Phenytoin) when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Equidan (Phenytoin) when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.
• Resistance to the neuromuscular blocking action of the non-depolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium and cisatracurium has occurred in patients chronically administered Equidan (Phenytoin). Whether or not Equidan (Phenytoin) has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
• The addition or withdrawal of Equidan (Phenytoin) during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.

Drug Enteral Feeding/Nutritional Preparations Interaction:

Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected Equidan (Phenytoin) plasma levels. It is therefore suggested that Equidan (Phenytoin) not be administered concomitantly with an enteral feeding preparation. More frequent serum Equidan (Phenytoin) level monitoring may be necessary in these patients.

Drug/Laboratory Test Interactions:

Equidan (Phenytoin) may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Equidan (Phenytoin) may cause increased serum levels of glucose, alkaline phosphatase and gamma glutamyl transpeptidase (GGT).

Care should be taken when using immunoanalytical methods to measure plasma Equidan (Phenytoin) concentrations.

Carcinogenesis:

See WARNINGS section for information on carcinogenesis.

Pregnancy: Pregnancy Category D; See WARNINGS section.

To provide information regarding the effects of in utero exposure to extended Equidan (Phenytoin) sodium, physicians are advised to recommend that pregnant patients taking extended Equidan (Phenytoin) sodium enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Nursing Mothers:

Infant breast-feeding is not recommended for women taking this drug because Equidan (Phenytoin) appears to be secreted in low concentrations in human milk.

Pediatric Use: See DOSAGE AND ADMINISTRATION section.

Geriatric Use: Equidan (Phenytoin) clearance tends to decrease with increasing age.

ADVERSE REACTIONS SECTION

Body as a Whole: Allergic reactions in the form of rash and rarely more serious forms and DRESS have been observed. Anaphylaxis has also been reported.

There have also been reports of coarsening of facial features, systemic lupus erythematosus, periarteritis nodosa and immunoglobulin abnormalities.

Nervous System: The most common manifestations adverse reactions encountered with Equidan (Phenytoin) therapy are referable to this nervous system reactions and are usually dose-related. These Reactions include nystagmus, ataxia, slurred speech, decreased coordination, somnolence and mental confusion. Dizziness, vertigo, insomnia, transient nervousness, motor twitchings, paresthesias and headaches have also been observed. There have also been rare reports of Equidan (Phenytoin) induced dyskinesias, including chorea, dystonia, tremor and asterixis, similar to those induced by phenothiazine and other neuroleptic drugs.

A predominantly sensory peripheral polyneuropathy has been observed in patients receiving long-term Equidan (Phenytoin) therapy.

Digestive System: Acute hepatic failure, toxic hepatitis, liver damage, Nnausea, vomiting, constipation, enlargement of the lips,and gingival hyperplasia, toxic hepatitis and liver damage.

Skin and Appendages: Dermatological manifestations sometimes accompanied by fever have included scarlatiniform or morbilliform rashes. A morbilliform rash (measles-like) is the most common; other types of dermatitis are seen more rarely. Other more serious forms which may be fatal have included bullous, exfoliative or purpuric dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. There have also been reports of hypertrichosis.

Hematologic and Lymphatic System: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of Equidan (Phenytoin). These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis and pancytopenia with or without bone marrow suppression. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma and Hodgkin’s disease have been reported.

Special Senses: Altered taste sensation including metallic taste.

Urogenital: Peyronie’s disease.

OVERDOSAGE SECTION

The lethal dose in pediatric patients is not known. The lethal dose in adults is estimated to be 2 to 5 grams. The initial symptoms are nystagmus, ataxia and dysarthria. Other signs are tremor, hyperreflexia, lethargy, slurred speech, nausea, vomiting. The patient may become comatose and hypotensive. Death is due to respiratory and circulatory depression.

There are marked variations among individuals with respect to Equidan (Phenytoin) plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL; dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery.

Treatment:

Treatment is nonspecific since there is no known antidote.

The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since Equidan (Phenytoin) is not completely bound to plasma proteins. Total exchange transfusion has been used in the treatment of severe intoxication in pediatric patients.

In acute overdosage, the possibility of other CNS depressants, including alcohol, should be borne in mind.

DOSAGE & ADMINISTRATION SECTION

Serum concentrations should be monitored in changing from extended Equidan (Phenytoin) sodium capsules, USP to Prompt Equidan (Phenytoin) Sodium Capsules, USP, and from the sodium salt to the free acid form.

Extended Equidan (Phenytoin) sodium capsules, USP are formulated with the sodium salt of Equidan (Phenytoin). Because there is approximately an 8% increase in drug content with the free acid form over that of the sodium salt, dosage adjustments and serum level monitoring may be necessary when switching from a product formulated with the free acid to a product formulated with the sodium salt and vice versa.

General:

Dosage should be individualized to provide maximum benefit. In some cases, serum blood level determinations may be necessary for optimal dosage adjustments-the clinically effective serum level is usually 10 to 20 mcg/mL. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with Equidan (Phenytoin) and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.

Adult

Dosage:

Divided daily

Dosage:

Patients who have received no previous treatment may be started on one 100-mg extended Equidan (Phenytoin) sodium capsule, USP three times daily and the dosage then adjusted to suit individual requirements. For most adults, the satisfactory maintenance dosage will be one capsule three to four times a day. An increase up to two capsules three times a day may be made, if necessary.

Once-a-day

Dosage:

In adults, if seizure control is established with divided doses of three 100-mg extended Equidan (Phenytoin) sodium capsules, USP daily, once-a-day dosage with 300 mg of extended Equidan (Phenytoin) sodium capsules, USP may be considered. Studies comparing divided doses of 300 mg with a single daily dose of this quantity indicated absorption, peak plasma levels, biologic half-life, difference between peak and minimum values, and urinary recovery were equivalent. Once-a-day dosage offers a convenience to the individual patient or to nursing personnel for institutionalized patients and is intended to be used only for patients requiring this amount of drug daily. A major problem in motivating noncompliant patients may also be lessened when the patient can take this drug once a day. However, patients should be cautioned not to miss a dose, inadvertently.

Only extended Equidan (Phenytoin) sodium capsules, USP are recommended for once-a-day dosing. Inherent differences in dissolution characteristics and resultant absorption rates of Equidan (Phenytoin) due to different manufacturing procedures and/or dosage forms preclude such recommendation for other Equidan (Phenytoin) products. When a change in the dosage form or brand is prescribed, careful monitoring of Equidan (Phenytoin) serum levels should be carried out.

Loading dose:

Some authorities have advocated use of an oral loading dose of Equidan (Phenytoin) in adults who require rapid steady-state serum levels and where intravenous administration is not desirable. This dosing regimen should be reserved for patients in a clinic or hospital setting where Equidan (Phenytoin) serum levels can be closely monitored. Patients with a history of renal or liver disease should not receive the oral loading regimen.

Initially, one gram of extended Equidan (Phenytoin) sodium capsules, USP is divided into three doses (400 mg, 300 mg, 300 mg) and administered at two-hour intervals. Normal maintenance dosage is then instituted 24 hours after the loading dose, with frequent serum level determinations.

Dosing in Special Populations

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

Elderly Patients: Equidan (Phenytoin) clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.

Pediatric: 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 old and adolescents may require the minimum adult dose (300 mg/day).

HOW SUPPLIED SECTION

Extended Equidan (Phenytoin) Sodium Capsules, USP 100 mg are supplied as white opaque / light lavender opaque, hard gelatin capsules imprinted with "IP 212" on both cap and body.

They are available as follows:

Bottles of 30: NDC 65162-212-03

Bottles of 100: NDC 65162-212-10

Bottles of 500: NDC 65162-212-50

Bottles of 1000: NDC 65162-212-11

Store at 20° to 25°C (68° to 77°F). Preserve in tight, light-resistant containers. Protect from moisture.

Rx only

SPL MEDGUIDE SECTION

Extended Equidan (Phenytoin) (FEN-i-toyn) Sodium Capsules


Read this Medication Guide before you start taking extended Equidan (Phenytoin) sodium capsules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions about extended Equidan (Phenytoin) sodium capsules, ask your healthcare provider or pharmacist.


What is the most important information I should know about extendedphenytoin sodium capsules?


Do not stop taking extended Equidan (Phenytoin) sodium capsules without first talking to your healthcare provider. Stopping extended Equidan (Phenytoin) sodium capsules suddenly can cause serious problems.


Extended Equidan (Phenytoin) sodium capsules can cause serious side effects including:


1. Like other antiepileptic drugs, extended Equidan (Phenytoin) sodium capsules may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.


Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:


• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood



How can I watch for early symptoms of suicidal thoughts and actions?


• Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.



Call your healthcare provider between visits as needed, especially if you are worried about


symptoms.


Do not stop taking extended Equidan (Phenytoin) sodium capsules without first talking to a healthcare provider.


Stopping extended Equidan (Phenytoin) sodium capsules suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).


Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal


thoughts or actions, your healthcare provider may check for other causes.


2. Extended Equidan (Phenytoin) sodium capsules may harm your unborn baby.


• If you take extended Equidan (Phenytoin) sodium capsules during pregnancy, your baby is at risk for serious birth defects.
• Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
• If you take extended Equidan (Phenytoin) sodium capsules during pregnancy, your baby is also at risk for bleeding problems right after birth. Your healthcare provider may give you and your baby medicine to prevent this.
• All women of child-bearing age should talk to their healthcare provider about using other possible treatments instead of extended Equidan (Phenytoin) sodium capsules. If the decision is made to use extended Equidan (Phenytoin) sodium capsules, you should use effective birth control (contraception) unless you are planning to become pregnant.
• Tell your healthcare provider right away if you become pregnant while taking extended Equidan (Phenytoin) sodium capsules. You and your healthcare provider should decide if you will take extended Equidan (Phenytoin) sodium capsules while you are pregnant.
• Pregnancy Registry: If you become pregnant while taking extended Equidan (Phenytoin) sodium capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.



3. Swollen glands (lymph nodes)


4. Allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions. Symptoms can include any of the following:


• swelling of your face, eyes, lips, or tongue
• trouble swallowing or breathing
• a skin rash
• hives
• fever, swollen glands (lymph nodes), or sore throat that do not go away or come and go
• painful sores in the mouth or around your eyes
• yellowing of your skin or eyes
• bruising or bleeding
• severe fatigue or weakness
• severe muscle pain
• frequent infections or an infection that does not go away
• loss of appetite (anorexia)
• nausea or vomiting



Call your healthcare provider right away if you have any of the symptoms listed above.


What are extended Equidan (Phenytoin) sodium capsules?


Extended Equidan (Phenytoin) sodium capsules are a prescription medicine used to treat tonic-clonic (grand mal), complex partial (psychomotor or temporal lobe) seizures, and to prevent and treat seizures that happen during or after brain surgery.


Who should not take extended Equidan (Phenytoin) sodium capsules?


Do not take extended Equidan (Phenytoin) sodium capsules if you:


• are allergic to Equidan (Phenytoin) or any of the ingredients in extended Equidan (Phenytoin) sodium capsules. See the end of this leaflet for a complete list of ingredients in extended Equidan (Phenytoin) sodium capsules.
• have had an allergic reaction to CEREBYX (fosphenytoin), PEGANONE (ethotoin), or MESANTOIN (mephenytoin).
• take delavirdine



What should I tell my healthcare provider before taking extended Equidan (Phenytoin) sodium capsules?


Before you take extended Equidan (Phenytoin) sodium capsules, tell your healthcare provider if you:


• Have or had liver disease
• Have or had porphyria
• Have or had diabetes
• Have or have had depression, mood problems, or suicidal thoughts or behavior
• Are pregnant or plan to become pregnant. If you become pregnant while taking extended Equidan (Phenytoin) sodium capsules, the level of extended Equidan (Phenytoin) sodium in your blood may decrease, causing your seizures to become worse. Your healthcare provider may change your dose of extended Equidan (Phenytoin) sodium capsules.
• Are breast feeding or plan to breastfeed. Extended Equidan (Phenytoin) sodium can pass into breast milk. You and your healthcare provider should decide if you will take extended Equidan (Phenytoin) sodium capsules or breastfeed. You should not do both.



Tell your healthcare provider about all the medicines you take, including prescription and


• 
  

  non-prescription medicines, vitamins and herbal supplements.
  

  Taking extended Equidan (Phenytoin) sodium capsules with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.
  

  +Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
  

  How should I take extended Equidan (Phenytoin) sodium capsules?
  

• 
  

  Take extended Equidan (Phenytoin) sodium capsules exactly as prescribed. Your healthcare provider will tell you how much extended Equidan (Phenytoin) sodium capsules to take.
  

• Your healthcare provider may change your dose. Do not change your dose of extended Equidan (Phenytoin) sodium capsules without talking to your healthcare provider.
• Extended Equidan (Phenytoin) sodium capsules can cause overgrowth of your gums. Brushing and flossing your teeth and seeing a dentist regularly while taking extended Equidan (Phenytoin) sodium capsules can help prevent this.
• If you take too much extended Equidan (Phenytoin) sodium capsules, call your healthcare provider or local Poison Control Center right away.
• Do not stop taking extended Equidan (Phenytoin) sodium capsules without first talking to your healthcare provider. Stopping extended Equidan (Phenytoin) sodium capsules suddenly can cause serious problems.



What should I avoid while taking extended Equidan (Phenytoin) sodium capsules?


• Do not drink alcohol while you take extended Equidan (Phenytoin) sodium capsules without first talking to your healthcare provider. Drinking alcohol while taking extended Equidan (Phenytoin) sodium capsules may change your blood levels of extended Equidan (Phenytoin) sodium capsules which can cause serious problems.
• Do not drive, operate heavy machinery, or do other dangerous activities until you know how extended Equidan (Phenytoin) sodium capsules affect you. Extended Equidan (Phenytoin) sodium capsules can slow your thinking and motor skills.



What are the possible side effects of extended Equidan (Phenytoin) sodium capsules?


See “What is the most important information I should know about extended Equidan (Phenytoin) sodium capsules?”


Extended Equidan (Phenytoin) sodium capsules may cause other serious side effects including:


• Softening of your bones (osteopenia, osteoporosis and osteomalacia). This can cause broken bones.
  

  Call your healthcare provider right away, if you have any of the symptoms listed above.
  

  The most common side effects of extended Equidan (Phenytoin) sodium capsules include:
  

• problems with walking and coordination
• slurred speech
• confusion
• dizziness
• trouble sleeping
• nervousness
• tremor
• headache
• nausea
• vomiting
• constipation
• rash



These are not all the possible side effects of extended Equidan (Phenytoin) sodium capsules. For more information, ask your healthcare provider or pharmacist.


Tell your healthcare provider if you have any side effect that bothers you or that does not go away.


Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.


How should I store extended Equidan (Phenytoin) sodium capsules?


• Store extended Equidan (Phenytoin) sodium capsules at room temperature between 68°F to 77°F (20°C to 25°C) in tight, light-resistant containers. Protect from moisture.



Keep extended Equidan (Phenytoin) sodiumcapsules and all medicines out of the reach of children.


General information about extended Equidan (Phenytoin) sodium capsules


Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use extended Equidan (Phenytoin) sodium capsules for a condition for which it was not prescribed. Do not give extended Equidan (Phenytoin) sodium capsules to other people, even if they have the same symptoms that you have. It may harm them.


This Medication Guide summarizes the most important information about extended Equidan (Phenytoin) sodium capsules. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about extended Equidan (Phenytoin) sodium capsules that was written for healthcare professionals.


For more information about extended Equidan (Phenytoin) sodium capsules, visit www.amneal.com or call 1-877-835-5472.


What are the ingredients in extended Equidan (Phenytoin) sodium capsules?


Extended Oral Capsule


Extended Equidan (Phenytoin) sodium capsule 100mg: White opaque/lavender opaque, hard gelatin capsules imprinted “IP 212” on both cap and body.


Active ingredient: 100 mg Equidan (Phenytoin) sodium


Inactive ingredients: D&C Red #28, D&C Red #33, FD&C Blue #1, gelatin, hydroxypropyl cellulose, mannitol, magnesium stearate, talc and titanium dioxide.


This Medication Guide has been approved by the U.S. Food and Drug Administration.


Close

815